Harrison Internal Medicine

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W H O Te c h n i c a l R e p o r t S e r i e s
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The Selection and Use of Essential Medicines

This report presents the recommendations of the WHO
Expert Committee responsible for updating the WHO
Model List of Essential Medicines and WHO Model List of
Essential Medicines for Children. It contains a summary of
the evidence presented and the Committee’s consideration,
justifications and recommendations for additions, deletions
and changes to medicines on the Model Lists.
Annexes to the main report include the 2019 WHO Model

List of Essential Medicines (21st edition) and the 2019 WHO
Model List of Essential Medicines for Children (7th edition).
The Selection and Use
In addition, all medicines on the Model Lists are presented
according to their Anatomical Therapeutic Chemical (ATC)
classification codes.
of Essential Medicines
WHO Technical Report Series

Report of the WHO Expert Committee on Selection and Use of Essential
Medicines, 2019 (including the 21st WHO Model List of Essential Medicines
and the 7th WHO Model List of Essential Medicines for Children)
ISBN 978 92 4 121030 0

SELECTED WHO PUBLICATIONS OF RELATED INTEREST
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provide objective and reliable information and advice in the field of human health, a Prioritization of pathogens to guide discovery, research and development of new
responsibility that it fulfils in part through its extensive programme of publications. antibiotics for drug-resistant bacterial infections, including tuberculosis (2017)
The Organization seeks through its publications to support national health strategies WHO/EMP/IAU/2017.12
and address the most pressing public health concerns of populations around the world. WHO guidelines on use of medically important antimicrobials in food-producing
animals (2017)
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practical manuals, handbooks and training material for specific categories of health
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care, and health promotion for individuals and communities. Progress towards better Guidelines for the treatment of malaria, 3rd edition (2015)
health for all also demands the global dissemination and exchange of information ISBN 9789241549127
that draws on the knowledge and experience of all WHO’s Member countries and the
collaboration of world leaders in public health and the biomedical sciences. Updated recommendations on first-line and second-line antiretroviral regimens
and post-exposure prophylaxis and recommendations on early infant diagnosis of
To ensure the widest possible availability of authoritative information and guidance on HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the
health matters, WHO secures the broad international distribution of its publications use of antiretroviral drugs for treating and preventing HIV infection (2018)
and encourages their translation and adaption. By helping to promote and protect WHO/CDS/HIV/18.51
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to achieving the Organization’s principal objective – the attainment by all people of the hepatitis C virus infection (2018)
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1 0 2 1

This report contains the views of an international group of experts, and

does not necessarily represent the decisions or the stated policy of the World Health Organization
The selection and use of essential medicines: report of the WHO Expert Committee on Selection and
Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the
7th WHO Model List of Essential Medicines for Children).
(WHO Technical Report Series, No. 1021)
ISBN 978-92-4-121030-0
ISSN 0512-3054
© World Health Organization 2019

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Contents
Executive summary vii
List of participants xxxv
Declaration of interests for Expert Committee Members and
Temporary Advisers xxxvii
1. Introduction 1
2. Open session 2
3. Follow-up items and EML Working Groups 3
4. Summary of changes 13
5. Applications for the 21st Model List of Essential Medicines and the
7th Model List of Essential Medicines for Children 19
Section 6: ANTI-INFECTIVE MEDICINES 19
6.2 Antibacterials 19
Antibiotics for typhoid fever 19
Antibiotics for surgical prophylaxis 27
Antibiotics for oral and dental infections 39
Ceftazidime + avibactam – addition - EML 47
Ceftolozane + tazobactam – addition – EML 52
Delafloxacin – addition – EML 57
Eravacycline – addition – EML 61
Meropenem + vaborbactam – addition – EML 66
Omadacycline – addition – EML 70
Plazomicin– addition – EML 75
Antituberculosis medicines – new formulations for addition – EML and EMLc 79
Antituberculosis medicines – formulations for deletion – EML 84
Antituberculosis medicines – intravenous formulations for addition – EML
and EMLc 87
Bedaquiline – addition – EMLc 92
Capreomycin and kanamycin – deletion – EML and EMLc 96
Delamanid – change age restriction – EMLc 99
Group C antibiotics for MDR-TB – new indication – EML and EMLc 102
Isoniazid – new formulation (oral liquid) – EMLc 109
6.4 Antiviral medicines 114
Antiretrovirals – formulations for deletion – EML and EMLc 114
Ritonavir – new formulation – EML and EMLc 118
Lopinavir + ritonavir – new formulation – EML and EMLc 123
Dolutegravir – addition – EMLc 127
Raltegravir – new formulation – EML and EMLc 133
Dolutegravir + lamivudine + tenofovir disoproxil fumarate – addition – EML 138
Glecaprevir + pibrentasvir – addition – EML 144
6.5 Antiprotozoal medicines 150
Sulfadoxine + pyrimethamine – new indication IPTi – EMLc 150
Sulfadoxine + pyrimethamine – new indication IPTp – EML 155
Amodiaquine with sulfadoxine + pyrimethamine – addition – EMLc 161
Fexinidazole – addition – EML and EMLc 166
6.6 Medicines for ectoparasitic infections 173
Ivermectin – new indication scabies – EML and EMLc 173
Section 7: ANTIMIGRAINE MEDICINES 179
7.1 For treatment of acute attack 179
Sumatriptan – addition – EML 179
Section 8: IMMUNOMODULATORS AND ANTINEOPLASTICS 188
8.1 Immunomodulators for non-malignant disease 188
Medicines for multiple sclerosis – addition – EML and EMLc 188
TNF-alfa inhibitors for chronic inflammatory diseases – addition – EML
and EMLc 202
8.2 Antineoplastics and supportive medicines 214
Cancer medicines for children – addition/new indication – EMLc 214
Cancer medicines for children – text clarifications 227
Arsenic therapies – addition – EML and EMLc 232
Medicines for cervical cancer – new indication – EML 241
Pegaspargase – addition – EML and EMLc 251
Pertuzumab – addition – EML 257
Rituximab – new formulation – EML 271
Trastuzumab – new formulation – EML 276
Trastuzumab emtansine – addition – EML 281
Tyrosine-kinase inhibitors for non-small cell lung cancer – addition – EML 293
Medicines for multiple myeloma – addition – EML 302
Anti PD-1/PD-L1 Immune checkpoint inhibitors – addition – EML and EMLc 314
Medicines for prostate cancer – addition – EML 332
Section 10: MEDICINES AFFECTING THE BLOOD 339
10.2 Medicines affecting coagulation 339
Direct oral anticoagulants (DOACs) – dabigatran, rivaroxaban, apixaban,
edoxaban – addition – EML 339
Section 12: CARDIOVASCULAR MEDICINES 356
12.3 Antihypertensive medicines 356
Fixed-dose combination antihypertensives – addition – EML 356
12.5 Antithrombotic medicines 367
Alteplase – addition – EML 367
Section 17: GASTROINTESTINAL MEDICINES 373
17.2 Antiemetic medicines 373
Aprepitant – addition – EML and EMLc 373
Ondansetron – square box – EML and EMLc 380
17.5 Medicines used in diarrhoea 383
Oral rehydration salts (ORS) and zinc (co-packaged) – new formulation –
EMLc 383
Section 18: MEDICINES FOR ENDOCRINE DISORDERS 387
18.5 Insulin and other medicines used for diabetes 387
Long-acting insulin analogues (including biosimilars) – addition – EML 387
18.6 Medicines for hypoglycaemia 405
Diazoxide – addition – EMLc 405
iv
18.7 Thyroid hormones and antithyroid medicines 411
Medicines for first-line treatment of primary hyperthyroidism – review –
EML and EMLc 411
Section 22: MEDICINES FOR REPRODUCTIVE HEALTH AND PERINATAL CARE 417
22.3 Uterotonics 417
Carbetocin (heat-stable) – addition – EML 417
Mifepristone-misoprostol – change to listing – EML 422
Misoprostol – deletion of prevention of PPH indication – EML 429
Tranexamic acid – new indication – EML 434
Section 24: MEDICINES FOR MENTAL AND BEHAVIOURAL DISORDERS 441
Methylphenidate – addition – EML and EMLc 441
24.2 Medicines used in mood disorders 450
Escitalopram – addition – EML 450
Fluoxetine – addition of square box – EML 450
Section 25: MEDICINES ACTING ON THE RESPIRATORY TRACT 457
25.1 Antiasthmatic and medicines for chronic obstructive pulmonary disease 457
Tiotropium – addition – EML 457
Section 27: VITAMINS AND MINERALS 463
Iodine – change to listing – EML and EMLc 463
Multiple micronutrient powders – addition – EMLc 465
Annex 1 471
WHO Model List of Essential Medicines (2019) 471
Annex 2 545
WHO Model List of Essential Medicines for Children (2019) 545
Annex 3 597
The Anatomical Therapeutic Chemical (ATC) Classification System 597
Annex 4 627
Alphabetical list of essential medicines (with ATC classification code numbers) 627
v
Executive summary
This summary reports the recommendations made by the WHO Expert Committee on the
Selection and Use of Essential Medicines for the 2019 Essential Medicines Lists update.
The 22nd meeting of the WHO Expert Committee on the Selection and Use of Essential Medicines
took place in Geneva, Switzerland, from 1 to 5 April 2019. The aim of the meeting was to review
and update the 20th WHO Model List of Essential Medicines (EML) and the 6th WHO Model List of
Essential Medicines for Children (EMLc).
The Expert Committee considered 65 applications, including proposals to add 53 new
medicines and new formulations of 19 existing medicines, extend the indications for 34 listed
medicines, and to remove 10 medicines or formulations from the lists. The Expert Committee
also considered reports and recommendations from the EML Antibiotics and Cancer Medicines
Working Groups. In accordance with applicable procedures,1 the Expert Committee evaluated
the scientific evidence for the comparative effectiveness, safety and cost-effectiveness of the
medicines in question.
In summary, the Expert Committee:
■■ recommended the addition of 28 new medicines to the EML (12 to the core list
and 16 to the complementary list);
■■ recommended the addition of 23 new medicines to the EMLc (6 to the core list
and 17 to the complementary list);
■■ recommended adding additional indications for 26 currently listed medicines;
■■ recommended the addition of new formulations of 16 currently listed medicines;
■■ recommended the deletion of 9 medicines and of specific formulations of a further
4 medicines; and
■■ rejected 21 applications for inclusion, change or deletion of 31 medicines.
The recommendations are briefly described below in order of their appearance on the Model
Lists according to the classification.
A full summary of changes to the Model Lists is shown in Table 1. The applications not
recommended are listed in Table 2.
1
WHO medicines strategy. Geneva: World Health Organization: 2001. See: http://www.who.int/selection_
medicines/committees/subcommittee/2/eeb1098%5b1%5d.pdf.
vii
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Section 6: Anti-infective medicines

Section 6.2: Antibacterials
AWaRe classification of antibiotics
The Expert Committee noted the adoption and utilization of the Access, Watch and Reserve
(AWaRe) classification of antibiotics on the EML by several Member States including the
endorsement of AWaRe by the G20 Health Ministers in 2018.2 Furthermore, a new target
indicator based on AWaRe was adopted that specifies a country-level target of at least 60%
of antibiotic consumption being from the Access group. This indicator is intended to monitor
access to essential medicines and progress towards universal health coverage under the WHO
13 th General Programme of Work.3 The Committee recognized the emerging role of the AWaRe
groups for stewardship and quality improvement programmes.
The Expert Committee recommended that specific listing of antibiotics in the EML and the
allocation of antibiotics to the different AWaRe groups should be distinguished from each other,
recognizing their distinct albeit complementary purposes. The Committee acknowledged that
EML-listed antibiotics represent a parsimonious, evidence-based selection of essential narrow
spectrum antibiotics for first- and second-choice empiric treatment of most common bacterial
infections and a tool for stewardship. However, the AWaRe classification should extend beyond the
EML to all commonly used antibiotics globally. The Committee acknowledged the contributions
of the EML Antibiotics Working Group and endorsed the Working Group’s recommendations for
AWaRe classification of 177 commonly used antibiotics, to better support antibiotic monitoring
and stewardship activities. The Expert Committee recommended the development of an AWaRe
classification database as a searchable resource for countries.
Antibiotics not classified as Access, Watch or Reserve

The Committee recommended, based on the advice of the EML Antibiotics Working Group, that
WHO may wish to consider creating an additional group in the AWaRe classification database
for antibiotics whose use is not evidence-based, nor recommended in high quality international
guidelines, particularly fixed-dose combinations of multiple broad-spectrum antibiotics.
WHO Technical Report Series, No. 1021, 2019
Antibiotics in this group are not included on the Model Lists.

The AWaRe classification database will be published as an Online Appendix to the 2019 Model
Lists and Technical Report of the meeting.
The Expert Committee recommended the re-structuring of Section 6.2 to better accommodate
AWaRe classification, and that antibiotics on the EML be listed in revised sub-sections according
to AWaRe groups, replacing the existing sub-sections based on chemical structure (e.g.,
2
Declaration: G20 Meeting of Health Ministers (4th October 2018, Mar del Plata, Argentina. See: http://
www.g20.utoronto.ca/2018/2018-10-04-health.pdf.
3
WHO Thirteenth General Programme of Work, 2019–2023;WHO Impact Framework. See: http://apps.
who.int/gb/ebwha/pdf_files/EB144/B144_7-en.pdf.
viii
Executive summary
beta-lactam and other antibacterials). The subsequent sub-sections within Section 6.2 are
re‑numbered accordingly:
–– 6.2.1: Access group antibiotics

–– 6.2.2: Watch group antibiotics
–– 6.2.3: Reserve group antibiotics
–– 6.2.4: Antileprosy medicines
–– 6.2.5: Antituberculosis medicines
Additions, changes and deletions

The Expert Committee recommended for inclusion three new recently registered antibiotics for
treatment of multi-drug resistant infections caused by pathogens ranked as “Critical Priority” on
the WHO Priority pathogens list 4 and classified under AWaRe as Reserve antibiotics: ceftazidime +
avibactam, meropenem + vaborbactam and plazomicin. Four recently registered antibiotics were
not recommended for EML inclusion, but were classified under AWaRE for monitoring purposes
(ceftolozane + tazobactam, eravacycline and omadacycline as Reserve; delafloxacin as Watch).
The Committee recommended first- and second-choice empiric antibiotic treatment options for
enteric fever, surgical prophylaxis and progressive apical dental abscess on the EML and EMLc,
including the addition of cefuroxime (for surgical prophylaxis), classified under AWaRe as a Watch
group antibiotic.
The Committee recommended the removal of aztreonam, fourth- and fifth-generation
cephalosporins (as classes), tigecycline and daptomycin from the EML and EMLc as these
antibiotics did not meet the revised criteria for inclusion on the Model Lists as individual Reserve
group agents (see 6.2.3 Reserve group antibiotics, below). Furthermore, the Committee agreed
that fourth-generation cephalosporins should be re-classified as Watch group as they did not
meet the revised criteria for classification as Reserve. The Committee also recommended the re-
classification of faropenem from the Watch to the Reserve group due to its high potential for
inappropriate use. It is an orally available formulation with a broad-spectrum activity, inappropriate
use of which may further the spread of carbapenemase-producing Enterobacteriaceae.
Section 6.2.1: Access group antibiotics

This category includes antibiotics that have activity against a wide range of commonly
encountered susceptible pathogens while showing lower resistance potential than antibiotics in
Watch and Reserve groups. The following 19 Access group antibiotics are recommended as first
or second choice empiric treatment options for infectious syndromes reviewed by the Expert
Committee, and are listed as individual medicines on the Model Lists to promote optimal use
and with the goal of improving global “access to Access” antibiotics.
4
Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug-
resistant bacterial infections, including tuberculosis. See: https://apps.who.int/iris/handle/10665/311820.
ix
Access group antibiotics included on the 2019 Model Lists

Amikacin Cloxacillin
Amoxicillin Doxycycline
Amoxicillin + clavulanic acid Gentamicin
Ampicillin Metronidazole
Benzathine benzylpenicillin Nitrofurantoin
Benzylpenicillin Phenoxymethylpenicillin
Cefalexin Procaine benzylpenicillin
Cefazolin Spectinomycin
Chloramphenicol Sulfamethoxazole + trimethoprim
Clindamycin –
Section 6.2.2: Watch group antibiotics

The Watch group includes antibiotics that have higher resistance potential and includes
most of the highest priority agents among the list of critically important antimicrobials (CIA)
for human medicine 5 and/or antibiotics that are at relatively high risk of selection of bacterial
resistance. These medicines should be prioritized as key targets of national and local stewardship
programmes and monitoring. The following 11 Watch group antibiotics are recommended
as essential first or second choice empiric treatment options for a limited number of specific
infectious syndromes and are listed as individual medicines on the WHO Model Lists.
Watch group antibiotics included on the 2019 Model Lists

Azithromycin Ciprofloxacin
Cefixime Clarithromycin
Cefotaxime Meropenem
Ceftazidime Piperacillin + tazobactam
Ceftriaxone Vancomycin
Cefuroxime
5
Critically important antimicrobials for human medicine, 6th Revision. See: https://apps.who.int/iris/
handle/10665/312266.
x
Executive summary
Section 6.2.3: Reserve group antibiotics

The Reserve group includes antibiotics that should be reserved for treatment of confirmed or
suspected infections due to multidrug-resistant organisms. Reserve group antibiotics should be
considered as ‘last resort’ options. Seven selected Reserve group antibiotics are listed as individual
medicines on the WHO Model Lists as they have a favourable benefit-risk profile and proven
activity against Critical Priority” or “High Priority” pathogens as identified by the WHO priority
pathogens list, most notably carbapenem-resistant Enterobacteriaceae. These antibiotics should
be globally accessible, but their use should be tailored to highly specific patients and settings,
when alternatives are not suitable or have failed. To preserve their effectiveness these Reserve
group antibiotics should be prioritized as key targets of national and international stewardship
programmes including regular monitoring and reporting of their use.
Reserve group antibiotics included on the 2019 Model Lists

Ceftazidime + avibactam Meropenem + vaborbactam
Colistin Plazomicin
Fosfomycin (intravenous) Polymyxin B
Linezolid
EML Antibiotics/AWaRe Working Group

The Expert Committee acknowledged that the existing EML listings and the classification
of individual medicines to specific AWaRe groups may change slightly over time, due to the
evolving epidemiology of infectious diseases and antimicrobial resistance, changes in the
availability of antibiotics and emergence of new scientific evidence. The ongoing revision and
consolidation of the antibiotics included on the EML and of AWaRe classification is a key activity of
the Working Group, with the aim of balancing the objectives of preserving antibiotic effectiveness
while guaranteeing necessary access. Therefore, the Committee recommended the continuation
of the activities of the EML Antibiotics/AWaRe Working Group.
The Committee recommended that the Working Group should assess the adoption of the AWaRe
classification across countries and further explore how AWaRe can assist in activities to promote
optimal antibiotic stewardship. Some areas needing more investigation are the incorporation of
AWaRe in national essential medicines lists and clinical practice guidelines, and the adaptation
of AWaRe for educational activities to improve antibiotic use. The Committee recommended
the Working Group develop antibiotic stewardship algorithms for Reserve antibiotics to define
how these medicines should be used and how their misuse can be prevented. This includes the
identification of evidence gaps for the recommended uses in clinical practice. The Committee
noted that the current regulatory approval process for new antibiotics, most of which qualify for
the Reserve category due to their activity against priority multidrug-resistant pathogens (usually
carbapenem-resistant pathogens), does not result in adequate evidence to judge their role for
xi
their optimal clinical use and guide appropriate policy interventions. The Working Group should
identify and document these evidence gaps and propose research strategies for how to address
them. In general, the AWaRe groups, the WHO priority pathogens list and the WHO list of critically
important antimicrobials should become more closely aligned with regard to definitions and
terminology to avoid confusion and the Working Group should support and expand this effort.
Additional proposed activities of the Working Group include the development of policy
documents assessing optimal antibiotic dosage and treatment duration for common infectious
syndromes in both adults and children. This information, together with the Model Lists and
AWaRe classification should inform production of a WHO handbook outlining antibiotic
treatment guidance for high-burden bacterial syndromes. This information should also be made
available in an easily accessible electronic format, e.g. by incorporating this information into the
electronic EML.
Section 6.2.4: Antituberculosis medicines

The Committee recommended the inclusion of meropenem and of amoxicillin + clavulanic acid
on the complementary list of the EML and EMLc for the new indication of treatment for multidrug-
resistant tuberculosis (MDR-TB). The Committee recommended that imipenem + cilastatin could
be considered as an alternative to meropenem for use in adults. The Committee expressed
concern in relation to increased use of carbapenem antibiotics (classified as Watch group) in the
empiric treatment of MDR-TB and the development of carbapenem resistance and recommended
that ongoing monitoring for the development of resistance be undertaken.
The Committee recommended the addition of several new formulations of currently listed
medicines for use in children: cycloserine, ethambutol, ethionamide, isoniazid, levofloxacin,
linezolid and moxifloxacin. The addition of child-friendly formulations of antituberculosis
medicines is fully in line with the latest WHO guideline recommendations on the management
of MDR- and isoniazid-resistant TB.
The Committee recommended the deletion of capreomycin and kanamycin from the
complementary list of the EML and EMLc, noting that their use is no longer recommended in
WHO guidelines due to increased treatment failure and toxicity when compared to alternative
oral therapeutic options. The Committee also recommended the deletion from the EML of fixed-
dose combination of ethambutol + isoniazid, and specific formulations/strengths of fixed-dose
combinations of isoniazid + pyrazinamide + rifampicin and isoniazid + rifampicin, no longer
recommended in WHO guidelines due to their association with higher rates of treatment failure.
The Committee recommended the addition of bedaquiline to the complementary list of the
EMLc for the treatment of MDR-TB in children aged 6 years and older, as extrapolation of evidence
from adult data suggests good efficacy and benefits outweigh risks. The Committee did not
recommend a change to the age restriction (≥6 years) that applies to the listing of delamanid
on the Model Lists, as the evidence used to support the lowering of the age limit in the WHO
Guidelines used a formulation and strength of delamanid that is not currently commercially
available, nor bioequivalent to the formulation and strength included in the EMLc.
xii
Executive summary
The Committee did not recommend the addition of injectable formulations of ethambutol,
isoniazid, p-aminosalicylic acid (PAS) and rifampicin: the Committee noted that WHO recommends
oral treatment regimens, ideally administered in fixed-dose combinations. The Committee also
noted that the availability of the proposed injectable agents was limited and recognized the
potential for inappropriate use of prolonged parenteral anti-TB medicines. The Committee did not
recommend the addition of a new strength formulation of isoniazid oral liquid, giving preference
to dispersible tablet formulations.
Section 6.4.2: Antiretrovirals

For the treatment of human immunodeficiency virus (HIV) infection, the Committee
recommended the addition of the fixed-dose combination of dolutegravir + lamivudine +
tenofovir disoproxil fumarate to the EML, and the addition of dolutegravir to the EMLc, in line with
recommendations in the latest WHO Guidelines. The Committee also recommended addition of
new formulations of raltegravir, ritonavir, and lopinavir + ritonavir. Formulations of abacavir +
lamivudine and zidovudine were recommended for deletion, while formulations of raltegravir
and ritonavir proposed for deletion were recommended to be retained until the availability of
newer, preferred formulations is assured.
Section 6.4.4.2: Medicines for hepatitis C

This section of the list has been amended to differentiate between pangenotypic and non-
pangenotypic direct-acting antivirals, and other antivirals for hepatitis C virus infection.
Section 6.4.4.2.1: Pangenotypic direct-acting antiviral combinations

The Committee recommended the addition of the fixed dose combination of glecaprevir +
pibrentasvir to the EML for the treatment of adult patients with chronic hepatitis C virus infection
based on evidence of pangenotypic effectiveness with acceptable safety, as supported by
current WHO guidelines. The Committee noted that the EML now contains multiple pangenotypic
treatment options for hepatitis C (sofosbuvir + velpatasvir, sofosbuvir/daclatasvir, glecaprevir
+ pibrentasvir) and recommended that they be considered as therapeutically equivalent to
facilitate selection and procurement at country level.
Section 6.4.4.2.2: Non-pangenotypic direct-acting antiviral combinations

The Committee also recommended the deletion from the EML of simeprevir, whose place in
therapy has been superseded by the pangenotypic options. Other non-pangenotypic treatments
could be considered for deletion in the future.
Section 6.5.3.2: (Antimalarial medicines) for chemoprevention

The Committee recommended listing of fixed-dose combination formulations of sulfadoxine
+ pyrimethamine on the EML for the new indication of intermittent preventive treatment of
malaria in pregnancy (IPTp), and on the EMLc for the new indication of intermittent preventive
treatment of malaria in infancy (IPTi); and the addition of co-packaged formulations of
xiii
amodiaquine and sulfadoxine + pyrimethamine dispersible tablets to the EMLc for seasonal
malaria chemoprevention, in line with recommendations in WHO guidelines for the treatment
of malaria.
Section 6.5.5.1: African trypanosomiasis

The Committee recommended the addition of fexinidazole to the EML and EMLc as an orally-
administered treatment for treatment of 1st and 2 nd stages of human African trypanosomiasis
due to Trypanosoma brucei gambiense infection.
Section 6.6: Medicines for ectoparasitic infections (New)

The Committee recommended listing of ivermectin on the EML and EMLc for the new indication
of treatment of scabies, in a new sub-section of the list for ectoparasitic infections. The Committee
noted the potential advantages of single-dose oral administration of ivermectin compared to
topically administered alternatives in terms of improved compliance.
Section 7: Antimigraine medicines

The Committee did not recommend the addition of sumatriptan to the EML for the treatment of
adult patients with acute migraine. The Committee noted that available evidence supports the
greater effectiveness of sumatriptan compared to placebo, but evidence comparing sumatriptan
with analgesics currently included on the EML for treatment of migraine (aspirin and paracetamol)
showed varying results, including no difference in effect. At its next meeting, the Committee
would welcome a review of additional data of the role in therapy of sumatriptan in the context
of other migraine therapies and current guideline recommendations.
Section 8: Immunomodulators and antineoplastics (Re-named)

Section 8.1: Immunomodulators for non-malignant disease (Re-named)
Anti-TNF biologics for chronic inflammatory conditions: The Committee recommended the
addition of adalimumab to the complementary list of the EML and EMLc for use in the treatment
of chronic inflammatory autoimmune disorders – rheumatoid arthritis, ankylosing spondylitis,
juvenile idiopathic arthritis and Crohn disease based on a positive benefit-risk profile as second-
line treatment (after methotrexate). Adalimumab is listed with a square box, representative of the
class of tumour necrosis factor alpha (TNF-α) inhibitors, including biosimilars. Alternatives were
limited to etanercept and infliximab on the EMLc and to etanercept, infliximab, certolizumab
pegol and golimumab on the EML. The Committee recognized that these medicines are associated
with a significant budget impact to health systems as they are used for long periods and are
often highly priced. However, the availability of several therapeutically equivalent alternatives
and increased availability of biosimilar products could lead to more market competition and
reduced prices.
Medicines for multiple sclerosis: The Committee recognized the public health need for
effective and affordable treatments for multiple sclerosis (MS) but did not recommend the
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Executive summary
addition to the EML and EMLc of glatiramer acetate, fingolimod and ocrelizumab at this time.
The Committee acknowledged the application’s approach to increase access to MS treatments
by prioritizing selected treatment options. However, the Committee noted that some relevant
therapeutic options for MS were not included in the application (azathioprine and natalizumab)
or were not given full consideration (rituximab). The superiority of presented medicines over other
therapeutic options in the outcomes considered (benefits, harms, affordability) did not clearly
emerge. The Committee would therefore welcome a revised application that comprehensively
reviews the relative roles of relevant available medicines for MS.
Section 8.2: Antineoplastic and supportive medicines (Re-named)

This section has been updated and amended to include sub-sections that better represent the
pharmacologically diverse medicines currently listed:
–– 8.2.1: Cytotoxic medicines

–– 8.2.2: Targeted therapies
–– 8.2.3: Immunomodulators
–– 8.2.4: Hormones and antihormones
–– 8.2.5: Supportive medicines
Applications for new cancer medicines were the received from various sources, including a WHO
Secretariat-led effort to engage with expert stakeholders through the Cancer Medicines Working
Group to identify and prioritize the most effective cancer medicines for indications where they
have clinically relevant benefits.
The Committee recommended listing for a number of new high-priced cancer medicines for
specific indications on the complementary list of the EML.
Melanoma : nivolumab (with a square box indicating pembrolizumab as a therapeutically
equivalent alternative) for first-line monotherapy in patients with unresectable and metastatic
melanoma. Both these medicines demonstrated highly relevant increases in overall survival and
represent the first medicines on the EML for metastatic melanoma.
Multiple myeloma : bortezomib, lenalidomide, thalidomide and melphalan for the treatment of
patients with newly-diagnosed multiple myeloma in both non-transplant and transplant eligible/
available settings. These medicines demonstrated large improvements in survival with acceptable
safety and represent the first medicines on the EML for multiple myeloma.
Lung cancer : erlotinib (with a square box indicating afatinib and gefitinib as therapeutically
equivalent alternatives) for first-line treatment of epidermal growth factor receptor (EGFR)
mutation-positive advanced non-small cell lung cancer. These medicines demonstrated relevant
survival benefits (similar to that of cytotoxic chemotherapy) and offer better toxicity profiles and
improved quality of life compared to chemotherapy.
Prostate cancer : abiraterone for the treatment of patients with metastatic castration-resistant
prostate cancer. Abiraterone demonstrated relevant survival benefits for patients and an
xv
acceptable safety profile. It is associated with potential advantages in terms of emerging dosing
strategies, lower pill burden and availability of generics, which would be associated with cost-
savings compared to similarly effective enzalutamide. Enzalutamide was not recommended for
listing on the EML.
Leukaemias (EML and EMLc) : arsenic (oral and IV formulations) for use in the treatment of
patients with acute promyelocytic leukaemia. Arsenic-containing regimens were associated with
less toxicity, high response rates and greater survival benefits compared to standard regimens.
Pegaspargase was recommended for treatment of patients with acute lymphoblastic leukaemia as
it is associated with less immunogenicity and antibody development compared to asparaginase.
The listings of some cancer medicines currently on the EML were recommended to be extended
to include new indications of cervical cancer and multiple myeloma. Additionally, listing of 10
medicines currently included on the EML were recommended to be extended to the EMLc and
additional indications were recommended for 11 cancer medicines currently included on the
EMLc to improve access to these medicines for children. Refer to Table 1 for details.
The applications for cancer medicines that were not recommended for listing on the EML were:
–– nivolumab, pembrolizumab and atezolizumab for the treatment of non-small

cell lung cancer, as the Committee considered that their place in therapy for this
condition is still evolving and that more data with longer follow-up are needed
to better demonstrate estimates of their actual magnitude of benefit;
–– pertuzumab for human epidermal growth factor receptor 2 (HER2)-positive
breast cancer, as the evidence did not demonstrate a clinically meaningful
survival benefit in early stage disease. A large overall survival benefit has been
demonstrated in a single trial in metastatic disease, but similar results have not
been seen in other trials. The Committee recommended further independent
analysis of data from existing and ongoing trials be undertaken to inform
future consideration for EML listing.
–– Trastuzumab emtansine for HER2 positive breast cancer, because while it
demonstrates a relevant survival benefit, its use as second-line treatment of

metastatic disease was considered not to be a priority in the context of treatment
of breast cancer, and alternative EML-listed options are available.
–– Subcutaneous formulations of rituximab and trastuzumab, as the Committee
was concerned that listing of these formulations, for which biosimilars are not
yet available, could limit competition and therefore limit access for patients.
EML Cancer Medicines Working Group

The Expert Committee acknowledged the work of the EML Cancer Medicines Working Group and
endorsed the Working Group recommendations that WHO adopt a threshold for benefit of at least
four to six months survival gain to be considered as candidates for EML inclusion. The Committee
acknowledged the role of the European Society For Medical Oncology (ESMO) Magnitude of
xvi
Executive summary
Clinical Benefit Scale 6 (ESMO–MCBS) as a screening tool to identify cancer treatments that have
potential therapeutic value that warrants full evaluation for EML listing. Potential new EML cancer
medicines, in general, should have a score on the ESMO-MCBS of A or B in the curative setting
and of 4 or 5 in the non-curative setting. These scores would support a medicine being evaluated
by the Expert Committee for inclusion in the EML through a full application.
The Committee recommended the continuation and further expansion of the activities of the
Working Group. This should include the updated revision of treatment protocols for cancers
previously considered by the Committee and identification of new cancer medicines that meet
the above-mentioned criteria to be candidates for consideration of inclusion on the EML.
The Working Group should also review the issues being experienced at country level in relation
to implementation of EML cancer medicine recommendations and access to cancer medicines.
The Committee recommended the need for consolidation of cancer medicine recommendations
and EML listings through a broader technical advisory group meeting, with country engagement
to support implementation within a UHC perspective.
Section 10: Medicines affecting the blood

Section 10.2: Medicines affecting coagulation
The Committee recommended the addition of dabigatran to the core list of the EML, with a
square box (representative of the direct oral anticoagulants including apixaban, edoxaban and
rivaroxaban) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial
fibrillation, and for the treatment of venous thromboembolism. These medicines have a similar
overall benefit-risk profile compared to warfarin, are associated with a lower risk of major bleeding,
and may be particularly beneficial in settings where warfarin monitoring is not available.
Section 12: Cardiovascular medicines

Section 12.3: Antihypertensive medicines
The Committee recommended the addition of four, two-drug fixed-dose combination formulations
to the core list of the EML for the treatment of hypertension: lisinopril + amlodipine, lisinopril
+ hydrochlorothiazide, telmisartan + amlodipine and telmisartan + hydrochlorothiazide. Each
component is listed with a square box as representative of the relevant pharmacological classes.
The Committee accepted that fixed-dose combinations may confer advantages for patients over
single medicines given concomitantly in terms of better adherence and reduced pill burden.
However, the Committee considered that the ongoing availability of single agent antihypertensive
medicines remains critical to allow treatment modification where necessary.
6
For European Society For Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (ESMO–MCBS),
see: https://www.esmo.org/score/cards.
xvii
Section 12.5.2: Thrombolytic medicines

The Committee recommended the addition of alteplase to the complementary list of the EML
for use in patients diagnosed with acute ischaemic stroke. The Committee noted that alteplase
thrombolysis is associated with reductions in death and dependence when administered within
4.5 hours of the onset of stroke symptoms. Optimal use will require timely and highly organized
care pathways, in facilities equipped and capable of managing stroke patients.
Section 17: Gastrointestinal medicines

Section 17.2: Antiemetic medicines
The Committee recommended the addition of aprepitant to the complementary list of the
EML and EMLc for management of chemotherapy-induced nausea and vomiting in patients
undergoing moderately- to highly-emetogenic chemotherapy, as it has been shown to be
more effective than standard antiemetics. The Committee also recommended the addition of a
square box to the current listings of ondansetron on the EML and EMLc, indicating therapeutic
equivalence among 5HT3 receptor antagonists.
Section 17.5: Medicines used in diarrhoea

The Expert Committee recommended listing on the core list of the EMLc of a co-packaged
presentation of oral rehydration salts and zinc sulfate tablets, noting the recommendations for
co-administration of the two components in the management of diarrhoea in children. The co-
packaged product was considered practical, and likely to support better adherence to treatment.
Section 18: Medicines for endocrine disorders (Re-named)

This section has been updated and amended to include only medicines for endocrine disorders
in revised sub-sections as follows:
–– 18.1: Adrenal hormones and synthetic substitutes

–– 18.2: Androgens
–– 18.3: Estrogens
–– 18.4: Progestogens
–– 18.5: Medicines for diabetes
–– 18.6: Medicines for hypoglycaemia
–– 18.7: Thyroid hormones and antithyroid medicines
Contraceptives and other medicines for reproductive health have been transferred to Section 22
(see below).
Section 18.5: Medicines for diabetes

The Committee acknowledged that insulin is a life-saving essential medicine for which a
compelling public health need exists. Yet, despite being available for almost 100 years, achieving
xviii
Executive summary
reliable, equitable and affordable access to insulin remains a public health challenge in many
countries. The Committee recognized the need for a wider understanding of the complexities
of access to insulin and the current insulin market and recommended WHO to prioritize the
coordination of a series of actions to address the issues of insulin access and affordability.
This WHO coordinated approach should aim at tackling the different aspects of the current
situation of sub-optimal access to insulin in many countries. This includes:
–– establishment of a WHO technical working group on access to insulin;

–– consultation with Member States and other stakeholders to identify/clarify
barriers to access at country level;
–– strategies to address current regulatory barriers for biosimilar insulins, including
the expansion of the WHO Prequalification Programme;
–– development of a comprehensive approach to address insulin prices, including
new mechanisms for pooled procurement through UN supply agencies (e.g.
UNICEF and UNDP) and through providing support for countries;
–– identification of evidence and research gaps regarding insulin use and supply,
including setting-specific differences in clinical practice and health systems.
The Committee did not recommend the addition of insulin analogues to the EML, reiterating
the conclusion of the 2017 Expert Committee, that while long-acting insulin analogues are
an effective treatment for type 1 diabetes, the available evidence shows efficacy and safety
advantages of analogues compared to human insulin which are insufficiently large to justify
the cost differential that continues to exist. In the absence of other coordinated actions, the
Committee considered that the inclusion of insulin analogues for adults on the EML would be
inadequate to address the underlying issues of poor access and affordability of insulins. The
Committee would therefore welcome a report that comprehensively describes the actions that
are undertaken over the next two years and an application that reviews in greater depth the
current challenges for optimal global access and the role of insulin analogues in children.
Section 18.6: Medicines for hypoglycaemia

The Committee recommended addition of diazoxide on the complementary list of the EMLc for
the management of hypoglycaemia secondary to prolonged hyperinsulinism, based on a positive
benefit-to-risk ratio and for its impact on reducing the serious neurological consequences of
untreated hyperinsulinism in newborns.
Section 18.7: Thyroid hormones and antithyroid medicines

The Committee recommended the addition of methimazole with a square box to the core list of
the EML and to the complementary list of the EMLc for the treatment of primary hyperthyroidism.
Carbimazole is a therapeutically equivalent alternative. The Committee also recommended that
the square box be removed from the listing of propylthiouracil on the EML. Propylthiouracil
remains the recommended first-line treatment for women in the first trimester of pregnancy, and
in patients for whom first-line treatment with methimazole (or carbimazole) is not appropriate
xix
or available. Propylthiouracil remains listed on the complementary list of the EMLc for use in
patients for whom alternative first-line treatment is not appropriate or available.
Section 19: Immunologicals

Section 19.3: Vaccines
This section was updated by the Secretariat for consistency and alignment with the most recent
WHO immunization policy recommendations and vaccine position papers. Dengue vaccine was
added to the EML and EMLc for use in some high-risk populations, in line with the September
2018 dengue vaccine WHO position paper.7
Section 22: Medicines for reproductive health and perinatal care

(Re-named)
This section has been updated and amended to include contraceptives and other medicines for
reproductive health, maternal and neonatal care (from Sections 18, 22 and 29).
Section 22.3: Uterotonics

The Committee recommended the addition of heat-stable carbetocin injection to the core list
of the EML for the prevention of postpartum haemorrhage based on similar effects compared
to oxytocin for efficacy and safety outcomes. The Committee agreed that heat-stable carbetocin
may offer advantages over oxytocin in some settings as it does not require cold chain transport
or refrigerated storage.
The Committee did not recommend deletion of the indication of prevention of post-partum
haemorrhage for misoprostol, noting that misoprostol is recommended in WHO guidelines as
an alternative to oxytocin in settings where injectable uterotonics are not available or cannot be
safely administered.
The Committee recommended the transfer of mifepristone – misoprostol from the complementary
to the core list of the EML, and removal of the note accompanying the listing stating, “Requires
close medical supervision”, based on the evidence presented that close medical supervision is
not required for its safe and effective use. The Committee also recommended the addition of a
co-packaged presentation of mifepristone and misoprostol to the core list of the EML.
Recalling that their role and responsibility is to provide WHO with technical guidance in relation
to the selection and use of essential medicines, the Committee noted that its mandate did not
extend to providing advice regarding the statement “Where permitted under national law and
where culturally appropriate”. Subsequent to the Committee meeting, the Director-General, in
consultation with the Department of Essential Medicines and Health Products, decided that no
change to the statement be made.
7
Dengue vaccine: WHO position paper (2018). See: https://apps.who.int/iris/bitstream/handle/10665/
274315/WER9336.pdf?ua=1.
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Executive summary
Section 22.6: Other medicines administered to the mother

The Committee recommended the addition of tranexamic acid to the core list of the EML for
the new indication of treatment of postpartum haemorrhage (PPH), to be used as part of the
standard PPH treatment package, including fluid replacement, uterotonics surgical and non-
surgical interventions, in accordance with WHO guidelines.
Section 24: Medicines for mental and behavioural disorders

The Committee did not recommend inclusion of methylphenidate on the Model Lists for the
treatment of attention-deficit hyperactivity disorder (ADHD) due to uncertainties in the estimates
of benefit, and concerns regarding the quality and limitations of the available evidence for both
benefit and harm.
Section 24.2.1: Medicines used in depressive disorders

The Committee recommended the addition of a square box to the listing of fluoxetine on
the core list of the EML for the treatment of depressive disorders. The Committee noted that
medicines within the pharmacological class of selective serotonin reuptake inhibitors (SSRI)
have demonstrated efficacy, but can differ in terms of pharmacokinetics, adverse events and
drug‑interaction profiles. The availability of different SSRIs as essential medicines may be
beneficial at the country level to expand therapeutic alternatives for patients and support better
procurement. The Committee considered that it was not necessary to add escitalopram to the
EML, as the addition of the square box to fluoxetine would allow the selection of escitalopram
at national level.
Section 25: Medicines acting on the respiratory tract

The Committee recommended the addition of tiotropium to the core list of the EML, with a
square box as representative of the pharmacological class of long-acting muscarinic antagonists
(LAMA) for the treatment of chronic obstructive pulmonary disease (COPD), based on evidence of
effectiveness in controlling COPD symptoms and reducing exacerbations, and acceptable safety.
Section 27: Vitamins and minerals

The Committee recommended a correction to the listed strength of iodine capsules to 190 mg, to
accurately reflect the quantitative composition of this product.
The Committee recommended the addition of multiple micronutrient powders to the core list
of the EMLc for the prevention of anaemia in infants and children, noting that a standardized
product monograph is to be included in the United States Pharmacopoeia.
Section 29: Medicines for diseases of joints

Formerly Section 30. Re-numbered following the transfer of medicines specific for neonatal care
to Section 22. The former Section 30 has been deleted.
xxi
Follow up decisions from the 2017 Expert Committee meeting

Oseltamivir
The Committee noted the advice from the WHO Secretariat that the WHO Guidelines for clinical
management of influenza are in the process of being updated, but the recommendations of
the guideline development group were not yet available. The Committee recommended that
no change be made to the current listing for oseltamivir on the Model Lists until the updated
guidelines and supporting evidence can be reviewed.
Ready-to-use therapeutic food

The Committee did not recommend the addition of ready-to-use therapeutic food (RUTF) to
the Model Lists for the treatment of severe acute malnutrition, but again acknowledged the
effectiveness of this product for this condition. The Committee considered that the comprehensive
report prepared by the WHO Department of Nutrition in response to the request of the previous
Expert Committee, highlighted the divided opinions and ongoing uncertainty of the implications
at country level of listing RUTF as a medicine on the Model List.
Working Group on Transparency and Access to Clinical Trial Data

The Committee reiterated its recommendation from 2017 to establish a working group on
transparency and timely public disclosure of all clinical trial results and available data. The Working
Group should identify strategic actions to address factors known to impact the availability of
reliable data informing applications for the inclusion or removal of medicines on the Model Lists.
Such factors include selective outcome reporting, publication bias and open access to clinical
trial results. This Working Group could also action the recommendation made by the Expert
Committee for further independent analysis of data for pertuzumab in breast cancer.
Improving access to and affordability of essential medicines

Throughout the meeting, the Committee repeatedly noted and discussed the issue of improving
access to high-priced essential medicines (e.g. insulin, immunomodulators and new cancer
medicines) and the issue of affordability for health systems and patients.
The Committee acknowledged the limited role of WHO in price-setting at the country level, but
identified several different actions that could contribute to making some of the recently listed
essential medicines more affordable at the country level:
1. A wider adoption of biosimilars.

2. Expanding the remit of the Medicines Patent Pool.
3. The role of pooled procurement/tendering.
4. Use of flexibilities enshrined in the WHO TRIPS agreement.
5. Other existing instruments.
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Executive summary
1. Biosimilars
With the addition of new biological medicines to the Model Lists in 2019, the Committee
recognized that biologicals, including biosimilars, are associated with a significant budget
impact to health systems. However, the availability of several therapeutically equivalent
alternatives and the increasing availability of biosimilar products could lead to greater market
competition, improved patient access and reduced costs. Access to biosimilars is critical for
achieving affordable access to many biological medicines including new cancer treatments
and immunomodulators for chronic inflammatory conditions such as rheumatoid arthritis. The
Committee noted, with concern, the limited progress to date with access to biosimilars of some
essential medicines (e.g. rituximab).
The Committee recommended that WHO expand its Prequalification Programme to include
biosimilars of medicines listed on the EML, such that they are routinely evaluated along with the
reference product, to ensure accessibility and affordability to quality-assured products.
The Expert Committee considered the issue of interchangeability of biosimilar products as a
very important one for wider access and a crucial aspect to foster competition. The Committee
recommended that the EML Secretariat develops a concept note to summarize all the issues
and barriers to full interchangeability for wider access to affordable biosimilars for consideration
by the Expert Committee in 2021.
Finally, the Committee considered that where biosimilars of listed essential medicines exist, these
are considered therapeutically equivalent also for procurement purposes.
2. The expanded role of the Medicines Patent Pool

The Medicines Patent Pool (MPP), a public health organization funded by Unitaid, has played
a significant role in facilitating affordable access to essential medicines in the field of HIV and
hepatitis C virus (HCV) through its public health-oriented licences with originator companies.
To date, the MPP has licences on 14 medicines on the WHO EML. Licensing through the MPP of
patented essential medicines for the treatment of tuberculosis (e.g. bedaquiline) would also be a
welcome contribution to improving access.
The recent expansion of the MPP to other patented essential medicines beyond HIV, hepatitis C
and tuberculosis represents a real opportunity to facilitate affordable access to some of the
new medicines that have been added to the list this year in low and middle-income countries
(LMICs). Licensing through the MPP could, for example, contribute to facilitating access to some
of the cancer medicines, the novel oral anticoagulants, the new antibiotics and the heat-stable
formulation of carbetocin. In the case of cancer, it would be important that the MPP also explore
the application of its model to biotherapeutics so as to facilitate early entry of biosimilars through
voluntary licensing agreements in LMICs.
xxiii
3. The role of pooled procurement and tendering

The square box symbol () is primarily intended to indicate similar clinical performance within
a pharmacological class of medicines on the EML. The listed medicine should be the example
of the class for which there is the best evidence for effectiveness and safety. In some cases, this
may be the first medicine that is licensed for marketing; in other instances, subsequently licensed
compounds may be safer or more effective. Where there is no difference in terms of efficacy
and safety data, the listed medicine should be the one that is generally available at the lowest
price, based on international drug price information sources. Examples of pharmacological
classes with established therapeutic equivalence include proton pump inhibitors, ACE inhibitors
and erythropoietins.
More recently, the square box has been selectively applied to some listings, indicating specific
acceptable alternative options such as for morphine and enoxaparin. A square box was applied
to three pangenotypic regimens for hepatitis C, to indicate similar clinical performance across
the combination regimens.
When there are multiple options within the same pharmacological class or in the same
therapeutic area there can be substantial market competition that can allow for price reductions.
Large price reductions can be the result of tendering processes at the country or local level.
Applying the square box concept can improve outcomes in pooled procurement activities at
national or sub-national levels, and has the advantage of improving transparent governance.
The Committee recommended a comprehensive review of medicines listed with a square box
on the Model Lists be undertaken for consideration at its next meeting. The review will provide
greater clarity for countries regarding application of the square box concept for national essential
medicines lists selection and procurement.
4. Use of TRIPS flexibilities in line with the Doha Declaration on TRIPS and
Public Health
Application and management of intellectual property should contribute to innovation and
promotion of public health, in line with WHO Global strategy and plan of action on public health,
innovation and intellectual property.

Member States have the possibility to make use of the provisions that provide public health
flexibilities contained in the Agreement on Trade-Related Aspects of Intellectual Property Rights,
including the public health flexibilities recognized by the Doha Ministerial Declaration on the TRIPS
Agreement and Public Health in order to promote access to essential medicines.
5. Other existing instruments

Countries can define different pricing policies on how prices are set and negotiated at the
national level. However, medicines prices are the end result of a number of measures, actions and
contextual factors (such as market size and cost structures) acting at a country level. These can
involve different stakeholders that include regulators, reimbursement systems/third-party payers,
and competition authorities.
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Executive summary
Competition law and policies are also instruments available to governments in addressing
public health concerns, competition policy has an important role to play in ensuring access to
medical technology and fostering innovation in the pharmaceutical sector.8
All applications and documents reviewed by the Expert Committee are available on the WHO
website at: https://www.who.int/selection_medicines/committees/expert/22/en/.
Table 1
Recommended additions, changes and deletions on the 2019 EML and EMLc
EML – New medicines added EMLc – New medicines added

Medicine Indication Medicine Indication
Abiraterone Prostate cancer  Adalimumab Chronic systemic
inflammatory conditions
 Adalimumab Chronic systemic All-trans retinoid Acute promyelocytic

inflammatory conditions acid (ATRA) leukaemia
Alteplase Thrombolytic Aprepitant Nausea and vomiting
Aprepitant Nausea and vomiting Arsenic trioxide Acute promyelocytic

leukaemia
Arsenic trioxide Acute promyelocytic Bedaquiline Tuberculosis

leukaemia
Bortezomib Multiple myeloma Ceftazidime + Reserve antibiotic

avibactam
Carbetocin Post-partum Cefuroxime Surgical prophylaxis

haemorrhage
Ceftazidime + Reserve antibiotic Dasatinib Imatinib-resistant chronic

avibactam myeloid leukaemia (CML)
Cefuroxime Surgical prophylaxis Dengue vaccine Vaccine
 Dabigatran Anticoagulant Diazoxide Hypoglycaemia
Dengue vaccine Vaccine Dolutegravir HIV
Dolutegravir + HIV  Enoxaparin Anticoagulant

lamivudine +
tenofovir
 Erlotinib Lung cancer Fexinidazole Human African

trypanosomiasis
8
Promoting access to medical technologies and innovation: intersections between public health,
intellectual property and trade. See: http://www.who.int/iris/handle/10665/78069.
xxv
Table 1 continued
EML – New medicines added EMLc – New medicines added
Fexinidazole Human African Fluorouracil Nasopharyngeal cancer,
trypanosomiasis metastatic colorectal
cancer, early colon cancer,
early rectal cancer
Glecaprevir + Hepatitis C Imatinib Chronic myeloid

pibrentasvir leukaemia,
gastrointestinal stromal
tumour
Lenalidomide Multiple myeloma Irinotecan Metastatic colorectal

cancer
 Lisinopril + Hypertension  Methimazole Hyperthyroidism

 amlodipine
 Lisinopril + Hypertension Multiple Prevention of anaemia

 hydrochlorothi micronutrient
azide powders
Melphalan Multiple myeloma Nilotinib Imatinib-resistant CML
Meropenem + Reserve antibiotic Oxaliplatin Metastatic colorectal

vaborbactam cancer, early colon
cancer
 Methimazole Hyperthyroidism Pegaspargase Acute lymphoblastic

leukaemia
 Nivolumab Metastatic melanoma Procarbazine Hodgkin lymphoma
Pegaspargase Acute lymphoblastic RIF oral arsenic Acute promyelocytic

leukaemia formulation leukaemia
Plazomicin Reserve antibiotic Rituximab Diffuse large B-cell

lymphoma
RIF oral arsenic Acute promyelocytic

formulation leukaemia
 Telmisartan + Hypertension
 amlodipine
 Telmisartan + Hypertension
 hydrochlorothi
azide
Thalidomide Multiple myeloma
 Tiotropium COPD
xxvi
Executive summary
EML - New/changed indications EMLc - New/changed indications

Amoxicillin Dental abscess Amoxicillin Dental abscess
Amoxicillin + Surgical prophylaxis, Amoxicillin + Surgical prophylaxis,

clavulanic acid MDR‑TB clavulanic acid MDR‑TB
Azithromycin Enteric fever Azithromycin Enteric fever
Carboplatin Cervical cancer Bleomycin Kaposi sarcoma
Cefazolin Surgical prophylaxis Cefazolin Surgical prophylaxis
Ceftriaxone Enteric fever Ceftriaxone Enteric fever
Ciprofloxacin Enteric fever Ciprofloxacin Enteric fever
Cisplatin Cervical cancer Cisplatin Nasopharyngeal cancer
Cyclophosphamide Multiple myeloma Cyclophosphamide Diffuse large B cell

lymphoma
Dexamethasone Multiple myeloma Cytarabine Acute myeloid leukaemia,

acute promyelocytic
leukaemia
Doxorubicin Multiple myeloma Daunorubicin Acute promyelocytic

leukaemia
Gentamicin Surgical prophylaxis Doxorubicin Diffuse large B cell

lymphoma, Kaposi
sarcoma
Ivermectin Scabies Gentamicin Surgical prophylaxis
Meropenem MDR-TB Hydroxycarbamide Chronic myeloid

leukaemia
Metronidazole Surgical prophylaxis Ivermectin Scabies
Phenoxymethyl Dental abscess Mercaptopurine Acute promyelocytic

penicillin leukaemia
Prednisolone Multiple myeloma, Meropenem MDR-TB

prostate cancer
Sulfadoxine + Malaria - Intermittent Methotrexate Acute promyelocytic

pyrimethamine preventive treatment in leukaemia
pregnancy
Tranexamic acid Post-partum Metronidazole Surgical prophylaxis

haemorrhage
Phenoxymethyl Dental abscess

penicillin
xxvii
Table 1 continued
EML - New/changed indications EMLc - New/changed indications
Prednisolone Diffuse large B-cell
lymphoma
Sulfadoxine + Malaria – intermittent

pyrimethamine preventive treatment in
infancy
Vincristine Diffuse large B-cell

lymphoma, Kaposi
sarcoma
EML – New formulation/strength EMLc – New formulation/strength

Calcium folinate Tablet 5 mg and 25 mg Amodiaquine Co-package
with sulfadoxine +
pyrimethamine
Cyclophosphamide Tablet 50 mg Calcium folinate Tablet 5 mg and 25 mg
Etoposide Capsule 50 mg Cyclophosphamide Tablet 50 mg
Mifepristone- Co-package Cycloserine Solid oral dosage form

misoprostol 125 mg
Raltegravir Granules 100 mg Ethambutol Dispersible tablet 100 mg
Ritonavir Oral powder 100 mg Ethionamide Dispersible tablet 125 mg
Etoposide Capsule 50 mg
Isoniazid Dispersible tablet 100 mg
Levofloxacin Dispersible tablet 100 mg
Linezolid Dispersible tablet 150 mg
Lopinavir + Granules 40 mg + 10 mg
ritonavir
Moxifloxacin Dispersible tablet 100 mg
ORS + zinc sulfate Co-package
Raltegravir Granules 100 mg
Ritonavir Oral powder 100 mg
xxviii
Executive summary
EML – Medicines/formulations deleted EMLc – Medicines/formulations deleted

Abacavir + Dispersible tablet 60 mg Abacavir + Dispersible tablet 60 mg
lamivudine + 30 mg lamivudine + 30 mg
Aztreonam Powder for injection Aztreonam Powder for injection

1 g; 2 g 1 g; 2 g
Capreomycin Powder for injection 1 g Capreomycin Powder for injection 1 g
Daptomycin Powder for injection Daptomycin Powder for injection

350 mg, 500 mg 350 mg, 500 mg
Ethambutol + Tablet 400 mg + 150 mg Fifth-generation Powder for injection

isoniazid cephalosporins: 400 mg; 600 mg
e.g., ceftaroline
Fifth-generation Powder for injection Fourth-generation Powder for injection

cephalosporins: 400 mg; 600 mg cephalosporins: 500 mg; 1 g; 2 g
e.g., ceftaroline e.g., cefepime
Fourth-generation Powder for injection Kanamycin Powder for injection 1 g

cephalosporins: 500 mg; 1 g; 2 g
e.g., cefepime
Isoniazid + Tablet 150 mg + 500 mg Tigecycline Powder for injection

pyrazinamide + + 150 mg 50 mg
rifampicin
Isoniazid + Tablet 60 mg + 60 mg; Zidovudine Dispersible tablet 60 mg

rifampicin 150 mg + 150 mg
Kanamycin Powder for injection 1 g
Simeprevir Capsule 150 mg
Tigecycline Powder for injection

50 mg
Zidovudine Dispersible tablet 60 mg
Other changes to listings

Clofazimine Replace ‘capsule’ with ‘solid oral dosage form’ EML and EMLc
Rifabutin Replace ‘capsule’ with ‘solid oral dosage form’ EML
Propylthiouracil Remove square box, add note “for use when alternative EML
first-line treatment is not appropriate or available; and
in patients during the first trimester of pregnancy”
xxix
Table 1 continued
Propylthiouracil Add note “for use when alternative first-line treatment EMLc
is not appropriate or available”
Fluoxetine Add square box EML
Iodine capsules Amend strength from 200 mg to 190 mg EML and EMLc
Ondansetron Add square box EML and EMLc
Mifepristone- Transfer from complementary to core list, remove note EML

misoprostol regarding requirement for close medical supervision
Changes to terminology of indications

2017 2019
Infections Chlamydia trachomatis Sexually transmitted infection due to
Chlamydia trachomatis
Neisseria gonorrhoeae Gonorrhoea
Trichomonas vaginalis Trichomoniasis
Cancers Acute myelogenous leukaemia Acute myeloid leukaemia
Wilms tumour Nephroblastoma (Wilms tumour)
Changes to sections and sub-sections of the Model Lists

2017 2019
Section 6.2: Antibacterials
6.2.1 Beta-lactam medicines 6.2.1 Access group antibiotics
6.2.2 Other antibacterials 6.2.2 Watch group antibiotics
6.2.3 Antileprosy medicines 6.2.3 Reserve group antibiotics
6.2.4 Antituberculosis medicines 6.2.4 Antileprosy medicines
6.2.5 Antituberculosis medicines
6.6 Medicines for ectoparasitic infections
Section 6.4.4.2: Medicines for hepatitis C
6.4.4.2.1 Nucleotide polymerase inhibitors 6.4.4.2.1  Pangenotypic direct-acting

antiviral combinations
xxx
Executive summary
Table 1 continued
2017 2019
6.4.4.2.2 Protease inhibitors 6.4.4.2.2 Non-pangenotypic direct-acting
antiviral combinations
6.4.4.2.3 NS5A inhibitors 6.4.4.2.3 Other antivirals for hepatitis C
6.4.4.2.4 Non-nucleoside polymerase 6.4.4.2.4 Deleted

inhibitors
6.4.4.2.5 Other antivirals 6.4.4.2.5 Deleted
Section 8: RENAMED - Immunomodulators and antineoplastics (was Antineoplastics and

immunosuppressives)
8.1 Immunosuppressive medicines 8.1 Immunomodulators for non-malignant

disease
8.2 Cytotoxic and adjuvant medicines 8.2 Antineoplastics and supportive medicines
8.2.1 Cytotoxic medicines
8.2.2 Targeted therapies
8.2.3 Immunomodulators
8.2.4 Hormones and antihormones
8.2.5 Supportive medicines
8.3 Hormones and antihormones 8.3 Deleted
Section 18: RENAMED - Medicines for endocrine disorders (formerly Hormones, other endocrine
medicines and contraceptives)
18.1 Adrenal hormones and synthetic 18.1 Adrenal hormones and synthetic
substitutes substitutes
18.2 Androgens 18.2 Androgens
18.3 Contraceptives 18.3 Estrogens
18.4 Estrogens 18.4 Progestogens
18.5 Insulins and other medicines used for 18.5 Medicines for diabetes
diabetes
18.6 Ovulation inducers 18.6 Medicines for hypoglycaemia
18.7 Progestogens 18.7 Thyroid hormones and antithyroid

medicines
18.8 Thyroid hormones and antithyroid 18.8 Deleted

medicines
xxxi
Table 1 continued
2017 2019
Section 22: RENAMED - Medicines for reproductive health and perinatal care (formerly Oxytocics
and antioxytocics)
22.1 Oxytocics 22.1 Contraceptives
22.2 Antioxytocics (tocolytics) 22.2 Ovulation inducers
22.3 Uterotonics
22.4 Antioxytocics (tocolytics)
22.5 Other medicines administered to the

mother
22.6 Medicines administered to the neonate
Section 29: RENAMED – Medicines for diseases of joints (formerly Specific medicines for
neonatal care)
29.1 Medicines administered to the neonate 29.1 Medicines used to treat gout
29.2 Medicines administered to the mother 29.2 Disease modifying agents used in
rheumatoid disorders (DMARDs)
29.3 Juvenile joint diseases
Section 30: DELETED (formerly Medicines for diseases of joints)
30.1 Medicines used to treat gout 30.1 Deleted
30.2 Disease-modifying agents used in 30.2 Deleted

rheumatoid disorders (DMARDs)
30.3 Juvenile joint diseases 30.3 Deleted

xxxii
Executive summary
Table 2
Applications and medicines not recommended for 2019 EML and EMLc
ADDITIONAL MEDICINES
Addition of anti-PD-1 immune checkpoint inhibitors for treatment of non-small EML

cell lung cancer
(atezolizumab, nivolumab, pembrolizumab)
Addition of newly registered antibiotics for treatment of infections due to multi- EML
drug resistant organisms (including AWaRe classification)
(ceftolozane + tazobactam, delafloxacin, eravacycline, omadacycline)
Addition of medicines for treatment of multiple sclerosis EML & EMLc

(fingolimod, glatiramer acetate, ocrelizumab)
Addition of long-acting insulin analogues for treatment of type 1 diabetes EML

(insulin detemir, insulin glargine, insulin degludec)
Addition of enzalutamide for treatment of metastatic castration-resistant EML

prostate cancer
Addition of escitalopram for treatment of major depressive disorder EML
Addition of methylphenidate for treatment of attention-deficit hyperactivity EML & EMLc

disorder
Addition of pertuzumab for use in the treatment of breast cancer EML
Addition of sumatriptan for treatment of migraine EML
Addition of trastuzumab emtansine (TDM-1) for use in the treatment of breast EML
cancer.
ADDITIONAL FORMULATIONS/STRENGTHS
New injectable formulation of ethambutol for treatment of drug-susceptible EML & EMLc
tuberculosis
New injectable formulation of isoniazid for treatment of drug-susceptible EML & EMLc
tuberculosis
New strength of isoniazid oral liquid for treatment of drug-susceptible EMLc

tuberculosis
New injectable formulation of p-aminosalicylic acid for treatment of drug- EML & EMLc
susceptible tuberculosis
New injectable formulation of rifampicin for treatment of drug-susceptible EML & EMLc
tuberculosis
New subcutaneous formulation of rituximab for use in the treatment of EML

lymphoma and leukaemia
New subcutaneous formulation of trastuzumab for use in the treatment of EML

breast cancer.
xxxiii
Table 2 continued
NEW INDICATIONS
New indication for 5-fluorouracil for treatment of cervical cancer in the curative EML
setting.
DELETIONS
Deletion of misoprostol for the indication for prevention of postpartum EML

haemorrhage
Deletion of antiretroviral formulations for treatment of HIV infection EML & EMLc
(raltegravir 100 mg tablets, ritonavir 400 mg/5 mL oral liquid)
AGE RESTRICTIONS
Change to age restriction for use of delamanid in children with multi-drug EMLc
resistant tuberculosis
xxxiv
List of participants
Committee Members
Zeba Aziz, Professor of Oncology and Hematology/Consultant Oncologist & Hematologist,
Hameed Latif Hospital, Lahore, Pakistan
Franco Cavalli, Scientific Director, Oncology Institute of Southern Switzerland, Ospedale San
Giovanni, Bellinzona, Switzerland
Graham Cooke, NIHR Professor of Infectious Diseases, Department of Medicine, Imperial College,
London, United Kingdom (Chair)
Sumanth Gandra, Assistant Professor, Division of Infectious Diseases, Washington University
School of Medicine in St Louis, USA
Armando Genazzani, Professor of Pharmacology, Università del Piemonte Orientale, Italy
Gregory Kearns, Paediatric clinical pharmacologist and Professor of Paediatrics at the University
of Arkansas for Medical Sciences, Arkansas, United States
Gabriela Prutsky Lopez, Senior associate consultant in pediatrics at the Mayo Clinic Health
System; and Founder of Unidad de Conocimiento y Evidencia (CONEVID), Universidad Peruana
Cayetano Heredia, Lima, Peru
Nizal Sarrafzadegan, Professor of Internal Medicine & Cardiology, Isfahan University, Iran and
Affiliate Professor of the Faculty of Medicine, School of Population and Public Health in the
University of British Columbia in Vancouver, Canada
Mike Sharland, Professor of Paediatric Infectious Diseases; Lead Consultant Paediatrician,
Paediatric Infectious Diseases Unit, St George’s University Hospitals NHS Foundation Trust,
London, United Kingdom
Shalini Sri Ranganathan, Professor in Pharmacology and Specialist in Paediatrics, University of
Colombo, Colombo, Sri Lanka (Vice-Chair)
Fatima Suleman, Professor in the Discipline of Pharmaceutical Sciences at the University of
KwaZulu-Natal, South Africa (Rapporteur)
Worasuda Yoongthong, Director of Regional and Local Consumer Health Product Protection
and Promotion Division, and Director of the Health Products Entrepreneurship Promotion
Division, Food and Drug Administration of Thailand, Nonthaburi, Thailand
Mei Zeng, Professor and Director, Department of Infectious Diseases and Chief, Infectious
Diseases Unit, Children’s Hospital of Fudan University, Shanghai, China
Temporary Advisers
Andrea Biondi, Professor of Paediatrics, Department of Paediatrics, University of Milano-Bicocca,
Italy
Elisabeth de Vries, Professor of Medical Oncology at the University Medical Center, Groningen,
the Netherlands
xxxv
Monica Imi, Medical internist, practicing clinician and technical adviser to the Ministry of Health,
Kampala, Uganda
Gilbert Kokwaro, Pharmacist and health systems specialist; Director of Institute of Healthcare
Management and Professor of Health Systems Research at Strathmore University, Kenya;
Professor of Pharmaceutics, Nairobi University, Kenya
Apologies - Temporary Advisers

Maria Auxilliadora Oliveira, Senior Professor and Researcher, National School of Public Health,
Oswaldo Cruz Foundation, Ministry of Health, Brazil
UN Agencies
United Nations Population Fund (UNFPA)
Alfonso Barragues, Deputy Director, UNFPA Geneva Office, Geneva, Switzerland
United Nations Children’s Fund (UNICEF)
Akthem Fourati, Chief, Medicine & Nutrition Centre, UNICEF Supply Division, Copenhagen,
Denmark
WHO Regions
WHO Regional Office for Africa
Jean-Baptiste Nikiema, Acting HTI Team Leader, Health Technologies and Innovations,
Brazzaville, Republic of the Congo
WHO Regional Office for the Americas/Pan American Health Organization
Alexandra Guta, Specialist in Medicines and Technologies, Washington DC, United States
WHO Regional Office for Europe
Hanne Bak Pedersen, Programme Manager, Health Technologies and Pharmaceuticals,
Copenhagen, Denmark
WHO Headquarters Geneva - Secretariat

Nicola Magrini, Secretary of the Expert Committee on Selection and Use of Essential Medicines;
Innovation, Access and Use, Department of Essential Medicines and Health Products
Bernadette Cappello, Technical Officer, EML Secretariat, Innovation, Access and Use, Department
of Essential Medicines and Health Products
Benedikt Huttner, Consultant, EML Secretariat, Innovation, Access and Use, Department of
Essential Medicines and Health Products
Lorenzo Moja, Technical Officer, EML Secretariat, Innovation, Access and Use, Department of
Clive Ondari, Director a.i., Department of Essential Medicines and Health Products
xxxvi
Declaration of interests for Expert Committee
Members and Temporary Advisers
Declaration of Interest, and management of any disclosures, is an important process governed
by the WHO Guidelines for Declaration of Interests (WHO Experts). The WHO Essential Medicines
Secretariat identified and screened a number of individuals, considered for participation at the
22nd Expert Committee on the Selection and Use of Essential Medicines, in different capacities –
as Members and Temporary Advisers.
The screening process required a close and detailed review of all the potential Members and
Temporary Advisers and their disclosures prior to confirming participation. In this regard, the
WHO Essential Medicine Secretariat rigorously examined each potential participant. Guidance
from the Office of Compliance, Risk Management and Ethics was additionally sought.
The declaration of interest process, resulted in the participation of Expert Committee Members
and Temporary Advisers as reported in the list of participants.
Expert Committee Members and Temporary Advisers who declared having no conflicts of
interests were: Zeba Aziz, Andrea Biondi, Sumanth Gandra, Armando Genazzani, Monica Imi,
Maria Auxiliadora Oliveira; Gabriela Prutsky-Lopez, Nizal Sarrafzadegan, Fatima Suleman, Worasuda
Yoongthong and Mei Zeng.
The following Expert Committee Members declared interests that were determined not to
represent a conflict of interest:
Dr Franco Cavalli disclosed being a President of the World Oncology Forum, The World Oncology
Forum is funded exclusively from independent, non-commercial sources. This is an unpaid activity.
Dr Graham Cooke disclosed having chaired the Lancet Gastroenterology & Hepatology
Commission on Accelerating the Elimination of Viral Hepatitis, for which he is unpaid. Dr Cooke
also declared having received minimal honoraria for a speaking engagement in 2017 from
Merck and Gilead Sciences Inc. respectively on subjects not related to the work of the Essential
Medicine Secretariat. He has additionally received a minimal honoraria from Edixomed Ltd to
provide advice on study designs to test nitric oxide, a treatment not related to any application
under evaluation at this meeting. Conflicts of interests declared by Dr Cooke were considered
minor and did not require further management.
Dr Gregory Kearns disclosed a consultancy contract as a paediatric pharmacology adviser with
Boehringer Ingelheim that will commence after the Expert Committee meeting. This is a paid
activity at a level of remuneration below the threshold of US$ 5 000. This was considered not to
represent a conflict.
Dr Mike Sharland disclosed being the chair of the Department of Health’s Expert Advisory
Committee on Antimicrobial Prescribing, Resistance and Healthcare Associated Infection (APRHAI);
leading the NeoAMR Project, an initiative to address neonatal sepsis launched by the Global
Antibiotic Research and Development Partnership (GARDP), a joint programme of WHO and the
Drugs for Neglected Diseases initiative (DNDi) in support of the Global Action Plan for Antimicrobial
xxxvii
Resistance. All positions are unpaid. Dr Sharland also declared that his institution, St George’s
University London, has received research funding from GARDP to support the development of
academic activities, including observational cohort studies, on antibiotic use in children. GARDP is
funded exclusively from independent, non-commercial sources. As a GARDP advisor, Dr Sharland
was involved in discussion on several antibiotics, particularly fosfomycin and polymyxin B,
antibiotics included in AWaRe and under discussion at this meeting. As the mandate of GARDP
largely coincides with WHO – to drive the global response to antimicrobial resistance and set
health priorities – and all R&D activities are limited to neglected diseases to deliver not-for-profit,
needs-driven R&D, Dr Sharland declaration was considered not to represent a conflict.
Professor Shalini Sri Ranaganathan declared that she has received research funding from
Colombo University, where she is employed, to conduct a survey on availability and affordability
of essential medicines for children in Sri Lanka. This was determined not to represent a conflict.
Temporary Advisers
Dr Elisabeth de Vries participated as a Temporary Adviser and disclosed having served as an
expert member of Data Safety Monitoring Committees for trials promoted by a non-profit
research programme (National Surgical Adjuvant Breast and Colon Project) and for-profit
companies (Daiichi Sankyo, Merck, Synthon, Sanofi and Pfizer). The matters under consideration
by the Data Safety Monitoring Committees are not related to medicines under evaluation or the
work of the 22nd Expert Committee on the Selection and Use of Essential Medicines. Dr de Vries
chairs the Magnitude of Clinical Benefit Scale Working Group of the European Society for Medical
Oncology (ESMO-MCBS), the Cancer Medicines Working Group of ESMO, and the Response
Evaluation Criteria in Solid Tumours (RECIST) Working Group. It is noted that ESMO is a non-
governmental organization in official relations with WHO. All positions are unpaid. Through her
involvement in the above mentioned ESMO and RECIST panels, Dr de Vries was involved in the
evaluation of medicines to be considered by this Expert Committee (abiraterone, atezolizumab,
enzalutamide, nivolumab, pembrolizumab, pertuzumab, trastuzumab emtansine).
Her institution (University of Groningen) is involved in early phase clinical trials to explore the
therapeutic and diagnostic/prognostic roles of cancer medicines and biomarkers receiving
institutional funding from Amgen, Astra Zeneca, Bayer, Chugai, CytomX, Genentech, G1
Therapeutics, Nordic Nanovector, Radius Health, Roche, Synthon. These trials are not directly
related to medicines for which applications are to be evaluated at this meeting. After reviewing
Dr de Vries declarations, it was determined she could participate as a Temporary Adviser.
Dr Gilbert Kokwaro disclosed an appointment as Chair of the Universal Health Coverage Advisory
Panel for Kenya. The Advisory Panel will develop a package of essential medicines that will form
the benefits package to be provided under the UHC programme in Kenya. This was considered
not to represent a conflict and it was determined that he could participate as a Temporary Adviser.
It is noted that the names and brief biographies of all the Committee Members and Temporary
Advisers were made publicly available for comment ahead of the meeting.
xxxviii
1. Introduction
The 22nd meeting of the World Health Organization (WHO) Expert Committee
on the Selection and Use of Essential Medicines was held from 1 to 5 April 2019,
in Geneva, Switzerland.
The meeting agenda included 65 applications involving over 100
medicines for addition, deletion, amendment and review in order to update the
WHO Model List of Essential Medicines (EML) and WHO Model List of Essential
Medicines for Children (EMLc). In addition, reports and recommendations made
by two EML Working Groups were also submitted for consideration.
The meeting was opened by Mariângela Simão, Assistant Director-
General, Medicines, Vaccines and Pharmaceuticals, on behalf of WHO Director-
General, Dr Tedros Adhanom Ghebreyesus. Dr Simão welcomed Committee
Members and Temporary Advisers, representatives from WHO regional offices,
nongovernmental organizations (NGOs) and other participants.
In her opening remarks Dr Simão described the importance of the
Model Lists of Essential Medicines to Member States as a standard reference for
medicines, and a valuable tool for policy-makers to optimize selection and use of
medicines at the national level to ensure access in the context of universal health
coverage (UHC). She highlighted the roles of the Model Lists in priority-setting
and informing reimbursement policies, both as an intrinsically positive list, and
also by looking at medicines that have been assessed and not recommended for
listing on the basis of uncertain benefit or safety. Furthermore, she highlighted the
functions of the Model Lists as a guide for better procurement and competition
among similar treatments, as a guide for expanding the mandate of the WHO
Prequalification Programme and the Medicines Patent Pool, and as a tool for
UHC and health financing.
With reference to the meeting agenda, Dr Simão highlighted some of the
key topics to be considered by the Expert Committee including applications for
new cancer medicines, the review of the Access, Watch and Reserve (AWaRe)
classification of antibiotics, medicines for multiple sclerosis, and policy-oriented
discussions around biosimilars and medicines affordability and availability.
In particular, the ongoing challenges and complexities of access to insulin
were highlighted as important factors in the Committee’s consideration of the
application for inclusion of insulin analogues.
Dr Simão acknowledged the work already undertaken by Committee
Members and Temporary Advisers in reviewing applications and thanked
them for their preparation. She reminded them of their obligations to provide
advice to the Organization in their individual capacities as experts, and not as
representatives of their governments, institutions or organizations. On behalf of
the Director-General, she offered special thanks to the Committee for dedicating
their time to this valuable work.
1
2. Open session
The open session of the meeting was chaired by Mariângela Simão, Assistant
Director-General, Access to Medicines, Vaccines and Pharmaceuticals, on behalf
of the Director-General, and was attended by a variety of interested parties,
representatives of non-governmental organizations and representatives of WHO
Member States.
Nicola Magrini, Secretary of the Expert Committee delivered an update
on current activities of the EML Secretariat, methodology for the Model List
update, and the impact and implementation of recommendations made by the
previous Expert Committee.
Manica Balasegaram, Executive Director of the Global Antibiotic
Research and Development Partnership (GARDP) presented the work being
undertaken by GARDP, in collaboration with WHO and the Drugs for Neglected
Diseases initiative (DNDi), on antimicrobial resistance and antibiotic research
and development (R&D).
Nav Persaud, Assistant Professor at the University of Toronto, presented
details of a global database of national essential medicine lists from 137 countries,
which allows comparison and benchmarking with the Model List and comparison
between countries.
Additional presentations and/or statements of relevance to the agenda of
the Expert Committee were made by the following participants:
–– Rosa Guiliani, European Society for Medical Oncology
–– Hans Hogerzeil, Health Action International and the Lancet
Commission on Essential Medicines
–– Greg Perry, International Federation of Pharmaceutical
Manufactures & Associates
–– Thiru Balasubramanian, Knowledge Ecology International
–– Esteban Burrone, Medicines Patent Pool

–– Myriam Henkens, Medicins Sans Frontières
–– Patrick Durisch, Public Eye
–– Tom Frieden, Resolve to Save Lives
Copies of the presentations and statements are available on the WHO
website.9
9
Available at: https://www.who.int/selection_medicines/committees/expert/22/en/.
2
3. Follow-up items and EML Working Groups
Follow-up items from the 2017 Expert Committee meeting
Ready-to-use therapeutic food
The Expert Committee considered the comprehensive report prepared by the
WHO Department of Nutrition in response to the request of the previous Expert
Committee for the proposal to include ready-to-use therapeutic food (RUTF) on
the Model List.10
The Expert Committee acknowledged once again the efficacy of RUTF
for the dietary management of uncomplicated severe acute malnutrition in
children under 5 years of age, many in non-hospitalized settings. However,
the report highlighted the divided opinions and ongoing uncertainty of the
country level implications of including RUTF as a medicine on the Model List.
The Committee felt that the report did not fully address the concerns held
by the 2017 Expert Committee. The Committee recognized that the report
highlighted that adding RUTF to the Model List could have unknown or
unintended consequences such as more restricted access, increased costs and
could potentially hamper local production. The Committee recommended that
a comprehensive risk-mitigation plan for these potential consequences would
be highly relevant for any future consideration of the inclusion of RUTF on
the Model List. The Committee noted that there is work currently underway
to establish standards and guidelines for RUTF under the Codex alimentarius,
regarding production, nutritional aspects and labelling in order to facilitate
harmonization for the requirements of RUTF at an international level.
In the absence of such standards, and without a clear indication of the
potential consequences and implications at country level of including RUTF on
the Model List, and without the reassurance of a risk-mitigation plan to address
any consequences, the Expert Committee did not recommend the addition of
RUTF to the core list of the EMLc.
With regard to questions around the eligibility of RUTF to be added to
the EML as a food/nutritional product rather than a medicine, the Committee
noted that the Model Lists already include non-medicine products when they
form part of a comprehensive WHO policy or strategy (e.g. condoms) and that
RUTF would be eligible for future consideration for inclusion on the Model Lists,
provided the concerns around the potential consequences of listing on access
can be addressed.
10
Available at: https://www.who.int/selection_medicines/committees/expert/22/applications/rutf_nhd-
report/en/.
3
Oseltamivir
The Expert Committee recalled the recommendation of the 2017 Expert
Committee that oseltamivir be considered for deletion in 2019 unless new
information supporting its use in seasonal and pandemic outbreaks is provided.
The Committee noted the advice from the WHO Secretariat that the WHO
Guidelines for clinical management of influenza are in the process of being
updated and a meeting of the Guideline Development Group (GDG) was held
in March 2019, but the recommendations of the GDG were not yet available.
As part of the guideline development process, a systematic review (SR) of the
effect of antiviral treatments for influenza was conducted, but the results were not
yet available. This review, yet to be published or presented to the GDG, updated
previous SRs and considered non-randomized studies.
The Expert Committee accepted that the updated recommendations
and SR would represent new information relevant to any decision regarding
the inclusion or deletion of oseltamivir for treatment of influenza on the Model
Lists. The Committee therefore decided that any decision regarding the potential
deletion of oseltamivir from the Model List should take into consideration this
new evidence, and that the current listing for oseltamivir should be maintained
until such time that this evidence can be reviewed.
EML Cancer Medicines Working Group

Following the recommendation of the 2017 Expert Committee, the EML Cancer
Medicines Working Group was established in March 2018 to support the work
of the Committee by identifying cancer medicines for potential inclusion on
the Model Lists and by establishing clear principles that can serve as a guide for
selection of optimal treatments. The Working Group was mandated to propose
clear principles that can serve as a guide for selection of optimal cancer medicines
for EML inclusion through a review of the available tools for assessing the
magnitude of clinical benefit, and meaningful thresholds for clinical and public
health relevance of cancer medicines. A meeting of the Working Group was held
in March 2018 in Geneva. The report of the Working Group meeting,11 together
with two commissioned reports outlining: 1) temporal trends in oncology
trials;12 and 2) how to prioritize the selection of essential cancer medicines13
were presented to the 2019 Expert Committee for consideration.
11
Available at: https://www.who.int/selection_medicines/committees/expert/22/applications/CMWG_
meeting_report.pdf?ua=1.
12
Available at: https://www.who.int/selection_medicines/committees/expert/22/applications/CMWG_
temporal_trends_report-rev1.pdf?ua=1.
13
Available at: https://www.who.int/selection_medicines/committees/expert/22/CMWG_Report_Fojo.
pdf?ua=1.
4
Follow-up items and EML Working Groups
The Expert Committee endorsed the Working Group’s recommendations

that WHO adopts in general, a threshold for benefit of at least four to six months
survival gain for new cancer medicines to be considered as candidates for EML
inclusion. A range was preferred over a specific threshold (e.g. four months)
given the uncertainty associated with how clinical trial data relates to real-world
benefits, and may differ between different cancers.
The Expert Committee endorsed the role of the European Society for
Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale14 (ESMO–MCBS)
as a screening tool to identify cancer treatments that have potential therapeutic
value that warrants full evaluation for EML inclusion. Potential new EML cancer
medicines, in general, should have a score on the ESMO-MCBS of A or B in the
curative setting and of 4 or 5 in the non-curative setting. These scores would
support a medicine being evaluated by the Expert Committee for inclusion in
the EML through a full application.
With regard to other attributes of new cancer medicines and clinical
evidence requirements to support their inclusion on the EML, the Expert
Committee recommended the following general principles:
■■ Clinical data from more than one trial is usually required.
■■ Data from high quality randomized trials is considered most
important, and must be mature in order to assess the impact of the
medicine on overall survival, and to show consistent results across
different trials.
■■ Randomized trials should compare efficacy of new regimens to
current best standard of care (e.g. regimen, dose) rather than to
available but sub-optimal comparators.
■■ Additional information to inform the deployment of cancer regimens
in countries with varying resources and capacity would be useful.
■■ Trials that define the need for maintenance therapy and the length
of maintenance. Shorter treatment durations that compromise
efficacy only marginally (or not at all) might substantially reduce
outlays and allow more patients to access treatment.
■■ Trials that demonstrate superiority are preferred to non-inferiority
trials for new drugs, rather than an absence of inferiority to the
relevant comparator(s). However, non-inferiority trials can be
informative in some circumstances, eg, comparison of different
dosing regimens or treatment durations;
14
Available at: https://www.esmo.org/Guidelines/ESMO-MCBS.
5
■■ Consideration should be given to disease stage and line of therapy:

efficacy of cancer medicines is usually less in more advanced stages
of disease, and when used in advanced lines of treatment; therefore,
medicines that are effective in the first-line treatment setting are
more clinically meaningful and therefore highly desirable.
■■ The inclusion of a cancer medicine on the EML for a given indication
does not imply that the medicine should be considered essential for
other indications.
The Expert Committee acknowledged the valuable work of the Working
Group and recommended the continuation and further expansion of the Working
Group’s activities. Activities over the next biennium should include the update of
treatment regimens for cancers previously considered by the Expert Committee
and the identification of new cancer medicines that meet the above criteria.
The Working Group should also review the issues being experienced
at country level in relation to the implementation of EML cancer medicine
recommendations and access to cancer medicines.
The Expert Committee also recommended the need for consolidation
of cancer medicine recommendations and EML listings through a broader
technical advisory group meeting in 2020, with country engagement to support
implementation within a UHC perspective. This meeting should also be aimed
at sharing these approaches with a larger group of cancer experts and important
stakeholders and engage with countries in their implementation capacity.
EML Antibiotics Working Group

Two meetings of the EML Antibiotics Working Group were held during the
intervening period since the last Expert Committee meeting: in September 2017
and August 2018. The Working Group submitted three reports for consideration
by the Expert Committee: 1) a review of the AWaRe classification of antibiotics
and proposed amendments and expansion; 2) guidance on paediatric dosing

regimens for EML Access antibiotics in children;15 and 3) optimal duration of
antibiotic therapy.16
Review of the AWaRe classification and EML listings of antibiotics

The Expert Committee noted the adoption and utilization of the Access, Watch
and Reserve (AWaRe) classification of antibiotics on the EML by several Member
15
Available at: https://www.who.int/selection_medicines/committees/expert/22/applications/ABWG_
paediatric_dosing_AB.pdf.
16
Available at: https://www.who.int/selection_medicines/committees/expert/22/applications/ABWG_
optimal_duration_AB.pdf.
6
States including the endorsement of AWaRe by the G20 Health Ministers in

2018.17 A new target indicator based on AWaRe was also adopted by WHO under
its 13th General programme of work.18 It specifies a country level target of at least
60% of antibiotic consumption being from the Access group. This indicator
is intended to monitor access to essential medicines and progress towards
UHC. The Committee recognized the emerging role of the AWaRe groups for
stewardship and quality improvement programmes, complementary to the
specific listing of antibiotics as essential medicines.
The Expert Committee recommended that specific listing of antibiotics
in the EML and the classification of antibiotics into the different AWaRe groups
should be distinguished from each other, recognizing their distinct, albeit
complementary, purposes. The Committee acknowledged that EML-listed
antibiotics represent a parsimonious, evidence-based selection of essential
narrow spectrum antibiotics for first- and second-choice empiric treatment of
most common bacterial infections and a tool for stewardship. The Committee
noted that the existing AWaRe groupings did not include a range of antibiotics
used internationally and this impeded data collection and use. The Committee
therefore recommended that the AWaRe classification should extend beyond
the EML to all commonly used antibiotics globally, to better support antibiotic
monitoring and stewardship activities. The Expert Committee recommended
the development of an AWaRe classification database as a searchable tool
for countries.
The Committee also recommended, based on the advice of the Working
Group, that WHO consider creating an additional group in the AWaRe
classification database for antibiotics whose use is not evidence-based, nor
recommended in high-quality international guidelines, particularly fixed-dose
combinations of multiple broad-spectrum antibiotics. Antibiotics in this group
are not included on the Model Lists.
The Committee considered the proposals by the Working Group for
amendments to the AWaRe classification of antibiotics to expand the AWaRe
classification to include antibiotics and antibiotic classes not included in the
2017 iteration. Furthermore, the Committee agreed that fourth-generation
cephalosporins should be re-classified as Watch group, as they did not meet
the criteria for classification as Reserve. The Committee also recommended the
re-classification of faropenem from Watch to Reserve due to its high potential
for inappropriate use. It is an orally available formulation with broad-spectrum
activity, inappropriate use of which may further the spread of carbapenemase-
producing Enterobacteriaceae.
17
Available at: http://www.g20.utoronto.ca/2018/2018-10-04-health.pdf.
18
Available at: http://apps.who.int/gb/ebwha/pdf_files/EB144/B144_7-en.pdf.
7
With regard to the EML listing of antibiotics, the Committee endorsed

revised criteria for the inclusion of Reserve group antibiotics on the Model
List. Namely, Reserve group antibiotics should be included individually on the
Model List when they have a favourable benefit–risk profile and proven activity
against “Critical Priority” or “High Priority” pathogens as identified by the WHO
priority pathogens list, most notably carbapenem-resistant Enterobacteriaceae.
Subsequently, the Committee recommended the removal of aztreonam, fourth-
and fifth-generation cephalosporins (as classes), tigecycline and daptomycin
from the EML and EMLc as these antibiotics did not meet the revised criteria for
inclusion on the Model Lists as individual Reserve group agents.
In summary, 19 Access group antibiotics and 11 Watch group antibiotics
are now included individually on the 2019 Model Lists as first or second choice
empiric treatment options for infectious syndromes reviewed by the Expert
Committee. Seven Reserve group antibiotics are listed individually as last-
resort treatment options for infections due to multidrug-resistant organisms.
The Committee recommended the re-structuring of Section 6.2 by AWaRe
groups, such that antibiotics on the Model Lists are listed in revised sub-sections
accordingly, replacing the existing sub-sections based on chemical structure.
The revised EML AWaRe listing of antibiotics is summarized in Table 1.
The antibiotics classified into AWaRe groups has been revised and
expanded in 2019 to include 177 specific, commonly used antibiotics. A general
summary of the antibiotics and antibiotic classes classified is presented in Table 2.
The full AWaRe classification database of antibiotics is available as an online
appendix to this report.19
19
Available at: https://apps.who.int/iris/bitstream/handle/10665/327957/WHO-EMP-IAU-2019.11-eng.xlsx.
8
Table 1
Antibiotics included on the 2019 Model Lists of Essential Medicines by AWaRe groups
6.2.1 Access group 6.2.2 Watch group 6.2.3 Reserve group

antibiotics antibiotics antibiotics
Amikacin Azithromycin Ceftazidime + avibactam
Amoxicillin Cefixime Colistin
Amoxicillin + clavulanic acid Cefotaxime Fosfomycin (intravenous)
Ampicillin Ceftazidime Linezolid
Benzathine benzylpenicillin Ceftriaxone Meropenem + vaborbactam
Benzylpenicillin Cefuroxime Plazomicin
Cefalexin Ciprofloxacin Polymyxin B
Cefazolin Clarithromycin
Chloramphenicol Meropenem
Clindamycin Piperacillin + tazobactam
Cloxacillin Vancomycin (oral)
Doxycycline Vancomycin (intravenous)
Gentamicin
Metronidazole
Nitrofurantoin
Phenoxymethylpenicillin
Procaine benzylpenicillin
Spectinomycin
Sulfamethoxazole +
trimethoprim
Italic font indicates listing on the complementary list.
9
Table 2
Summary of AWaRe classification of antibiotics
Access group Aminoglycosides (unless included in Watch or Reserve)

Amphenicols
Beta-lactams with beta-lactamase inhibitors
First-generation cephalosporins
Penicillins (unless included in Watch)
Tetracyclines (unless included in Watch or Reserve)
Trimethoprim, alone or in combination with sulfonamides
Clindamycin
Metronidazole
Nitrofurantoin
Spectinomycin
Watch group Aminoglycosides (unless included in Access or Reserve)
Anti-pseudomonal penicillins with beta-lactamase inhibitors
Carbapenems (unless included in Reserve)
Watch group Carboxypenicillins
Fluoroquinolones
Glycopeptides (unless included in Reserve)
Macrolides (unless included in Reserve)
Penicillins (unless included in Access)
Tetracyclines (unless included in Access or Reserve)
Second generation cephalosporins
Third generation cephalosporins (unless included in Reserve)
Fourth generation cephalosporins
Rifamycins
Clofoctol
Fosfomycin (oral formulation)
Fusidic acid
Reserve group Carbapenems (unless included in Watch)
Monobactams
Third generation cephalosporins (unless included in Watch)
Polymyxins
Glycopeptides (unless included in Watch)
Macrolides (unless included in Watch)
Oxazolidinones
Tetracyclines (unless included in Access or Watch)
Daptomycin
Faropenem
Fosfomycin (IV formulation)
Tigecycline
10
Dosing and duration reports

The Expert Committee noted the reports presented on paediatric dosing
regimens for Access antibiotics and on optimal duration of antibiotic therapy.
The Committee considered that these reports were valuable work that could be
further expanded to inform the development of antibiotic guidance tools for
countries.
To this end, the Committee recommended the development of clinical
guidance summaries for each infectious syndrome, for both adults and
children, as a useful tool for countries to implement EML recommendations
and stewardship interventions using AWaRe. These summaries should include
information on choice of antibiotic, recommended daily dose, optimal dosing
frequency, and optimal duration of therapy. Guidance on when not to prescribe
or use antibiotics should also be incorporated. Management and treatment
algorithms for infectious syndromes could also be included.
The Expert Committee acknowledged the valuable work of the Working
Group and recommended the continuation and expansion of the Working
Group’s activities. Activities over the next biennium should include:
–– continued evaluation and review of the AWaRe classification of
antibiotics, including potential inclusion on the Model Lists;
–– review of new infectious syndromes for which antibiotics could
be considered for inclusion on the Model Lists by the Expert
Committee;
–– development of clinical guidance on optimal antibiotic dosing
and dosing frequency for adults and children to inform the
clinical guidance summaries;
–– development of clinical guidance on optimal antibiotic treatment
duration for clinical infection syndromes reviewed by the Expert
Committee, to inform the clinical guidance summaries.
–– development, in collaboration with key relevant stakeholders, of
the clinical guidance summaries and management and treatment
algorithms as educational tools for optimal use;
–– development of potential models of stewardship tools and
processes using AWaRe, including metrics of optimal prescribing.
EML Working Group on Transparency and Access to Clinical Trial Data

The Expert Committee reiterated its recommendation from 2017 to establish a
Working Group on transparency and timely public disclosure of all clinical trial
results and available data. The Working Group should identify strategic actions
to address factors known to impact the availability of reliable data informing
11
applications for the inclusion or removal of medicines on the Model Lists. Such
factors include selective outcome reporting, publication bias and open access to
clinical trial results. This Working Group could also action the recommendation
made by the Expert Committee for further independent analysis of data for
pertuzumab in breast cancer.
12
4. Summary of changes
Changes to sections of the Model Lists
Refer to Table 1 of the Executive summary for details of changes to sections and
sub-sections of the Model Lists.
Additions to Model Lists

Section 6.2.2 : Cefuroxime was added to the core list of the EML and EMLc as a
Watch group antibiotic for surgical prophylaxis.
Section 6.2.3 : Ceftazidime + avibactam, meropenem + vaborbactam and
plazomicin were added to the complementary list of the EML as Reserve group
antibiotics for treatment of infections due to multidrug-resistant organisms.
Ceftazidime + avibactam was added to the complementary list of the EMLc.
Section 6.2.4 : Bedaquiline was added to the complementary list of the EMLc
for the treatment of multidrug-resistant tuberculosis in children aged 6 years
and older.
Section 6.4.2 : For treatment of HIV infection, a fixed-dose combination of
dolutegravir + lamivudine + tenofovir was added to the core list of the EML,
and single-agent dolutegravir was added to the core list of the EMLc.
Section 6.4.4.2.1: Fixed-dose combination of glecaprevir + pibrentasvir was
added to the core list of the EML as a pan-genotypic treatment for adult patients
with chronic hepatitis C virus infection.
Section 6.5.5.1: Fexinidazole was added to the core list of the EML and EMLc for
the treatment of human African trypanosomiasis.
Section 8.1: Adalimumab with a square box, representative of the class of anti-
tumour necrosis factor alpha (TNF-α) biologics, was added to the complementary
list of the EML and EMLc for use in the treatment of chronic inflammatory
autoimmune disorders (rheumatoid arthritis, ankylosing spondylitis, juvenile
idiopathic arthritis and Crohn disease). Alternatives are limited to etanercept
and infliximab on the EMLc and to etanercept, infliximab, certolizumab pegol
and golimumab on the EML.
Section 8.2.1: Arsenic trioxide, pegaspargase and realgar-Indigo naturalis
formulation (RIF) were added to the complementary list of the EML and EMLc
for treatment of leukaemias. Melphalan was added to the complementary list of
the EML for treatment of multiple myeloma. Fluorouracil, irinotecan, oxaliplatin
and procarbazine were added to the complementary list of the EMLc for selected
indications for which they are already included on the EML.
13
Section 8.2.2 : Bortezomib was added to the complementary list of the EML for
the treatment of multiple myeloma. Erlotinib with a square box (gefitinib and
afatinib are alternatives) was added to the complementary list of the EML for
the treatment of epidermal growth factor receptor (EGFR) mutation-positive
advanced non-small lung cancer. All-trans retinoid acid, dasatinib, imatinib,
nilotinib and rituximab were added to the complementary list of the EMLc for
selected indications for which they are already included on the EML.
Section 8.2.3 : Lenalidomide and thalidomide were added to the complementary
list of the EML for the treatment of multiple myeloma. Nivolumab with a square
box (pembrolizumab as an alternative) was added to the complementary list of
the EML for the treatment of metastatic melanoma.
Section 8.2.4 : Abiraterone was added to the complementary list of the EML for
the treatment of metastatic castration-resistant prostate cancer.
Section 10.2 : Dabigatran with a square box (apixaban, edoxaban and rivaroxaban
are alternatives) was added to the core list of the EML for prevention of stroke
and systemic embolism in patients with non-valvular atrial fibrillation, and
for treatment of venous thromboembolism. Enoxaparin with a square box
(nadroparin and dalteparin as alternatives) was added to the core list of the EMLc.
Section 12.3 : Four fixed-dose combination formulations were added to the
core list of the EML for treatment of hypertension: lisinopril + amlodipine,
lisinopril + hydrochlorothiazide, telmisartan + amlodipine and telmisartan +
hydrochlorothiazide. Each component is listed with a square box as representative
of the relevant pharmacological classes.
Section 12.5.2 : Alteplase was added to the complementary list of the EML for
use as a thrombolytic in patients diagnosed with acute ischaemic stroke.
Section 17.2 : Aprepitant was added to the complementary list of the EML and
EMLc for management of chemotherapy-induced nausea and vomiting in
patients undergoing moderately- to highly-emetogenic chemotherapy.
Section 18.6 : Diazoxide was added to the complementary list of the EMLc for
the management of hypoglycaemia secondary to prolonged hyperinsulinism.
Section 18.7 : Methimazole with a square box (carbimazole as an alternative) was
added to the core list of the EML and the complementary list of the EMLc for the
treatment of primary hyperthyroidism.
Section 19.3 : Dengue vaccine was added to the EML and EMLc for use in some
high-risk population in line with the recommendations in the Dengue vaccine:
WHO position paper – September 2018.
14
Summary of changes
Section 22.3 : A heat-stable formulation of carbetocin was added to the core list
of the EML for the prevention of postpartum haemorrhage.
Section 25 : Tiotropium with a square box, representative of long-acting

muscarinic antagonists (LAMAs), was added to the core list of the EML for the
treatment of chronic obstructive pulmonary disease (COPD).
Section 27 : Multiple micronutrient powders were added to the core list of the
EMLc for the prevention of anaemia in infants and children.
Deletions from Model Lists

Section 6.2.3 : Aztreonam, daptomycin, fourth- and fifth-generation
cephalosporins, and tigecycline were deleted from the EML and EMLc.
Section 6.2.4 : Capreomycin and kanamycin were deleted from the EML and
EMLc. Ethambutol + isoniazid tablet 400 mg + 150 mg, isoniazid + pyrazinamide
+ rifampicin tablet 150 mg + 500 mg + 150 mg, and isoniazid + rifampicin tablets
60 mg + 60 mg and 150 mg + 150 mg were deleted from the EML.
Section 6.4.2 : Abacavir + lamivudine dispersible tablet 60 mg + 30 mg, and

zidovudine dispersible tablet 60 mg were deleted from the EML and EMLc.
Section 6.4.4.2 : Simeprevir was deleted from the EML.
New indications
Section 6.2.1 : The new indication of treatment for progressive apical dental
abscess was added for amoxicillin and phenoxymethylpenicillin on the EML and
EMLc. The new indication of surgical prophylaxis was added for amoxicillin +
clavulanic acid, cefazolin, gentamicin and metronidazole on the EML and EMLc.
Section 6.2.2 : The new indication of treatment for enteric fever was added for
azithromycin, ceftriaxone and ciprofloxacin on the EML and EMLc.
Section 6.2.5 : Amoxicillin + clavulanic acid and meropenem were included on

the complementary list of the EML and EMLc for the new indication of treatment
of multidrug-resistant tuberculosis (MDR-TB).
Section 6.6 : Ivermectin was included on the core list of the EML and EMLc for
the new indication of treatment of scabies.
Section 6.5.3.2 : New indications of intermittent preventive treatment in

pregnancy (IPTp) and intermittent preventive treatment in infants (IPTi) were
included for sulfadoxine + pyrimethamine in malaria.
15
Section 8.2 : Additional indications for multiple cancer medicines were included
the complementary list of the EML and EMLc as follows:
–– Cervical cancer (EML): carboplatin, cisplatin
–– Multiple myeloma (EML): cyclophosphamide, doxorubicin,
dexamethasone, prednisolone
–– Prostate cancer (EML): prednisolone
–– Kaposi sarcoma (EMLc): bleomycin, doxorubicin, vincristine
–– Nasopharyngeal cancer (EMLc): cisplatin
–– Diffuse large B-cell lymphoma (EMLc): cyclophosphamide,
doxorubicin, vincristine, prednisolone
–– Acute myeloid leukaemia (EMLc): cytarabine
–– Acute promyelocytic leukaemia (EMLc): cytarabine,
daunorubicin, mercaptopurine, methotrexate
–– Chronic myeloid leukaemia (EMLc): hydroxycarbamide
Section 22.5 : Tranexamic acid was included in the core list of the EML for the
new indication of treatment of postpartum haemorrhage.
New formulation and/or strength

Section 6.2.5 : Additional formulations and/or strengths of medicines for
treatment of tuberculosis were included in the EMLc as follows:
–– Cycloserine: solid oral dosage form 125 mg
–– Ethambutol: dispersible tablet 100 mg
–– Ethionamide: dispersible tablet 125 mg
–– Isoniazid: dispersible tablet 100 mg
–– Levofloxacin: dispersible tablet 100 mg

–– Linezolid: dispersible tablet 150 mg
–– Moxifloxacin: dispersible tablet 100 mg
Section 6.4.2 : Additional formulations and/or strengths of medicines for HIV
infection were included in the EML and EMLc as follows:
–– Lopinavir + ritonavir (EMLc): granules 40 mg + 10 mg (listed as
“solid oral dosage form”)
–– Raltegravir (EML and EMLc): granules for oral suspension 100 mg
–– Ritonavir (EML and EMLc): oral powder 100 mg
16
Summary of changes
Section 6.5.3.2 : Co-packaged presentations of amodiaquine and sulfadoxine

+ pyrimethamine dispersible tablets were included on the EMLc for seasonal
malaria chemoprevention in children.
Section 8.2 : Additional formulations and/or strengths of multiple cancer
medicines were included the complementary list of the EML and EMLc as
follows:
–– Calcium folinate (EML and EMLc): tablet 5 mg and 25 mg
–– Cyclophosphamide (EML and EMLc): tablet 50 mg
–– Etoposide (EML and EMLc): tablet 50 mg
Section 17.5 : A co-packaged presentation of oral rehydration salts (ORS) and
zinc sulfate tablets was included on the core list of the EMLc.
Section 22.3 : A co-packaged presentation of mifepristone and misoprostol was
included on the core list of the EML.

Sections 2.3 and 17.2 : addition of a square box to the listing of ondansetron on
the EML and EMLc.
Section 6.2.5 : replaced “capsule” with “solid oral dosage form” in the listings for
clofazimine and rifabutin.
Section 18.7 : removal of the square box on the EML listing for propylthiouracil
and addition of notes on the EML and EMLc regarding use when alternative
first-line treatment is not appropriate or available.
Section 22.3 : transfer the listing of mifepristone-misoprostol from the
complementary to the core list of the EML and removal of the note regarding
the requirement for close medical supervision.
Section 24.2.1 : addition of a square box to the listing of fluoxetine on the EML.
Section 27: amendment to the strength of iodine capsules from 200 mg to 190 mg
on the EML and EMLc from 200 mg to 190 mg.
Applications not recommended

Section 6.2.3: addition of ceftolozane + tazobactam, delafloxacin, eravacycline and
omadacycline for treatment of infections due to multidrug-resistant organisms.
Section 6.2.4 : addition of injectable formulations of ethambutol, isoniazid,
p-aminosalicylic acid and rifampicin; new strength formulation of isoniazid oral
17
liquid; change to the age restriction associated with the listing of delamanid for
the treatment of tuberculosis.
Section 6.4.2 : deletion of raltegravir 100 mg tablets and ritonavir 400 mg/5 mL
oral liquid formulations for treatment of HIV infection.
Section 7.1 : addition of sumatriptan for treatment of acute migraine.
Section 8.1 : addition of fingolimod, glatiramer acetate and ocrelizumab for the
treatment of multiple sclerosis.
Section 8.2 : addition of nivolumab, pembrolizumab and atezolizumab for the
treatment of non-small cell lung cancer; pertuzumab and trastuzumab emtansine
for treatment of HER-2 positive breast cancer; enzalutamide for treatment of
metastatic castration-resistant prostate cancer; subcutaneous formulations of
rituximab and trastuzumab; extension of indications for fluorouracil to include
treatment of cervical cancer in the curative setting.
Section 18.5.1 : addition of long-acting insulin analogues for treatment of type 1
diabetes.
Section 22.3 : deletion of the indication of prevention of post-partum
haemorrhage for misoprostol.
Section 24 : addition of methylphenidate for treatment of attention-deficit
hyperactivity disorder (ADHD); addition of escitalopram for the treatment of
depressive disorders.
Refer to the individual application summaries in this Report for full details of
the Expert Committee’s recommendations.
18
5. Applications for the 21st Model List of Essential
Medicines and the 7th Model List of Essential Medicines
for Children
Section 6: ANTI-INFECTIVE MEDICINES
6.2 Antibacterials
Antibiotics for typhoid fever
Typhoid and paratyphoid (enteric) fever
Applicant(s)
Christine Dolecek, Sunil Pokharel, Buddha Basnyat, Piero Olliaro; Centre for
Tropical Medicine and Global Health, University of Oxford, United Kingdom
Introduction
Enteric fever, a bloodstream infection caused by Salmonella enterica serovars
Typhi and Paratyphi, causes a major public health burden, especially in
children and young adults in resource-limited settings. Recent estimates put
the burden of enteric fever at 16 million cases and an estimated 150 000 deaths
per year (1). Resistance to first-line treatments (multidrug resistance (MDR)
defined as resistance against chloramphenicol, ampicillin and trimethoprim/
sulfamethoxazole) and to fluoroquinolone antibiotics is now ubiquitous at the
global level (2). Resistant infections cause high clinical failure rates and prolonged
carriage, increasing the risk of complications (intestinal haemorrhage, gut
perforation and encephalopathy) in the individual patient, and lead to continued
transmission in families and their communities (3). There are now very few
effective treatment options. Worryingly, extensively drug-resistant (XDR) S. Typhi
strains, combining MDR, resistance to fluoroquinolones and third-generation
cephalosporins, have recently been reported in Pakistan (4). The most recent
WHO Guidelines for the diagnosis, treatment and prevention of typhoid were
published in 2003, and are now outdated particularly in an era of widespread
drug resistance (5).
Antibiotic treatment and sanitation have been the only widely used
intervention aimed at reducing the burden of enteric fever. Vaccines have been
underutilized. The recent decision of Gavi, the Vaccine Alliance, to support the
introduction of the new typhoid conjugate vaccine, Typbar-TCV, into the routine
immunization schedules of eligible countries will help, but may take many years
to be fully implemented and effective in endemic countries (6).
In addition to antimicrobial resistance, there are several issues in
the management of enteric fever. The sensitivity of blood culture is low, only
19
approximately 40% of patients with enteric fever will have a positive blood
culture (5, 7). In low- and middle-income countries, blood culture facilities
are often not available. There are no rapid tests with acceptable sensitivity and
specificity (3, 5). Treatment is usually empirical.
Summary of evidence (from the application)

The application identified two Cochrane systematic reviews that evaluated
antibiotic treatment of typhoid fever.
A 2011 Cochrane systematic review of 26 trials involving 3033 patients
evaluated fluoroquinolones for treatment of typhoid and paratyphoid fever
(8). The review did not include comparisons with antibiotics that are no
longer recommended for use in enteric fever (e.g. norfloxacin due to its poor
bioavailability).
Antibiotic resistance is an important consideration for efficacy; an
earlier version of this SR combined different generations of fluoroquinolones
in one sub-group, stratified according to the prevalence of MDR and nalidixic-
resistant (NaR) strains (9). However, the updated version grouped studies by each
fluoroquinolone individually. Results are presented as risk ratios (RR; 95%CI)
for categorical data and mean difference (MD; 95%CI) for continuous data.
Ciprofloxacin versus chloramphenicol
Four trials (293 patients) compared ciprofloxacin to chloramphenicol, only one
trial included children above 12 years of age, none of the trials reported the
prevalence of MDR and NaR strains. For clinical failure, the results favoured
ciprofloxacin (RR 0.24, 95%CI 0.07 to 0.82), although confidence intervals were
wide, due to the small sample size (low quality evidence). Fever clearance time
(FCT) (two trials; 147 patients) also favoured ciprofloxacin, the mean difference
(MD) was −62.46 hours (95%CI −75.52 to −49.39) (moderate quality evidence).
Small numbers of events occurred for microbiological failure (two trials,
142 patients; RR 0.05, 95%CI 0.00 to 0.81) (low quality evidence) and relapse
(four trials, RR 0.15, 95%CI 0.02 to 1.15) (low quality evidence). The results for
serious adverse events (two trials) were indeterminate (RR 0.99, 95%CI 0.18
to 5.52) (very low quality evidence) and for non-serious adverse events (four
trials), the results were comparable (RR 1.00, 95%CI 0.61 to 1.64), but with wide
confidence intervals (low quality evidence) (8).
Ofloxacin versus chloramphenicol
Four trials (247 patients) compared ofloxacin to chloramphenicol. The results
for clinical failure were in favour of ofloxacin, but with wide confidence
intervals (RR 0.15, 95%CI 0.03 to 0.64) (low quality evidence). Fever clearance
time (two trials, 140 patients) followed the same trends as clinical failures, the
MD was −75.85 hours (95%CI −88.52 to −63.17) (moderate quality evidence).
20
Applications for the 21st EML and the 7th EMLc
Due to the small numbers of events, the results for microbiological failure
(three trials, RR 0.16, 95%CI 0.02 to 1.07) (low quality evidence) and relapse
(RR 0.14, 95%CI 0.01 to 2.65) (low quality evidence) were indeterminate. For
serious adverse events (one trial), the RR was not estimable due to zero events.
For non-serious adverse event (four trials), the results were comparable, with a
RR of 1.06 and wide confidence intervals (95%CI 0.60 to 1.87) (low quality).
The SR included one trial (252 patients) that compared gatifloxacin
(which was not proposed in the application for EML listing), versus
chloramphenicol (RR for clinical failure was 0.79, 95%CI 0.32 to 1.96) (7). Non-
serious adverse events favoured gatifloxacin (RR 0.58, 95%CI 0.44 to 0.78).
Ciprofloxacin/ofloxacin versus cotrimoxazole and ampicillin/amoxicillin

The application reported comparisons of ciprofloxacin versus cotrimoxazole
(two trials, 132 patients), ofloxacin versus cotrimoxazole (one trial, 99 patients),
ofloxacin versus ampicillin (one trial, 40 patients), ofloxacin versus amoxicillin
(one trial, 50 patients). However, due to the small sample sizes the results were
indeterminate and the individual outcomes were assessed as low or very low
quality. Therefore, cotrimoxazole and ampicillin/amoxicillin were not proposed
in the application for EML listing.
Ciprofloxacin/ofloxacin versus cefixime

The comparisons of ciprofloxacin versus cefixime and ofloxacin versus cefixime
were each based on one trial. Due to the weakness and low/very low quality of
the evidence, cefixime was not proposed in the application for EML listing.
A randomized controlled trial that compared gatifloxacin versus cefixime
(158 patients), was stopped early by the Independent Data Safety and Monitoring
Board due to the high number of failures (19/70) in the cefixime arm (RR 0.04,
95%CI 0.01 to 0.31) (p<0.001) (10). This trial was included in the SR but was not
part of the comparisons evaluated in the application for inclusion in the EML.
Ciprofloxacin versus ceftriaxone

For this comparison, only one trial (42 adult participants) was available. Due
to the very small number of patients, the result was indeterminate. There is no
estimate for FCT and adverse events were not reported. The overall quality of the
evidence was accessed as very low. More than 50% of strains were MDR.
Ofloxacin versus ceftriaxone

For this comparison, only one trial (47 adult participants) was available. More
than 50% of strains were MDR, no NaR was reported. For clinical failure, a non-
significant result in favour of ofloxacin was reported, (RR 0.09, 95%CI 0.01 to
1.46), the MD in FCT was −115 hours (95%CI −150.67 to −79.33).
21
Ciprofloxacin versus azithromycin

For this comparison, only one trial (64 participants) was available. Due to the
small sample size (0 events in both arms), clinical failure, microbiological failure
and relapse were not estimable. The MD for FCT was −12 hours (95%CI −24.39
to 0.39). The quality of the evidence was low/very low.
Ofloxacin versus azithromycin
Two trials were available (213 patients) for this comparison. Clinical failure
favoured azithromycin with a RR of 2.2 (95%CI 1.23 to 3.94) (high quality of
evidence), the MD in FCT of 30.41 hours (95%CI −22.12 to 82.93) (moderate
quality evidence) supported azithromycin. The higher failure rates in the
ofloxacin arm in the more recent of the two trials, reflected the increasing
prevalence of NaR S. typhi isolates in this region.
The systematic review included one azithromycin trial (287 patients),
that compared gatifloxacin to azithromycin (11). Gatifloxacin and azithromycin
had similar high efficacy (RR for clinical failure 0.98, 95%CI 0.32 to 2.96) in this
setting with high proportions of NaR S. typhi strains.
A 2008 Cochrane systematic review of seven trials involving 773 patients
evaluated azithromycin for treatment of uncomplicated typhoid and paratyphoid
fever (12).
The comparison azithromycin versus chloramphenicol (one trial, 77
patients) showed a benefit for azithromycin, but due to the small sample size and
wide confidence intervals no inferences can be made (odds ratio (OR) for clinical
failure 0.16, 95%CI 0.01 to 3.4 (low quality evidence)). Four trials (564 patients)
compared azithromycin to the fluoroquinolones (including gatifloxacin) and
were discussed above.
Two trials (132 patients) compared azithromycin versus ceftriaxone.
Clinical failure (OR 2.58, 95%CI 0.48 to 13.87) and FCT (MD 9.12 h. 95%CI
−1.11 to 19.36) favoured ceftriaxone (moderate quality evidence). No data were

available to assess adverse events.
The application described a systematic search for randomized controlled
trials (RCTs) in enteric fever to supplement evidence obtained from the two SRs.
The majority of identified RCTs had small sample sizes, few events and lacked
sufficient power to detect significant differences. Four trials with sample sizes
greater than 30 patients in each arm were reviewed. Two trials had zero events
for clinical failure. A trial of gatifloxacin versus ofloxacin (218 culture-positive
patients) showed similar numbers of treatment failures in both arms (hazard
ratio, HR 0.81, 95%CI 0.25 to 2.65), however the FCT was significantly shorter
in the gatifloxacin arm (HR 1.59, 95%CI 1.16 to 2.18) in this setting with high
NaR (13). Similar proportions of patients experienced adverse events, most of
which were mild (Grade 1 or Grade 2).
22
A trial of gatifloxacin versus ceftriaxone (116 culture-positive patients)

showed similar number of failures in the intention-to-treat (ITT) patients, but in
the culture-confirmed patients, the comparison favoured ceftriaxone (HR 0.24,
95%CI 0.08 to 0.73) (14). Treatment failure was associated with the emergence of
high-level fluoroquinolone resistance in S. typhi, requiring the trial to be stopped.
A similar number of non-serious adverse events occurred in each treatment
group, and no serious events were reported.
Guidelines (from the application)

The 2003 WHO guidelines on the diagnosis, treatment and prevention of typhoid
fever (5) make the following recommendations for treatment of uncomplicated
typhoid fever, based on susceptibility of infection:
–– Fully sensitive: a fluoroquinolone (ofloxacin or ciprofloxacin)
as optimal therapy. Chloramphenicol, amoxicillin or
sulfamethoxazole + trimethoprim are alternatives.
–– Multidrug resistance: a fluoroquinolone or cefixime as optimal
therapy. Azithromycin or cefixime are alternatives.
–– Quinolone resistance: azithromycin or ceftriaxone as optimal
therapy. Cefixime is an alternative.
The 2012 WHO pocket book recommendations for management of
common childhood conditions (15) make the following recommendations for
the treatment of typhoid fever in children:
–– Children with typhoid fever should be treated with a
fluoroquinolone (i.e. ciprofloxacin, gatifloxacin, ofloxacin and
perfloxacin) as a first-line treatment for 7–10 days (strong
recommendation, moderate quality evidence).
–– If response to treatment is poor, consider drug-resistant
typhoid and treat with a second-line antibiotic such as a third-
generation cephalosporin or azithromycin for 5–7 days (strong
recommendation, moderate quality evidence).
–– Where drug resistance to antibiotics among salmonella isolates is
known, follow national guidelines according to local susceptibility
data (strong recommendations, moderate quality evidence).
Rationale for antibiotic selection (from the application)

Although recommended in the 2003 WHO guidelines, ampicillin/amoxicillin
and trimethoprim-sulfamethoxazole were not proposed in the application for
inclusion in the EML for typhoid fever due to the lack of data showing any benefit
over comparators based on evidence from the SRs identified.
23
Chloramphenicol is recommended in the 2003 WHO guidelines but

not in the 2012 WHO pocket book. There has been conflicting evidence from
smaller trials, however, a large trial showed similar efficacy to gatifloxacin, a
fourth-generation fluoroquinolone, but higher numbers of Grade 1 and 2 adverse
events. Due to the need to monitor blood counts, the long treatment duration
and the availability of alternative drugs, chloramphenicol was not proposed in
the application for inclusion on the EML.
The application proposed the inclusion of ofloxacin and ciprofloxacin on
the EML and EMLc, supported by evidence from the SRs and clinical practice
guidelines (CPGs). More clinical trials evaluating ofloxacin have been performed,
however, ofloxacin is not currently included on the EML. As ciprofloxacin is
currently listed and has similar clinical performance, for parsimony, ciprofloxacin
only could be considered.
Although included in the 2003 WHO guidelines, the evidence from the
SRs did not support listing of cefixime. In comparisons with fluoroquinolones,
cefixime, showed higher number of failures and longer FCTs, however, in
comparisons with chloramphenicol, it compared favourably.
The application also proposed listing ceftriaxone and azithromycin on
the EML and EMLc for typhoid fever, supported by evidence from SR and CPGs.
Committee considerations (additional evidence, dose/duration, costs, etc.)

The Expert Committee agreed that knowledge of the local resistance patterns
for S. typhi and S. paratyphi strains was critical for making empiric treatment
choices in the treatment of enteric fever, noting that there are reports of high
rates of fluoroquinolone resistance in some settings. This is the first time
the Expert Committee has considered resistance patterns in making specific
recommendations for empiric treatment.
The Expert Committee considered the various antibiotics proposed in
the application under the guiding principle of parsimony and selected first- and
second-choice antibiotics for this indication for inclusion on the EML and EMLc.
EML listings
Antibiotics proposed for both EML and EMLc unless specified
Endorsement indicates those antibiotics currently included on EML/EMLc
First choice Second choice

Endorsement Ciprofloxacin (except where high
prevalence of fluoroquinolone
resistance exists)
Azithromycin
Ceftriaxone
24
Committee recommendations
The Expert Committee endorsed listing of ciprofloxacin, ceftriaxone and
azithromycin as first-choice treatments for typhoid and paratyphoid (enteric)
fever on the core list of the EML and EMLc. Ciprofloxacin is recommended as
first-choice in settings with low prevalence of fluoroquinolone resistance, while
ceftriaxone and azithromycin are recommended first-choice treatments in
settings where there is a high prevalence of fluoroquinolone resistance.
Ciprofloxacin, azithromycin and ceftriaxone are all classified as Watch
group antibiotics (Section 6.2.2).
Following the principle of parsimony, the Expert Committee did not
recommend the addition of ofloxacin for this indication, noting that ofloxacin
and ciprofloxacin have demonstrated similar clinical performance for this
indication in clinical trials.
References
1. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a
systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1151–
210.
2. Levine MM, Simon R. The Gathering Storm: Is Untreatable Typhoid Fever on the Way? mBio.
2018;9(2).
3. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Engl J Med. 2002;347(22):
1770–82.
4. Klemm EJ, Shakoor S, Page AJ, Qamar FN, Judge K, Saeed DK, et al. Emergence of an Extensively
Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid
Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins. mBio. 2018;9(1).
5. World Health Organization. Background document: The diagnosis, treatment and prevention of
typhoid fever. Geneva: World Health Organization; 2003.
6. Gavi. New typhoid vaccine to receive Gavi support [website]. Geneva: Gavi; 2018. (https://
www.gavi.org/library/news/statements/2018/new-typhoid-vaccine-to-receive-gavi-support/,
accessed 7 March 2019).
7. Arjyal A, Basnyat B, Koirala S, Karkey A, Dongol S, Agrawaal KK, et al. Gatifloxacin versus
chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial.
Lancet Infect Dis. 2011;11(6):445–54.
8. Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, et al. Fluoroquinolones for treating
typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. 2011(10):CD004530.
9. Thaver D, Zaidi AK, Critchley JA, Azmatullah A, Madni SA, Bhutta ZA. Fluoroquinolones for treating
typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. 2008(4):CD004530.
10. Pandit A, Arjyal A, Day JN, Paudyal B, Dangol S, Zimmerman MD, et al. An open randomized
comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever.
PLoS One. 2007;2(6):e542.
11. Dolecek C, Tran TP, Nguyen NR, Le TP, Ha V, Phung QT, et al. A multi-center randomised controlled
trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in
children and adults in Vietnam. PLoS One. 2008;3(5):e2188.
25
12. Effa EE, Bukirwa H. Azithromycin for treating uncomplicated typhoid and paratyphoid fever
(enteric fever). Cochrane Database Syst Rev. 2008(4):CD006083.
13. Koirala S, Basnyat B, Arjyal A, Shilpakar O, Shrestha K, Shrestha R, et al. Gatifloxacin versus ofloxacin
for the treatment of uncomplicated enteric fever in Nepal: an open-label, randomized, controlled
trial. PLoS Negl Trop Dis. 2013;7(10):e2523.
14. Arjyal A, Basnyat B, Nhan HT, Koirala S, Giri A, Joshi N, et al. Gatifloxacin versus ceftriaxone for
uncomplicated enteric fever in Nepal: an open-label, two-centre, randomised controlled trial.
15. WHO. Recommendations for management of common childhood conditions. Evidence for
technical update of pocket book recommendations. Newborn conditions, dysentery, pneumonia,
oxygen use and delivery, common causes of fever, severe acute malnutrition and supportive care.
Geneva: World Health Organization; 2012. Available from http://www.who.int/maternal_child_
adolescent/documents/management_childhood_conditions/en/, accessed 10 September 2019.
26
Antibiotics for surgical prophylaxis
Surgical antibiotic prophylaxis
Applicant(s)
WHO Department of Service Delivery and Safety (SDS)
Introduction
Surgical site infections (SSIs) are the most frequent health care-associated
infection (HAI) in low- and middle-income countries (LMICs) and the second
most frequent HAI in Europe and the United States of America (1–4). In LMICs:
11% of patients who undergo surgery are infected in the process. In Africa,
infection is the most frequent complication in surgery and up to 20% of
women who have a caesarean section develop a postoperative wound infection,
compromising both their health and the ability to care for their infants (WHO,
unpublished data, 2017; (5)). SSIs are mainly caused by bacteria that enter through
incisions made during surgery. Some involve only skin and subcutaneous tissue,
but others are more serious and involve muscle, fascia, organ spaces or implanted
material (6).
SSIs are associated with longer postoperative hospital stays and may
require additional surgical procedures and even intensive care, thus resulting in a
higher attributable morbidity and mortality (7). They also add a financial burden
to the health care system and patient out- of-pocket costs. In the Unites States,
they contribute to patients spending more than 400 000 extra days in hospital at
a cost of an additional US$ 10 billion per year (8).
Surgical antibiotic prophylaxis (SAP) is one of the pillars of SSI prevention
and is defined as the prevention of infectious complications by administering
an effective antimicrobial agent prior to exposure to contamination during
surgery (9). It has also been described as “the rational, safe and effective use
of antimicrobial agents for the prevention of (initial) SSIs” (10) and as “the use
of antibiotics to prevent postoperative infection” (11). WHO provides strong
recommendations on the administration of SAP prior to surgical incision when
indicated, depending on the type of operation, its timing and duration. However,
SAP is often used inappropriately in many settings around the world and this
misuse diminishes patient safety and increases acquisition and transmission
of antimicrobial resistance (AMR) in surgical services. Inappropriate SAP
mainly consists of incorrect antibiotic choice, dose, timing and/or means of
administration, and/or duration.
27
Results of a WHO global survey conducted in 2014 20 showed that

inappropriate SAP duration is a major problem worldwide, with prolongation
of antibiotic use beyond international standards (that is, one preoperative dose
and repetition during the intervention if necessary, according to specific criteria)
in 43.5% of procedures on average. The frequency of prolongation was higher
than 60% in African, Eastern Mediterranean and Western Pacific countries.
Inappropriate SAP is particularly frequent in LMICs (12–16).
Based on these and other findings, and considering the central role of
SAP in SSI prevention, there is need for standardized, evidence-based global
guidance on appropriate SAP, which involves several key aspects based on high
quality evidence: correct antibiotic choice, dose, timing, route of administration
and duration.

The application presented the results of a rapid systematic literature review of SRs
on SAP. Inclusion criteria were that the SR addressed the effect of intravenous
SAP on SSIs and either: (1) recommended SAP; (2) recommended a specific
agent; and/or (3) provided a head-to-head comparison of antibiotics used for
SAP. In addition, SRs based on insufficient evidence (for example, one or two
RCTs with small sample sizes) were excluded. (Refer to the application for full
details of the search strategy and study selection).
Seventeen systematic reviews were included: 13 compared SAP regimens
for specific procedure types including: neurosurgery (17, 18); neck surgery (19,
20); cardiac surgery (21, 22); upper gastrointestinal surgery (23); colorectal surgery
(24, 25); caesarean section (26); gynaecological surgery (27); hernia surgery
(28); and plastic surgery (29). Three compared specific SAP regimens for several
procedure types combined (cardiac-, vascular-, orthopaedic- and neurosurgery;
cardiac-, vascular- and orthopaedic surgery; and cardiac- and orthopaedic
surgery) (30–32). One specifically addressed SAP for methicillin-resistant
Staphylococcus aureus (MRSA) SSI prevention (33). The included SRs provided
evidence that was generally in line with the recommendations for SAP from the
evidence-based guideline issued jointly in 2013 by the American Society of
Health System Pharmacists (ASHP), the Infectious Diseases Society of America
(IDSA), the Surgical Infection Society (SIS) and the Society for Healthcare
Epidemiology of America (SHEA) (10) (see Guidelines section, below).

The application presented the results of systematic review and inventory of
available relevant evidence-based SAP guidelines and protocols. Inclusion criteria
20
https://www.who.int/gpsc/5may/global-surveys/en/
28
were that the guideline was: (1) issued by a country, region or organization/
society (that is, not adopted locally or by a single centre); (2) issued within the
past five years; and (3) based on a systematic, evidence-based approach. (Refer
to the application for full details of the search strategy and guideline selection).
Thirty records were included: 19 records met all three inclusion criteria
(9–11, 34–49). Ten met the first two criteria, but did not rely on a systematic
evidence-based approach (50–59) and one, which included recommendations
on all relevant types of surgery, was systematically updated, but not issued in a
national context or by a scientific society (60). The 11 records that did not meet
all three inclusion criteria were deemed relevant as they were of high quality and/
or addressed unique situations, such as LMICs or paediatric settings.
All identified guidelines covered at least one of the most common
surgical procedures. The most frequently recommended first-line antibiotics
(first-choice antibiotics and second-choice agents as alternatives to first-choice)
for SAP across all procedures were cefazolin, by far, followed by cefuroxime, then
metronidazole (in combination with another agent), gentamicin and ampicillin-
sulbactam. The most frequently recommended second-line antibiotics to be
used for SAP in cases of known immediate severe or delayed severe penicillin
hypersensitivity were vancomycin, clindamycin, gentamicin and metronidazole
across all procedures.
When considering wound classification (61–63), the most frequently
recommended first-line antibiotics in clean surgical procedures with potential
severe consequences of infection and/or procedures involving implantation
of foreign material (for example, cardiac, breast or hernia surgery, central and
peripheral vascular surgery, orthopaedic [excluding arthroscopy or neurosurgery]
and non-cardiac thoracic surgery) were a first-generation cephalosporin
(cefazolin), by far, followed by a second-generation cephalosporin (cefuroxime).
The most frequently recommended second-line antibiotics to be used in cases
of known immediate severe or delayed severe penicillin hypersensitivity were
vancomycin and clindamycin, both as single agents. For some procedures, some
guidelines also mentioned a combination of vancomycin and gentamicin (cardiac
and central vascular surgery) or a combination of clindamycin and gentamicin
(breast surgery, hernia repair) or gentamicin and metronidazole (hernia repair)
as possible second-line alternatives.
In clean-contaminated surgical procedures (for example, head and neck,
abdominal, gynaecological, obstetric, urologic and vascular surgery), the most
frequently recommended first-line antibiotic was cefazolin (usually combined
with metronidazole), by far, followed by metronidazole (in combination with
another agent), then cefuroxime, cefoxitin, ampicillin-sulbactam and gentamicin.
The most frequently recommended second-line antibiotic to be used in cases
of known immediate severe or delayed severe penicillin hypersensitivity was
29
gentamicin, followed by clindamycin, then metronidazole and vancomycin. For

most procedures, guidelines recommended a combination of gentamicin with
either clindamycin or vancomycin or metronidazole as possible second-line
alternatives.
Many guidelines recommended to consider the use of vancomycin across
procedures in addition to the recommended agent(s) as a single pre-operative
dose for patients known to be colonized with MRSA or at high risk for MRSA
colonization (for example, recently hospitalized patients, nursing home residents,
haemodialysis patients) or in the absence of screening data (10, 11, 53, 56, 59, 60).

The application proposed the antibiotics of choice for SAP for inclusion on the
EML by type of surgical procedures and provided alternative options when
the first-line choices are unavailable or contraindicated due to severe allergy.
The proposed antibiotics were selected by consensus at a meeting of technical
experts after consideration of the review findings.
Among first-line antibiotics, the first choice recommended for most
procedures was cefazolin or its second-generation equivalent, cefuroxime. It was
noted that ceftriaxone and other antibiotics are often inappropriately used as
first-line SAP options in many LMICs.
Experts stressed the importance of ensuring that cefazolin and/or
cefuroxime are broadly available worldwide at a reasonable price and as good
quality products with good manufacturing practice labelling.
For patients with confirmed immediate severe or delayed severe
penicillin hypersensitivity, a non–beta-lactam antibiotic must be used instead.
It was emphasized that the second-line antibiotics listed are sub-optimal and
should only be used in cases of known or highly suspected allergies. However,
appropriate documentation of allergies prior to surgery is not common practice
in all settings, particularly in LMICs.
It was agreed that there is no good reason to use ceftriaxone for SAP
as it belongs to the EML Watch group (64). In addition, it is included in the
WHO highest priority, critically important antimicrobials (CIA) list (65) as it is a
third-generation cephalosporin, and thus has a high risk of selection of bacterial
resistance (in particular, extended spectrum beta-lactamase [ESBL]-producing
enterobacteriacae). Therefore, ceftriaxone should be reserved for the limited
number of infectious conditions where it is indicated for therapeutic purposes.
Conversely, it is widely overused, including for SAP for which ceftriaxone
has no indication and does not add any value as it does not offer additional
coverage for ESBL. It is also inferior to other antibiotics (for example, cefazolin)
for methicillin-sensitive S. aureus and creates an unnecessary risk of collateral
damage to the gut flora given its high biliary penetration.
30
Considering the high resistance rates to quinolones in LMICs and

the fact that they feature in the EML Watch category (64) and are among the
highest priority antimicrobials in the CIA list (65), participants agreed that the
combination of an aminoglycoside (gentamicin or tobramycin) plus metronidazole
is generally preferable as second-line antibiotics. However, for patients with
renal insufficiency, quinolones may be more appropriate. Quinolones should be
reserved for special circumstances where no other options are available. When
they are used, ciprofloxacin should generally be favoured over levofloxacin.
It was noted that many hospitals in the United States have begun
administering azithromycin in addition to cefazolin for pregnant women
undergoing caesarean sections, based on the results of a RCT published in 2016
showing a 50% reduction in SSIs compared to a control group (66). Experts
agreed that this study represents valuable evidence, but it would be premature to
consider this option in the EML based on the results of a single study conducted
in a high-income country (HIC). As additional evidence emerges, it might be
appropriate to add adjunctive azithromycin as a first-line option for caesarean
section in future editions of the EML.
Antibiotics proposed in the application
PROCEDURE FIRST-LINE ALTERNATIVES

(when allergic to
first-line choices)
Neck surgery
- clean No SAP No SAP No SAP
- clean-contaminated Cefazolin (or cefuroxime) Amoxicillin + Clindamycin plus
plus metronidazole clavulanic acid gentamicin
Cardiac surgery (in Cefazolin (or cefuroxime) N/A Vancomycin

general)
Thoracic surgery (non- Cefazolin (or cefuroxime) N/A Vancomycin

cardiac)
Breast surgery Cefazolin (or cefuroxime) N/A Vancomycin
Upper gastrointestinal Cefazolin (or cefuroxime) N/A Clindamycin plus

tract surgery gentamicin
Hepato-pancreato- Cefazolin (or cefuroxime) Amoxicillin + Gentamicin plus

biliary surgery + clavulanic acid metronidazole
Cholecystectomya
Hernia surgery Cefazolin (or cefuroxime) N/A Vancomycin
31
Table continued
PROCEDURE FIRST-LINE ALTERNATIVES
(when allergic to
first-line choices)
Appendectomy Cefazolin (or cefuroxime) N/A Gentamicin plus
plus metronidazole metronidazole
Colorectal surgery Cefazolin (or cefuroxime) Amoxicillin + Gentamicin plus

plus metronidazole clavulanic acid metronidazole
Hysterectomy Cefazolin (or cefuroxime) Amoxicillin + Clindamycin plus

clavulanic acid gentamicin
Caesarean section Cefazolin (or cefuroxime) Amoxicillin + Clindamycin plus

clavulanic acid gentamicin
Central vascular Cefazolin (or cefuroxime) N/A Vancomycin

surgery
Peripheral vascular Cefazolin (or cefuroxime) N/A Vancomycin

surgery
Orthopaedic Cefazolin (or cefuroxime) N/A Vancomycin

surgery (excluding
arthroscopy)
Bone fracture surgery Cefazolin (or cefuroxime) N/A Vancomycin
Urologic
- prostate surgery Cefazolin (or cefuroxime) Gentamicin Gentamicin
- laparoscopic No SAP No SAP No SAP
nephrectomy
- laparotomy Cefazolin (or cefuroxime) N/A Gentamicin
nephrectomy and
partial nephrectomy
Neurosurgery – Cefazolin (or cefuroxime) N/A Vancomycin

cranium/spine
a Biliary tract open surgery or endoscopic in high-risk patients: factors that indicate a high risk of infectious
complications in laparoscopic cholecystectomy include emergency procedures; diabetes; long procedure
duration; intraoperative gallbladder rupture; age >70 years; conversion from laparoscopic to open
cholecystectomy; American Society of Anesthesiologists classification of three or greater; episode of colic
within 30 days before the procedure; re-intervention of less than one month for a non-infectious complication;
acute cholecystitis; bile spillage; jaundice; pregnancy; non-functioning gallbladder; immunosuppression; and
insertion of a prosthetic device. As a number of these risk factors are not possible to determine before the
surgical intervention, it may be reasonable to give a single dose of antimicrobial prophylaxis to all patients
undergoing laparoscopic cholecystectomy (10).
32

The Expert Committee agreed with the views of the technical expert group that
key factors for appropriate SAP include selecting the right antibiotic, taking into
account the surgical procedure (as well as probable causative microorganisms
and their resistance patterns based on SSI surveillance), route of administration,
dosing, patient allergies and cost/availability; administering the antibiotic at
the right time; and avoiding prolongation of the antibiotic after completion of
the operation. For SAP to be effective, the tissue concentration of the antibiotic
must be above the minimal inhibitory concentration at the time of incision and
throughout the procedure. This depends on the half-life of the antibiotic chosen
and may require re-dosing accordingly during the procedure.
The Expert Committee agreed that administering SAP close to the time
of incision is important for antibiotics with a short half-life and, in general, this
could avoid the need for re-dosing during the procedure (depending again on
the half-life of the particular antibiotic used). For example, administration closer
to the incision time (<60 minutes) can be considered for antibiotics with a short
half-life such as cefazolin.
The Expert Committee noted the key considerations for dosing and
re‑dosing identified by the technical expert group:
■■ Observational data suggest that higher serum and tissue levels
throughout the surgical procedure reduce the risk of SSIs.
■■ Higher doses should be favoured, as long as there are no concerns
about toxicity.
■■ Re-dosing should generally be provided after twice the half-life of
the antibiotic has passed since the initial preoperative dose.
■■ There is little evidence to support weight-based dosing, but higher
doses of cephalosporins may be advisable in morbidly obese patients.
EML listings

Endorsement Cefazolin Amoxicillin + clavulanic acid
(alone or in combination with) Gentamicin
Metronidazole
Addition Cefuroxime
33
The Expert Committee considered the various antibiotics proposed in the
application under the guiding principle of parsimony and selected first- and
second-choice antibiotics for this indication for inclusion. In line with previous
decisions for infectious syndromes, alternatives for use in case of allergy were
not recommended.
The Expert Committee endorsed listing of cefazolin, alone or in
combination with metronidazole as first-choice options, and of amoxicillin +
clavulanic acid and gentamicin as second-choice options for surgical prophylaxis
on the core list of the EML and EMLc, as Access group antibiotics (Section 6.2.1).
The Committee also recommended the addition of cefuroxime to the core
list of the EML and EMLc as a second-choice option for surgical prophylaxis, as a
Watch group antibiotic (Section 6.2.2), as an alternative to cefazolin.
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38
Antibiotics for oral and dental infections
Antibiotics for oral/dental infections
Applicant(s)
Mark Loeb, Dominik Mertz, Paul Alexander; McMaster University
Introduction
Antibiotics are the most widely prescribed category of medicines used by general
dental practitioners, a group that was shown to be responsible for 7–11% of all
antimicrobials prescribed, and for 45% of all prescriptions of metronidazole (1, 2).
Studies have also shown a wide variation in the prescribing habits suggesting
inappropriate use of antibiotics in this setting (3–8).
Dentoalveolar infections are polymicrobial in nature, mostly strictly
anaerobic Gram-positive cocci and Gram-negative rods mixed with facultative
anaerobic flora (9–12). The types of infections where antibiotics may be used
include periodontitis, pulpitis, pericoronitis, acute necrotizing ulcerative
gingivitis, and periodontal abscesses. The choice of antibiotics is typically
empirical in the treatment of these infections. Drainage and removal of the
cause of the infection is key in infections such as abscesses, with antibiotics
to be considered in certain patients such as those with systemic illness or
immunocompromised individuals.

The application presented the results of a search undertaken for systematic
reviews and meta-analyses of systemic antibiotic therapy for dental infections.
A total of 20 systematic reviews were included covering chronic periodontitis,
apical periodontitis and acute apical abscess, and irreversible pulpitis.
Chronic periodontitis
Although patient important outcomes such as pain or quality of life would have
been optimal, the outcomes reported in the literature for periodontitis were
surrogate markers of activity such as reduction in probing depth, improvement
in clinical attachment level, and bleeding on probing. Microbiological outcomes
were disregarded as they were not considered to be of high patient importance.
The scope of the identified systematic reviews ranged from assessment of the
overall effect of antibiotics, to assessment of specific antibiotics or specific sub-
populations such as diabetics or smokers.
SRs of any antibiotics for any patients
A systematic review and network meta-analysis of 14 RCTs of systemic
antibiotics for patients with periodontitis reported that using metronidazole or
39
a combination of amoxicillin and metronidazole as an adjuvant to scaling and

root planing (SRP) improved clinical attachment gain and reduction in probing
depth compared to no antibiotics (13). A greater gain in clinical attachment
level (MD 1.08 mm) and reduction in probing depth (1.05 mm) was noted with
metronidazole, and clinical attachment level (0.45 mm) and probing depth
(0.53 mm) with amoxicillin/metronidazole. These antibiotics showed a better
effect than doxycycline.
A systematic review of 14 RCTs compared systemic antibiotics in
combination with scaling and root planing compared to SRP alone (14). They
found that systemic antibiotics significantly improved pocket depth reduction
and clinical attachment gain. Results suggested that metronidazole with
amoxicillin was the most potent combination.
A systematic review of systemic antibiotics for non-surgical periodontal
therapy identified a single eligible RCT in which benefit was noted in probing
depth reduction (0.9 mm) and clinical attachment gain (0.7 mm). However, the
authors concluded that findings were insufficient at this time and larger RCT
with longer follow up was needed (15).
SRs of amoxicillin with metronidazole
A systematic review of 20 RCTs comparing efficacy of amoxicillin and
metronidazole adjunctive to SRP compared to SRP alone found a beneficial
effect of adjunctive antibiotic therapy for probing depth reduction (0.86 mm,
(95%CI 0.65 to 1.07 mm) and clinical attachment level gain 0.75 mm (95%CI
0.40 to 1.09) (16).
Another systematic review of six RCTs evaluated the effectiveness of
amoxicillin and metronidazole as an adjunct to full-mouth SRP compared to
full-mouth SRP alone. Adjunctive antibiotic treatment was associated with
significant clinical attachment gain (0.42 mm, 95%CI 0.23 to 0.61) and probing
depth reduction (0.58 mm, 95%CI 0.39 to 0.77) (17).
A systematic review of six RCTs that assessed the effect of adjunctive

antibiotics for refractory periodontitis found greater reduction in probing depth
and in loss of clinical attachment level with antibiotics compared to debridement
alone across all studies, however a meta-analysis was not conducted. The authors
concluded that no firm conclusions could be drawn due to the low quality of the
evidence (18).
A systematic review of 18 RCTs found no clinically important difference
between amoxicillin plus metronidazole compared to no antibiotics as an adjunct
to non-surgical treatment of periodontitis (19).
SRs of metronidazole alone
A systematic review of three RCTs that assessed metronidazole as an adjuvant
to SRP found benefit of the antibiotic with respect to probing depth reduction
40
(0.18 mm, 95%CI 0.09 to 0.28) and clinical attachment (0.10 mm, 95%CI 0.08
to 0.12) (20). Another, older systematic review of eight RCTs also found that
metronidazole may offer a benefit for periodontitis in pockets of 4 mm and
greater, but only for short-term outcomes (21).
SRs of azithromycin
Two systematic reviews (6 and 14 RCTs) comparing azithromycin as an
adjuvant therapy for SRP to SRP alone both reported significant beneficial effects
of azithromycin for outcomes of probing depth, clinical attachment level and
bleeding on probing (22, 23).
SRs of doxycycline
A systematic review of three RCTs assessed the long-term efficacy of systemic
use of low-dose (sub-antimicrobial dose) doxycycline (SSD, 20 mg twice daily)
as an adjunctive treatment to SRP compared to SRP alone (24). Significant
reductions in probing depth reduction (0.9 mm, 95%CI 0.43 to 1.37), clinical
attachment gain (0.88 mm, 95%CI 0.08 to 1.67), changes in plaque index, gingival
index and gingival crevicular fluid at the nine-months stage were observed with
adjunctive doxycycline. The authors concluded that the evidence supported
a 3-month course of low-dose doxycycline. However, two of the studies were
conducted by the same author, and all three studies were conducted in Turkey,
potentially limiting the generalizability of the finding. The two studies driving
the effect were both evaluated as being at high risk of bias.
SRs in smokers
Three systematic reviews of trials of antibiotic therapy in smokers with chronic
periodontitis yielded variable findings of no benefit (25), inconsistent findings
(26) and statistically significant benefit of questionable clinical relevance (27)
associated with adjunctive antibiotic therapy.
SRs in diabetics
Two systematic reviews of trials of antibiotic therapy in diabetic patients both
reported benefits associated with antibiotic therapy for the outcome of probing
depth reduction, but not for other outcomes (28, 29).
Apical periodontitis and acute apical abscess
A Cochrane systematic review and meta-analysis of two RCTs (62 participants)
comparing penicillin to placebo (with surgical intervention and analgesics)
found no significant differences for pain or swelling between groups. The authors
concluded that there were insufficient data to determine the effects of systemic
antibiotics (30). Another systematic review of eight RCTs comparing antibiotics
to placebo or no pharmacotherapy for acute apical abscesses found no benefit of
41
antibiotics as an adjuvant to surgical intervention. However, a single identified

study showed a benefit of azithromycin over amoxicillin+clavulanic acid in terms
of reduction of pain, with no benefit for the co-primary outcome “absence of
infection” (31).
Irreversible pulpitis
A Cochrane systematic review of systemic antibiotics for pulpitis was based only
on one small trial which included the use of penicillin for which there was a lack
of significant differences in outcomes between groups (32).

The application presented the results of a search undertaken of clinical practice
guidelines for recommendations on the use of antibiotics for dental infections.
Chronic periodontitis
A 2015 clinical practice guideline developed by an expert panel convened by the
American Dental Association on the prevention and treatment of periodontal
diseases in primary care recommended use of systemic sub-antimicrobial dose
doxycycline (20 mg twice daily for three to nine months) as an adjunct to
SRP. The recommendation was made based on moderate evidence of a small
net benefit in clinical attachment level from 11 RCTs (813 participants). There
was also a weak recommendation for other systemic antimicrobials as adjunct
therapy to SRP which showed a similar effect size as sub-antimicrobial dose
doxycycline but more significant risk for harm based on 24 RCTs (33).
2014 guidelines published by the Scottish Dental Clinical Effectiveness
Programme recommended against the use of antimicrobials for chronic
periodontitis or peri-implantitis due to a lack of convincing evidence (34).
The European Society of Endodontology position statement recommended

against the use of antibiotics in patients with acute apical periodontitis and acute
apical abscess and emphasized the importance of surgical drainage. However, a
recommendation for adjunctive antibiotics was made for the following patient
groups: medically compromised patients (not defined in detail) and patients with
systemic involvement (fluctuant swelling, temperature >38 degrees C, malaise,
lymphadenopathy, trismus), and patients with progressive infections where
referral to oral surgeons may be necessary (rapid <24 h severe infection, cellulitis,
spreading infections, osteomyelitis). They also recommended against antibiotic
treatment in patients with chronic apical periodontitis with a sinus tract. In the
sub-group of patients with an indication for antibiotics treatment, penicillin VK
(phenoxymethylpenicillin) was the first choice, while amoxicillin, amoxicillin
+ clavulanic acid, and metronidazole were recommended after 48–72 hours
42
if penicillin VK fails. Further listings include clindamycin, clarithromycin,

azithromycin for penicillin allergic patients. Duration should be re-assessed after
2–3 days, with a statement that 3–7 days is often sufficient (35).
The Canadian Collaboration on Clinical Practice Guidelines in
Dentistry (CCCD) also recommend against the use of antibiotics for acute
apical periodontitis and acute apical abscess as no benefit had been shown over
drainage alone. They suggest that antibiotics may be helpful in the setting of
systemic complications (fever, lymphadenopathy, cellulitis), diffuse swelling or
in patients with medical indications. There is a statement that no antibiotic can
be recommended over another, and that antibiotics may be used if drainage is
not possible (36).
The European Society of Endodontology position statement recommends against
the use of antibiotics for the treatment of irreversible pulpitis (35).

Periodontitis
The application stated that the overall evidence on antibiotics as an adjunct to
SRP for periodontitis was limited, conflicting, and in general at high risk of bias.
Where benefits had been shown, the summary estimates tended to be small to
modest and as such of questionable clinical benefit. Also, recommendations in the
two clinical practice guidelines identified were conflicting. It seems reasonable
to conclude that the majority of patients likely do not benefit significantly from
adjunctive systemic antibiotics, and as such the potential negative effects are
outweighing the potential benefits. There might be a sub-group of patients who
may clinically benefit from adjunctive antibiotics, but the current evidence does
not allow drawing firm conclusions what these sub-groups might be. It does not
seem that large treatment effects can be seen in smokers or diabetics, and as such
these groups should not be treated any differently from others.
If, in a specific patient there is a perceived potential benefit with antibiotic
treatment, low-dose long-term doxycycline that may have the least ecologic
impact, or short-term courses with amoxicillin/metronidazole, seem to be the
most promising regimens.
The systematic reviews identified in the application provided no evidence
supporting the routine use of antibiotics for apical periodontitis and acute
apical abscess. The identified guidelines also recommend against the use of
antibiotics for the majority of patients, emphasizing the importance of source
control and drainage. However, the guidelines recommend antibiotic use for
sub-groups of patients at risk for complicated/severe infections that may not be
43
controlled with drainage alone. In the absence of convincing evidence preferring

one antibiotic regimen over the other, we agree with the European guideline
listing phenoxymethylpenicillin or amoxicillin, with the potential of adding
metronidazole if first-line treatment fails. For penicillin-allergic patients, the
use of clindamycin seems to be the best option given the microbiology of
periodontal infections.
There is insufficient evidence to support the use of antibiotics for irreversible
pulpitis. Guidelines do not support antibiotics for this indication.

The Expert Committee noted that the evidence supporting antibiotic use in
the treatment of oral and dental infections is limited and did not recommend
EML listing of antibiotics for most dental conditions, including acute or chronic
periodontitis or irreversible pulpitis.
EML listings

Endorsement Amoxicillin
Phenoxymethylpenicillin
The Expert Committee endorsed listing of amoxicillin and phenoxymethylpenicillin
on the core list of the EML and EMLc as first-choice treatment for progressive
(systemically complicated) apical dental abscess. These antibiotics are also

recommended as first-choice treatment of apical dental abscess in medically
compromised patients.
Amoxicillin and phenoxymethylpenicillin are classified as Access group
antibiotics (Section 6.2.1).
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systemic antibiotics in patients with untreated aggressive periodontitis: a systematic review and
meta-analysis. J Periodontal Res. 2015;50(6):689–706.
15. Fritoli A, Goncalves C, Faveri M, Figueiredo LC, Perez-Chaparro PJ, Fermiano D, et al. The effect of
systemic antibiotics administered during the active phase of non-surgical periodontal therapy or
after the healing phase: a systematic review. J Appl Oral Sci. 2015;23(3):249–54.
16. Zandbergen D, Slot DE, Niederman R, Van der Weijden FA. The concomitant administration of
systemic amoxicillin and metronidazole compared to scaling and root planing alone in treating
periodontitis: a systematic review. BMC Oral Health. 2016;16:27.
17. Sgolastra F, Petrucci A, Gatto R, Monaco A. Effectiveness of systemic amoxicillin/metronidazole
as an adjunctive therapy to full-mouth scaling and root planing in the treatment of aggressive
periodontitis: a systematic review and meta-analysis. J Periodontol. 2012;83(6):731–43.
18. Santos RS, Macedo RF, Souza EA, Soares RS, Feitosa DS, Sarmento CF. The use of systemic
antibiotics in the treatment of refractory periodontitis: A systematic review. J Am Dent Assoc.
2016;147(7):577–85.
19. McGowan K, McGowan T, Ivanovski S. Optimal dose and duration of amoxicillin-plus-
metronidazole as an adjunct to non-surgical periodontal therapy: A systematic review and meta-
analysis of randomized, placebo-controlled trials. J Clin Periodontol. 2018;45(1):56–67.
20. Sgolastra F, Severino M, Petrucci A, Gatto R, Monaco A. Effectiveness of metronidazole as an
adjunct to scaling and root planing in the treatment of chronic periodontitis: a systematic review
and meta-analysis. J Periodontal Res. 2014;49(1):10–9.
21. Elter JR, Lawrence HP, Offenbacher S, Beck JD. Meta-analysis of the effect of systemic
metronidazole as an adjunct to scaling and root planing for adult periodontitis. J Periodontal
Res. 1997;32(6):487–96.
45
22. Renatus A, Herrmann J, Schonfelder A, Schwarzenberger F, Jentsch H. Clinical Efficacy of

Azithromycin as an Adjunctive Therapy to Non-Surgical Periodontal Treatment of Periodontitis:
A Systematic Review and Meta-Analysis. J Clin Diagn Res. 2016;10(7):Ze01–7.
23. Zhang Z, Zheng Y, Bian X. Clinical effect of azithromycin as an adjunct to non-surgical treatment
of chronic periodontitis: a meta-analysis of randomized controlled clinical trials. J Periodontal
Res. 2016;51(3):275–83.
24. Sgolastra F, Petrucci A, Gatto R, Giannoni M, Monaco A. Long-term efficacy of subantimicrobial-
dose doxycycline as an adjunctive treatment to scaling and root planing: a systematic review and
meta-analysis. J Periodontol. 2011;82(11):1570–81.
25. Chambrone L, Vargas M, Arboleda S, Serna M, Guerrero M, de Sousa J, et al. Efficacy of Local and
Systemic Antimicrobials in the Non-Surgical Treatment of Smokers With Chronic Periodontitis:
A Systematic Review. J Periodontol. 2016;87(11):1320–32.
26. Angaji M, Gelskey S, Nogueira-Filho G, Brothwell D. A systematic review of clinical efficacy
of adjunctive antibiotics in the treatment of smokers with periodontitis. J Periodontol.
2010;81(11):1518–28.
27. Assem NZ, Alves MLF, Lopes AB, Gualberto ECJ, Garcia VG, Theodoro LH. Antibiotic therapy as an
adjunct to scaling and root planing in smokers: a systematic review and meta-analysis. Braz Oral
Res. 2017;31:e67.
28. Grellmann AP, Sfreddo CS, Maier J, Lenzi TL, Zanatta FB. Systemic antimicrobials adjuvant to
periodontal therapy in diabetic subjects: a meta-analysis. J Clin Periodontol. 2016;43(3):250–60.
29. Rovai ES, Souto ML, Ganhito JA, Holzhausen M, Chambrone L, Pannuti CM. Efficacy of Local
Antimicrobials in the Non-Surgical Treatment of Patients With Periodontitis and Diabetes:
A Systematic Review. J Periodontol. 2016;87(12):1406–17.
30. Cope AL, Francis N, Wood F, Chestnutt IG. Systemic antibiotics for symptomatic apical periodontitis
and acute apical abscess in adults. Cochrane Database Syst Rev. 2018;9:CD010136.
31. Matthews DC, Sutherland S, Basrani B. Emergency management of acute apical abscesses in the
permanent dentition: a systematic review of the literature. J Can Dent Assoc. 2003;69(10):660.
32. Agnihotry A, Fedorowicz Z, van Zuuren EJ, Farman AG, Al-Langawi JH. Antibiotic use for
irreversible pulpitis. Cochrane Database Syst Rev. 2016;2:CD004969.
33. Smiley CJ, Tracy SL, Abt E, Michalowicz BS, John MT, Gunsolley J, et al. Evidence-based clinical
practice guideline on the nonsurgical treatment of chronic periodontitis by means of scaling
and root planing with or without adjuncts. J Am Dent Assoc. 2015;146(7):525–35.

34. Matthews DC. Prevention and treatment of periodontal diseases in primary care. Evid Based
Dent. 2014;15(3):68–9.
35. Segura-Egea JJ, Gould K, Sen BH, Jonasson P, Cotti E, Mazzoni A, et al. European Society
of Endodontology position statement: the use of antibiotics in endodontics. Int Endod J.
2018;51(1):20–5.
36. Canadian Collaboration on Clinical Practice Guidelines in D. Clinical practice guideline on
treatment of acute apical abscess (AAA) in adults. Evid Based Dent. 2004;5(1):8.
46
Ceftazidime + avibactam – addition - EML
Ceftazidime + avibactam ATC Code: J01DD52
Proposal
The application requested the inclusion on the EML of ceftazidime + avibactam as
a last-resort treatment option for infections due to multidrug-resistant organisms
(MDROs).
Applicant
EML Secretariat on behalf of the EML Antibiotics Working Group
WHO Technical Department

EML/EMLc
EML and EMLc
Section
6.2.3 Reserve group antibiotics
Dose form(s) & strengths(s)

Powder for injection: 2 g + 0.5 g in vial
Core/Complementary
Complementary
Individual/Square box listing

Individual
Background (if relevant, eg. resubmission, previous EC consideration)

This combination antibiotic had not previously been considered for inclusion
on the EML. Ceftazidime is third-generation cephalosporin listed on the
EML complementary list and classified within the Watch group. Avibactam
is a non-beta-lactam beta-lactamase inhibitor active against certain types of
carbapenemases (e.g. KPC and OXA-48 but not active against metallo-beta-
lactamases).
Public health relevance (burden of disease)

Antibiotic-resistant bacteria are a significant threat to public health, both in HICs
as well as LMICs (1–3). A recent study estimated that infections with antibiotic-
47
resistant bacteria were responsible for approximately 33 000 attributable deaths

in Europe in 2015 (1). Fewer data are available for LMICs, but a retrospective
study in ten hospitals in India found that resistant pathogens were associated
with two to three times higher mortality than infections with susceptible strains
after adjusting for several confounders (2).
Over the past decade there has been increasing spread of multidrug-
resistant Gram-negative pathogens such as carbapenemase-producing
Enterobacteriaceae (4). The Global Antimicrobial Resistance Surveillance System
(GLASS) report published in 2018 found high levels of carbapenem resistance
in Enterobacteriaceae and non-fermenters in many of the LMICs providing
data for the report (2). The 2015 WHO Global action plan on antimicrobial
resistance calls for the development of new antimicrobial medicines (3). To
provide a framework for this endeavour, in 2017 WHO published a priority list
of antibiotic-resistant bacteria (5). The “Priority 1: critical” category includes
four types of pathogens, all of which are Gram-negative: carbapenem-resistant
Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae; and
third-generation cephalosporin-resistant Enterobacteriaceae (6).
Summary of evidence: benefits (from the application)

Several RCTs have been conducted comparing ceftazidime + avibactam to
carbapenems or best available therapy for complicated intra-abdominal
Infections (cIAIs) and complicated urinary tract infection (cUTIs) (7–10). Of
note, all but one of the RCTs (7) included patients based on clinical syndromes
and not based on the presence of infections confirmed to be caused by MDROs.
In that ‘descriptive’ trial of patients with cUTI (plus some patients with cIAI)
caused by ceftazidime-resistant Gram-negatives, ceftazidime + avibactam
treatment resulted in similar clinical response compared to best available therapy.
So far, few data on the real-life clinical use of ceftazidime + avibactam
have been published. A retrospective single centre study at the University

of Pittsburgh Medical Centre in the United States examined outcomes of 109
patients with bacteraemia caused by carbapenem-resistant Klebsiella pneumoniae
(97% of which were Klebsiella pneumoniae carbapenemase (KPC) producers)
over the time period from 2009 to 2017. The 30-day survival rate was 92% (12/13)
in patients treated with ceftazidime + avibactam versus 69% (66/96) for patients
treated with other regimens, but this obviously has to be interpreted with caution
given the many potential confounding factors (11).
Published data about use of ceftazidime + avibactam in children is very
scarce and limited to a Phase I study and case reports (12–14). However, two Phase
II RCTs have been conducted in children with cUTIs and cIAI and are awaiting
publication (ClinicalTrials.gov Identifier: NCT02475733 and NCT02497781). Of
note, ceftazidime + avibactam may have a role in combination with aztreonam to
48
treat infections caused by Enterobacteriaceae producing metallo-beta-lactamases

at least until the combination of aztreonam with avibactam becomes available
(15, 16).
Summary of evidence: harms (from the application)

In the RCTs the incidence of adverse events in the groups treated with
ceftazidime + avibactam was similar to the control groups (7–10). However, in
a meta-analysis of eight RCTs including 4093 patients, serious adverse events
(SAEs) were more common with ceftazidime + avibactam (RR 1.24, 95%CI 1.00
to 1.54, I2 = 0%) but detailed data regarding the nature of these SAE were not
available (17).
Additional evidence (not in the application)

N/A
WHO Guidelines
There are no available WHO guidelines for the treatment of infections due to
MDROs.
Costs/cost-effectiveness
United Kingdom: Basic National Health Service (NHS) price: 10 vial pack
£ 857.00 = £ 257.1 (about US$ 340) per day (standard dosing).
Few data are available regarding the cost-effectiveness of ceftazidime
+ avibactam. A decision analytic model presented at the IDWeek conference
in October 2018 aimed to estimate the cost-effectiveness of treatment with
ceftazidime + avibactam compared with colistin for a hypothetical cohort of
patients with pneumonia and bacteraemia caused by carbapenemase-resistant
Enterobacteriaceae over a 12-month period. The researchers assumed a 41%
mortality with colistin treatment, a 23% (and hence very large) absolute reduction
in mortality with ceftazidime + avibactam, daily costs of ceftazidime + avibactam
of US$ 1080, a 42% incidence of nephrotoxicity with colistin treatment, a 56%
probability of transfer to long-term care and a 1.8 fold improved odds of discharge
home with ceftazidime + avibactam treatment (18). The authors estimated an
incremental cost-effectiveness ratio for ceftazidime + avibactam compared with
colistin of US$ 110 300 per quality-adjusted life-year (QALY).
Availability
Ceftazidime + avibactam has US Food and Drug Administration (FDA) and
European Medicines Agency (EMA) approval for cUTI and cIAI (for cIAI in
combination with metronidazole) (11). EMA lists “HAP and other infections due
to Gram-negative bacteria with limited treatment options” as a further indication.
49
Other considerations
The Committee noted that there was very limited clinical trial evidence of the
efficacy of recently approved antibiotics for infections caused by carbapenem-
resistant bacteria, with activity against this type of infection based on studies
with small sample sizes, methodological limitations and including heterogenous
populations. The Committee was concerned that the current regulatory approval
process for novel agents effective against “critical priority” pathogens (according
to the WHO priority pathogens list (5)) does not adequately inform the urgent
public health need for clear evidence-based guidance on the optimal management
of these infections, which are associated with important morbidity and mortality.
The Expert Committee recommended the inclusion of ceftazidime + avibactam
on the complementary list of the EML and EMLc for the treatment of infections
caused by carbapenem-resistant organisms, which are pathogens classified as
“critical priority” in the WHO Priority Pathogen List.
The Committee agreed with the EML Antibiotic Working Group’s
recommendation that this antibiotic should be classified in the AWaRe Reserve
group.
The Committee recommended further collaboration between relevant
stakeholders to design and implement strategic public health orientated studies
that will help to inform the choice of optimal single or combination treatment
of both novel and older antibiotics for adults and children in different settings,
with the goal of improving clinical outcomes, minimizing toxicity and reducing
selection of resistance.
References
1. Cassini A, Hogberg LD, Plachouras D, Quattrocchi A, Hoxha A, Simonsen GS, et al. Attributable
deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in

the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet
Infect Dis. 2019:19(1):56–66.
2. Gandra S, Tseng KK, Arora A, Bhowmik B, Robinson ML, Panigrahi B, et al. The mortality burden
of multidrug-resistant pathogens in India: a retrospective observational study. Clin Infect Dis.
2019;69(4): 563–570.
3. Global action plan on antimicrobial resistance. Geneva: World Health Organization; 2015.
4. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae.
Virulence. 2017;8(4):460–9.
5. Prioritization of pathogens to guide discovery, research and development of new antibiotics for
drug-resistant bacterial infections, including tuberculosis. Geneva: World Health Organization;
2017. Available from: https://apps.who.int/iris/handle/10665/311820, accessed 30 October 2019.
50
6. Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al. Discovery, research,
and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and
tuberculosis. Lancet Infect Dis. 2018;18(3):318–27.
7. Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, et al. Ceftazidime-avibactam or best
available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas
aeruginosa complicated urinary tract infections or complicated intra-abdominal infections
(REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16(6):661–73.
8. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al. Efficacy and Safety of
Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated
Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3
Program. Clin Infect Dis. 2016;62(11):1380–9.
9. Qin X, Tran BG, Kim MJ, Wang L, Nguyen DA, Chen Q, et al. A randomised, double-blind, phase
3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus
meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J
Antimicrob Agents. 2017;49(5):579–88.
10. Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, et al. Ceftazidime-
avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections,
Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis.
2016;63(6):754–62.
11. Pogue JM, Bonomo RA, Kaye KS. Ceftazidime/avibactam, Meropenem/vaborbactam or both?
Clinical and formulary considerations. Clin Infect Dis. 2019; 68(3):519–524.
12. Bradley JS, Armstrong J, Arrieta A, Bishai R, Das S, Delair S, et al. Phase I Study Assessing the
Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in
Hospitalized Pediatric Patients. Antimicrob Agents Chemother. 2016;60(10):6252–9.
13. Rodriguez BA, Girotto JE, Nicolau DP. Ceftazidime/Avibactam and Ceftolozane/Tazobactam:
Novel Therapy for Multidrug Resistant Gram Negative Infections in Children. Curr Pediatr Rev.
2018;14(2):97–109.
14. Tamma PD, Fan Y, Bergman Y, Sick-Samuels AC, Hsu AJ, Timp W, et al. Successful Treatment of
Persistent Burkholderia cepacia Complex Bacteremia with Ceftazidime-Avibactam. Antimicrob
Agents Chemother. 2018;62(4). pii: e02213–17.
15. Hobson CA, Bonacorsi S, Fahd M, Baruchel A, Cointe A, Poey N, et al. Successful treatment of a
bacteremia due to NDM-1-producing Morganella morganii with Aztreonam and Ceftazidime-
avibactam combination in a pediatric patient with hematologic malignancy. Antimicrob Agents
Chemother. 2018; 63(2). pii: e02463–18.
16. Barlow G, Morice A. Successful treatment of resistant Burkholderia multivorans infection in a
patient with cystic fibrosis using ceftazidime/avibactam plus aztreonam. J Antimicrob Chemother.
2018;73(8):2270–1.
17. Sternbach N, Leibovici Weissman Y, Avni T, Yahav D. Efficacy and safety of ceftazidime/avibactam:
a systematic review and meta-analysis. J Antimicrob Chemother. 2018;73(8):2021–9.
18. Sfeir M, Satlin M, Calfee DP, Simon MS. Cost-Effectiveness of Ceftazidime–Avibactam Compared
With Colistin for Treatment of Carbapenem-Resistant Enterobacteriaceae Bacteremia and
Pneumonia. Open Forum Infect Dis. 2018;5: S539–S40.
51
Ceftolozane + tazobactam – addition – EML
Ceftolozane + tazobactam ATC Code: J01DI54
Proposal
The application requested the inclusion on the EML of ceftolozane + tazobactam as
a last-resort treatment option for infections due to multi-drug resistant organisms
(MDROs).
Applicant

EML/EMLc
EML
Section

Powder for injection: 1 g + 0.5 g in vial
Core/Complementary
Complementary

Individual listing

Ceftolozane + tazobactam is the combination of a new cephalosporin with a
structure similar to ceftazidime with a beta-lactam inhibitor that has been in
clinical use for decades (tazobactam). Ceftolozane + tazobactam retains in vitro
activity against some strains of multidrug-resistant P. aeruginosa and against
Enterobacteriaceae producing ESBL. It only has limited activity against Gram-
positive pathogens and anaerobes (1).

52

resistant Gram-negative pathogens such as carbapenemase producing
four types of pathogens, all of which are Gram-negative: carbapenem resistant

Ceftolozane + tazobactam has been assessed in two non-inferiority RCTs, one for
cUTI and one for cIAI (8, 9). Of note, in the cUTI trial levofloxacin was used as
comparator agent, a highly debatable choice given that resistance to levofloxacin
in Gram-negatives isolated in urine cultures at baseline was nearly 10 times more
prevalent at baseline (2.7% for C+T vs 26.7% for levofloxacin) (9). An RCT in
ventilator-associated pneumonia is currently being conducted (ClinicalTrials.gov
Identifier: NCT01853982).
A retrospective cohort study in of 101 patients treated with ceftolozane +
tazobactam in 22 Italian centres for a variety of infections causes by P. aeruginosa,
including 51% of extensively drug-resistant (XDR) strains, showed overall clinical
success of 83.2% and a good safety profile (10). A secondary analysis of the 150 of
1346 (11.1%) patients with ESBL-producing organisms in the original two RCTs
reported high clinical cure rates with ceftolozane + tazobactam (overall 97.4%),
better than the comparators (82.6% for levofloxacin (cUTI only) and 88.5% for
meropenem (cIAI only)) (11). The major methodological limitations of these
studies mean, however, that the data have to be interpreted with caution.
Data for children are scarce and no specific recommendations regarding
use in the paediatric population can be made (12, 13).

In the two non-inferiority Phase III RCTs published so far adverse events (AE)
occurred with similar frequency in the ceftolozane + tazobactam and comparator
53
groups with headache and gastrointestinal symptoms being the most frequent
AE (8, 9).

N/A
WHO Guidelines
MDROs.
United States: About US$ 1140 for 10 vials (1/0.5g) => about US$ 340 per day
A decision-analytic Monte Carlo simulation model aimed to assess the costs
of empiric treatment with ceftolozane + tazobactam versus or piperacillin/
tazobactam in hospitalized adults with cUTI due to Gram-negative pathogens
in the United States setting. The study co-authored by multiple employees of
the producer of ceftolozane + tazobactam estimated an incremental cost-
effectiveness ratio of US$ 6128 per QALY (14). A similar study in the United
Kingdom, for patients with cIAI estimated an incremental cost-effectiveness ratio
of £ 4350 per QALY in favour of ceftolozane + tazobactam (with metronidazole)
compared to piperacillin/tazobactam (15).
Availability
Ceftolozane + tazobactam has been approved for the treatment of cIAI and
cUTI, including acute pyelonephritis in the United States and European Union.
N/A
The Expert Committee did not recommend the addition of ceftolozane +
tazobactam to the EML. The Committee noted that although ceftolozane +
tazobactam is active against some strains of carbapenem-resistant P. aeruginosa,
it lacks activity against carbapenemase-producing Enterobacteriaceae, which
is more prevalent in the community and represents a greater public health
threat. Alternative antibiotics are included on the list that are effective against
carbapenem-resistant P. aeruginosa.
group.
54
References
1. Giacobbe DR, Bassetti M, De Rosa FG, Del Bono V, Grossi PA, Menichetti F, et al. Ceftolozane/
tazobactam: place in therapy. Expert Rev Anti Infect Ther. 2018;16(4):307–20.
Infect Dis. 2019; 19(1):56–66.
2019;69(4):563–570.
4. Global action plan on antimicrobial resistance. Geneva: World Health Organization; 2015. Available
from https://www.who.int/antimicrobial-resistance/global-action-plan/en/, accessed 30 October
2019.
Virulence. 2017;8(4):460–9.
8. Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, et al. Ceftolozane/
Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of
Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI). Clin
Infect Dis. 2015;60(10):1462–71.
9. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam
compared with levofloxacin in the treatment of complicated urinary-tract infections,
including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet.
2015;385(9981):1949–56.
10. Bassetti M, Castaldo N, Cattelan A, Mussini C, Righi E, Tascini C, et al. Ceftolozane/tazobactam for
the treatment of serious P. aeruginosa infections: a multicenter nationwide clinical experience.
Int J Antimicrob Agents. 2018.
11. Popejoy MW, Paterson DL, Cloutier D, Huntington JA, Miller B, Bliss CA, et al. Efficacy of
ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-
producing Escherichia coli and Klebsiella pneumoniae: a pooled analysis of Phase 3 clinical trials.
J Antimicrob Chemother. 2017;72(1):268–72.
12. Bradley JS, Ang JY, Arrieta AC, Larson KB, Rizk ML, Caro L, et al. Pharmacokinetics and Safety of
Single Intravenous Doses of Ceftolozane/Tazobactam in Children With Proven or Suspected
Gram-Negative Infection. Pediatr Infect Dis J. 2018;37(11):1130–6.
13. Tamma SM, Hsu AJ, Tamma PD. Prescribing Ceftolozane/Tazobactam for Pediatric Patients:
Current Status and Future Implications. Paediatr Drugs. 2016;18(1):1–11.
14. Kauf TL, Prabhu VS, Medic G, Borse RH, Miller B, Gaultney J, et al. Cost-effectiveness of ceftolozane/
tazobactam compared with piperacillin/tazobactam as empiric therapy based on the in-vitro
surveillance of bacterial isolates in the United States for the treatment of complicated urinary
tract infections. BMC Infect Dis. 2017;17(1):314.
55
15. Prabhu V, Foo J, Ahir H, Sarpong E, Merchant S. Cost-effectiveness of ceftolozane/tazobactam plus

metronidazole compared with piperacillin/tazobactam as empiric therapy for the treatment of
complicated intra-abdominal infections based on the in-vitro surveillance of bacterial isolates in
the UK. J Med Econ. 2017;20(8):840–9.
56
Delafloxacin – addition – EML
Delafloxacin ATC Code: J01MA23
Proposal
The application requested the inclusion of delafloxacin on the complementary
list of the EML as a last-resort treatment option for infections due to multidrug-
resistant organisms (MRDOs).
Applicant

EML/EMLc
EML
Section
6.2.2 Watch group antibiotics

Tablet: 450 mg
Lyophilized powder for injection: 300 mg
Core/Complementary
Complementary

Individual

Delafloxacin had not previously been considered for inclusion on the EML. It
is a new fluoroquinolone which, compared to the older molecules of this class,
has activity against methicillin-resistant S. aureus (MRSA) (1, 2). It has been
approved for treatment of skin and soft tissue infections based on two Phase III
multicentre, double-blind non-inferiority trials (3, 4).

57

provide a framework for this endeavour, in 2017 WHO published a priority
list of antibiotic-resistant bacteria (9). “Priority 1: critical” category includes

In the two Phase III trials in adult patients with acute bacterial skin and skin
structure infections, delafloxacin fulfilled criteria for non-inferiority compared
to linezolid and vancomycin/aztreonam respectively (3, 4). In respective trials,
one third and one fourth of patients had infections due to MRSA.
A trial comparing delafloxacin to moxifloxacin (or linezolid in the
case of confirmed MRSA) in patients with community-acquired pneumonia
(NCT02679573) has been completed in 2018 but results have not yet been
published.

A review of the safety data of the two Phase III non-inferiority RCTs and additional
Phase I and II trials showed few discontinuations (<1%) due to treatment-related
adverse events (3, 4, 11). The proportion of patients with AEs was similar
to the proportion observed in the comparator arms. No fluoroquinolone-
specific AE such as tendinitis or neuropathy were observed in the delafloxacin
arm. Gastrointestinal events (notably diarrhoea), headache and infusion site
pain were the most frequently reported AEs. Adverse events associated with
fluoroquinolones (tendinitis, myopathy, dysglycaemia, neuropathy, neurotoxicity)
were not more frequent when compared with vancomycin/aztreonam with the
caveat that the combined Phase III trials only included 1492 patients and rare,
potentially severe events were unlikely to be detected.
There are no data for use of delafloxacin in children, and similar to other
fluoroquinolones it is not recommended for use in patients younger than 18 years.
58

Delafloxacin has been suggested as a treatment option for gonorrhoea with good
in vitro activity even against strains with reduced susceptibility to ciprofloxacin
(12). The results of an open-label, multicentre study with 460 participants
with uncomplicated gonorrhoea was recently published (13). Patients were
randomized (2:1) to either a single oral dose of 900 mg of delafloxacin or 250 mg
of intramuscular ceftriaxone. Delafloxacin did not fulfil the predefined criteria
for non-inferiority for the primary outcome urogenital cure (85.1% (194/228)
vs 91.0% (91/100); 95%CI −13.18% to 1.36%; the lower bound of the CI thus
exceeding the pre-specified −10% non-inferiority margin).
WHO Guidelines
There are no available WHO guidelines for the treatment of infections due
to MDROs. Delafloxacin is not mentioned in the 2016 WHO Guidelines
for the treatment of Neisseria gonorrhoeae (issued before the availability of
delafloxacin) (14).
Approximately US$ 260 per day
Availability
Delafloxacin is approved in the United States and Europe for the treatment of
acute bacterial skin and skin structure infections.
N/A
The Expert Committee did not recommend the addition of delafloxacin to
the EML. The Committee noted that although delafloxacin has demonstrated
activity against some MRSA strains ranked as “high priority” on the WHO
priority pathogens list, effective alternatives are currently available on the
EML. In addition, delafloxacin was not associated with greater activity against
“critical priority” pathogens compared to other, older fluoroquinolones currently
available on the Model List.
The Expert Committee agreed with the EML Antibiotic Working Group’s
recommendation that this antibiotic should be classified in the AWaRe Watch
group.
59
References
1. Jorgensen SCJ, Mercuro NJ, Davis SL, Rybak MJ. Delafloxacin: Place in Therapy and Review of
Microbiologic, Clinical and Pharmacologic Properties. Infect Dis Ther. 2018;7(2):197–217.
2. Saravolatz LD, Stein GE. Delafloxacin: A New Anti-methicillin-resistant Staphylococcus aureus
Fluoroquinolone. Clin Infect Dis. 2019;68(6):1058-62. Clin Infect Dis. 2019;68(6):1058-62.
3. Pullman J, Gardovskis J, Farley B, Sun E, Quintas M, Lawrence L, et al. Efficacy and safety of
delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin
structure infections: a Phase 3, double-blind, randomized study. J Antimicrob Chemother.
2017;72(12):3471–80.
4. O’Riordan W, McManus A, Teras J, Poromanski I, Cruz-Saldariagga M, Quintas M, et al. A Comparison
of the Efficacy and Safety of Intravenous Followed by Oral Delafloxacin With Vancomycin Plus
Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections: A Phase 3,
Multinational, Double-Blind, Randomized Study. Clin Infect Dis. 2018;67(5):657–66.
Infect Dis. 2019; 19(1):56–66.
6. Gandra S, Tseng KK, Arora A, Bhowmik B, Robinson ML, Panigrahi B, et al. The mortality burden of
multidrug-resistant pathogens in India: a retrospective observational study. Clin Infect Dis. 2019;
69(4): 563–570.
Available from: https://apps.who.int/iris/handle/10665/311820, accessed 30 October 2019.
Virulence. 2017;8(4):460–9.
11. Lodise T, Corey R, Hooper D, Cammarata S. Safety of Delafloxacin: Focus on Adverse Events of
Special Interest. Open Forum Infect Dis. 2018;5(10):ofy220.

12. Soge OO, Salipante SJ, No D, Duffy E, Roberts MC. In Vitro Activity of Delafloxacin against Clinical
Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance. Antimicrob
Agents Chemother. 2016;60(5):3106–11.
13. Hook EW, 3rd, Golden MR, Taylor SN, Henry E, Tseng C, Swerdlow J, et al. Efficacy and safety of
single dose oral delafloxacin compared with intramuscular ceftriaxone for uncomplicated
gonorrhea treatment: an open-label, non-inferiority, Phase 3, multicenter, randomized study. Sex
Transm Dis. 2019 (epub ahead of print).
14. Guidelines for the treatment of Neisseria gonorrhoeae. Geneva: World Health Organization;
2016.
60
Eravacycline – addition – EML
Eravacycline ATC Code: J01AA13
Proposal
The application requested the inclusion of eravacycline on the complementary
resistant organisms (MRDOs).
Applicant

EML/EMLc
EML
Section

Core/Complementary
Complementary

Individual

Eravacycline had not previously been considered for inclusion on the EML.
Eravacycline is a fully synthetic tetracycline antibiotic that has a spectrum of
activity similar to tigecycline and maintains its activity in the presence of two
common resistance mechanisms: ribosomal protection and active drug efflux.
It retains activity against most ESBL producing Enterobacteriaceae and some
strains of carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii
but has limited activity against Pseudomonas aeruginosa (1–4).
61


Eravacycline achieved the predefined criteria for non-inferiority compared
with ertapenem in one trial and meropenem in another trial in the treatment of
cIAI in hospitalized adults (11, 12). A further trial has been conducted in adult
patients with cUTI using levofloxacin as comparator, but the results have so
far only been published on cinicaltrials.gov (NCT01978938) and eravacycline
“did not achieve its primary endpoint of statistical non-inferiority compared to
levofloxacin” (13).
Like for other tetracyclines, eravacycline use is not recommended in
children younger than 8 years and pregnant or breastfeeding women due to the
risk of tooth discoloration and enamel hypoplasia. A Phase I multicentre study
to assess the pharmacokinetics and safety of intravenous (IV) eravacycline in
children aged 8 to 18 years is currently recruiting patients (ClinicalTrials.gov
Identifier: NCT03696550).

In the trials comparing eravacycline to a carbapenem (ertapenem and
meropenem respectively) more treatment-emergent AEs were observed in the
eravacycline treatment groups (11, 12). The difference was mostly attributable
to nausea and phlebitis.
62

N/A.
WHO Guidelines
MDROs.
United States: wholesale acquisition cost of US$ 175 per day of treatment (14).
No cost-effectiveness data are available.
Availability
Eravacycline has been approved in the United States and the European Union
for the treatment of cIAI in adults.
Safety concerns exist for tigecycline, a pharmacologically similar agent with a
similar spectrum of activity to eravacycline, with an increased risk of mortality
compared with other antimicrobials being reported (15–17). The FDA issued
a boxed warning about this risk in 2013 (18). In a separate recommendation
made during the meeting, the Expert Committee recommended the removal of
tigecycline from the EML and EMLc.
The Expert Committee did not recommend the addition of eravacycline to
the EML. The Committee considered that although eravacycline demonstrates
activity against some strains of carbapenemase-producing Enterobacteriaceae,
there are some concerns with regard to efficacy, as eravacycline failed to
demonstrate non-inferiority compared to levofloxacin in one RCT for cUTI.
In addition, the Committee considered that there could be safety concerns,
with no long-term safety data currently available. The Committee noted
pharmacological similarities between eravacycline and tigecycline, and the
reported increased mortality associated with tigecycline in some meta-analyses.
recommendation that eravacycline be classified in the AWaRe Reserve group.
63
References
1. Livermore DM, Mushtaq S, Warner M, Woodford N. In Vitro Activity of Eravacycline against
Carbapenem-Resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents
Chemother. 2016;60(6):3840–4.
2. Seifert H, Stefanik D, Sutcliffe JA, Higgins PG. In-vitro activity of the novel fluorocycline
eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob
Agents. 2018;51(1):62–4.
3. Zhanel GG, Baxter MR, Adam HJ, Sutcliffe J, Karlowsky JA. In vitro activity of eravacycline
against 2213 Gram-negative and 2424 Gram-positive bacterial pathogens isolated in Canadian
hospital laboratories: CANWARD surveillance study 2014-2015. Diagn Microbiol Infect Dis.
2018;91(1):55–62.
4. Zhanel GG, Cheung D, Adam H, Zelenitsky S, Golden A, Schweizer F, et al. Review of Eravacycline, a
Novel Fluorocycline Antibacterial Agent. Drugs. 2016;76(5):567–88.
Infect Dis. 2019; 19(1):56–66.
69(4): 563–570.
Virulence. 2017;8(4):460–9.
11. Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, et al. Assessing the Efficacy and Safety of
Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-

Negative Infections Treated With Eravacycline (IGNITE 1) Trial: A Randomized Clinical Trial. JAMA
Surg. 2017;152(3):224–32.
12. Solomkin JS, Gardovskis J, Lawrence K, Montravers P, Sway A, Evans D, et al. IGNITE4: Results
of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs. Meropenem in the
Treatment of Complicated Intra-Abdominal Infections. Clin Infect Dis. 2019;69(6):921–929.
13. Tetraphase Pharmaceuticals Inc. (2015). Tetraphase announces top-line results from IGNITE2
phase 3 clinical trial of eravacycline in cUTI [website]. (https://ir.tphase.com/news-releases/
news-release-details/tetraphase-announces-top-line-results-ignite2-phase-3-clinical, accessed
20 March 2019).
14. Tetraphase Pharmaceuticals Inc. (2018). Tetraphase Pharmaceuticals announces commercial
launch of Xerava in the United States [website]. (https://ir.tphase.com/news-releases/news-
release-details/tetraphase-pharmaceuticals-announces-commercial-launch-xeravatm, accessed
20 March 2019).
64
15. McGovern PC, Wible M, El-Tahtawy A, Biswas P, Meyer RD. All-cause mortality imbalance in the
tigecycline phase 3 and 4 clinical trials. Int J Antimicrob Agents. 2013;41(5):463–7.
16. Shen F, Han Q, Xie D, Fang M, Zeng H, Deng Y. Efficacy and safety of tigecycline for the treatment
of severe infectious diseases: an updated meta-analysis of RCTs. Int J Infect Dis. 2015;39:25–33.
17. Prasad P, Sun J, Danner RL, Natanson C. Excess deaths associated with tigecycline after approval
based on noninferiority trials. Clin Infect Dis. 2012;54(12):1699–709.
18. US Food and Drug Administration (2013). FDA Drug Safety Communication: FDA warns of
increased risk of death with IV antibacterial Tygacil (tigecyclne) and approves new Boxed
Warning [website]. (https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-
communication-fda-warns-increased-risk-death-iv-antibacterial-tygacil-tigecycline, accessed
20 March 2019).
65
Meropenem + vaborbactam – addition – EML
Meropenem + vaborbactam ATC Code: J01DH52
Proposal
The application requested the inclusion on the EML of meropenem +
vaborbactam as a last-resort treatment option for infections due to multidrug-
resistant organisms (MDROs).
Applicant

EML/EMLc
EML
Section

Powder for injection: 1 g + 1 g
Core/Complementary
Complementary

Individual

Meropenem + vaborbactam is a combination of the carbapenem meropenem with
the non-suicidal cyclic boronic acid–based beta-lactamase inhibitor vaborbactam
(1, 2). Vaborbactam inhibits Ambler class A and C beta-lactamases, of which
KPC-carbapnemases and some extended spectrum beta-lactamases are currently
the clinically most relevant examples. Metallo-beta-lactamases (e.g. NDM, VIM)
and class D beta-lactamases are not inhibited by vaborbactam.

66

four types of pathogens, all of which are Gram-negative: carbapenem-resistant

As of December 2018, meropenem + vaborbactam was assessed in two Phase
III RCTs (9, 10). The TANGO I trial showed non-inferiority of meropenem
+ vaborbactam versus piperacillin + tazobactam for the treatment of cUTI
(infection with a pathogen resistant to standard antibiotics was not an inclusion
criterion) (9). The TANGO II trial, a Phase III, multicentre, multinational, open-
label randomized clinical trial, compared meropenem + vaborbactam to the
best available therapy (BAT; often a combination of antibiotics) in patients with
a variety of infections caused by carbapenem-resistant Enterobacteriaceae and
showed decreased 28-day all-cause mortality (15.6% (5/32) vs BAT 33.3% (5/15))
with meropenem + vaborbactam compared to BAT, with a wide confidence
interval given the small sample size (95%CI of difference, −44.7% to 9.3%) (10).

In the TANGO I and TANGO II trials adverse events were similar in the
meropenem + vaborbactam group and in the comparator group.

N/A
WHO Guidelines
MDROs.
67
United States: about US$ 200 for 1 g + 1 g, equivalent to US$ 1200 for an average
daily dose of 2 g + 2 g every 8 hours.
No data about cost-effectiveness are available.
Availability
Meropenem + vaborbactam is approved by the FDA for patients 18 years of age
and older with cUTI, including pyelonephritis.
EMA approved its use in the European Union for:
■■ cUTI, including pyelonephritis, a sudden and severe infection causing
the kidneys to swell and which may permanently damage them;
■■ cIAI;
■■ hospital-acquired pneumonia, including ventilator associated
pneumonia;
■■ bacteria in the blood associated with any of the infections listed
above;
■■ infections due to aerobic Gram-negative organisms in adults with
limited treatment options.
efficacy of recently approved antibiotics against carbapenem-resistant infections,
with activity based on small sample size studies including heterogenous
populations. The Committee was concerned that the current regulatory approval
process for novel agents effective against the WHO priority pathogen list
“critical priority” pathogens does not adequately inform the urgent public
health need for clear evidence-based guidance on the optimal management of
these infections, which are associated with high mortality.
The Expert Committee recommended the inclusion of meropenem +
vaborbactam on the complementary list of the EML of meropenem +
vaborbactam for the treatment of infections caused by carbapenem-resistant
organisms which are pathogens classified as “critical priority” in the WHO
priority pathogen list.
group.
stakeholders to design and implement strategic public health-orientated studies
68
that will help to inform the choice of optimal single or combinations of both
novel and older antibiotics for adults and children in different settings, with the
goal of improving clinical outcomes, minimizing toxicity and reducing selection
of resistance.
References
1. Cho JC, Zmarlicka MT, Shaeer KM, Pardo J. Meropenem/Vaborbactam, the First Carbapenem/beta-
Lactamase Inhibitor Combination. Ann Pharmacother. 2018;52(8):769–79.
2. Lee YR, Baker NT. Meropenem-vaborbactam: a carbapenem and beta-lactamase inhibitor
with activity against carbapenem-resistant Enterobacteriaceae. Eur J Clin Microbiol Infect Dis.
2018;37(8):1411–9.
Infect Dis. 2019; 19(1):56–66.
2019; 69(4):563–570.
Virulence. 2017;8(4):460–9.
2017.
9. Kaye KS, Bhowmick T, Metallidis S, Bleasdale SC, Sagan OS, Stus V, et al. Effect of Meropenem-
Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial
Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial. JAMA.
2018;319(8):788–99.
10. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, Mathers AJ, Bassetti M, Vazquez J, et al.
Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with
Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial.
Infect Dis Ther. 2018;7(4):439–55.
69
Omadacycline – addition – EML
Omadacycline ATC Code: to be assigned
Proposal
The application requested the inclusion of omadacycline on the complementary
Applicant

EML/EMLc
EML
Section
6.2.3 Reserve group antibiotic

Tablet: 300 mg
Core/Complementary
Complementary

Individual

Omadacycline had not previously been considered for inclusion on the EML.
Omadacycline, a recently approved tetracycline antibiotic, has a broad spectrum
of activity against many Gram-positive and Gram-negative pathogens, including
methicillin-resistant Staphylococcus aureus (MRSA) (1). MRSA is ranked as a
“high priority” pathogen on the WHO priority pathogens list (2).

70


Several RCTs of omadacycline had been conducted or were currently ongoing,
but at the time of writing the application the results had not yet been published
in the peer-reviewed literature.
■■ Omadacycline versus moxifloxacin for the treatment of community-
acquired bacterial pneumonia (CABP) (NCT02531438), Phase
III, double-blind, multicentre non-inferiority RCT (2015–2017)
in 774 adult patients with CABP. Primary outcome: Number of
participants with early clinical response 81.1% vs 82.7% (difference
−1.6 percentage points, 95%CI −7.1 to 3.8).
■■ Omadacycline versus linezolid for the treatment of acute bacterial
skin and skin structure infections (ABSSSI) (NCT02378480), Phase
III, double-blind, multicentre non-inferiority RCT (2015-2016):
results not yet available.
■■ Oral omadacycline versus oral linezolid for the treatment of
ABSSSI (NCT02877927), Phase III, double-blind, multicentre non-
inferiority RCT (2016–2017) in 735 adult patients with ABSSSI,
Primary outcome: Early clinical response 87.5% vs 82.5% (difference
+5.0 percentage points, 95%CI −0.2 to 10.3).
■■ Oral omadacycline versus oral nitrofurantoin for the treatment of
cystitis (NCT03425396): trial still recruiting.
71
The results of NCT02531438 and NCT02378480 have since been published (see
additional evidence).

See additional evidence.

Two noninferiority RCTs of omadacycline in adults with CABP and ABSSSI
were published in February 2019.
A double-blind, noninferiority (10 percentage point margin) RCT
allocated adults with CABP to either omadacycline or moxifloxacin with possible
transition to the oral equivalent after three days for a total treatment duration
of between 7 and 14 days. The primary outcome was early clinical response
(according to predefined criteria) at 72 to 120 hours. Omadacycline fulfilled
criteria for noninferiority for early clinical response (81.1% vs 82.7%, difference,
−1.6 percentage points; 95%CI −7.1 to 3.8) (8). The frequency of adverse events
(AE) was similar in both groups, with gastrointestinal side effects being the
most commonly observed AE (10.2% vs 18.0%). There was a slight imbalance
in mortality with eight deaths occurring in the omadacycline group versus
four in the moxifloxacin group, disproportionately affecting patients with more
severe pneumonia.
A second double-blind, noninferiority (10 percentage point margin)
trial, randomly assigned adults with ABSSSI to treatment with omadacycline
or linezolid with possible transition to the oral equivalent after three days for
a total treatment duration between 7 and 14 days. The primary outcome was
early clinical response (48–72 hours), defined as survival, absence of rescue
antibiotic therapy and ≥ 20% reduction in lesion size. Omadacycline fulfilled
criteria for non-inferiority for early clinical response (84.8% vs 85.5%, difference
−0.7 percentage points, 95%CI −6.3 to 4.9) (9). The frequency of adverse events
was similar in both groups, with gastrointestinal side effects being the most
commonly observed AE (18.0% vs 15.8%).
WHO Guidelines
multidrug-resistant organisms.
No information regarding costs available.
Few data are available regarding the cost-effectiveness of omadacycline.
A modelling study estimated potential cost savings with omadacycline treatment
compared with inpatient IV vancomycin treatment in patients with acute
72
bacterial skin and skin-structure infections by shifting care to the outpatient

setting due to the availability of an oral formulation of omadacycline (10). The
study assumed that a large proportion (50%) of patients would continue with
IV vancomycin (rather than a switch to an oral agent), limiting applicability
to ‘real-world’ scenarios. It was noted that the first author of this study was an
employee of the pharmaceutical company producing omadacycline.
Availability
The drug has been approved for the treatment of community acquired bacterial
pneumonia and acute bacterial skin and skin structure infections in the United
States (11).
N/A
The Expert Committee did not recommend the addition of omadacycline to
the EML. The Committee considered that although omadacycline demonstrates
activity against both Gram-positive and Gram-negative pathogens, including
MRSA, available data for its effectiveness and safety are currently limited. The
Committee noted the finding of potentially increased mortality associated with
omadacycline in one RCT of patients with community-acquired pneumonia.
recommendation that omadacycline be classified in the AWaRe Reserve group.
References
1. Montravers P, Tran-Dinh A, Tanaka S. The role of omadacycline in skin and soft tissue infections.
Curr Opin Infect Dis. 2018;31(2):148–54.
Infect Dis. 2019; 19(1):56–66.
69(4): 563–570.
Virulence. 2017;8(4):460–9.
73
8. Stets R, Popescu M, Gonong JR, Mitha I, Nseir W, Madej A, et al. Omadacycline for Community-
Acquired Bacterial Pneumonia. N Engl J Med. 2019;380(6):517–27.
9. O’Riordan W, Green S, Overcash JS, Puljiz I, Metallidis S, Gardovskis J, et al. Omadacycline for
Acute Bacterial Skin and Skin-Structure Infections. N Engl J Med. 2019;380(6):528–38.
10. LaPensee K, Lodise T. Potential Cost-Savings with Once-Daily Aminomethylcycline Antibiotic
versus Vancomycin in Hospitalized Patients with Acute Bacterial Skin and Skin Structure
Infections. Am Health Drug Benefits. 2018;11(9):449–59.
11. Markham A, Keam SJ. Omadacycline: First Global Approval. Drugs. 2018;78(18):1931–7.
74
Plazomicin– addition – EML
Plazomicin ATC Code: to be assigned
Proposal
The application requested the inclusion of plazomicin on the complementary list
of the EML as a last-resort treatment option for infections due to multidrug-
Applicant

EML/EMLc
EML
Section

Injection: 50 mg/mL in 10 mL vial (500 mg/10 mL concentrate for solution for
infusion)
Core/Complementary
Complementary

Individual

Plazomicin had not previously been considered for inclusion on the EML.
Plazomicin is a next-generation aminoglycoside that is not affected by many
aminoglycoside-modifying enzymes of Enterobacteriaceae that inactivate
other types of aminoglycosides (1, 2). This makes it a potentially useful drug
for the treatment of carbapenemase-producing Enterobacteriaceae since
aminoglycosides are not affected by carbapenemase production (metallo-
beta-lactamases may be an exception since they often are associated with
genes for methylases affecting and inactivating all types of aminoglycosides,
including plazomicin).
75


See additional evidence.

Like all aminoglycosides plazomicin is potentially nephrotoxic. Increases in
serum creatinine levels of 0.5 mg or more per decilitre (≥40 μmol per litre)
above baseline occurred in 7.0% of patients in the plazomicin group and in 4.0%
in the meropenem group in the non-inferiority trial comparing plazomicin to
meropenem for patients with cUTIs (see additional evidence) (9).

Results of a non-inferiority trial comparing plazomicin to meropenem for
patients with cUTIs were published in January 2019 (9). 609 patients with a
diagnosis of cUTI were randomly allocated 1:1 to IV plazomicin or meropenem
with the option for oral step-down treatment after at least 4 days of IV treatment
with a total treatment duration of 7 to 10 days of therapy. The primary outcome
was “composite cure” (clinical cure and microbiologic eradication) at day 5, and
15 to 19 days after treatment start in the microbiologic modified ITT population.
Plazomicin fulfilled the non-inferiority criteria for both endpoints (with a
prespecified non-inferiority margin of 15 percentage points): 88.0% (168/191) vs
76
91.4% (180/197) (difference, −3.4 percentage points; 95%CI −10.0 to 3.1) and
81.7% (156/191) vs 70.1% (138/197) (difference, 11.6 percentage points; 95%CI
2.7 to 20.3) respectively.
WHO Guidelines
MDROs.
United States: Dosing is weight-based but a dose of 1000 mg for a 70 kg person
with good renal function is reported to be approximately US$ 750.
No data regarding the cost-effectiveness of plazomicin compared to
other treatment options are available.
Availability
Plazomicin is approved by the FDA for patients 18 years of age or older for the
treatment of cUTI, including pyelonephritis caused by the following susceptible
microorganism(s): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and
Enterobacter cloacae. An application has been filed in Europe by the producing
company but is currently pending.
efficacy of recently approved antibiotics against carbapenem-resistant infections,
with activity based on small sample size studies including heterogenous
populations. The Committee was concerned that the current regulatory
approval process for novel agents effective against the WHO priority pathogen
list “critical priority” pathogens does not adequately inform the urgent public
health need for clear evidence-based guidance on the optimal management of
these infections, which are associated with high mortality.
The Expert Committee recommended the inclusion of plazomicin on the
complementary list of the EML for the treatment of infections caused by
carbapenem-resistant organisms that are classified as “critical priority” in the
WHO priority pathogen list.
group (Section 6.2.3).
stakeholders to design and implement strategic public health-orientated studies
77
that will help to inform the choice of optimal single or combinations of both
novel and older antibiotics for adults and children in different settings, with the
goal of improving clinical outcomes, minimizing toxicity and reducing selection
of resistance.
References
1. Shaeer KM, Zmarlicka MT, Chahine EB, Piccicacco N, Cho JC. Plazomicin: A Next-Generation
Aminoglycoside. Pharmacotherapy. 2019;39(1):77–93.
2. Theuretzbacher U, Paul M. Developing a new antibiotic for extensively drug-resistant pathogens:
the case of plazomicin. Clin Microbiol Infect. 2018;24(12):1231–3.
Infect Dis. 2019; 19(1):56–66.
69(4): 563–570.
Virulence. 2017;8(4):460–9.
2017.
9. Wagenlehner FME, Cloutier DJ, Komirenko AS, Cebrik DS, Krause KM, Keepers TR, et al. Once-
Daily Plazomicin for Complicated Urinary Tract Infections. N Engl J Med. 2019;380(8):729–40.
78

Antituberculosis medicines – new formulations for addition – EML and EMLc
Cycloserine ATC Code: J04AB01

Ethambutol ATC Code: J04AK02
Ethionamide ATC Code: J04AD03
Isoniazid ATC Code: J04AC01
Levofloxacin ATC Code: J01MA12
Linezolid ATC Code: J01XX08
Moxifloxacin ATC Code: J01MA14
Clofazimine ATC Code: J04BA01
Rifabutin ATC Code: J04AB04
Proposal
The application requested:
–– the addition of various new formulations of currently listed
medicines for tuberculosis (TB) for use in children;
–– amendments to the dosage form terminology used to describe
clofazimine and rifabutin.
Applicant
Stop TB Partnership/Global Drug Facility

Comments on the application were received from the WHO Global TB
Programme. The technical unit advised that it supported the application, which
was developed in consultation with the Global TB Programme, and was fully in
line with the latest WHO recommendations on the management of multidrug-
resistant TB (MDR-TB), rifampicin-resistant TB (RR-TB) and isoniazid-resistant
TB. The technical unit stated that the addition of child-friendly formulations of
second-line antituberculosis medicines will greatly benefit children with drug-
resistant tuberculosis.
EML/EMLc
EML and EMLc
Section
79

Cycloserine: solid oral dose form 125 mg (add)
Ethambutol: dispersible tablet 100 mg (add)
Ethionamide: dispersible tablet 125 mg (add)
Isoniazid: dispersible tablet 100 mg (add)
Levofloxacin: dispersible tablet 100 mg (add)
Linezolid: dispersible tablet 150 mg (add)
Moxifloxacin: dispersible tablet 100 mg (add)
Clofazimine: capsule to solid oral dosage form 50 mg, 100 mg (amend)
Rifabutin: capsule to solid oral dosage form 150 mg (amend)
Core/Complementary
Core: ethambutol, isoniazid, rifabutin
Complementary: clofazimine, cycloserine, ethionamide, levofloxacin, linezolid,
moxifloxacin

Individual

All of the medicines for which additional formulations are requested for listing
are currently included on the Model Lists in various formulations and strengths.
In 2007, the World Health Assembly called for WHO to promote the
development of child-friendly medicines with a particular focus on treatment
for HIV, tuberculosis, malaria and chronic disease (1).
In 2017, the Expert Committee recommended the addition to the EMLc
of two fixed-dose combination, child-friendly dispersible tablet formulations of
isoniazid + rifampicin +/– pyrazinamide for use in children with drug-sensitive
tuberculosis infection. The Committee considered that the availability of these

age-appropriate formulations would offer benefits including appropriate dosing,
ease of administration and reduced pill burden (2).

It is estimated that of the 10 million people who developed TB in 2017, 1 million
of them were children. Children aged <15 years accounted for 7.1% of the 6.4
million new or relapsed cases of TB notified to national TB programmes and
reported to WHO. Children aged <15 years accounted for 15% and 10% of total
TB deaths among HIV-negative and HIV-positive people, respectively – higher
than their share of estimated cases, suggesting poorer access to diagnosis and
treatment (3).
80

Evidence for the clinical effectiveness of the medicines was evaluated at the time
of their individual listings.
Paediatric-friendly formulations
The proposed new formulations are mostly dispersible formulations, meaning
they can be mixed in liquid, making it easier to get the correct doses and for
children to swallow. They are flavoured to overcome the bitterness associated
with breaking, crushing and otherwise manipulating adult formulations.
The proposed formulations are at lower strengths, aligned with the
dosing needs of children according to the 2019 update of the WHO consolidated
guidelines on drug-resistant tuberculosis treatment (4). With the exception of
linezolid 150 mg dispersible tablet (which is still in development), the proposed
formulations are all quality-assured, either through the WHO Prequalification
for Medicines Programme, or by the Global Fund Expert Review Panel.
Amended dosage form terminology
Until recently there has been a single supplier of clofazimine in a capsule
formulation. This creates a risk to the global supply security of this key
medicine, especially as it is increasing in importance and will likely have greater
use in national programmes. Many organizations have worked to improve the
supply security and have new suppliers developing clofazimine; in 2018 a new
tablet formulation of clofazimine was quality-assured and is now eligible for
procurement by programmes. The current listing on the Model List refers only
to clofazimine capsules. The specificity of having the dosage form limited to
only capsules could create a barrier to accessing the new tablet formulations.
This situation also applies to other products, such as rifabutin capsules, where
it is possible that different manufacturing approaches could mean that products
may be produced in tablet and/or capsule formulations. Having robust quality
assurance approaches, such as the WHO Prequalification for Medicines
Programme, ensures that the efficacy of the medicines remains regardless of
the formulation.

Evidence for the safety of the medicines was evaluated at the time of their
individual listings.

N/A
81
WHO Guidelines
These medicines are all recommended the most recent WHO guidelines for
treatment of drug-sensitive tuberculosis (2017) (5), treatment of latent TB
infection (2018) (6), treatment of isoniazid mono-resistant TB (2018) (7) and
treatment of drug-resistant TB (2019) (4).
No information was provided in the application.
Availability
The proposed new formulations are in the Stop TB Partnership’s Global Drug
Facility product catalogue and are reportedly being procured by programmes.
N/A
The Expert Committee recommended the addition of the proposed dispersible
tablet formulations of ethambutol and isoniazid to the core list of the EMLc,
and of cycloserine, ethionamide, levofloxacin, linezolid and moxifloxacin to the
complementary list of the EMLc for the treatment of children with drug-sensitive
and drug-resistant TB.
The Committee considered that the availability of quality-assured, age-
appropriate formulations will help improve access to effective treatment for
children with TB.
The Committee also recommended the requested amendments to the
dosage form terminology for clofazimine and rifabutin.
References
1. Resolution WHA60.20. Better medicines for children. In: Sixtieth World Health Assembly,
Geneva, 14–23 May 2007. Resolutions and decisions. Geneva: World Health Organization; 2007.
Available from: http://apps.who.int/gb/ebwha/pdf_files/WHASSA_WHA60-Rec1/E/reso-60-en.
pdf, accessed 30 October 2019.
2. The selection and use of essential medicines. Report of the WHO Expert Committee, 2017
(including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of
Essential Medicines for Children) (WHO Technical Report Series, No. 1006). Geneva: World
Health Organization; 2017. Available from https://apps.who.int/iris/bitstream/handle/10665/
259481/9789241210157-eng.pdf, accessed 30 October 2019.
3. Global tuberculosis report 2018. Geneva: World Health Organization; 2018. Available from
https://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf, accessed
30 October 2019.
82
4. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World

Health Organization; 2019. Available from: https://apps.who.int/iris/bitstream/handle/10665/
5. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update.
Geneva: World Health Organization; 2017. Available from: https://apps.who.int/iris/bitstream/
handle/10665/255052/9789241550000-eng.pdf, accessed 30 October 2019).
6. Latent tuberculosis infection: Updated and consolidated guidelines for programmatic
management. Geneva: World Health Organization; 2018. Available from https://www.who.int/
tb/publications/2018/latent-tuberculosis-infection/en/, accessed 30 October 2019.
7. WHO treatment guidelines for isoniazid-resistant tuberculosis: Supplement to the WHO
treatment guidelines for drug-resistant tuberculosis. Geneva: World Health Organization; 2018.
Available from: https://apps.who.int/iris/bitstream/handle/10665/260494/9789241550079-eng.
83
Antituberculosis medicines – formulations for deletion – EML
Ethambutol + isoniazid ATC Code: J04AM03

Isoniazid + pyrazinamide + rifampicin ATC Code: J04AM05
Isoniazid + rifampicin ATC Code: J04AM02
Proposal
The application requested the removal from the EML of specific fixed-dose
combination formulations/strengths of ethambutol + isoniazid, isoniazid
+ pyrazinamide + rifampicin, and isoniazid + rifampicin based on updated
recommendations in WHO guidelines.
Applicant
WHO Global TB Programme

Global TB Programme
EML/EMLc
EML
Section

Ethambutol + isoniazid: Tablet 400 mg + 150 mg
Isoniazid + pyrazinamide + rifampicin: Tablet: 150 mg + 500 mg + 150 mg (For
intermittent use three times weekly)
Isoniazid + rifampicin: Tablet 60 mg + 60 mg and 150 mg + 150 mg (For

intermittent use three times weekly)
Core/Complementary
Core

Individual
Background
Abbreviations used for tuberculosis (TB) medicines:
H = isoniazid, R = rifampicin, Z = pyrazinamide, E = ethambutol
84

N/A

N/A

N/A

N/A
WHO Guidelines
The proposed deletions are in alignment with recommendations made in current
WHO guidelines for treatment of tuberculosis.
Ethambutol + isoniazid (= HE)
The 2010 WHO Treatment of tuberculosis guidelines (1) recommended that the
two-month rifampicin regimen, 2HRZE/6HE, should be phased out, based on
evidence that showed it to be associated with more relapses and deaths than the
six-month rifampicin regimen, 2HRZE/4HR.
Isoniazid + pyrazinamide + rifampicin/isoniazid + rifampicin
The 2017 WHO guidelines for treatment of drug-susceptible tuberculosis and
patient care (2) reviewed the effectiveness of intermittent (three times weekly)
dosing schedules of TB medicines in both the intensive and continuation phases
of treatment. Evidence showed that patients who received three times weekly
dosing had a higher risk of treatment failure, disease relapse and acquired drug
resistance than patients who received daily dosing.
N/A
Availability
N/A
Alternative strength fixed-dose formulations of isoniazid + pyrazinamide +
rifampicin and isoniazid + rifampicin remain available on the EML for use in
daily dosing regimens.
85
The Expert Committee recommended the deletion of the proposed formulations
from the core list of the EML, noting the advice of the WHO Global TB
Programme that their use is no longer recommended in current WHO guidelines
based on evidence that treatment regimens involving these formulations have
been associated with greater rates of treatment failure, relapse, mortality and
acquired drug resistance.
References
1. Treatment of tuberculosis guidelines, 4th edition. Geneva: World Health Organization; 2010.
Available from https://apps.who.int/iris/bitstream/handle/10665/44165/9789241547833_eng.pdf,
accessed 30 October 2019.
Geneva: World Health Organization; 2017. Available from https://apps.who.int/iris/bitstream/
handle/10665/255052/9789241550000-eng.pdf, accessed 30 October 2019.
86
Antituberculosis medicines – intravenous formulations for addition – EML and EMLc
Ethambutol ATC Code: J04AK02

p-aminosalicylic acid ATC Code: J04AA01
Rifampicin ATC Code: J04AB02
Proposal
Four separate applications requested addition of injectable formulations of
ethambutol, isoniazid, p-aminosalicylic acid (PAS) and rifampicin to the EML
and EMLc for treatment of drug-susceptible tuberculosis in combination with
other first-line medicines.
Applicant
INCURE CU

Comments on the applications were received from the WHO Global TB
Programme. The technical unit advised that it did not support inclusion of the
proposed IV formulations of tuberculosis (TB) medicines emphasizing the
following:
–– WHO recommends oral treatment regimens, ideally administered
in fixed-dose combinations (where such formulations exist) for
the treatment of drug-sensitive TB.
–– WHO has recently updated treatment guidelines for MDR-TB
and RR-TB, recommending that injectable agents are no longer
among the priority medicines when designing longer MDR-TB
regimens.
–– In view of these WHO policy recommendations, in the large
majority of TB patients, IV administration for first- or second-line
medicines is not indicated.
–– For the majority of indications listed in the applications for IV
formulations, patients can be treated with oral formulations, if
necessary, using alternative forms of oral administration.
–– For adult patients with drug-sensitive TB, a four-drug regimen is
recommended; therefore, with only three of the four medicines
available as intravenous formulations, patients would still be
required to take pyrazinamide orally.
87
EML/EMLc
EML and EMLc
Section

Ethambutol: injection 1000 mg and 2000 mg
Isoniazid: injection 300 mg, 500 mg and 900 mg
p-aminosalicylic acid: injection 3 g, 9 g and 12 g
Rifampicin: injection 450 mg and 600 mg
Core/Complementary
Core

Individual

Ethambutol, isoniazid, PAS and rifampicin are all currently included on the EML
and EMLc in oral dose forms.

Worldwide, tuberculosis is one of the top 10 causes of death, and the leading cause
from a single infectious agent. In 2017, TB caused an estimated 1.3 million deaths
among HIV-negative people, and there were an additional 300 000 deaths from
the disease among HIV-positive people. There were an estimated 10.0 million
new cases of TB, equivalent to 133 cases per 100 000 population (1).
The IV formulations are proposed in the applications for use in cases of

severe forms of disease, such as central nervous system (CNS) TB or TB sepsis,
patients with gastrointestinal diseases and reduced oral absorption rates, and
other patient groups unwilling or unable to take oral dose forms.
There is evidence that there is a decrease in the functional absorptive
area of the intestine in TB patients, resulting in reduced serum concentrations
of orally administered antituberculosis drugs. Patients with malabsorption
syndromes can require higher doses to achieve minimum therapeutic levels
(2, 3). Malabsorption of anti-mycobacterial drugs has been reported HIV-
coinfected patients (4, 5).
A retrospective cohort study in Brazil found that among TB patients
admitted to intensive care units (ICU), over 90% have acute respiratory failure
88
(ARF) and require mechanical ventilation. The in-hospital mortality rate for
ICU-admitted patients was around 65% (6).
CNS TB has been reported to account for 5–10% of extrapulmonary
TB cases and approximately 1% of all TB cases (7). It is associated with high
morbidity and mortality (8).
No information was provided in the applications regarding the
proportion of total TB cases that would require IV treatment.

The clinical benefits and place in therapy of these medicines (per se) are well
established and have been evaluated previously by the Expert Committee.
Limited pharmacokinetic data were presented in the applications
indicating higher achievable concentrations with IV versus oral formulations,
which is to be expected from IV administration where 100% bioavailability
is achieved.

The adverse events (AE) associated with the medicines, rather than of the
proposed IV formulations, were described in the applications. The safety profiles
of these medicines are well established and have been evaluated previously by
the Expert Committee. It is reasonable to assume that the known safety profiles
would be applicable to the IV formulations.

An RCT investigating the efficacy and safety of IV chemotherapy during the
intensive treatment phase in patients newly diagnosed with pulmonary TB was
identified during the review process (9). 92 patients were randomized to receive
oral treatment with isoniazid, rifampicin, pyrazinamide and ethambutol or
IV isoniazid, IV rifampicin, IV ethambutol and oral pyrazinamide. Alleviation
of chest symptoms (cough, dyspnoea, chest pain) and intoxication symptoms
(weakness, loss of appetite, fatigue, night sweats, increased body temperature)
was more rapid in the IV therapy group. No serious adverse events associated
with IV therapy were observed.
WHO Guidelines
WHO guidelines recommend ethambutol, isoniazid, rifampicin and PAS in
treatment regimens for drug-susceptible TB and MDR-TB/RR-TB (10, 11).
The guidelines recommend the use of oral, preferably fixed-dose
combination therapy for TB treatment.
In the WHO Target regimen profiles for TB treatment, it is recommended
that IV formulations be reserved for cases of severe forms of disease such as CNS
TB or TB sepsis (12).
89
Due to the limited availability of the proposed IV formulations on world markets,
no information on the comparative cost and cost-effectiveness of these products
are available. The applications suggest that the IV formulations will be more
expensive than the currently available oral formulations.
Availability
The proposed formulations have limited market approval and global availability:
IV ethambutol: Germany, Kazakhstan, Switzerland, Tajikistan, Ukraine and
Uzbekistan.
IV isoniazid: Italy, Kazakhstan, Ukraine, United Kingdom, United States and
Uzbekistan.
IV PAS: Belarus, Germany and Ukraine.
IV rifampicin: United States.
N/A
The Expert Committee did not recommend the addition of injectable
formulations of ethambutol, isoniazid, PAS and rifampicin to the EML and
EMLc for treatment of drug-susceptible TB in combination with other first-
line medicines.
The Committee noted that WHO guidelines recommend use of oral,
preferably fixed-dose combination therapy for TB, but acknowledged that
parenteral administration of TB medicines may be useful in a small number
of critically unwell patients unable to tolerate oral therapy or patients with TB
meningitis. The Committee considered that the inclusion of these parenteral

TB formulations on the EML could result in inappropriate use of parenteral
therapy in patients otherwise able to take oral therapy.
The Committee also noted that the global market availability of these
products was limited, and the comparative cost unknown.
References
30 October 2019.
2. Kuzhko MM, Butov DO, Hulchuk NM, Avramchuk OV, Protsyk LM, Kuzhko ZF. Clinical case of using
intravenous forms of anti-tuberculosis drugs to improve the treatment efficiency of tuberculosis
in patients with malabsorption syndrome. J Pulm Respir Med. 2015;5(269).
90
3. Frame RN, Johnson MC, Eichenhorn MS, Bower GC, Popovich J, Jr. Active tuberculosis in the
medical intensive care unit: a 15-year retrospective analysis. Crit Care Med. 1987;15(11):1012–4.
4. Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME, et al. Low
antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother. 1996;30(9):
919–25.
5. Gordon SM, Horsburgh CR, Jr., Peloquin CA, Havlik JA, Jr., Metchock B, Heifets L, et al. Low serum
levels of oral antimycobacterial agents in patients with disseminated Mycobacterium avium
complex disease. J Infect Dis. 1993;168(6):1559–62.
6. Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT. Mortality among patients with
tuberculosis requiring intensive care: a retrospective cohort study. BMC Infect Dis. 2010;10:54.
7. Cherian A, Thomas SV. Central nervous system tuberculosis. Afr Health Sci. 2011;11(1):116–27.
8. Efsen AM, Panteleev AM, Grint D, Podlekareva DN, Vassilenko A, Rakhmanova A, et al. TB
meningitis in HIV-positive patients in Europe and Argentina: clinical outcome and factors
associated with mortality. 2013;2013:373601.
9. Butov D, Feshchenko Y, Kuzhko M, Gumeniuk M, Butova T. Efficacy and safety of intravenous
chemotherapy during intensive treatment phase in patients with newly diagnosed pulmonary
tuberculosis. Adv Respir Med. 2018; 86(4):159-167.
Geneva: World Health Organization; 2017. Available from https://apps.who.int/iris/bitstream/ha
ndle/10665/255052/9789241550000-eng.pdf, accessed 30 October 2019.
11. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health
Organization; 2019. Available from https://apps.who.int/iris/bitstream/handle/10665/311389/
9789241550529-eng.pdf, accessed 30 October 2019.
12. World Health Organization. Target regimen profiles for TB treatment: candidates: rifampicin-
susceptible, rifampici-resistant and pan-TB treatment regimens. 2016. Geneva, World
Health Organization. Available from https://apps.who.int/iris/bitstream/handle/10665/250044/
91
Bedaquiline – addition – EMLc
Bedaquiline ATC Code: J04AK05
Proposal
The application requested the addition of bedaquiline to the complementary list
of the EMLc as a reserve second-line medicine for the treatment of multidrug-
resistant tuberculosis (MDR-TB) in children aged 6 years and older.
Applicant

Global TB Programme
EML/EMLc
EMLc
Section

Tablet 100 mg
Core/Complementary
Complementary

Individual

In 2015, bedaquiline was included on the complementary list of the EML as a
reserve second-line medicine for treatment of MDR-TB in adults (1).

It is estimated that of the 10 million people who developed TB in 2017, 1 million
of them were children. Children aged <15 years accounted for 7.1% of the
6.4 million new or relapsed cases of TB notified to national TB programmes
and reported to WHO. Children aged <15 years accounted for 15% and 10%
of total TB deaths among HIV-negative and HIV-positive people, respectively –
92
higher than their share of estimated cases, suggesting poorer access to diagnosis
and treatment. In 2017, it was estimated that about 558,000 new MDR-TB/
RR‑TB cases emerged and about 230,000 MDR-TB/RR‐TB patients died (2).
The contribution of bedaquiline to MDR‐TB regimens is crucial to
compose regimens, particularly in frequent situations in which other effective
and safe medicines are not available. In a substantial proportion of MDR-TB/RR‐
TB patients the susceptibility to fluoroquinolones is lost and other TB medicines
cannot be given because of safety concerns. Reports of sporadic cases and
outbreaks of MDR-TB and XDR-TB among patients not previously treated for
TB attests to the transmissibility of such strains, an additional public health
concern, making the provision of effective treatment for all M/XDR‐TB patients
very important. The likelihood of treatment success in MDR‐TB patients
diminishes with the acquisition of additional drug resistance. Bedaquiline can
increase the prospects of lasting cure in these patients.
The WHO Global TB Programme considers that bedaquiline should also
be viewed as an essential medicine in children aged 6 years and older following
the update by WHO of its treatment recommendations for adults and children
with MDR-TB/RR‐TB in December 2018 (3).

As part of the WHO guideline development process, a meta-analysis of individual
patient data with 13 104 records from 53 studies in 40 countries was used to
evaluate treatment success of bedaquiline. This dataset was largely composed of
adult patients, with only 181 of the 13 104 (1.4%) cases being under 15 years
of age.
Paediatric data for bedaquiline were reviewed to explore the extent to
which adult data could be extrapolated to children. The focus of this review
was on safety and pharmacologic exposure data available from two ongoing
paediatric studies of bedaquiline: TMC207‐C211 and IMPAACT P1108 (4).
Assuming that bedaquiline exposure-response (efficacy) profiles could be
extrapolated from adults to children, the WHO Guideline Development Group
concluded that the bedaquiline doses evaluated in the trials did not appear to
produce bedaquiline exposures that would put children aged 6 to 17 years at
greater risk of therapeutic failure.

With regard to harms, the Guideline Development Group concluded that the
safety risk of bedaquiline in children aged 6 years and older did not appear to
exceed that observed in adults. However, it was noted that children included in
the trials were all HIV negative and had limited exposure to other QT-interval
prolonging medicines (4).
93

N/A
WHO Guidelines
The 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment
(3) make the following recommendation with regard to bedaquiline:
“Bedaquiline should be included in longer MDR-TB regimens for
patients aged 18 years or more (strong recommendation, moderate certainty in
the estimates of effect). Bedaquiline may also be included in longer MDR-TB
regimens for patients aged 6–17 years (conditional recommendation, very low
certainty in the estimates of effect).”
The updated guidelines include a weight-based dosage regimen for
children 6–17 years:
15–29 kg: 2 x 100 mg tablets once daily for two weeks, then 1 x 100 mg tablet once
daily on Monday, Wednesday and Friday for 22 weeks;
>29 kg: 4 x 100 mg tablets once daily for 2 weeks then 1 x 100 mg tablets once
daily on Monday, Wednesday and Friday for 22 weeks (equivalent to the adult
dose).
Bedaquiline is available via the Global Drug Facility (GDF), at a price of US$ 400
for a 6-month course of adult treatment (5). There is a marked differential in
the price of bedaquiline between HICs and countries eligible for concessional
pricing through the GDF. Prices for a 6-month course of adult treatment have
been reported as EUR 26 481 in Italy (6), £ 18 880 in the United Kingdom (7) and
US$ 26 500 in the Republic of Korea (8).
Availability
Bedaquiline is manufactured by Janssen Pharmaceuticals. It is available to eligible

countries through the GDF.
The Committee recalled that bedaquiline is associated with an increased risk of
QT interval prolongation, which may be further increased when bedaquiline is
administered with other medicines that prolong the QT interval. The Committee
also noted the potential for drug–drug interactions between bedaquiline and
other commonly co-prescribed medicines. These factors should be taken into
consideration when bedaquiline is prescribed.
94
The Expert Committee recommended the addition of bedaquiline to the
complementary list of the EMLc for the treatment of MDR-TB in children
aged 6 years and older, in line with updated WHO treatment guidelines. The
Committee noted that the extrapolation of evidence from adult data to children
suggested therapeutic bedaquiline exposure in children and no increased
safety risk.
References
(including the 19th WHO Model List of Essential Medicines and the 5rd WHO Model List of
Essential Medicines for Children) (WHO Technical Report Series, No. 994). Geneva: World Health
9789241209946_eng.pdf, accessed 30 October 2019.
30 October 2019.
4. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Annexes 3–9. Geneva:
World Health Organization; 2019. Available from https://apps.who.int/iris/bitstream/handle/
10665/311389/9789241550529-eng.pdf, accessed 30 October 2019.
5. Stop TB Partnership - Global Drug Facility (GDF) - GDF Products List [website]. (http://www.
stoptb.org/gdf/drugsupply/bedaquiline.asp, accessed 22 February 2019).
6. Codecasa LR, Toumi M, D’Ausilio A, Aiello A, Damele F, Termini R, et al. Cost-effectiveness of
bedaquiline in MDR and XDR tuberculosis in Italy. J Mark Access Health Policy. 2017;5(1):1283105.
7. Wolfson LJ, Walker A, Hettle R, Lu X, Kambili C, Murungi A, et al. Cost-effectiveness of adding
bedaquiline to drug regimens for the treatment of multidrug-resistant tuberculosis in the UK.
PLoS One. 2015;10(3):e0120763.
8. Park HY, Ku HM, Sohn HS, Seo HS, Yung Lee H, Hwa Lim K, et al. Cost-effectiveness of Bedaquiline
for the Treatment of Multidrug-resistant Tuberculosis in the Republic of Korea. Clin Ther.
2016;38(3):655-67.e1–2.
95
Capreomycin and kanamycin – deletion – EML and EMLc
Capreomycin ATC Code: J04AB30

Kanamycin ATC Code: J01GB04
Proposal
The application requested the removal from the EML and EMLc of capreomycin
and kanamycin for use in treatment regimens for multidrug-resistant tuberculosis
(MDR-TB).
Applicant

Global TB Programme
EML/EMLc
EML and EMLc
Section

Capreomycin: Powder for injection 1 g (as sulfate) in vial
Kanamycin: Powder for injection 1 g (as sulfate) in vial
Core/Complementary
Complementary

Individual
Background
N/A

N/A

N/A
96

N/A

N/A
WHO Guidelines
The proposed deletions are in alignment with recommendations in the 2019
update of the WHO consolidated guidelines on drug-resistant tuberculosis treatment
(1). One of the key outcomes of the updated guidelines was a re‑classification of
medicines recommended for inclusion in regimens for MDR-TB/RR-TB.
Capreomycin and kanamycin had previously been recommended as
Group B, second-line injectable agents along with amikacin and streptomycin
(2). The 2019 guidelines no longer recommend the use of capreomycin and
kanamycin as treatment options. Use of capreomycin and kanamycin was
associated with poorer outcomes when compared with regimens not containing
these medicines in the latest data analysis.
N/A
Availability
N/A
Amikacin and streptomycin remain available on the Model List for use in
treatment regimens for drug-resistant TB.
The Expert Committee recommended the deletion of capreomycin and
kanamycin from the complementary list of the EML and EMLc, noting the advice
of the WHO Global TB Programme that their use is no longer recommended
in WHO guidelines due to evidence that regimens involving these agents were
associated with worse outcomes compared with regimens that did not include
them, and that fully oral regimens should be preferred for most patients.
References
97
2. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update (WHO/HTM/TB/2016.4).

Geneva,World Health Organization. 2016. Available from https://apps.who.int/iris/bitstream/
handle/10665/250125/9789241549639-eng.pdf, accessed 30 October 2019.
98
Delamanid – change age restriction – EMLc
Delamanid ATC Code: J04AK06
Proposal
The application requested a change to the age restriction that applies to the listing
of delamanid on the Model Lists.
Applicant

Global TB Programme
EML/EMLc
EML and EMLc
Section

Tablet 50 mg
Core/Complementary
Complementary

Individual

In 2017, delamanid was added to the EMLc as a reserve second-line drug for
multidrug-resistant tuberculosis (MDR-TB) in children aged 6–17 years. The
current Model Lists include an age limit for delamanid of >6 years.

N/A

As part of the MDR-TB guideline development process, paediatric data
for delamanid were reviewed to examine whether the recommendations for
delamanid use in children could be lowered to children under 6 years of age.
99
Safety and pharmacologic exposure data were available from ongoing paediatric
studies (1). The WHO Guideline Development Group (GDG) concluded that
based on the pharmacokinetic data, exposure profiles in children aged 3 to
5 years were comparable to adults and no higher than in children aged 6 and
older. From the available data, there were no safety signals distinct from those
reported in adults observed in children aged three to five years. The GDG
concluded that extrapolations of efficacy and safety should be restricted to
children 3 years of age and older.

N/A

Children aged 3 to 5 years in the trials were administered delamanid at a dose of
25 mg twice daily, using a scored, dispersible paediatric formulation that is not
currently available.
The only source of delamanid is the 50 mg adult formulation which
poses potential problems when considered for children under 6 years of age.
The adult and paediatric formulations of delamanid are not bioequivalent
or interchangeable. Equal doses of each formulation achieve different
concentrations in the body. Substituting the adult formulation for the paediatric
formulation will result in higher delamanid exposures than would be expected
from the paediatric formulation.
In addition, splitting or crushing of the adult tablet for administration
to children will affect the stability of the medicine and result in pill fragments
that are exceedingly bitter.
WHO Guidelines
(2) make the following recommendation with regard to delamanid: “Delamanid

may be included in the treatment of MDR-TB/RR-TB patients aged 3 years or
more on longer regimens (conditional recommendation, moderate certainty in
the estimates of effect.”
No information provided.
Availability
Delamanid 50 mg tablets are manufactured by Otsuka Pharmaceutical, Japan.
They are available to eligible countries through the Global Drug Facility. The
25 mg paediatric dispersible tablet formulation is not currently commercially
available.
100
N/A
The Expert Committee did not recommend the requested change to the age
restriction that applies to the listing of delamanid on the Model Lists. The
Committee noted that pharmacokinetic data used to inform the guideline
development process used a different formulation of delamanid to that currently
included on the Model Lists, which is not commercially available at this time, nor
has it been demonstrated to be bioequivalent to the available, listed formulation.
References
1. WHO consolidated guidelines on drug-resistant tuberculosis treatment (Annexes 3–9). Geneva:
10665/311390/WHO-CDS-TB-2019.3-eng.pdf, accessed 30 October 2019.
101
Group C antibiotics for MDR-TB – new indication – EML and EMLc
Group C antibiotics for MDR-TB

Amoxicillin + clavulanic acid ATC Code: J01CR02
Imipenem + cilastatin ATC Code: J01DH51
Meropenem ATC Code: J01CR02
Proposal
The application requested listing on the complementary list for the new indication
of treatment of multidrug-resistant tuberculosis (MDR-TB) of:
–– amoxicillin + clavulanic acid (EML and EMLc)
–– imipenem + cilastatin; (EML only) and
–– meropenem (EML and EMLc)
Applicant

Global TB Programme
EML/EMLc
EML and EMLc
(EML only for imipenem + cilastatin)
Section

Amoxicillin + clavulanic acid:
–– tablet: 500 mg (as trihydrate) + 125 mg (as potassium salt);
–– powder for oral liquid: 125 mg + 31.25 mg per 5 mL; 250 mg +
62.5 mg per 5 mL
Imipenem + cilastatin:
–– powder for injection: 250 mg (as monohydrate) + 250 mg (as
sodium salt); 500 mg (as monohydrate) + 500 mg (as sodium
salt) in vial
Meropenem:
–– powder for injection 500 mg; 1 g (anhydrous) in vial
102
Core/Complementary
Complementary

Individual

These medicines have not been previously considered for use in MDR-TB.
Amoxicillin + clavulanic acid and meropenem are currently included in the
EML and EMLc for use as first- and second-choice treatment of specified
infectious syndromes. Imipenem + cilastatin is noted as an acceptable alternative
to meropenem for most clinical situations. Amoxicillin + clavulanic acid is
classified as an AWaRe Access group antibiotic, while meropenem (and other
carbapenems) are categorized as AWaRe Watch group antibiotics.

It is estimated that 558 000 new MDR-/RR-TB cases emerged in the world in
2017 and 230 000 patients died of this form of tuberculosis (1). Between 25 000
and 32 000 children are estimated to develop MDR-TB each year (2). Many of
these cases go undetected and are not placed on appropriate treatment, increasing
the risk of transmission of drug-resistant strains and death. In 2017, countries
reported that about 139 000 people started MDR-TB treatment worldwide. The
effectiveness of these efforts varies considerably, and data reported for treatment
outcomes in recent years show that only about half the MDR-/RR-TB patients
complete their treatment successfully. Among patients with XDR-TB the
likelihood of successful outcomes is even lower. Patients who are not cured –
often because their treatment fails or is interrupted – risk persistent disease or
death. Given these low levels of treatment success, all efforts must be made to
ensure that effective medications to treat drug-resistant TB become more widely
available to the patients who need them, particularly in low-resource settings
that carry the largest burden of MDR-/RR-TB (1).
The most recent data analysis conducted for the 2018 WHO MDR-TB
treatment guidelines revision attests to the effectiveness of the carbapenems
– imipenem + cilastatin and meropenem – in patients for whom other agents
cannot be used to compose an adequate regimen, such as those with strains
resistant to fluoroquinolones or who develop drug intolerance (3).

A typical longer MDR-TB regimen starts with a combination of at least four TB
medicines considered to be effective, primarily from Groups A and B (Table 1).
The three proposed medications have a particular role in the composition of
103
longer treatment regimens for patients with MDR-/RR-TB, particularly those

who have additional resistance or intolerance to one or more of the agents
in Groups A and B. In such cases, the regimen is strengthened by Group C
agents. Both carbapenems in this application belong to Group C and must
be administered with clavulanic acid, which is only available in formulations
combined with amoxicillin. Amoxicillin + clavulanic acid is not considered
an additional effective TB agent, and should not be used without imipenem +
cilastatin or meropenem.
Table 1
Grouping of medicines recommended for use in longer MDR-TB regimens (3)
Groups Medicine
Group A Levofloxacin or moxifloxacin
Bedaquiline
Linezolid
Group B Clofazimine
Cycloserine or terizidone
Group C Ethambutol
Delamanid
Pyrazinamide
Imipenem + cilastatin or meropenem
Amikacin (or streptomycin)
Ethionamide or prothionamide
p-aminosalicylic acid
Mycobacterium tuberculosis (MTB) is resistant to most beta-lactam antibiotics

because it contains the gene blaC, which encodes an extended spectrum beta-
lactamase (4). BlaC beta-lactamase is only transiently inhibited by most beta-
lactamase inhibitors (i.e. sulbactam and tazobactam) except for clavulanic acid,
which irreversibly inhibits it (4, 5). The use of amoxicillin + clavulanic acid against
MTB has had mixed results. Of note, clavulanic acid is not available commercially
without amoxicillin. An early bactericidal activity (EBA) study from South Africa
showed no benefit of amoxicillin + clavulanic acid over the control (6). A study
from Pakistan examining the minimum inhibitory concentration (MIC) of drug-
resistant clinical isolates of MTB found that 98% of the isolates were resistant to
amoxicillin + clavulanic acid (7). Another EBA study showed that over 7 days,
104
amoxicillin + clavulanic acid reduced the sputum colony-forming units (CFU) by

an average of 0.1 log10 cfu/mL per day (in comparison, isoniazid reduced CFU
by 0.27 log10 cfu/mL per day) (8). However, the mild efficacy of amoxicillin +
clavulanic acid may not be shared by all the beta-lactam antibiotics. Meropenem is
hydrolyzed five times slower than amoxicillin + clavulanic acid by blaC (4, 5) and
there have been several studies evaluating its activity (combined with clavulanic
acid) against MTB (9). In vitro studies have shown that the combination of
clavulanic acid improves the MIC of meropenem from 8 to 1 μg/mL (10), that
this combination sterilizes aerobic and anaerobic MTB cultures and was active
against drug susceptible and XDR-TB strains (5). Results have been mixed with
respect to the effect of meropenem + clavulanic acid on mouse mortality and
on MTB CFUs in the lung and spleen (10–13). The combination of imipenem +
cilastatin with clavulanic acid also has activity against MTB, although in some
studies meropenem + clavulanic acid seems to be superior (5).
Human data are sparse (case-control studies, case reports) (11, 14), but
meropenem with clavulanic acid as part of regimens (usually also containing
linezolid) for patients with MDR-TB and XDR-TB has shown improved culture
conversion and survival (15–17).
The updated WHO guidelines reported the relative and absolute
effects for treatment failure or relapse and death (versus treatment success) for
medicines used in longer regimens from the main IPD-MA dataset of 13 104
records from 53 studies in 40 countries (3, 18).
For imipenem + cilastatin or meropenem, the adjusted odds ratio for
treatment failure/relapse versus treatment success was 0.4 (95%CI 0.2 to 0.7)
(n=206). In absolute terms, 11 fewer (95%CI 19 to 3 fewer) treatment failures/
relapses per 100 patients treated (very low certainty evidence). For death versus
treatment success the adjusted OR was 0.2 (95%CI 0.1 to 0.5) (n=204). In
absolute terms, 18 fewer (95%CI 27 to 8 fewer) deaths per 100 patients treated
(very low certainty evidence).

Evidence for the safety of these medicines has been considered previously. The
common and uncommon adverse effects associated with these medicines are
well known.

N/A
WHO Guidelines
(3) include the following recommendations regarding longer treatment regimens
for MDR-/RR-TB:
105
■■ In MDR-/RR-TB patients on longer regimens, all three Group A

agents and at least one Group B agent should be included to ensure
that treatment starts with at least four TB agents likely to be effective,
and that at least three agents are included for the rest of treatment
after bedaquiline is stopped. If only one or two Group A agents are
used, both Group B agents are to be included. If the regimen cannot
be composed with agents from Groups A and B alone, Group C
agents are added to complete it (conditional recommendation, very
low certainty in the estimates of effect).
■■ Imipenem + cilastatin or meropenem may be included in the
treatment of MDR-/RR-TB patients on longer regimens (conditional
recommendation, very low certainty in the estimates of effect).
Reported costs from the Global Drug Facility product catalogue (19) are:
Imipenem + cilastatin 500 mg + 500 mg powder for injection: US$ 31–36/10 vials
Meropenem 1 g powder for injection: US$ 3.70/vial
Amoxicillin + clavulanic acid 500 mg + 125 mg tablets: US$ 10.21–13.28/
100 tablets
Amoxicillin + clavulanic acid 125 mg/31.25 mg oral suspension: US$ 1.21/bottle
Availability
The proposed medicines are widely available globally and already included for
other indication on the EML and EMLc.
N/A
The Expert Committee recommended the inclusion of meropenem and of
amoxicillin + clavulanic acid on the complementary list of the EML and EMLc
for the new indication of use in the treatment of MDR-TB. The Committee
recommended that imipenem could be considered as an alternative to meropenem
for use in adults, and that the EML should note this accordingly.
The Committee noted the limited clinical evidence base, and the
very low certainty in the estimates of effect associated with the carbapenems
in MDR‑TB treatment regimens. However, the Committee accepted the public
health need for effective treatments for MDR-TB and considered that the
updated WHO guideline recommendations would be supported by the inclusion
of these medicines on the EML.
106
The Committee expressed some concern in relation to increased use

of carbapenem antibiotics in the empiric treatment of MDR-TB and the
development of carbapenem resistance, and recommended that ongoing
monitoring for the development of resistance be undertaken.
References
30 October 2019.
2. Jenkins HE, Yuen CM. The burden of multidrug-resistant tuberculosis in children. Int J Tuberc
Lung Dis. 2018;22(5):3–6.
9789241550529-eng.pdf, accessed 26 September 2019.
4. Hugonnet JE, Blanchard JS. Irreversible inhibition of the Mycobacterium tuberculosis beta-
lactamase by clavulanate. Biochemistry. 2007;46(43):11998–2004.
5. Hugonnet JE, Tremblay LW, Boshoff HI, Barry CE, 3rd, Blanchard JS. Meropenem-clavulanate
is effective against extensively drug-resistant Mycobacterium tuberculosis. Science. 2009;
323(5918):1215–8.
6. Donald PR, Sirgel FA, Venter A, Parkin DP, Van de Wal BW, Barendse A et al. Early bactericidal
activity of amoxicillin in combination with clavulanic acid in patients with sputum smear-
positive pulmonary tuberculosis. Scand J Infect Dis. 2001;33(6):466–9.
7. Ahmed I, Jabeen K, Inayat R, Hasan R. Susceptibility testing of extensively drug-resistant and
pre-extensively drug-resistant Mycobacterium tuberculosis against levofloxacin, linezolid, and
amoxicillin-clavulanate. Antimicrob Agents Chemother. 2013;57(6):2522–5.
8. Chambers HF, Kocagoz T, Sipit T, Turner J, Hopewell PC. Activity of amoxicillin/clavulanate in
patients with tuberculosis. Clin Infect Dis. 1998;26(4):874–7.
9. Gonzalo X, Drobniewski F. Is there a place for beta-lactams in the treatment of multidrug-
resistant/extensively drug-resistant tuberculosis? Synergy between meropenem and amoxicillin/
clavulanate. J Antimicrob Chemother. 2013;68(2):366–9.
10. Solapure S, Dinesh N, Shandil R, Ramachandran V, Sharma S, Bhattacharjee D et al. In vitro
and in vivo efficacy of beta-lactams against replicating and slowly growing/nonreplicating
Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013;57(6):2506–10.
11. Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC. Imipenem for treatment of
tuberculosis in mice and humans. Antimicrob Agents Chemother. 2005;49(7):2816–21.
12. Veziris N, Truffot C, Mainardi JL, Jarlier V. Activity of carbapenems combined with clavulanate
against murine tuberculosis. Antimicrob Agents Chemother. 2011;55(6):2597–600.
13. England K, Boshoff HI, Arora K, Weiner D, Dayao E, Schimel D, et al. Meropenem-clavulanic acid
shows activity against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother.
2012;56(6):3384–7.
14. Dooley KE, Obuku EA, Durakovic N, Belitsky V, Mitnick C, Nuermberger EL. World Health
Organization group 5 drugs for the treatment of drug-resistant tuberculosis: unclear efficacy or
untapped potential? J Infect Dis. 2013;207(9):1352–8.
107
15. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S et al. Efficacy and safety
of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/
XDR-TB. Eur Respir J. 2013;41(6):1386–92.
16. Payen MC, De Wit S, Martin C, Sergysels R, Muylle I, Van Laethem Y et al. Clinical use of the
meropenem-clavulanate combination for extensively drug-resistant tuberculosis. Int J Tuberc
Lung Dis. 2012;16(4):558–60.
17. Dauby N, Muylle I, Mouchet F, Sergysels R, Payen MC. Meropenem/clavulanate and linezolid
treatment for extensively drug-resistant tuberculosis. Pediatr Infect Dis J. 2011;30(9):812–3.
18. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Annexes 3–9. Geneva:
10665/311390/WHO-CDS-TB-2019.3-eng.pdf, accessed 30 October 2019.
18. Stop TB Partnership | Global Drug Facility (GDF) – GDF Product Catalogue [website]. [cited
2017 Jul 7]. (http://www.stoptb.org/gdf/drugsupply/pc2.asp?CLevel=2&CParent=4, accessed
26 September 2019).
108
Isoniazid – new formulation (oral liquid) – EMLc
Proposal
The application requested addition of a new strength formulation of isoniazid
oral liquid to the core list of the EMLc for treatment and preventive therapy of
tuberculosis (TB) in infants and children.
Applicant
INCURE CU

Comments on the application were received from the WHO Global TB
Programme. The technical unit highlighted the current WHO recommendations
and available alternative treatment options for latent tuberculosis infection
(LTBI) and advised that the addition to the EMLc of the proposed new strength
oral liquid formulation of isoniazid may not add value.
EML/EMLc
EMLc
Section

Oral liquid 100 mg/5 mL
Core/Complementary
Core

Individual

Isoniazid oral liquid 50 mg/5 mL has been included on the EMLc since 2007.
Solid oral dose forms of isoniazid have been included on the EML since 1977.
The recommended dose for isoniazid in children for treatment of TB or
isoniazid preventive treatment (IPT) is 10 mg/kg per day (range 7–15 mg/kg);
maximum dose 300 mg/day (1).
109

About 1.7 billion people globally are estimated to have a latent TB infection, and
are thus at risk of developing active TB disease during their lifetime (2).
IPT for LTBI is indicated for an asymptomatic contact or a contact in
whom TB disease has been excluded if the contact is less than 5 years of age
or who is living with HIV (regardless of age). Preventive therapy for young
children with LTBI who have not yet developed TB disease will greatly reduce
the likelihood of TB disease developing during childhood (3).
Six months’ daily monotherapy with isoniazid is the standard treatment
for both adults and children living in countries with either high or low TB
incidence (4).

Several systematic reviews have demonstrated the preventive efficacy of isoniazid
monotherapy. A systematic review of RCTs involving people living with HIV
showed that isoniazid monotherapy reduces the overall risk for TB by 33% (RR
0.67; 95%CI 0.51 to 0.87), and the preventive efficacy reached 64% for people
with a positive TST (RR 0.36; 95%CI 0.22 to 0.61). Furthermore, the efficacy
of the 6-month regimen was not significantly different from that of 12 months’
daily isoniazid monotherapy (RR 0.58; 95%CI 0.3 to 1.12) (5).
A recent systematic review of RCTs also showed a significantly greater
reduction in TB incidence among participants given the 6-month regimen than
in those given a placebo (odds ratio (OR), 0.65; 95%CI 0.50 to 0.83) (6).
This application requested only the addition of a new strength
formulation of isoniazid oral liquid.

The safety profile of isoniazid is well known. Evidence for the safety of isoniazid
was evaluated at the time of original listing.

N/A
WHO Guidelines
The 2018 WHO guidelines for programmatic management of latent tuberculosis
(4) make the following recommendations regarding TB preventive therapy
in children:
–– Infants aged <12 months living with HIV who are in contact with
a case of TB and are investigated for TB should receive six months
of isoniazid preventive treatment (IPT) if the investigation shows
110
no TB disease (Strong recommendation, moderate quality evidence.

Updated recommendation).
–– Children aged >12 months living with HIV who are considered
unlikely to have TB disease on the basis of screening for symptoms
and who have no contact with a case of TB should be offered
six months of IPT as part of a comprehensive package of HIV
prevention and care if they live in a setting with a high prevalence
of TB (Strong recommendation, low quality evidence. Existing
recommendation).
–– All children living with HIV who have successfully completed
treatment for TB disease may receive isoniazid for an additional
six months (Conditional recommendation, low quality evidence.
Existing recommendation).
–– HIV-negative children aged under 5 years who are household
contacts of people with bacteriologically confirmed pulmonary TB
and who are found not to have active TB on an appropriate clinical
evaluation or according to national guidelines should be given
TB preventive treatment (Strong recommendation, high quality
evidence. Updated recommendation).
–– In countries with a low TB incidence, adults, adolescents
and children who are household contacts of people with
bacteriologically confirmed pulmonary TB should be
systematically tested and treated for LTBI (Strong recommendation,
high to moderate quality evidence. Existing recommendation).
–– In countries with a high TB incidence, children aged under
5 years, adolescents and adults who are household contacts of
people with bacteriologically confirmed pulmonary TB who are
found not to have active TB by an appropriate clinical evaluation
or according to national guidelines may be given TB preventive
treatment (Conditional recommendation, low quality evidence.
New recommendation).
No information was provided in the application regarding the cost of this product.
Availability
The application stated that the product is available in Azerbaijan, Georgia,
Kazakhstan, Kenya, Kyrgyzstan, Moldova, Namibia, Tajikistan, Turkmenistan,
Uganda, Ukraine and Uzbekistan.
111
No information was provided on the regulatory status of this product. It

does not appear to have current regulatory approval from a stringent regulatory
authority (SRA).
Isoniazid oral liquid (any strength) is not currently included in the Stop
TB Partnership/Global Drug Facility medicine catalogue.
The application stated that the currently available 50 mg/mL oral liquid
formulation is not available in many countries, and is less convenient than
the proposed strength formulation, requiring a greater volume to deliver the
prescribed dose.
The application stated that dispersible tablet formulations have limitations
insofar as they cannot always meet weight-based dosing requirements as they
cannot be divided.
A separate application from the Stop TB Partnership/Global Drug Facility
requested listing of isoniazid 100 mg dispersible tablet. Unlike isoniazid oral
liquid, quality-assured isoniazid dispersible tablet products are available through
the GDF.
The Expert Committee did not recommend the addition of a new strength
formulation of isoniazid oral liquid to the core list of the EMLc for treatment
and preventive therapy of tuberculosis in infants and children. The Committee
considered that quality-assured dispersible tablet formulations of TB medicines
represent a preferred treatment option to oral liquid formulations. The Committee
considered that an additional strength oral liquid formulation of isoniazid would
be unlikely to add value to patients or TB treatment programmes.
In addition, with the separate recommendation made at this meeting
to add isoniazid 100 mg dispersible tablets to the EMLc, the Committee
recommended that the existing isoniazid oral liquid formulation (50 mg/mL)
could be considered for removal from the EMLc in 2021.
References
1. Guidance for national tuberculosis programmes on the management of tuberculosis in children.
2nd edition. Geneva: World Health Organization; 2014. Available from https://www.who.int/tb/
publications/childtb_guidelines/en/, accessed 30 October 2019.
30 October 2019.
3. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV
infected persons. Cochrane Database Syst Rev. 2000(2):CD001363.
112
4. Latent tuberculosis infection: updated and consolidated guidelines for programmatic

management. Geneva: World Health Organization; 2018.
5. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV
infected persons. Cochrane Database Syst Rev. 2010(1):CD000171.
6. Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ. Treatment of Latent
Tuberculosis Infection: An Updated Network Meta-analysis. Ann Intern Med. 2017;167(4):248–55.
113
6.4 Antiviral medicines

6.4.2 Antiretrovirals
Antiretrovirals – formulations for deletion – EML and EMLc
ARV formulations for deletion ATC Code: various
Proposal
The application requested the deletion of various antiretroviral (ARV)
formulations from the core list of the EML and EMLc.
Applicant
WHO HIV Department

HIV Department
EML/EMLc
EML and EMLc
Section

Zidovudine: tablet (dispersible, scored) 60 mg
Abacavir + lamivudine: tablet (dispersible, scored) 60 mg (as sulfate) + 30 mg
Ritonavir: oral liquid 400 mg/5 mL
Raltegravir: tablet (chewable) 100 mg
Core/Complementary
Core

Individual

Separate applications to the 2019 Expert Committee requested the inclusion
of new formulations of ritonavir (oral powder 100 mg) and raltegravir (oral
granules 100 mg).
114

N/A

Recommendations were made by the WHO HIV Department to delete the
antiretroviral formulations from the EML and EMLc in order to achieve
alignment between the 2018 WHO interim guidelines for antiretroviral regimens
(1), and The 2018 optimal formulary and limited-use list for paediatric ARVs (2).
Zidovudine (AZT) 60 mg dispersible scored tablet was removed from
the latest limited-use list. Zidovudine 60 mg is available in dual fixed-dose
combination formulations with lamivudine that can be combined with an
abacavir 60 mg dispersible scored tablet to deliver a triple nucleoside regimen
during TB treatment.
Abacavir + lamivudine (ABC/3TC) 60 mg + 30 mg dispersible scored
tablet was removed from the latest optimal formulary. It has been replaced
with ABC/3TC 120 mg + 60 mg dispersible scored tablet to minimize market
fragmentation while decreasing pill burden for older children. The double
strength formulation was included on the EML and EMLc in 2017.
Ritonavir oral liquid 400 mg/5 mL was removed from the latest limited-
use List. Cold chain requirements, poor palatability and short shelf-life has
limited use of this product. Alternative formulations of ritonavir are preferred.
Raltegravir 100 mg scored chewable tablets were replaced by the 25 mg
strength on the latest optimal formulary in order to optimize dosing flexibility
to provide raltegravir-based regimens across all weight bands for first- and
second-line treatment.

N/A

N/A
WHO Guidelines
The proposed deletions are in alignment with recommendations in the 2018
WHO guidelines and paediatric ARV formulary.
N/A
Availability
N/A
115
–– Zidovudine oral solution 50 mg/5 mL remains included on the
Model Lists for postnatal prophylaxis or neonatal use.
–– Zidovudine in fixed-dose combination with nevirapine and/or
lamivudine remains included on the Model Lists.
–– Abacavir + lamivudine 120 mg + 60 mg scored dispersible tablets
remain included on the Model Lists.
–– Ritonavir heat-stable tablets 25 mg and 100 mg remain included
on the Model Lists. A separate recommendation was made at this
meeting to add ritonavir 100 mg oral powder.
–– Raltegravir tablets 400 mg and chewable tablets 25 mg remain
included on the Model Lists. A separate recommendation was
made at this meeting to add raltegravir 100 mg oral granules.
The Committee recommended deletion of zidovudine 60 mg dispersible scored
tablet and of abacavir + lamivudine 60 mg + 30 mg dispersible scored tablet from
the EML and EMLc, noting they are no longer included in the current WHO
guidelines for paediatric HIV treatment, and that suitable alternatives are already
included on the Model Lists and available for use.
The Committee recommended that ritonavir oral liquid and raltegravir
100 mg chewable tablets be retained on the Model Lists at this time. The
Committee considered that until the availability is well established of
the alternative formulations of these medicines recommended in separate
applications to this meeting, (i.e. ritonavir 100 mg oral powder and raltegravir
100 mg oral granules), deletion of the existing formulations could be premature.
The existing formulations could be flagged for deletion without further
discussion in 2021 unless an application is received in support of their retention.
The Committee recommended deletion of zidovudine 60 mg dispersible scored
tablet and of abacavir + lamivudine 60 mg + 30 mg dispersible scored tablet
from the EML and EMLc, noting they are no longer included in the current
WHO guidelines for paediatric HIV treatment, and that suitable alternatives are
already included on the Model Lists and available for use.
The Committee recommended that ritonavir oral liquid and raltegravir
100 mg chewable tablets be retained on the Model Lists at this time. The
Committee considered that until the availability is well established of the
alternative formulations of these medicines recommended in separate
116
applications to this meeting, (i.e. ritonavir 100 mg oral powder and raltegravir
100 mg oral granules), deletion of the existing formulations could be premature.
The existing formulations could be flagged for deletion without further
discussion in 2021 unless an application is received in support of their retention.
References
1. Updated recommendations on first-line and second-line antiretroviral regimens and post-
exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines,
supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and
preventing HIV infection. World Health Organization, Geneva. December, 2018. Available from
https://apps.who.int/iris/bitstream/handle/10665/277395/WHO-CDS-HIV-18.51-eng.pdf?ua=1,
accessed 26 September 2019.
2. The 2018 optimal formulary and limited-use list for paediatric ARVs. Geneva, Switzerland: World
Health Organization; 2018. Available from http://apps.who.int/iris/bitstream/handle/10665/
273153/WHO-CDS-HIV-18.15-eng.pdf?ua=1, accessed 26 September 2019.
117
6.4.2.3 Protease inhibitors

Ritonavir – new formulation – EML and EMLc
Ritonavir ATC Code: J05AE03
Proposal
The application requested the addition of a new formulation of ritonavir (RTV)
to the core list of the EML and EMLc for the treatment of HIV infection.
Applicant
WHO HIV Department

HIV Department
EML/EMLc
EML and EMLc
Section

Oral powder 100 mg in sachet
Core/Complementary
Core

Individual

Single-agent ritonavir (RTV) has been included on the EMLc since 2007.
Currently listed formulations are oral liquid 400 mg/5 mL and heat-stable tablets
25 mg and 100 mg.
In a separate application to the 2019 Expert Committee, ritonavir oral
liquid was proposed for deletion from the EML and EMLc.

Despite an impressive reduction in mother-to-child transmission of HIV in
recent years, 180 000 new paediatric infections occurred in 2017. There are now
1.8 million children living with HIV, the vast majority in sub-Saharan Africa (1).
118
Evidence shows that in the absence of antiretroviral therapy (ART), over 50%
of HIV-infected infants progress to AIDS and death by the age of 2 years (2),
but the introduction of paediatric ART has changed HIV infection in children
from a life-threatening illness to a chronic but manageable infection. Despite
recognition of the advantages of early treatment, paediatric treatment coverage
still only reaches 52% of children eligible for treatment (1) and in 2017 an
estimated 110 000 HIV/AIDS-related deaths occurred in children <15 years of
age (3).
Children are at particular risk of acquiring TB, although good
epidemiologic data has been difficult to collect. A 2016 systematic review and
meta-analysis of opportunistic and other infections among HIV-infected
children in LMICs confirmed a high incidence rate (12.3% in ART-naive and
8.8% in ART-exposed) of TB co-infection in this population (4). Among children
with TB, the WHO estimates that HIV prevalence, in countries with moderate
to high prevalence, ranges from 10 to 60% with the variation in rates depending
on the background rates of HIV infection (5).

RTV is used only for pharmacologic boosting of other protease inhibitors
(PI). The amount of RTV used depends on the PI used as the active ARV,
but most PIs currently recommended as second- or third-line antiretroviral
therapy (ART) require 100 mg of RTV combined with the adult dose of the PI.
Paediatric patients may use differing amounts of RTV in boosted PI regimens
based on their weight.
Evidence supporting the use of RTV as a pharmacologic booster for
second- and third-line PIs has previously been accepted by the EML which
notes: “Ritonavir is recommended for use in combination as a pharmacological
booster, and not as an antiretroviral in its own right.”
Since 2010, WHO has recommended the approach of ‘super-boosting’
LPV/r with additional ritonavir (RTV) (1:1 instead of 4:1 LPV/r ratio, i.e.
equal doses of LPV and RTV) to manage rifampicin-based TB co-treatment in
children on an LPV/r-based regimen (6). Although HIV therapy is life-long, the
use of the RTV super-boosted LPV/r regimen is only used for the duration of
TB treatment with rifampicin.
A retrospective review of ART regimens and outcomes in HIV/
TB coinfected children younger than 2 years in South Africa suggested that
super-boosted LPV/r led to better outcomes and less toxicity than earlier PI
regimens (7). The adequacy of the super-boosted regimen was confirmed
in a pharmacokinetic study conducted in South Africa, which demonstrated
that LPV trough concentrations in children receiving super-boosted LPV/r
and rifampicin were non-inferior to LPV concentrations in children off TB
therapy (8).
119
RTV oral powder is currently listed as a limited use formulation on

the optimal paediatric ARV formulary for superboosting of LPV/r during TB
co‑treatment and boosting non-coformulated PIs (9).

Evidence for the safety of ritonavir has been considered previously.
The adverse event profile of ritonavir observed during paediatric clinical
trials has been reported as similar to that for adult patients. Vomiting, diarrhoea
and skin rash/allergy were the only drug-related clinical adverse events of
moderate to severe intensity observed in greater than or equal to 2% of paediatric
patients enrolled in clinical trials. Grade 3–4 laboratory abnormalities occurring
in greater than 3% of paediatric patients who received treatment with ritonavir
either alone or in combination with reverse transcriptase inhibitors were
neutropenia (9%), hyperamylasaemia (7%), thrombocytopenia (5%), anaemia
(4%), and elevated aspartate aminotransferase (AST) (3%) (10).
The South African retrospective study evaluating PI-based ART in
children younger than 2 years of age, also receiving TB treatment, concluded
there were only few treatment interruptions due to toxicity. This suggests
that the use of boosted LPV/r and TB treatment in this group was generally
well tolerated. The authors also noted there were no significant differences in
the proportions of children with Grade 3/4 alanine aminotransferase (ALT)
elevations in the TB cotreatment groups while receiving TB treatment compared
to children on LPV/r alone (7).

N/A
WHO Guidelines
WHO guidelines for paediatric HIV treatment recommend the approach of
‘super-boosting’ LPV/r with additional RTV (1:1 instead of 4:1 LPV/r ratio, i.e.
equal doses of LPV and RTV) to manage rifampicin-based TB cotreatment in
children on an LPV/r-based regimen (6).
No cost or cost-effectiveness information is currently publicly available for
ritonavir oral powder.
The manufacturer has made a general commitment to employ market-
specific pricing strategies as part of their commitment to access to medicines (11).
Availability
Ritonavir oral powder is available internationally from Abbvie Inc. Generic
brands are not currently available.
120
N/A
The Expert Committee recommended the addition of the new formulation
of ritonavir oral powder 100 mg to the core list of the EML and EMLc for the
treatment of HIV infection, in line with recommendations in current WHO
guidelines, noting the importance of the availability of quality, age-appropriate
paediatric dosage forms of antiretroviral medicines.
References
1. Global AIDS Update 2018 – Miles to Go, Breaking Barriers, Righting Injustices. Geneva: Joint United
Nations Programme on HIV/AIDS; 2018. Available from http://www.unaids.org/sites/default/files/
media_asset/miles-to-go_en.pdf, accessed 26 September 2019.
2. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality of infected
and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet.
2004;364(9441):1236–43.
3. UNAIDS Core Epidemiology Slides. Geneva: Joint United Nations Programme on HIV/AIDS; 2018.
Available from http://www.unaids.org/en/resources/documents/2018/core-epidemiology-slides,
4. B. Lajoie MR, Drouin O, Bartlett G, Nguyen Q, Low A, Gavriilidis G, et al. Incidence and Prevalence
of Opportunistic and Other Infections and the Impact of Antiretroviral Therapy Among HIV-
infected Children in Low- and Middle-income Countries: A Systematic Review and Meta-analysis.
Clin Infect Dis. 2016;62(12):1586–94.
5. Venturini E, Turkova A, Chiappini E, Galli L, de Martino M, Thorne C. Tuberculosis and HIV
co‑infection in children. BMC Infect Dis. 2014;14 Suppl 1:S5.
6. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV
infection: Recommendations for a public health approach - Second edition. Geneva: World Health
Organization; 2016. Available from http://www.who.int/hiv/pub/arv/arv-2016/en/, accessed
26 September 2019.
7. Frohoff C, Moodley M, Fairlie L, Coovadia A, Moultrie H, Kuhn L, et al. Antiretroviral therapy
outcomes in HIV-infected children after adjusting protease inhibitor dosing during tuberculosis
treatment. PLoS One. 2011;6(2):e17273.
8. Rabie H, Denti P, Lee J, Masango M, Coovadia A, Pillay S, et al. Lopinavir-ritonavir super-boosting
in young HIV-infected children on rifampicin-based tuberculosis therapy compared with
lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study. Lancet
HIV. 2019;6(1):e32-e42
9. The 2018 optimal formulary and limited-use list for paediatric ARVs. Geneva, Switzerland: World
Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. Available from http://apps.who.int/iris/
bitstream/handle/10665/273153/WHO-CDS-HIV-18.15-eng.pdf?ua=1, accessed 26 September
2019.
10. U.S. Food and Drug Administration. Norvir package insert, November 15, 2018. Available
from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209512s004lbl.pdf, accessed
26 September 2019.
121
11. Our commitment to access to medicines [website]. North Chicago: AbbVie. (https://www.abbvie.
com/content/dam/abbvie-dotcom/uploads/PDFs/our-commitment-to-access-to-medicines-
2.pdf, accessed 26 September 2019).
122
Lopinavir + ritonavir – new formulation – EML and EMLc
Lopinavir + ritonavir ATC Code: J05AR10
Proposal
The application requested addition of a new formulation of lopinavir + ritonavir
(LPV/r) fixed-dose combination to the core list of the EMLc for the treatment of
children with HIV infection.
Applicant
WHO HIV Department

HIV Department
EML/EMLc
EMLc
Section

Oral granules: 40 mg + 10 mg in sachet
Core/Complementary
Core

Individual

Fixed-dose combinations of LPV/r have been included on the EMLc since 2007.
Currently listed formulations are oral liquid 400 mg +100 mg/5 mL, heat-stable
tablets 100 mg + 25 mg and capsules containing oral pellets 40 mg + 10 mg.

Evidence shows that in the absence of ART, over 50% of HIV-infected infants
123
progress to AIDS and death by the age of 2 years (2), but the introduction of
paediatric ART has changed HIV infection in children from a life-threatening
illness to a chronic but manageable infection. Despite recognition of the
advantages of early treatment, paediatric treatment coverage still only reaches
52% of children eligible for treatment (1) and in 2017 an estimated 110 000 HIV/
AIDS-related deaths occurred in children <15 years of age (3).

The effectiveness of LPV/r in HIV-infected adult and paediatric patients has
been demonstrated in a variety of clinical settings and populations, and has
been previously reviewed. The data supporting use of the oral pellets (also
LPV/r 40 mg/10 mg) was considered by the Expert Committee in 2017. LPV/r
oral granules are expected to be used in the same settings and for the same
patient population as the LPV/r pellets.
Since the previous EML application for LPV/r pellets was submitted,
additional data on this dosage form have been reported. The LIVING Study
conducted in Kenya and Uganda evaluated use and acceptability of LPV/r
pellets in 723 infants and young children from 3 kg to <25kg. As of the July
2018 report, 303 patients had reached week 48 of treatment; 266 had HIV RNA
data available for the week 48 visit. At 48 weeks, 49–60% of patients across four
age groups had HIV RNA <50 copies/mL (4). These data suggest that the oral
granules will also be an acceptable formulation in young infants.
LPV/r oral pellets and oral granules are currently listed as optimal
formulations and are listed collectively as a ‘solid oral dosage form 40 mg/10 mg’
on The 2018 optimal formulary and limited-use list for paediatric ARVs (5).
These two formulations are listed to be used with two nucleoside reverse
transcriptase inhibitors (NRTIs) for alternative first-line or second-line treatment
for infants and children below 10 kg or unable to swallow 100 mg/25 mg tablets
whole. The optimal paediatric ARV formulary was first developed in 2011 to
address this challenge and now provides guidance to streamline the selection of
paediatric ARV dosage forms to those that conform to a list of criteria, including
dosing flexibility, user-friendliness, optimization of supply chain management,
and availability of quality-assured products in resource-limited settings.

Evidence for the safety of LPV/r in paediatric patients has been previously
evaluated. The LPV/r oral granules formulation is expected to have the same
safety and tolerability as other LPV/r formulations.

N/A
124
WHO Guidelines
Based on evidence from randomized controlled trials showing the superiority
of LPV/r-based regimens over nevirapine (NVP)-based regimens for treating
young children, the WHO 2013 guidelines first recommended the use of LPV/
r-based treatment in children younger than 3 years (36 months) of age where
feasible, regardless of NNRTI exposure (6).
In the WHO 2016 Consolidated guidelines on the use of antiretroviral
drugs for treating and preventing HIV infection, LPV/r in combination with two
NRTIs is recommended as the preferred regimen in infants and children younger
than 3 years (7). The recommended NRTI backbone in this age group is either
abacavir (ABC) or zidovudine (ZDV) plus lamivudine (3TC).
In the updated recommendations on first-line and second-line
antiretroviral regimens and post-exposure prophylaxis and recommendations on
early infant diagnosis of HIV published in 2018, WHO elevated the integrase
inhibitors dolutegravir (DTG) and raltegravir (RAL) in combination with two
NRTIs to first-line treatment for infants and children (8). However, LPV/r
formulations remain alternate first-line treatment in patients younger than
3 years of age and as second-line therapy in older children who have received
an integrase inhibitor. Lack of dosing recommendations for young infants (for
DTG) and lack of availability (for RAL) of integrase inhibitors will likely mean
continued use of LPV/r in young patients for several years.
The application reported a price per patient per year (PPPY) for LPV/r oral
granules of US$ 281 based on WHO dosing guidelines for the 3 to 9.9 kg weight
band. This is similar to the PPPY for LPV/r oral pellets, but more expensive than
LPV/r oral liquid.
It has previously been proposed that cost savings associated with freight
and storage are associated with LPV/r oral pellets compared to oral liquid.
Availability
The US FDA granted tentative approval to Mylan’s LPV/r 40 mg/10 mg oral
granules in August 2018.
N/A
The Expert Committee recommended the addition of a new formulation
of lopinavir + ritonavir (LPV/r) oral granules 40 mg + 10 mg fixed-dose
combination to the core list of the EMLc for the treatment of children with HIV
125
infection, in line with recommendations in current WHO guidelines, noting

the importance of the availability of quality, age-appropriate paediatric dosage
forms of antiretroviral medicines.
The Committee recommended the new LPV/r oral granules and the
existing LPV/r capsules containing oral pellets should be listed collectively as
“solid oral dosage form”, for consistency with the the 2018 optimal paediatric
ARV formulary.
References
1. Global AIDS Update 2018 – Miles to Go, Breaking Barriers, Righting Injustices. Geneva: Joint
United Nations Programme on HIV/AIDS; 2018. Available from http://www.unaids.org/sites/
default/files/media_asset/miles-to-go_en.pdf, accessed 29 September 2019.
2004;364(9441):1236–43.
4. Andrieux‐Meyer I, Salami O, Omollo R, Egondi T, Waweru M, Odiambo S, et al. Pellets’ formulation
of Lopinavir/ritonavir in children: 48‐week evolution of viral suppression across age categories in
the LIVING study. Abstract WEAB0204. J Int AIDS Soc. 2018;21(S6):e25148.
5. The 2018 optimal formulary and limited-use list for paediatric ARVs. Geneva: World Health
Organization; 2018. Available from http://apps.who.int/iris/bitstream/handle/10665/273153/
WHO-CDS-HIV-18.15-eng.pdf?ua=1, accessed 29 September 2019.
infection: recommendations for a public health approach. Geneva: World Health Organization;
2013. Available from http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf,
infection: Recommendations for a public health approach - Second edition. Geneva: World Health
Organization; 2016. Available from http://www.who.int/hiv/pub/arv/arv-2016/en/, accessed

29 September 2019.
supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating
and preventing HIV infection. Geneva: World Health Organization; 2018. Available from https://
apps.who.int/iris/bitstream/handle/10665/277395/WHO-CDS-HIV-18.51-eng.pdf?ua=1, accessed
29 September 2019.
126
6.4.2.4 Integrase inhibitors

Dolutegravir – addition – EMLc
Dolutegravir ATC Code: J05AX12
Proposal
The application requested the addition of dolutegravir to the core list of the
EMLc for treatment of HIV infection in paediatric patients weighing 25 kg
or more.
Applicant
WHO HIV Department

HIV Department
EML/EMLc
EMLc
Section

Tablet 50 mg
Core/Complementary
Core

Individual

Dolutegravir was added to the core list of the EML in 2017 for treatment of
adult patients.

There are now 1.8 million children living with HIV, the vast majority in sub-
Saharan Africa. Evidence shows that in the absence of ART, over 50% of HIV-
infected infants progress to AIDS or death by the age of 2 years (1), but the
introduction of paediatric ART has changed HIV infection in children from a
life-threatening illness to a chronic but manageable infection. Despite recognition
127
of the advantages of early treatment, paediatric treatment coverage still only

reaches 52% of children eligible for treatment (estimated 940 000) and in 2017
an estimated 110 000 HIV/AIDS-related deaths occurred in children <15 years
of age (2).
Although there is limited clinical experience globally with use of
dolutegravir (DTG) in children, it is recommended in this population based
on extrapolation of efficacy from the larger, and more diverse adult studies
(3). Regulatory and normative bodies including the WHO (and its paediatric
working groups) and the US FDA have accepted the concept of extrapolation of
efficacy of ARVs in paediatric patients based on bridging pharmacokinetic (PK)
data and supporting safety information. Thus, the most recent WHO treatment
guidelines for paediatric use of DTG are based primarily on aligning PK data
collected in children receiving DTG in clinical trials to adult PK targets.

Dolutegravir has been shown to be effective in diverse adult patient populations
enrolled in multiple clinical trials conducted internationally. The results of
these adult clinical trials were reviewed in the dossier submitted to support
inclusion of dolutegravir 50 mg as first-line ART in the EML in 2017 and are not
reproduced here.
The paediatric data published to date comprises two ongoing clinical
trials and several observational cohort reports. The trials on which WHO
treatment and dosing recommendations are based include the IMPAACT P1093
study, sponsored by the U.S. National Institutes of Health, and the ODYSSEY
study, sponsored by the Paediatric European Network for Treatment of AIDS-ID.
PK and safety data from these trials have been reported and reviewed as new
weight band cohorts have been completed. Both trials are evaluating paediatric
patients as young as 4 weeks of age using a dispersible tablet, but data for the
younger/smaller patients are not available at this time.

IMPAACT P1093 is an ongoing single-arm, open-label trial of DTG in
children with HIV. FDA approval of DTG for use in children weighing as low
as 40 kg was based on data from 23 treatment-experienced, integrase strand
transfer inhibitor (INSTI)-naive adolescents (4). Intensive PK evaluations were
performed on the first 10 participants, nine of whom weighed ≥40 kg and
received dolutegravir 50 mg and one of whom weighed 37 kg and received DTG
35 mg. These doses resulted in exposures comparable to those seen in adults
receiving 50 mg once daily. At 48 weeks, 61% of participants had achieved HIV
RNA concentration <50 copies/mL. By week 144, 39% and 30% of participants
had achieved HIV RNA concentrations <400 copies/mL and <50 copies/mL,
respectively. All who experienced virologic failure were reported to be non-
adherent. A younger cohort of children aged ≥6 to <12 years were also enrolled
128
in IMPAACT P1093, with those weighing ≥30 kg to <40 kg receiving the 35 mg

dose and those weighing ≥40 kg receiving the 50 mg dose. At 48 weeks, data
from 23 participants demonstrated a favourable safety profile, adequate PK and
virologic efficacy, with HIV RNA concentrations of <50 copies/mL achieved in
74% of participants. These data led to FDA approval of the lower strength film-
coated tablets (10 mg plus 25 mg) for children with HIV weighing at least 30 kg.
Using similar data, the European Medicines Agency (EMA) approved
the lower strength film-coated tablets for children aged ≥6 years and weighing
≥15 kg based on population PK modelling and simulation analyses (5). The
EMA approved doses of 20 mg for children weighing 15 kg to <20 kg and 25 mg
doses for those weighing 20 kg to <30 kg. Because the available PK data in
these weight bands were very limited and the observed trough concentrations
(Ctrough) were lower than expected, the FDA did not approve dosing for children
weighing <30 kg.
The ODYSSEY trial is enrolling both treatment-naive and -experienced
paediatric patients in the EU, Thailand and several African countries, and initially
evaluated the EMA-approved doses for children weight > 15kg. A total of 674
children <18 years of age were enrolled; 282 starting dolutegravir as first-line
therapy and 392 starting second-line therapy (6). Nested pharmacokinetic sub-
studies within ODYSSEY are evaluating simplified paediatric dosing aligned with
WHO-recommended weight bands. PK data have been reported from a cohort
of children >25 kg switching to the 50 mg adult tablet (n=27). These children
receiving the 50 mg film-coated tablet achieved exposures similar to those of
adults. When given to children 14 to <25 kg, the DTG 25 mg film-coated tablet
resulted in lower exposure than the adult target exposure, particularly Ctrough.
The lower Ctrough was more marked in the 20 to <25 kg group. Higher doses are
currently under study in these weight bands and doses have been adjusted for
lower weight bands (7, 8).
After careful review and discussion, the WHO-convened Paediatric
Antiretroviral Working Group endorsed the simplified dosing using the
dolutegravir 50 mg tablet in children weighing >25kg.
In the adult clinical studies to date, dolutegravir-based regimens were
either non-inferior or superior in efficacy to comparator regimens containing
other integrase inhibitors, boosted protease inhibitors and NNRTIs, regardless of
patient population. In patients initiating first-line treatment, successful virologic
suppression occurred in more patients receiving DTG than the comparators.
There are no comparative paediatric trials available but both the WHO working
groups and multiple regulatory agencies (including the U.S. FDA and the EMA)
endorse the concept of extrapolating efficacy from well-designed, adequately-
powered adult trials on the basis of similar pharmacokinetic profile and
supplemental safety data.
129

A French, retrospective, multicentre cohort study evaluated 50 adolescents who
initiated dolutegravir-based ART. In this cohort, only one patient discontinued
DTG-based treatment because of a significant adverse effects (dizziness and sleep
disturbance) (9). Another cohort of adolescents reported from Barcelona received
the fixed-dose combination product Triumeq (abacavir 600 mg/dolutegravir
50 mg/lamivudine 300 mg). No serious safety concerns were reported, however,
patients complained about the size of the tablet and six reported having to crush
or split the tablet in order to swallow it, potentially contributing to adherence
issues (10).
In the original clinical trials, patients on dolutegravir experienced
significantly fewer incidences of nervous system disorders and psychiatric
disorders than those receiving efavirenz, however, there have been post-
marketing reports of neuropsychiatric events (such as insomnia or depression)
among adults receiving DTG-based treatment since its approval. Causality for
these events has been difficult to determine as many patients are reported to
have a previous history of psychiatric symptoms.
In a surveillance study of birth outcomes among pregnant women
on ART in Botswana, an increased rate of neural tube defects was observed
among infants born to women who were receiving dolutegravir at the time of
conception (11). As children and young adolescents mature, and before they
become sexually active, paediatric and adolescent providers should discuss this
potential risk with patients who are receiving or initiating dolutegravir and their
caregivers. The WHO 2018 interim guidelines (3) note the following in their
guidance on this topic:
–– Dolutegravir appears to be safe when started later in pregnancy:
after the period of risk of neural tube defects and after the first
trimester.
–– Adolescent girls and women of childbearing potential who do not

currently want to become pregnant can receive DTG together with
consistent and reliable contraception; hormonal contraception
and DTG have no reported or expected drug–drug interactions
although data are limited.

N/A
WHO Guidelines
The WHO-recommended dose of DTG in integrase inhibitor treatment naive
adults and paediatric patients weighing more than 25 kg is one tablet (50 mg)
once daily (3). Dolutegravir should be given together with two NRTIs appropriate
130
for paediatric patients (i.e. abacavir plus lamivudine or zidovudine plus

lamivudine). In addition, the WHO 2018 interim guidelines also recommend
that DTG in combination with an optimized NRTI backbone is the preferred
second-line regimen for children with approved DTG dosing for whom non-
DTG-based regimens are failing.
The indicative average price per patient per year (PPPY) for dolutegravir 50 mg
tablets is approximately US$ 50 for children weighing between 25 and 35 kg.
This price is lower than PPPY for other ARVs suitable for children.
In November 2015, the Clinton Health Access Initiative (CHAI),
UNAIDS, and Unitaid announced a pricing agreement for DTG 50 mg single
tablets that had been brokered with Aurobindo Pharma (12). Under the
agreement, Aurobindo agreed to make generic DTG 50 mg tablets available at a
price of US$ 44.00 PPPY (or US$ 3.67 per pack).
Availability
Dolutegravir 50 mg tablets are manufactured by multiple pharmaceutical
companies, including generic and WHO prequalified manufacturers.
N/A
The Expert Committee recommended the addition of dolutegravir 50 mg tablets
to the core list of the EMLc for treatment of HIV infection in paediatric patients
weighing 25 kg or more, in combination with an optimized NRTI backbone
regimen, in line with recommendations in current WHO guidelines.
The Committee acknowledged the important need to expand HIV
treatment options for children. The Committee noted the available evidence for
use of dolutegravir in children was largely limited to pharmacokinetic and safety
data from two ongoing paediatric trials, but considered that extrapolation of
efficacy from adult trials was acceptable.
References
2004;364(9441):1236–43.
131

and preventing HIV infection. Geneva: World Health Organization; 2018. Available from
https://apps.who.int/iris/bitstream/handle/10665/277395/WHO-CDS-HIV-18.51-eng.pdf?ua=1
with accompanying Annex 3: Dosages of ARV drugs. World Health Organization, Geneva.
December, 2018. Available from https://www.who.int/hiv/pub/guidelines/ARV_Guidelines-2018-
Annex3.pdf?ua=1. Both accessed 29 September 2019.
4. Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E et al. Safety, Pharmacokinetics and
Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week
Results from IMPAACT P1093. Pediatr Infect Dis J. 2015;34(11):1207–13.
5. Summary of Product Characteristics: Tivicay [website]. London: European Medicines Agency;
2014. (https://www.ema.europa.eu/documents/product-information/tivicay-epar-product-infor
mation_en.pdf, accessed 29 September 2019).
6. Moore C, Kekitinwa A, Kaudha E, Lugemwa A, Mujuru H, Cotton M et al. ODYSSEY: A randomised
trial evaluating the efficacy and toxicity of dolutegravir-based antiretroviral therapy compared to
standard of care in HIV-infected children starting first-line or second-line therapy: design, current
status and baseline characteristics. Abstract 34. 10th International Working on HIV Pediatrics.
21–22 July 2018, Amsterdam, The Netherlands. Reviews in Antiviral Therapy & Infectious Diseases.
2018;8:37.
7. Bollen P, Turkova A, Mujuru H, Musiime V, Amuge P, Lugemwa A et al. Steady-state
pharmacokinetics and early safety data in HIV-infected African children weighing 14 to <25kg
on film-coated dolutegravir 25mg tablets in the ODYSSEY trial. Abstract 22. 10th International
Working on HIV Pediatrics. 21–22 July 2018, Amsterdam, The Netherlands. Reviews in Antiviral
Therapy & Infectious Diseases 2018;8:27.
8. Turkova A, Bollen P, Kaudha E, Chidziva E, Lugemwa A, Kekitiinwa A et al. Steady-state
pharmacokinetics and early safety data in HIV-infected African children weighing ≥25kg after
switching to 50mg film-coated dolutegravir tablets in the ODYSSEY trial. Abstract 3. 10th
International Working on HIV Pediatrics. 21–22 July 2018, Amsterdam, The Netherlands. Reviews
in Antiviral Therapy & Infectious Diseases. 2018;8:5.
9. Briand C, Dollfus C, Caseris M et al. Abstract: Dolutegravir-based cART in vertically HIV-1-infected
adolescents, real-world setting.” 24th Conference on Retroviruses and Opportunistic Infections.
Seattle, WA. 2017.
10. Bossacoma Busquets F, Noguera-Julian A, Sanchez E, Fortuny C. Dolutegravir plus abacavir/

lamivudine works in adolescents, but size matters. J Antimicrob Chemother. 2017;72(10):2958–60.
11. Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time
of Conception. N Engl J Med. 2018;379(10):979–81.
12. Three new agreements announced with the potential to expand access to innovative HIV
treatment in low- and middle-income countries [Press Release]. Harare/Geneva: UNAIDS; 2015.
Available from http://www.unaids.org/en/resources/presscentre/pressreleaseandstatement
archive/2015/november/20151130_PR_CHAI_UNITAID, accessed 29 September 2019.
132
Raltegravir – new formulation – EML and EMLc
Raltegravir ATC Code: J05AX08
Proposal
The application requested the addition of a new formulation of raltegravir to the
core list of the EML and EMLc for the treatment of HIV infection.
Applicant
WHO HIV Department

HIV Department
EML/EMLc
EML and EMLc
Section

Granules for oral suspension 100 mg in sachet
Core/Complementary
Core

Individual

Raltegravir was added to the Model Lists in 2017 for use in pregnant women
and as a second-line treatment option for children in accordance with WHO
guidelines. Currently listed formulations include 400 mg tablets and 25 mg and
100 mg chewable tablets.
In a separate application to the 2019 Expert Committee, raltegravir
100 mg chewable tablet formulation was proposed for deletion from the EML
and EMLc.

133
Evidence shows that in the absence of ART, over 50% of HIV-infected infants
progress to AIDS and death by the age of 2 years (2), but the introduction of
paediatric ART has changed HIV infection in children from a life-threatening
illness to a chronic but manageable infection. Despite recognition of the
advantages of early treatment, paediatric treatment coverage still only reaches
52% of children eligible for treatment (1) and in 2017 an estimated 110 000
HIV/AIDS-related deaths occurred in children <15 years of age (3).

Data supporting general effectiveness of raltegravir in adults has been
considered previously. The application only presented evidence relevant to the
use of raltegravir granules for oral suspension.
Data from IMPAACT P1066, a Phase I/II open-label multicentre trial
to evaluate the pharmacokinetic profile, safety, tolerability and efficacy of
RAL in HIV-infected children (4) have been considered previously, and are not
reproduced here.
The safety and pharmacokinetics of raltegravir granules for oral
suspension were evaluated in 42 full-term HIV-1-exposed neonates at high
risk of acquiring HIV-1 infection in a Phase I, open-label, multicentre clinical
study (IMPAACT P1110) (5). Cohort 1 neonates received 2 single doses of RAL
powder for oral suspension: the first within 48 hours of birth and the second at
7 to 10 days of age. Cohort 2 neonates received daily dosing of RAL powder for
oral suspension for 6 weeks: 1.5 mg/kg once daily starting within 48 hours of
birth through Day 7 (week 1); 3 mg/kg twice daily on Days 8 to 28 of age (weeks
2 to 4); and 6 mg/kg twice daily on Days 29 to 42 of age (weeks 5 and 6). Sixteen
neonates were enrolled in Cohort 1 and 26 in Cohort 2; all infants received a
standard of care ARV drug regimen for prevention of mother-to-child HIV
transmission. All enrolled neonates were followed for safety for a duration of
24 weeks. HIV-1 status was assessed by nucleic acid test at birth, week 6 and
week 24 and all remained HIV-1 negative.
IMPAACT P1066 also enrolled HIV-infected infants and toddlers from
4 weeks to less than 2 years of age who had received prior antiretroviral therapy
either as prophylaxis for prevention of mother-to-child transmission and/or as
combination antiretroviral therapy for treatment of HIV infection. Raltegravir
granules for oral suspension was administered in combination with an optimized
background regimen, and without regard to food. None of the enrolled subjects
were completely treatment naive (all had prenatal/in utero ARV exposure or
postnatal prophylaxis or treatment). Of the 26 treated subjects, 24 subjects were
included in the week 48 efficacy analyses. All 26 treated subjects were included
for safety analyses. At week 48, 45% achieved HIV RNA <50 copies/mL and 67%
134
achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase
from baseline to week 48 was 527 cells/mm3 (7.3%) (6). A recent follow-up
publication reports the outcomes of those patients receiving raltegravir at the
final selected doses through 240 weeks of treatment. In this analysis, 13 of 15
infants receiving raltegravir oral granules for 240 weeks achieved virologic success
(>1 log decrease in HIV RNA from baseline or HIV RNA <400 copies/mL) (7).
Raltegravir granules for oral suspension is currently listed as a limited
use formulation on the optimal formulary and limited-use list for neonatal
treatment only.

Evidence of the safety and tolerability of raltegravir has been previously
considered. The overall safety of raltegravir in paediatric patients, including
neonates, was similar to that observed in adults.
Overall, the safety profile in paediatric patients, including neonates,
is similar to that observed in adults. Raltegravir is metabolized primarily by
UGT1A1 (the same metabolic pathway as bilirubin) and UGT1A1 activity is
greatly reduced in neonates. Concerns regarding potential competition with
bilirubin for albumin binding sites and resulting jaundice in infants have not
been borne out. The dose recommended in neonates takes into consideration
the rapidly increasing UGT1A1 activity and drug clearance in this age group (5).

N/A
WHO Guidelines
The WHO 2018 updated recommendations on first- and second-line ARV
regimens make the following recommendations in relation to raltegravir-based
regimens in children:
–– A raltegravir-based regimen may be recommended as an
alternative first-line regimen for infants and children for
whom approved dolutegravir dosing is not available (condition
recommendation, low-certainty evidence).
–– A raltegravir-based regimen is recommended as the preferred
first-line regimen for neonates (conditional recommendations,
very-low-certainty evidence).
Raltegravir-based regimens for neonates are recommended for use for
no longer than three months, when transition to LPV/r solid formulations is
possible (8).
135
The reported price per patient per year for raltegravir oral granules is US$ 260.
No cost-effectiveness information for this formulation is currently available.
Availability
Raltegravir granules for oral suspension are manufactured by Merck Sharp &
Dohme Ltd.
Raltegravir granules for oral suspension are not recommended in pre-term
neonates or in paediatric patients weighing less than 2 kg.
The Expert Committee recommended the addition of a new formulation
of raltegravir granules for oral suspension 100 mg to the core list of the EML
and EMLc for the treatment of HIV infection, in line with recommendations
in current WHO guidelines. The Committee considered that this formulation
of raltegravir could facilitate treatment of neonates and paediatric patients,
and would be a suitable alternative for adult and paediatric patients for whom
dolutegravir is not available or is not tolerated.
References
2004;364(9441):1236–43.
4. Nachman S, Zheng N, Acosta EP, Teppler H, Homony B, Graham B et al. Pharmacokinetics, safety,
and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin
Infect Dis. 2014;58(3):413–22.
5. Isentress U.S. package insert. Silver Spring: U.S. Food and Drug Administration; 2018. Available
from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022145s038,205786s007,02
03045s015lbl.pdf, accessed 29 September 2019.
6. Nachman S, Alvero C, Acosta EP, Teppler H, Homony B, Graham B et al. Pharmacokinetics and 48-
Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency Virus
Type-1-Infected Children 4 Weeks to 2 Years of Age. J Pediatric Infect Dis Soc 2015;4(4):e76–83.
136
7. Nachman S, Alvero C, Teppler H, Homony B, Rodgers AJ, Graham BL et al. Safety and efficacy at
240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-
randomised, multicentre trial. Lancet HIV. 2018;5(12):e715–e22.
29 September 2019.
137
Fixed-dose combinations
Dolutegravir + lamivudine + tenofovir disoproxil fumarate – addition – EML
Dolutegravir + lamivudine + tenofovir ATC Code: to be assigned

disoproxil fumarate
Proposal
The application requested the addition of a fixed-dose combination formulation
of dolutegravir, lamivudine and tenofovir disoproxil fumarate (TLD) to the core
list of the EML for treatment of HIV infection in adults and adolescents.
Applicant
WHO HIV Department

HIV Department
EML/EMLc
EML
Section
6.4.2 Antiretrovirals – fixed-dose combinations

Tablet 50 mg + 300 mg + 300 mg (disoproxil fumarate equivalent to 245 mg
tenofovir disoproxil)
Core/Complementary
Core

Individual

This fixed-dose combination (FDC) had not been previously considered by the
Expert Committee for addition to the EML. The component medicines are all
included individually on the EML.

In 2017, UNAIDS reported there were 36.9 million people living with HIV/
AIDS globally, 1.8 million new HIV-1 infections, and 940 000 thousand HIV-
138
related deaths (1). Over 95% of infected people live in low- and middle-
income countries (LMICs) with inadequate resources to effectively combat the
epidemic. While some countries have achieved declines in new HIV infections
among adults of 50% or more, global data show that many others have not
made measurable progress and others have experienced worrying increases in
new HIV infections. Overall, approximately 21.7 million people were receiving
antiretroviral therapy (ART) in 2017, but this is estimated to represent only 59%
of people living with HIV.
Early and effective ART not only significantly improves the health
of those people living with HIV, but also reduces transmission of the disease
as shown in the recently reported START study (2). For this reason, WHO
released guidelines in 2015 calling for treatment for all people with HIV. Easy to
administer, highly effective, safe treatment options remain desperately needed
in many areas of the world to meet the UNAIDS ‘90-90-90’ targets, which call
for 90% of people living with HIV to know their status, 90% of those with known
infection to be on ART, and 90% of those on ART to be virally suppressed (i.e.
on successful therapy) by the year 2020 (3).

The efficacy of dolutegravir (DTG) has been demonstrated in ART-naive subjects
in three randomized, controlled, multinational, Phase III studies: SPRING-2 (4),
SINGLE (5) and FLAMINGO (6). The findings of these studies were evaluated
in the 2017 consideration of dolutegravir by the Expert Committee and are not
reproduced here.
The safety, tolerability and efficacy of a dolutegravir-based regimen was
evaluated in a prospectively-enrolled, open-label cohort of 564 Indian adults
receiving dolutegravir in combination with other ARVs (primarily tenofovir
disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC)) as
either first- or second-line therapy. Among the treatment naive patients initiating
DTG plus TDF/3TC or TDF/FTC, all had viral suppression at the 6 month
follow‑up, and overall, viral suppression occurred in 82.9% at six months (7).
The NAMSAL ANRS study randomized HIV-infected adults in
Cameroon to receive either a dolutegravir-based regimen (TLD) (n=310) or
an efavirenz-containing regimen (TLE-400) (n=303) for first-line treatment.
Preliminary efficacy results at 48 weeks on treatment indicate the proportion
of patients with HIV RNA <50 copies/mL was 74.5% in the TLD arm and
69% in the TLE-400 arm. Fewer patients with initial HIV RNA levels >100 000
copies/mL had virologic suppression to <50 copies/mL: 66.2% in the TLD arm
and 61.5% in the TLE-400 arm. In this study, viral suppression with TLD was
numerically higher but not statistically superior to TLE-400; NNRTI resistance
was an important determinant of TLE-400 failure (8).
139
In the clinical studies to date, dolutegravir-based regimens were

either non-inferior or superior in efficacy to comparator regimens containing
other integrase inhibitors, boosted protease inhibitors and NNRTIs regardless
of patient population. In patients initiating first-line treatment, successful
virologic suppression occurred in more patients receiving dolutegravir than the
comparators. A systematic review and meta-analysis conducted by WHO in 2016
concluded that among treatment-naive patients, treatment with an integrase
inhibitor (particularly DTG) plus two NRTIs, had superior efficacy and tolerance
to the current standard of care regimens of efavirenz plus two NRTIs (9).

The overall safety profile of dolutegravir in adults compared favourably to other
ARVs included in the clinical trials reported previously.
There have been multiple reports of neuropsychiatric events among
patients receiving dolutegravir-based treatment since its approval. Although
dolutegravir appears to result in fewer of these events compared to efavirenz in
comparative clinical trials (5), some patients receiving dolutegravir experience
episodes of insomnia or depression. Causality for these events has been difficult
to determine as many patients are reported to have a previous history of
psychiatric symptoms.
In the South Indian cohort of first- and second-line patients, dolutegravir-
based regimens were well tolerated. Mean alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) decreased slightly in the cohort during the
6-month evaluation period, mean haemoglobin increased slightly, and kidney
function remained stable. In this cohort, sleep disturbances and neuropsychiatric
symptoms were not reported. The frequency of opportunistic infections
decreased from 7.4% prior to starting DTG to 3.3% after six months follow up.
None of the patients in this cohort discontinued DTG during the evaluation
period. Four deaths were reported (two sepsis and two cytomegalovirus (CMV)
encephalitis, considered unrelated to ARVs) (7).

A nationwide birth outcomes surveillance programme conducted in
Botswana began collecting data in women initiating dolutegravir in 2014.
An initial report of pregnant women who began taking either a dolutegravir-
(n=1729) or efavirenz-based (n=4593) treatment regimen identified no difference
in risk for adverse birth outcomes, even among those beginning treatment
during the first trimester (i.e. post-conception ART) (10). However, an interim
analysis of a second surveillance study of women becoming pregnant while
already receiving ART (i.e. pre-conception ART) identified an excess number
of neural tube defects among infants of women receiving a dolutegravir-based
regimen. Neural tube defects were observed in 4 of 426 (0.94%) infants born to
women receiving dolutegravir compared to 14 of 11 300 (0.12%) infants born
to women receiving any other ART regimen and 61 of 66 057 (0.09%) infants
140
born to HIV-uninfected women. Although none of the affected women were

receiving folate supplements, no other risk factors for neural tube defects have
been identified (11). This study is ongoing and expects to have a final analysis
in 2019. While awaiting the final study results and data from other sources,
WHO recommends counselling for women of childbearing potential and access
to effective contraception in those receiving dolutegravir. However, they also
suggest that an efavirenz-based regimen remains safe and effective in women
who plan to become pregnant (12).
The NRTI backbone of TDF/3TC has an extensive history of use in ART
globally and has accumulated a favourable safety and tolerability profile. Initial
concerns regarding potentially serious renal and bone toxicity due to the TDF
component have not been borne out over years of clinical experience although it
requires dose adjustment in patients with significant renal impairment and so is
not generally used in this sub-group.
In addition, the potential risks and benefits of wide implementation
of TLD were evaluated in a 2018 modelling exercise conducted by a group
of independent researchers. The group used existing data to estimate HIV
transmission and disease progression (taking into account drug resistance,
drug potency, differential viral suppression and clinical outcomes) to compare
outcomes of different ART regimens in various scenarios. In their model, the
greatest number of disability-adjusted life-years was averted in the scenario
providing TLD to all adult patients without restrictions over 20 years compared
to adults based on intent to have children and/or dependent on documentation
of viral suppression (13).

N/A
WHO Guidelines
The 2016 WHO Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing HIV infection recommended TDF plus 3TC as a
preferred nucleoside/tide backbone in first-line therapy and dolutegravir 50 mg
in combination with TDF and 3TC as an alternative first-line regimen (14). In
addition, these guidelines reiterate the WHO conclusion that FDCs and once-
daily regimens are most preferred. At that time, TLD was not available as an
FDC. In the most recent WHO treatment guidelines update (July 2018), a DTG-
based regimen is recommended as a preferred first-line regimen for adults and
adolescents living with HIV who are initiating antiretroviral therapy (12).
Various sources indicate an average price per patient per year for the FDC of
US$ 74. This price is comparable to other first-line regimens.
141
A pricing agreement was announced in July 2017 by the governments

of South Africa and Kenya, together with UNAIDS, CHAI, the Bill & Melinda
Gates Foundation, Unitaid, the UK Department for International Development,
PEPFAR, USAID, and the Global Fund, with Aurobindo and Mylan.
Under the agreement, Aurobindo and Mylan agreed to offer TLD
at approximately US$ 75 PPPY. This lower price is accessible to public sector
purchasers in over 92 LMICs worldwide.
Availability
This product is currently available for procurement from multiple suppliers
(including WHO prequalified manufacturers).
N/A
The Expert Committee recommended the addition of the fixed-dose combination
formulation of dolutegravir + lamivudine + tenofovir disoproxil fumarate to the
core list of the EML for treatment of HIV infection in adults and adolescents.
The Committee noted the demonstrated efficacy and safety of DTG-based
regimens in treatment-naive patients, and that DTG-based regimens are now
recommended as preferred first-line therapy in WHO Guidelines for adults and
adolescents initiating antiretroviral treatment.
The Committee also considered that the availability of fixed-dose
combinations of antiretroviral therapies provides benefits to patients in terms
of ease of administration and reduced pill burden, which can contribute to
improved therapeutic adherence.
References
2. Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S et al. Initiation of Antiretroviral
Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795–807.
3. 90–90–90 - An ambitious treatment target to help end the AIDS epidemic. Geneva: Joint United
Nations Programme on HIV/AIDS; 2017. Available from http://www.unaids.org/sites/default/
files/media_asset/miles-to-go_en.pdf, accessed 29 September 2019.
4. Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM et al. Once-daily dolutegravir
versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2
study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis.
2013;13(11):927–35.
142
5. Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F et al. Dolutegravir plus
abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807–18.
6. Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, et al. Once-daily dolutegravir
versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96
week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015;2(4):e127–36.
7. Kumarasamy N, Prabhu S, Chandrasekaran E, Poongulali S, Pradeep A, Chitra D et al. Safety,
Tolerability, and Efficacy of Generic Dolutegravir-containing Antiretroviral Therapy Regimens
Among South Indian Human Immunodeficiency Virus-infected Patients. Clin Infect Dis.
2019;68(6):1048-51.. Clin Infect Dis. 2019;68(6):1048–51
8. Cournil A, Kouanfack C, Eymard-Duvernay S, Lem S, Mpoudi-Ngole M, Omgba P et al. Dolutegravir
versus an efavirenz 400 mg-based regimen for the initial treatment of HIV-infected patients in
Cameroon: 48-week efficacy results of the NAMSAL ANRS 12313 trial. Abstract O342. J Int AIDS
Soc. 2018;21(S8):16.
9. Kanters S, Vitoria M, Doherty M, Socias ME, Ford N, Forrest JI et al. Comparative efficacy and
safety of first-line antiretroviral therapy for the treatment of HIV infection: a systematic review
and network meta-analysis. Lancet HIV. 2016;3(11):e510–e20.
10. Zash R, Jacobson DL, Diseko M, Mayondi G, Mmalane M, Essex M et al. Comparative safety of
dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in
Botswana: an observational study. Lancet Glob Health. 2018;6(7):e804–e10.
11. Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time
of Conception. N Engl J Med. 2018;379(10):979–81.
29 September 2019.
13. Phillips AN, Venter F, Havlir D, Pozniak A, Kuritzkes D, Wensing A et al. Risks and benefits of
dolutegravir-based antiretroviral drug regimens in sub-Saharan Africa: a modelling study. Lancet
HIV. 2019;6(2):e116–e27.
infection: Recommendations for a public health approach - Second edition. Geneva: World
Health Organization; 2016. Available from http://www.who.int/hiv/pub/arv/arv-2016/en/,
143
6.4.4 Antihepatitis medicines

6.4.4.2 Medicines for hepatitis C
Glecaprevir + pibrentasvir – addition – EML
Glecaprevir + pibrentasvir ATC Code: J05AP57
Proposal
The application requested addition of the fixed-dose combination of glecaprevir
+ pibrentasvir to the core list of the EML for the treatment of adult patients with
chronic hepatitis C virus infection, genotypes 1 to 6.
Applicant
AbbVie Inc.

WHO Global Hepatitis Programme
EML/EMLc
EML
Section
6.4.4.2.1 Pangenotypic direct-acting antiviral combinations

Tablet 100 mg + 40 mg
Core/Complementary
Core

Individual
Background
Neither this fixed-dose combination (FDC) nor its individual components have
been previously considered by the Expert Committee for addition to the EML.

Globally in 2015, it was estimated that 71 million persons were living with chronic
HCV infection and nearly 400 000 died from cirrhosis or hepatocellular cancer.
144
The Global health sector strategy on viral hepatitis was endorsed by the
World Health Assembly in 2016 and proposes the elimination of viral hepatitis
as a public health threat by 2030 by achieving a 90% reduction in incidence
and a 65% reduction in mortality. This requires 90% of infection persons to be
diagnosed, and 80% of diagnosed persons to be treated (1).

In Phase II and III registrational studies, glecaprevir + pibrentasvir has shown
high sustained viral response rates at 12 weeks (SVR12) across all hepatitis C
genotypes and in key patient sub-populations (patients with chronic kidney
disease, organ transplant recipients, patients coinfected with HIV and patients
with compensated cirrhosis).
The application described SVR12 rates greater than 95% for all treated
genotypes:
Genotype Intervention Proportion SVR12 (n/N) 95%CI

GT1 12 weeks 99.7% (331/332) 99.1 to 100.0
GT2 8 weeks 98.5% (135/137) 96.5 to 100.0
GT2 12 weeks 99.5% (195/196) 98.5 to 100.0
GT3 12 weeks 95.3% (222/233) 94.2 to 98.9
GT4 12 weeks 99.0% (95/96) 94.3 to 99.8
GT5 12 weeks 100% (21/21) 84.5 to 100.0
GT6 12 weeks 100% (30/30) 88.6 to 100.0
Among all GT1–6-infected subjects who received the recommended

duration of treatment with glecaprevir + pibrentasvir, regardless of renal function,
cirrhosis status, presence of HIV co-infection, treatment naive or treatment
experienced, 97.4% (1252/1287) achieved SVR12 (2).
High SVR12 rates were also reported for GT1–6-infected subjects in key
patient sub-populations:
Sub-population Intervention Proportion

SVR12 (n/N)
Chronic kidney disease (CKD) (+/- haemodialysis) 12 weeks 98.1% (102/104)
Post liver/renal transplant 12 weeks 98.0% (98/100)
HCV/HIV-1 co-infection (with or without cirrhosis) 12 or 8 weeks 98.2% (165/168)
145
Table continued
Sub-population Intervention Proportion
SVR12 (n/N)
Compensated cirrhosis NR 95.3% (222/233)
NS5A inhibitor (only) experienced 16 weeks 94.4% (17/18)
PI (only) experienced 12 weeks 100% (27/27)
Both NS5A and PI experienced 16 weeks 81.3% (13/16)
The application described the findings of two randomized, Phase III,

open-label studies that evaluated the safety and effectiveness of glecaprevir +
pibrentasvir compared to sofosbuvir + ribavirin in Japanese patients with HCV
GT2 (CERTAIN-2, Study M15-828) (3), and compared to sofosbuvir + daclatasvir
in treatment-naive, non-cirrhotic HCV GT3 patients (ENDURANCE-3, Study
M13-594) (4). In each study, glecaprevir + pibrentasvir was found to be non-
inferior to the comparator treatments for the percentage of patients achieving
SVR12.
Real-world data for glecaprevir + pibrentasvir also support the effectiveness
demonstrated in the Phase 2 and 3 trials (5–9).

The application stated the safety assessment for glecaprevir + pibrentasvir in
subjects with compensated liver disease (with or without cirrhosis) were derived
from Phase II and III studies that evaluated 2369 subjects infected with GT 1,
2, 3, 4, 5 or 6 HCV who received treatment for 8, 12 or 16 weeks. The overall
proportion of subjects who permanently discontinued treatment due to adverse
reactions was 0.1%. The most common adverse reactions were reported as
headache (13.2%), fatigue (11.4%) and nausea (7.6%). These adverse reactions
occurred at a similar frequency in patients receiving placebo or sofosbuvir +

daclatasvir. Seven deaths were reported in the Phase II and III analysis set,
none of which were considered to be related to the study drug. No apparent
differences were observed in adverse event profiles by sex, race, ethnicity or
baseline body mass index (BMI). The incidence of serious adverse events and
adverse events of Grade 3 or higher was higher in patients aged 65 years or
older compared to patients under 65 years. No other differences by age in the
proportion of subjects reporting any adverse event, discontinuations or deaths
were observed.
Real-world data for glecaprevir + pibrentasvir also support the safety
demonstrated in clinical trials (5–9).
146

A systematic review of treatment options for chronic hepatitis C virus infection,
genotypes 1–6 was conducted to inform the 2018 WHO Guidelines for the care
and treatment of persons diagnosed with chronic hepatitis C virus infection (10,
11). The review found that the proportion of patients treated with glecaprevir +
pibrentasvir who achieved SVR12 ranged from 83% to 98%. GRADE assessments
of the quality of evidence were high for GT1–3 and very low for GT4–6. For
safety outcomes, the review assessed discontinuations due to adverse events
(DAEs), serious adverse events (SAEs) and mortality. The pooled proportions
for DAEs, SAEs and mortality for glecaprevir + pibrentasvir was 1%, 2% and 1%,
respectively. GRADE assessments of the quality of evidence were moderate for
DAEs and high for SAEs and mortality.
WHO Guidelines
The 2018 WHO Guidelines for the care and treatment of persons diagnosed with
chronic hepatitis C virus infection (1) recommend:
–– the use of pangenotypic direct-acting antiviral (DAA) regimens for
the treatment of chronic HCV infection in persons aged 18 years
and older (conditional recommendation, moderate quality
evidence);
–– glecaprevir + pibrentasvir as a pangenotypic treatment option for
adults with or without compensated cirrhosis.
In a 2017 cost-effectiveness analysis in the United States, glecaprevir + pibrentasvir
was shown to be a dominant pan-genotypic treatment option compared to
current standard practices providing most favourable health outcomes at lowest
cost (2). Health outcomes included quality-adjusted life-years (QALYs) and
number needed to treat (NNT) to achieve a QALY, SVR or avoid an adverse liver
event. In this analysis, glecaprevir + pibrentasvir was compared to two treatment
strategies: (i) sofosbuvir + ledipasvir for GTs 1 and 4, and sofosbuvir + velpatasvir
for GTs 2, 3, 5 and 6; and (ii) grazoprevir + elbasvir for GTs 1 and 4, and sofosbuvir
+ velpatasvir for GTs 2, 3, 5 and 6. A 12-week regimen course of glecaprevir +
pibrentasvir was assumed to cost US$ 27 929 USD (at 2017 wholesale acquisition
drug costs). Cost-effectiveness results in other countries may vary based on the
different pricing of glecaprevir + pibrentasvir and other DAAs.
Availability
Glecaprevir + pibrentasvir has marketing approval and is commercially available
in 58 countries globally. AbbVie and the Medicines Patent Pool have entered into
a royalty-free licensing agreement to accelerate access in 99 LMICs. Through
147
this agreement, AbbVie will allow WHO prequalified generic manufacturers to

license, manufacture and supply generic versions. AbbVie is also considering
the inclusion of glecaprevir + pibrentasvir on the WHO List of Prequalified
Medicinal Products.
N/A
The Expert Committee recommended the addition of the fixed-dose combination
of glecaprevir + pibrentasvir to the core list of the EML for the treatment of adult
patients with chronic hepatitis C virus infection, based on evidence of pan-
genotypic effectiveness and an acceptable safety profile. The Committee noted
that this combination is one of three pan-genotypic combinations recommended
in the current WHO guidelines for treatment of hepatitis C and is suitable for
use in patients with or without compensated cirrhosis.
The Committee noted that the manufacturer and the Medicines Patent
Pool (MPP) have entered into a licensing agreement for this product to accelerate
access in 99 LMICs. However, the Committee noted with concern that some
LMICs with a high burden of hepatitis C are not included in this agreement
and encouraged the manufacturer and the MPP to address this issue to ensure
patients in these high-burden countries have equitable access.
The Committee recommended that the hepatitis C medicines section of
the Model List be amended to differentiate between pangenotypic (glecaprevir
+ pibrentasvir, sofosbuvir + daclatasvir and sofosbuvir + velpatasvir), non-
pangenotypic direct acting antivirals, and other antivirals for hepatitis C. The
pangenotypic regimens should be considered as therapeutically equivalent to
facilitate selection and procurement by countries at national level.
The Expert Committee then considered whether it was appropriate to
delete non-pangenotypic treatments for hepatitis C, and recommended the

deletion of simeprevir, whose place in therapy was now superseded by the pan-
genotypic options. The Committee recommended that other non-pangenotypic
treatments could be considerd for deletion from the EML in the future.
References
1. Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus
infection. Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/
bitstream/handle/10665/273174/9789241550345-eng.pdf, accessed 29 September 2019.
2. Saab S, Parisé H, Virabhak S, Johnson S, Pinsky B, Sanchez Y. Pan‐genotypic hepatitis C treatment
with glecaprevir/pibrentasvir achieves greatest improvements in quality‐adjusted life‐years and
lifetime risk reductions in liver‐related morbidity and mortality vs standards of care: a cost‐utility
analysis. Poster Abstract 1578. Hepatology. 2017;66(S1):843A.
148
3. Abbvie - M15-828 Clinical Study Report – Final. A Randomized, Open-Label, Active Comparator,
Multicenter Study to Evaluate the Efficacy and Safety of ABT-493/ABT-530 in Japanese Adults
with Genotype 2 Chronic Hepatitis C Virus Infection (CERTAIN-2) [website]. (https://www.abbvie.
com/content/dam/abbvie-dotcom/clinical-trials/glecaprevir_pibrentasvir_M15-828_Redacted.
pdf, accessed 29 September 2019).
4. Abbvie - M13-594 Clinical Study Report - Final. A Randomized, Open-Label, Active-Controlled,
Multicenter Study to Compare Efficacy and Safety of ABT-493/ABT-530 to Sofosbuvir Co-
Administered with Daclatasvir in Adults with Chronic Hepatitis C Virus Genotype 3 Infection
(ENDURANCE-3) [website]. (https://www.abbvie.com/content/dam/abbvie-dotcom/clinical-trials/
glecaprevir_pibrentasvir_M13-594_Redacted.pdf, accessed 29 September 2019).
5. Belperio P, Shahoumian T, Loomis T, Mole L, Backus LI. Real‐World Effectiveness of Glecaprevir/
Pibrentasvir in 1,941 Patients with Hepatitis C Genotypes 1 through 4. Poster Abstract 703.
Hepatology. 2018;68(S1):417A-418A.
6. Curry MP, Bacon BR, Flamm SL, Marks M, Milligan S, Tsai NCS et al. Preferences in Clinical
Practice with Glecaprevir/Pibrentasvir (GLE‐PIB), Ledipasvir/ Sofosbuvir (LDV‐SOF), and
Sofosbuvir/Velpatasvir (SOF‐VEL); Data from the Trio Network. Poster Abstract 678. Hepatology.
2018;68(S1):402A.
7. D’Ambrosio R, Pasulo L, Puoti M, Vinci M, Schiavini M, Lazzaroni S et al. Real-world effectiveness
and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C. J Hepatol. 2019;
70(3):379–387.
8. Puigvehi M, Albillos A, Viu A, Hernandez Guerra MN, Fernandez I, Prieto M et al. Effectiveness and
Safety of Glecaprevir/Pibrentasvir for the Pangenotypic Treatment of Chronic Hepatitis C: Results
from a Spanish Cohort (Hepa‐C). Poster Abstract 601. Hepatology. 2018;68(S1):657A.
9. Wiegand J, Naumann U, Stoehr A, Sick C, John C, Teuber G et al. Glecaprevir/Pibrentasvir for the
Treatment of Patients with Chronic Hepatitis C Virus Infection: Updated Real‐World Data from
the German Hepatitis C‐Registry. Poster Abstract 611. Hepatology. 2018;68(S1):364A.
10. Zoratti M. Web Annex 3.1. Adult hepatitis C virus treatment systematic review. In: Guidelines
for the care and treatment of persons diagnosed with chronic hepatitis C virus infection.
handle/10665/277215/WHO-CDS-HIV-18.36-eng.pdf, accessed 29 September 2019.
11. Zoratti M. Web Annex 3.2. Adult hepatitis C virus treatment systematic review: supporting
evidence. In: Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C
virus infection. Geneva: World Health Organization; 2018. Available from https://apps.who.int/
iris/bitstream/handle/10665/277216/WHO-CDS-HIV-18.37-eng.pdf, accessed 29 September 2019.
149
6.5 Antiprotozoal medicines

6.5.3 Antimalarial medicines
6.5.3.2 For chemoprevention
Sulfadoxine + pyrimethamine – new indication IPTi – EMLc
Sulfadoxine + pyrimethamine ATC Code: P01BD51
Proposal
The application requested listing of sulfadoxine + pyrimethamine fixed-dose
combination tablet on the core list of the EMLc for the new indication of
intermittent preventive treatment (of malaria) in infancy (IPTi).
Applicant
WHO Global Malaria Programme

Global Malaria Programme
EML/EMLc
EMLc
Section
6.5.3.2 Antimalarial medicines – For chemoprevention

Tablet 250 mg + 12.5 mg
Core/Complementary
Core

Individual

Sulfadoxine + pyrimethamine 500 mg + 25 mg tablets are currently included on
the EML and EMLc for use in combination with artesunate 50 mg for the curative
treatment of malaria.
150

Malaria is one of the leading causes of illness, death and lost economic
productivity globally. In 2017, there were an estimated 219 million malaria
cases worldwide, the majority of which occurred in the African region (92%,
200 million cases) (1). Of the 435 000 deaths due to malaria globally in 2017,
266 000 (61%) were in children under 5 years of age.

The application presented the findings of a pooled analysis of six randomized,
placebo-controlled trials in 7930 infants that investigated the efficacy and safety
of IPTi with sulfadoxine + pyrimethamine (IPTi-SP) in four African countries
with moderate to high transmission of malaria, when administered to infants at
the time of routine vaccination according to the WHO Expanded Programme
on Immunization (EPI) (2).
From the pooled analysis, the combined estimate of protective efficacy
of IPTi-SP against clinical malaria in infants aged up to 1 year of age was 30.3%
(95%CI 19.8% to 39.4%, p<0.0001).
IPTi-SP was also associated with protective efficacy in infants up to 1 year
of age for anaemia (21.3% (95%CI 8.3% to 32.5%, p=0.002)), all-cause hospital
admissions (22.9% (95%CI 10.0% to 34.0%, p=0.001)), and hospital admissions
associated with malaria parasitaemia (38.1% (95%CI 12.5% to 56.2%, p=0.007)).

SP for intermittent preventive treatment in infancy is generally well tolerated.
Studies showed no evidence of any adverse effects of SP-IPTi on infants’
serological responses to vaccines (e.g. DTP, polio, hepatitis B, Haemophilus
influenzae B, yellow fever or measles). A rebound effect in terms of greater
susceptibility to malaria after termination of SP-IPTi, although reported in some
studies, was not found in the pooled analysis, where the pooled estimate of
protective efficacy of IPTi-SP against clinical malaria for the potential rebound
period was 9.5% (95%CI 0.3% to 17.8%, p=0.044) (2).
Surveillance of molecular markers of SP resistance should accompany
SP-IPTi, in particular the distribution and prevalence of Pfdhps 540 mutations,
which is a surrogate measure of SP efficacy.
Use pf IPTi-SP is contraindicated in individuals with known
hypersensitivity to pyrimethamine, sulfonamides and related compounds and
infants receiving a sulfa-based medication for treatment or prophylaxis, including
co-trimoxazole (trimethoprim–sulfamethoxazole), which is widely used as
prophylaxis against opportunistic infections in HIV-infected infants.
151

A 2011 systematic review of the cost and the cost-effectiveness of malaria
interventions found that the median financial cost of IPTi-SP for protecting one
person for one year was US$ 0.60 (range US$ 0.48 to US$ 1.08) (3).
A study by Conteh et al of the cost-effectiveness of IPTi in sub-Saharan
Africa found the cost per malaria episode averted for IPTi-SP was very low,
US$ 1.36 to US$ 4.03 based on trial specific data (US$ 0.68 to US$ 2.27 on pooled
analysis). The authors concluded that IPTi delivered with the EPI was a highly
cost-effective intervention against clinical malaria (4).
WHO Guidelines
A 2010 WHO policy recommendation on IPTi-SP recommends the co-
administration of SP-IPTi with DTP2, DTP3 and measles immunization to
infants, through routine EPI in countries in sub-Saharan Africa, in areas with
moderate-to-high malaria transmission (i.e. annual entomological inoculation
rates ≥10), and where parasite resistance to SP is not high – defined as a
prevalence of the pfdhps 540 mutation of ≤50% (5).
This recommendation was not re-evaluated during the guideline
development process for the 2015 WHO Guidelines for the treatment of malaria
(3rd edition). The same recommendation is included in the 2015 Guidelines,
however the quality of evidence was not formally assessed (6).
No information was provided in the application.
Availability
A paediatric formulation of sulfadoxine + pyrimethamine 250 mg + 12.5 mg is
currently under assessment by the WHO Prequalification Programme.
The administered dose of IPTi-SP depends on the weight of the child:

■■ Children weighing less than 5 kg should be given 125 mg sulfadoxine
and 6.25 mg pyrimethamine.
■■ Children weighing 5 kg or more should be given 250 mg sulfadoxine
and 12.5 mg pyrimethamine.
The successful implementation of SP-IPTi requires that national malaria control
and EPI programmes work together. WHO, working with UNICEF developed an
implementation guide which provides the necessary technical and operational
152
information and tools for country-level policy-makers and programme managers

to decide on how to include SP-IPTi with immunization services (7). In areas
where SP-IPTi is implemented each child will be given SP three times in their
first year of life when they receive routine vaccinations as follows:
■■ First SP-IPTi dose (SP-IPTi1) when DTP2/Penta2 (or combo)
vaccination is given (i.e. 8-10 weeks of age)
■■ Second SP-IPTi dose (SP-IPTi2) when DTP3/Penta3 (or combo)
vaccination is given (12-14 weeks of age)
■■ Third SP-IPTi dose (SP-IPTi3) at the time of measles vaccination
(nine months)
The exact timing of the doses may vary according to the national
immunization schedule for DTP and measles vaccination.
The Expert Committee recommended listing of sulfadoxine + pyrimethamine
250 mg + 12.5 mg fixed-dose combination tablet on the core list of the EMLc
for the new indication of intermittent preventive treatment (of malaria) in
infancy (IPTi) on the basis of demonstrated efficacy and acceptable safety, and
in alignment with WHO malaria guideline recommendations.
The Expert Committee noted the lack of evidence of the impact of the
use of SP-IPTi on antimicrobial resistance, and encouraged further assessment
and monitoring in this regard within programme delivery.
References
1. World Malaria Report 2018. Geneva: World Health Organization; 2018. Available from https://
apps.who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf?ua=1, accessed 29
September 2019.
2. Aponte JJ, Schellenberg D, Egan A, Breckenridge A, Carneiro I, Critchley J et al. Efficacy and safety of
intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants:
a pooled analysis of six randomised, placebo-controlled trials. Lancet. 2009;374(9700):1533–42.
3. White MT, Conteh L, Cibulskis R, Ghani AC. Costs and cost-effectiveness of malaria control
interventions--a systematic review. Malar J. 2011;10:337.
4. Conteh L, Sicuri E, Manzi F, Hutton G, Obonyo B, Tediosi F et al. The cost-effectiveness of
intermittent preventive treatment for malaria in infants in Sub-Saharan Africa. PLoS One. 2010;
5(6):e10313.
5. WHO Policy recommendation on Intermittent Preventive Treatment during infancy with
sulphadoxine-pyrimethamine (SP-IPTi) for Plasmodium falciparum malaria control in Africa.
Geneva: World Health Organization; 2010. Available from https://www.who.int/malaria/news/
WHO_policy_recommendation_IPTi_032010.pdf, accessed 29 September 2019.
153
6. Guidelines for the treatment of malaria - 3rd edition. Geneva: World Health Organization; 2015.
Available from http://apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.pdf?ua
=1&ua=1, accessed 29 September 2019.
7. Intermittent preventive treatment for infants using sulfadoxine-pyrimethamine (SP-IPTi) for
malaria control in Africa: Implementation Field Guide. Geneva: World Health Organization; 2011.
Available from https://apps.who.int/iris/bitstream/handle/10665/70736/WHO_IVB_11.07_eng.
pdf, accessed 29 September 2019.
154
Sulfadoxine + pyrimethamine – new indication IPTp – EML
Sulfadoxine + pyrimethamine ATC Code: P01BD51
Proposal
The application requested listing of sulfadoxine + pyrimethamine (SP) fixed-
dose combination tablet on the core list of the EML for the new indication of
intermittent preventive treatment (of malaria) in pregnancy (IPTp).
Applicant

EML/EMLc
EML
Section
6.5.3.2 Antimalarial medicines - For chemoprevention

Tablet 500 mg + 25 mg
Core/Complementary
Core

Individual

Sulfadoxine + pyrimethamine 500 mg + 25 mg tablets are currently included
on the EML and EMLc for use in combination with artesunate 50 mg for the
curative treatment of malaria.

Malaria is one of the leading causes of illness, death, and lost economic
productivity globally. While there has been successful scale up and use of critical
commodities, malaria still resulted in over 219 million cases and more than
435 000 deaths in 2017; most of the deaths occurred in children under 5 years of
age and pregnant women (1).
155
In sub-Saharan Africa (SSA), over 30 million pregnant women are

annually exposed to infection from malaria (2). Of these, an estimated 10 000
pregnant women and up to 200 000 newborns die from malaria in pregnancy
(MiP), primarily due to infection with Plasmodium falciparum (3). Furthermore,
recent data indicate that up to 20% of stillbirths in SSA are attributable to
MiP (4).
WHO recommends that IPTp-SP be given to all pregnant women at
each antenatal care visit, starting as early as possible in the second trimester (i.e.
not during the first trimester) (5). Each IPTp-SP dose should be given at least
one month apart, with at least three doses during each pregnancy. The expected
benefits of IPTp-SP include:
–– Prevention of the adverse consequences of malaria on maternal
and fetal outcomes, such as placental infection, clinical
malaria, maternal anaemia, fetal anaemia, low-birth-weight
and neonatal mortality (6).
–– A cost-effective intervention for both prevention of maternal
malaria and reduction of neonatal mortality in areas with
moderate or high malaria transmission (7).
–– Protection against both neonatal mortality (protective efficacy
18%) and low-birth-weight (21% reduction) under routine
programme conditions (8).
To date, 39 African countries have adopted this policy. However, there
is an unacceptably low proportion of eligible pregnant women receiving IPTp
with quality-assured SP: only an estimated 22% of pregnant women received
three doses of IPTp-SP in 2017 (1). It has been estimated that if all women with
at least three antenatal care visits in Africa received IPTp-SP, that an additional
215 000 (95% credible interval (crI) 128 000 to 318 000) low-birth-weight
deliveries could be prevented (9).

The application presented the findings of a systematic review of seven trials (6281
pregnancies) in which a direct comparison of two doses of IPTp-SP with three or
more doses at least one month apart was evaluated (10). The trials were conducted
in Burkina Faso, Kenya, Malawi, Mali and Zambia between 1996 and 2008. In
comparison with two doses of SP, three or more doses was associated with:
■■ increased mean birth weight by an average of 56 g (95%CI 29 to 83;
seven trials, 2190 participants, high quality evidence);
■■ fewer low-birth-weight infants by about 20% (relative risk (RR) 0.80;
95%CI 0.69 to 0.94; absolute risk reduction, 33 per 1000 (95%CI 10 to
52); NNT = 31; seven trials, 2190 participants, high quality evidence);
156
■■ reduced placental parasitaemia by about 50% (RR, 0.51; 95%CI 0.38

to 0.68; absolute risk reduction, 31 per 1000 (95%CI 20 to 39); six
trials, 1436 participants, high quality evidence); and
■■ reduced maternal parasitaemia by about 33% (RR, 0.68; 95%CI 0.52
to 0.89; seven trials, 2096 participants, moderate quality evidence).
The reduction in risk for low-birth-weight was consistent for a wide
range of levels of resistance to SP.

There were no differences in rates of serious adverse events between treatment
groups in the systematic review mentioned above (10).
IPTp-SP is generally very well tolerated. Mild and transient side-effects
including nausea, vomiting, weakness and dizziness have been reported by some
women, particularly with the first dose. Studies have demonstrated that side-
effects tend to decrease with the administration of further doses (11, 12).
The adverse effects reported are mainly those associated with
sulfonamides, including gastrointestinal disturbances, headache, dizziness and
skin reactions such as photosensitivity, rash, pruritus, urticaria and slight hair loss
(13–16). Potentially fatal skin reactions, namely erythema multiforme, Stevens–
Johnson syndrome and toxic epidermal necrolysis, have also been reported.
Demonstrated drug–drug interactions have been observed between
SP and high doses (>5 mg) folic acid resulting in reduced efficacy of SP
(17). Concurrent use with trimethoprim, alone or in combination with
sulfamethoxazole should be avoided due to increased risk of severe cutaneous
reactions (18).
There is limited evidence of potential teratogenicity when SP is used
during the first trimester of pregnancy (13, 19). Use of SP during the first
trimester is not recommended.

N/A
WHO Guidelines
The 2015 WHO Guidelines for the treatment of malaria (5) make the following
recommendation regarding IPTp-SP:
In malaria-endemic areas in Africa, provide IPTp-SP to all women in
their first or second pregnancy as part of antenatal care. Dosing should start
in the second trimester and doses should be given at least one month apart,
with the objective of ensuring that at least three doses are received (strong
recommendation, high quality evidence).
157
SP is an inexpensive medicine, and most countries already have a delivery
system for IPTp-SP in place, which is often integrated into a comprehensive
focused antenatal care (FANC) package.
In comparison to placebo, in Mozambique, delivery of two doses
of IPTp-SP has been estimated to cost US$ 41.46 (95%CI 20.50 to 96.70) per
maternal outpatient visit averted. This same study estimated an incremental
cost effectiveness ratio (ICER) of US$ 1.08 (95%CI 0.43 to 3.48) per disability-
adjusted life-year (DALY) averted (7). Additionally, using data from seven
countries, the incremental cost-effectiveness of three or more doses of IPTp-SP
(compared to two doses) has been estimated at US$ 7.28 (20).
The WHO recommendations on intermittent screening and treatment in
pregnancy and the safety of ACTs in the first trimester (21) state that IPTp-SP
remains highly cost-effective in preventing the adverse consequences of malaria
on maternal and fetal outcomes, and should therefore be actively scaled up in
line with the current WHO recommendations. The threshold level of malaria
transmission below which IPTp-SP is no longer cost-effective has not been
identified. Therefore, in areas where IPTp-SP is implemented and transmission
has been reduced to low levels as a result of successful control strategies, WHO
recommends continued IPTp-SP implementation until the area approaches
interruption of transmission.
Availability
Quality assured sulfadoxine + pyrimethamine 500 mg + 25 mg tablets are
available from Guilin Pharmaceuticals (China) with WHO prequalification
status. Quality-assured sulfadoxine + pyrimethamine 500 mg/25 mg tablets are
also available from Remedica Pharmaceuticals (Cyprus).
Starting as early as possible in the second trimester, IPTp-SP is recommended

for all pregnant women at each scheduled antenatal care visit until the time of
delivery, provided that the doses are given at least one month apart. IPTp-SP
should ideally be administered as directly observed therapy (DOT) of three
tablets sulfadoxine + pyrimethamine 500 mg + 25 mg giving the total required
dosage of 1500 mg + 75 mg SP.
The Expert Committee recommended the listing of sulfadoxine + pyrimethamine
500 mg + 25 mg fixed-dose combination tablet on the core list of the EML for
the new indication of intermittent preventive treatment of malaria in pregnancy
(IPTp) on the basis of demonstrated efficacy in terms of improved outcomes
158
for mothers and newborns, and acceptable safety, and in alignment with WHO
malaria treatment guidelines.
use of SP-IPTp on antimicrobial resistance, and encouraged further assessment
and monitoring in this regard within programme delivery.
References
1. World Malaria Report 2018. Geneva: World Health Organization; 2018. Available from https://
apps.who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf?ua=1, accessed 29
September 2019.
2. Dellicour S, Tatem AJ, Guerra CA, Snow RW, ter Kuile FO. Quantifying the number of pregnancies
at risk of malaria in 2007: a demographic study. PLoS Med. 2010;7(1):e1000221.
3. The contribution of malaria control to maternal and newborn health. Progress and impact series:
Number 10, July 2014. Geneva: World Health Organization and Roll Back Malaria Partnership.
Available from https://apps.who.int/iris/bitstream/handle/10665/126340/9789241507219_eng.
pdf, accessed 29 September 2019.
4. Lawn JE, Blencowe H, Waiswa P, Amouzou A, Mathers C, Hogan D et al. Stillbirths: rates, risk factors,
and acceleration towards 2030. Lancet. 2016;387(10018):587-603.
Available from: http://apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.pdf,
6. Menendez C, Bardaji A, Sigauque B, Sanz S, Aponte JJ, Mabunda S et al. Malaria prevention with
IPTp during pregnancy reduces neonatal mortality. PLoS One. 2010;5(2):e9438.
7. Sicuri E, Bardaji A, Nhampossa T, Maixenchs M, Nhacolo A, Nhalungo D et al. Cost-effectiveness of
intermittent preventive treatment of malaria in pregnancy in southern Mozambique. PLoS One.
2010;5(10):e13407.
8. Eisele TP, Larsen DA, Anglewicz PA, Keating J, Yukich J, Bennett A et al. Malaria prevention in
pregnancy, birthweight, and neonatal mortality: a meta-analysis of 32 national cross-sectional
datasets in Africa. Lancet Infect Dis. 2012;12(12):942–9.
9. Walker PG, Floyd J, Ter Kuile F, Cairns M. Estimated impact on birth weight of scaling up
intermittent preventive treatment of malaria in pregnancy given sulphadoxine-pyrimethamine
resistance in Africa: A mathematical model. PLoS Med. 2017;14(2):e1002243.
10. Kayentao K, Garner P, van Eijk AM, Naidoo I, Roper C, Mulokozi A et al. Intermittent preventive
therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine
and risk of low birth weight in Africa: systematic review and meta-analysis. JAMA. 2013;309(6):
594–604.
11. Clerk CA, Bruce J, Affipunguh PK, Mensah N, Hodgson A, Greenwood B et al. A randomized,
controlled trial of intermittent preventive treatment with sulfadoxine-pyrimethamine,
amodiaquine, or the combination in pregnant women in Ghana. J Infect Dis. 2008;198(8):1202–11.
12. Tagbor H, Bruce J, Browne E, Randal A, Greenwood B, Chandramohan D. Efficacy, safety, and
tolerability of amodiaquine plus sulphadoxine-pyrimethamine used alone or in combination for
malaria treatment in pregnancy: a randomised trial. Lancet. 2006;368(9544):1349–56.
159
13. Peters PJ, Thigpen MC, Parise ME, Newman RD. Safety and toxicity of sulfadoxine/pyrimethamine:
implications for malaria prevention in pregnancy using intermittent preventive treatment. Drug
Saf. 2007;30(6):481–501.
14. Luntamo M, Kulmala T, Mbewe B, Cheung YB, Maleta K, Ashorn P. Effect of repeated treatment
of pregnant women with sulfadoxine-pyrimethamine and azithromycin on preterm delivery in
Malawi: a randomized controlled trial. Am J Trop Med Hyg. 2010;83(6):1212–20.
15. Maokola W, Chemba M, Hamisi Y, Mrisho M, Shirima K, Manzi F et al. Safety of sulfadoxine/
pyrimethamine for intermittent preventive treatment of malaria in infants: evidence from large-
scale operational research in southern Tanzania. Int Health. 2011;3(3):154–9.
16. Mutabingwa TK, Muze K, Ord R, Briceno M, Greenwood BM, Drakeley C et al. Randomized trial of
artesunate+amodiaquine, sulfadoxine-pyrimethamine+amodiaquine, chlorproguanal-dapsone
and SP for malaria in pregnancy in Tanzania. PLoS One. 2009;4(4):e5138.
17. Ouma P, Parise ME, Hamel MJ, Ter Kuile FO, Otieno K, Ayisi JG et al. A randomized controlled trial
of folate supplementation when treating malaria in pregnancy with sulfadoxine-pyrimethamine.
PLoS Clin Trials. 2006;1(6):e28.
18. Gimnig JE, MacArthur JR, M’Bang’ombe M, Kramer MH, Chizani N, Stern RS et al. Severe
cutaneous reactions to sulfadoxine-pyrimethamine and trimethoprim-sulfamethoxazole in
Blantyre District, Malawi. Am J Trop Med Hyg. 2006;74(5):738–43.
19. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy
and the risk of birth defects. N Engl J Med. 2000;343(22):1608–14.
20. Fernandes S, Sicuri E, Kayentao K, van Eijk AM, Hill J, Webster J et al. Cost-effectiveness of two
versus three or more doses of intermittent preventive treatment for malaria during pregnancy
in sub-Saharan Africa: a modelling study of meta-analysis and cost data. Lancet Glob Health.
2015;3(3):e143–53.
21. Recommendations on intermittent screening and treatment in pregnancy and the safety of ACTs
in the first trimester. Geneva: World Health Organization; 2015. Available from https://www.who.
int/malaria/publications/atoz/istp-and-act-in-pregnancy.pdf, accessed 29 September 2019.
160
Amodiaquine with sulfadoxine + pyrimethamine – addition – EMLc
Amodiaquine with sulfadoxine + ATC Code: P01BA06,

pyrimethamine P01BD51
Proposal
The application requested the addition of co-packaged amodiaquine with
sulfadoxine + pyrimethamine to the core list of the EMLc for seasonal malaria
chemoprevention (SMC) in children.
Applicant

EML/EMLc
EMLc
Section
6.5.3.2 Antimalarial medicines - For chemoprevention

Co-packaged amodiaquine dispersible tablet 76.5 mg (as hydrochloride)
[3 tablets] and sulfadoxine + pyrimethamine dispersible tablet 250 mg + 12.5 mg
[1 tablet]
Co-packaged amodiaquine dispersible tablet 153 mg (as hydrochloride)
[3 tablets] and sulfadoxine + pyrimethamine dispersible tablet 5000 mg + 25 mg
[1 tablet]
Core/Complementary
Core

Individual

Amodiaquine and sulfadoxine + pyrimethamine are both listed on the EMLc for
use in combination with artesunate for the curative treatment of malaria. These
medicines have not previously been considered for use in malaria prophylaxis/
prevention.
161

Malaria is one of the leading causes of illness, death and lost economic
productivity globally. In 2017, there were an estimated 219 million malaria
cases worldwide, the majority of which occurred in the African region (92%,
200 million cases) (1). Of the 435 000 deaths due to malaria globally in 2017,
266 000 (61%) were in children under 5 years of age.
Across the Sahel sub-region in Africa, most childhood morbidity and
mortality from malaria occurs during the rainy season, which is generally
short. Giving effective antimalarial medicines – at full treatment doses and at
appropriate intervals during this period – has been shown to prevent illness and
death from malaria in children.
The interventions currently recommended by WHO for the control of
malaria are use of long-lasting insecticidal mosquito nets and/or indoor residual
spraying for vector control, prompt access to diagnostic testing of suspected
cases and treatment of confirmed cases with effective artemisinin-based
combination therapy. In addition to these, other interventions recommended
for specific high-risk groups in areas of high transmission include intermittent
preventive treatment in pregnancy (IPTp) and infancy (IPTi). With the changing
epidemiology of malaria, there has been a progressive shift from a ‘one size fits
all’ approach to targeting malaria control strategies to specific populations and/
or locations for maximal effectiveness. In line with this approach and on the
basis of new evidence, WHO recommends an additional intervention against
Plasmodium falciparum malaria: seasonal malaria chemoprevention (SMC). The
objective of preventive treatment is to prevent malarial illness by maintaining
therapeutic drug levels in the blood throughout the period of greatest risk (2).

A 2012 Cochrane systematic review of seven trials (12 589 participants) evaluated
the effects of seasonal malaria chemoprophylaxis compared with no prophylaxis

in children aged 6 years or less living in areas of West Africa with seasonal
malaria transmission (3). In three studies, amodiaquine (AQ) and sulfadoxine
+ pyrimethamine (SP) was administered monthly at full treatment doses, two
studies used SP every two months, and one study used SP and artesunate
monthly, during the malaria transmission season.
In comparison with no chemoprophylaxis, SMC was associated with
markedly reduced clinical malaria episodes (rate ratio (RR) 0.26, 95%CI 0.17
to 0.38) and serious malaria episodes (RR 0.17, 95%CI 0.1 to 0.76). SMC may
also be associated with a reduction in mortality (RR 0.66, 95%CI 0.31 to 1.39)
and a reduction in moderately severe anaemia (RR 0.71, 95%CI 0.52 to 0.98).
The findings were consistent in trials in which there was high (>90%) use of
insecticide-treated bednets (3).
162

AQ + SP are safe and well tolerated when used at the recommended doses and
regimens. Both drugs have been used for decades for malaria treatment, and SP
is currently used for intermittent preventive treatment of malaria in pregnancy
and in infancy.
Both AQ and SP are also used in combination with artesunate as
artemisinin-based combination therapy, which is used for the treatment of
uncomplicated malaria in many endemic countries.
In Senegal, where nearly 800 000 treatment courses of SP + AQ within
SMC have been given to children, no serious adverse events attributable to these
drugs were observed during intensive pharmacovigilance based on spontaneous
reporting (4).
AQ + SP is generally well tolerated in children. Mild side-effects may
occur, of which the most common is vomiting associated with intake of AQ.
No serious adverse events attributable to AQ + SP have been reported in trials
involving children (5–7).
SMC with AQ + SP is contraindicated in children receiving sulfa-
based medication for treatment or prophylaxis, including sulfamethoxazole
+ trimethoprim, which is widely used as prophylaxis against opportunistic
infections in HIV-infected infants.

N/A
WHO Guidelines
The 2015 WHO Guidelines for the treatment of malaria recommend SMC with
monthly AQ + SP for all children aged less than 6 years during each transmission
season in areas with highly seasonal malaria transmission in the sub-Sahel
region of Africa (strong recommendation, high quality evidence) (8).
The guideline recommendation was informed by the Cochrane systematic
review mentioned above (3).
Evaluation of the cost of delivering SMC in large field trials shows that the
greatest costs are associated with delivering the drugs and the incentives paid to
health workers. In Gambia, the cost of SMC delivery by village health workers
was estimated to be US$ 1.63 per child per year (9). In Senegal, where SMC was
delivered by community health workers paid a daily rate and supervised by the
health post nurse, the overall cost at 46 health posts was estimated to be US$ 0.5
per child per month, or approximately US$ 1.50 per child per year (10). The cost
of SMC is similar to those of other malaria control interventions (11).
163
Availability
Co-packaged sulfadoxine + pyrimethamine and amodiaquine tablets are
currently available on the market from three manufacturers and have been
prequalified by the WHO Prequalification Programme.
N/A
The Expert Committee recommends the addition of co-packaged amodiaquine
with sulfadoxine + pyrimethamine to the core list of the EMLc for seasonal
malaria chemoprevention in children on the basis of acceptable safety and
demonstrated benefits for reducing clinical malaria episodes, serious malaria
episodes and reduced rates of mortality and anaemia, and in alignment with
WHO malaria guidelines.
use of amodiaquine with sulfadoxine + pyrimethamine for SMC on antimicrobial
resistance, and encouraged further assessment and monitoring in this regard
within programme delivery.
References
1. World Malaria Report 2018. Geneva: World Health Organization; 2018. Available from https://apps.
who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf, accessed 29 September
2019.
2. World Health Organization. WHO Policy Recommendation: Seasonal malaria chemoprevention
(SMC) for Plasmodium flaciparum malaria control in highly seasonal transmission areas of the
Sahel sub-region in Africa. March 2012. Available from https://www.who.int/malaria/mpac/
feb2012/smc_policy_recommendation.pdf, accessed 29 September 2019.
3. Meremikwu MM, Donegan S, Sinclair D, Esu E, Oringanje C. Intermittent preventive treatment

for malaria in children living in areas with seasonal transmission. Cochrane Database Syst Rev.
2012(2):CD003756.
4. Cisse B, Ba EH, Sokhna C, JL ND, Gomis JF, Dial Y et al. Effectiveness of Seasonal Malaria
Chemoprevention in Children under Ten Years of Age in Senegal: A Stepped-Wedge Cluster-
Randomised Trial. PLoS Med. 2016;13(11):e1002175.
5. Dicko A, Diallo AI, Tembine I, Dicko Y, Dara N, Sidibe Y et al. Intermittent preventive treatment
of malaria provides substantial protection against malaria in children already protected by an
insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial. PLoS
Med. 2011;8(2):e1000407.
6. Konate AT, Yaro JB, Ouedraogo AZ, Diarra A, Gansane A, Soulama I et al. Intermittent preventive
treatment of malaria provides substantial protection against malaria in children already
protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind,
placebo-controlled trial. PLoS Med. 2011;8(2):e1000408.
164
7. Sokhna C, Cisse B, Ba el H, Milligan P, Hallett R, Sutherland C et al. A trial of the efficacy, safety and
impact on drug resistance of four drug regimens for seasonal intermittent preventive treatment
for malaria in Senegalese children. PLoS One. 2008;3(1):e1471.
Available from http://apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.pdf,
9. Bojang KA, Akor F, Conteh L, Webb E, Bittaye O, Conway DJ et al. Two strategies for the delivery
of IPTc in an area of seasonal malaria transmission in the Gambia: a randomised controlled trial.
PLoS Med. 2011;8(2):e1000409.
10. Pitt C, Ndiaye M, Conteh L, Sy O, Hadj Ba E, Cisse B et al. Large-scale delivery of seasonal malaria
chemoprevention to children under 10 in Senegal: an economic analysis. Health Policy Plan.
2017;32(9):1256–66.
11. Seasonal malaria chemoprevention with sulfadoxine-pyrimethamine plus amodiaquine in
children: a field guide. Geneva: World Health Organization; 2013. Available from https://apps.
who.int/iris/bitstream/handle/10665/85726/9789241504737_eng.pdf, accessed 29 September
2019.
165
6.5.5 Antitrypanosomal medicines

6.5.5.1 African trypanosomiasis
Fexinidazole – addition – EML and EMLc
Fexinidazole ATC Code: P01CA03
Proposal
The application requested listing of fexinidazole on the core list of the EML and
EMLc for treatment of human African trypanosomiasis due to Trypanosoma
brucei gambiense infection.
Applicant
Sanofi-aventis groupe

Comments on the application were received from the WHO Department of
Neglected Tropical Diseases. The technical unit advised that it supported the
inclusion of fexinidazole on the Model Lists and considered that its introduction
could result in important advantages in the management of human African
trypanosomiasis.
EML/EMLc
EML and EMLc
Section

Tablet 600 mg
Core/Complementary
Core

Individual

Fexinidazole had not previously been considered for inclusion on the Model Lists.
The Model Lists currently include pentamidine and suramin sodium for
treatment of 1st stage African trypanosomiasis and eflornithine, melarsoprol and
nifurtimox for treatment of 2 nd stage African trypanosomiasis (1).
166

Human African trypanosomiasis (HAT), or sleeping sickness, is one of the most
neglected tropical diseases (NTDs). Without diagnosis and treatment, HAT is
usually fatal as the parasites multiply in the body, cross the blood–brain barrier
and invade the central nervous system at the late stage of the disease.
Human African trypanosomiasis takes two forms, depending on the
parasite involved: Trypanosoma brucei gambiense HAT and Trypanosoma brucei
rhodesiense HAT. T. b. rhodesiense causes an acute, rapidly progressive and fatal
disease and is present in 3% of HAT cases. T. b. gambiense is responsible for 97%
of HAT cases (2) and evolves to a fatal outcome between two and three years
after infection (3).
As of October 2012, 7106 annual cases of T. b. gambiense HAT had been
reported worldwide. With the increased efforts of control programmes and
availability of combination therapy with eflornithine and nifurtimox (NECT)
therapy, only 1420 gambiense HAT cases worldwide were reported to WHO
in 2017, the lowest level since the start of the systematic global data collection
75 years ago (4). However, the incidence is suspected to be under reported due to
different elements. The Democratic Republic of Congo (DRC) bears the majority
of disease burden (83–84% of the reported cases in 2012, 2015 and 2016 (4).
In view of the success in control of the disease, T. b. gambiense was
included in the WHO ‘roadmap’ for elimination and control of neglected tropical
diseases. A target date was set for global elimination of HAT as a public health
problem (<1 case/10 000 inhabitants in at least 90% of endemic areas) by 2020
with complete interruption of transmission in Africa targeted for 2030 (5).

Evidence of efficacy is based on data from three (yet to be published) clinical
efficacy and safety studies (DNDiFEX004, DNDiFEX005, and DNDiFEX006),
using data from 749 patients with HAT (from study sites in DRC and Central
African Republic), 619 of which were treated with fexinidazole. FEX006 included
125 paediatric patients aged between 6 and 15 years weighing 20 kg or more.
FEX004 compared fexinidazole and NECT in 394 adult patients (aged
≥15 years) with late stage 2 HAT. The success rate was 91.2% for fexinidazole
and 97.6% for the NECT combination. The primary objective of the study was
met. Fexinidazole was considered an acceptable treatment as the difference in
response compared to NECT was <13% in favour of NECT at 18 months after
the end of treatment (EOT). In the primary analysis, the difference in success rate
between groups remained within the margin of acceptable difference (−6.4%,
97.06% CI −11.2% to −1.6%). However, in the sub-population of patients with
cerebrospinal fluid white blood cell count (CSF-WBC) >100 /μL the efficacy was
86.9% in the fexinidazole arm versus 98.7%% in the NECT arm, and therefore
167
the risk of failure was higher in this sub-group with fexinidazole. The follow-up
analysis of the success rate at 24 months on the complete population (n=389)
yielded similar findings to those with partial data for 24 months at the primary
analysis timepoint (n=345) with only two new failures (one in each group).
FEX005 was an open-label single-arm cohort study of efficacy and
safety of fexinidazole in 230 adult patients with stage 1 or early stage 2 HAT. The
success rate with fexinidazole at 12 months after the EOT (98.7%; 95%CI 96.2%
to 99.7%), was greater than an unacceptable rate of 80%. No difference was seen
in efficacy at 12 months according to the stage of the disease. The success rate at
18 months improved slightly between the initial and follow-up analysis due to the
inclusion of the additional 69 patients in the follow-up analysis (all successes):
97.8% (95%CI 95.0 to 99.3) vs 96.9% (95%CI 92.9 to 99.0) in the initial analysis.
FEX006 was an open-label single-arm prospective study of efficacy and
safety of fexinidazole in 125 children aged ≥6 years and <15 years weighing
over 20 kg with any stage HAT. The success rate with fexinidazole at 12 months
after the EOT (97.6%; 95%CI 93.1% to 99.5%) was greater than an unacceptable
rate of 80% and compatible with a target rate of 92%. The success rate at 18
months improved slightly between the initial and follow-up analysis due to the
inclusion of the additional 40 patients in the follow-up analysis (all successes):
98.4% (95%CI 94.3 to 99.8), vs 97.6% (95%CI 91.8% to 99.7%) in the initial
12-month analysis.

Pooled analyses of data from FEX004, FEX005 and FEX006, revealed findings
consistent with observations from the individual study analyses, with regard
to the incidence of treatment emergent adverse events (TEAEs), TEAEs that
occurred between baseline and end of hospitalization (EOH), TEAEs that
occurred after EOH, and TEAEs that were considered by the Investigator as
possibly related to treatment. A total of 577 of 619 (93%) patients experienced
TEAEs. Overall, 506 of 619 (82%) patients reported a total of 2026 possibly
related TEAEs between initiation of treatment and EOT, with most being mild
or moderate. In study FEX004 in patients with late stage 2 disease, the overall
incidence of TEAEs was comparable between treatment groups (93.6% with
fexinidazole vs 92.3% with NECT).
The most commonly reported TEAEs across all fexinidazole-treated
patients (≥10% of patients) were vomiting (42%), headache (37%), nausea
(35%), asthenia (27%), insomnia (23%), tremor (22%), decreased appetite (20%),
dizziness (19%), dyspepsia (14%) and feeling hot (10%).
Comparing overall TEAEs between fexinidazole and NECT in late
stage 2 patients, there were notable differences between treatment groups;
these included higher rates in the NECT arm of pyrexia, chills, hyperkalaemia,
convulsions and procedural pain; and higher rates in the fexinidazole arm of
168
insomnia, tremor, headache, asthenia, nausea, dizziness, hypocalcaemia, feeling

hot, hypoalbuminaemia, abdominal pain (upper), chest pain and dyspepsia.
Vomiting was reported in a similar percentage of patients. All other TEAEs
occurred with similar frequency with NECT and fexinidazole in late stage 2
HAT patients, suggesting that the AEs were related to the underlying disease
or that both treatments were associated with increased risk of the events to
similar extents.
With regard to risk of QT prolongation, fexinidazole has been associated
with QTcF interval increases and its use is contraindicated in patients at risk of
QT prolongation, uncorrected electrolyte abnormalities, symptomatic cardiac
arrhythmia, clinically relevant bradycardia, severe congestive cardiac failure or
family history of sudden death.
Central nervous system/psychiatric events as well as emesis/vomiting
were observed with fexinidazole treatment. Asymptomatic reversible neutropenia
and elevated liver enzymes that were found at different dose regimens in Chagas
disease patients were not reported in HAT patients with the treatment regimen
used in the HAT studies.

N/A
WHO Guidelines
Fexinidazole received a positive opinion by the European Medicines Agency
(EMA) under Article 58 on 15 November 2018. It is not yet included in the WHO
guidelines or any other national guidelines. However, WHO sleeping sickness
treatment guidelines will be under revision in order to consider integration of
fexinidazole as part of the therapeutic options to treat gambiense HAT.
Drugs for HAT are provided free of charge to the WHO via a public–private
partnership between WHO/Sanofi (pentamidine, melarsoprol and eflornithine)
and WHO/Bayer AG (suramin, nifurtimox).
Under a signed agreement between Sanofi and WHO, drugs are
donated to WHO, to be used exclusively for the treatment of HAT. Requests for
supplies are made to WHO by governments of disease-endemic countries and
organizations working in association with these governments. Stock control and
shipment of the drugs are undertaken by Médecins sans Frontières-Logistique
according to the agreement. Transport costs to countries are paid by Sanofi
through its partnership with WHO.
Similar to NECT and other HAT drugs, fexinidazole will be distributed
free of charge through the WHO Neglected Tropical Diseases Department to
169
national sleeping sickness control programmes (NSSCPs) and from there to

treatment centres. The product will not be available through wide logistics of
pharmacies or out of the predefined distribution system. No return on investment
is expected.
With NECT, indirect costs including transport to hospital, food and
hospitalization costs are born by the patients. They should be significantly
reduced with fexinidazole when patients are not hospitalized and can be treated
close to their home.
Availability
Fexinidazole is a new oral treatment for sleeping sickness disease and is not yet
distributed.
An application for fexinidazole was submitted to European Medicines
Agency (EMA) through Article 58 of Regulation (EC) No 726/2004. Article 58
is a mechanism whereby the EMA may give a scientific opinion, in cooperation
with the WHO, for the evaluation of medicinal products intended to prevent
or treat diseases of major public interest and exclusively intended for markets
outside the European Community. A positive opinion from EMA was given on
15 November 2018 for the following indication:
“Fexinidazole Winthrop is indicated for the treatment of both the first-
stage (haemo-lymphatic) and the second-stage (meningo-encephalitic) of human
African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense in adults
and children ≥6 years old and weighing ≥20 kg. Fexinidazole should be used in
line with official recommendations”
However, lower efficacy of fexinidazole as compared to NECT has been
seen in a sub-group of patients. Patients with cerebrospinal fluid white blood
count (CSF-WBC) >100/µL should only be treated with fexinidazole if no other
adequate treatment (e.g. NECT) is available or tolerated.
Registrations in DRC and Uganda are also scheduled. Further registrations

in other endemic African countries are not planned due to the specific registration
regulatory picture for human African trypanosomiasis products and related
distribution systems.
Since 2009, NECT has become the first-line therapy for stage 2 HAT due to T. b.
gambiense and has improved the prognosis of treated patients (6), replacing
monotherapy with eflornithine. NECT treatment requires a minimum health
infrastructure and personnel to administer two slow infusions every day for
seven days, on top of an oral treatment every 8 hours for 10 days, requiring
systematic hospitalization, as well as being resource consuming for skilled
health staff in the environment in which HAT patients live (remote, poor
170
areas with little health infrastructure). NECT is not recommended for early
stage disease, instead, patients are treated with pentamidine administered via
intramuscular injections.
Second line-therapy for stage 2 HAT due to T. b. gambiense includes
melarsoprol, an organoarsenic compound, which is highly toxic and to which
resistance has developed (7). Intravenous injections of melarsoprol are painful
and can cause phlebitis. The drug has been administered by use of lengthy
and complicated dosing schedules, however, an abbreviated 10-day regimen of
melarsoprol has been developed.
The limitations associated with current HAT therapy include mandatory
hospitalization and need for equipment and skilled and trained health staff to
administer IV infusions and/or injections. The repeated infusions needed with
current HAT therapy are not only painful but increase the risk of infection for
the patient.
The distribution of treatment to remote health facilities due to heavy
components (38 kg per box which includes four treatments comprising drugs,
solvents and equipment), is also a costly logistical challenge (8).
Fexinidazole is orally administered once daily with food for 10 days.
Recommended dosage regimens are according to body weight.
The Expert Committee recommended the listing of fexinidazole on the core list
of the EML and EMLc for treatment of human African trypanosomiasis due to
Trypanosoma brucei gambiense infection.
The Committee noted that fexinidazole was demonstrated in clinical
trials to have success rates within acceptable margins compared to NECT, and
acceptable safety. The Committee acknowledged that as an orally administered
treatment, use of fexinidazole may offer both patient and health system advantages
compared to parenteral administration of other medicines for this disease.
The Committee noted that fexinidazole would be provided free of charge
through the WHO NTD department to national sleeping sickness control
programmes and treatment centres, and could contribute to the goal of disease
eradication, particularly in areas where access to health facilities is limited.
References:
Essential Medicines for Children). Geneva: World Health Organization; 2017. (WHO Technical
Report Series, No. 1006). Available from https://apps.who.int/iris/bitstream/handle/10665/
2. Franco JR, Cecchi G, Priotto G, Paone M, Diarra A, Grout L et al. Monitoring the elimination of
human African trypanosomiasis: Update to 2014. PLoS Negl Trop Dis. 2017;11(5):e0005585.
171
3. Simarro PP, Diarra A, Ruiz Postigo JA, Franco JR, Jannin JG. The human African trypanosomiasis
control and surveillance programme of the World Health Organization 2000-2009: the way
forward. PLoS Negl Trop Dis. 2011;5(2):e1007.
4. Global Health Observatory data repository - Number of new reported cases (T.b. gambiense) -
Data by country [website]. Last updated 20 September 2016. Geneva: World Health Organization;
2016. (http://apps.who.int/gho/data/node.main.A1636, accessed 30 October 2019).
5. Control and surveillance of human African trypanosomiasis: report of a WHO Expert Committee
2013. WHO Technical Report Series, No. 984. Geneva: World Health Organization; 2013.
6. Simarro PP, Franco J, Diarra A, Postigo JA, Jannin J. Update on field use of the available drugs for
the chemotherapy of human African trypanosomiasis. Parasitology. 2012;139(7):842–6.
7. Bisser S, N’Siesi FX, Lejon V, Preux PM, Van Nieuwenhove S, Miaka Mia Bilenge C et al. Equivalence
trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of
second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis. 2007;195(3):322–9.
8. Simarro PP, Cecchi G, Franco JR, Paone M, Diarra A, Ruiz-Postigo JA, et al. Mapping the capacities
of fixed health facilities to cover people at risk of gambiense human African trypanosomiasis. Int
J Health Geogr. 2014;13:4.
172

Ivermectin – new indication scabies – EML and EMLc
Ivermectin ATC Code: P02CF01
Proposal
The application requested listing of ivermectin on the core list of the EML and
EMLc for the new indication of treatment of scabies.
Applicant
International League of Dermatological Societies
International Alliance for the Control of Scabies
WHO Department of Control of Neglected Tropical Diseases

Department of Control of Neglected Tropical Diseases
EML/EMLc
EML and EMLc
Section

Tablet (scored) 3 mg
Core/Complementary
Core

Individual

Ivermectin is currently included on the EML and EMLc as an intestinal
anthelminthic and antifilarial treatment.
Only topical therapies for scabies (benzyl benzoate and permethrin) are
currently included on the Model Lists.
173

Scabies is seen in all countries. In many resource-poor settings, prevalence
rates of infestation can exceed 20% of the population and the most vulnerable
members of society, children (1) and the elderly, are at highest risk.
In 2015, the global prevalence of scabies was over 200 million (2).
Globally, scabies was responsible for 0.21% of disability-adjusted life-years
(DALYs) from all conditions studied by the Global Burden of Disease Study
2015 (2).
A major complication of scabies with lasting consequences for health,
seen most in resource-poor settings, is symptomatic acute glomerulonephritis
(AGN), which was reported in 10% of children in a survey in northern Australia,
while 24% had microscopic haematuria (3). AGN was closely linked to skin sores
due to streptococcal infection, and scabies was identified as the principal cause.
Scabies infestation is also an epidemiological risk factor for rheumatic fever and
there is a strong association with scabies-associated streptococcal infections (4).
One study has identified a possible link between scabies and bacterial sepsis
caused by Staphylococcus aureus in infants in the Gambia (5).
Household economic loss due to scabies is also a major problem in
resource-poor communities. A study in rural Mexico indicated that families
were spending a significant part of their household income on ineffective topical
treatment of scabies (US$ 24) over each 3-month period, impacting the ability
to purchase other commodities, including food (6).
Scabies in resource-poor environments is therefore both a potential
cause of serious morbidity and a source of financial burden. Its high prevalence
places a huge burden on stretched health care resources.

The application presented the results of a 2018 Cochrane systematic review of 15
studies (1896 participants) comparing topical permethrin, systemic ivermectin
or topical ivermectin for treatment of scabies (7).

The response to oral ivermectin was found to be equivalent to the
response to topical permethrin, two and four weeks after treatment. 200 μg/kg
oral ivermectin (was associated with slightly lower rates of complete clearance
after one week compared to permethrin 5% cream. Using the average clearance
rate of 65% in the trials with permethrin, the illustrative clearance with
ivermectin was 43% (RR 0.65, 95%CI 0.54 to 0.78; 613 participants, six studies;
low certainty evidence).
After two weeks, there was no significant difference (illustrative clearance
of permethrin 74% compared to ivermectin 68%; RR 0.91, 95%CI 0.76 to 1.08;
459 participants, five studies; low certainty evidence). In this review, there
did not appear to be any advantage in repeated treatments in conventional
174
cases of scabies. Hence treatment with one to three doses of ivermectin or

one to three applications of permethrin led to little or no difference in rates
of complete clearance after four weeks follow‐up (illustrative cures with
one to three applications of permethrin 93% and with one to three doses of
ivermectin 86%; RR 0.92, 95%CI 0.82 to 1.03; 581 participants, five studies; low
certainty evidence).
Seven days after treatment with oral ivermectin 200 μg/kg or one
application of permethrin 5% lotion, there was little or no difference in complete
clearance rates (illustrative cure rates: permethrin 73%, ivermectin 68%; RR 0.93,
95%CI 0.74 to 1.17; 120 participants, one study; moderate certainty evidence).
After two weeks, one initial dose of systemic ivermectin compared to one
application of permethrin lotion produced similar complete clearance rates
(extrapolated cure rates: 67% in both groups; RR 1.00, 95%CI 0.78 to 1.29;
120 participants, one study; low certainty evidence).
The application also presented the findings of numerous individual
studies of ivermectin versus various topical agents for scabies that supported
the comparative effectiveness of oral ivermectin (8–18).
The application presented evidence of the effectiveness of ivermectin for
treating scabies when delivered through mass drug administration programmes.
Studies in Solomon Islands (19, 20), Australia (21), Brazil (22) and Fiji (23) all
showed mass drug administration of ivermectin to be an effective public health
intervention.
There is some evidence from case reports and case series that oral
ivermectin (with or without topical scabicides) is effective in the treatment of
crusted scabies (24–28). Crusted scabies is a hyper-transmissible form of scabies
where patients are infected with very large populations of scabies mites. It is
mainly seen in those who are immunocompromised including HIV-infected
individuals, transplant recipients and those on high doses immuno-modulating
drugs or biologic agents; it may also occur in endemic settings in apparently
healthy individuals. It is rare but can cause a major problem with transmission
to susceptible populations.

Evidence for the safety of ivermectin has been evaluated when it was considered
for listing on the EML for other indications.
In terms of safety of oral ivermectin for treatment of scabies, the
Cochrane systematic review reported moderate certainty evidence of no
withdrawals due to adverse events in either the oral ivermectin or topical
permethrin treatment groups. There was moderate certainty evidence of little
or no difference between treatment groups for the proportion of participants
who experienced at least one adverse event two weeks after initiation of
175
treatment. After four weeks, ivermectin was associated with a larger proportion
of participants with at least one adverse event (RR 1.30, 95%CI 0.35 to 4.83;
502 participants, four studies; low certainty evidence).
Most side-effects reported in other studies were transient and mild.
Loose stool, fatigue and headache were most frequently reported, and the
incidence among the randomized control trials of all side-effects was highest in
the studies involving children.
When ivermectin is administered to subjects with high Loa loa
microfilariaemia, severe adverse reactions such as neurological signs,
encephalopathy and coma have been reported (29). In Loa loa endemic countries,
potential coinfection with this parasite has to be considered prior to using
ivermectin.
There were a total of 1656 reports for ivermectin in VigiBase (out of a
total of over 14 million reports in the database). Reports in males and females
were of similar proportions. The majority of reports were in adults aged 18 years
and older. The most commonly reported adverse drug reactions (ADRs) for
ivermectin alone and ivermectin co-administered with albendazole included
pruritus, headache, dizziness, vomiting, rash, urticarial and diarrhoea. Most
reported ADRs were considered to be minor and transient.
Safety of ivermectin in pregnant women or children under 15 kg body
weight has not been established.

N/A
WHO Guidelines
WHO guidelines on the treatment of skin and oral HIV-associated conditions
in children and adults (30) recommend treatment with oral ivermectin (200 μg/
kg) for mild/moderate scabies in HIV-infected children and adults if topical

permethrin treatment is not feasible or there is a poor response (Strong
recommendation, low quality evidence). The guidelines also recommend two
doses of oral ivermectin for treatment of HIV-infected children ≥15 kg and
adults with severe or crusted scabies.
The application stated that no cost-benefit analyses on the use of ivermectin in
scabies have been undertaken, but proposes that effective interventions with
ivermectin may reduce personal, institutional and governmental expenditure.
Availability
Ivermectin has wide market availability. Generic brands are available.
176
N/A
The Expert Committee recommended listing of ivermectin on the core list of the
EML and EMLc for the new indication of treatment of scabies. The Committee
noted that oral ivermectin treatment is associated with comparable effectiveness
to topical therapies and has acceptable safety. The Committee also noted the
effectiveness of ivermectin as a public health intervention when delivered via
mass drug administration programmes.
The Committee considered that the ease of oral administration compared
to topical administration may also represent an advantage for patients in terms
of compliance.
References
1. Kearns T, Clucas D, Connors C, Currie BJ, Carapetis JR, Andrews RM. Clinic attendances during the
first 12 months of life for Aboriginal children in five remote communities of northern Australia.
PLoS One. 2013;8(3):e58231.
2. Karimkhani C, Colombara DV, Drucker AM, Norton SA, Hay R, Engelman D et al. The global
burden of scabies: a cross-sectional analysis from the Global Burden of Disease Study 2015.
3. Streeton CL, Hanna JN, Messer RD, Merianos A. An epidemic of acute post-streptococcal
glomerulonephritis among aboriginal children. J Paediatr Child Health. 1995;31(3):245–8.
4. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the
heart to the throat? Lancet Infect Dis. 2004;4(4):240–5.
5. Mulholland EK, Ogunlesi OO, Adegbola RA, Weber M, Sam BE, Palmer A et al. Etiology of serious
infections in young Gambian infants. Pediatr Infect Dis J. 1999;18(10 Suppl):S35–41.
6. Hay RJ, Estrada Castanon R, Alarcon Hernandez H, Chavez Lopez G, Lopez Fuentes LF, Paredes
Solis S et al. Wastage of family income on skin disease in Mexico. BMJ. 1994;309(6958):848.
7. Rosumeck S, Nast A, Dressler C. Ivermectin and permethrin for treating scabies. Cochrane
Database Syst Rev. 2018;4:CD012994.
8. Chhaiya SB, Patel VJ, Dave JN, Mehta DS, Shah HA. Comparative efficacy and safety of topical
permethrin, topical ivermectin, and oral ivermectin in patients of uncomplicated scabies. Indian J
Dermatol Venereol Leprol. 2012;78(5):605–10.
9. Mushtaq A, Khurshid K, Pal SS. Comparison of efficacy and safety of oral ivermectin with topical
permethrin in treatment of scabies. JPAD. 2010;20:227–31.
10. Rohatgi V, S. Reddy N, Vagge D. A prospective, randomized, open labelled, comparative study of
efficacy and cost effectiveness of permethrin and ivermectin in 5-15 years age group patients
with scabies in a tertiary care hospital. Indian J Pharmacol. 2013;45:S45.
11. Manjhi PK, Sinha RI, Kumar M, Sinha KI. Comparative study of efficacy of oral ivermectin versus
some topical antiscabies drugs in the treatment of scabies. J Clin Diagn Res. 2014;8(9):Hc01–4.
12. Bachewar NP, Thawani VR, Mali SN, Gharpure KJ, Shingade VP, Dakhale GN. Comparison of safety,
efficacy, and cost effectiveness of benzyl benzoate, permethrin, and ivermectin in patients of
scabies. Indian J Pharmacol. 2009;41(1):9–14.
177
13. Ly F, Caumes E, Ndaw CA, Ndiaye B, Mahe A. Ivermectin versus benzyl benzoate applied once or
twice to treat human scabies in Dakar, Senegal: a randomized controlled trial. Bull World Health
Organ. 2009;87(6):424–30.
14. Brooks PA, Grace RF. Ivermectin is better than benzyl benzoate for childhood scabies in developing
countries. J Paediatr Child Health. 2002;38(4):401–4.
15. Goldust M, Rezaee E, Raghifar R, Naghavi-Behzad M. Ivermectin vs. lindane in the treatment of
scabies. Ann Parasitol. 2013;59(1):37–41.
16. Goldust M, Rezaee E, Raghifar R. Comparison of oral ivermectin versus crotamiton 10% cream in
the treatment of scabies. Cutan Ocul Toxicol. 2014;33(4):333–6.
17. Madan V, Jaskiran K, Gupta U, Gupta DK. Oral ivermectin in scabies patients: a comparison with
1% topical lindane lotion. J Dermatol. 2001;28(9):481–4.
18. Sule HM, Thacher TD. Comparison of ivermectin and benzyl benzoate lotion for scabies in
Nigerian patients. Am J Trop Med Hyg. 2007;76(2):392–5.
19. Lawrence G, Leafasia J, Sheridan J, Hills S, Wate J, Wate C et al. Control of scabies, skin sores and
haematuria in children in the Solomon Islands: another role for ivermectin. Bull World Health
Organ. 2005;83(1):34–42.
20. Marks M, Taotao-Wini B, Satorara L, Engelman D, Nasi T, Mabey DC et al. Long Term Control
of Scabies Fifteen Years after an Intensive Treatment Programme. PLoS Negl Trop Dis. 2015;
9(12):e0004246.
21. Kearns TM, Speare R, Cheng AC, McCarthy J, Carapetis JR, Holt DC et al. Impact of an Ivermectin
Mass Drug Administration on Scabies Prevalence in a Remote Australian Aboriginal Community.
PLoS Negl Trop Dis. 2015;9(10):e0004151.
22. Worth C, Heukelbach J, Fengler G, Walter B, Liesenfeld O, Hengge U et al. Acute morbidity
associated with scabies and other ectoparasitoses rapidly improves after treatment with
ivermectin. Pediatr Dermatol. 2012;29(4):430–6.
23. Romani L, Whitfeld MJ, Koroivueta J, Kama M, Wand H, Tikoduadua L et al. Mass Drug
Administration for Scabies Control in a Population with Endemic Disease. N Engl J Med. 2015;
373(24):2305–13.
24. Nofal A. Variable response of crusted scabies to oral ivermectin: report on eight Egyptian patients.
J Eur Acad Dermatol Venereol. 2009;23(7):793–7.
25. Ortega-Loayza AG, McCall CO, Nunley JR. Crusted scabies and multiple dosages of ivermectin.
J Drugs Dermatol. 2013;12(5):584–5.

26. Roberts LJ, Huffam SE, Walton SF, Currie BJ. Crusted scabies: clinical and immunological findings
in seventy-eight patients and a review of the literature. J Infect. 2005;50(5):375–81.
27. Sandre M, Ralevski F, Rau N. An elderly long-term care resident with crusted scabies. Can J Infect
Dis Med Microbiol. 2015;26(1):39–40.
28. Yee BE, Carlos CA, Hata T. Crusted scabies of the scalp in a patient with systemic lupus
erythematosus. Dermatol Online J. 2014;20(10).
29. WHO African Programme for Onchocerciasis Control (WHO/APOC). Programme for the Elimination
of Neglected Diseases in Africa (PENDA): Strategic Plan of Action and Indicative Budget 2016–
2025 Ouagadougou: APOC; 2013. Available from http://www.who.int/apoc/en_apoc_strategic_
plan_2013_ok.pdf, accessed 29 September 2019.
30. Guidelines on the treatment of skin and oral HIV-associated conditions in children and adults.
handle/10665/136863/9789241548915_eng.pdf, accessed 30 October 2019.
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Section 7: ANTIMIGRAINE MEDICINES

7.1 For treatment of acute attack
Sumatriptan – addition – EML
Sumatriptan ATC Code: N02CC01
Proposal
The application requested the addition of sumatriptan to the core list of the EML
for the treatment of adult patients with acute migraine.
Applicant
Medicines and Medical Devices Area, Health Care and Welfare Directorate,
Community Care Service, Emilia-Romagna Region
WHO Collaborating Centre in Evidence-Based Research Synthesis and Guideline
Development, Emilia Romagna Health Care and Welfare Directorate

Department of Mental Health and Substance Abuse
EML/EMLc
EML
Section
7.1 Antimigraine medicines – For treatment of acute attack

Tablet 50 mg
Core/Complementary
Core

Individual

An application requesting addition of sumatriptan to the EML was considered by
the Expert Committee in 2007. The Committee considered that the application
was generally of poor quality and provided only a limited review of the evidence.
Overall, the evidence provided in the application did not support the public
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health need or comparative effectiveness, safety and cost-effectiveness of

sumatriptan. The Committee therefore recommended that sumatriptan not be
added to the Model List (1).
The EML currently lists acetylsalicylic acid tablets and paracetamol
tablets for treatment of acute migraine attacks.

Headache disorders are a public health concern given the associated disability
and financial costs to society. As headache disorders are most troublesome in the
productive years (i.e. late teens to 50s), estimates of their financial cost to society
– mainly from lost working hours and reduced productivity – are massive. In the
United Kingdom, for example, some 25 million working- or school-days are lost
every year because of migraine alone (2).
The main source of data about the burden of migraine worldwide is
the Global Burden of Disease (GBD) Study (2016), although its estimates refer
mainly to a selected population of high-income countries, while data from
important and populous low- and middle-income countries, such as Bangladesh,
Democratic Republic of Congo, Egypt, Indonesia, Viet Nam, South Africa and
several other countries in sub-Saharan Africa, are lacking.
According to the GBD study, 1.04 billion (95% uncertainty interval [UI]
1.00 to 1.09) people were estimated to have a migraine in 2016 (3).
Migraine has a profound effect on well-being and general functioning,
not only during the acute attack, but also in terms of work performance, family
and social relationships, and school achievement. Migraine carries a substantial
individual, societal and economic burden, ranking as the second cause of
disability (4).
According to the GBD study, in 2016 migraine was estimated to have
caused 45.1 million (95%UI 29.0 to 62.8) years of life lived with disability
(YLDs), and in 2017 overall 5.54% (95%CI 3.91 to 7.5) of total YLDs were
attributed to migraine (5).
Even though the burden of migraine worldwide is considerable, accurate
diagnosis, quality of care and rates of drug utilization are still insufficient across
countries and settings. Worldwide, only 40% of people with migraine are
professionally diagnosed (6).

The application identified clinical evidence on efficacy of sumatriptan in adults
and children and adolescents with acute migraine attack from systematic reviews
(SR) and randomized controlled trials (RCT) and ongoing studies. Clinical
practice guideline recommendations were also presented.
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Children and adolescents

A 2016 Cochrane systematic review of 27 trials involving 7630 participants
compared any pharmacological intervention by any route of administration for
symptomatic acute treatment of a migraine attack in children (under 12 years of
age) and adolescents (12 to 17 years of age). Acceptable comparators included
placebo or other active drug treatments. The primary outcome was the percentage
of pain-free participants at two hours (7). Most data on triptans in children and
adolescents came from treatment with sumatriptan. Only intranasal sumatriptan
has been studied in clinical trials in children.
A pooled estimate of six studies of oral sumatriptan in adolescents with
acute migraine showed no difference between oral sumatriptan and placebo in
reaching pain freedom at 2 hours. In absolute terms, the proportion of patients
that were pain-free at two hours with sumatriptan was 21.7% vs 20% with placebo
(risk difference (RD) 1.7%, 95%CI −4.3 to 7.1).
For studies involving sumatriptan via any route of administration, for
the primary outcome of pain-free at two hours, clinical trials in adolescents show
superiority of sumatriptan vs placebo, while in children the estimate does not
reach statistical significance. Absolute estimates show that 49.3% of children on
(intranasal) sumatriptan vs and 23.6% with placebo were pain-free at two hours
(RD 25.7%, 95%CI 10.0 to 39.6), while 34.8% of adolescents on sumatriptan vs
25.1% on placebo (RD 9.7%, 95%CI 4.8 to 14.4).
Triptans considered as a class (regardless of the formulation) showed
superiority vs placebo in reaching the primary outcome both among children
(RD 16.3, 95%CI 6.2 to 25.9) and adolescents (RD 7.6%, 95%CI 5.4 to 9.7).
Adults
Two systematic reviews provided evidence for the efficacy and safety of
sumatriptan in adults.
An analysis of pooled data from 18 studies showed 50 mg oral
sumatriptan to be more effective than placebo for the pain-free outcome at two
hours for any pain intensity at baseline. Similarly, pooled data from 21 studies
of 100 mg oral sumatriptan showed slightly higher estimates. Numbers needed
to treat (NNT) ranged from 3 to 6.1. The certainty in the estimates was rated
as high, according to GRADE. Results for outcomes of sustained pain freedom
at 24 hours and use of rescue medicine also showed clinically meaningful
differences and NNTs in favour of sumatriptan (8).
Compared to active comparators, efficacy of sumatriptan was comparable
to that of other triptans except for eletriptan 40 mg an 80 mg, which showed
significantly greater efficacy. Four studies compared sumatriptan 50 mg and
100 mg with effervescent acetylsalicylic acid (ASA) 1000 mg (two studies, 726
participants) and ASA 900 mg + metoclopramide 10 mg (two studies, 575
participants), respectively. The pooled analysis of the former comparison showed
181
no statistically significant differences relative to the pain-free outcome at two

hours, while in the latter a significant difference in favour of sumatriptan 100 mg
was observed. In absolute terms, 32.3% of patients treated with sumatriptan
50 mg and 26.4% of those on ASA 1000 mg were pain-free at two hours (RD 15%
in favour of sumatriptan). Sumatriptan 100 mg was compared to paracetamol
1000 mg + metoclopramide 10 mg relative to the outcome headache relief at two
hours (two studies, 1035 participants), showing no difference (8).
A network meta-analysis (NMA) by the Canadian Agency for Drugs and
Technologies in Health (CADTH) compared the relative efficacy, effectiveness
and safety of triptans alone or in combination with other drugs, all administration
routes, any dose, compared with other triptans, non-steroidal anti-inflammatory
drugs (NSAIDs), acetylsalicylic acid (ASA), paracetamol, ergots, opioids in the
treatment of acute migraine attacks in adults (>18 years of age) (9). Overall,
considering all administration routes, freedom from pain at two hours was
achieved in 18% to 50% of patients with acute migraine taking standard dose
triptans. Sumatriptan 50 mg provided pain freedom at two hours in 27.7%
(95%CI 24.6 to 31%) of patients, compared with 10.60% (95%CI 10.0 to 11.3%)
for placebo. Triptans showed to be effective in the largest proportion of patients
on the outcome “headache relief at two hours”: 42% to 76% of patients, compared
to 26.70% (95%CI 25.7% to 27.7%) for placebo. Fifty percent of patients taking
sumatriptan 50 mg (95%CI 46.3% to 53.1%) had a headache relief at two
hours (9).
Two additional RCTs not included in the systematic reviews provided
data that did not change the conclusions of the SRs (10, 11).

The application identified safety data of sumatriptan in adults and children and
adolescents from systematic reviews and RCTs and one observational study.
Children and adolescents

No safety data were available on oral sumatriptan in children. Overall, triptans
in children did not show a higher frequency of adverse events (AEs) compared
to placebo. For intranasal sumatriptan, the risk difference for any AEs was
statistically higher than placebo. The overall frequency of any AEs in adolescents
taking triptans was higher than placebo although most were considered mild (7).
Adults
Among 20 049 patients treated with oral sumatriptan (25 mg to 300 mg),
only two treatment-related serious AEs were reported: one after treating with
sumatriptan 85 mg (heart palpitations), one after treating with sumatriptan
300 mg (chest tightness and pressure). Withdrawals due to AEs were uncommon:
in placebo-controlled studies, excluding those using high doses of sumatriptan
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(>100 mg), the rate of AE withdrawal among patients treated with sumatriptan
was equivalent to that of placebo (0.71% (45/6349) and 0.65% (19/2926),
respectively). Any AEs were more common in patients treated with sumatriptan
(particularly at the 100 mg dose) than placebo (8).
Pooled estimates of comparisons of sumatriptan versus other triptans
did not show significant differences for any AEs. Sumatriptan 100 mg was
associated with a higher frequency of AEs compared to ASA and paracetamol
in combination with metoclopramide (8).
An industry-funded SR and NMA assessed the tolerability of treatments
administered by oral route in adults (>18 years of age) with acute migraine.
The SR included 141 RCTs evaluating triptans, NSAIDs or barbiturates in any
combination, without any other limitation regarding sample size or treatment
concealing (12). The quality of the included studies was not formally assessed and
the results should be interpreted with caution.
Data from direct comparisons were available for sumatriptan versus.
placebo (39 studies), naproxen (six studies), naproxen + sumatriptan (four
studies), selective cox-inhibitors (one study), ergotamine (one study), paracetamol
(one study), eletriptan (three studies), rizatriptan (eight studies), naratriptan
(two studies), zolmitriptan (four studies) and almotriptan (two studies).
Sumatriptan showed a significantly higher incidence of any AEs than
placebo (OR 1.80, 95%CI 1.57 to 2.05), as well as sumatriptan + naproxen,
zolmitriptan and rizatriptan. Sumatriptan, sumatriptan + naproxen zolmitriptan,
rizatriptan, eletriptan and paracetamol showed a higher frequency of treatment-
related AEs vs placebo (sumatriptan OR 2.23, 95%CI 1.86 to 2.70).
Serious adverse events (SAEs) show estimates with wide CIs (SAEs
are uncommon, many trials reported zero events in at least one arm, and the
definition of SAE varied among trials).
A meta-analysis of six observational studies assessed the risk of
pregnancy outcomes (major congenital malformations (MCM), prematurity and
spontaneous abortion) of women with migraine prenatally exposed to triptans,
comparing them with those of women with migraine not taking triptans and
with healthy women (13). Pooled analysis showed that the rate of MCM and
prematurity was not increased among women with migraine taking triptans
during pregnancy when compared with women with migraine not taking
triptans. Women exposed to triptans during pregnancy showed a higher rate
of spontaneous abortion. Women with migraine not taking triptans compared
to healthy controls showed a higher risk of MCM, however this difference was
observed on a relatively small sample of triptan-exposed women (n=178). The
estimates should be interpreted with caution as they were not adjusted for
potential confounders and the overall certainty was rated as very low.
A systematic review by the UK National Clinical Guideline Centre found
conflicting evidence of very low quality regarding pregnancy outcomes from
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a pooled analysis of three observational studies that compared women with

migraine who took triptans during pregnancy and women with migraine who
did not (14). The guideline panel concluded that the evidence reviewed, although
inconclusive, did not indicate an increased risk of triptan use during pregnancy.
The Sumatriptan, Naratriptan and Treximet Pregnancy Registry is a
prospective, observational, uncontrolled, international study sponsored by
GlaxoSmithKline. The registry collected pregnancy data of women exposed at
any time during their pregnancy to sumatriptan, naratriptan or the combination
of sumatriptan and naproxen sodium from health care providers enrolled
on a voluntary basis in 18 countries. Data were gathered during 16 years of
observation, including a total of 904 exposed pregnant women, with 689
pregnancy outcomes. Six-hundred-and-ten women (67%) with 626 pregnancy
outcomes (91%) had been exposed to sumatriptan. The frequency of major birth
defects following any trimester of exposure to sumatriptan was 4.2% (24/576;
95%CI 2.7 to 6.2). The same frequency was observed considering 528 pregnancy
outcomes after exposure during the first trimester (4.2% 95%CI 2.6% to 6.5%).
The authors compared these data with those from other observational studies,
showing birth defect frequencies of 4–5% among migraineurs, concluding
that there is no signal of teratogenicity associated with major birth defects
for sumatriptan (15). These results should be interpreted with caution, due
to numerous limitations. Certainty in the estimates was rated very low using
GRADE.
Triptans can induce vasoconstriction that may potentially increase the
risk of cardiovascular events. A meta-analysis of four observational studies
assessed the risk of severe cardiovascular events among persons with migraine
taking triptans or ergotamine. The authors distinguished the risk of cardiovascular
events and stroke associated with the intensity (number of prescribed/dispensed
doses) and with the recency of migraine-specific use. Pooled analysis showed no
significant differences in the overall risk of cardiovascular events of patients with
migraine treated with triptans (intensity of treatment) as compared with controls

(OR 0.86; 95%CI 0.52 to 1.43, I2 24.5%). Due to the high heterogeneity of results
of the included studies, pooled analysis of the risk of cardiovascular events and
stroke in relation to recency was not performed (16). Certainty in the estimates
was rated as low using GRADE.

N/A
WHO Guidelines
In 2007, WHO in collaboration with Lifting the Burden and with the European
Headache Federation published guidance on the management of common
headache disorders in primary care (17). This guidance recommended stepped
184
management of acute migraine attacks, treating three attacks at each step

before proceeding to the next, starting from common analgesics (such as
acetylsalicylic acid, ibuprofen, diclofenac, ketoprofen, naproxen or – where
these are contraindicated – paracetamol) followed, if needed, by antiemetics
(such as domperidone or metoclopramide). Triptans were recommended at the
second step, among specific drugs, to be offered to all patients failing step one.
The starting recommended formulation was oral, subcutaneous sumatriptan
was suggested when all other triptans are ineffective. Analgesics only were
recommended for children.
Sumatriptan (50 mg or 100 mg) is recommended as the first-line
monotherapy treatment in adults by the SIGN guideline, with the suggestion of
trying other triptans in case of failure (18).
The NICE guideline recommends an oral triptan in monotherapy or
combined with NSAID or paracetamol in adults and children. In young subjects
(12–17 years of age) nasal triptan is preferred (14).
The Canadian Headache Society guideline recommends sumatriptan,
or another triptan, for moderate–severe migraine attacks in adults. If triptan in
monotherapy is insufficient, it is recommended the association with naproxen
sodium 500 mg (19).
According to SIGN and NICE guidelines, triptans can be used for
treatment of acute migraine during pregnancy and in women in childbearing age.
Cost-effectiveness modelling suggested that common analgesics (acetylsalicylic
acid in particular) are the most cost-effective strategy for managing acute episodic
migraine (20).
A triptan in combination with acetylsalicylic acid or paracetamol are
potentially cost-effective interventions, although with a higher absolute cost, that
however would be largely offset by savings in terms of gained health (14).
All triptans are available as generic drugs, but sumatriptan has the lowest
price in most countries, including LMICs. Oral eletriptan shows superiority to
oral sumatriptan relative to all relevant outcomes. However, eletriptan is, on
average, substantially more expensive than sumatriptan even considering the
non-proprietary name preparations.
Availability
Sumatriptan is available globally in branded and generic forms.
Sumatriptan was not proposed for inclusion in the EMLc by the applicant
because:
185
–– oral sumatriptan is not licensed in children and has not been

studied in RCTs;
–– oral sumatriptan has been studied in adolescents 12 to 17 years
of age with episodic migraine showing no superiority versus
placebo in reaching pain freedom at two hours;
–– intranasal sumatriptan has been studied in adolescents 12 to
17 years of age showing to be more effective than placebo and is
licensed in such patients by some regulatory agencies in high-
income countries. However, since the intranasal inhalation of the
drug needs patient training, the effectiveness of this preparation
observed in clinical trials may not be directly applicable in
settings where training is impractical or not possible. Moreover,
the cost-effectiveness of intranasal sumatriptan is substantially
lower than oral sumatriptan.
The Committee did not recommend the addition of sumatriptan to the core list
of the EML for the treatment of adult patients with acute migraine.
The Committee noted that the available evidence supported the superior
effectiveness of sumatriptan compared to placebo, but that evidence comparing
sumatriptan with currently listed analgesics (aspirin and paracetamol) showed
varying results, including no difference in effect.
However, the Committee also noted that sumatriptan is recommended
as first-line therapy for migraine in many international guidelines, and would
welcome a future review of additional data of the role of sumatriptan in the
context of other migraine therapies.
References
(including the 15th Model List of Essential Medicines) (WHO Technical Report Series No. 946).
Geneva: World Health Organization; 2007.
2. Headache disorders (WHO fact sheets). Available from http://www.who.int/news-room/fact-
sheets/detail/headache-disorders, accessed 29 September 2019.
3. GBD 2016 Headache Collaborators. Global, regional and national burden of migraine and
tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study
2016. Lancet Neurol. 2018;17(11):954–76.
4. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under
50s: will health politicians now take notice? J Headache Pain. 2018;19(1):17.
5. Global Burden of Disease Study 2016 data portal [website]. Seattle: Institute for Health Metrics
and Evaluation, University of Washington; 2017. (https://vizhub.healthdata.org/gbd-compare/,
accessed 29 September 2019).
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6. Saylor D, Steiner TJ. The Global Burden of Headache. Semin Neurol. 2018;38(02):182–90.
7. Richer L, Billinghurst L, Linsdell MA, Russell K, Vandermeer B, Crumley ET et al. Drugs for the acute
treatment of migraine in children and adolescents. Cochrane Database Syst Rev. 2016;4:CD005220.
8. Derry CJ, Derry S, Moore RA. Sumatriptan (subcutaneous route of administration) for acute
migraine attacks in adults. Cochrane Database Syst Rev. 2012(2):CD009665.
9. Cameron C, Kelly S, Hsieh SC, Murphy M, Chen L, Kotb A et al. Triptans in the Acute Treatment of
Migraine: A Systematic Review and Network Meta-Analysis. Headache. 2015;55 Suppl 4:221–35.
10. Tepper SJ, Cady RK, Silberstein S, Messina J, Mahmoud RA, Djupesland PG et al. AVP-825 breath-
powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg oral
sumatriptan in the acute treatment of migraines (The COMPASS study): a comparative randomized
clinical trial across multiple attacks. Headache. 2015;55(5):621–35.
11. Pini LA, Guerzoni S, Cainazzo M, Ciccarese M, Prudenzano MP, Livrea P. Comparison of tolerability
and efficacy of a combination of paracetamol + caffeine and sumatriptan in the treatment of
migraine attack: a randomized, double-blind, double-dummy, cross-over study. J Headache Pain.
2012;13(8):669–75.
12. Thorlund K, Toor K, Wu P, Chan K, Druyts E, Ramos E et al. Comparative tolerability of treatments
for acute migraine: A network meta-analysis. Cephalalgia. 2017;37(10):965–78.
13. Marchenko A, Etwel F, Olutunfese O, Nickel C, Koren G, Nulman I. Pregnancy outcome following
prenatal exposure to triptan medications: a meta-analysis. Headache. 2015;55(4):490–501.
14. Headaches in over 12s: diagnosis and management (Clinical guideline CG150) [website]. London:
National Institute for Health and Care Excellence; 2015. (https://www.nice.org.uk/guidance/
CG150, accessed 29 September 2019).
15. Ephross SA, Sinclair SM. Final results from the 16-year sumatriptan, naratriptan, and treximet
pregnancy registry. Headache. 2014;54(7):1158–72.
16. Roberto G, Raschi E, Piccinni C, Conti V, Vignatelli L, D’Alessandro R et al. Adverse cardiovascular
events associated with triptans and ergotamines for treatment of migraine: systematic review of
observational studies. Cephalalgia. 2015;35(2):118–31.
17. Steiner TJ, Paemeleire K, Jensen R, Valade D, Savi L, Lainez MJ et al. European principles of
management of common headache disorders in primary care. J Headache Pain. 2007;8 Suppl
1:S3–47.
18. Scottish Intercollegiate Guidelines Network S. Pharmacological management of migraine. 2018.
19. Worthington I, Pringsheim T, Gawel MJ, Gladstone J, Cooper P, Dilli E et al. Canadian Headache
Society Guideline: acute drug therapy for migraine headache. Can J Neurol Sci. 2013;40(5 Suppl
3):S1–S80.
20. Linde M, Steiner TJ, Chisholm D. Cost-effectiveness analysis of interventions for migraine in four
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187
Section 8: IMMUNOMODULATORS AND ANTINEOPLASTICS

8.1 Immunomodulators for non-malignant disease
Medicines for multiple sclerosis – addition – EML and EMLc
Glatiramer acetate ATC Code: L03AX13

Fingolimod ATC Code: L04AA27
Ocrelizumab ATC Code: L04AA36
Proposal
The application requested the addition of glatiramer acetate, fingolimod and
ocrelizumab to the complementary list of the EML and EMLc for use in the
treatment of multiple sclerosis.
Applicant
Multiple Sclerosis International Federation (MSIF)

Department of Mental Health and Substance Abuse
EML/EMLc
EML and EMLc
Section

Glatiramer acetate: injection 20 mg/mL, 40 mg/mL
Fingolimod: capsule 0.25 mg, 0.5 mg

Ocrelizumab: injection 300 mg/10 mL in 10 mL vial
Core/Complementary
Complementary

Individual

In 2015, the Expert Committee reviewed an application requesting addition
of azathioprine to the EML for the treatment of multiple sclerosis (MS).
The Committee acknowledged the significant public health burden of MS
188
but noted the availability of a number of well-established and more recent

immunomodulating medicines for this condition. The Committee therefore
recommended that a comprehensive review be undertaken of all medicines used
for the management of relapsing–remitting and other forms of MS for future
consideration (1).
The Multiple Sclerosis International Federation (MSIF) is a non-state
actor in official relations with WHO. They convened a taskforce of global experts
in MS research and care to submit an application for disease-modifying therapies
(DMTs) for the treatment of MS to be included on the EML. All approved DMTs
used for the treatment of MS were summarized by comparative effectiveness
in a variety of clinical settings based on the recently published ECTRIMS/
EAN (European Committee for Treatment and Research for Multiple Sclerosis/
European Association of Neurology) Guideline on the pharmacological treatment
of people with MS (2). A comparison was also made with the American Academy
of Neurology guidelines on DMTs in MS (3).
Of the multiple therapies used for treating MS, the application
prioritized three medications to be included on the EML. Prioritization was
based on their efficacy/safety profiles, tolerability/liveability, monitoring needs,
route of administration, licensed use in paediatric-onset and primary progressive
MS, safety profile in pregnancy, and availability of generic and/or biosimilar
substitutes.

Multiple sclerosis is an immune-mediated disorder of the central nervous system
(grey and white matter) characterized by inflammation, demyelination and
degenerative changes including neuroaxonal loss and progressive brain and spinal
cord atrophy. Approximately 85% of those with MS initially experience relapses
and remissions of neurological symptoms, (relapsing–remitting MS, RRMS), with
relapses often associated with new areas of central nervous system inflammation.
Gradual worsening in this population, with or without additional inflammatory
events, is known as secondary progressive MS. Progressive changes can occur at
any time in the disease course, but usually become more prominent over time.
Approximately 15% of people diagnosed with MS have a progressive course from
disease onset (primary progressive MS). Some with primary progressive MS may
have typical relapses later in their disease course, after a progressive course has
been established (4, 5).
In 2013, there were more than 2.3 million people with MS worldwide
(6, 7). The incidence and prevalence of MS are rising, with studies showing
significantly larger numbers than was previously estimated (8–15). Women are
disproportionally affected, with prevalence in females two to three times that in
males (7, 16). Although the cause is not fully understood, MS is considered to
have complex causality blending genetic risk and environmental factors. People
189
can be diagnosed throughout the age range, though MS is most often diagnosed
between the ages of 20 and 50 years. Onset may also occur in childhood, and
it is estimated that 3% to 10% of all individuals with MS experience their first
attack prior to age 18 years (17). The incidence of paediatric-onset MS in
North American and European studies has been reported to be between 0.13 to
0.6 cases per 100 000 children (18).
Symptoms of MS negatively impact functional abilities and quality of life,
and often include overwhelming fatigue, mood and cognitive changes, mobility
impairment, sensory impairment, visual disturbances, sexual dysfunction, and
impaired bowel and bladder control. People with MS report lower health-related
quality of life compared to other populations – including those with other
chronic illnesses. The prevalence of depression is estimated to be 70% in people
with MS (19).
The goal of treatment is to reduce the long-term burden of the disease,
i.e. to delay disability progression and to prevent secondary progressive MS
(20). Quality of life and the socioeconomic burden of MS are closely linked to
disability, therefore, delaying and preventing disability worsening will have a
major impact for individuals with the disease and for society (21).

Glatiramer acetate
Three trials (3217 patients) compared glatiramer acetate with placebo in patients
with RRMS with follow up ranging from 52 to 104 weeks (22–24). Compared
to placebo, glatiramer acetate lowered annualized relapse rates for follow ups of
52–96 weeks (mean difference (MD) −0.14, 95%CI −0.21 to −0.06, moderate
quality evidence, n=2117, two studies) and resulted in more patients free from
relapse at one to two years follow up (RR 1.17, 95%CI 1.10 to 1.24, moderate
quality evidence, n=2360, three studies). Glatiramer acetate was also shown to
result in a lower number of cumulative gadolinium-enhancing (GAD) lesions

(MD −0.73, 95%CI −1.15 to −0.31, high quality evidence, n=1325, one
study) and new or newly enlarging T2 lesions at 6 and 12 months follow up
(MD −1.94, 95%CI −3.03 to −0.85, high quality evidence, n=1325, one study)).
Low quality evidence showed a non-statistically significant effect on disability at
two years follow up (RR 0.86, 95%CI 0.66 to 1.11, n=964, two studies).
Four trials compared glatiramer acetate to interferon in patients with
RRMS (25–28). At two years’ follow up, the number of participants free from
relapse did not significantly differ (RR 0.98, 95%CI 0.90 to 1.06, moderate quality
evidence, n=2175, 3 studies), nor did extent of disability worsening (RR 1.07,
95%CI 0.83 to 1.31, one study).
One trial (970 patients) compared glatiramer acetate to placebo for
patients with primary-progressive MS (29). There was a non-significant effect on
190
the number of participants with disability worsening (RR 0.87, 95%CI 0.75 to
1.02) and longer time to disability worsening (HR 0.87, 95%CI 0.71 to 1.07) in
the glatiramer acetate group.
Fingolimod
Two trials compared fingolimod with placebo in patients with RRMS, with
two years follow up (30, 31). A larger proportion of patients were free from
relapse at two years in the fingolimod arm (RR 1.44, 95%CI 1.28 to 1.63,
moderate quality evidence, n=2355). The annualized relapse rate was also lower
in the fingolimod arm (MD −0.21, 95%CI −0.25 to −0.16, moderate quality
evidence). Fingolimod-treated patients had a lower risk of disability worsening
compared to placebo (RR 0.71, 95%CI 0.56 to 0.90, moderate quality evidence,
n=2355). Patients also had fewer new or newly enlarged T2 lesions (RR 2.16,
95%CI 1.77 to 2.63, moderate quality evidence, n=1192) and fewer GAD lesions
(MD −0.87, 95%CI −1.10 to −0.64, moderate quality evidence, n=1216, two
studies) at two years follow up. According to one study, fingolimod reduced
percent change in brain volume at one to two years follow up (MD 0.3, 95%CI
0.16 to 0.44, moderate quality evidence, n=685).
One trial compared fingolimod with interferon in patients with RRMS
(32). Moderate quality evidence showed that participants in the fingolimod
arm had lower annualized relapse rates (MD −0.17, 95%CI −0.26 to −0.08,
n=860), and more participants were free from relapse at one year (RR 1.19,
95%CI 1.11 to 1.29, n=860) than the interferon group. Fingolimod was also
associated with fewer new or newly enlarged T2 lesions (MD −0.90, 95%CI
−1.62 to −0.18, n=733) and GAD lesions (MD −0.28, 95%CI −0.50 to −0.06,
n=728). There was no significant difference in extent of disability progression
between fingolimod and interferon in the trial.
A Phase III trial investigated the safety and efficacy of fingolimod versus
interferon beta-1a, in 215 children and adolescents (ages 10 to 17) with MS.
Fingolimod significantly reduced annualized relapse rates by 82% (absolute
difference, 0.55; 95%CI 0.36 to 0.74; relapses RR 0.18, 95%CI 0.11 to 0.30) over
a period of up to two years compared to interferon beta-1a; reduced the number
of new or newly enlarged T2 lesions up to 24 months by 53% (RR 0.47, 95%CI
0.36 to 0.62) and reduced the average number of gadolinium-enhancing T1
(Gd+) lesions per scan at 24 months by 66.0% (RR 0.34, 95%CI 0.22 to 0.54).
Fingolimod was associated with a higher rate of serious adverse events (16.8% vs
6.5%) (33).
One trial (970 participants) compared fingolimod with placebo in
patients with primary-progressive MS (34). There was no difference in disability
progression at 156 weeks follow up between fingolimod or placebo (RR 0.93,
95%CI 0.80 to 1.08, moderate quality evidence). The adjusted annualized relapse
rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute
191
difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary
end point of the annualized rate of new or newly enlarged lesions on T2-weighted
magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with
interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%;
P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in
88.8% of patients who received fingolimod and 95.3% of those who received
interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in
the fingolimod group and included infection (in four patients) and leukopenia
(in two patients). Six patients had convulsions. Serious adverse events occurred
in seven patients (6.5%) in the interferon beta-1a group and included infection
(in two patients) and supraventricular tachycardia (in one patient).
Ocrelizumab
A Phase II trial compared ocrelizumab (low and high dose) and placebo in
patients with RRMS. At the end of the 24 weeks participants in both ocrelizumab
groups had lower numbers of active brain lesions compared to the placebo group
(89%, 95%CI 68 to 97, lower in low dose ocrelizumab group and 96%, 95%CI
89 to 99, lower in high dose ocrelizumab group). Annualized relapse rates over
the 24 weeks were 0.13 (95%CI 0.03 to 0.29) in the low dose ocrelizumab group
and 0.17 (95%CI 0.05 to 0.35) in the high dose ocrelizumab group compared to
the 0.64 rate (95%CI 0.43 to 0.94) of the placebo group. Findings also showed that
both doses of ocrelizumab were effective in reducing MRI and clinical disease
activity (35).
Two Phase III clinical trials, OPERA I and OPERA II, compared the
effects of ocrelizumab (600 mg every 24 weeks) with interferon beta-1b (44 µg
three times a week) for 96 weeks. Clinical outcomes from 1656 participants
show significantly reduced annualized relapse rates with ocrelizumab compared
to interferon beta-1a at two years (MD −0.13, 95%CI −0.18 to −0.08) thus
meeting its primary endpoint. Secondary outcomes showed ocrelizumab had
lower rate of disability progression. For the total trial period of 96 weeks, the
rate of disability progression at 24 weeks was 6.9% vs 10.5% in the ocrelizumab
and interferon beta-1a groups, respectively (HR 0.60; 95%CI 0.43 to 0.84).
Patients in the ocrelizumab group also had fewer GAD lesions (36).
One trial compared ocrelizumab to placebo in patients with primary
progressive MS. The ocrelizumab group had a greater time to disability
progression at 120 weeks follow up when confirmed at both 12 weeks (HR 0.76,
95%CI 0.59 to 0.98, high quality evidence, n=732) and 24 weeks (HR 0.75,
95%CI 0.58 to 0.97, high quality evidence, n=732) (37).
Rituximab
A 2013 Cochrane systematic review found one trial comparing rituximab to
placebo in 104 adult patients with RRMS (38). The mean number of total GAD
192
lesions, the primary endpoint of this double-blind Phase II trial, was significantly
decreased in patients receiving rituximab after 12, 16, 20 and 24 weeks (−5.0,
95%CI −9.99 to −0.01). The proportion of patients with relapses was significantly
reduced in the rituximab group, both after 24 weeks (14.5% vs 34.3% in the
placebo group; p=0.02) and 48 weeks (20.3% vs 40.0%, p=0.04) (39). A Phase II
open-label study of 26 patients with RRMS receiving rituximab at baseline and
six months found that mean annualised relapse rate reduced from 1.27 to 0.23,
and mean number of GAD lesions reduced from 1.31 to 0.05 at week 48 and 0.0
at week 72. Mean number of new or newly enhancing T2 lesions also decreased
from 0.92 at week 4 to 0.0 at week 72 (40).
A randomized controlled trial (439 participants) compared rituximab
versus placebo in patients with primary progressive MS (41). Patients were
randomized (2:1) to receive two intravenous doses (two weeks apart) of
rituximab (n=292) or placebo (n=147) infusions every 24 weeks, for 96 weeks.
Results showed that fewer in the rituximab group (30.2%) experienced 12 weeks
confirmed disease progression during 96 weeks compared to 38.5% in the
placebo group, but the difference did not reach statistical significance (p=0.14).
However, in a predefined sub-analysis, rituximab showed a significant effect
in patients with active MRI lesions or aged less than 51 years. This effect was
comparable with the effect seen in the ocrelizumab trial, which only included
patients below the age of 55.
Real-world data on treatment with rituximab in MS was available from a
study that examined the disease course of 822 MS patients, 557 with RRMS, 198
with secondary progressive MS and 67 with primary progressive MS, who were
followed for a mean duration of 22 months (42). RRMS patients treated with
rituximab had a yearly relapse rate of 0.044 during the study period. In total,
5.2% of the patients stopped treatment because of side-effects or disease activity.
The ratio of GAD lesions per MRI dropped significantly from approximately
three months after treatment initiation, and was in total 0.054, present in 2.2%
of MRIs. Moreover, the registry data suggest that the treatment efficacy of
rituximab in RRMS could exceed the effect of fingolimod, dimethyl fumarate
and beta-interferons. In addition, adherence was higher and side-effects were
comparable to all other drugs (43, 44).

The application presented a summary description of adverse events associated
with glatiramer acetate, fingolimod and ocrelizumab, and their associated
frequencies, as reported in the respective approved prescribing information
documents.
Common and very common adverse events associated with glatiramer
acetate include injection site reactions, lipoatrophy, vasodilation, rash, dyspnoea,
chest pain and lymphadenopathy.
193
Common and very common adverse events associated with fingolimod

include headache, influenza, diarrhoea, back pain, elevated liver enzymes, cough,
first-dose bradycardia, macular oedema, lymphopenia and bronchitis.
Common and very common adverse events associated with ocrelizumab
include infusion reactions and infections. Ocrelizumab has also been associated
with a possible increased risk of malignancies.

Glatiramer acetate
A 2016 Cochrane systematic review of six trials (2904 participants) compared
the safety and efficacy of glatiramer acetate and beta-interferons (45). Both
medicines showed similar clinical efficacy at 24 months (three studies) for
number of participants with relapse (RR 1.04, 95%CI 0.87 to 1.24) or confirmed
progression (RR 1.11, 95%CI 0.91 to 1.35). At 36 months, results from a single
study suggested that relapse rates were higher in the IFN group than in the GA
group (RR 1.40, 95%CI 1.13 to 1.74). However, greater and faster reduction in
MRI lesion load accrual was observed in IFN‐treated compared with GA‐treated
participants with MS (MD for T2 weighted lesion volume −0.58, 95%CI −0.99
to −0.18). Reviewers interpretation of overall evidence quality was cautious: the
number of studies and participants was limited, the heterogeneity among studies
was high and the clinical relevance of scales to measure disease progression was
considered doubtful. The number of participants who withdrew from or dropped
out of the study because of adverse events was available for four studies (2685
participants; 93%). No differences were found between the two treatment groups
(RR 0.95, 95%CI 0.64 to 1.40). Results were similar for severe adverse events
(RR 0.99, 95%CI 0.63 to 1.56).
A 2018 network meta-analysis including direct and indirect evidence,
including 24 trials published between 1987 and 2015, yielded a more precise
estimate of effectiveness for both interferon beta-1a once a week versus placebo
(HR 0.73, 95%CI 0.53 to 1.00) and glatiramer acetate (HR 0.76, 95%CI 0.60
to 0.97) at three months (46). There was little evidence of superiority of one
drug over another but ranking of the medicines suggested that interferon
beta‑1a three times weekly had the highest cumulative probability of superiority.
Interpretation of these findings should take into consideration the short length
of follow up, the high risk of bias across studies, and the potential differences
among trials that may act as effect modifiers and introduce bias in the network
meta-analysis. This review also considered discontinuation due to adverse
events, at different follow up times. Evidence that one medicine was more likely
to lead to discontinuation than another was limited, as the confidence intervals
were wide: more discontinuation were observed with interferon beta-1a three
times weekly versus placebo (RR 2.49, 95%CI 0.89 to 6.95) and with glatiramer
acetate (RR 2.36, 95%CI 0.74 to 7.53).
194
Fingolimod
A 2016 Cochrane systematic review of six trials (5512 participants) compared
the safety and efficacy of fingolimod versus placebo or other disease modifying
treatment for RRMS (47). Compared to placebo, fingolimod at 24 months
increased the probability of being relapse‐free (RR 1.44, 95%CI 1.28 to 1.63);
moderate quality of evidence), little or no difference in preventing disability
progression was observed (RR 1.07, 95%CI 1.02 to 1.11; primary clinical
endpoints; low quality evidence). Benefit was observed for other measures
of inflammatory disease activity including annualized relapse rate and GAD
lesions. No significant increased risk of discontinuation due to adverse events
was observed for fingolimod at recommended dose compared to placebo at six
and 24 months. No significant increased risk of discontinuation due to serious
adverse events was observed for fingolimod 0.5 mg compared to placebo at six
and 24 months. A significant increased risk of discontinuation due to serious
adverse events was found for fingolimod 5.0 mg (RR 2.77, 95%CI 1.04 to 7.38)
compared to placebo at six months.
Compared to intramuscular interferon beta‐1a, there was moderate
quality evidence fingolimod 0.5 mg at one year slightly increased the number of
participants free from relapse (RR 1.18, 95%CI 1.09 to 1.27) or from GAD lesions
(RR 1.12, 95%CI 1.05 to 1.19), and decreased the relapse rate (rate ratio 0.48,
95%CI 0.34 to 0.70). There was no observed advantage for preventing disability
progression (RR 1.02, 95%CI 0.99 to 1.06; low quality evidence).
There was a greater likelihood of participants discontinuing fingolimod,
compared to other DMTs, due to adverse events at six months (RR 3.21, 95%CI
1.16 to 8.86), but there was no significant difference versus interferon beta‐1a at
12 months (RR 1.51, 95%CI 0.81 to 2.80; moderate quality evidence). A higher
incidence of adverse events was suggestive of the lower tolerability rate of
fingolimod compared to interferon‐beta 1a.
WHO Guidelines
None available.
The cost-effectiveness of disease modifying treatments for MS have been assessed
in multiple systematic reviews involving studies conducted in high-income
countries in Europe and North America (48–51). The studies reported that DMTs
(including glatiramer acetate, fingolimod, ocrelizumab and rituximab) were
potentially cost-effective but several studies reported costs that were likely to be
above particular countries’ willingness to pay thresholds. Limitations of these
studies noted in these reviews included the lack of head-to-head comparisons
between different DMTs, variation in time-horizons, and variation in end-points.
There were no cost-effectiveness studies identified from LMICs.
195
Though there is significant variance globally, a North American study

suggested that approximately 60% of people with MS are unemployed (52),
accounting for about one third of the total economic burden of MS (53). In
addition to a loss in productivity, people with MS will have additional care
needs with advancing age and disease severity. The economic burden of MS
per patient and year ranges from approximately US$ 24 666 to US$ 51 678 (54).
These amounts represent direct costs, which include in and out patient care,
medications, medical procedures and social services as well as indirect costs
related to loss of employment, disability benefits, early pension plans, and loss of
productivity for spouses or family members providing informal care and death.
Given the most frequent age of presentation (young adults), it is important to
note that MS has both physical and cognitive impact, and also impacts the family
development of the patients, as well as, determines a socioeconomic impact on
society as a whole.
Availability
Glatiramer acetate has marketing approval in many countries. Generic versions
of glatiramer acetate are available in some countries – for example, in India,
the Russian Federation and the United States. Secondary patents concerning
glatiramer acetate are active in some jurisdictions.
Fingolimod also has marketing approval in many countries. Price and
availability of fingolimod vary globally. Generic versions are available. The
main product patent on fingolimod appears not to have been filed in the LMIC
jurisdictions surveyed and expires between 2016 and 2018 in some European
countries and 2019 in the United States.
Ocrelizumab has marketing approval in 68 high- and middle-income
countries. Ocrelizumab is protected by a product patent expiring in 2023 in
many jurisdictions. It is likely that biosimilar ocrelizumab cannot enter the
market where this patent has been granted before 2023.
Rituximab has marketing approval for indications other than multiple

sclerosis in high-, middle- and low-income countries. Biosimilar versions of
rituximab have been approved in numerous countries, including Australia,
Bolivia, Chile, India, Peru, the Republic of Korea, and the European Union.
Use in pregnancy
A pregnancy registry maintained by the marketing company of branded
glatiramer acetate captured over 7000 pregnancies exposed to glatiramer acetate.
It did not find an increase in spontaneous abortions, premature births, neonatal
complications or birth defects (55). No significant differences were observed in
birth weight of babies born to mothers exposed to glatiramer during pregnancy
196
compared with mothers not exposed to glatiramer acetate during pregnancy.

Evidence supports the use of branded glatiramer acetate in pregnant women
who are recommended to remain on treatment to manage disease activity.
Fingolimod is a teratogen class C agent and should be considered an
absolute contraindication in pregnancy and breastfeeding based on its known
teratogenicity in animal studies and post-marketing data.
Ocrelizumab is known to cross the placental barrier and is recommended
to be avoided during pregnancy unless the potential benefit to the mother
outweighs the potential risk to the fetus. There are no adequate data on the
developmental risk associated with use of ocrelizumab in pregnant women.
For rituximab, a large cohort study found that out of 153 pregnancies,
90 resulted in live births (56). Twenty-two infants were born prematurely;
with one neonatal death at six weeks. Eleven neonates had haematologic
abnormalities; none had corresponding infections. Two congenital malformations
were identified.
The European League Against Rheumatism (EULAR) considered use of
rituximab before pregnancy and during pregnancy (57). Based on a systematic
literature and consensus among experts, the recommendation considered that
rituximab should be replaced by other medication before conception. It should
be used during pregnancy only when no other pregnancy-compatible drug can
effectively control maternal disease.
The Expert Committee acknowledged the important public health burden of MS
and the need for effective and affordable treatments and noted the large number
of supporting letters that were received in relation to the application.
The Committee appreciated the approach taken in the application to
propose a limited number of essential medicines for MS, but noted that the
superiority of the presented medicines over other therapeutic options in terms of
benefits, harms and affordability did not clearly emerge.
The Committee noted that some commonly used treatments were not
included (e.g. azathioprine, natalizumab, dimethyl fumarate, cladribine) or were
not given full consideration (rituximab) and the reasons for their exclusion were
not clear. The Committee also noted ongoing development in international MS
guidelines and would welcome a revised application for EML inclusion in the
future that considers the relative roles of all available medicines for MS.
In particular, the Committee noted the evidence presented in the
application in relation to rituximab. The Committee agreed that rituximab could
have a relevant clinical role in treatment of MS, and recommended that any future
application should include evidence for rituximab versus active comparators, not
just placebo.
197
The Committee, therefore, did not recommend the addition of glatiramer

acetate, fingolimod and ocrelizumab to the Model Lists at this time, and would
welcome a revised application which comprehensively reviews the relative roles
of relevant available medicines for MS.
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TNF-alfa inhibitors for chronic inflammatory diseases – addition – EML and EMLc
Etanercept ATC Code: L04AB01

Infliximab ATC Code: L04AB02
Adalimumab ATC Code: L04AB04
Certolizumab pegol ATC Code: L04AB05
Golimumab ATC Code: L04AB06
Proposal
The application requested the addition of anti-tumour necrosis factor (TNF)
biologic medicines etanercept, infliximab and adalimumab (and biosimilars) to
the EML and EMLc and of certolizumab pegol and golimumab to the EML for the
treatment of severe chronic inflammatory autoimmune disorders: rheumatoid
arthritis, ankylosing spondylitis, juvenile idiopathic arthritis and Crohn disease.
Applicant
Centre for Global Health - University of Ottawa

Management of NCDs, Disability, Violence & Injury Prevention
EML/EMLc
EML and EMLc
Section

Etanercept (ETN): injection 25 mg/mL, 50 mg/mL

Infliximab (IFX): powder for injection 100 mg
Adalimumab (ADA): injection 40 mg/0.8 mL, 40 mg/0.4 mL
Certolizumab pegol (CZP): injection 200 mg/mL
Golimumab (GOL): injection 50 mg/0.5 mL, 100 mg/mL
Core / Complementary
Complementary
Individual / Square box listing

Square box
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Anti-TNF biologic medicines had not previously been considered for inclusion
on the Model Lists.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can affect
multiple joints, connective tissues, muscles, tendons and fibrous tissues. It is
a chronic disabling condition causing severe pain and deformity. The global
prevalence of RA in 2017 was 0.27%. Countries from all income levels are
affected (1).
Ankylosing spondylitis (AS) is a type of chronic inflammatory arthritis that
primarily affects the spine and sacroiliac joints and ligaments. Individuals with
AS have increased risk for developing articular and extra-articular manifestations
that further compound the negative health outcomes and prognosis (2). The
pooled global prevalence of AS has been estimated at 0.18%, with the highest
prevalence seen in Europe, North America (3) and in individuals who are human
leukocyte antigen (HLA)-B27 positive with a family member with the disease (4).
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease
affecting children under the age of 16 years. There are limited epidemiological
data for JIA, likely due to lack of standard diagnostic criteria (5, 6). However,
recent estimates indicate that the prevalence varies from 3.8 to 400/100 000 and
after directly standardizing for age and gender, the pooled prevalence is 70.2
[62.9 to 78.1]/100 000 (6).
Crohn disease is a chronic autoimmune disorder characterized by severe
inflammation of any part of the gastrointestinal tract, but most commonly
occurs in the lower part of the small intestine and the colon. Crohn disease is a
lifelong systemic condition with deliberating symptoms that negatively affect an
individual’s quality of life. Most people will need surgery and/or drug treatment.
As such, it is associated with high morbidity, mortality, and substantial costs
to the health care system. Although the incidence is the highest in western
nations, it is greatly accelerating in Asia, South America and Africa (7). The
overall burden of Crohn disease remains high with prevalence exceeding 0.3%
in North America, Oceania, and many countries in Europe (7). The prevalence
has especially risen in the paediatric population in the past 15 years (8).

Early RA
A systematic review of 16 RCTs (6908 participants) compared anti-TNF biologics
to conventional synthetic disease modifying anti-rheumatic drugs (csDMARD)
as monotherapy (n=13) or combination therapy (n=3). One RCT compared TNF
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and non-TNF biologic therapies. The majority of the included studies were rated
as medium risk of bias (ROB) (9).
Overall, the results of a network meta-analysis revealed that when anti-
TNF biologics were combined with methotrexate (MTX), patients achieved
higher response rates (as measured by ACR50 (50% change in RA activity
measures)) compared to MTX alone: ETN + MTX relative risk (RR) 1.49, 95%CI
1.27 to 1.74; moderate strength of evidence; ADA + MTX RR 1.35, 95%CI 1.15
to 1.59; low strength of evidence; CZP + MTX RR 1.20, 95%CI 1.04 to 1.38;
low strength of evidence; IFX + MTX RR 1.57, 95%CI 1.30 to 1.88; insufficient
strength of evidence (9).
Results also indicated that the combination of anti-TNF biologics plus
MTX were favoured in comparison to biologic monotherapy. The ACR50
response rate was significantly higher for ADA + MTX than ADA monotherapy
(RR 1.52, 95%CI 1.28 to 1.80; moderate evidence) and ETN + MTX than ETN
monotherapy (RR 1.57, 95%CI 1.23 to 2.02) (9).
Anti-TNF combinations were also associated with benefits compared to
MTX monotherapy for the outcome measures of remission, radiographic changes
or functional capacity (9).
Advanced RA
A systematic review of 98 RCTs evaluated the comparative efficacy of different
treatment options for advanced RA. Of these, 61 studies were included to
determine the efficacy of anti-TNF biologics. Of the 88 studies assessed for risk
of bias, half were judged to have a high ROB and only 10 were considered to have
a low ROB overall; the rest (39%) had an unclear ROB overall (10).
ETN + MTX (odds ratio (OR) 3.95, 95% credible interval (CrI) 2.29 to
7.51), IFX + MTX (OR 3.00, 95%CrI 1.78 to 5.08), ADA + MTX (OR 3.99, 95%CrI
2.84 to 5.62), CZP + MTX (OR 5.35, 95%CrI 3.42 to 8.67) and GOL + MTX
(OR intravenous (IV) 2.90, 95%CrI 1.21 to 7.12; OR subcutaneous (SC) 6.00,
95%CrI 3.27 to 11.35) all produced greater ACR 50 responses when compared
to MTX monotherapy. Anti-TNF biologics in combination with MTX were also
associated with greater odds of achieving ACR 50 response compared to MTX
in combination with another conventional synthetic disease-modifying anti-
rheumatic drug (csDMARD). With the exception of Infliximab, all the anti-TNF
biologics in combination with MTX produced a comparable ACR 50 response to
csDMARD triple therapy (10).
There were no significant differences in radiographic progression for any
anti-TNFs in combination with MTX compared to csDMARD double or triple
therapy. There were statistically significant higher odds of achieving remission
among those who were treated with anti-TNF biologics in combination with
MTX compared to MTX. Anti-TNF biologics in combination with MTX also
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produced more favourable odds of remission compared to a csDMARD plus

MTX (10).
CZP + MTX, achieved a statistically significant improvement in the
DAS28 (Disease Activity Score 28) compared to MTX monotherapy. IFX,
ADA, CZP and GOL (IV and SC) all in combination with MTX produced a
significantly lower disability score and higher physical health-related quality of
life scores compared to MTX monotherapy. Intravenous GOL and CZP both in
combination with MTX produced higher mental health-related quality of life
than MTX. Patients treated with ETN, ADA or CZP all in combination with
MTX had lower pain scores than MTX monotherapy. CZP + MTX produced a
significantly lower fatigue score than MTX monotherapy (10).
Ankylosing spondylitis
A systematic review of 21 short-term RCTs involving 3308 participants assessed
the benefits and harms of anti-TNF biologics in comparison with placebo, other
drugs or usual care in the treatment of AS. Most included studies had low or
unclear risk of bias (4).
Patients receiving anti-TNF biologics were found to be three to four
times more likely to achieve an Assessment in SpondyloArthritis International
Society (ASAS) 40 response by six months compared to placebo (ETN RR 3.31,
95%CrI 2.38 to 4.53; IFX RR 4.07, 95%CrI 2.80 to 5.74; ADA RR 3.53, 95%CrI
2.49 to 4.91; GOL RR 2.90, 95%CrI 1.90 to 4.23) (high strength of evidence).
The number needed-to-treat (NNT) to receive this response ranged from 3 to 5.
No significant difference was found for ASAS 40 response between the anti-TNF
biologics (4). Moderate strength evidence found that patients receiving anti-TNF
biologics were also significantly more likely than placebo to achieve ASAS partial
remission. The NNT to detect a minimally clinically important difference of
0.7 points for physical functioning ranged from 2 to 4. There was high strength
evidence that ETN, IFX, ADA and GOL all had significantly lower BASFI (Bath
Ankylosing Spondylitis Functional Index) scores compared to placebo. Low
to moderate strength evidence suggested that anti-TNF biologics have a small
impact on reducing spinal inflammation, however the clinical relevance of this
was not clear (4).
Juvenile idiopathic arthritis
A systematic review of 100 full-text articles and conference abstracts (67 RCTs)
evaluating the efficacy and safety of interventions for JIA included eight RCTs
comparing anti-TNF biologics (11).
This review found that patients receiving ETN 0.4 mg/kg were more
likely to maintain a disease response measured by the American College of
Rheumatology (ACR) Pediatric (PEDI) 30 compared to patients receiving
placebo (RR 1.91, 95%CrI 1.28 to 2.59). No other anti-TNF biologics showed
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statistically significant differences compared to placebo for this outcome. There

were no significant differences between anti-TNF biologics and methotrexate in
combination with placebo. Indirect estimates of the head-to-head comparisons of
anti-TNF biologics did not demonstrate statistically significant differences (11).
The number of active joints decreased for 0.2 mg/kg and 0.4 mg/kg ETN
(mean difference (MD) −11.23, 95%CrI −18.16 to −4.59 and MD −11.01, 95%
CrI −14.59 to −7.52, respectively) and the number of joints with limited range
of motion decreased for 0.4 mg/kg ETN only (MD −5.15, CrI −9.5 to −0.8) (11).
Crohn disease
A systematic review comparing the efficacy of therapies for induction and
maintenance of remission in adult patients with Crohn disease included 15 trials
involving anti-TNF therapies (IFX: one for induction and two for maintenance;
ADA: four for induction and three for maintenance; CZP: four for induction
and one for maintenance) and five additional studies evaluating combination
therapies with IFX (12). All but one study assessed remission using the Crohn
Disease Activity Index (CDAI) less than 150. Most of the included studies were
assessed to have unclear risk of bias. Other limitations of this study have been
identified in the literature that may limit the applicability of the results (13).
However, additional network meta-analyses have found similar effectiveness of
anti-TNFs against placebo in the induction and maintenance of remission for
Crohn disease even after accounting for these differences (14–16).
Compared to placebo, IFX (odds ratio (OR) 2.8, 95%CrI 1.4 to 7.2), IFX
plus azathioprine (OR 4.3, 95%CrI 2.0 to 9.8) and ADA (OR 2.9, 95%CrI 1.6
to 5.5) all had over 99% probability of being superior at inducing remission in
Crohn patients. These same drugs also proved to be superior to azathioprine/6-
mercaptopurine (OR 2.3, 95%CrI 1.3 to 5.0, OR 3.4, 95%CrI 1.9 to 6.3, and OR
3.4, 95%CrI 1.9 to 6.3). IFX plus azathioprine was 2.7 times more likely to induce
remission compared to methotrexate (95%CrI 1.9 to 6.3). IFX + azathioprine

(OR 3.1, 95%CrI 1.4 to 7.7) and ADA (OR 2.1, 95%CrI 1.0 to 4.6) were found to
be superior to CZP for inducing remission (12).
For maintenance of remission, IFX (OR 2.8, 95%CrI 1.8 to 4.5), IFX plus
azathioprine (OR 5.2, 95%CrI 2.8 to 11), ADA (OR 5.1, 95%CrI 3.3 to 8.1)
and CZP (OR 2.0, 95%CrI 1.4 to 3.0) all had over 99% probability of being
superior to placebo. ADA (OR 2.9, 95%CrI 1.6 to 5.1), IFX (OR 1.6, 95%CrI 1.0
to 2.5) and IFX plus azathioprine (OR 3.0, 95%CrI 1.7 to 5.5) all had greater
odds at achieving maintenance of remission compared to azathioprine/6-
mercaptopurine). IFX + azathioprine (OR 2.6, 95%CrI 1.3 to 6.0) and ADA
(OR 2.5, 95%CrI 1.4 to 4.6) were found to be superior to CZP for maintenance
of remission. IFX plus azathioprine was superior to IFX monotherapy for
maintenance of remission (OR 1.8, 95%CrI 1.0 to 3.8) (12).
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A systematic review comparing efficacy of pharmacologic interventions

for preventing relapse of Crohn disease after surgery found that anti-TNF
monotherapy was the most effective therapy for post-operative prophylaxis,
with large effect sizes relative to all other strategies including antibiotics,
immunomodulator monotherapy, immunomodulators with antibiotics, budesonide
(clinical relapse: RR, 0.02 to 0.20; endoscopic relapse: RR, 0.005 to 0.04) (17).

Uncommon yet serious adverse events for anti-TNF biologics include serious
infection, malignancy and lymphoma, neurologic effects and cardiac failure.
A 2011 Cochrane Systematic Review assessed the potential adverse effects
of anti-TNF biologics: etanercept (39 RCTs), infliximab (40 RCTs), adalimumab
(22 RCTs), certolizumab pegol (six RCTs) and golimumab (eight RCTs) alone or
in combination with other therapies. This review found that compared to control,
CZP was associated with a higher odds of serious adverse effects (OR 1.57, 95%CI
1.06 to 2.32) and serious infections (OR 4.75, 95%CI 1.52 to 18.45) and IFX was
associated with higher odds of total adverse events (OR 1.55, 95%CI 1.01 to 2.35)
and withdrawals due to adverse events (OR 2.34, 95%CI 1.40 to 4.14) (18).
Early RA
The network meta-analysis for early RA found no significant differences in serious
adverse events or discontinuations attributable to adverse events between MTX
monotherapy and any of the anti-TNF biologics (low strength of evidence). IFX
+ MTX also did not differ from csDMARD combination therapies (low strength
of evidence). Anti-TNF therapy with a csDMARD did not differ significantly
in serious adverse events or discontinuations attributable to adverse events
compared to TNF biologic monotherapy (moderate strength of evidence) (9).
Advanced RA
The systematic review for advanced RA found that there were no significant
differences in serious adverse events or withdrawals attributable to adverse
events between the anti-TNF biologics in combination with MTX and MTX
monotherapy. ETN + MTX had lower odds of withdrawals attributable to adverse
events compared to a csDMARD in combination with MTX (OR 0.33, 95%CrI
0.11 to 0.89). There was insufficient evidence to detect any differences in anti-
TNF treatment comparisons for mortality, serious infections, tuberculosis,
cancer, leukaemia, lymphoma, congestive heart failure, major adverse cardiac
events and herpes zoster. A pairwise meta-analysis found no statistically
significant difference in mortality for IFX + MTX and MTX monotherapy.
Additional pairwise meta-analyses found that there were no differences in serious
infections for patients treated with the ETN, IFX or GOL (plus MTX) versus
MTX alone. There was insufficient evidence for this outcome for ADA + MTX.
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A pooled estimate from two trials comparing ETN monotherapy and MTX
combination therapy, found that were no significant differences in cancer, and
a pairwise meta-analysis found no significant differences between IFX + MTX
and MTX groups (10).
Ankylosing spondylitis
Pooled results for all anti-TNF biologics demonstrated a moderate level of
evidence that there is an increased risk of withdrawals due to adverse events
compared to placebo (Peto OR 2.44, 95%CI 1.26 to 4.72), with an absolute
increase of 1% (95%CI 0% to 2%). There was no difference in risk for serious
adverse events (Peto OR 1.45, 95%CI 0.85 to 2.48). ETN (25 and 50 mg) was the
only anti-TNF biologic that had an individual increase in withdrawals due to
adverse events versus placebo (RR 3.65, 95%CI 1.27 to 11.79) with an absolute
increased harm of 2% (95%CrI 0.2% to 8%). The effect of ETN compared to
placebo for serious adverse events was uncertain. There was uncertainty reported
for adverse effects or withdrawals due to adverse effects between either ADA,
GOL or IFX and placebo. The strength of evidence was moderate for all safety
outcomes (4).
Juvenile idiopathic arthritis
The systematic review for JIA found that biologics were safe in short-term use
among both polyarticular course and active systemic patients. For polyarticular
course, one RCT found that no serious adverse effects or withdrawals due to
adverse effects occurred for high or low doses of ETN. Another RCT found no
withdrawals due to adverse events occurred for ADA with or without methotrexate
and few withdrawals due to adverse events (11).
Crohn disease
IFX + azathioprine (OR 0.27, 95%CrI 0.08 to 0.72) and ADA monotherapy (OR
0.43, 95%CrI 0.26 to 0.69) were associated with significantly lower odds of total
withdrawals compared to placebo. Similarly, IFX + azathioprine was associated
with significantly lower odds of total withdrawals compared to Azathioprine/6-
mercaptopurine (OR 0.39, 95%CrI 0.14 to 0.98) and methotrexate (OR 0.29,
95%CrI 0.07 to 0.93) (12).
For withdrawals due to adverse events, IFX (OR 2.7, 95%CrI 1.6 to 4.7)
and IFX + azathioprine (OR 3.2, 95%CrI 1.6–6.1) had significantly greater odds
of withdrawals due to adverse events compared to placebo. Adalimumab had over
a 99% probability of having less withdrawals due to adverse events than placebo
(OR 0.48, 95%CrI 0.31 to 0.74). CZP (OR 0.23, 95%CrI 0.13 to 0.40) and ADA
(OR 0.12, 95%CrI 0.06 to 0.24) had significantly less odds of withdrawals due
to adverse events compared to azathioprine/6-mercaptopurine and methotrexate
(CZP: OR 0.07, 95%CrI 0.01 to 0.28 and ADA: OR 0.04, 95%CrI 0.00 to 0.16).
208
Infliximab monotherapy had significantly lower odds of withdrawals due to

adverse events compared to methotrexate (OR 0.21, 95%CrI 0.02 to 0.93) (12).
Anti-TNF comparisons indicated that ADA (OR 0.0, 95%CrI 0.24 to
0.96) and IFX + azathioprine (OR 0.32, 95%CrI 0.09 to 0.94) have significantly
lower odds of total withdrawals than CZP. ADA had lower odds of withdrawals
due to adverse events than CZP (OR 0.55, 95%CrI 0.32 to 0.93) and IFX (OR
0.18, 95%CrI 0.09 to 0.34). IFX + azathioprine (OR 3.6, 95%CrI 1.7 to 7.5) and
IFX monotherapy (OR 3.1, 95%CrI 1.7 to 5.8) had significantly greater odds
of withdrawals due to adverse events than CZP. IFX + azathioprine also had
greater odds than ADA of withdrawals due to adverse events (OR 6.5, 95%CrI
3.0 to 14) (12).

N/A
WHO Guidelines
None available
The application presented details of available information on drug costs for the
anti-TNF biologics from Australia, Canada, the United Kingdom and the United
States. These medicines are associated with a significant budget impact to health
systems due to both price and volume of use.
In addition, the application identified and summarized the findings
numerous economic evaluations conducted primarily in Canada, the United
Kingdom and the United States involving anti-TNF biologics for the indications
proposed for EML listing (19–35).
Availability
These medicines have wide marketing approval globally. Biosimilars are available
for ETN, IFX and ADA.
The Committee noted that most of the evidence presented in the application
comes from countries with low levels of tuberculosis and/or hepatitis B infection.
Reactivation of latent tuberculosis infection and hepatitis B in patients receiving
anti-TNF biologics has been reported (36, 37), and this risk should be taken into
consideration when anti-TNF biologics are considered in settings where there is
a higher burden of TB and hepatitis B.
209
The Committee recognized that these auto-immune disorders are highly
debilitating and that there is a public health need for effective treatments for
patients who do not respond adequately to first-line treatments (e.g. methotrexate).
The Expert Committee recommended the addition of adalimumab with a
square box to the complementary list of the EML and EMLc for the second-line
treatment of severe chronic inflammatory autoimmune disorders (rheumatoid
arthritis, ankylosing spondylitis, juvenile idiopathic arthritis and Crohn disease)
on the basis of the positive benefit to harm profile of these medicines.
For adult patients, therapeutically equivalent alternatives to adalimumab
are limited to etanercept, infliximab, certolizumab pegol and golimumab. For
children, therapeutically equivalent alternatives should be limited to etanercept
and infliximab.
The Committee also recognized that these medicines are associated
with a significant budget impact on health systems. However, the availability
of several therapeutically equivalent alternatives and the increasing availability
of biosimilar products could lead to more market competition. The Committee
recognized a potential expansion of the role of the Medicines Patent Pool to
biological medicines such as these as an opportunity to facilitate affordable
access. Quality-assured available biosimilars of these medicines should also be
considered as therapeutically equivalent for procurement purposes.
The Expert Committee recommended that WHO take action to facilitate
access to these medicines through the WHO pre-qualification programme, and
through collaboration with partners such as the Medicines Patent Pool.
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18. Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK et al. Adverse
effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst
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for rheumatoid arthritis in a commercially insured population. J Manag Care Spec Pharm.
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8.2 Antineoplastics and supportive medicines

Cancer medicines for children – addition/new indication – EMLc
Cancer medicines for children ATC Code: various
Proposal
The application proposed an extension of adult cancer indications to paediatrics
and corresponding inclusion on the EMLc. The proposal involves both the
inclusion of new indications for some cancer medicines currently on the EMLc
and the addition of selected new cancer and supportive care medicines to the
EMLc. The proposed listing extensions are presented in the following table:
New medicines to be added to the EMLc – extending adult indications to children

Medicine Paediatric indication(s)
All-trans retinoic acid (ATRA) Acute promyelocytic leukaemia
Dasatinib Imatinib-resistant chronic myeloid leukaemia
Enoxaparin For use as anticoagulant
Hydroxycarbamide Chronic myeloid leukaemia
Imatinib Chronic myeloid leukaemia
Gastrointestinal stromal tumour
Irinotecan Metastatic colorectal cancer
Nilotinib Imatinib-resistant chronic myeloid leukaemia
Oxaliplatin Early stage colon cancer
Metastatic colorectal cancer
Procarbazine Hodgkin lymphoma

Rituximab Diffuse large B-cell lymphoma
Zoledronic acid Malignancy-related bone disease
New indications for existing medicines on the EMLc
Indication Medicine(s)
Kaposi sarcoma Bleomycin
Doxorubicin
Vincristine
Nasopharyngeal cancer Cisplatin
Fluorouracil
214
Table continued
New indications for existing medicines on the EMLc
Indication Medicine(s)
Diffuse large B-cell lymphoma Cyclophosphamide
Doxorubicin
Prednisolone
Vincristine
Colorectal cancers Cisplatin
Fluorouracil
Acute promyelocytic leukaemia Cytarabine
Daunorubicin
Mercaptopurine
Methotrexate
Acute myeloid leukaemia Cytarabine
Applicant
Catherine Lam, Scott C. Howard

Management of NCDs, Disability, Violence & Injury Prevention. The technical
unit advised that it supports the proposal to extend the listing of specified cancer
medicines and indications on the EML to the EMLc.
EML/EMLc
EMLc
Section
8.2 Antineoplastic and supportive medicines

Various
Core/Complementary
Complementary

Individual
215

The proposed medicines and corresponding indications had not previously been
considered for inclusion on the EMLc.
The application applied the following rationale in proposing the medicines
and indications for inclusion on the EMLc:
■■ The medicine must already be listed on the EML or EMLc.
■■ The indications listed for adults are also diagnosed in children aged
12 years and under.
■■ The medicines have been reported for treatment in children aged
12 years and under for the same indication as listed on the EML for
treatment in adults.
■■ Published literature supports the extension of the indication to
children, including clinical studies, peer-reviewed consensus
documents and/or clinical guidelines support the medicine’s role as
standard of care.

Cancer is a leading cause of death for children globally with the most common
cancer types occurring in children being leukaemias, lymphomas and central
nervous system tumours (1). Childhood cancers generally cannot be prevented
nor screened for, so improving outcomes for children with cancer relies on early
and accurate diagnosis and access to effective treatments.
In 2018, WHO launched the Global Initiative for Childhood Cancer,
to provide leadership and technical assistance to Member States to build and
sustain high quality childhood cancer programmes. The goal of this initiative is
to achieve at least 60% survival for all children with cancer globally by 2030 (2).

Acute promyelocytic leukaemia (APML)

New medicine: all-trans retinoic acid (ATRA)
New indication: cytarabine, daunorubicin, mercaptopurine, methotrexate
The median age of children with APML has been reported as 10 years (3).
Standard regimens used for children with APML include ATRA (3, 4), with
prior randomized trial data demonstrating significant disease-free survival
improvement for children randomized to receive ATRA vs not (48% at 5 years,
vs 0%, p<0.0001), with overall survival rates sustained at 10 years (5). The use
of ATRA is acknowledged in standard guidelines for the treatment of APML,
and is considered to be a paradigm for a targeted approach to the treatment of
leukaemia (6–10). The treatment of APML is typically provided in the context
216
of poly-chemotherapy, involving cytarabine, daunorubicin, mercaptopurine and

methotrexate (3–5).
Acute myeloid leukaemia (AML)
New indication: cytarabine
The safety and effectiveness of cytarabine for the treatment of childhood AML
have been evaluated in controlled clinical trials (11–13). It is considered the
standard of care, used internationally for children with AML, as in adults (14, 15).
Chronic myeloid leukaemia (CML)
New medicines: imatinib, dasatinib, nilotinib, hydroxycarbamide
CML is a very rare disease in children, estimated to be responsible for 2% of all
leukaemias in children less than 15 years of age with an annual incidence of one
case per million children in that age range (16). The tyrosine kinase inhibitors
introduced a chance of cure for CML, with long lasting disease control and
significantly improved outcomes (17).
Imatinib has shown clinical benefit in children with CML, with results
comparable to those seen in adults (18). In particular, a clinical study of the
use of imatinib in patients aged less than 18 years with CML in the chronic
phase demonstrated the efficacy, safety and long-term benefit of imatinib in
children (19).
Dasatinib and nilotinib have been used in children with CML including
(but not limited to) imatinib-resistant cases. A Phase II trial of dasatinib in 113
paediatric patients with CML demonstrated a complete cytogenetic response was
achieved in 76% of imatinib-resistant patients, with an acceptable safety profile
that did not include pleural or pericardial effusion, commonly seen in dasatinib-
treated adults (20). The effectiveness and safety of nilotinib in children with CML
has also been reported (21). Nilotinib has been approved by the United States
FDA for treatment of paediatric patients with newly diagnosed or resistant CML
on the basis of the results from two open-label, single-arm trials involving 69
patients (22, 23). For imatinib-resistant patients, the major molecular response
rate was 40.9%. No new safety concerns were reported, noting transient and
manageable laboratory abnormalities: hyperbilirubinaemia and moderate to
severe transaminitis.
Hydroxycarbamide has a recognized debulking/cytoreductive role for
myeloid malignancies and for palliative purpose in all settings. In addition,
hydroxycarbamide can have an important role in settings where resource
limitations affect access to imatinib or other tyrosine kinase inhibitors, to allow
commencement of antineoplastic therapy (24). A general expert consensus
recommendation for childhood CML includes hydroxycarbamide as standard
initial therapy in all settings, while awaiting confirmatory diagnostic testing
results as well as initial clinical response (25).
217
Gastrointestinal stromal tumour (GIST)

New medicine: imatinib
Imatinib is the preferred treatment for molecularly-selected GIST in adults and
children, where c-KIT sensitive mutations are demonstrated. Paediatric GISTs
represent a distinct entity, and may be associated with genetic syndromes (such
as Carney Triad, Carney-Stratakis syndrome or neurofibromatosis 1 (NF1)/
Von Recklinghausen disease). It is also less common for paediatric patients
with GIST to have the activating mutations in KIT and platelet-derived growth
factor receptor alpha (PDGFRA) seen in adults. Data on the effectiveness and
activity of imatinib in paediatric GIST is scarce, as it is a very rare entity (1–2%
of all the cases). Children less than 18 years of age typically have more indolent
disease with more favourable prognosis than in adults (approximating 100%
five-year overall survival), as reported in a long-term retrospective analysis of
a large observational study, that included a sub-group of 28 patients in this age
group (26).
Diffuse large B-cell lymphoma (DLBCL)
New medicine: rituximab
New indication: cyclophosphamide, doxorubicin, prednisolone, vincristine
Different studies of DLBCL have established a role for rituximab in paediatric
populations, with studies often spanning all age groups including adults and
children starting at age 9 years (27), and confirming efficacy and safety in children
(28). Rituximab is administrated in the context of a combination regimen with
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) (27, 28).
CHOP alone may be administered in settings where rituximab is not available.
Kaposi sarcoma
New indication: bleomycin, doxorubicin, vincristine
Kaposi sarcoma in children primarily occurs as either endemic (HIV-unrelated)

or epidemic (HIV-related) disease. According to the data known from registries
and literature, Kaposi’s sarcoma primarily occurs in the elderly population of the
Mediterranean region, while the occurrence in children is restricted to smaller
series (29). Data from paediatric cohorts and clinical trials showed a median age
of diagnosis at 8 years old. Chemotherapy indicated for Kaposi sarcoma includes
bleomycin, vincristine and doxorubicin (30–34). One of the regimens combining
doxorubicin, bleomycin and vincristine (ABV) has reported 80% remission for
stage I HIV-positive patients treated in South Africa (32). Bleomycin, vincristine
and doxorubicin have also been included as standard treatment agents in
international expert consensus recommendations (35).
218
Nasopharyngeal cancer
New indication: cisplatin, fluorouracil
Nasopharyngeal carcinoma (NPC) is the most commonly diagnosed head
and neck malignant neoplasm in China and South-East Asian countries, but
is considered relatively rare among children. Treatment schemes are typically
adapted for children from adult-based regimens. Cisplatin-based regimens are
the standard of care for children with NPC. Together with cisplatin, fluorouracil
(5-FU) is included in standard regimens for children with NPC, with standard
administration of two courses 21 days apart (36–39). The use of cisplatin
including as a radiosensitizer (with concomitant cisplatin and radiation therapy)
following cisplatin/5-FU in the systemic treatment of NPC in children is
recognized as standard across different institutions and countries, extrapolating
from the adult treatment experience (40–43).
Colon and rectal cancers
New medicine: irinotecan, oxaliplatin
New indication: cisplatin, fluorouracil
While very rare, colorectal cancers can occur in children (reported in as young
as nine months old) and typically utilize the same chemotherapy agents as in
adults, including 5-FU for the neoadjuvant treatment of rectal cancer, 5-FU and
oxaliplatin for the adjuvant treatment of colon and rectal tumours, and 5-FU,
oxaliplatin and irinotecan for advanced or metastatic colorectal cancer (44–47).
Hodgkin lymphoma
New medicine: procarbazine
Procarbazine is commonly included as a drug of choice in children for the
treatment of Hodgkin lymphoma. According to clinical guidelines and literature,
procarbazine is a standard inclusion in multi-agent chemotherapy regimens
for Hodgkin lymphoma in children (48, 49). For the paediatric population,
multiple regimens containing procarbazine are used, in particular BEACOPP
that contains bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,
procarbazine, and prednisone. It is often used in more resource-limited settings.
Local selection and use should consider known gonadotoxicity and effects on
male fertility (50).
Malignancy-related bone disease
New medicine: zoledronic acid
Although certain malignancy-related bone diseases, such as osteonecrosis, occur
more often in older children, patients as young as age 4 to 6 years have been
affected and required treatment (51–53). The administration of zoledronic acid
in paediatric oncology appears safe, and may result in improved bone strength
219
and pain control. In a retrospective chart review of inpatients and outpatients

less than 21 years old who received zoledronic acid at the Children's Hospital of
Philadelphia, safety of the bisphosphonate was assessed. The safety profile was
consistent with the known experience in adults, including preventable alterations
in calcium levels, with no major side-effects reported (51).
Anti-coagulation
New medicines: enoxaparin
The use of low molecular weight heparin (LMWH) as an anticoagulant is
considered standard of care for prophylaxis and treatment in children, including
but not limited to children with cancer. Malignancy as well as treatment-related
factors such as immobilization and central venous access can increase risk for
thrombosis (54). Enoxaparin as standard antithrombotic therapy is used as a first
option in routine practice in many settings (55–57).

Not reported separately in the application.

A randomized, multicentre, open-label Phase III trial (OS2006) compared
standard chemotherapy with or without zoledronic acid in 318 patients aged
between 5 years and 50 years (median 15.5 years) with newly diagnosed high-
grade osteosarcoma (58). The trial results indicated that zoledronic acid did not
improve event-free survival, percentage of good histological response or overall
survival. No significant differences in toxicity or orthopaedic complications
were observed between treatment groups. The trial was stopped after the second
interim analysis for futility and the authors concluded that the use of zoledronic
acid in osteosarcoma patients was not recommended.
A retrospective analysis of the use of zoledronic acid for treatment
of chemotherapy related osteonecrosis in 20 children and adolescents with

osteonecrosis found that zoledronic acid was well tolerated and improved joint
pain in the majority of patients (53). However, among patients with osteonecrosis
of the hip, the majority had progressive joint destruction requiring arthroplasty,
despite treatment with zoledronic acid.
WHO Guidelines
None available
Not reported in the application.
220
Availability
The proposed medicines are already included on the EML and/or EMLc.
The Expert Committee recognized the public health need for access to cancer
therapies for children. The Committee acknowledged that there is limited clinical
trial evidence available for the use of many cancer medicines in children, and
that it is often necessary to rely on extrapolated data from trials in adults, clinical
consensus and/or clinical practice guidelines, that lend support to a medicine’s
role as the standard of care in paediatric patients.
The Expert Committee recommended the addition to the complementary list
of the EMLc of ATRA, dasatinib, fluorouracil, imatinib, irinotecan, nilotinib,
oxaliplatin, procarbazine and rituximab for the paediatric cancer indications
outlined in the table below.
The Committee also recommended the extension of the current listings
on the EMLc of bleomycin, doxorubicin, vincristine, cisplatin, cyclophosphamide,
prednisolone, cytarabine, daunorubicin, mercaptopurine, methotrexate, cytarabine
and hydroxycarbamide to include the indications outlined in the table below.
The Committee also recommended the addition to the core list of the
EMLc of enoxaparin with a square box for use as an anticoagulant in children.
The Expert Committee did not recommend the addition of zoledronic acid
to the complementary list of the EMLc for the treatment of malignancy-related
bone disease. The Committee noted that data for its use in children are scant and
fragmented. The Committee was also concerned that the effects of zoledronic acid
in some paediatric cancers (e.g. osteosarcoma) were largely negative, and that
there are insufficient long-term safety data of bisphosphonate use in paediatric
cancer patients to be reassured of an acceptable benefit–to–harm ratio.
Furthermore, the Committee noted that although use of bisphosphonates
in paediatric patients has been reported to be well tolerated, the impact of use in
the context of patients with actively growing skeleton is not yet fully known.
New medicines for EMLc

All-trans retinoic acid Acute promyelocytic leukaemia
Dasatinib Imatinib-resistant chronic myeloid leukaemia
Fluorouracil Nasopharyngeal carcinoma
Early-stage colon cancer
Early-stage rectal cancer
221
Table continued
New medicines for EMLc
Imatinib Chronic myeloid leukaemia
Gastrointestinal stromal tumour
Irinotecan Metastatic colorectal cancer
Nilotinib Imatinib-resistant chronic myeloid leukaemia
Oxaliplatin Early stage colon cancer
Procarbazine Hodgkin lymphoma
Rituximab Diffuse large B-cell lymphoma
 Enoxaparin Anticoagulant (core list)
Extension of indications for currently listed medicines
Bleomycin Kaposi sarcoma
Doxorubicin Kaposi sarcoma
Vincristine Kaposi sarcoma
Cisplatin Nasopharyngeal carcinoma
Cyclophosphamide Diffuse large B-cell lymphoma
Prednisolone Diffuse large B-cell lymphoma
Cytarabine Acute promyelocytic leukaemia
Daunorubicin Acute promyelocytic leukaemia
Mercaptopurine Acute promyelocytic leukaemia
Methotrexate Acute promyelocytic leukaemia

Cytarabine Acute myelogenous leukaemia
Hydroxycarbamide Chronic myeloid leukaemia
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226
Cancer medicines for children – text clarifications
Medicines for children with cancer – text clarifications
Proposal
The application requested amendments to the text of the listings for a number of
medicines and cancer indications on the EMLc:
1. Include alternate common names for some currently listed cancer
medicines.
2. Include alternate common names for some listed indications.
3. Revised diagnosis terminology for germ cell tumours.
4. Alignment and addition of formulations.
5. Inclusion of variant formulations of listed medicines.
6. Addition of usage and supportive indications.
Applicant
Catherine Lam, Scott C. Howard.

Management of NCDs, Disability, Violence and Injury Prevention. The technical
unit advised that it generally supported the text clarifications proposed in the
application.
EML/EMLc
EML and EMLc
Section

Various
Core/Complementary
Complementary

Individual
227

N/A

N/A
Summary of request (from the application)

1. The application proposed inclusion of the following alternate, commonly used
names for medicines currently listed on the EML and EMLc:
Current medicine name Proposed alternatives

Calcium folinate Leucovorin; Folinic acid
Dactinomycin Actinomycin; Actinomycin-D
Etoposide VP-16
Fluorouracil 5-Fluorouracil (5-FU)
Hydroxycarbamide Hydroxyurea
Mercaptopurine 6-mercaptopurine (6-MP)
Tioguanine 6-thioguanine (6-TG)
Lidocaine Lignocaine
Ciclosporin Cyclosporine; Cyclosporin
Aciclovir Acyclovir
2. The application proposed inclusion of the following alternate, commonly used

names for diagnoses/indications currently included on the EML and EMLc:
Current indication Proposed alternative

Acute myelogenous leukaemia Acute myeloid leukaemia
Wilms tumour Nephroblastoma
3. The application proposed replacing the indications of ovarian and testicular

germ cell tumours with the broader term “malignant germ cell tumour” to
include other common locations where children develop malignant germ cell
tumours (e.g., sacrococcygeal, mediastinal), as they are treated with the same
chemotherapy agents.
228
4. The application proposed the following formulation amendments and

additions:
Medicine Proposed formulation(s) for EML and EMLc

Dexamethasone Include the same formulations of dexamethasone
for use in cancer therapy as are currently included in
Section 2.3 for palliative care indications.
Calcium folinate - Add an oral solution formulation that can be made
extemporaneously from IV formulation (strength
not specified).
- Add 5 mg and 25 mg tablets.
Cyclophosphamide Add 50 mg tablet/capsule.
Etoposide - Add 50 mg capsule.
- Add oral liquid 20 mg/mL.
Mercaptopurine Add 20 mg/mL suspension.
Methotrexate Add 20 mg/mL oral liquid.
5. The application proposed the addition of variant formulations of the following

medicines:
Current medicine Proposed variant

Prednisolone Prednisone (multiple strength tablets).
Etoposide Etoposide phosphate 100 mg/mL.
Lidocaine Lidocaine 2.5% + prilocaine 2.5% topical formulation.
6. The application proposed inclusion of usage and supportive-care indications

for the following listed medicines:
Medicine Proposed indication(s)

Allopurinol “for patients at risk of tumour lysis”
Calcium folinate “in combination as supportive care agent, in regimens
with higher dose methotrexate to decrease side-
effects of methotrexate, or in some regimens with
fluorouracil to increase anticancer effects”
Mesna “in combination as supportive care agent, in regimens
with higher doses of ifosfamide or cyclophosphamide
to mitigate toxicity”
229
Table continued
Medicine Proposed indication(s)
Methotrexate “for high-dose and intrathecal administration, must
ensure ONLY preservative-free methotrexate is used”
Vincristine “must ensure NEVER delivered via intrathecal
administration as fatal”
 Morphine “codeine should not be used as a substitute for pain
management in children”

N/A

N/A
WHO Guidelines
None available
N/A
Availability
N/A
N/A
Following consideration of the proposals in the application, the Expert Committee
made the following recommendations:
1. The additional alternate common names for medicines should
not be added to the Model Lists. The current listings refer to the
international non-proprietary names (INN) of the medicines. INN
is the preferred nomenclature for medicines on the Model Lists.
2. The indication terminology for acute myelogenous leukaemia and
Wilms tumour should be amended as proposed, as this would be
consistent with ICD-11 terminology for these indications.
230
3. The indication of “malignant germ cell tumour” should not replace

the indications of ovarian and testicular germ cell tumour as the
Committee has not reviewed evidence for use of the relevant
medicines in the treatment of germ cell tumours other than ovarian
and testicular. Extending the indication to all germ cell tumours
would require a full application.
4. With regard to formulation amendments, the Committee
recommended that formulations of dexamethasone should be
consistently listed across different sections of the list(s). The
Committee also recommended that proposed new strengths
of existing dose forms of calcium folinate, cyclophosphamide,
etoposide should be added. However, the Committee did not
recommend listing of the new dose forms for these medicines, and
for mercaptopurine and methotrexate.
5. The Committee did not recommend the separate listing of
prednisone with prednisolone, noting that the square box listing
of prednisolone should be interpreted as including prednisone as
an alternative. The Committee did not recommend the listing of
etoposide phosphate as a variant of etoposide, as it considered that
a full application would be appropriate to consider the clinical place
of this medicine as an alternative to etoposide. The Committee also
did not recommend listing for topical lidocaine + prilocaine, again
considering that a full application would be required for this new
combination product.
6. The Committee recommended including the indication “tumour
lysis syndrome” with the listing for allopurinol. The Committee
did not recommend including the other proposed supportive care
indications with the listings of calcium folinate and mesna. Nor
did the Committee recommend the proposed cautionary text for
methotrexate and vincristine. The Committee acknowledged the
critical importance of these messages, but considered that this
text was better suited for clinical practice guidelines, medication
safety information and product packaging, than on the Model
Lists. The Committee did not recommend the proposed cautionary
text about codeine with the listing for morphine. The Committee
noted that codeine is not listed on the EMLc, and that alternatives
to morphine are specified in the current listing as being limited to
hydromorphone and oxycodone.
231
Arsenic therapies – addition – EML and EMLc
Arsenic trioxide ATC Code: L01XX27

Realgar-Indigo naturalis formula (RIF) ATC Code: N/A
Proposal
The application proposed the inclusion of arsenic therapies on the EML for the
treatment of acute promyelocytic leukaemia (APML).
Applicant
Scott C. Howard
Professor, University of Tennessee Health Science Center
Secretary General, International Pediatric Oncology Society (SIOP)

unit advised that it supported the inclusion of arsenic therapies for acute
promyelocytic leukaemia on the EML. The technical unit stated that arsenic,
used in combination with ATRA and chemotherapy, is curative in its use and is
generally accepted as the standard of care.
EML/EMLc
EML and EMLc
Section

Arsenic trioxide: Injection 1 mg/mL
Realgar-Indigo naturalis formula (RIF): tablet 270 mg
Core/Complementary
Complementary

Individual

Arsenic trioxide was previously considered by the Expert Committee in 2015
for treatment of APL as part of a comprehensive review of cancer medicines (1).
232
The Committee noted that addition of arsenic trioxide as consolidation therapy

for acute promyelocytic leukaemia (APML) did not produce a clinically relevant
increase in overall survival in naive patients. The Committee also noted the
extremely high price and low availability of arsenic trioxide and considered that
this would be unaffordable in many low- and middle-income countries (LMICs).
This new application focuses on clinical trial results that have been published
in the past few years and examines the oral arsenic preparation realgar-Indigo
naturalis formula (RIF), which has not been previously submitted. RIF represents
a feasible and inexpensive alternative to intravenous arsenic trioxide that could
benefit patients in LMICs.
Currently listed medicines for treatment of APML on the EML are all-
trans retinoic acid (ATRA), cytarabine, daunorubicin, mercaptopurine and
methotrexate. These medicines are not currently included on the EMLc for
this indication.

The GLOBOCAN initiative estimates the worldwide incidence of new leukaemia
cases for 2018 to be 437 033, with an age-standardized rate (ASR) of 5.2 per
100 000 per year (2). Mortality was 309 006 worldwide, with an ASR of 3.5
per 100 000 per year. The ASR was higher (3.6 per 100 000) in countries with
“high human development” than in countries of “low human development”
(2.7 per 100 000). However, over time, differences are becoming less evident.
Unfortunately, the International Agency for Research on Cancer (IARC) does
not sub-classify leukaemias into acute and chronic, and myeloid or lymphoid, in
its GLOBOCAN analysis.
APML accounts for 10% of AML cases and its incidence in Europe is
estimated to be 1/1 000 000 people (3).

A 2009 systematic review of the effectiveness of arsenic in APML patients
included five RCTs with 328 cases (4). All the RCTs focused on the comparison
of ATRA plus arsenic regimen with ATRA monotherapy. Meta-analysis showed
that the effect sizes for time to complete remission, two-year disease-free survival
rate and relapse rate were −1.20 (95%CI −1.68 to −0.72), 8.64 (95%CI 1.66 to
45.00), and 0.21 (95%CI 0.09 to 0.47), respectively. The authors concluded that
arsenic added to ATRA-based regimens improved remission rates and event-
free survival.
A 2019 review conducted for the UK National Institute for Health and
Care Excellence (NICE) led the NICE Appraisal Committee to recommend
approval of arsenic trioxide for newly diagnosed and relapsed APL (5). The review
presented three RCTs, in newly diagnosed APML patients and in patients with
relapsed APML. In newly diagnosed cases, results showed that more patients
233
having ATRA plus arsenic regimen were alive at 50 months compared with
people having ATRA in combination with idarubicin (99% vs 93%; p=0.007).
The number of cumulative relapses at 50 months were also lower in the arsenic
regimen when compared to the alternative regimen (2% vs 14%; p=0.001). At
four years, results from a second trial showed a significant difference in event-
free survival (91% vs 70%; p=0.002) favouring ATRA plus arsenic regimen.
However, results for overall survival were less certain (93% vs 89%; p=0.250).
The only included trial presented for relapsed/refractory patients compared
ATRA plus arsenic regimen with arsenic regimen, a comparison that is not
relevant to assess the potential benefits associated with arsenic regimens.
In patients with newly diagnosed APML, several studies included and
not included in the previously cited systematic reviews have confirmed the
superiority of the ATRA plus arsenic regimen over ATRA/chemotherapy in
children, adults and elderly patients (6–11). Many international cooperative
group and single centre studies have documented the superiority of ATRA plus
arsenic therapy over ATRA plus chemotherapy (usually anthracyclines), with
higher remission rates, and absolute improvements in disease-free and overall
survival ranging from 5% to 20% (11–21). Low-risk patients can be cured up
to 98% of the time with protocols comprising ATRA plus arsenic (21, 22).
The relevant advantage in the two-year event-free survival with the ATRA
plus arsenic regimen is likely to be driven by the lower mortality from causes
other than relapse (e.g. reduced severe haematologic toxicity as compared to
chemotherapy) together with similar antileukaemic efficacy of arsenic trioxide.
High-risk patients have cure rates above 85% using protocols that include
ATRA, arsenic, and chemotherapy (21, 23). A 2016 meta-analysis showed that in
patients treated with an ATRA plus arsenic regimen the risk of death was more
than halved as compared to patients receiving ATRA plus chemotherapy (HR
0.44, 95%CI 0.24 to 0.82) (24).
Arsenic-based regimens are also effective for relapsed patients with
APML, many of whom (about 80%) can have their lives significantly prolonged
(25–28). Although protocols with arsenic alone have proven curative for some
patients on both first-line and relapsed settings, the highest cure rates have been
documented with combinations of ATRA and arsenic therapy used in newly
diagnosed patients.
Arsenic-containing medications are now available from several suppliers
in both intravenous and oral formulations, which has decreased cost and
increased feasibility of arsenic-containing therapy for APML (29).
Realgar-indigo naturalis formula (RIF) has proven effective in adults and
children with first-line and relapsed APL in large randomized controlled trials,
with event-free survival of 95%–100% for newly diagnosed patients, comparable
to outcomes in the control arms that received intravenous arsenic trioxide, and
five-year overall survival rates close to 90% (7, 30–34).
234

Arsenic-based regimens for APML are less toxic than chemotherapy-based
regimens. Grade 3 or 4 neutropenia and thrombocytopenia, including episodes
lasting more than 15 days, were significantly more frequent both during induction
therapy and after each consolidation course in the ATRA and chemotherapy
group than in the ATRA and arsenic trioxide group (11, 22, 35). However, it
is associated with QTc prolongation, which can lead to cardiac dysrhythmias
in patients who receive other drugs that prolong the QTc interval (36). Cardiac
toxicity is rare in APML patients who receive arsenic therapy and can largely be
prevented by avoiding drug–drug interactions and careful monitoring. Arsenic-
based regimens have lower rates of second cancers than anthracycline-based
regimens (though not statistically significant in the small studies conducted to
date) (37). Finally, oral arsenic (RIF) has similar safety profile when compared
to arsenic trioxide in patients with APML (38).

N/A
WHO Guidelines
None available
Arsenic trioxide was found to be highly cost-effective for relapsed APML
in Canada using prices that were current prior to the availability of generic
formulations (39). Cost-effectiveness in the first-line setting would be expected
to be even higher, with very high remission rates and long-term survival, and
decreased need for hospitalization, blood products and supportive care. Use of an
oral arsenic available at a low price point would improve cost-effectiveness even
more by removing the need for daily infusions with cardiac monitoring.
Costs associated with oral arsenic are about half of those associated
with intravenous arsenic. In an RCT the median total medical costs were
US$ 13 183.49 in the RIF group compared with US$ 24 136.98 in the arsenic
trioxide group (40). The large difference in costs was mostly caused by the
varying costs of maintenance treatment. During induction therapy the length
of hospitalization for the RIF group was significantly shorter than that for the
arsenic trioxide group (24 vs 31 days). During maintenance treatment, in the RIF
group the estimated medical costs to treat a patient at home were US$ 2047.14
compared with US$ 11 273.81 to treat a patient in the arsenic trioxide group in
an outpatient setting.
235
Availability
The United States Food and Drug Administration (FDA) approved arsenic
trioxide in 2002 for relapsed APML and in 2017 for newly diagnosed patients.
The European Medicines Agency (EMA) has granted marketing
authorization for arsenic trioxide for newly diagnosed in relapsed APL in 2002
(provisional approval) and 2010 (full approval). Main patents have expired
(2019) but secondary patents might remain active in some jurisdictions. Several
generics are available (in India).
Realgar-Indigo naturalis formula (RIF) is available as 270 mg tablets
and it is produced by the Yifan Pharmaceutical Co (Tianchang, China). RIF
contains Realgar (tetra-arsenic tetrasulfide As4S4 , 30 mg per tablet), Indigo
naturalis (125 mg per tablet), Radix salvia miltiorrhizae (50 mg per tablet), Radix
pseudostellariae (45 mg per tablet), and garment film (a cover to contain the
drug components; 20 mg per tablet) (29, 38). The dose for first-line and relapsed
acute promyelocytic leukaemia is 60 mg/kg/day divided into three daily doses
(20 mg/kg/dose). It is the only oral arsenic formulation commercially available
and, as such, warrants special consideration, especially for use in LMICs, where
the high cost of intravenous arsenic trioxide and the need for daily intravenous
arsenic trioxide infusions over many months may pose important access and
safety concerns.
Arsenic trioxide-based regimens require daily intravenous infusions during
the arsenic-containing component of therapy. This means that patients must
stay near the treatment centre to receive daily infusions for six weeks during
remission-induction therapy followed by four four-week blocks. Infusions are
given over 1–2 hours and ideally administration should occur in an infusion
centre or hospital setting with availability of cardiac monitoring and resuscitation
capabilities. Oral arsenic makes delivery of therapy more feasible in countries,
and is of particular relevance in LMICs, where logistical and financial barriers

are numerous.
Diagnosis of acute promyelocytic leukaemia depends on clinical findings
(haemorrhage and coagulopathy), laboratory findings (leucocytosis, anaemia,
thrombocytopenia), morphology (presence of myeloid blasts containing Auer
rods), and documentation of the t(15;17) chromosome translocation in the
leukaemia blasts by cytogenetics, fluorescence in situ hybridization (FISH), or
polymerase chain reaction (PCR). Risk stratification of patients allows each to
receive the appropriate intensity of therapy to achieve cure, and includes a low-
risk group, defined as patients whose presenting white blood cell count is less
than 10 000 and a high-risk group (all other patients).
236
The Committee endorsed the recommendations of the Cancer Medicine
Working Group with regard to the proposed threshold of four to six months of
overall survival benefit as a guiding principle for prioritizing cancer medicines
for inclusion on the EML, and applied this principle to the consideration arsenic-
containing regimens for APML.
The Expert Committee recommended the addition of arsenic therapies
(intravenous arsenic trioxide and oral realgar-Indigo naturalis formulation)
to the complementary list of the EML and EMLc for use in combination with
ATRA for treatment of patients with APML, both newly diagnosed and relapsed.
In consideration of a separate application of cancer medicines for children,
the Committee also recommended the addition of ATRA to the EMLc, and
extending the listings on the EMLc of cytarabine, daunorubicin, mercaptopurine
and methotrexate to include APML.
The Committee noted that treatment with ATRA plus arsenic was
associated with high response rates and significant improvements in event-free
and overall survival compared to ATRA plus chemotherapy, and has a more
favourable toxicity profile.
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Medicines for cervical cancer – new indication – EML
Cisplatin ATC Code: L01XA01

Carboplatin ATC Code: L01XA02
Paclitaxel ATC Code: L01CD01
Fluorouracil ATC Code: L01BC02
Proposal
The application requested listing for cisplatin, carboplatin, paclitaxel and
fluorouracil for the additional indication of treatment of invasive cervical cancer.
Applicant
WHO Department for Management of Noncommunicable Diseases

Management of Noncommunicable Diseases, Disability, Violence and Injury
Prevention
EML/EMLc
EML
Section

As currently listed
Core/Complementary
Complementary

Core

As part of the comprehensive review of cancer medicines on the EML undertaken
in 2015, the Expert Committee recommended the addition of single-agent
cisplatin to the complementary list of the EML for the treatment of early-stage
cervical cancer for use concurrently with radiotherapy in women at high risk of
recurrence following surgery (1).
All of the medicines proposed in this application for cervical cancer
are included on the EML. However, carboplatin, paclitaxel and fluorouracil lack
241
a specific endorsement for the indication of cervical cancer, and the listing for
cisplatin is specific for use as a radiosensitizer.

Cervical cancer is the fourth most common cancer among women globally,
with an estimated 570 000 new cases and 311 000 deaths annually in 2018 (2).
The burden of cervical cancer is estimated to increase by almost 50%, reaching
460 000 related deaths by 2040, of which the large majority will occur in low- and
middle-income countries (LMICs). Currently, the majority of cases in LMICs are
diagnosed at late stage, as a result of delayed clinical presentation and untimely
referral of symptomatic patients to the appropriate pathway of care for diagnosis
and treatment (3).
In response to a rising public health problem, the United Nations Joint
Global Programme on Cervical Cancer Prevention and Control was established
in 2016, as an inter-Agency programme to engage partners and key stakeholders,
providing technical expertise to orient an evidence-based policy for cervical
cancer planning and provide pragmatic solutions (4).
The elimination of cervical cancer is a priority in the Sustainable
Development Goals (SDG) agenda, contributing to the reduction of premature
mortality due to noncommunicable diseases by one-third by 2030 and the
realization of universal health coverage, in terms of access to essential health
care interventions and financial risk protection (5, 6). The final aim is to reduce
drastically the incident cases of cervical cancer per year, through prevention
(human papilloma virus vaccination) and early detection (cervical cancer
early detection and screening, and treatment of pre-invasive cancer) along
with treatment of more advanced forms through diagnosis, cancer surgery and
radiotherapy, systemic therapy and palliative care services (7).

Cisplatin
Cisplatin is a critical cytotoxic agent for the treatment of cervical cancer for
radiotherapy is appropriate (8–12). It is also a key agent (alone or in combination
with other agents) for the management of advanced disease, that is not amenable
to locoregional control alone (i.e. surgery, radiotherapy, chemoradiotherapy
(13–15).
Clinical trials of cisplatin 50 mg/m2 every three weeks as monotherapy
for cervical cancer provided disappointing results for disease control (objective
response rate (ORR, 20%; progression-free survival (PFS), approximately three
months) and poor survival (overall survival (OS), approximately eight months)
(16, 17).
242
When combined with other cytotoxic agents, improved outcomes have

been reported. A Phase III clinical trial tested the combination of cisplatin and
paclitaxel against cisplatin monotherapy, for FIGO IV B (metastatic), recurrent
(after locoregional treatments) or persistent (not responding to locoregional
treatments) cervical cancer (n=280) (18). The addition of paclitaxel increased
the ORR (19% to 36%) and the median PFS (2.8 to 4.8 months), with no relevant
difference in overall survival. However, 92% of patients had prior exposure
to cisplatin, the majority pre-treated with a cisplatin-paclitaxel combination
regimen. Different cisplatin combinations have been compared with cisplatin
monotherapy in another trial enrolling patients with stage IV B recurrent or
persistent cervix uteri carcinoma (19). Patients in the experimental arm received
either cisplatin 50 mg/m2 plus topotecan (Cto) 0.75 mg/m2 every three weeks
or MVAC (cisplatin, vinblastine, doxorubicin and cisplatin); the standard arm
consisted of single-agent cisplatin 50 mg/m2 every three weeks (n=364). The
escalated polychemotherapy (Cto or MVAC) showed a longer PFS (median PFS
2.9 vs 4.6 months; RR 0.76, 95%CI 0.58 to 0.94) and OS (median OS 6.5 vs
9.4 months, RR 0.76, 95%CI 0.60 to 0.99) when compared to monotherapy. The
greatest effect size on survival was observed in cisplatin-naive patients, where
the gain of OS was 6.6 months vs 1.9 months in pre-exposed patients.
The open-label, randomized, Phase III JCOG0505 trial compared
cisplatin or carboplatin in combination with paclitaxel, in a non-inferiority (NI)
design, with a NI-margin of 1.29 for hazard ratio (HR) of OS. The schedules
used were: paclitaxel 135 mg/m2 plus cisplatin 50 mg/m2 every three weeks and
paclitaxel 135 mg/m2 plus carboplatin 5 mg/mL/min (area-under-the-curve)
each three weeks (n=253) (20). 98% of patients had a good performance
status (WHO-ECOG scale 0-1), 83% presenting with squamous histology, 79%
previously irradiated and 48% pre-exposed to cisplatin. The trial met the primary
endpoint and confirmed carboplatin-based to be non-inferior to cisplatin‑based
chemotherapy, reporting HR 0.99, (90%CI, 0.79 to 1.25), and median OS of
18.3 and 17.5 months, respectively. Median PFS was 6.9 and 6.2 months. An
exploratory sub-group analysis showed cisplatin to provide a greater effect size
in platinum-naive patients, with a median OS of 23 months and 13 months for
cisplatin and carboplatin, respectively. The sub-group analysis also favoured
carboplatin and paclitaxel over cisplatin combination for platinum-resistant
and platinum-intermediate sensitive disease (platinum-free interval inferior to
6 months or between 6–12 months), suggesting that carboplatin can still provide
a benefit after cisplatin failure and, otherwise, that cisplatin provides the greatest
effect in the naive and eligible patients (HR for platinum-resistant in cisplatin
pre-treated patients: 0.57; HR for platinum-intermediate: 0.71). However, all
platinum pre-treated patients were exposed to cisplatin and none to carboplatin,
suggesting that the re-challenge with the same platinum compound would be less
effective and an inter-class switch preferred, where possible.
243
The 2009 GOG-204 Phase III clinical trial compared four different
cisplatin-containing doublet combinations for stage IVB, recurrent or persistent
cervical carcinoma patients (21). Patients were enrolled to receive vinorelbine,
gemcitabine, topotecan or paclitaxel in combination as doublets with cisplatin
50 mg/m2 each three weeks (n=513). Patients presented predominantly with
squamous cell (80–88%) persistent (74–80%) cervical cancer, mostly pre-treated
with cisplatin and radiotherapy (70–81%). The trial was interrupted after
513 patients enrolled, as the futility analysis proved the different combinations
to be non-superior to cisplatin plus paclitaxel. ORR ranged between 22% and
29%; median PFS between 4–5.8 months and OS 10–12.9 months. Nevertheless,
paclitaxel–cisplatin showed the highest response rate (29%), median PFS (5.8
months) and median OS (12.8 months).
The use of cisplatin requires the fulfilment of specific criteria for treatment
initiation, particularly a conserved glomerular kidney function. Patients are
considered to be cisplatin- unfit if presenting one of more of the following
characteristics: Eastern Clinical Oncology Group (ECOG) performance status
(PS) of 2 or more; creatinine clearance of less than 60 mL/minute; treatment-
related hearing loss of Grade 2 or more according to the Common Terminology
Criteria for Adverse Events (CTCAE) system and treatment-related neuropathy
of Grade 2 or more (22).
Carboplatin
Guidelines include carboplatin in the treatment of advanced disease for cisplatin-
unfit patients, as a category 1 treatment (according to National Comprehensive
Cancer Network (NCCN) guidelines) (15). The role of carboplatin is highlighted
in the present submission as an alternative in cisplatin-unfit patients, both as
radiosensitizer and systemic agent for combination treatment in the locally
advanced, refractory, relapsed and metastatic settings. The acknowledgment of
carboplatin as an agent for cervical cancer is relevant for the specific anatomic
topography and local invasiveness of the disease. Different series have described
hydronephrosis in 20–35% of cervical cancer patients, with possible retrograde
kidney parenchyma impairment, due to the close anatomical proximity of the
ureter with genitourinary organs. A Nigerian analysis of the renal status of
patients with cervical cancer prior to commencement of treatment, reported
one-third of patients having a clinically significant urethral involvement or
obstruction and nearly 10% having a kidney dysfunction for related parenchyma
disease (23).
Carboplatin has been shown in a sub-group analysis of the JCOG0505
trial to provide a greater benefit in cisplatin pre-treated patients compared to
cisplatin (20). These findings were confirmed in a retrospective analysis of a
cohort of Asian patients treated with paclitaxel combined either with cisplatin
or carboplatin (n=116) (24). In the curative setting, the role of carboplatin
244
must be restricted to the patients unfit for cisplatin but still eligible to receive
a curative treatment, in the context of a concomitant chemoradiotherapy, as a
radiosensitizer.
Data on the efficacy of concurrent weekly carboplatin with radiotherapy
in the treatment of cervical cancer have been evaluated in a recent meta-analysis,
exploring whether differences between cisplatin and carboplatin exist when
used as radiosensitizers (25). Twelve studies (1698 patients) were eligible for
meta-analysis. Complete response (CR), PFS and OS were assessed. The use of
carboplatin provided a lower rate of CR (OR 0.53, 95%CI 0.34 to 0.82); lower
PFS and OS were assessed at 3 years, with HR of 0.71 and 0.70, indicative of
a potential difference. However, the authors concluded that carboplatin should
still be a priority for cisplatin-ineligible patients, as it is the preferable alternative
choice of treatment.
Paclitaxel
As previously described, paclitaxel represents the optimal partner of chemotherapy
platinum- based doublets for the treatment of advanced disease. The doublet
cisplatin plus paclitaxel (or carboplatin plus paclitaxel, in cisplatin-ineligible
patients) is the recommended regimen for advanced cervical cancer, as reported
by the principal guidelines (13–15). In a large randomized Phase III clinical
trial (GOG-204), paclitaxel showed a greater effect size and a manageable safety
profile, when compared with the combinations with topotecan, gemcitabine
and vinorelbine (21).
Fluorouracil
Fluorouracil (5-FU) has a role as a radiosensitizer and is extensively used across
different cancer indications. For cervical cancer, women with high-risk disease
are eligible to receive concomitant adjuvant chemoradiotherapy. The features of
high risk are defined as: positive pelvic lymph nodes, positive surgical margins,
and positive parametrium. The use of adjuvant chemotherapy in combination
with radiotherapy has been tested in a clinical trial, enrolling 268 patients with
clinical stage FIGO IA2 and IIA carcinoma of the cervix, treated with radical
hysterectomy and pelvic lymph node dissection, and found to have lymph node
involvement, invaded parametrium and positive margins (11). Patients received
cisplatin as a bolus of 70 mg/m2 followed by 5-FU as continuous IV infusion over
96 hours at 1000 mg/m2 every three weeks, for four cycles concomitantly with
radiotherapy for the first and second cycle. The pelvic radiotherapy consisted of
1.7 Gy per day on days 1 to 5 of each week, for a total of 29 fractions (49.3 Gy).
Around one-third of patients presented with involvement of parametria, and
85% presented with metastatic pelvic lymph nodes after surgery. The addition
of chemotherapy to radiotherapy showed a gain in overall survival, with 10%
245
more patients alive at four years (OS 81% vs 71% at four years; HR 1.96, CI not
reported, p=0.007). The projected progression-free survival at four years was 80%
vs 63% (HR 2.01, p=0.003), favouring the chemotherapy + radiotherapy arm.
The role of 5-FU as a radiosensitizer agent has been investigated in three
clinical trials for stage IB2 to IVA cervical cancer patients (8, 26, 27). The three
trials reported similar results, supporting the use of cisplatin-based chemotherapy,
including the combination of cisplatin and 5-FU, as radiosensitizer in as an
adjunct to radiotherapy for locally advanced cervical cancer: HRs for OS ranged
between 0.52 (stage IB2- IVA) and 0.72 (stage IIB-IVA).

Cisplatin and carboplatin
In the JCOG0505 trial, cisplatin or carboplatin in combination with paclitaxel
were associated with similar proportions of patients who terminated treatment
because of intolerable adverse events, 9.5% in the carboplatin group and 11.8%
in the cisplatin group (20). Most patients experience haematological toxicity
from the medication combination including neutropenia, thrombocytopenia
and anaemia, all of which are typically rapidly reversible upon discontinuation
of agents (28, 29).
Cisplatin is highly emetogenic, prophylactic antiemetics are necessary
to reduce nausea and vomiting in all patients (30). Mild peripheral neuropathy
is common. Patients should be followed carefully, and dose reduction or
discontinuation may be required for moderate or severe symptoms. Ototoxicity is
observed with cisplatin and is more common with increasing dose and number
of cycles. Audiometry should be considered to monitor patients with toxicity;
vestibular defects are less common. Serious renal toxicity caused by cisplatin can
be significant and may result in electrolyte abnormalities. Hypomagnesaemia,
hypocalcaemia and hypokalaemia should be followed and deficits addressed.
Intravenous hydration both before and after administering cisplatin is necessary

to reduce the incidence of renal toxicity (31).
Paclitaxel
Paclitaxel is associated with infusion reactions in about 30% of patients; most
reactions are mild and easily managed (32, 33). Paclitaxel frequently causes
alopecia and peripheral neuropathy, which is often mild and reversible (32, 34).
Fluorouracil
The use of adjuvant chemotherapy (cisplatin followed by 5-FU), in combination
with radiotherapy, is associated with an increase in Grade 4 adverse events,
mostly haematological toxicity (Grade 4 adverse events: 17% vs 4%; Grade 3 and
4 granulocytopenia: 29% vs 2%) compared to radiotherapy alone (11).
246

N/A
WHO Guidelines
None available
An economic analysis of cisplatin alone versus cisplatin doublets in women with
advanced or recurrent cervical cancer evaluated the impact of: (i) extending the
use of cytotoxic agents to the advanced disease, with a highlight on systemic
therapy; and (ii) the use of 5-FU and carboplatin as alternative radiosensitizers
(35). The cost analysis showed that chemotherapy medicine costs for six cycles
of cisplatin was US$ 89 while for cisplatin plus paclitaxel it was US$ 489. The
highest chemotherapy cost was for gemcitabine plus cisplatin at US$ 18 306.
According to the major effect size and manageable safety profile, the combination
of cisplatin and paclitaxel was the most cost-effective option for the treatment of
advanced cervical cancer, and, to a large extent, more cost-effective than cisplatin
monotherapy. Sensitivity analyses confirmed that cisplatin plus paclitaxel would
be the regimen of choice. For the same setting, another model showed that the
incremental cost-effectiveness ratio for combination cisplatin plus paclitaxel
compared to cisplatin alone was US $13 654 per quality-adjusted life-year (QALY)
gained (36).
Availability
Originator and generic brands of the proposed medicines are available.
N/A
The Expert Committee recommended extending the indications for cisplatin,
carboplatin and paclitaxel on the complementary list of the EML to include
treatment of invasive cervical cancer. The Committee considered that the
evidence presented demonstrated these medicines to be associated with relevant
survival benefits for patients. The Committee noted that regimens including
these medicines are considered standard care in the curative and non-curative
settings for cervical cancer.
Cisplatin is currently listed for use in the curative setting as a
radiosensitizer and its listing is recommended to be extended to include the non-
curative setting. Carboplatin is recommended for listing both in the curative
247
and non-curative settings, and paclitaxel is recommended for listing in the non-
curative setting.
The Expert Committee did not recommend extending the indications
for fluorouracil to include treatment of cervical cancer in the curative setting.
The Committee noted that when combined with radiotherapy, fluorouracil alone
or in combination with cisplatin, was not associated with additional benefit
compared to radiotherapy alone or cisplatin plus radiotherapy.
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18. Moore DH, Blessing JA, McQuellon RP, Thaler HT, Cella D, Benda J et al. Phase III study of cisplatin
with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the
cervix: a gynecologic oncology group study. J Clin Oncol. 2004;22(15):3113–9.
19. Long HJ, 3rd, Bundy BN, Grendys EC, Jr., Benda JA, McMeekin DS, Sorosky J et al. Randomized phase
III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic
Oncology Group Study. J Clin Oncol. 2005;23(21):4626–33.
20. Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T et al. Paclitaxel Plus
Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-
Label Randomized Phase III Trial JCOG0505. J Clin Oncol. 2015;33(19):2129–35.
21. Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH et al. Phase III trial
of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical
carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27(28):4649–55.
22. Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK et al. Treatment of patients
with metastatic urothelial cancer “unfit” for Cisplatin-based chemotherapy. J Clin Oncol.
2011;29(17):2432–8.
23. Abdus-salam AA ADB, Abdus-salam RA,. Renal Status of Patients with Cervical Cancer Prior to
Treatment Commencement. Tropical Journal of Nephrology. 2009;4(1):17–20.
24. Friedlander M, Grogan M, Force USPST. Guidelines for the treatment of recurrent and metastatic
cervical cancer. Oncologist. 2002;7(4):342–7.
25. Xue R, Cai X, Xu H, Wu S, Huang H. The efficacy of concurrent weekly carboplatin with radiotherapy
in the treatment of cervical cancer: A meta-analysis. Gynecol Oncol. 2018;150(3):412–9.
26. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE et al. Pelvic radiation with concurrent
chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl
J Med. 1999;340(15):1137–43.
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27. Rose PG, Ali S, Watkins E, Thigpen JT, Deppe G, Clarke-Pearson DL et al. Long-term follow-up of
a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination
chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a
Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(19):2804–10.
28. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB et al. Paclitaxel plus
platinum-based chemotherapy versus conventional platinum-based chemotherapy in women
with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361(9375):2099–106.
29. Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M et al. Evaluation of
new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the
Gynecologic Cancer Intergroup. J Clin Oncol. 2009;27(9):1419–25.
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cancer with Cisplatin or Cisplatin containing regimens: a cost effective analysis. J Cancer.
2012;3:454–8.
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Pegaspargase – addition – EML and EMLc
Pegaspargase ATC Code: L01XX24
Proposal
The application requested the addition of pegaspargase (PEGylated Escherichia
coli asparaginase) to the EML and EMLc for use in the treatment of acute
lymphoblastic leukaemia (ALL).
Applicant
Scott C. Howard
Professor, University of Tennessee Health Science Center
Secretary General, International Paediatric Oncology Society (SIOP)

unit advised that it supported the inclusion of pegaspargase and related approved
biotherapeutics to the EML and EMLc, considering that the application requested
inclusion of a related formation to an existing listed medicine within the same
class (asparaginase).
EML/EMLc
EML and EMLc
Section

Solution for injection 3,750 units/5 mL in vial
Core/Complementary
Complementary

Individual listing, including approved, quality-assured biosimilars.

Pegaspargase had not previously been considered by the Expert Committee for
addition to the EML. Native E. coli asparaginase is currently included on the EML
and EMLc for treatment of ALL.
251
Asparaginases represent a therapeutic group including native E. coli

asparaginase, PEGylated E. coli asparaginase, Erwinia asparaginase, and
biosimilars. When asparaginases are used at the recommended dose and schedule,
and when use is not limited by hypersensitivity or neutralizing antibodies, any
of these three asparaginases effectively treat ALL.

Acute lymphoblastic leukaemia (ALL) is a rare haematological malignancy.
Globally, from 2003 to 2007, the age-standardized incidence rate of ALL ranged
from 1.08 to 2.12 per 100 000 person-years. ALL accounts for approximately 25%
of all cancers (80% of leukaemias) in children. The disease is far less common in
adults (<1% of all cancers) where is associated with much lower cure rate that
that achievable for children (1).
Allergic reactions to native E. coli asparaginase occur in 20% to 42% of
patients with ALL, and silent (asymptomatic) neutralizing antibody formation
in another 30 to 40%, such that around two thirds of patients do not complete
all their required asparaginase unless they have access to a second asparaginase
product, usually Erwinia asparaginase (2–10).
Hypersensitivity or silent antibody formation necessitate a change to
another form of asparaginase. The supply of Erwinia asparaginase has been
limited to high-income countries, and supply is often insufficient to meet the
needs of patients who react to first-line native E. coli asparaginase.
When no second product is available (or an allergy occurs to the alternate
asparaginase), the inability to complete asparaginase treatment increases the
risk of relapse, which is associated with poor prognosis, with survival after
relapse ranging from 20% to 50% (11). Furthermore, relapse therapy entails
intense salvage chemotherapy followed by allogeneic stem cell transplantation,
which greatly increases treatment costs (9). Minimization of allergic reactions to
the initial form of asparaginase improves outcomes and reduces costs.

PEGylation of E. coli asparaginase to create pegaspargase increases the half-life
of asparaginase and decreases immunogenicity and allergic reactions/antibody
formation from 20–42% to 2–11% (12).
The UKALL 2003 trial used pegaspargase in a schedule that included
several days of glucocorticoids prior to each dose of pegaspargase in low- and
intermediate-risk patients. Glucocorticoid pre-treated patients had a 1% rate of
allergic reaction and five-year event-free survival of around 95% (13).
Patients in the high-risk arm received several doses of pegaspargase
without preceding glucocorticoids and had a reaction rate of 6%, such that in the
whole study the reaction rate was 2% (13, 14). These findings led to a change in
clinical practice, and modification of existing ALL treatment protocols to include
252
glucocorticoid pre-treatment before each pegaspargase dose, to reduce the

incidence of allergic reactions, thus allowing patients to complete asparaginase
therapy and reducing the need for a second-line asparaginase (e.g. Erwinia).
Asparaginase products have different molecular structures, different
half-lives, and different clinical activities per unit. Pegaspargase is six to nine
times more potent than native E. coli asparaginase and each dose lasts 2–3 weeks
instead of 2–3 days. Modern ALL protocols require lower doses and fewer doses
of pegaspargase to provide the asparaginase needed for patients.
Treatment strategies using pegaspargase as initial therapy are more
effective because they reduce the rates of hypersensitivity and neutralizing
antibodies from a total of 50–65% (including both) to 10–15% (including both)
and thus allow more patients to continue first-line asparaginase and complete all
doses of the treatment protocol. Completion of all doses of first-line asparaginase
reduces the risk of relapse and thus reduces costs associated with salvage therapy
(15). It also reduces the need for second-line Erwinia asparaginase, which is not
available in many countries (especially LMICs) and which has suffered from
recurrent shortages and stock-outs even in high-income countries (HICs).

No data were presented in the application in relation to the comparative safety
of pegaspargase.

A randomized, open-label Phase III trial compared the relative toxicity and
efficacy of intravenous (IV) pegaspargase and intramuscular (IM) native E coli
asparaginase in 463 children with newly diagnosed ALL who had achieved
complete remission following induction therapy (16). Five-year disease-free
survival was similar between treatment groups: 90% vs 89% for IV pegaspargase
and IM native E coli asparaginase treated patients, respectively (p=0.58). There
was no significant difference in the frequency of asparaginase-related toxicities
(allergy, pancreatitis or thrombotic or bleeding adverse events) between the
treatment groups: 28% vs 26% in the pegaspargase and native E. coli asparaginase
groups, respectively (p=0.60). Pegaspargase was associated with less anxiety
than native E. coli asparaginase. The most common adverse events of Grade 3 or
higher were infections (bacterial or fungal) and occurred at a similar rate in both
treatment groups.
A retrospective study compared the efficacy and safety of pegaspargase
and native E. coli asparaginase in 122 adolescents and adults with newly diagnosed
ALL (17). Both treatments demonstrated comparable complete remission rates
(95.65 vs 90.79%), median overall survival (14.07 vs 16.29 months) and median
relapse-free survival (10.00 vs 8.57 months). Pegaspargase-treated patients aged
253
less than 35 years had a higher median relapse-free survival time compared
with E. coli asparaginase-treated patients (10.93 vs 8.97 months; p=0.037). Both
treatments were found to be acceptably tolerable and demonstrated similar
incidences of allergy, hepatic toxicity, pancreatic lesions, and bleeding and
coagulation effects.
In patients with relapsed ALL, and with hypersensitivity to native E. coli
asparaginase, pegaspargase treatment was associated with similar tolerability as
in newly diagnosed patients (18).
WHO Guidelines
None available.
The application estimated that, on average, the ratio of the number of vials of
E. coli asparaginase needed versus vials of pegaspargase was 10.3 (assuming
no obesity and no vial sharing between patients) meaning that a per-vial price
of pegaspargase that is 10.3 times greater than that of a vial of native E. coli
asparaginase would be cost-neutral, without considering differences in efficacy.
Costs for native E. coli asparaginase were reported as between US$ 150–
177 per vial, compared to US$ 1300–1400 per vial for pegaspargase in Europe
and Latin America.
Availability
Pegaspargase is marketed by Servier Pharmaceuticals. Biosimilars of pegaspargase
are in development in some jurisdictions.
The risk of allergic hypersensitivity reactions to asparaginase therapy increases
with the number of doses and up to one third of patients experience a reaction by
the fourth dose. This is one of the highest reported sensitivity reactions reported
from chemotherapy drugs. Approximately 10% of reactions are life-threatening.
Reactions involving the formation of silent neutralizing antibodies
result in inactivation of asparaginase and reduced serum asparaginase activity
levels. This results in a low therapeutic threshold of the drug. For these patients,
therapeutic drug monitoring is essential, but not generally available in LMICs.
The Expert Committee recommended the addition of pegaspargase to the
complementary list of the EML and EMLc for use in the treatment of acute
lymphoblastic leukaemia. The listing should indicate that quality-assured
biosimilars of pegaspargase should also be considered as essential.
254
The Committee noted pegaspargase was associated with less

immunogenicity and development of neutralizing antibodies than native
asparaginase, which may offer advantages in terms of improved patient adherence
enabling completion of treatment, thereby reducing the risk of relapse.
References
1. Katz AJ, Chia VM, Schoonen WM, Kelsh MA. Acute lymphoblastic leukemia: an assessment of
international incidence, survival, and disease burden. Cancer Causes Control. 2015;26(11):1627–
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2. Schore RJ, Devidas M, Bleyer A, Reaman GH, Winick N, Loh ML et al. Plasma asparaginase activity
and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase
on Children’s Oncology Group AALL07P4(). Leuk Lymphoma. 2019:1–9.
3. Russell HV. Asparaginase products in upfront acute lymphoblastic leukemia therapy: Value,
location, and style. Pediatr Blood Cancer. 2019;66(1):e27497.
4. Salzer W, Bostrom B, Messinger Y, Perissinotti AJ, Marini B. Asparaginase activity levels and
monitoring in patients with acute lymphoblastic leukemia. Leuk Lymphoma. 2018;59(8):1797–
806.
5. Fernandez CA, Smith C, Yang W, Mullighan CG, Qu C, Larsen E et al. Genome-wide analysis links
NFATC2 with asparaginase hypersensitivity. Blood. 2015;126(1):69–75.
6. Fernandez CA, Smith C, Yang W, Date M, Bashford D, Larsen E et al. HLA-DRB1*07:01 is associated
with a higher risk of asparaginase allergies. Blood. 2014;124(8):1266–76.
7. Vrooman LM, Stevenson KE, Supko JG, O’Brien J, Dahlberg SE, Asselin BL et al. Postinduction
dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve
outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia:
results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01.
J Clin Oncol. 2013;31(9):1202–10.
8. Liu C, Kawedia JD, Cheng C, Pei D, Fernandez CA, Cai X et al. Clinical utility and implications of
asparaginase antibodies in acute lymphoblastic leukemia. Leukemia. 2012;26(11):2303–9.
9. Kawedia JD, Liu C, Pei D, Cheng C, Fernandez CA, Howard SC et al. Dexamethasone exposure
and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia. Blood.
2012;119(7):1658–64.
10. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC et al. Treating childhood acute
lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360(26):2730–41.
11. Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL et al. Factors influencing survival
after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group study. Leukemia.
2008;22(12):2142–50.
12. Pieters R, Hunger SP, Boos J, Rizzari C, Silverman L, Baruchel A et al. L-asparaginase treatment in
acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer. 2011;117(2):238–49.
13. Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R et al. Treatment reduction for children
and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual
disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14(3):199–209.
14. Pui CH. Reducing delayed intensification therapy in childhood ALL. Lancet Oncol. 2013;14(3):
178–9.
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15. Kloos RQH, van Litsenburg RRL, Wolf S, Wismans L, Kaspers GJL, Uyl-de Groot CA et al. A cost-
effectiveness analysis of Erwinia asparaginase therapy in children with acute lymphoblastic
leukemia. Pediatr Blood Cancer. 2019;66(1):e27458.
16. Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O’Brien JE et al. Intravenous pegylated
asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed
childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial.
Lancet Oncol. 2015;16(16):1677–90.
17. Liang J, Shi P, Guo X, Li J, He L, Wang Y et al. A retrospective comparison of Escherichia coli and
polyethylene glycol-conjugated asparaginase for the treatment of adolescents and adults with
newly diagnosed acute lymphoblastic leukemia. Oncol Lett. 2018;15(1):75–82.
18. Heo YA, Syed YY, Keam SJ. Pegaspargase: A Review in Acute Lymphoblastic Leukaemia. Drugs.
2019;79(7):767–77.
256
Pertuzumab – addition – EML
Pertuzumab ATC Code: L01XC13
Proposal
The application requested the addition of pertuzumab to the complementary
list of the EML for the treatment of early stage and metastatic human epidermal
growth factor receptor 2 (HER2) positive breast cancer.
Applicant
F. Hoffmann-La Roche Ltd.

unit advised that it did not support inclusion of pertuzumab on the EML at
this time, though noting with interest ongoing studies of pertuzumab in the
neoadjuvant and metastatic settings.
EML/EMLc
EML
Section

Concentrated solution for IV infusion 420 mg/14 mL in 14 mL vial
Core/Complementary
Complementary

Individual

Pertuzumab, in combination with trastuzumab and docetaxel, is indicated
for treatment of patients with HER2-positive metastatic or locally recurrent,
unresectable breast cancer who have not received prior anti-HER2 therapy or
chemotherapy for metastatic disease.
Pertuzumab, in combination with trastuzumab and chemotherapy, is
indicated for:
257
■■ neoadjuvant treatment of patients with HER2-positive, locally

advanced, inflammatory, or early stage breast cancer;
■■ adjuvant treatment of patients with HER2-positive early breast
cancer at high risk of recurrence.
Pertuzumab has not previously been considered for EML inclusion.
Trastuzumab, another anti-HER2 treatment, is currently included on the EML
for treatment of early stage and metastatic HER2 positive breast cancer. Multiple
cytotoxic medicines, including docetaxel, are included on the EML for early stage
and metastatic breast cancer.

Breast cancer is the leading cause of cancer death among women globally,
responsible for 15% of all cancer deaths. In 2018, the global cancer burden
increased to 18.1 million cases, causing 9.6 million deaths (1). Changes in
lifestyle, life expectancy and reproductive factors are responsible in many low-
and middle-income countries (LMICs) for a sharp increase in the incidence
of breast cancer, and the number of deaths as a percentage of incident cases is
greater than that seen in high-income countries (HICs). For example, in 2008,
this figure was 24% in HICs, 38% in high-middle-income countries, 40% in low-
middle-income and 48% in low-income (2).
The HER2 receptor has emerged as one of the most important
targets for the treatment of breast cancer. HER2 is involved in regulating cell
growth, survival, and differentiation (3). Amplification and/or overexpression
of HER2 occurs in approximately 18%–22% of breast cancers (4, 5). HER2
amplification/overexpression (HER2-positivity) is associated with increased
tumour aggressiveness, higher rates of recurrence, and increased mortality
(5–10). The median age of patients presenting with HER2-positive breast cancer
is in the mid-50s, approximately five years younger than the general breast
cancer population (11).

In the early breast cancer setting, surgery is the main modality of local
treatment. Surgery and/or radiotherapy can control loco-regional disease in
the majority of patients. Neoadjuvant therapy is given prior to surgery and
has become commonly used in patients with newly diagnosed breast cancer.
Neoadjuvant therapy is the primary modality of therapy for patients with
inflammatory breast cancer, regardless of tumour size (12). If standard
neoadjuvant chemotherapy has been completed, usually there is no need for
additional postoperative chemotherapy.
Data from four Phase III trials has shown that the use of trastuzumab,
for the adjuvant treatment of HER2-positive breast cancer reduces the relative
risk of relapse by about 50% and the risk of death by about 30% (13–15). In these
studies, trastuzumab was administered either sequentially or concurrently with
258
standard chemotherapy regimens consisting of anthracyclines and/or taxanes.

However, despite the marked improvements conferred by adjuvant trastuzumab
in these studies, a significant percentage of HER2-positive breast cancer patients
still relapsed and ultimately died from metastatic disease (16).

Metastatic or locally recurrent, unresectable breast cancer
The Phase III CLEOPATRA study was a randomized, multicentre, double-blind,
placebo-controlled clinical trial that evaluated the efficacy of pertuzumab in
808 patients with HER2-positive, metastatic or locally recurrent, unresectable
breast cancer who had not received previous anti-HER2 therapy or chemotherapy
for metastatic disease (17–19). The primary efficacy endpoint was progression-
free survival (PFS) assessed by an independent review facility (IRF). Key
secondary efficacy endpoints included overall survival (OS) and quality of life
(QoL) assessed through the Functional Assessment of Cancer Therapy–Breast
(FCT–B) quality-of-life questionnaire. Patients were randomized to receive
pertuzumab plus trastuzumab plus docetaxel (Ptz + T + D) or placebo plus
trastuzumab plus docetaxel (Pla + T + D).
The CLEOPATRA study found a statistically significant and clinically
relevant improvement in IRF-assessed PFS in the pertuzumab arm compared
with the placebo arm (HR 0.62, 95%CI 0.51 to 0.75; p<0.001), with an increase
of 6.1 months in median PFS (12.4 months in the placebo arm vs 18.5 months in
the pertuzumab arm). The advantage in PFS appeared soon after the treatment
is started (9 weeks), and was maintained from this point onwards. Benefit was
observed in all pre-specified sub-groups tested.
At the data cut-off date for final OS analysis (February 2014) the results
demonstrated a statistically significant improvement in survival with Ptz + T +
D compared with Pla + T + D. Median OS was prolonged in the Ptz + T + D
arm compared with the Pla + T + D arm (56.5 months vs 40.8 months; HR 0.68,
95%CI 0.56 to 0.84, p<0.001) (19). Sensitivity analyses defined to explore the
impact of crossover on the OS result confirmed the robustness of the results in
the intention-to-treat (ITT) population. Sub-group analyses of final OS were
consistent with the analysis in the whole ITT population and confirmed results
from previous analyses.
At the time of data cut-off, according to the investigator-assessed ITT-
analysis of PFS, events had occurred in 78.8% of patients in the Pla + T + D arm
and 70.6% of patients in the Ptz + T + D arm (19). The treatment benefit of
Ptz + T + D compared with Pla + T + D was maintained in the updated analysis
of investigator-assessed PFS (HR 0.68, 95%CI 0.58 to 0.80). The median PFS
durations of 12.4 months in the placebo arm and 18.7 months in the pertuzumab
arm were consistent with results from the previous analyses. Exploratory sub-
259
group analyses of investigator-assessed PFS indicated a treatment benefit with

Ptz + T + D over Pla + T + D in all sub-groups analysed, and were consistent with
the result in the whole ITT population, and with results from previous analyses.
In patients treated with pertuzumab–trastuzumab-based combinations,
239 of 402 (59.5%) patients in the pertuzumab arm and 229 of 404 (56.7%)
patients in the placebo arm experienced a decrease from baseline of ≥5 points in
a subset of the FACT-B questionnaire. Kaplan–Meier analysis showed a similar
time decline of health-related QoL (HRQoL) between the two treatment arms
(HR 0.97; 95%CI 0.81 to 1.16), showing that the combination of pertuzumab
and trastuzumab with docetaxel had no major adverse impact on HRQoL (20).
Neoadjuvant treatment of locally advanced, inflammatory, or early stage breast cancer
The Phase II NeoSphere study was a multicentre, randomized, open-label study
that evaluated the efficacy of pertuzumab as neoadjuvant treatment in 417
patients with HER2-positive locally advanced, inflammatory, or early stage breast
cancer (21, 22). Patients were randomized to receive trastuzumab plus docetaxel
(T + D), pertuzumab plus trastuzumab plus docetaxel (Ptz + T + D), pertuzumab
plus trastuzumab (Ptz + T), or pertuzumab plus docetaxel (Ptz + D).
The primary efficacy endpoint was rate of breast pathologic complete
response (bpCR), defined as the proportion of patients with an absence of
invasive neoplastic cells in the breast following primary systemic therapy (in
situ disease might remain; nodal status not considered), also known as ypT0/is.
Secondary efficacy endpoints included clinical PFS.
Efficacy results for the primary endpoint (9 March 2012 clinical cut-off
date) showed a statistically significant and clinically meaningful improvement
in bpCR rate in patients receiving Ptz + T + D compared with patients receiving
T + D as neoadjuvant therapy (45.8% vs 29.0%). A consistent pattern of results
was observed regardless of pathological complete response (pCR) definition,
with a higher pCR (ypT0/is N0) rate also reported in patients receiving Ptz + T
+ D compared with T + D (39.3% vs 21.5%). bpCR rates were lower in the sub-
group of patients with hormone receptor-positive disease (ranging from 5.9%
to 26.0% among the four arms) than in the sub-group with hormone receptor-
negative disease (ranging from 27.3% to 63.2%), but the difference in pCR still
favoured Ptz + T + D compared with T + D (21).
Point estimates of PFS (defined as the time from the date of randomization
to the first documentation of progressive disease or death) and DFS from the
five-year analysis were consistent with the benefit shown from the addition
of pertuzumab to trastuzumab plus docetaxel in the primary analysis of pCR
(regardless of the definition of pCR used) but confidence intervals were wide and
included the null value. Hazard ratios for PFS and DFS were 0.69 (95%CI 0.34 to
1.40) and 0.60 (95%CI 0.28 to 1.27), respectively, indicating a lower risk of PFS
and DFS events in the Ptz + T + D arm compared with the T + D arm (22).
260
The efficacy of pertuzumab as neoadjuvant treatment was also assessed

in the TRYPHAENA study, a multicentre, randomized, open-label Phase II study
conducted in 225 patients with HER2-positive locally advanced, inflammatory,
or early stage breast cancer (23, 24).
The primary endpoint was cardiac safety during the neoadjuvant
treatment period. The key efficacy endpoint was pCR rate (ypT0/is). Additional
efficacy endpoints included DFS, PFS and OS. Patients were randomized to
receive one of three neoadjuvant regimens:
■■ Three cycles of pertuzumab plus trastuzumab plus 5-fluorouracil,
epirubicin and cyclophosphamide (FEC) followed by three cycles of
pertuzumab plus trastuzumab plus docetaxel (Ptz + T + FEC/Ptz +
T + D).
■■ Three cycles of FEC followed by three cycles of pertuzumab plus
trastuzumab plus docetaxel (FEC/Ptz + T + D).
■■ Six cycles of carboplatin plus pertuzumab plus trastuzumab plus
docetaxel (C + Ptz + T + D). Randomization was stratified by breast
cancer type (operable, locally advanced, or inflammatory) and
hormone receptor status.
High pCR rates were observed in all three treatment arms. A consistent
pattern of results was observed regardless of pCR definition. pCR rates were
lower in the sub-group of patients with hormone receptor-positive disease
(ranging from 46.2% to 50.0% in the three arms) than in patients with hormone
receptor-negative disease (ranging from 65.0% to 83.8%).
Long-term analyses of DFS and OS were conducted when median
follow up exceeded 60 months in all trial arms. DFS at 3 years was 87% (95%CI
79 to 95) in patients treated with Ptz + T + FEC/Ptz + T + D, 88% (95%CI 80
to 96) in patients treated with FEC/Ptz + T + D, and 90% (95%CI 82 to 97) in
patients treated with C + Ptz + T + D (3-year DFS was 89% (95%CI 81 to 96)
in the first group, 89% (95%CI 81 to 96) in the second group and 87% (95%CI
80 to 95) in the third group). Three-year OS followed a similar pattern: 94%
(95%CI 89 to100) in the first group, 94% (95%CI 89 to 100) in the second group
and 93% (95%CI 87 to 99) in the third group.
Adjuvant Treatment of early breast cancer with a high risk of recurrence
The Phase III APHINITY study was a randomized multicentre, double-blind,
placebo-controlled trial that evaluated the safety and efficacy of pertuzumab plus
trastuzumab plus chemotherapy compared with placebo plus trastuzumab plus
chemotherapy in 4805 patients with operable, HER2-positive primary breast
cancer (25).
The primary efficacy endpoint was invasive disease-free survival
(IDFS), defined as time from randomization to ipsilateral invasive breast cancer
261
recurrence, contralateral invasive breast cancer, distant recurrence, or death due

to any cause. Other efficacy endpoints were DFS and OS.
At the clinical cut-off date, IDFS events had occurred in 171 patients
(7.1%) in the pertuzumab-containing arm compared with 210 patients (8.7%)
in the comparator arm. Treatment with pertuzumab-containing therapy resulted
in a borderline significant improvement in IDFS, corresponding to a 19%
relative reduction in the risk of relapse or death (HR 0.81, 95%CI 0.66 to 1.00).
Estimates of IDFS event-free rates were 94.1% vs 93.2% at three years and 92.3%
vs 90.6% at four years in the pertuzumab and comparator arms, respectively. The
addition of pertuzumab to trastuzumab and chemotherapy reduced the rate of
distant recurrences as first site of recurrence (4.7% vs 5.8%) and at any time in
the study 5.0% vs 6.0%).
Interim OS results numerically favoured patients in the pertuzumab
arm, but with only 26% of the events required for the final planned OS analysis,
the data were immature at the primary data cut-off. There was no significant
treatment effect with regard to mortality between treatment arms at this first
interim overall survival analysis (HR 0.89, 95%CI 0.66 to 1.21).
Sub-group analysis across multiple, pre-specified, clinically relevant
sub-groups showed that the IDFS improvements were seen for patients in the
pertuzumab arm in the sub-group with node-positive disease. Improved IDFS
was observed irrespective of the hormone receptor status, but the benefit of
adding pertuzumab to trastuzumab and chemotherapy was more marked in
patients with hormone receptor-negative disease (HR 0.76, 95%CI 0.56 to 1.04)
than for patients with hormone receptor-positive disease (HR 0.86, 95%CI
0.66 to 1.13), indicating a 24% and 14% reduction in the risk of recurrence or
death, respectively.

Overall, data indicate that pertuzumab is well tolerated as monotherapy and
that it can be given in combination with trastuzumab and a range of other

therapeutic agents with manageable additional toxicity. No unexpected toxicities
were encountered other than those that are known for agents that target the
HER family of receptors. Serious or severe infusion-related symptoms have
been rarely observed in patients receiving pertuzumab. A low level of cardiac
toxicities, predominantly asymptomatic declines in left ventricular ejection
fraction (LVEF), has been reported. In the pivotal Phase III CLEOPATRA trial,
the rates of symptomatic and asymptomatic left ventricular systolic dysfunction
were not higher in patients receiving Ptz + T + D than in those receiving
Pla + T + D (17). However, patients who have received prior anthracyclines or
radiotherapy to the chest area may be at higher risk of decreased LVEF.
There is a limited amount of data from the use of pertuzumab in pregnant
women. Studies in animals have shown reproductive toxicity and pertuzumab is
262
not recommended during pregnancy and in women of childbearing potential not

using contraception (26).
Metastatic breast cancer
In the Phase III CLEOPATRA trial in patients with HER2-positive metastatic
breast cancer (N = 808), the safety profile of Ptz + T + D at the time of the latest
clinical cut-off (11 February 2014) was generally similar to that of Pla + T + D
(17, 19). The most common adverse event (AE) in both arms combined was
alopecia (an AE associated with docetaxel), followed by diarrhoea, neutropenia,
nausea, fatigue and rash. The safety profile of pertuzumab plus trastuzumab and
docetaxel in patients who crossed over (after initially being treated with placebo
plus trastuzumab and docetaxel) was consistent with the safety profile observed
in patients treated with pertuzumab plus trastuzumab and docetaxel from the
beginning of the study. The majority of AEs following crossover from placebo to
pertuzumab were Grade 1–2.
The ongoing Phase II PERTAIN study investigated the efficacy and
safety of first-line trastuzumab plus an aromatase inhibitor (AI), with or without
pertuzumab in patients with HER2 positive and hormone receptor positive
metastatic or locally advanced breast cancer (27). All-grade AEs occurred
in 96.1% of patients taking pertuzumab + trastuzumab + AI and in 98.4% of
patients taking trastuzumab + AI. The incidence of Grade ≥3 AEs was higher
in the pertuzumab treatment arm (50.4% vs 38.7%). The most common Grade
≥3 events reported (occurring in ≥5% of patients in either treatment arm) were
hypertension, diarrhoea and neutropenia.
The Phase III PHEREXA study assessed the efficacy and safety of
trastuzumab plus capecitabine, with or without pertuzumab in patients with HER2
positive metastatic breast cancer with disease progression despite trastuzumab-
based therapy and prior taxane (28). The safety profile of the pertuzumab-
containing regimen was consistent with previous pertuzumab studies and no
new safety signals were observed. Almost all patients experienced an AE. The
most common AEs were diarrhoea, palmar-plantar erythrodysesthesia (PPE)
syndrome and nausea. The incidence of diarrhoea was higher in those patients
who received pertuzumab. The incidence of Grade ≥3 AEs was lower in those
patients who received pertuzumab. The incidence of serious adverse events
(SAEs) was similar in the two treatment arms. The incidence of cardiac disorders,
particularly LVD, was higher in patients who received pertuzumab (3.2% vs
7.5%). There was a total of 213 deaths, the majority of which were due to disease
progression. Of these 213 deaths, 98 occurred in the pertuzumab arm.
Early breast cancer
In the Phase II NeoSphere study (21), the most frequently occurring AEs during
neoadjuvant treatment were alopecia, neutropenia, diarrhoea, nausea, fatigue,
263
rash and mucosal inflammation. The overall safety profile of Ptz + T + D (Arm
B) was comparable to that of T + D (Arm A). The tolerability of pertuzumab
plus docetaxel (Arm D) was also broadly comparable to that of Arm B. Patients
receiving trastuzumab and pertuzumab only (Arm C) reported fewer AEs across
most body systems compared to patients who also received chemotherapy. At
the final clinical cut-off date, the safety profile observed was consistent with what
has been previously reported for the neoadjuvant, adjuvant and post-treatment
follow-up periods, indicating that the combination of trastuzumab, pertuzumab
and docetaxel was generally well tolerated. In addition, no late safety concerns
(including delayed cardiac toxicity) have emerged.
In the Phase II TRYPHAENA study (23), the most common AEs
were diarrhoea, alopecia, nausea, neutropenia, vomiting, fatigue, anaemia,
dyspepsia and thrombocytopenia. The safety profile observed was consistent
with what has been previously reported for the neoadjuvant, adjuvant and post-
treatment follow-up periods, indicating that these combinations, whether given
sequentially after or concomitantly with anthracycline-based or concomitantly
with carboplatin-based treatment were generally well tolerated. In addition,
there were no unexpected findings regarding cardiac safety.
In the ongoing Phase III APHINITY study (25), the most common
AEs (≥30% in either treatment arm) were diarrhoea, nausea, alopecia, fatigue,
vomiting, arthralgia, and constipation. The incidence of most of the common AEs
was similar between treatment arms except for diarrhoea, nausea and fatigue,
which were higher in the Ptz + T + chemotherapy arm, and arthralgia, which was
higher in the Pla + T + chemotherapy arm. The incidence of Grade ≥3 AEs during
the overall study treatment period was higher in the Ptz + T + chemotherapy
arm than in the Pla + T + chemotherapy arm (64.2% patients in the Ptz + T +
chemotherapy arm and 57.3% patients in the Pla + T + chemotherapy arm). The
proportion of patients who experienced at least one AE that led to the withdrawal
of pertuzumab or placebo was similar in the two treatment arms. The cardiac
event rates were low in both treatment arms.

The Phase III MARIANNE randomized controlled trial studied untreated HER2
positive metastatic breast cancer patients receiving T-DM1 plus pertuzumab,
T-DM1 plus placebo, or a combination of trastuzumab with a taxane (paclitaxel
or docetaxel) (29, 30). Approximately 30% of trial participants had been treated
with trastuzumab in the adjuvant/neoadjuvant setting. The final MARIANNE
results showed similar overall survival in the three treatment arms, with
all regimens resulting in median OS greater than 50 months. Notably, in
MARIANNE, the median OS of patients treated with trastuzumab and a taxane
(50.9 months) was longer than that reported in the CLEOPATRA trial for
trastuzumab plus docetaxel (40.8 months) and closer to the median OS of 56.5
264
months reported in CLEOPATRA for trastuzumab, docetaxel, and pertuzumab.

Results from MARIANNE demonstrate the central role of trastuzumab, an
anti-HER 2 medicine included into the WHO Model List, in the management
of HER2‐positive metastatic breast cancer, where median survival times longer
than four years can be achieved.
Technology appraisal guidance documents released by National Institute
for Health and Care Excellence on pertuzumab in early and metastatic breast
cancer noted considerable uncertainty on incremental cost-effectiveness ratio
(ICER) for pertuzumab as compared to control, given uncertainty on long
treatment benefit associated with the medicine (31, 32). In the United Kingdom,
pertuzumab is priced at £ 2395 per 420 mg vial (excluding value-added tax; price
referring to 2018). The company has a commercial arrangement that makes
pertuzumab available to the National Health Service with a discount. The size of
the discount is commercial in confidence.
WHO Guidelines
None available.
Metastatic breast cancer
The application did not provide data in the context of metastatic breast cancer.
Early breast cancer
The application reported on a budget impact model developed by F. Hoffmann-
La Roche assessing the cost impact of pertuzumab on further lines of treatment
based on the reduction of metastatic events compared to trastuzumab + docetaxel.
Long-term cost savings associated with event-free survival were estimated on
a five-year time horizon. Cost and epidemiological data were derived from the
Italian context but were not provided in the application. 1300 HER2-positive
early breast cancer patients were considered eligible for neoadjuvant treatment
with pertuzumab in the first year after launch. Average cost savings per year per
patient for subsequent lines of treatment in Italy could go up to € 2800 three
years after launch. In the third year after launch, the costs savings in later lines
of treatment are estimated to be € 3.6 million resulting in accumulated costs of
€ 6.2 million within the first three years (33).
Cost-effectiveness analyses based on the Canadian setting, and the
NeoSphere and TRYPHAENA trials, suggested that the addition of pertuzumab
resulted in increased life-years and quality-adjusted life-years (QALYs). The
incremental cost per QALY ranged from US$ 25 388 (CAD; NeoSphere analysis)
to US$ 46 196 (TRYPHAENA analysis). Sensitivity analyses resulted in cost-
effectiveness ratios ranging from US$ 9230 to US$ 64 421 (34).
265
The application reported on the results of an additional cost-effectiveness

analysis based on costs derived from the Italian context. Few details were
provided. The study concluded that the addition of pertuzumab in adjuvant
therapy induces a cost increase ranging between € 23 000 and € 28 000 per patient
for a gain of 0.45 to 1.00 QALY (35).
Availability
As of 7 June 2018, pertuzumab has been approved in more than 100 countries
worldwide.
Based on results of the CLEOPATRA study (17, 19, 20), pertuzumab received a
score of 4 on the ESMO-MCBS v1.1 for use in the first-line metastatic treatment
setting (36).
Based on results of the NeoSphere study (21, 22), pertuzumab received a
score of C on the ESMO-MCBS v1.1 for use in the neoadjuvant setting in early
breast cancer (36).
Based on results of the APHINITY study (25), pertuzumab received a
score of 4 on the ESMO-MCBS v1.1 for use in the adjuvant setting in early breast
cancer (36).
The Committee endorsed the recommendations of the EML Cancer Medicine
for inclusion on the EML, and applied this principle to the consideration of
pertuzumab.
The Committee acknowledged that pertuzumab was associated with
a relevant survival benefit, well beyond the established threshold, as first-

line treatment of metastatic breast cancer, based on the results reported in the
CLEOPATRA trial. However, the Committee expressed reservations about
the generalizability of CLEOPATRA results in metastatic breast cancer and
consistency of the clinical effectiveness of pertuzumab among studies both in
early and metastatic breast cancer. These reservations are expanded below.
The Committee noted that only approximately 10% of patients in
CLEOPATRA had received trastuzumab in the adjuvant or neoadjuvant setting.
The Committee was concerned that the observed survival gains may not
therefore be generalizable to patients with metastatic disease who have received
prior adjuvant or neoadjuvant trastuzumab, making the magnitude of benefit
in this population sub-group uncertain. The Committee also noted the results
reported in the MARIANNE trial, where pertuzumab in combination with
266
T-DM1 was not shown to have greater clinical benefit compared to trastuzumab
plus chemotherapy or T-DM1 alone. The Committee was unable to reconcile the
differences in the outcomes reported in the MARIANNE and CLEOPATRA trials.
The Committee also noted that the relevant survival gains observed
in CLEOPATRA for metastatic breast cancer were not replicated in trials of
pertuzumab in early stage breast cancer. The Committee accepted that trial
results suggest pertuzumab offers a small incremental overall and disease-free
survival benefit compared to placebo, based on an analysis at around three years
median follow-up. The Committee considered that continued follow up was
important to assess long-term overall survival, but thought it unlikely that the
magnitude of benefit would be greater with longer follow-up, given that anti-
HER2 treatments are typically associated with a reduction in early recurrences,
followed by a plateau effect.
The Committee therefore did not recommend the addition of pertuzumab
to the complementary list of the Model List for the treatment of early stage and
metastatic HER2 positive breast cancer. The Committee considered that the
available evidence did not demonstrate a clinically meaningful survival benefit
in early stage disease, and that there was important uncertainty surrounding the
estimated magnitude of survival benefit in metastatic disease, with results seen in
CLEOPATRA not replicated in other trials.
It was Committee’s view that questions associated with differences in
results from the CLEOPATRA and MARIANNE trials should be resolved by
integration of the raw, individual patient trial data and independent re-analysis
following a set of pre-planned hypotheses. The Committee recommended that
WHO considers requesting access to the raw clinical trial data from CLEOPATRA
and MARIANNE from the applicant, for an independent re-analysis arranged by
WHO, and present the report of any such independent re-analysis to the 2021
Expert Committee for consideration.
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Rituximab – new formulation – EML
Rituximab ATC Code: L01XC02
Proposal
The application requested the addition of new subcutaneous (SC) injection
formulations of rituximab to the complementary list of the EML for use in the
treatment of diffuse large B-cell lymphoma, chronic lymphocytic leukaemia and
follicular lymphoma.
Applicant
F. Hoffmann-La Roche Ltd

unit advised that it did not support the inclusion of SC rituximab at this time,
suggesting that the addition of this formulation could be considered as evidence
emerges regarding real-world evidence of SC formulations providing reduced
costs of care for the health workforce and/or facilities.
EML/EMLc
EML
Section

Injection (subcutaneous) 1400 mg/11.7 mL in 15 mL vial
–– Diffuse large B-cell lymphoma
–– Follicular lymphoma
Injection (sub-cutaneous) 1600 mg/13.4 mL in 20 mL vial (CLL)
–– Chronic lymphocytic leukaemia
Core/Complementary
Complementary

Individual
271

Rituximab intravenous (IV) injection was added to the complementary list of the
EML in 2015 for treatment of diffuse large B-cell lymphoma, follicular lymphoma
and chronic lymphocytic leukaemia (1).

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-
Hodgkin lymphoma (NHL), accounting for more than 30% of lymphoma
incidence (2). The crude incidence of DLBCL in Europe has been reported as
3.8/100 000/year, increasing with age (2).
Follicular lymphoma is the second most frequent sub-type, accounting
for approximately 20% of the overall NHL incidence (3, 4). Follicular lymphoma
(FL) occurs most commonly in middle-aged patients and the elderly, with a
median age at diagnosis of approximately 60 years (5, 6).
Chronic lymphocytic leukaemia (CLL) is the most common form of
adult leukaemia in Western Europe, accounting for 25%–40% of all leukaemias
(7–9) with approximately 2–6 new cases in every 100 000 individuals per year
(8, 10). CLL is more prevalent in the elderly, with an estimated median age at
first diagnosis of approximately 70 years (11) and with a male to female ratio of
approximately 2:1 (9).

Evidence for the clinical effectiveness of rituximab was evaluated at the time of
listing in 2015.
The SABRINA trial investigated non-inferiority of the pharmacokinetic
profile, efficacy and safety of SC rituximab (in combination with chemotherapy)
with IV rituximab (in combination with chemotherapy) in patients with
previously untreated FL (12). Results showed that rituximab SC 1400 mg provides
non-inferior pharmacokinetics (PK) (Ctrough /AUC), as well as comparable efficacy
and safety to rituximab IV. The point estimate for complete response (CR or
unconfirmed complete response (CRu)) was numerically higher in the IV arm
compared with the SC 1400 mg arm (34.8%, 95%CI 26.9 to 43.2 vs 28.2%,
95%CI 20.9 to 36.3). A higher proportion of patients in the IV arm (85.1%,
95%CI 78.1 to 90.5) achieved an overall response (CR, CRu and partial response
(PR)) compared with patients in the SC 1400 mg arm (80.3%, 95%CI 72.8 to
86.5), whereas the rate of partial response was similar between the two arms
(50.4%, 95%CI 41.8 to 58.9 vs 52.1%, 95%CI 43.6 to 60.6) (13, 14).
The SAWYER trial investigated non-inferiority of the PK profile, efficacy
and safety of 1600 mg SC rituximab (in combination with chemotherapy) with
IV rituximab (in combination with chemotherapy) in patients with previously
untreated chronic lymphocytic leukaemia (15). Response rates were similar for
the IV and SC arms, with an overall response rate of 80.7% (95%CI 70.9 to 88.3)
272
and 85.2% (95%CI 76.1 to 91.9) in the IV and SC arms, respectively. Complete
response rate point estimates were 33.0% (95%CI 23.3 to 43.8) and 26.1% (95%CI
17.3 to 36.6) in the IV and SC arms, respectively. Overall the results confirmed
that rituximab SC 1600 mg has a comparable benefit/risk profile to that of
rituximab IV 500 mg/m2.

Evidence for the safety of rituximab was evaluated at the time of listing in 2015.
The safety profile of rituximab SC formulation was reported to be
comparable to that of the intravenous formulation, with the exception of local
injection site reactions. Administration-related reactions were very common
in patients receiving the SC rituximab formulation in the SparkTera (16) and
SABRINA (12) trials, reported in up to 50% of patients at some time during
treatment. Symptoms included pain, swelling, induration, haemorrhage, erythema,
pruritis and rash. The majority of the reactions following SC administration were
reported as mild or moderate.

N/A
WHO Guidelines
None available.
No information was provided in the application regarding comparative drug
costs of the SC and IV rituximab formulations, including biosimilars.
The application stated that IV administration takes approximately three
to four hours, which can incur high costs on patients, health care professionals
and the health care system. The SC formulation can be administered via
hand-held syringe in less than ten minutes plus follow-up time and thus has
the potential to realize considerable cost savings. A time and motion study
of SC versus IV rituximab found time savings for patients and health care
professionals associated with SC administration of rituximab compared to IV
administration (17).
The Committee considered that whether time savings would be realized
to the full extent found in the study was uncertain, given that rituximab is
administered with other intravenous chemotherapy.
Availability
Rituximab SC 1400 mg has regulatory approval and market availability in more
than 60 countries globally. The 1600 mg strength is approved and available in
around 20 countries.
273
The Committee noted the correspondence from the European Society for
Medical Oncology (ESMO) requesting recognition of biosimilars of rituximab
and trastuzumab on the EML. The Committee agreed that quality-assured
biosimilars of these monoclonal antibodies represent an opportunity for
expanding affordable access to cancer medicines for health systems.
The Committee did not recommend the addition of new subcutaneous injection
formulations of rituximab to the complementary list of the EML for use in the
treatment of diffuse large B-cell lymphoma, chronic lymphocytic leukaemia and
follicular lymphoma.
The Committee acknowledged the potential benefits of the subcutaneous
formulation over the listed intravenous formulation. However, with the
availability of biosimilar versions of intravenous rituximab, the Committee was
concerned that listing of the subcutaneous formulation, for which biosimilars are
not yet available, could limit competition and therefore limit access for patients.
To help improve access, the Committee recommended the current listing
for intravenous rituximab on the EML should indicate that quality-assured
biosimilars of rituximab should also be considered as essential medicines. In
addition, the Expert Committee recommended that WHO continue to facilitate
access to biosimilars through the Prequalification programme and WHO
Collaborative Registration Procedure.
References
(including the 19th WHO Model List of Essential Medicines and the 5rd WHO Model List
of Essential Medicines for Children) (WHO Technical Report Series, No. 994). Geneva: World

189763/9789241209946_eng.pdf, accessed 30 October 2019.
2. Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A et al. Diffuse large
B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-
up. Ann Oncol. 2015;26 Suppl 5:v116–25.
3. Zinzani PL. Lymphoma: diagnosis, staging, natural history, and treatment strategies. Semin Oncol.
2005;32(1 Suppl 1):S4–10.
4. Winter JN, Gascoyne RD, Van Besien K. Low-grade lymphoma. Hematology Am Soc Hematol Educ
Program. 2004:203–20.
5. Rohatiner AZ, Lister TA. The clinical course of follicular lymphoma. Best Pract Res Clin Haematol.
2005;18(1):1–10.
6. Vitolo U, Ferreri AJ, Montoto S. Follicular lymphomas. Crit Rev Oncol Hematol. 2008;66(3):248–61.
7. Watson L, Wyld P, Catovsky D. Disease burden of chronic lymphocytic leukaemia within the
European Union. Eur J Haematol. 2008;81(4):253–8.
274
8. Ghia P, Ferreri AM, Caligaris-Cappio F. Chronic lymphocytic leukemia. Crit Rev Oncol Hematol.
2007;64(3):234–46.
9. Ikram N, Hassan K, Tufail S. Chronic Lymphocytic Leukaemia (CLL) - An Overview. Int J Pathol.
2003;1:48–59.
10. Eichhorst B, Dreyling M, Robak T, Montserrat E, Hallek M. Chronic lymphocytic leukemia: ESMO
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22 Suppl
6:vi50–4.
11. Mulligan SP, Tam CS. Chronic lymphocytic leukemia: diagnosis and clinical staging. In: Keating
MJ, Tam CS, editors. Advances in the treatment of B-cell chronic lymphocytic leukemia. London:
Future Medicine; 2012. p. 6–15.
12. Davies A, Merli F, Mihaljevic B, Mercadal S, Siritanaratkul N, Solal-Celigny P et al. Efficacy and
safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of
follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol.
2017;4(6):e272–e82.
13. Davies A, Merli F, Mihaljevic B, Siritanaratkul N, Solal-Celigny P, Barrett M et al. Pharmacokinetics
and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a
randomised phase 3 study. Lancet Oncol. 2014;15(3):343–52.
14. Davies A, Barrett M, Berge C. Primary Clinical Study Report – Protocol BO22334 – A two-stage
phase III, international, multi-center, randomized, controlled, open-label study to investigate the
pharmacokinetics, efficacy and safety of rituximab SC in combination with CHOP or CVP versus
rituximab IV in combination with CHOP or CVP in patients with previously untreated follicular
lymphoma followed by maintenance treatment with either rituximab SC or rituximab IV – Report
No. 1058994. 2014.
15. Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N et al. Pharmacokinetics,
safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as
treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised
controlled non-inferiority trial. Lancet Haematol. 2016;3(3):e128–38.
16. Salar A, Avivi I, Bittner B, Bouabdallah R, Brewster M, Catalani O et al. Comparison of subcutaneous
versus intravenous administration of rituximab as maintenance treatment for follicular
lymphoma: results from a two-stage, phase IB study. J Clin Oncol. 2014;32(17):1782–91.
17. De Cock E, Kritikou P, Sandoval M, Tao S, Wiesner C, Carella AM et al. Time Savings with Rituximab
Subcutaneous Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in
Eight Countries. PLoS One. 2016;11(6):e0157957.
275
Trastuzumab – new formulation – EML
Trastuzumab ATC Code: L01XC03
Proposal
The application requested the addition of a subcutaneous injection formulation
of trastuzumab to the complementary list of the EML for use in the treatment of
early stage and metastatic HER2 positive breast cancer.
Applicant

unit advised that it did not support the inclusion of SC trastuzumab at this time,
suggesting that the addition of this formulation could be considered as evidence
emerges regarding real-world use of SC formulations providing reduced costs of
care for the health workforce and/or facilities.
EML/EMLc
EML
Section

Injection (subcutaneous) 600 mg/5 mL in 5 mL vial
Core/Complementary
Complementary

Individual

Trastuzumab powder for intravenous injection was added to the complementary
list of the EML in 2015 for treatment of early stage and metastatic human
epidermal growth factor receptor 2 (HER2)-positive breast cancer (1).
276

Breast cancer is the most common form of malignancy in women (2). In 2018,
the number of new breast cancer cases was over 2 million, with over 626 000
deaths (3).
The HER2 receptor is an important target for the treatment of breast
cancer. Amplification and/or overexpression of HER2 occurs in approximately
18% to 22% of breast cancers (4, 5). HER2 amplification/overexpression (HER2-
positivity) is associated with increased tumour aggressiveness, higher rates of
recurrence, and increased mortality (5–10). Approximately 15% to 20% of deaths
from breast cancer are likely to be due to HER-positive disease.

Evidence for the clinical effectiveness of trastuzumab was evaluated at the time
of listing in 2015.
The current application presented the results of the Phase III study
BO22227, which was designed to demonstrate non-inferiority of treatment
with SC trastuzumab (600 mg every three weeks) and IV trastuzumab (8 mg/kg
loading dose, 6 mg/kg maintenance every three weeks) based on co-primary
pharmacokinetic and efficacy endpoints, (trastuzumab Ctrough at pre-dose
cycle 8, and pathological complete response (pCR) rate at definitive surgery,
respectively) (11).
The pharmacokinetic results for the co-primary endpoint, C trough pre-
dose cycle 8, showed non-inferiority of trastuzumab SC to trastuzumab IV, with
dose adjusted by body weight.
Efficacy results for the co-primary end point of pCR also showed non-
inferiority of trastuzumab SC to trastuzumab IV. 595 patients with HER2-
positive, operable or locally-advanced breast cancer including inflammatory
breast cancer received eight cycles of either trastuzumab IV or trastuzumab SC
concurrently with chemotherapy, followed by surgery, and continued therapy
with trastuzumab IV or SC as originally randomized for 10 additional cycles, for
a total of one year of treatment. pCR rates were 40.7 % (95%CI 34.7 to 46.9) in
the trastuzumab IV arm and 45.4 % (95%CI 39.2% to 51.7%) in the trastuzumab
SC arm, a difference of 4.7 percentage points in favour of the trastuzumab SC
arm. The lower boundary of the one-sided 97.5% confidence interval for the
difference in pCR rates was −4.0.
Analyses with longer-term follow-up of a median duration exceeding
40 months and 70 months supported the non-inferior efficacy of the SC
formulation with comparable results of both event-free survival (EFS) and
overall survival (OS).
277

Evidence for the safety of trastuzumab was evaluated at the time of listing
in 2015.
The current application stated that no new safety signals were reported in
in Study MO28048, which investigated the safety and tolerability of trastuzumab
SC as adjuvant therapy in HER2 positive early breast cancer (EBC) patients
who were enrolled in either a trastuzumab SC vial cohort or a trastuzumab SC
administration system cohort (12). Treatment of lower body weight patients with
trastuzumab SC fixed dose in adjuvant EBC was not associated with increased
safety risk, adverse events or serious adverse events, compared to the higher body
weight patients (13).
The final results of study BO22227 at a median follow up exceeding
70 months were also consistent with the known safety profile for trastuzumab IV
and trastuzumab SC, and no new safety signals were observed (11).

N/A
WHO Guidelines
None available.
No information was provided in the application regarding comparative drug
costs of the SC and IV trastuzumab formulations, including biosimilars.
The application stated that IV administrations take approximately one
hour, which can incur high costs on patients, health care professionals and the
health care system. The SC formulation can be administered over five minutes
via a hand-held syringe or a single-use injection device (SID) and thus has
the potential to realize considerable cost savings. A time and motion study of
SC versus IV trastuzumab found time savings for patients and health care
professionals associated with SC administration of trastuzumab compared to IV
administration (14).
The Committee considered that whether time savings would be realized
to the full extent found in the study was uncertain, given that trastuzumab is
administered with other intravenous chemotherapy.
Availability
The SC formulation of trastuzumab has regulatory approval and market
availability in around 100 countries globally.
278
The Committee noted the correspondence from the European Society for
Medical Oncology (ESMO) requesting recognition of biosimilars of rituximab
and trastuzumab on the EML. The Committee agreed that quality-assured
biosimilars of these monoclonal antibodies represent an opportunity for
expanding affordable access to cancer medicines for health systems.
The Committee did not recommend the addition of new subcutaneous injection
formulations of trastuzumab to the complementary list of the EML for use in
the treatment of early stage and metastatic HER2 positive breast cancer.
The Committee acknowledged the potential benefits of the sub-
cutaneous formulation over the listed intravenous formulation. However,
with the availability of biosimilar versions of intravenous trastuzumab, the
Committee was concerned that listing of the sub-cutaneous formulation, for
which biosimilars are not yet available, could limit competition and therefore
limit access for patients.
To help improve access, the Committee recommended the current listing
for intravenous trastuzumab on the EML should indicate that quality-assured
biosimilars of trastuzumab can also be considered as essential medicines. In
addition, the Committee recommended that WHO continue to facilitate access
to biosimilars through the Prequalification programme and WHO Collaborative
Registration Procedure.
References
2. Global Cancer Observatory: Cancer Today [website]. Lyon: International Agency for Research on
Cancer; 2018. (https://gco.iarc.fr/today, accessed 29 September 2019).
Cancer J Clin. 2018;68(6):394–424.
Oncologist. 2009;14(4):320–68.
279
9. Brown M, Tsodikov A, Bauer KR, Parise CA, Caggiano V. The role of human epidermal growth factor
receptor 2 in the survival of women with estrogen and progesterone receptor-negative, invasive
breast cancer: the California Cancer Registry, 1999-2004. Cancer. 2008;112(4):737–47.
11. Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB et al. Subcutaneous versus
intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical
stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial.
Lancet Oncol. 2012;13(9):869–78.
12. Gligorov J, Ataseven B, Verrill M, De Laurentiis M, Jung KH, Azim HA et al. Safety and tolerability
of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor
receptor 2-positive early breast cancer: SafeHer phase III study’s primary analysis of 2573 patients.
Eur J Cancer. 2017;82:237–46.
13. Jung KH, Ataseven B, Verrill M, Pivot X, De Laurentiis M, Al-Sakaff N et al. Adjuvant Subcutaneous
Trastuzumab for HER2-Positive Early Breast Cancer: Subgroup Analyses of Safety and Active
Medical Conditions by Body Weight in the SafeHer Phase III Study. Oncologist. 2018;23(10):
1137–43.
14. De Cock E, Pivot X, Hauser N, Verma S, Kritikou P, Millar D et al. A time and motion study of
subcutaneous versus intravenous trastuzumab in patients with HER2-positive early breast cancer.
Cancer Med. 2016;5(3):389–97.
280
Trastuzumab emtansine – addition – EML
Trastuzumab emtansine (T-DM1) ATC Code: L01XC14
Proposal
The application requested the addition of trastuzumab emtansine (T-DM1) to
the complementary list of the EML for the treatment of unresectable, locally
advanced and metastatic human epidermal growth factor receptor 2 (HER2)-
positive breast cancer.
Applicant

unit advised that it did not support inclusion of trastuzumab emtansine on
the EML at this time, though noting recent studies demonstrating its utility as
second-line therapy in metastatic and non-metastatic settings. At the current
time, given the narrow gain in overall survival and small benefit on disease-
control, the technical unit considered that trastuzumab did not currently meet
criteria as a priority medicine for breast cancer.
EML/EMLc
EML
Section

Powder for injection 100 mg in vial
Powder for injection 160 mg in vial
Core/Complementary
Complementary

Individual
281

Trastuzumab emtansine (T-DM1), as a single agent, is indicated for the treatment
of adult patients with human epidermal growth factor receptor 2 (HER2)-
positive, unresectable locally advanced or metastatic breast cancer (MBC) who
had previously received trastuzumab and a taxane, separately or in combination.
Both trastuzumab and taxanes are already included in the WHO Model List.
T-DM1 was considered for inclusion on the EML by the Expert Committee
in 2017 and was not recommended. At that time the Committee acknowledged
the significant public health burden of breast cancer and noted the availability
of other medicines for this condition (e.g. pertuzumab, lapatinib), which have
never been proposed for evaluation for inclusion on the EML. The Committee
considered that it would have been preferable to consider T-DM1 as part of a
comprehensive review encompassing additional medicines, compared with the
standard of care, better understanding the additional value and implications of
adding them to national EMLs.
Trastuzumab is currently included on the EML for treatment of metastatic
HER2-positive breast cancer. EML-listed cytotoxic medicines for metastatic
breast cancer include capecitabine, cyclophosphamide, docetaxel, doxorubicin,
paclitaxel and vinorelbine. EML-listed hormonal therapies for MBC include
anastrozole and tamoxifen.

Breast cancer is the leading cause of cancer death among women globally,
responsible for 15% of all cancer deaths. In 2018, the global cancer burden
increased to 18.1 million cases, causing 9.6 million deaths (1). Changes in
lifestyle, life expectancy and reproductive factors are responsible in many low-
and middle-income countries (LMICs) for a sharp increase in the incidence
of breast cancer, and the number of deaths as a percentage of incident cases is
greater than that seen in high-income countries. For example, in 2008, this figure
was 24% in high-income countries, 38% in high-middle-income countries, 40%

in low-middle-income and 48% in low-income (2).
The HER2 receptor has emerged as one of the most important targets
for the treatment of breast cancer. HER2 is involved in regulating cell growth,
survival, and differentiation (3). Amplification and/or overexpression of
HER2 occurs in approximately 18%–22% of breast cancers (4, 5). HER2
amplification/overexpression (HER2-positivity) is associated with increased
tumour aggressiveness, higher rates of recurrence, and increased mortality (5–
10). The median age of patients presenting with HER2-positive breast cancer is
in the mid-50s, approximately five years younger than the general breast cancer
population (11).
At the early stage, breast cancer is usually operable and can be treated
with curative intent. However, approximately 20%–35% of patients experience
282
relapse (12) and those with metastatic or unresectable disease are generally
incurable. Such tumours often continue to express high levels of HER2 (13).
Patients with metastatic disease have a 5-year life expectancy of approximately
18% in Europe (14).

Locally advanced and metastatic breast cancer
The efficacy of single-agent T-DM1 at a dose of 3.6 mg/kg every three weeks
has been investigated in Phase II and III trials in HER2-positive advanced
breast cancer.
The pivotal Phase III EMILIA trial was a randomized, multicentre,
international, two-arm, open-label clinical trial that evaluated the efficacy and
safety of treatment with T-DM1 was compared with the efficacy and safety of
treatment with lapatinib plus capecitabine in 991 patients with HER2-positive,
unresectable, locally advanced or metastatic breast cancer who had been
previously treated with trastuzumab and a taxane (15, 16). The primary efficacy
endpoints were overall survival (OS) and independent review committee-
assessed progression-free survival (PFS). The study demonstrated a statistically
significant improvement in both PFS (9.6 months vs 6.4 months, HR 0.65, 95%CI
0.59 to 0.77) and OS (30.9 months vs 25.1 months, HR 0.68, 95%CI 0.55 to 0.85)
for T-DM1 compared with lapatinib plus capecitabine. The final OS analysis was
scheduled to be conducted after the occurrence of 632 deaths. At the data cut-off
date for this analysis (December 2014), median OS was prolonged in patients
treated with T-DM1 (29.9 months) when compared with patients treated with
capecitabine plus lapatinib (25.9 months; HR 0.75, 95%CI 0.64 to 0.88) (16).
The comparator regimen of lapatinib plus capecitabine used in the
EMILIA trial has not been considered for inclusion on the Model List.
The Phase III TH3RESA trial was a randomized, open-label, multicentre
trial that compared T-DM1 with treatment of physician’s choice in 602 patients
with progressive HER2-positive advanced breast cancer, previously treated
with at least two HER2-directed regimens (17, 18). The study demonstrated a
statistically significant improvement in both PFS (6.2 months vs 3.3 months,
HR 0.53, 95%CI 0.42 to 0.66) and OS (median not reached at that time vs 14.9,
HR 0.55, 95%CI 0.37 to 0.83) for T-DM1 compared with treatment of physician’s
choice (17). At the data cut-off date for final OS analysis (February 2015), median
OS was prolonged in patients treated with T-DM1 compared with treatment
of physician’s choice (22.7 months vs 15.8 months; HR 0.68, 95%CI 0.54 to
0.85) (18).
Early breast cancer
The Phase III KRISTINE study evaluated neoadjuvant T-DM1 plus pertuzumab
compared with docetaxel, carboplatin and trastuzumab plus pertuzumab in
283
444 patients with HER2-positive early breast cancer (19). The study found that
total pathological complete response rates (a surrogate outcome for survival)
were higher in patients receiving trastuzumab emtansine plus pertuzumab or
docetaxel, carboplatin, than trastuzumab plus pertuzumab. However, OS was not
significantly different between treatment groups (HR 1.21, 95%CI 0.37 to 3.96).
Event-free survival significantly favoured trastuzumab-containing regimens,
without T-DM1 (HR 2.61, 95%CI 1.36 to 4.98) (20).
In the KATHERINE study, adjuvant T-DM1 significantly improved
Invasive disease–free survival rates compared to trastuzumab group in 1486
patients with residual disease following neoadjuvant chemotherapy plus
trastuzumab-based anti-HER2 treatment (HR for invasive disease or death 0.50,
95%CI 0.39 to 0.64) (21). OS did not significantly differ (HR 0.70, 95%CI 0.47
to 1.05). These results are based on an early interim analysis based on few events.

The safety profile of T-DM1 in MBC is based on pooled data from 1871
patients receiving single-agent T-DM1 treatment at 3.6 mg/kg every three
weeks (Studies TDM3569g, TDM4258g, TDM4374g, TDM4688g, TDM4450g/
BO21976, TDM4370g/BO21977, TDM4788g/BO22589, TDM4997g/BO25734
and TDM4529g/BO25430). The most common adverse events (AEs) for single-
agent T-DM1 (AEs in ≥25% of patients) were nausea, fatigue and headache (22).
The Phase III EMILIA study compared T-DM1 with lapatinib plus
capecitabine treatment, in patients with HER2-positive locally-advanced or
metastatic breast cancer (15). In accordance with the differing mechanisms
of action, the safety profile of T-DM1 was different from that of lapatinib plus
capecitabine, as shown by differences in incidence of common AEs. In the
T-DM1 arm, the most common events (occurring in at least 25% of patients)
were nausea, fatigue, thrombocytopenia, headache, constipation, diarrhoea
and increased aspartate aminotransferase, whereas the most common events
associated with lapatinib plus capecitabine treatment were diarrhoea, palmar-

plantar erythrodysesthesia syndrome, nausea, vomiting, fatigue and rash (Roche,
data on file). Fewer patients were reported with AEs of Grade 3 or higher, and
serious adverse events (SAEs) in the T-DM1 arm than in the lapatinib plus
capecitabine arm.
In the Phase III TH3RESA study, fewer patients receiving T-DM1
than those receiving treatment of physician’s choice had AEs of Grade 3 or
higher. Grade 3 or higher thrombocytopenia was reported more frequently in
patients receiving T-DM1 (≥2% more patients than in the TPC arm), whereas
patients receiving TPC reported more Grade ≥3 neutropenia, leukopenia, febrile
neutropenia and diarrhoea (17).
Cardiac safety of T-DM1 in patients with early breast cancer was evaluated
in the Phase II study TDM4874g/BO22857 (23). There were no events of
284
symptomatic heart failure. One patient discontinued T-DM1 treatment as a result

of an asymptomatic left ventricular ejection fraction (LVEF) decline. The most
common AEs while receiving T-DM1 (in at least 20% of patients) were nausea,
headache, epistaxis, asthenia, pyrexia, fatigue, arthralgia, thrombocytopenia
and myalgia. The most common Grade 3 or higher AEs (>2%) reported while
receiving T-DM1 were thrombocytopenia, alanine transaminase (ALT) increase,
aspartate aminotransferase (AST) increase, neutropenia, and hypertension; all of
which occurred in less than 10% of patients.
In the neoadjuvant KRISTINE (BO28408) study, safety was better
in the T-DM1 + pertuzumab arm compared with trastuzumab, pertuzumab
plus chemotherapy, with a lower incidence of, Grade 3 or higher: 13.0% in
the T-DM1 + pertuzumab arm vs 64.4% in the trastuzumab, pertuzumab plus
chemotherapy arm; serious AEs: 4.9% in T-DM1 + pertuzumab arm vs 28.8%
in trastuzumab, pertuzumab plus chemotherapy arm; and AEs leading to
treatment discontinuation: 3.1% in the T-DM1 + pertuzumab arm vs 8.7% in the
trastuzumab, pertuzumab plus chemotherapy arm. The most common Grade 3–4
adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab
group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with T-DM1 plus
pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%]
vs 0). No deaths were reported during neoadjuvant treatment (19).
The overall safety profile of the T-DM1 arm in the adjuvant KATHERINE
(BO27938) study was consistent with the known safety profile of T-DM1 (21).
Any-grade AEs were more common in the T-DM1 arm (98.8% vs 93.3%).
Adverse events leading to randomized treatment discontinuation occurred in 133
(18.0%) T-DM1–treated patients and 15 (2.1%) trastuzumab-treated patients.
The most common adverse events leading to discontinuation in the T-DM1
arm were laboratory abnormalities (platelet count decreased (4.2%), blood
bilirubin increased (2.6%), aspartate aminotransferase increased (1.6%), alanine
aminotransferase increased (1.5%)), peripheral sensory neuropathy (1.5%), and
ejection fraction decreased (1.2%). The most common Grade 3 or higher adverse
events were decreased platelet count (5.7%) and hypertension (2.0%) in the
T-DM1 group. Serious adverse events occurred in 94 patients (12.7%) receiving
T-DM1. One fatal adverse event of intracranial haemorrhage after subject fall
occurred in the T-DM1 arm. Adjudicated cardiac events occurred in four patients
(0.6%) in the trastuzumab arm and in one patient in the T-DM1 arm (0.1%).

The following is a summary of additional evidence presented as part of the 2017
Expert Committee consideration of T-DM1 in 2017 (24).
A 2016 meta-analysis of nine studies evaluated the safety and efficacy of
T-DM1 in advanced HER2-positive breast cancer. The overall hazard ratios for
PFS and OS were calculated by meta-analysing, respectively, three (EMILIA (15),
285
TH3RESA (17), BO21976 (25)) and two (EMILIA, TH3RESA,) controlled trials.
Median PFS significantly favoured T-DM1; difference ranged from 2.9 months
to 5 months (total HR 0.60; 95%CI 0.53 to 0.69). Cumulative OS was associated
with an improved survival for T-DM1 compared with treatment physician’s
choice (odds ratio (OR) 0.60; 95%CI 0.48 to 0.75). Heterogeneity was low in
both analyses.
The National Institute for Health and Care Excellence (NICE) published
its technology appraisal for T-DM1, assessing efficacy and cost–effectiveness
(26–28). As part of the process, NICE reviewed evidence submitted by Roche,
clinical experts and other stakeholders; clinical evidence came primarily
from EMILIA and TH3RESA clinical trials. Because head-to-head treatment
comparisons were available only for lapatinib in combination with capecitabine
(LC), the company conducted a Bayesian network meta-analysis using a fixed-
effect model involving five clinical trials (EMILIA, CEREBEL, EGF100151,
NCT00777101 and GBG26). NICE’s Evidence Review Group (ERG), reviewing
Roche’s submission, repeated the network meta-analysis using a random-effects
model. From the ERG’s model, compared with LC, T-DM1 was associated with
a 32% decrease in hazard of death (HR 0.68, 95% credible Interval (CrI) 0.37 to
1.25) and a 35% reduction in the hazard of tumour progression or death (HR
0.65, 95%CrI 0.35 to 1.20). However, the authors report that CrI values “do not
rule out the possibility that T-DM1 is less efficacious than comparators” (28).
After analysing the technology appraisal, NICE concluded that T-DM1
was clinically effective for treatment for HER2-positive, unresectable, locally
advanced or metastatic breast cancer after treatment with trastuzumab and a
taxane, but ultimately did not find it to be cost effective at the price that Roche
was offering at the time (27).
Comparison with trastuzumab
Trastuzumab is associated with relevant benefits in HER2-positive breast
cancer patients. In a systematic review of eight studies, total 11 991 patients,

the combined HRs for OS and disease-free survival (DFS) significantly favoured
trastuzumab-containing regimens (HR 0.66, 95%CI 0.57 to 0.77; p<0.00001;
and HR 0.60, 95%CI 0.50 to 0.71; p<0.00001, respectively) (29). Currently, a
combination of trastuzumab with a taxane is considered to be the standard of
care (i.e. first-line) in metastatic breast cancer. Medicines in this regimen are
included on the WHO EML.
The Phase III MARIANNE randomized controlled trial studied
untreated HER2-positive metastatic breast cancer patients receiving T-DM1
plus pertuzumab, T-DM1 plus placebo, or a combination of trastuzumab with
a taxane (paclitaxel or docetaxel) (30, 31). At the cut-off date of May 2016,
therapies containing T-DM1 were non-inferior to trastuzumab and taxane
treatments for PFS. However, OS curves essentially overlapped (trastuzumab
286
+ taxane vs trastuzumab emtansine + placebo, HR 0.93, 95%CI 0.73 to 1.20;

trastuzumab + taxane vs trastuzumab emtansine + pertuzumab HR 0.86, 95%CI
0.67 to 1.11) with survival medians approaching one another (trastuzumab +
taxane 50.86 months, trastuzumab emtansine + placebo 53.68, trastuzumab
emtansine + pertuzumab 51.78) (32). T-DM1 was better tolerated, contributing
to better quality of life secondary endpoints and less treatment discontinuation
related to adverse events (31).
WHO Guidelines
None available.
A Canadian study demonstrated that the use of T-DM1 for the management
of HER2-positive metastatic breast cancer results in substantial savings to the
public health care system when the costs of treatment related AEs are taken into
account, due to less toxicity compared with lapatinib plus capecitabine (33). The
findings were confirmed in sensitivity analyses in which the number and costs
of AEs were changed, however, the magnitude of cost savings varied. Whether
the same findings would be realized in other countries and health care systems
is not known.
T-DM1 has been accepted as a cost-effective treatment option in eligible
patients with HER2-positive metastatic breast cancer in the United Kingdom
(34), Canada (35), Australia (36), Scotland (37), Ireland (38), France (39), and
Sweden (40).
Availability
T-DM1 was first granted marketing approval in United States on February
2013, followed by the European Union (EU) and Japan in the same year. As
of 15 November 2018, T-DM1 has been approved in more than 100 countries
worldwide.
Based on results of the EMILIA study (15, 41), T-DM1 received a score of 4 on
the ESMO-MCBS v1.1 for use in the metastatic breast cancer setting as second-
line therapy after trastuzumab failure (42).
The U.S. National Comprehensive Cancer Network (NCCN) v3,
25 October 2018 clinical guidelines and compendium recommend use of T-DM1
as a first-line treatment option for patients with HER2-positive MBC in patients
not eligible for pertuzumab-trastuzumab plus a taxane. Based on the trial data
from Study BO22589/TDM4788g that demonstrated T-DM1 is noninferior
with better quality of life compared with trastuzumab plus taxane, and possibly
287
better tolerated for some patients, the NCCN panel included T-DM1 as one of
the first-line options for the treatment of patients with HER2-positive MBC.
Pertuzumab, trastuzumab, and a taxane, however, remain the preferred first-
line regimen for HER2-positive metastatic disease based on data demonstrating
improved overall survival compared with trastuzumab and a taxane. T-DM1
as first-line therapy should be considered only in patients not suitable for the
preferred treatment (43).
The American Society of Clinical Oncology (ASCO) clinical practice
guideline recommends the use of T-DM1 for the treatment of HER2-positive
advanced breast cancer that has progressed during or after first-line HER2-
targeted therapy (Evidence quality: High; Strength of recommendation: Strong)
(44). The same guideline also recommends the use of T-DM1 in patients whose
HER2-positive breast cancer has progressed during or after second-line or
greater HER2-targeted therapy if they have not previously been treated with
T-DM1 (44).
Updated European Society for Medical Oncology (ESMO) guidelines
recommend T-DM1 in patients who have progressed through at least one line of
trastuzumab-based therapy based on its OS benefit (Category IA) (45).
trastuzumab emtansine. The Committee acknowledged that for second-line
treatment of metastatic breast cancer, trastuzumab emtansine was associated
with a relevant survival benefit, within the range of the established threshold.
However, the Committee noted that survival benefits did not meet the four to six
month threshold when trastuzumab emtansine was used as first-line treatment

in the metastatic setting, or in early stage breast cancer.
Existing EML-listed options are available for metastatic disease and
may be suitable alternatives (e.g., trastuzumab, taxanes, etc.). However, the
Committee noted the current challenges in achieving full access to trastuzumab
in many settings. Taking this into account, trastuzumab emtansine for second-
line treatment of metastatic disease (i.e. late in the care pathway) was considered
to be a lower priority for EML inclusion at this time.
Compared to the 2017 application, the Committee noted that few new
clinical data were included in the current application and that the request was
not based on a comprehensive review encompassing additional breast cancer
medicines, compared with the standard of care, which would allow countries to
understand the additional value of adding each option to national EMLs.
288
The Expert Committee therefore did not recommend the addition of

trastuzumab emtansine to the complementary list of the EML for the treatment
of unresectable, locally advanced and metastatic HER2-positive breast cancer.
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292
Tyrosine-kinase inhibitors for non-small cell lung cancer – addition – EML
Afatinib ATC Code: L01XE13

Erlotinib ATC Code: L01XE03
Gefitinib ATC Code: L01XE02
Proposal
The application requested the addition of epidermal growth factor receptor
(EGFR) tyrosine kinase inhibitors (TKIs) to the complementary list of the EML
for first-line treatment of EGFR mutation positive, non-small cell lung cancer.
Applicant
Dr Sumitra Thongprasert

unit advised that it supported the inclusion of EGFR TKIs on the EML, stating
that there is sufficient evidence that these medicines are equivalent or superior
to existing listed medicines, based on updated meta-analysis and real-world data,
particularly in middle-income countries.
EML/EMLc
EML
Section

Afatinib: capsule 20 mg, 40 mg, 50 mg
Erlotinib: capsule 100 mg, 150 mg
Gefitinib: capsule 250 mg
Core/Complementary
Complementary

Square box
293

EGFR TKIs have been considered and rejected for inclusion on the EML on
two previous occasions in 2015 and 2017. In each case, the Expert Committee
acknowledged that individual patients with a drug-sensitive EGFR mutation may
derive benefit from TKI therapy, which has been associated with similar efficacy
and more favourable tolerability compared to cytotoxic chemotherapy. However,
the requirements to screen patients for suitability for treatment must be taken
into account by health systems (1, 2).
Cytotoxic chemotherapy currently included on the EML for treatment
of non-small cell lung cancer (NSCLC) includes carboplatin, cisplatin, etoposide,
gemcitabine, paclitaxel and vinorelbine.

Lung cancer is the most commonly diagnosed cancer globally, and the leading
cause of cancer death, with estimated 2 million new cases and 1.7 related deaths
in 2018. The economic impact of lung cancer has been estimated at around
US$ 8 billion in lost productivity in the BRICS countries (Brazil, Russia, India,
China and South Africa) (3).
Moreover, in the absence of wide coverage of effective screening
programmes on a global scale, lung cancer diagnoses occur in advanced stage
in more than 60% of cases, with highly regional variability (4, 5). The mutational
pattern of NSCLC varies across the different regions, with a higher prevalence in
Asia Pacific (up to 76% of patients) and the lowest registered in Oceania (12%).
Africa, Europe and North America registered the same rate of EGFR-mutated
NSCLC, at around 20% (6–8).
Non-squamous NSCLC has been linked to gene mutations in EGFR.
This disease, given its incidence, comprises a high burden and leads to a high
mortality. However, with advances in cancer gene-directed treatment, the
outcome of the disease has improved. The response rate doubled as compared
to chemotherapy, the progression free survival (PFS) doubled and the median
survival time increased to nearly three years if patients receive both the targeted
medicines and chemotherapy together (the median survival time for patient
receiving chemotherapy only is approximately 10 months, in historical series).

The application reported the findings and recommendations for EGFR-mutated
NSCLC from the 2018 European Society For Medical Oncology (ESMO) Clinical
Practice Guidelines for diagnosis, treatment and follow up of metastatic non-
small cell lung cancer (9).
The ESMO guidelines state that EGFR-TKIs are the standard of care for
first-line treatment for advanced EGFR-mutated NSCLC (level of evidence: I;
grade of recommendation: A).
294
EGFR mutation as an oncogenic target has proven predictive power in

NSCLC from multiple Phase III trials of EGFR-TKIs versus platinum-based
chemotherapy (10–15). The improvement in objective response rate (ORR)
and progression free survival (PFS) is consistent across all age groups, genders,
smoking status and performance status. However, none of the above studies
demonstrated an overall survival benefit for a EGFR-TKI over platinum-based
chemotherapy, likely due to the high level of crossover (16).
The use of EGFR-TKI as first-line therapy has been associated with
a greater benefit than as second-line treatment after chemotherapy for PFS
(12.9 months vs 9.0 months (HR 0.78, 95%CI 0.61 to 0.98. p=0.034)), ORR
(67.8% and 55.6%, respectively, p=0.001). Overall survival in patients receiving
first-line TKI followed by second-line chemotherapy was longer than in patients
receiving TKI second-line after chemotherapy (30.7 months vs 27.2 months
(HR 0.69, 95%CI 0.50 to 0.94, p=0.02) (17).
Evidence supports the continuation of EGFR-TKI treatment beyond
radiological progression in patients who are clinically stable (18). EGFR-TKI
use in combination with local radiation therapy in patients with oligoprogressive
disease, has also been shown to be associated with significantly longer PFS (19).
The IMPRESS trial tested the continuation of gefitinib plus chemotherapy
with placebo plus chemotherapy in patients with EGFR mutation-positive
advanced NSCLC with progression after first-line gefitinib (20). The trial failed to
show a benefit of the continuation strategy of the EGFR-TKI as add-on strategy;
the continuation of gefitinib plus cisplatin and pemetrexed was detrimental to
OS when compared with placebo plus cisplatin and pemetrexed (hazard ratio
[HR] 1.44, 95%CI 1.07 to 1.94; p=0.016; median OS, 13.4 v 19.5 months).
Therefore, continuous use of EGFR-TKI in combination with chemotherapy is
not recommended.
The NEJ009 trial evaluated the efficacy of a combination of gefitinib
and carboplatin/pemetrexed in untreated advanced NSCLC patients with EGFR
mutations (21). Carboplatin/pemetrexed/gefitinib demonstrated better PFS
(mPFS: 20.9 vs 11.2 months, HR 0.49, 95%CI 0.39 to 0.62) and OS (mOS: 52.2 vs
38.8 months, HR 0.69, 95%CI 0.52 to 0.92) compared with gefitinib monotherapy
in advanced EGFR mutated NSCLC, representing a first-line therapy option.
The choice between first- (gefitinib or erlotinib, (reversible)) and
second-generation (afatinib, (irreversible)) EGFR-TKIs was investigated in
two randomized studies. The Phase IIB LUX-Lung 7 trial compared afatinib
with gefitinib (22). The study reported similar tumour ORR and a modest non-
clinically meaningful difference in PFS (mPFS 11.0 vs 10.9 months; HR 0.73,
95%CI 0.57 to 0.95, p=0.0165). OS was not statistically different (23). There was
no difference in OS in patients with EGFR exon 19 mutation, contrary to earlier
claims of benefit in this sub-group from the pooled analysis of LUX-Lung 3 and
LUX-Lung 6 studies (24).
295
ARCHER 1050 is a randomized Phase III study that compared

dacomitinib (a second-generation EGFR-TKI) with gefitinib in stage IV EGFR-
mutated lung cancer patients without central nervous system (CNS) metastasis
(25, 26). The study showed an improved PFS in the dacomitinib arm (mPFS
14.7 vs 9.2 months; HR 0.59, 95%CI 0.47 to 0.74, p<0.0001). The mOS was
34.1 months with dacomitinib vs 26.8 months with gefitinib (HR 0.76, 95%CI
0.58 to 0.993, p<0.04). The OS probabilities at 30 months were 56.2% and 46.3%
with dacomitinib and gefitinib, respectively.

The toxicity profile of EGFR-TKIs is generally clinically manageable, with 6%
of toxicity-related treatment discontinuation reported in one pooled analysis
(27, 28).
The use of EGFR-TKI was favoured over chemotherapy in quality of life
(QoL) analyses, reporting a longer time to clinical deterioration and maintained
overall QoL (29–31).
For afatinib, an extensive investigation of patient-reported symptoms and
health-related QoL benefits have been reported, showing that afatinib delayed
the time to deterioration for cough (HR 0.60, 95%CI 0.41 to 0.87; p=0.007)
and dyspnoea (HR 0.68, 95%CI 0.50 to 0.93; p=0.015), with more patients
on afatinib (64%) versus chemotherapy (50%) experiencing improvements in
dyspnoea scores (p=0.010), the cardinal symptom for lung cancer patients (32).
For erlotinib, a secondary analysis from the OPTIMAL (CTONG-0802) Phase
III clinical trial, showed that patients receiving erlotinib experienced clinically
relevant improvements in QoL compared with the chemotherapy group, across
different scales to assess general outcome and lung-specific subscales (33). Data
for gefitinib are still consistent with the findings for the other two EGFR-TKIs:
time to deterioration in physical and life well-being favoured gefitinib over
chemotherapy (HR of time to deterioration, 0.34, 95%CI 0.23 to 0.50; p<0.0001
and HR 0.43, 95%CI 0.28 to 0.65; p<0.0001, respectively) (29).

N/A
WHO Guidelines
N/A
A cost-effectiveness analysis performed by the Institute for Clinical and Economic
Review showed that the use of each of the first-line EGFR-TKI regimens resulted
in a 0.84 life-year gain in survival relative to chemotherapy. Quality-adjusted
life-years (QALYs) gained versus chemotherapy were also very similar, ranging
296
from 0.60 for gefitinib to 0.62 for afatinib and erlotinib. Incremental costs
versus chemotherapy were lower for gefitinib (approximately US$ 66 000) than
for the other EGFR-TKIs, as a function of a shorter duration of time spent in
the progression-free state (and a consequently shorter duration of treatment).
Cost-effectiveness estimates were similar across the EGFR-TKIs, ranging from
approximately US$ 110 000 to US$ 150 000 per QALY gained (34).
In another cost-effectiveness analysis, two different strategies were
compared: the ‘EGFR testing strategy’, in which EGFR mutation testing was
performed before treatment and patients with EGFR mutations received gefitinib
while those without mutations received standard chemotherapy, to the ‘no-
testing strategy,’ in which genetic testing was not conducted and all patients
were treated with standard chemotherapy. The authors concluded that the
combination use of gefitinib and EGFR testing can be considered a cost-effective
first-line therapy compared to chemotherapy such as carboplatin-paclitaxel for
the treatment for NSCLC in Japan (35).
Technology appraisal guidance issued by National Institute for Health
and Care Excellence (NICE) for first-line EGFR-TKIs gefitinib, erlotinib and
afatinib state that these medicines are recommended treatment options people
with locally advanced or metastatic EGFR mutation-positive NSCLC if the
manufacturers provide the drugs at agreed fixed or discounted prices (36–38).
Availability
Originator brands of afatinib, erlotinib and gefitinib are manufactured by
Boehringer Ingelheim, Roche and AstraZeneca, respectively. Generic brands are
becoming available.
Based on the results of the LUX-Lung 3 study (14, 32), afatinib received a score
of 4 on the ESMO-Magnitude of Clinical Benefit Scale (MCBS, v1.1) for first-line
use in metastatic EGFR+ NSCLC (39).
Based on the results of the OPTIMAL (40) and EURTAC (13) studies,
erlotinib received a score of 4 on the ESMO-MCBS v1.1 for use in metastatic
EGFR+ NSCLC (39).
Based on the results of the IPASS study (10, 41), gefitinib received a score
of 4 on the ESMO-MCBS v1.1 for first-line use in metastatic EGFR+ NSCLC (39).
for inclusion on the EML, and applied this principle to the consideration of the
tyrosine kinase inhibitors afatinib, erlotinib and gefitinib.
297
The Committee noted that afatinib, erlotinib and gefitinib were all scored
as 4/5 on the ESMO-MCBS v1.1 for this indication.
The Expert Committee recommended the addition of erlotinib with a
square box to the complementary list of the EML for first-line treatment of EGFR
mutation-positive advanced non-small cell lung cancer. Afatinib and gefitinib
should be considered as therapeutically equivalent alternatives. The Committee
noted that these medicines are associated with relevant survival benefits for
patients, acceptable toxicity and improvements in quality of life compared to
chemotherapy.
The Committee also noted that since these medicines were considered
for inclusion on the EML in 2015, generic versions of these medicines are more
widely available, as are quality-assured diagnostic molecular tests for EGFR
mutations.
References
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of Lung Cancer: Latest Trends, Disparities, and Tumor Characteristics. J Thorac Oncol. 2016;
11(10):1653–71.
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small cell lung cancer: a National Cancer Database survey. J Thorac Oncol. 2010;5(1):29–33.
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adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J
Cancer Res. 2015;5(9):2892–911.
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Medicines for multiple myeloma – addition – EML
Bortezomib ATC Code: L01XX32

Lenalidomide ATC Code: L01AX04
Thalidomide ATC Code: L04AX02
Proposal
The application requested the addition of bortezomib, lenalidomide and
thalidomide to the EML for the treatment of newly diagnosed multiple myeloma
patients in non-transplant settings.
Applicant
Dr Vanessa Piechotta, Dr Marius Goldkuhle, Prof Christof Scheid, Dr Nicole
Skoetz

unit advised that it supported the inclusion of these medicines on the EML.
The technical united noted that use of these medicines is either as part of pre-
autologous stem cell transplantation treatment in fit patients, or as an alternative
treatment in transplant-ineligible patients, although the difference in transplant
eligible and ineligible patients was not addressed in the application.
EML/EMLc
EML
Section
8.2.2 Targeted therapies (bortezomib)

8.2.3 Immunomodulators (lenalidomide, thalidomide)

Bortezomib: lyophilized powder for injection 3.5 g
Lenalidomide: capsule 25 mg
Thalidomide: capsule 50 mg
Core/Complementary
Complementary

Individual listing for each medicine.
302

Treatments for multiple myeloma had not previously been considered by the
Expert Committee for addition to the EML.
[Abbreviations: M = melphalan, P = prednisone, C = cyclophosphamide,
D = dexamethasone, V = bortezomib, R = lenalidomide, T = thalidomide].

Multiple myeloma (MM) is the second most common haematological malignancy
and accounts for 2.1% of all cancer deaths in the United States (1, 2). In 2018,
159 985 new MM cases and 106 105 MM deaths were estimated worldwide (3).
Globally, myeloma caused 2.1 million disability-adjusted life-years (DALYs) in
2016 (4). Globally, the incidence rate increased by 126% between 1990 and 2016
and is strongly related to age (4, 5). The largest increase has been observed in
low- and middle-income countries (LMICs) (4). Based on the latest statistics in
the United States, the median age of myeloma diagnosis across all races and both
genders is 69 years (2).
In high-income countries (HIC), autologous stem cell transplantation
(ASCT) is routinely used for younger patients with a good general state of health.
However, ASCT is not available in many LMICs (3). Lack of access to general
and specialized health care leads to wide disparities in survival rates between
HICs and LMICs. In the United Kingdom, for example, 47% of diagnosed MM
patients are predicted to survive at least five years (32.5% at least 10 years) (5).
In comparison, a five-year survival rate of only 7.6% was recently reported in
Nigeria, as a result of constraints in access to ASCT, unavailability of medicines
for MM and delayed diagnosis with more advanced presentations and related
organ failures (6). Of patients diagnosed with MM in Nigeria, up to one-third
qualify for renal dialysis as a result of MM-related end-stage nephropathy (7).
In non-transplant settings (no transplant-accessibility or transplant-
ineligibility), the introduction of immunomodulatory drugs and proteasome
inhibitors has led to an improvement in the overall survival of patients.
A retrospective analysis of 631 patients, who received an initial therapy of
bortezomib, lenalidomide or thalidomide, reported a median OS of 7.3 years
(95%CI 5.9 to not reached). In comparison, a median OS of 3.8 years (95%CI 3.1
to 4.6) was reported for 425 patients, whose initial therapy did not include these
agents (8). The lack of availability ASCT services is more common in LMICs.
Some regions of the world lack access to stem cell transplantation entirely; for
example, in sub-Saharan Africa there is no facility to deliver ASCT care for MM
patients outside of South Africa (4). This raises the issue of a public health urgency
requiring diversified actions including ensuring access to effective medicines,
and building capacity for transplant services. The application focused on the
transplant-ineligible/inaccessible setting, more applicable in LMICs, proposing
303
the inclusion in the EML of bortezomib, lenalidomide and thalidomide to

address an unmet medical need.

The application presented the findings of a rapid Cochrane network meta-analysis
conducted to compare the efficacy and safety of bortezomib, lenalidomide and
thalidomide versus the former standard treatment of melphalan and prednisone
(still used in many LMICs) for transplant-ineligible MM patients. Twenty-six
randomized controlled trials (11 403 participants) were eligible for inclusion
in the NMA: (Myeloma XI (9), EMN01 (10), FIRST (11), ECOG E1A06 (12),
MM-015 (13), HOVON 87 (14), Myeloma IX (15), GBRAM0002 (16), Kim
2007 (17), Ludwig 2009 (18), TMSG (19), HOVON 49 (20), IFM 99-06 (21),
GISMM2001-A (22), MM03 (23), IFM 01/01 (24), NMSG #12 (25), Katsuoka
2013 (26), UPFRONT (27), VISTA (28), GEM2005 (29), Mookerje 2017 (30),
SWOG S0777 (31), E1A05 (32), GIMEMA-MM-03-05 (33), NCT01274403 (34)).
Included participants were randomized to 21 different treatment regimens
involving fixed or continuous therapy with combination regimens involving
melphalan (M), prednisone (P), cyclophosphamide (C), dexamethasone (D),
bortezomib (V), lenalidomide (R) and thalidomide (T).
Overall survival was measured for all 21 treatment regimens and a total of
11 071 patients. The network was not fully connected and consisted of three sub-
networks comprising 30 pairwise comparisons. Compared to MP, four regimens
showed a significant, clinically meaningful improvement in overall survival:
Continuous VRDc (bortezomib, lenalidomide, dexamethasone) (HR 0.49,
95%CI 0.26 to 0.92), continuous VTMPc (bortezomib, thalidomide, melphalan,
prednisone) (HR 0.49, 95%CI 0.26 to 0.93), fixed RD (HR 0.63, 95%CI 0.40 to
0.99), and fixed TMP (thalidomide, melphalan, prednisone) (HR 0.75, 95%CI
0.58 to 0.97). The estimated differences in median OS compared to MP were 37.4
months for VRDc and VTMPc, 21.1 months for RD and 12.0 months for TMP.
The confidence in estimates for overall survival could be rated for RD, TMP, VMP,
and VRDc. The use of RD, TMP, and VRDc for first-line treatment of multiple
myeloma patients likely results in a large increase in overall survival (moderate
confidence in estimates). The use of VMP as initial myeloma therapy may result
in a large increase in overall survival (low confidence in estimates).
The clinical benefit of the treatments was assessed in the application
according to the ESMO-MCBS v1.1 (35). The application graded the magnitude
of clinical benefit as 4 (survival benefit compared to comparator >nine months
(36)) for VRDc, VTMPc, RD, RDc, VMP, RCPc and TMP. The Committee noted
that to date, the ESMO-MCBS v1.1 has been validated only for solid tumours
and that a version validated for haematological malignancies is in development.
(Unpublished data of ESMO-MCBS ratings for the proposed medicines were
shared with the Expert Committee).
304
Progression-free survival (PFS) was measured for all 21 treatment

regimens and a total of 10 389 patients. The network was not fully connected
and consisted of four sub-networks comprising 29 pairwise comparisons. In
general, continuous treatment regimens were superior to fixed MP, and 7 out of
11 compared bortezomib, lenalidomide or thalidomide combinations showed a
significant improvement of PFS compared to MP. The confidence in estimates
for PFS could be rated for RD, TMP, and VRDc, but could not be rated for VMP,
because VMP was not connected to MP in the network. The use of RD, TMP, and
VRDc for first-line treatment of MM patients likely results in a large increase in
PFS (moderate confidence in estimates).

Adverse events of Grade 3 and 4 were reported in nine studies for 13 treatment
regimens in 3318 patients, however the studies were not comparable in NMA.
Serious adverse events (SAEs) were reported in eight studies for 14
treatment regimens in 7306 patients. The relative risk (RR) for at least one SAE
was similar across treatment regimens. The confidence in estimates could only
be rated for VMP. There was moderate confidence in the estimates that VMP
likely increases occurrence of SAEs (RR 1.28, 95%CI 1.06 to 1.54).
Infections were reported in 15 studies for 17 treatment regimens in 7470
patients. The RR for infections tended to be slightly higher for patients receiving
lenalidomide-based therapies compared to patients receiving thalidomide-
based therapies. The RR for infections was also significantly higher in patients
receiving continuous therapies compared to fixed MP.
Polyneuropathies were reported in 18 studies for 19 treatment regimens
in 8978 patients. The RR for polyneuropathies was the highest in patients
receiving bortezomib-based therapies compared to MP (RR 88.22, (95%CI 5.36
to 1451.11) to 441.08 (95%CI 7.74 to 25 145.52)). The RR for polyneuropathy
appeared to be smaller for patients receiving lenalidomide-based therapies,
compared to patients receiving thalidomide-based therapies.
Thromboembolism was analysed from 13 studies for 13 treatment
regimens in 4 277 patients. The RR for thromboembolism was higher for patients
receiving continuous therapy compared to fixed duration MP (RR 3.91, (95%CI
0.41 to 37.12) to 13.09 (95%CI 1.03 to 167.25)). Patients receiving a thalidomide-
based therapy had a greater risk for thromboembolism compared to patients
receiving bortezomib- or lenalidomide-based therapies, or MP.
Withdrawals due to adverse events were reported in 16 studies for
19 treatment regimens in 7 052 patients. The RR to discontinue assigned
therapy was greater for patients receiving double or triple drug combinations
compared to MP alone (RR 1.06, (95%CI 0.63 to 1.81) to 8.92 (95%CI 3.82 to
20.84)). Study withdrawal was similar across bortezomib-, lenalidomide-, and
305
thalidomide-based regimens. There was no difference between double versus

triple drug combinations, or between fixed duration versus continuous therapy.
The confidence in estimates for withdrawals due to AEs was rated for RD, TMP,
VMP, and VRDc. Compared to MP, use of RD, TMP, and VRDc results in a large
increase in withdrawals due to AEs (high confidence in estimates). Use of VMP
probably results in little or no difference in withdrawals due to AEs (moderate
confidence in estimates).

The Committee also considered additional evidence, not presented in the
application, for the treatment of MM in the ASCT-eligible/accessible settings.
The standard treatment for ASCT-eligible MM patients involves
induction therapy followed by high-dose melphalan and ASCT with lenalidomide
maintenance.
A meta-analysis of four studies (1572 patients) compared bortezomib-
based induction therapy prior to ASCT with non-bortezomib-based induction
therapy. The studies compared bortezomib-dexamethasone with vincristine-
doxorubicin-dexamethasone (IFM 2005-01 trial); bortezomib-doxorubicin-
dexamethasone with vincristine-doxorubicin-dexamethasone (HOVON-65);
and bortezomib-thalidomide-dexamethasone with thalidomide-dexamethasone
(PETHEMA GEM05MENOS65 and GIMEMA MM-BO2005). The bortezomib-
based therapies were associated with longer PFS (+7.3 months; HR 0.75), longer
OS (+5% at 3 years, HR 0.80) and greater activity (complete response rates:
+14%, OR 2.05), compared to non-bortezomib-based therapies. Peripheral
neuropathy was reported more frequently in bortezomib treated patients
compared to non-bortezomib treated patients: 19% vs 7% (all Grade), and 3.3%
vs 2% (≥ Grade 3) (37).
A randomized controlled trial involving 525 patients with newly-
diagnosed MM evaluated the efficacy and safety of the addition of bortezomib

to lenalidomide and dexamethasone (SWOG S0777). Findings were consistent
with the thalidomide-containing regimens: the addition or bortezomib to
lenalidomide-dexamethasone was associated with gains in both PFS (+13
months, HR 0.71) and OS (+11 months, HR 0.71). Adverse events of Grade 3
or higher, and treatment discontinuations were also more common in the
bortezomib-treated group (38).
The Committee also considered the role of lenalidomide after ASCT,
as maintenance up to relapse and maximal tolerance. A meta-analysis of
three RCTs (CALGB/Alliance 100104 study, IFM 2005-02 Trial and the Italian
GIMEMA RV-MM-PI-209) involving 1208 patients evaluated the effect of
lenalidomide maintenance after ASCT in newly diagnosed MM. Lenalidomide
maintenance demonstrated a significant gain in both PFS and OS: PFS in
306
patients receiving lenalidomide was 29.3 months longer (HR 0.48, 95%CI 0.41
to 0.55). The 7-year survival rate was 62% with lenalidomide maintenance and
50% with placebo or observation (HR 0.75, 95%CI 0.63 to 0.90). The use of
lenalidomide resulted in more major adverse events than placebo. In particular,
an increased risk of secondary malignancies was observed, 6.1% vs 2.8%
with placebo/ no maintenance (39). The long-term follow-up data of CALGB
(Alliance) 100104 study showed a meaningful and significant OS gain in patients
receiving lenalidomide maintenance. After three interim analyses, the study
was unblinded at a median follow-up of 18 months, at which point 86 (67%)
of 128 patients without progressive disease in the placebo group chose to cross
over to the lenalidomide group. The analysis of survival on the intention-to-treat
population demonstrated an increase in 3-year OS of 8%, with 88% (95%CI 84 to
93) among patients in the lenalidomide group and 80% (95%CI 74 to 86) among
patients in the placebo group (HR 0.62, 95%CI 0.40 to 0.95) (40).
The Myeloma XI study more recently provided results consistent with
the previous clinical trials of lenalidomide maintenance, confirming a gain in
median PFS (39 months vs 20 months; HR 0.46, 95%CI 0.41 to 0.53; p<0,0001)
but not in OS (78.6% vs 75.8%; p=0,15). The analysis was published at 31 months
of median follow up (41). Notably, mature data for OS in ASCT-eligible settings
require long-term follow up. For this reason, PFS and myeloma response rates
have been agreed as valuable surrogate endpoints for OS and PFS is used as
primary endpoint to assess the benefit of anti-myeloma medicines (42).
WHO Guidelines
None available.
The application summarized the findings of a scoping review undertaken for
economic evidence that addressed treatment regimens based on bortezomib,
thalidomide or lenalidomide as first-line therapy in MM. The scoping review
identified two cost-analyses (43, 44), one cost-impact analysis (45) and one
retrospective study of claims data (46). Also identified was a health technology
assessment report by the National Institute for Health and Care Excellence
(NICE) (47).
Reported incremental cost-effective ratios in the NICE technology
appraisal ranged from £ 2234 per quality adjusted life year (QALY) to over
£ 300 000, compared to MP depending on the intervention (47).
A United States cost-analysis found the monthly on-treatment costs
(drug cost, medical costs and AE management costs) were lowest for MP alone
and highest for MPT. The total cost over 20 years for treatment with VMP and
MPT were almost or over twice as high than with MP alone. Compared to VMP,
307
MP was more effective with regard to costs per life-year and cost per QALY,
while compared to MPT, VMP was cost-saving (44).
A cost-impact model addressed the total costs associated with first-line
treatment of newly diagnosed MM who were ineligible for stem cell transplant in
France, Germany, Italy, Spain and the United Kingdom, modelled over five years.
Three scenarios were evaluated and compared. A baseline-scenario represented
the 2017 uptake of lenalidomide in the assessed countries. The market shares
in this scenario were 64% for bortezomib, 25% for thalidomide and 11% for
lenalidomide. The second scenario involved a steady increase of the uptake of
lenalidomide to 50% of the market in year five. The third scenario evaluated
a 20% increased uptake of the triple regimen carfilzomib, lenalidomide, and
dexamethasone as a second-line of treatment. Direct drug costs were averaged
from the listing prices across the five countries. The assumed annual treatment
costs for the baseline scenario ranged between € 40 692 and € 40 781 per patient
per year, while the total costs for an increased uptake of lenalidomide ranged
between € 41 559 and € 44 139 per patient per year. The difference between both
situations rose relatively steady from 2.13% of the total cost of the baseline
scenario in year one to 8.23% of the baseline scenario in year five. Across all
three scenarios the total treatment cost in the fifth year of treatment were lowest
for the baseline scenario. For the increased uptake of lenalidomide in first-line
therapy, the annual costs per patient in year five were € 44 139. For the 20%
uptake of the triplet regimen as second-line treatment, the total increase in year
five in total cost per patient and year was € 52 528 (45).
A retrospective study based on United States claims data from 2006 to
2013 assessed patient monthly direct costs and cost patterns over quarterly time
periods for patients with newly diagnosed MM treated with either bortezomib or
lenalidomide based regimens. Costs were evaluated for 444 patients with newly
diagnosed MM treated first-line with lenalidomide and 737 with bortezomib,
for which data from treatment initiation until next treatment was available. For
patients with first-line treatment with lenalidomide, the monthly treatment cost
decreased steadily from US$ 15 090 in the first to the third month since start
of treatment to US$ 5266 in month 19 or longer. In patients treated with first-
line bortezomib the monthly costs fell from US$ 16 126 in the first three months
of treatment to US$ 4833 in the 19th month or longer. Multivariable regression
unadjusted for factors such as age, sex, number of prescriptions before index
date for the beginning of first-line treatment, previous cancer history, etc.
showed mean total cost of US$ 7534 (standard deviation (SD) 3207) for patients
treated first-line with lenalidomide, compared to US$ 10 763 (SD 3938) in
patients receiving first-line bortezomib. Monthly pharmacy costs included in
the total monthly cost in the unadjusted analysis were US$ 4101 (SD 1931) and
US$ 4855 (SD 2431) for lenalidomide and bortezomib, respectively (46).
308
Availability
Bortezomib, lenalidomide and thalidomide have worldwide regulatory approval
for use in the treatment of MM. Originator and generic brands of all three
medicines are available.
N/A
The Committee acknowledged the treatment of MM to be complex and
recognized the need to provide the best available care within the context of
both non-transplant and transplant settings.
The Committee recommended the addition of bortezomib, lenalidomide
and thalidomide to the complementary list of the EML for the treatment of
multiple myeloma patients in both non-transplant and transplant eligible/
available settings, on the basis of good evidence showing large improvement
in survival outcomes with acceptable safety for patients with newly diagnosed
multiple myeloma.
With regard to MM treatment in transplant-eligible populations, the
Committee noted the additional evidence presented as part of the review
process supporting standard regimens used in the induction phase before
ASCT involving three-drug combinations: VTD (bortezomib, thalidomide,
dexamethasone), VCD (bortezomib, cyclophosphamide, dexamethasone),
PAD (bortezomib, doxorubicin, dexamethasone) and RVD (lenalidomide,
bortezomib, dexamethasone); and of the benefit of lenalidomide maintenance
therapy following ASCT.
In the non-transplant setting, the Committee acknowledged that the
proposed medicines are administered as part of treatment regimens involving
companion cytotoxic agents and/or steroids (melphalan, cyclophosphamide,
prednisone, dexamethasone). Accordingly, the Committee recommended the
addition of melphalan to the complementary list of the EML for treatment
of multiple myeloma, and that the current listings for cyclophosphamide,
doxorubicin, prednisone and dexamethasone be extended to include multiple
myeloma as an indication.
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Anti PD-1/PD-L1 Immune checkpoint inhibitors – addition – EML and EMLc
Atezolizumab ATC Code: L01XC32

Nivolumab ATC Code: L01XC17
Pembrolizumab ATC Code: L01XC18
Proposal
The application requested the addition of atezolizumab, nivolumab and
pembrolizumab to the complementary list of the EML for the following
indications:
Melanoma Non-small cell lung cancer

Atezolizumab N/A As second-line therapy in locally advanced
or metastatic non-small cell lung carcinoma
(NSCLC) after chemotherapy.
Nivolumab Early and As second-line therapy after chemotherapy
advanced stage failure in locally advanced or metastatic
NSCLC, regardless of PD-L1 status
Pembrolizumab Early and As first-line therapy in NSCLC expressing
advanced stage PD-L1≥50%, in second-line after
chemotherapy failure for NSCLC PD-L1≥1%
Applicant
Jean-Yves Douillard, Chief Medical Officer, European Society for Medical
Oncology (ESMO)


unit advised that it not support inclusion of these medicines on the EML at this
time, though noting with great interest the emerging data on long-term outcomes
in this clinically relevant class of medicines.
EML/EMLc
EML
Section
314

Atezolizumab: concentrate solution for infusion 1.2 g/20 mL
Nivolumab: concentrate solution for infusion 10 mg/mL
Pembrolizumab: powder for injection 50 mg
Core/Complementary
Complementary

Individual listings requested

Atezolizumab, nivolumab and pembrolizumab belong to the class of PD-1/ PD-
L1 immune-checkpoint inhibitors (ICI) and had not previously been considered
for inclusion on the EML.
The EML currently includes cytotoxic chemotherapies for NSCLC, but
there are no alternative medicines currently on the EML for the treatment of
metastatic melanoma.

Lung cancer is the most diagnosed and the leading cause of death for cancer
worldwide, with an estimated 2 million new cases and 1.7 million deaths in 2018
(1). Lung cancer is a highly lethal malignancy, with an economic impact estimated
around US$ 8 billion productivity lost in the BRICS countries (2). Moreover, in
the absence of a wide coverage of an effective screening programme in place on
global scale, lung cancer diagnoses occur in advanced stage in more than 60%
of cases, with highly regional variability (3–5). Over 80% of lung cancers are
classified as non-small cell lung cancer (NSCLC). Although targeted therapies
have redefined the therapeutic landscape for some patients, these therapies are
ineffective in patients whose tumours lack the particular genetic mutations/
alterations, constituting the majority of NSCLC patients. For this reason, ICI
therapy is becoming part of the treatment of such patients, in an attempt to
improve survival and quality of life. The ICIs targets are the immune-competent
cells, such as T-lymphocytes and antigen-presenting cells, releasing a tumour-
induced immunosuppressant milieu (e.g. PD-1, PD-L1) or strengthening the
immune-activating signals of the immune response (e.g. GITR, pro- inflammatory
interleukins, interferon-gamma) (6). The availability of ICIs in NSCLC addresses
an unmet need for patients considered to have a poor prognosis in advanced
stages, in the absence of an indication of targeted therapy.
Melanoma is the most lethal form of skin cancer. In 2018, nearly 300 000
new cases were diagnosed worldwide, with over 60 000 deaths (1). As a cancer
315
related to the exposure to sunlight, melanoma demonstrates greater variation

in incidence rates across different ethnic groups and is more commonly found
among fair-skinned Caucasian populations. Incidence of melanoma peaks at the
7th decade of life; however, though half of the diagnoses are in patients aged
between 55 and 74 years, melanoma is the most common cancer diagnosed in
adolescents and young adults 20–29 years and the most commonly diagnosed
cancers in young adults worldwide (7). Early detection and resection of melanoma
is the most effective treatment strategy, with a traditionally poor prognosis for
metastatic disease (8).

NSCLC (first-line)
Pembrolizumab
The Phase III KEYNOTE-024 study evaluated pembrolizumab as first-line
treatment in patients with advanced NSCLC showing PD-L1 expression ≥50%, in
the absence of epidermal growth factor receptor (EGFR) mutation or anaplastic
lymphoma kinase (ALK) translocations (non-oncogene-driven NSCLC) (9).
Approximately 30% of screened patients had tumour PD-L1 expression ≥50%.
305 patients were randomized to receive 200 mg pembrolizumab every three
weeks (up to two years) or 4-6 cycles of standard platinum-doublet chemotherapy.
Patients in the chemotherapy group were permitted to cross over to the
pembrolizumab group if they experienced disease progression. In the intention-
to-treat population, progression-free survival (PFS) and overall survival (OS)
were significantly longer in the pembrolizumab group than the chemotherapy
group (PFS: hazard ratio (HR) 0.50, 95%CI 0.37 to 0.68; p<0.001; OS: HR 0.60,
95%CI 0.41 to 0.89; p=0.005). Health-related quality of life measures also
favoured pembrolizumab (10).
An updated survival report with a 25.2 months median follow up,
confirmed the superiority of pembrolizumab over chemotherapy: the HR for

OS was 0.63 (95%CI 0.47 to 0.86), with a median OS of 30.0 months (95%CI
18.3–not reached) in the pembrolizumab arm and 14.2 months (95%CI 9.8 to
19.0) in the chemotherapy arm; the Kaplan-Meier estimate of OS at 12 months
was 70.3% (95%CI 62.3% to 76.9%) for the pembrolizumab group and 54.8%
(95%CI 46.4% to 62.4%) for the chemotherapy group (11). Eighty-two patients,
allocated to the chemotherapy arm, crossed over to receive pembrolizumab upon
meeting eligibility criteria. In term of magnitude of benefit, pembrolizumab
provided a gain of median OS of +15.8 months and +15.5% at one year.
Based on the KEYNOTE-024 trial results, the clinical benefit of
pembrolizumab in the first-line setting measured with the European Society
for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1
received a score of 4 (12).
316
The first-line use of pembrolizumab was investigated in NSCLC

other than PD-L1>50%, to assess if the benefit was conserved in unselected
populations of patients. The Phase III KEYNOTE-042 trial randomized patients
with NSCLC EGFR/ALK wild type showing PD-L1≥1%, both adenocarcinoma
and squamous NSCLC, to receive either pembrolizumab 200 mg every three
weeks or standard chemotherapy (paclitaxel plus carboplatin or pemetrexed
plus carboplatin), stratifying per PD-L1 expression at three thresholds of
PD-L1: ≥50%, ≥20% and ≥1% (13). 1274 patients were randomized: 637 to
each arm. 599 patients (47.0%) had PD-L1 ≥50%, 818 (64.2%) had ≥20%.
Pembrolizumab improved OS in NSCLC patients with PD-L1≥50% (HR 0.69,
95%CI 0.56 to 0.85), consistent with the results of Keynote-024 for the PD-L1
enriched population. The median OS (up to approximately 38 months) with the
PD-L1 inhibitor was 20.0 months vs 12.2 months with chemotherapy. The HR
for OS was 0.77 (95%CI 0.64 to 0.92) and 0.81 (95%CI 0.71 to 0.93) for PD‑L1
≥20% and ≥1%, respectively. In patients with limited expression of PD-L1
(1–49%) the stratified analysis of survival showed that OS reached 17.7 vs 13.0
months in PD-L1 ≥20% and 16.7 and 12.1 in PD-L1 ≥1%, respectively in these
sub-populations. However, an exploratory analysis of KEYNOTE-042 showed
that the survival advantage associated with pembrolizumab vs chemotherapy in
patients with a tumour proportion score between 1% to 49% was not relevant
(median OS: 13.4 vs 12.1 months; HR 0.92, 95%CI 0.77 to 1.11). The overall
benefit might be driven by the enriched population with high expression of
PD‑L1 as the preponderance of the OS benefit was seen in patients with ≥50%,
the only sub-group gaining more than six months overall survival.
NSCLC (second-line)
Pembrolizumab
The KEYNOTE-010 trial randomized 1034 patients with previously-treated
squamous (22% of the population) and non-squamous (70%) NSCLC with PD-
L1 expression of at least 1% of tumour cells to receive pembrolizumab (2 mg/kg
or 10 mg/kg, every three weeks) or docetaxel 75 mg/m2 every three weeks (14).
Approximately two thirds of NSCLC patients screened met the PD-L1 threshold
of 1%, and 28% showed high expression (≥50%), consistent with previous
findings in Keynote-024. Patients were stratified in PD-L1 1–49% and PD-L1
≥50%. OS was longer for pembrolizumab versus docetaxel (2 mg/kg, HR 0.71,
95%CI 0.58 to 0.88; 10 mg/kg, HR 0.61, 95%CI 0.49 to 0.75). Median overall
survival was 10.4 months (95%CI 9.4 to 11.9) for the pembrolizumab 2 mg/kg
group, 12.7 months (10.0 to 17.3) for the pembrolizumab 10 mg/kg group, and
8.5 months (95%CI 7.5 to 9.8) for the docetaxel group. One-year overall survival
was 43.2% vs 52.3% vs 34.6%.
317
Based on the KEYNOTE-010 trial results, the clinical benefit of

pembrolizumab in the second-line setting measured with the ESMO-MCBS v1.1
was scored at 5/5 (12).
In patients with a PD-L1 tumour proportion score of ≥50%, the greatest
benefit was observed for OS for pembrolizumab 2 mg/kg vs docetaxel with
HR 0.54 (95%CI 0.38 to 0.77; p=0.0002), and for pembrolizumab 10 mg/kg vs
docetaxel HR 0.50 (95%CI 0.36 to 0.70; p<0.0001). Median OS was 14.9 months
and 17.3 months for the 2 mg/kg and 10 mg/kg arms respectively, longer than
the chemotherapy arm (8.2 months). After the primary analysis, crossover from
docetaxel to pembrolizumab was allowed. 36 months overall survival rate was
23% for the pembrolizumab groups (pooling the two dose arms) vs 11% for
docetaxel (15).
Nivolumab
The role of nivolumab as second-line treatment of NSCLC has been
investigated two Phase III clinical trials: CheckMate-017 and CheckMate-057.
In CheckMate-017, 272 patients with squamous NSCLC were randomized to
receive nivolumab 3 mg/kg every two weeks, or docetaxel, at a dose of 75 mg/m2
every three weeks (16). The median OS was 9.2 months (95%CI 7.3 to 13.3) in
the nivolumab group vs 6.0 months (95%CI 5.1 to 7.3) in the docetaxel group.
The OS rate at one year was 42% (95%CI 34 to 50) in the nivolumab group vs 24%
(95%CI 17 to 31) in the docetaxel group. OS was improved in those who received
nivolumab (HR 0.59, 95%CI 0.44 to 0.79, p<0.001). The rate of confirmed
objective response was higher with nivolumab than with docetaxel (20%, 95%CI
14 to 28 vs 9%, 95%CI 5 to 15), p=0.008). The median PFS was 3.5 months (95%CI
2.1 to 4.9) in the nivolumab group and 2.8 months (95%CI 2.1 to 3.5) in the
docetaxel group, consistent with the mechanism of action of ICIs, where atypical
patterns of response are described (pseudo progression) and long-lasting post-
progression benefit persisting (17). The level of PD-L1 expression was neither
prognostic nor predictive of any of the efficacy endpoints.
Based on the CheckMate-017 trial results, the clinical benefit of
nivolumab in the second-line setting in squamous cell NSCLC measured with
the ESMO-MCBS v1.1 was scored at 5/5 (12).
In CheckMate-057, 582 patients with non-squamous NSCLC (e.g.
adenocarcinoma) were randomized to nivolumab or docetaxel (18). Nivolumab
improved OS compared to docetaxel: at the time of interim analysis, median
OS was 12.2 months (95%CI 9.7 to 15.0) for nivolumab and 9.4 months (95%CI
8.1 to 10.7) for docetaxel, with a HR of 0.73 (95%CI 0.59 to 0.89; p=0.002).
One-year OS rates were 51% (95%CI 45 to 56) and 39% (95%CI 33 to 45)
for nivolumab and docetaxel, respectively. The survival HRs per sub-group
318
analysis did not favour nivolumab over docetaxel in the EGFR-mutated NSCLC
population (oncogene-driven disease, HR 1.18) (19). Moreover, the EGFR wild-
type populations seemed to derive the greatest benefit, with HR 0.66 (95%CI
0.51 to 0.86).
Based on the CheckMate-057 trial results, the clinical benefit of
nivolumab in the second-line setting in non-squamous cell NSCLC measured
with the ESMO-MCBS v1.1 was scored at 5/5 (12).
In an updated analysis of CheckMate-017 and CheckMate-057, pooled
two-year OS favoured nivolumab in both squamous and non-squamous
NSCLC (squamous: 29%, 95%CI 24% to 34% vs 16%, 95%CI 12% to 20%;
non‑squamous: 23%, 95%CI 16% to 30% vs 8%, 95%CI 4% to 13%) (20). In
the pooled analysis of OS in the intention-to-treat population (n = 854) with
squamous (n = 272 (31.9%)) and non-squamous (n = 582 (68.1%)) NSCLC,
median OS was 11.1 months (95%CI 9.2 to 13.1 months) with nivolumab vs
8.1 months (95%CI 7.2 to 9.2 months) with docetaxel (HR 0.72, 95%CI 0.62
to 0.84). Higher PD-L1 expression levels were associated with greater OS
benefit with nivolumab (HR 0.42, 95%CI 0.28 to 0.63) in patients with ≥50%
PD-L1 expression, but a benefit was still observed in patients with <1% PD-L1
expression (HR 0.78, 95%CI 0.61 to 0.99). Among nivolumab-treated patients,
37% of confirmed responders with squamous NSCLC and 34% with non-
squamous NSCLC had ongoing responses after two years’ minimum follow up
and no patient in docetaxel group had an ongoing response. Consistent with
the primary analyses, two-year OS benefit with nivolumab versus docetaxel was
observed in patients with squamous NSCLC regardless of PD-L1 expression
level. However, in patients with non-squamous NSCLC, higher levels of PD-L1
were associated with a greater magnitude of OS benefit with nivolumab. NSCLC
with PD-L1<1% still derived greater benefit from ICI than chemotherapy:
in patients with ≥50% PD-L1 expression, the HR for OS on the basis of two
years’ minimum follow-up was 0.38 (95%CI 0.24 to 0.60) for patients with non-
squamous NSCLC.
Atezolizumab
The Phase III OAK trial randomized 850 immuno-oncology naive patients
with advanced squamous and non-squamous NSCLC previously treated with
one or two lines of chemotherapy to receive atezolizumab 1200 mg fixed dose
every three weeks or standard docetaxel 75 mg/m² every three weeks (21).
Treatment was administered until unacceptable toxicity or disease progression.
Atezolizumab could be continued beyond disease progression if clinical benefit
was demonstrated despite evidence of radiological disease progression on
computerized tomography (CT) scan, to rule out atypical pattern of response (i.e.
pseudo progression). No crossover to atezolizumab was allowed. Patients were
stratified by PD-L1 expression. OS was improved in the ITT study population
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with atezolizumab, reaching a median OS of 13.8 months (95%CI 11.8 to 15.7)

vs docetaxel (9.6 months, 95%CI 8.6 to 11.2), with HR 0.73 (95%CI 0.62 to 0.87,
p=0.0003).
Based on the OAK trial results, the clinical benefit of atezolizumab in the
second-line setting measured with the ESMO-MCBS v1.1 was scored at 5/5 (12).
Sub-group analysis showed a greater magnitude of benefit in patients
with higher PD-L1 expression, both assessed on tumour cells (TC) or immune-
infiltrating cells (IC): the net benefit gain in TC1/2/3 or IC1/2/3 population was
+5.4 months (HR 0.74, 95%CI 0.58 to 0.93, p=0.0102) and +5.5 months in
TC2/3 or IC2/3 population (HR 0.67, 95%CI 0.49 to 0.90, p=0.0080).
Metastatic melanoma
Pembrolizumab
The role of pembrolizumab was investigated in randomized trials and
cohort studies for metastatic or unresectable locally-advanced melanoma as
monotherapy, both in BRAF-mutated and wild-type tumours.
The Phase I Keynote-001 trial evaluated pembrolizumab 2 mg/kg and
10 mg/kg every two weeks in patients with advanced melanoma (22). Around
one third of the population was pre-treated with ipilimumab. The overall response
rate during receipt of therapy, across all doses, based on assessment by the
investigator according to immune-related response criteria was 38%. An updated
analysis showed an estimated five-year OS rate of 34% in all patients enrolled
(pre-treated with chemotherapy, targeted agents or ipilimumab) and 41% in
treatment-naive patients (23). Median OS was 23.8 months (95%CI 20.2 to 30.4)
and 38.6 months (95%CI 27.2–not reached) in pre-treated and treatment-naive
patients, respectively with a five-year PFS rates of 21% and 29%.
The Phase II Keynote-002 trial assessed the efficacy and safety of
pembrolizumab 2 mg/kg or 10 mg/kg every three weeks vs investigator-choice
chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine,

or oral temozolomide) in patients with ipilimumab-refractory melanoma (1:1
randomization, n=540 patients) (24, 25). Median OS was 13.4 months for 2 mg/
kg, 14.7 months for 10 mg/kg, and 11.0 months for chemotherapy. 18-months
OS rates were 40%, 44%, and 36%; 24-months rates were 36%, 38%, and 30%.
HR for OS was 0.86 (95%CI 0.67 to 1.10) for 2 mg/kg and 0.74 (95%CI 0.57
to 0.96) for 10 mg/kg, with no difference between doses (0.87, 95%CI 0.67 to
1.12). The benefit was consistent across the sub-groups, of age (younger or older
than 65 years), plasma lactate dehydrogenase (LDH) normal or elevated, sex
and BRAF status (mutant or wild-type).
Based on the Keynote-002 trial results, the clinical benefit of
pembrolizumab for melanoma in the second-line setting measured with the
ESMO-MCBS v1.1 was scored at 3/5 (12).
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The Phase III Keynote 006 trial assessed pembrolizumab (10 mg/kg every
two weeks or every three weeks) as first-line therapy for advanced melanoma,
versus ipilimumab (3 mg/kg), the standard of care at the time of the investigation
(26, 27). Median OS was not reached in either pembrolizumab group and was
16.0 months with ipilimumab (HR 0.68, 95%CI 0.53 to 0.87 for pembrolizumab
every two weeks vs ipilimumab and 0.68, 95%CI 0.53 to 0.86 for pembrolizumab
every 3 weeks vs ipilimumab). 24-month OS rate was 55% in the two- and three-
week group, and 43% in the ipilimumab group, showing limited differences
between pembrolizumab dosing schedules.
Nivolumab
The CheckMate 037 trial assessed the efficacy and safety of nivolumab (3 mg/kg
every two weeks) in ipilimumab-progressing patients, compared with standard
chemotherapy (dacarbazine, paclitaxel combined with carboplatin every three
weeks) (28). Confirmed objective responses were reported in 31.7% (95%CI
23.5 to 40.8) in the nivolumab group versus 10.6% (95%CI 3.5 to 23.1) in the
chemotherapy arm. However overall survival did not differ between arms, being
15.74 (12.88 to 19.88) in the nivolumab group and 14.39 (11.66 to 18.17) in the
investigator’s choice group (HR 0.95, 95%CI 0.73 to 1.24) (29).
CheckMate 066 tested nivolumab first-line versus dacarbazine, showing
a gain in OS of 73% vs 42% at 1 year (30, 31). Response rates also favoured
nivolumab, 40% vs 14%. Three-year OS survival rates were 51.2% (95%CI
44.1% to 57.9%) and 21.6% (95%CI 16.1% to 27.6%), respectively. The median
OS was 37.5 months (95%CI 25.5 months to not reached) in the nivolumab
group and 11.2 months (95%CI 9.6 to 13.0 months) in the dacarbazine group
(HR 0.46, 95%CI 0.36 to 0.59), with a net benefit of OS of +26.3 months.
CheckMate 067 tested the combination treatment of the two ICIs
nivolumab and ipilimumab against nivolumab monotherapy and ipilimumab
alone in a 1:1:1 ratio (32, 33). Median PFS was 11.5 months (95%CI 8.9 to 16.7)
with nivolumab plus ipilimumab, compared with 2.9 months (95%CI 2.8 to 3.4)
with ipilimumab (HR 0.42; 99.5% CI, 0.31 to 0.57) and 6.9 months (95%CI 4.3
to 9.5) with nivolumab (HR for the comparison with ipilimumab, 0.57, 99.5%CI
0.43 to 0.76, p<0.001). A subgroup analysis according to PD-L1 expression was
performed. Patients with tumours positive for PD-L1, achieved a median PFS
of 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab
group, but in patients with PD-L1–negative tumours, PFS was longer with the
combination therapy than with nivolumab alone (11.2 months (95%CI 8.0 to
not reached) vs 5.3 months (95%CI 2.8 to 7.1)). The four-year follow-up updated
results confirmed the earlier findings: median OS was not reached (95%CI 38.2
to not reached) in the nivolumab plus ipilimumab group, 36.9 months (95%CI
28.3 to not reached) in the nivolumab group, and 19.9 months (95%CI 16.9 to
24.6) in the ipilimumab group. The results of sub-group analyses suggested that
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the greatest benefit with the combination of nivolumab and ipilimumab versus
nivolumab alone may occur in the context of negative PD-L1 tumour expression.
In the subgroup of patients with PD-L1–positive tumours, both nivolumab
alone and nivolumab plus ipilimumab resulted in a similar prolongation of PFS
compared to ipilimumab alone. This finding suggested the role of immunotherapy
as monotherapy in “inflamed tumours”, showing high expression of PD-L1
and a role of combination therapy for “non-inflamed” tumours, for which the
combination ICI could derive a major benefit, acting synergistically on different
steps of immune activation.
The clinical benefit of nivolumab for first-line treatment of metastatic
melanoma measured with the ESMO-MCBS v1.1 was scored at 4/5 (12).
Early stage (resected) melanoma
The discussion around the role of immunotherapy in the adjuvant setting of
melanoma is ongoing, with data of OS expected to confirm the optimal strategy
of care, particularly between the ipilimumab and the PD-1 blockers, including
the safety profile.
Pembrolizumab
Pembrolizumab was assessed as an adjuvant agent in the Phase III Keynote 054
trial, for patients with stage III resected melanoma. Patients were randomized
to receive pembrolizumab 200 mg every three weeks for 18 doses or placebo
(n=1019) (34). Pembrolizumab showed a superior relapse-free survival rate,
from 61% to 75.4% at 12 months (HR 0.57, 95%CI 0.43 to 0.74); the data were
consisted across the PD-L1 pre-specified sub-groups.
Nivolumab
The CheckMate-238 trial compared high-dose ipilimumab versus nivolumab
3 mg/kg every two weeks up to 12 months (35). Patients with resected stage
III and IV, with no evidence of disease (NED) derived major benefit from
nivolumab: relapse-free survival at 12 months was 70.5% and 60.8%, respectively

(HR 0.65, 95%CI 0.51 to 0.83). At 24-months follow-up, nivolumab was shown
to be superior with +13% of relapse-free survival (35, 36). The benefit was
consistent across the sub-groups of PD-L1 expression, in PD-L1 less than 5% or
5% and more.

NSCLC first-line
Pembrolizumab
In Keynote 024, treatment-related adverse events (TRAE) occurred in 73.4% of
the patients in the pembrolizumab group and in 90.0% of the patients in the
chemotherapy group, of which 53.3% vs 26.6% were Grade 3 (moderate-severe)
322
to Grade 5 (toxic death) in the chemotherapy and pembrolizumab groups,

respectively. The treatment discontinuation rate was slightly higher in the
chemotherapy arm (10.7%) than the ICI arm (7.1%) due to these TRAEs (9).
TRAEs for pembrolizumab were consistent with an immune-mediated process,
meaning an autoimmune event or an immune-activation syndrome, the most
common being hypo- and hyper-thyroidism (9% and 8%, all Grade 1 and 2,
non-severe events not leading to discontinuation of therapy and registered as
laboratory transient and not clinically relevant alterations of plasma thyroid
hormones), diarrhoea (in 14.3% of the patients), fatigue (10.4%), and pyrexia
(10.4%) in the pembrolizumab group; for chemotherapy, the bone marrow
toxicity (anaemia in 44.0%) and traditional systemic TRAEs were observed
(nausea in 43.3% and fatigue in 28.7%); anti-emetic pre-medication was
allowed per protocol, consistent with institutional and international guidelines
for moderately to highly-emetogenic platinum-containing CT regimens in the
standard of care arm.
In Keynote 042, despite a longer duration of treatment exposure,
Grades 3 to 5 TRAEs occurred much less often with pembrolizumab than with
chemotherapy (17.8% vs 41.0%) (13). Grades 3 to 5 immune-related adverse
events and infusion reactions occurred more frequently among patients treated
with pembrolizumab than with chemotherapy (8.0% vs 1.5%). The respective
rates of treatment discontinuation (9.0% vs 9.4%) and treatment-related deaths
(2.0% vs 2.3%) were comparable between treatment arms.
NSCLC second-line
Pembrolizumab
In the Keynote-010 trial the safety profile favoured pembrolizumab with less
Grade 3–5 adverse events, namely 16% vs 35% in the chemotherapy arm,
and decreased appetite (14%) and fatigue (14%) for ICI and neutropenia (14%),
alopecia (33%), anaemia (13%) and oral mucositis (14%) for chemotherapy (14).
There was no difference in the efficacy or safety of pembrolizumab at 2 or
10 mg/kg.
Nivolumab
In the CheckMate-017, treatment-related adverse events, including haematologic
and non-haematologic events, occurred less frequently with nivolumab than
with docetaxel. In the nivolumab group, 58% of the patients had events of any
Grade, of which 7% were Grade 3 or 4; in the docetaxel group, this occurred in
86% of the patients of which 55% were Grade 3 or 4 (16). The safety profile was
consistent with the class side-effects, with no new signals of safety, namely the
most frequently reported TRAEs with nivolumab were fatigue and asthenia and
for docetaxel were neutropenia (33%; 10% febrile neutropenia), fatigue (33%),
alopecia (22%), nausea (23%) and peripheral neuropathy (11%). Respectively
323
3% and 10% of patients discontinued the treatment for an adverse event in the
ICI and CT arm.
In the CheckMate-057, the safety profile and pattern of adverse events in
non-squamous NSCLC patients were consistent with the data from squamous
population: treatment-related adverse events were observed in 69%/10%/5% in
nivolumab arm and 88%/54%/15% in docetaxel arm for any Grade/Grade 3-4/
discontinuation rate, respectively (18).
Atezolizumab
In the Phase III OAK trial, tolerability was better with atezolizumab, with 15%
of 609 patients treated with atezolizumab experiencing a Grade 3–4 treatment-
related toxicity compared with 43% of 578 patients treated with docetaxel (21).
Fatigue (87 patients (14%)), nausea (53 patients (9%)), decreased appetite
(52 patients (9%)), and asthenia (51 patients (8%)) were the most common
atezolizumab-related adverse events of any grade.
Metastatic melanoma
Pembrolizumab
Safety analysis showed a higher incidence of Grade 3–4 TRAEs in patients
receiving chemotherapy (26%) vs pembrolizumab (11% in the 2mg/kg group,
14% in the 10 mg/kg group) (24). The most common serious TRAEs observed
in the combined pembrolizumab treatment groups were diarrhoea and
pneumonitis. There were no treatment-related deaths. Treatment interruption
as a result of TRAEs was needed in 15 (8%) of 178 patients treated with
pembrolizumab 2 mg/kg, 15 (8%) of 179 patients treated with pembrolizumab
10 mg/kg, and 30 (18%) of 171 patients treated with chemotherapy. TRAEs
led to permanent treatment discontinuation in five (3%) patients given
pembrolizumab 2 mg/kg, 12 (7%) given pembrolizumab 10 mg/kg, and 10 (6%)
patients given chemotherapy.
In the Keynote 006 trial, around two thirds of the study population
experienced a TRAE; however, Grade 3 to 5 adverse events that were attributed
to a study drug by investigators occurred in 13.3% of patients receiving
pembrolizumab every two weeks, 10.1%, every three weeks and 19.9% of patients
receiving ipilimumab, respectively, with a safety profile favourable of the PD-1
blocker over CTLA-4 inhibitor (26). The rate of permanent discontinuation of a
study drug because of TRAEs was lower in each pembrolizumab group than in
the ipilimumab group (4.0%, 6.9%, and 9.4%, respectively).
Nivolumab
In the CheckMate 066 trial, treatment-related Grade 3/4 adverse events
occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of
205) of dacarbazine-treated patients (30, 31).
324
In the CheckMate 238 trial, nivolumab showed a major tolerability and

better safety profile with 14.4%/9.7% Grade 3 and 4 adverse events/treatment-
related discontinuation, compared with 45.6%/42.6% in the ipilimumab arm
(32, 33).
Early stage (resected) melanoma
No data were presented in the application regarding the safety of immune
checkpoint inhibitors for melanoma in the early/resected stage setting.

N/A
WHO Guidelines
None available.
NSCLC
The application presented a cost-effectiveness analysis of first-line pembrolizumab
in advanced non-oncogene driven NSCLC expressing high levels of PD-L1
(37). Data of safety and efficacy were derived from the Keynote 024 trial (13).
The analysis was conducted from the perspective of a United States third-party
public health care payer (updated to US$, year 2016 values). Pembrolizumab
would be expected to result in an incremental cost of US$ 98 281 per quality
adjusted life year (QALY) gained or an incremental cost of US$ 78 873 per life
year (LY) gained. Including cost of PD-L1 testing had a very small impact on the
model results. With a five-year time horizon, the ICER was US$ 99 998/LY and
US$ 122 024/QALY; with a 10-year time horizon, the ICER was US$ 83 065 and
US$ 103 101/QALY. Base-case results indicated that, compared with standard of
care over a 20-year time horizon, pembrolizumab would be expected to result in
an additional 1.31 LYs and an additional 1.05 QALYs gained.
In the second-line setting, a cost-effectiveness analysis was presented
for pembrolizumab versus docetaxel in the enriched population with PD-
L1>50%. Base case results for PD-L1 positive (TPS ≥50%) patients treated with
pembrolizumab showed a mean survival of 2.25 years (38). For docetaxel, a mean
survival time of 1.07 years was estimated. Expected QALYs were 1.71 and 0.76
for pembrolizumab and docetaxel, respectively. The incremental cost per QALY
gained with pembrolizumab vs docetaxel is US$ 168 619/QALY, which is cost-
effective in the United States using a threshold of three times GDP per capita.
Melanoma
The cost‑effectiveness of nivolumab for the treatment of advanced melanoma
patients has been investigated in the United Kingdom. A Markov state-transition
325
model was developed to estimate the lifetime costs and benefits of nivolumab
versus ipilimumab and dacarbazine for BRAF mutation-negative patients
and versus ipilimumab, dabrafenib, and vemurafenib for BRAF mutation-
positive patients (39). Nivolumab was the most cost-effective treatment option
in BRAF mutation-negative and mutation-positive patients, with incremental
cost-effectiveness ratios of £ 24 483 and £ 17 362 per QALY, respectively. A
similar analysis was performed for pembrolizumab in advanced melanoma in
Portugal (40). A cost-effectiveness model was developed to analyse the costs and
consequences of treatment with pembrolizumab compared to treatment with
ipilimumab in patients with advanced melanoma not previously treated with
ipilimumab. Pembrolizumab increased life expectancy in 1.57 undiscounted
life-years (LYs) and was associated with an increase in costs versus that of
ipilimumab. The estimated incremental cost-effectiveness ratio was € 47 221 per
QALY and € 42 956 per LY. The authors concluded that considering the usually
accepted thresholds in oncology, pembrolizumab is a cost-effective alternative
for treating patients with advanced melanoma in Portugal.
Availability
Atezolizumab (trade name Tecentriq, Genetech Inc.) is available as a 60 mg/mL
injection solution for intravenous use as 840 mg/14 mL and 1,200 mg/20 mL
single-dose vials.
Nivolumab (trade name Opdivo, Bristol-Myers Squibb) is available as a
10 mg/mL injection solution for intravenous use as 40 mg/4 mL, 100 mg/10 mL
and 240 mg/24 mL single-dose vials.
Pembrolizumab (trade name Keytruda, Merck Sharp & Dohme) is
available as 50 mg lyophyilized powder for intravenous injection and as a 25 mg/
mL injection solution for intravenous use as 100 mg/4mL single-dose vial.
As a result of the Keynote-024 trial, pembrolizumab was approved by the United

States Food and Drug Administration (FDA) and European Medicines Agency
(EMA) as first-line therapy for patients with NSCLC with high PD-L1 expression
(PD-L1≥50%) as assessed by immunohistochemistry. In the approval trial, the
PD‑L1 expression was assessed in FFPE tumour samples at a central laboratory
with the use of the commercially available PD-L1 IHC 22C3 pharmDx assay
(Dako) on histology specimens. However, the assessment of PD-L1 IHC of
cytology cell-block was as reliable as the histology assessment, in independent
assessments (20–22). The PD-L1 IHC 22C3 pharmDx assay is the companion
diagnostic of pembrolizumab first-line with the threshold of “high expression”
PD-L1 tumour proportion score of ≥50%. This finding is clinically relevant since
the collection of a histology sample may be challenging in lung cancer diagnosis,
particularly when bronchoscopy with fine-needle aspirations is used. In detail,
326
cell block cytology is a technique used in cytopathology (in addition to smears)

for evaluation of tissue from fine needle aspirations or fluid aspiration for
which the cells in solution are then concentrated via centrifuge from cytological
specimens into paraffin blocks that can be cut and stained by the same methods
used for histopathology. Based on this evidence, the use of the cell-block is
considered as a reliable specimen to assess the PD-L1 status, reducing the
need of more invasive procedures and increasing the likelihood to have an
informative specimen in term of prediction to treatment response with few
cytology materials.
Pembrolizumab as monotherapy is indicated in the first-line treatment
of advanced EGFR and ALK wild type NSCLC showing PD-L1 hyperexpression
i.e. PD-L1≥50% and for the second-line treatment of advanced NSCLC with
a PD-L1 tumour expression ≥1% after platinum-containing chemotherapy
failure, and in association with chemotherapy for the first-line treatment of
NSCLC, regardless of PD-L1 status. Moreover, pembrolizumab is indicated for
the first-line treatment of metastatic melanoma, with no biomarker for patients’
selection. Patients are treated with pembrolizumab until disease progression or
unacceptable toxicity.
for inclusion on the EML, and applied this principle to the consideration of the
immune checkpoint inhibitors.
The Committee noted that there were no treatment options for metastatic
melanoma currently included on the Model List. The Committee recommended
the addition of nivolumab and pembrolizumab to the complementary list of the
EML, for use as first-line monotherapy for treatment of patients with unresectable
and metastatic melanoma on the basis of evidence of significantly increased
overall survival for patients that met the recommended threshold for benefit,
and in the absence of other EML-listed treatment options. Listing should be for
nivolumab with a square box indicating pembrolizumab as a therapeutically
equivalent alternative. The Committee noted that nivolumab was scored as 4/5
on the ESMO-MCBS v1.1 for this indication.
The Committee considered that more mature data would be necessary
before listing of these medicines could be considered for use in adjuvant
indications of radically resected melanoma.
The Committee did not recommend listing of atezolizumab, nivolumab
or pembrolizumab for treatment of patients with metastatic NSCLC at this
time, as the Committee considered that their precise place in the treatment/
immunotherapy of this condition is still evolving. The Committee noted the
327
evidence of efficacy in the treatment of patients with metastatic NSCLC with

these agents. The Committee observed that the duration of follow up of the single
studies for first-line and second-line immunotherapy in trials for lung cancer was
generally shorter than three years, and considered that data from longer follow
up would better capture the actual magnitude of benefit. By the time of the next
Committee meeting in 2021, more mature data will be available for metastatic
NSCLC and also for use of these agents in locally advanced non-resectable
disease, and as adjuvant therapy.
Furthermore, the Committee noted that the landscape of clinical
development of cancer immunotherapy still has some areas of uncertainty with
regard to the optimal time for introduction of treatment (first- or second-line),
appropriate patient selection, and whether or not use of ICIs in combination with
other medicines is superior.
The Committee expressed concern about the potential budget impact
of oncology medicines, which could be an impediment to access, and countries
may not be able to list these medicines on their national EMLs. Therefore, the
Committee recommended that WHO engage stakeholders to find ways to
facilitate better access and affordability as a high priority through avenues such as
the Medicines Patent Pool, WHO prequalification and collaborative registration
procedures. The Committee also recommended ongoing activities of the EML
Cancer Medicines Working Group to include identification of obstacles to access
and affordability of cancer medicines, and pricing data collection.
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24. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C et al. Pembrolizumab versus
investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a
randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.
25. Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D et al. Final overall survival
for KEYNOTE-002: pembrolizumab (pembro) versus investigator-choice chemotherapy (chemo)
for ipilimumab (ipi)-refractory melanoma. Ann Oncol. 2016;27(suppl_6):11070.
26. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L et al. Pembrolizumab versus
Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521–32.
27. Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L et al. Pembrolizumab versus
ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised,
open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853–62.
28. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B et al. Nivolumab versus chemotherapy
in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate
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29. A Study to Compare BMS-936558 to the Physician’s Choice of Either Dacarbazine or Carboplatin
and Paclitaxel in Advanced Melanoma Patients That Have Progressed Following Anti-
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National Library of Medicine; 2017. Available from https://clinicaltrials.gov/ct2/show/results/
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30. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L et al. Nivolumab in previously
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4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–92.

34. Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S et al. Adjuvant Pembrolizumab
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35. Weber JS, Mandalà M, Vecchio MD, Gogas H, Arance AM, Cowey CL et al. Adjuvant therapy with
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High Levels of PD-L1 in the United States. Pharmacoeconomics. 2017;35(8):831–44.
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for Advanced Melanoma Treatment in Portugal. Value Health. 2017;20(8):1065–73.
331
Medicines for prostate cancer – addition – EML
Abiraterone ATC Code: L02BX03

Enzalutamide ATC Code: L02BB04
Proposal
The application requested the addition of abiraterone and enzalutamide to the
EML for use in the treatment of metastatic castration-resistant prostate cancer.
Applicant
Knowledge Ecology International

unit advised that it did not support the inclusion of abiraterone or enzalutamide
on the EML for management of castration-resistant prostate cancer at this time,
though noting with interest ongoing studies and more mature data that may
demonstrate significant benefit, particularly for overall survival.
EML/EMLc
EML
Section

Abiraterone: tablet 250 mg, 500 mg
Enzalutamide: capsule 40 mg
Core/Complementary
Complementary

Individual

In 2017, the Committee considered an application requesting inclusion of
enzalutamide on the EML for the treatment of prostate cancer, but did not
recommend inclusion, instead recommending a comprehensive review of prostate
cancer medicines including abiraterone to be considered at its next meeting (1).
332

Prostate cancer is the second most common cancer in men and the fourth most
common cancer overall. In 2018, approximately 1.3 million men were diagnosed
with prostate cancer (2). When patients are diagnosed with prostate cancer, if
they are treated early and tumours are localized, the prognosis is often favourable.
However, some patients will relapse, which in nearly all cases, leads to castration-
resistant prostate cancer (CRPC). At the CRPC stage, the disease is no longer
responsive to androgen deprivation therapy (ADT), thus limiting the available
treatment options.
There are currently six treatments being used to treat CRPC. Enzalutamide
and abiraterone acetate have several advantages over the other treatments. Four
of the other treatments are invasive and require IV administration, leukapheresis,
or the use of radiopharmaceuticals. Enzalutamide and abiraterone acetate are
the only daily oral tablets.

Enzalutamide
The application described the findings of two randomized placebo-controlled
Phase III studies of enzalutamide for treatment of mCRPC.
The AFFIRM trial randomly assigned 1199 men with metastatic CRPC
(mCRPC) who had previously taken docetaxel to 160 mg enzalutamide or placebo
daily (3). Both groups received continuing androgen deprivation therapy. Overall
survival (OS) favoured enzalutamide (18.4 months vs 13.6 months; HR 0.63,
95%CI 0.53 to 0.75; p<0.001). Progression-free survival (PFS) also favoured
enzalutamide (8.3 months vs 2.9 months; HR 0.40, 95%CI 0.35 to 0.47, p<0.001).
54% of enzalutamide-treated patients experienced a 50% or greater decrease in
prostate specific antigen (PSA) levels compared to only 2% in the control arm
(p<0.001).
The PREVAIL trial investigated enzalutamide in a first-line setting in men
with mCRPC who were chemotherapy naive. 1717 patients were randomized to
receive 160 mg enzalutamide or placebo daily (4). The study was stopped after
a planned interim analysis showed benefit for enzalutamide. Significantly fewer
deaths were reported in the treatment arm compared to placebo (28% vs 35%;
HR 0.71, 95%CI 0.60 to 0.84l p<0.001).
Abiraterone acetate
The application described the findings of two randomized placebo-controlled
Phase III studies of abiraterone for treatment of mCRPC.
The COU-AA-301 trial randomly assigned 1195 patients who had
failed prior docetaxel therapy to receive prednisone 5 mg twice daily with
either abiraterone 1000 mg daily or placebo (5). The primary endpoint was
333
overall survival and was significantly longer in the abiraterone-prednisone arm

compared to the control arm (14.8 months vs 10.9 months; HR 0.65, 95%CI
0.54 to 0.77; p<0.001). Abiraterone was also associated with significant benefit
compared to placebo for the secondary endpoints of time to PSA progression
(10.2 months vs 6.6 months; HR 0.58, 95%CI 0.46 to 0.73; p<0.001), and PFS
(5.6 months vs 3.6 months; HR 0.67, 95%CI 0.59 to 0.78; p<0.001).
The COU-AA-302 trial randomly assigned 1088 chemotherapy naive
patients with prostate cancer to receive abiraterone 1000 mg daily plus prednisone
5 mg twice daily or placebo plus prednisone (6). Median overall survival was
observed to be longer in abiraterone treated patients compared to the placebo
group (34.7 months vs 30.3 months; HR 0.81, 95%CI 0.70 to 0.93; p=0.0033).
Enzalutamide versus abiraterone acetate
The application described the findings of three studies in which enzalutamide
and abiraterone were compared.
A network meta-analysis of eight RCTs involving 8666 patients with
mCRPC compared the efficacy of abiraterone, enzalutamide and orteronel (7).
Pooled hazard ratios for the primary endpoint of overall survival were 0.71 and
0.78 for enzalutamide and abiraterone, respectively compared to control groups.
Enzalutamide also significantly improved PFS (HR 0.36), whereas abiraterone
was not associated with a significant improvement. Enzalutamide and abiraterone
were both associated with significant improvements in time to PSA progression
compared to controls (HR 0.20 and 0.56, respectively). There were no significant
associations for either drug with regard to the development of adverse events.
A retrospective study of patients with mCRPC receiving treatment with
enzalutamide (n=807) or abiraterone (n=2591) compared real-world treatment
patterns and adherence to therapy (8). Abiraterone-treated patients were found
to have higher medication possession ratios (MPRs) than enzalutamide-treated
patients, suggesting greater medication adherence to abiraterone. Abiraterone-

treated patients also had lower Kaplan-Meier rates of dose reduction.
A second retrospective study compared the combined duration of
prostate cancer treatments of mCRPC patients initiated on abiraterone
(n=2591) or enzalutamide (n=807) (9). Compared with patients initiated on
enzalutamide, patients initiated on abiraterone had fewer discontinuations of
mCRPC treatments (HR 0.73, p=0.004) or of any prostate cancer treatments
(HR 0.61, p=0.002) at three months and the result was maintained up to 24
months. The median duration of mCRPC treatments was 4.1 months longer for
patients initiated on abiraterone compared with those initiated on enzalutamide
(18.3 vs 14.2 months, p<0.001). Similarly, the median duration of any prostate
cancer treatment was longer for patients initiated on abiraterone compared with
those initiated on enzalutamide (not reached vs 22.2 months, p<0.001).
334

Enzalutamide
From the PROSPECT trial in patients with non-metastatic disease, adverse
events of Grade 3 or higher occurred in 31% of enzalutamide-treated patients
compared with 23% receiving placebo. The most commonly reported adverse
events occurring more frequently in the enzalutamide group included fatigue,
hot flush, hypertension, nausea and constipation (10).
From the AFFIRM trial in previously treated patients with mCRPC,
adverse events of Grade 3 or above were reported in 45.3% of patients in the
enzalutamide arm compared to 53.1% of placebo-treated patients. Enzalutamide-
treated patients experienced a higher incidence of any grade fatigue, diarrhoea,
hot flashes, musculoskeletal pain, headache and seizures compared to placebo-
treated patients. Adverse events causing death occurred in 3% and 4% of
enzalutamide- and placebo-treated patients, respectively (3).
From the PREVAIL trial in chemotherapy naive patients with mCRPC,
adverse events of Grade 3 or more were reported in 43% of the patients in the
enzalutamide group, and 37% in the placebo group. Common adverse events
occurring at least 2% more frequently in the enzalutamide group included
fatigue, back pain, constipation and arthralgia (4).
Abiraterone
In the COU-AA-301 trial, there were more deaths, treatment discontinuations,
and treatment discontinuations due to adverse events in the placebo arm versus
the abiraterone arm. Common adverse events occurring at similar frequency
between treatment groups were fatigue, back pain, nausea, constipation, bone
pain and arthralgia. Urinary tract infection was observed more frequently in
the abiraterone arm (5). The most common Grade 3 or greater adverse events
of special interest reported in the COU-AA-302 trial occurring more frequently
in the abiraterone arm were cardiac disorders (8% vs 4%), increased alanine
aminotransferase (6% vs <1%) and hypertension (5% vs 3%) (6).

A recent prospective randomized Phase II study (n=72) investigated the effect
of the administration of low dose abiraterone (250 mg daily) with a low-fat meal,
compared to standard dose abiraterone (1000 mg daily) administered under
fasting conditions (11). At 12 weeks, a greater effect on PSA was observed in the
low-dose arm compared with the standard dose arm (mean log change −1.59
vs −1.19) meeting the predefined non-inferiority criteria. The PSA response
rate was 58% and 50% in the low-dose and standard-dose arms, respectively.
Median PFS was approximately nine months in both groups. Androgen levels
decreased similarly in both arms. Abiraterone concentrations were higher in the
335
standard-dose group, yet there was no difference in PSA response or PFS. The
study authors considered these data could have significant pharmacoeconomic
implications and deserve consideration by prescribers, payers and patients.
However, the study also concludes that additional studies are required to
determine the long-term efficacy of this dosing strategy.
WHO Guidelines
None available.
Many of the cost-benefit studies have been done using the prices from originator
companies. Both drugs are now also available from generic suppliers, and as
competition among generic suppliers expands, prices should decline considerably.
Before generic entry, some publicly quoted prices for the active
pharmaceutical ingredient enzalutamide were in the range of US$ 6000 to
US$ 13 000 per kg. At US$ 6000 per kg, the cost of the active pharmaceutical
ingredient (API) for one 40 mg capsule of enzalutamide would be US$ 0.24
(US$ 0.006 per mg).
Prices of generic abiraterone acetate vary. One company offers 120 x
250 mg abiraterone acetate tablets for approximately US$ 238.40. The price for a
unit of the API is US$ 7947 per kg and US$ 0.007947 per mg.
It is anticipated that API costs could decline to between US$ 300 and
US$ 900 per kg over time for both products, in line with prices for tamoxifen
(US$ 271 per kg), capecitabine (US$ 393 per kg) and prednisolone (US$ 962
per kg). A decline of that magnitude would result in API costs of US$ 0.012
to US$ 0.036 per 40 mg capsule, or US$ 0.048 to US$ 0.144 per day, for
enzalutamide, and US$ 0.075 to US$ 0.225 per 250 mg tablet or US$ 0.30 to
US$ 0.90 per day for abiraterone acetate (without prednisone).
Technology appraisal guidance issued by the National Institute for
Health and Care Excellence (NICE) for enzalutamide and abiraterone state that
these medicines are recommended treatment options people with metastatic
hormone-relapsed prostate cancer if the manufacturers provide the drugs at
agreed fixed or discounted prices (12, 13). Similarly, the National Centre for
Pharmacoeconomics in Ireland approved reimbursement for enzalutamide and
abiraterone only after price negotiations were conducted.
The application summarized numerous studies that investigated the
cost-effectiveness of enzalutamide and abiraterone, noting that many study
authors were affiliated with the pharmaceutical manufacturers at the time of
publication. The studies cited used the high originator prices and are of limited
use when considering whether these medicines would be cost-effective in
resource-limited settings, when and where the medicines available at lower
prices from generic suppliers.
336
Availability
Enzalutamide and abiraterone acetate have worldwide regulatory approval.
There are many generic versions of abiraterone acetate available, while only a
single generic version of enzalutamide.
N/A
abiraterone and enzalutamide.
The Committee recommended the addition of abiraterone to the
complementary list of the EML for use in the treatment of metastatic castration-
resistant prostate cancer.
The Expert Committee acknowledged the significant public health
burden of prostate cancer, which afflicts an increasing number of people in all
countries, irrespective of income. The Committee recalled that the EML currently
includes docetaxel, bicalutamide and leuprorelin for use in the treatment of
metastatic prostate cancer. However, a significant proportion of patients will not
respond to these medicines and patients will ultimately develop resistance.
The Committee noted that abiraterone and enzalutamide have each
been shown to be effective treatments for metastatic castration-resistant prostate
cancer, both in chemotherapy-naive and in pre-treated patients. The Committee
noted that abiraterone had not shown any relevant clinical advantage over
enzalutamide in terms of efficacy outcomes or safety. However, the Committee
recognized the potential advantages offered by abiraterone in terms of emerging
dosing strategies (lower doses may be possible when administered with food),
reduced pill burden potentially improving adherence, wider availability of
generics and potential associated cost savings. Given that metastatic prostate
cancer often requires treatment over longer periods of time (i.e. above one
year) and that low dosing and availability of generics would be associated with
substantial cost savings, the Committee decided not to recommend listing
abiraterone with a square box indicating enzalutamide as an alternative. While
enzalutamide remains an effective therapeutic option for mCRPC, its use
instead of abiraterone could result in considerable additional expenditure at
country level, without additional clinical benefit. The Committee considered
that addition of abiraterone alone on the EML serves to support its use,
promoting competition between brand and generic medicines, and improving
access and affordability.
337
References
Cancer J Clin. 2018;68(6):394–424.
3. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et al. Increased survival with
enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97.
4. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS et al. Enzalutamide in
metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–33.
5. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al. Abiraterone and increased
survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005.
6. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN et al. Abiraterone acetate plus
prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic
castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised,
double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152–60.
7. Kang M, Jeong CW, Kwak C, Ku JH, Kim HH. Comparing the clinical efficacy of abiraterone
acetate, enzalutamide, and orteronel in patients with metastatic castration-resistant prostate
cancer by performing a network meta-analysis of eight randomized controlled trials. Oncotarget.
2017;8(35):59690–7.
8. Behl AS, Ellis LA, Pilon D, Xiao Y, Lefebvre P. Medication Adherence, Treatment Patterns, and Dose
Reduction in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Abiraterone
Acetate or Enzalutamide. Am Health Drug Benefits. 2017;10(6):296–303.
9. Pilon D, Behl AS, Ellis LA, Emond B, Lefebvre P, Dawson NA. Duration of Treatment in Prostate
Cancer Patients Treated with Abiraterone Acetate or Enzalutamide. J Manag Care Spec Pharm.
2017;23(2):225–35.
10. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U et al. Enzalutamide in Men with
Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018;378(26):2465–74.
11. Szmulewitz RZ, Peer CJ, Ibraheem A, Martinez E, Kozloff MF, Carthon B et al. Prospective
International Randomized Phase II Study of Low-Dose Abiraterone With Food Versus Standard
Dose Abiraterone In Castration-Resistant Prostate Cancer. J Clin Oncol. 2018;36(14):1389–95.
12. Enzalutamide for metastatic hormone-relapsed prostate cancer previously treated with a
docetaxel-containing regimen. Technology appraisal guidance [TA316]. London: National
Institute for Health and Care Excellence; 2014. Available from https://www.nice.org.uk/guidance/
ta316, accessed 29 September 2019.
13. Abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy
is indicated. Technology appraisal guidance [TA387]. London: National Institute for Health
and Care Excellence; 2016. Available from https://www.nice.org.uk/guidance/ta387, accessed
29 September 2019.
338
Section 10: MEDICINES AFFECTING THE BLOOD

10.2 Medicines affecting coagulation
Direct oral anticoagulants (DOACs) – dabigatran, rivaroxaban,
apixaban, edoxaban – addition – EML
Direct oral anticoagulants

Apixaban ATC Code: B01AF02
Dabigatran etexilate ATC Code: B01AE07
Edoxaban ATC Code: B01AF03
Rivaroxaban ATC Code: B01AF01
Proposal
Two applications requested the inclusion of direct oral anticoagulants (DOACs)
on the EML for the prevention of stroke and systemic embolism in patients
with nonvalvular atrial fibrillation (NVAF) and for treatment of venous
thromboembolism.
Applicants
1. Dr Mariachiara DiCesare, Dr Xinyi Leng, Dr Ezequiel Zaidel
2. Dr Ignacio Neumann, Dr Holger J Schunemann

Comments on the applications were received from the WHO Department of
unit advised that it supported the addition of DOACs to the complementary list
of the EML as they are effective medicines for which EML listing may improve
equity by making them more accessible to patients, and driving costs down.
EML/EMLc
EML
Section

Apixaban: tablet 2.5 mg, 5 mg
Dabigatran etexilate: capsule 110 mg, 150 mg
Edoxaban: tablet 30 mg, 60 mg
Rivaroxaban: tablet 15 mg, 20 mg
339
Core/Complementary
Core

1. Square box listing of dabigatran
2. Individual listing for each medicine

In 2015, the Committee rejected an application seeking inclusion of dabigatran,
rivaroxaban and apixaban as a therapeutic group on the EML for the treatment of
nonvalvular atrial fibrillation (NVAF). The Committee considered that although
the evidence presented indicated a favourable overall clinical benefit of DOACs
over warfarin, the absolute magnitude of benefit was limited, inconsistent across
trials and may be influenced by a number of factors, such as the quality of oral
anticoagulation (time in therapeutic range). The Committee considered that in
order for countries to maximize use of available resources, further research was
necessary to explore the unmet need in terms of anticoagulation in people unable
to be stabilized with warfarin and in clinical settings where access to warfarin
monitoring is not readily available. The Committee expressed some concern
regarding safety of DOACs, noting that there were currently no specific antidotes
that would reverse anticoagulant effects in case of emergency. The Committee
also acknowledged that the large difference in cost between DOACs and warfarin
was not proportional to the observed incremental clinical benefit. Full details
are available in the technical report of the 2015 Expert Committee meeting (1).

Atrial fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia (2)
and a major public health issue affecting 37.6 million individuals globally in
2017 (3). The incidence and prevalence of AF are expected to increase over the
next 30 years (4–6).
Without antithrombotic treatment, the risk of stroke in patients with
atrial fibrillation is around 5% per year, but it can be as high as 10% per year if
other risk factors are present (7). In a cohort of 15 400 individuals with atrial
fibrillation in 47 countries, the highest number of strokes occurred in patients
in Africa (incidence 89/1137 (8%) per year), China (incidence 143/2023 (7%) per
year), and Southeast Asia (incidence 88/1331 (7%) per year) (8).
In low and middle-income countries (LMICs), stroke is associated with
an increased mortality and significant disability, particularly in disadvantaged
populations (9–11). Additionally, according to a recent WHO survey of 177
countries, provisions for the treatment and rehabilitation of patients with stroke
are available in less than a quarter of public health care facilities in LMICs (12).
340
Deep venous thrombosis and pulmonary embolism are major contributors

to global disease burden. Their estimated annual incidence ranges from 0.7 to
2.7 per 1000 population in Western Europe, 1.1 to 2.4 per 1000 population in
North America and 0.2 to 1.6 per 1000 population in Latin America and Asia
(13). Additionally, venous thromboembolism markedly increases with age, with
incidences as high as 4.29 to 5.64 per 1000 population in individuals older than
70 years (14, 15). Thus, venous thromboembolism is likely to become an even
more prominent problem with aging populations.

Application 1 – NVAF:
This application presented the results of a meta-analysis that updated a published
meta-analysis of four randomized controlled trials (RCTs) by Ruff et al (16) with
data from the J-ROCKET AF trial (17) involving a total of 59 819 participants.
Compared with warfarin, DOACs were associated with a significantly reduced
risk of stroke and systemic embolism in patients with NVAF (risk ratio (RR) 0.80,
95%CI 0.71 to 0.91, p=0.003; absolute effect: 8 fewer events per 1000 (95%CI
3 fewer to 11 fewer). The quality of evidence was rated as high using GRADE.
This application also presented the results of a systematic literature
review of observational studies reporting real-world data for DOACs versus
vitamin K antagonists for the primary efficacy outcome of stroke and systemic
embolism. Of 23 studies included in the quantitative data synthesis, 12 studies
provided data for the primary efficacy outcome of stroke and systemic embolism
(18–29). In these studies, NOACs were associated with a reduced risk of stroke
and systemic embolism compared with warfarin in patients with NVAF RR
0.79, 95%CI 0.71 to 0.89, p<0.001; absolute effect: 5 fewer events per 1000
(95%CI 3 fewer to 7 fewer). The quality of evidence was rated as very low
using GRADE, due to the evidence being based on observational studies with
heterogenous findings.
When compared individually with warfarin, dabigatran, rivaroxaban and
apixaban were each associated with a lower risk of stroke and systemic embolism
than warfarin. No real-world data were available for edoxaban.
This application conducted a meta-analysis of eight systematic reviews (30–37)
and 13 randomized trials involving a total of 75 543 participants with AF and
one or two additional risk factors for stroke (17, 38–49). Participants were
randomized to a DOAC or warfarin (target international normalized ratio 2.0
to 3.0) and were followed for two to three years. Individuals with estimated
creatinine clearance of less than 30 mL per minute or a high risk of bleeding
were excluded.
341
Use of DOACs instead of vitamin K antagonists in individuals with

NVAF was associated with decreased mortality (RR 0.90, 95%CI 0.85 to 0.94,
high certainty evidence) and decreased risk of stroke (RR 0.83, 95%CI 0.72 to
0.96; absolute effect: 7 fewer events per 1000 (95%CI 11 fewer to 4 fewer), high
certainty evidence). Also, DOACs were found to probably decrease the risk of
systemic embolism (RR 0.74, 95%CI 0.48 to 1.13; absolute effect: 1 fewer event
per 1000 (95%CI 1 fewer to 0 fewer), moderate certainty evidence) and major
bleeding (RR 0.81, 95%CI 0.66 to 0.98; absolute effect: 11 fewer events per 1000
(95%CI 20 fewer to 1 fewer), moderate certainty evidence).
Application 2 – venous thromboembolism:
This application conducted a meta-analysis of 24 systematic reviews (50–73) and
12 randomized trials involving 28 876 participants with an objectively confirmed
symptomatic proximal deep venous thrombosis or pulmonary embolism (74–
85). Participants were randomized to a DOAC or to an initial treatment with
low molecular weight heparin (five to ten days) followed by dose-adjusted
warfarin (target international normalized ratio 2.0 to 3.0). Dabigatran was also
administered after an initial treatment of five to ten days with low molecular
weight heparin, while rivaroxaban, apixaban and edoxaban were administered
without initial parenteral anticoagulants. The length of the anticoagulation
varied across trials from three to twelve months. Individuals with estimated
creatinine clearance of less than 30 mL per minute or a high risk of bleeding
were excluded.
The analysis showed that the use of DOACs instead of vitamin K
antagonists in individuals with deep venous thrombosis or pulmonary embolism
likely has a small effect on mortality (RR 0.99, 95%CI 0.85 to 1.15; absolute
effect: 0 fewer events per 1000 (95%CI 6 fewer to 6 more), moderate certainty
evidence) and the risk of subsequent pulmonary embolism (RR 0.97, 95%CI
0.77 to 1.23; absolute effect: 1 fewer event per 1000 (95%CI 5 fewer to 5 more),
moderate certainty evidence). DOACs probably decrease the risk of a recurrent

deep venous thrombosis (RR 0.80, 95%CI 0.59 to 1.09; absolute effect: 5 fewer
events per 1000 (95%CI 11 fewer to 2 more), moderate certainty evidence) and
major bleeding (RR 0.63, 95%CI 0.47 to 0.84; absolute effect: 6 fewer events per
1000 (95%CI 9 fewer to 3 fewer), high certainty evidence).

Application 1:
From the updated meta-analysis of five RCTs (16, 17), DOACs were found to
be associated with a significantly lower risk of major bleeding compared with
warfarin (RR 0.86, 95%CI 0.74 to 0.99, p=0.04; absolute effect: 8 fewer events
per 1000 (95%CI 1 fewer to 16 fewer). The quality of the evidence was rated as
moderate using GRADE, downgraded due to inconsistency.
342
This application also presented the results of a systematic literature

review of observational studies reporting real-world data for DOACs versus
vitamin K antagonists for the primary safety outcome of major bleeding. Of
23 studies included in the quantitative data synthesis, 17 studies provided data
for the primary safety outcome (18, 20, 22–29, 86–92). In these studies, DOACs
were associated with a lower risk of bleeding compared with warfarin in NVAF
patients (RR 0.72, 95%CI 0.64 to 0.80. p<0.001; absolute effect 9 fewer events
per 1000 (95%CI 6 fewer to 11 fewer). The quality of evidence was rated as very
low using GRADE, due to the evidence being based on observational studies
with heterogenous findings.
When compared individually with warfarin, dabigatran, rivaroxaban
apixaban and edoxaban were each associated with a lower risk of major bleeding
than warfarin. No real-world data were available for edoxaban.
Application 2:
As reported above, randomized trial evidence suggests that DOACs are probably
associated with a lower risk of major bleeding than vitamin K antagonists in the
treatment of NVAF (RR 0.81, 95%CI 0.66 to 0.98; absolute effect: 11 fewer events
per 1000 (95%CI 20 fewer to 1 fewer), moderate certainty evidence) and venous
thromboembolism (RR 0.63, 95%CI 0.47 to 0.84; absolute effects 6 fewer events
per 1000 (95%CI 9 fewer to 3 fewer), high certainty evidence).
Large observational studies on real-world populations suggest that the
risk of bleeding with DOACs may be equivalent to or lower than the risk with
vitamin K antagonists.
■■ A large cohort of 156 005 adults with atrial fibrillation and venous
thromboembolism in the United Kingdom suggested a lower risk
of bleeding with apixaban in comparison with warfarin (HR 0.69,
95%CI 0.54 to 0.79 in individuals with atrial fibrillation; HR 0.60,
95%CI 0.46 to 0.79 in individuals without atrial fibrillation). Also,
investigators observed no significant differences in the risk of
bleeding for the comparisons of rivaroxaban vs warfarin (HR 1.12,
95%CI 0.99 to 1.26 in individuals with atrial fibrillation; HR 0.95,
95%CI 0.82 to 1.10 in individuals without atrial fibrillation) and
dabigatran vs warfarin (HR 0.87, 95%CI 0.72 to 1.04 in individuals
with atrial fibrillation; HR 0.98, 95%CI 0.71 to 1.35 in individuals
without atrial fibrillation) (25).
■■ A propensity-matched analysis of 76 940 individuals with non-
valvular atrial fibrillation of an administrative database from the
United States suggested a lower risk of bleeding with apixaban in
comparison to warfarin (HR 0.60, 95%CI 0.54 to 0.65) (29).
343
■■ A community-based population study of 59 525 adults with venous

thromboembolism in Canada and the United States showed a
similar risk of bleeding with DOAC and VKA (HR 0.99, 95%CI 0.84
to 1.16) (93).
■■ A propensity score matched analysis of 45 361 patients with
non‑valvular atrial fibrillation of an administrative database from
the United States, showed a lower risk of bleeding with dabigatran
(HR 0.69 95%CI 0.50 to 0.96) and apixaban (HR 0.53, 95%CI 0.39
to 0.71) in comparison to warfarin. In patients using rivaroxaban,
investigators observed a similar risk of bleeding in comparison to
warfarin (HR 0.98, 95%CI 0.83 to 1.17) (94).
■■ A propensity-matched cohort of 29 963 adults with venous
thromboembolism in Denmark, also suggested a similar risk of
bleeding with DOAC and VKA (HR 1.19, 95%CI 0.66 to 2.13) (95).
The application also reported data from recent and ongoing trials
involving specific antidotes for emergency reversal of anticoagulation in patients
receiving DOACs.
Idarucizumab is a monoclonal antibody fragment that has been
investigated for use in reversing the anticoagulant effect of dabigatran in the
RE‑VERSE AD trial in 503 patients with life-threatening bleeding or about
to undergo an urgent procedure (96). Following administration of 5 g of IV
idarucizumab, anticoagulation was completely reversed in 98% of patients within
four hours.
Andexanet alfa has recently been approved as an antidote for rivaroxaban
and apixaban based on results of two open label randomized trials of rivaroxaban
or apixaban compared to placebo (ANNEXA-R and ANNEXA-A). The primary
outcome of both trials was anti-factor Xa activity measured with a chromogenic
assay. The results showed a reduction of anti-factor Xa activity of 92±11% with

andexanet vs 18±15% with placebo in the rivaroxaban study and a reduction of
94±2% with andexanet vs 21±9% with placebo in the apixaban study (97). There
is an ongoing open-label, non-randomized trial (ANNEXA-4) evaluating the
effects of andexanet on clinical endpoints in patients with acute bleeding under
treatment with rivaroxaban or apixaban. In an interim report of this study, of the
47 patients available for analysis, 37 were judged as having good haemostasis by
an independent adjudication committee (98).

N/A
344
WHO Guidelines
There are no WHO guidelines currently available for the treatment of NVAF or
venous thromboembolism.
Oral anticoagulation with warfarin or DOACs (apixaban, dabigatran,
rivaroxaban) in patients with atrial fibrillation (AF) at high risk of stroke based on
a CHA2DS2-VASc score of 2 or more is recommended in multiple international
guidelines (99–102).
For management of venous thromboembolism, recent, yet to be
published, American and Latin American guidelines are reported to support
short-term anticoagulation in individuals at low risk of recurrence and indefinite
anticoagulation in individuals at high risk (e.g. unprovoked events). DOACs are
the preferred alternative over warfarin.
Reported monthly costs of DOACs in the two applications indicate that the
costs for DOACs range widely between countries: from US$ 20–50 per month
in Latin American countries, to US$ 90 per month in the United Kingdom, to up
to US$ 600 per month in the United States and Canada.
Application 1:
A 2016 systematic review of 54 studies from 21 countries reporting cost-
effectiveness analyses of DOACs (103) concluded that DOACs are cost-effective
in several countries, independent of their health system, direct costs of DOACs
and vitamin K antagonists, and costs of diseases. The authors defined a drug
as cost-effective when the incremental cost-effectiveness ratio was below the
willingness to pay value. Most studies used a conventional Markov decision
analysis model, and the rate of events was gathered from the RCTs of DOACs.
This application updated the systematic review, including 64 cost-
effectiveness analyses from 28 high- and middle-income countries. Most of them
used same criteria, but newer cost-effectiveness analyses from the United States
included costs from health care resource use and real-world data from health
systems to determine rate of stroke and bleeding rather than data solely from
randomized trials. All studies to date demonstrated that DOACs were a cost-
effective strategy. The studies included in the updated systematic review are
referenced in the application.
The application identified two systematic reviews of economic evaluation of any
DOAC versus vitamin K antagonists in patients with AF.
The first article identified was a systematic review of cost-utility analyses
of dabigatran, rivaroxaban or apixaban versus warfarin. This review included
345
18 primary studies conducted in North America and Europe. All but one used
a Markov model to extrapolate long-term data basing the calculation on the
effectiveness and safety results from landmark trials. The majority of the models
used the perspective of the payer. Thirteen models compared dabigatran versus
warfarin, four rivaroxaban versus warfarin and four apixaban versus warfarin.
Although there was some inconsistency among the conclusions of the individual
models, the large majority showed that DOACs were cost-effective with
ICERs below the willingness-to-pay thresholds and sometimes dominant over
warfarin (104).
The second article identified was a systematic review of cost-utility
analyses of apixaban versus warfarin. This review identified 26 primary studies
conducted in North America, Latin America and Europe. All the studies except
of one used a Markov model to extrapolate long-term data with the effectiveness
and safety results from landmark trials. The majority of the models used the
perspective of the payer with a lifetime horizon. The results showed that apixaban
was cost-effective with incremental cost effectiveness ratios (ICERs) below the
willingness-to-pay thresholds (105).
Application 2 – venous thromboembolism:
The application identified five cost comparisons between DOACs and VKA for
patients with venous thromboembolism. Four reports suggested that DOACs
are cost-saving compared with warfarin (106–109) and one study found an
equivalent cost between DOACs and vitamin K antagonists (110).
In addition, the application identified 14 economic evaluations that
compared the cost and effectiveness of DOACs versus vitamin K antagonists (107,
111–123). All suggested that DOACs are cost-effective compared to warfarin.
Availability
Dabigatran, manufactured by Boehringer Ingelheim, apixaban, manufactured by
Bristol-Myers Squibb, and rivaroxaban, manufactured by Bayer, all have wide

global regulatory approval.
Edoxaban, manufactured by Daiichi Sanyko Company, has regulatory
approval from regulatory authorities in the United States, Europe, Japan, Canada
and Nigeria.
N/A
The Committee recommended the addition of dabigatran with a square box
to the core list of the EML for the prevention of stroke and systemic embolism
in patients with nonvalvular atrial fibrillation and for treatment of venous
346
thromboembolism based on favourable efficacy and acceptable safety. The

square box refers to apixaban, edoxaban and rivaroxaban as therapeutically
equivalent alternatives.
The Committee noted that the DOACs demonstrated clinical benefits in
terms of reduced mortality, reduced risk of stroke or systemic embolism, and
were associated with fewer severe/major bleeding episodes compared to well-
controlled warfarin in patients with NVAF.
In the treatment of patients with venous thromboembolism, DOACs
were associated with small reductions in mortality, risk of subsequent/recurrent
thromboembolic events and major bleeding compared to low-molecular weight
heparin and vitamin K antagonists.
The use of DOACs may also have relevant health system benefits related
to the infrastructure required for warfarin treatment monitoring, as they do
not require laboratory monitoring. The Committee noted that DOACs have
higher daily treatment costs than warfarin, but have been found to be a cost-
effective intervention. It is recommended that countries take all these factors
into consideration when selecting anticoagulants to best suit their national and
local needs and circumstances.
The Committee recommended that WHO take action to facilitate access
to these medicines through the WHO prequalification programme, and through
collaboration with partners such as the Medicines Patent Pool.
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Section 12: CARDIOVASCULAR MEDICINES

12.3 Antihypertensive medicines
Fixed-dose combination antihypertensives – addition – EML
Lisinopril + amlodipine ATC Code: C09BB03

Lisinopril + hydrochlorothiazide ATC Code: C09BA03
Telmisartan + amlodipine ATC Code: C09DB04
Telmisartan + hydrochlorothiazide ATC Code: C09DA07
Proposal
The application proposed the addition of four two-drug fixed-dose combinations
(FDC) to the core list of the EML for use in the treatment of hypertension.
Applicant
Sandeep Kishore, Arnhold Institute for Global Health & Young Professionals
Chronic Disease Network;
Anthony Rodgers, The George Institute for Global Health
Marc Jaffe, Resolve to Save Lives, Viral Strategies and Kaiser Permanente Northern
California
Tom Frieden, Resolve to Save Lives, Vital Strategies

Comments on the application were received from the WHO Department for
Management of Noncommunicable Diseases, Disability, Violence and Injury
Prevention. The technical unit advised that it supported the inclusion of dual
FDC antihypertensives to the EML, stating that most people with hypertension
require more than one antihypertensive agent to achieve control and that FDCs
are likely to improve adherence to treatment.
EML/EMLc
EML
Section
12.3 Antihypertensive Medicines

Lisinopril + amlodipine: tablet 10 mg + 5 mg; 20 mg + 5 mg; 20 mg + 10 mg
Lisinopril + hydrochlorothiazide: tablet 10 mg + 12.5 mg; 20 mg + 12.5 mg; 20 mg
+ 25 mg
356
Telmisartan + amlodipine: tablet 40 mg + 5 mg; 80 mg + 5 mg; 80 mg + 10 mg

Telmisartan + hydrochlorothiazide: tablet 40 mg + 12.5 mg; 80 mg + 12.5 mg;
80 mg + 25 mg
Core/Complementary
Core

Square box listings as representative of the following pharmacological class
combinations:
–– ACE inhibitor + dihydropyridine calcium channel blocker
–– ACE inhibitor + thiazide or thiazide-like diuretic
–– Angiotensin receptor blocker + dihydropyridine calcium channel
blocker
–– Angiotensin receptor blocker + thiazide or thiazide-like diuretic
Square box listings of the components of the FDCs should be interpreted by
countries as limited to:
–– Lisinopril > any ACE inhibitor (ATC code C09AA--)
–– Telmisartan > any angiotensin receptor blocker (ATC code
C09CA--)
–– Amlodipine > any once-daily dihydropyridine calcium channel
blocker (intrinsically long-acting e.g. amlodipine, lercanidipine,
lacidipine; or modified-release e.g. nifedipine, felodipine)
–– HCTZ > chlortalidone or indapamide.

The pharmacological classes of angiotensin-converting enzyme (ACE) inhibitors,
angiotensin receptor blockers, calcium channel blockers and thiazide diuretics are
all represented on the EML with square box listings. The individual components
of the proposed FDCs are included on the EML either specifically (amlodipine,
hydrochlorothiazide) or as members of pharmacological classes represented by
square box listings (lisinopril (represented by enalapril), telmisartan (represented
by losartan)).
In 2017, an application for inclusion of an FDC of lisinopril +
hydrochlorothiazide on the EML was not recommended by the Committee. The
Committee considered that listing a single FDC of medicines for treatment of
hypertension would limit choice from the variety of combinations, component
medicines and dosages available that would be necessary to tailor therapy for
individual patients.
357
However, the Committee acknowledged that appropriate FDCs for

hypertension may have advantages over the single medicines given concomitantly,
including increased adherence and reduced pill burden. An explanatory note to
this effect was included in Section 12 of the EML (1).
To address the concerns of the 2017 Committee, the current application
proposed four different combinations, with each component qualified with a
square box, and with multiple dose options.

Cardiovascular diseases are the leading cause of death globally, responsible for
31% of total deaths in 2016. Hypertension is the leading modifiable risk factor
for cardiovascular disease. The global prevalence of hypertension (defined as
systolic and/or diastolic blood pressure more than or equal to 140/90 mmHg)
in adults was 24.1% in men and 20.1% in women in 2015. The number of
adults with hypertension has increased by over half a billion to 1.13 billion in
the 40 years to 2015, with the increase seen largely in low- and middle-income
countries (LMICs) (2).
In LMICs, nearly three quarters of patients treated for hypertension in
2010 did not have adequate blood pressure control (3). Data from the ALLHAT
trial (4) suggest that two or more antihypertensive medicines are required
by the majority of patients in order to achieve blood pressure targets below
140/90 mmHg.
A meta-analysis of 42 trials involving almost 11 000 participants found
that combination therapy using medicines from any two pharmacological
classes of thiazide diuretics, beta-blockers, ACE-inhibitors and calcium channel
blockers produces a greater blood pressure lowering effect than doubling the
dose of monotherapy (5). Greater blood pressure lowering effects have been
associated with greater reductions in cardiovascular events such as myocardial
infarction and stroke (6–9).

Dual versus monotherapy for initial treatment of hypertension
A systematic review conducted for the application of dual versus monotherapy
as initial treatment identified 33 randomized trials involving over 10 000
participants. Compared to patients receiving monotherapy, there was a 27%
increase in the rate of achieving blood pressure control among patients receiving
dual combination therapy.
The application also described the results of three studies that compared
initial combination antihypertensive treatment with alternative initial treatment
regimens including monotherapy, sequential monotherapy and stepped-care
(10–12). In all comparisons, combination therapy was associated with greater
improvements in blood pressure control, without an increase in adverse events.
358
Effects of combination therapy versus placebo on cardiovascular events

As in the 2017 application, the current application presented the same findings
of a review of 11 randomized controlled trials (RCTs) involving 35 208 patients
comparing combination antihypertensive treatment with placebo/no treatment
on cardiovascular outcomes and mortality (13–23). Combination therapy was
found to significantly reduce the risk of cardiovascular outcomes and mortality for
all studies combined, and to a greater extent when only the studies demonstrating
a reduction in systolic pressure of more than 6 mmHg were considered.
Review of RCTs assessing antihypertensive effects of the proposed FDCs
Lisinopril + hydrochlorothiazide
Two trials reported data for either the comparison of lisinopril + HCTZ versus
placebo or versus component monotherapy (24, 25). In both studies, combination
therapy was associated with a significant reduction in both systolic and/or
diastolic blood pressure.
Two trials reported data for the comparison of lisinopril + HCTZ with
alternative dual combination therapy (sustained release verapamil + trandolapril,
atenolol + chlorthalidone (25); and candesartan + HCTZ (26)). There were
no significant differences in the adjusted mean change from baseline in sitting
systolic or diastolic blood pressure between treatment groups.
Telmisartan + amlodipine
One trial reported data for various strength combinations of telmisartan (20–
80 mg) + amlodipine (2.5–10 mg) versus placebo (27). Six trials reported data
for various strengths of the combination compared with single component
monotherapy at the same or higher dose (28–33). All studied comparisons
favoured dual combination therapy for differences in mean systolic and diastolic
blood pressure.
One trial compared telmisartan 80 mg + amlodipine 5 mg with olmesartan
40 mg + HCTZ 12.5 mg (34). At six months, both combinations were associated
with significant reductions in mean systolic and diastolic blood pressure. There
was no significant difference between treatment groups.
Telmisartan + hydrochlorothiazide
Two trials reported data for the comparison of telmisartan + HCTZ versus placebo
(35, 36). In both studies, there were significant differences in both systolic and
diastolic blood pressure favouring combination therapy.
Three trials reported data for the comparison of telmisartan + HCTZ
versus telmisartan monotherapy (37–39). Combination therapy was significantly
more effective than the corresponding strength of telmisartan monotherapy in
reducing mean systolic and diastolic blood pressure.
359
Four trials reported data for the comparison of telmisartan + HCTZ

with the same combination at different doses of HCTZ (40), or different dual
combinations (36, 41, 42). Both doses of telmisartan + HCTZ (12.5 mg and
25 mg) produced reductions from baseline in adjusted mean seated systolic and
diastolic blood pressure, with the 25 mg HCTZ combination producing a greater
blood pressure lowering effect (40). Comparisons of telmisartan + HCTZ with
dual combination therapy with valsartan + HCTZ, showed that compared with
placebo, both combinations produced substantial reductions in blood pressure.
Patients treated with telmisartan + HCTZ had significantly greater reductions in
systolic and diastolic blood pressure than patients treated with valsartan + HCTZ
(36, 41). In the comparison of telmisartan + HCTZ versus dual combination
therapy with barnidipine (a calcium channel blocker) + losartan, blood pressure
was reduced in both treatment arms, however, the blood pressure-lowering effect
was greater in the barnidipine + losartan group (42).
Lisinopril + amlodipine
One small (n=15) cross-over trial compared lisinopril + amlodipine with
single component monotherapy (43). After one month, combination therapy
demonstrated a significant additional blood pressure-lowering effect compared
with each component as monotherapy.

The adverse event profiles of ACE inhibitors, angiotensin receptor blockers,
thiazide diuretics, and dihydropyridine calcium channel blockers are well
known. Safety data from the studies of the dual combination therapies presented
with the application are consistent with the known adverse event profiles of
these medicines.
An analysis of 33 placebo-controlled trials of antihypertensive therapy as
monotherapy or dual combination therapy found that dual therapy was associated
with adverse events at less than double the rate observed for monotherapy (7.5%
vs 5.2%) (44), suggesting that there is not an additive effect of dual therapy in
relation to adverse events.

N/A
WHO Guidelines
The HEARTS technical package for cardiovascular disease management in
primary care includes recommended treatment protocols for dual combination
antihypertensive treatment as both first- and second-line interventions for
hypertension (45, 46).
360
Dual combination antihypertensive therapy is recommended for use

in patients not controlled on monotherapy, and in selected patients as initial
therapy in multiple international guidelines including Europe (47), the United
States (48), India (49), Thailand (50) and China (51). Single pill FDCs are
recommended in most guidelines as an alternative to separate pills to improve
patient adherence. The 2018 European guidelines also recommended FDC
therapy as initial therapy in most patients (47).
The application presented a review of private sector prices in India of the
proposed FDCs versus their component monotherapies, which showed the FDC
prices to be similar or slightly lower than component monotherapies.
However, the Committee noted that this may not be the case in every
jurisdiction. For example, a review of the MSH International Medical Products
Price Guide (2015) reports the mean buyer prices to be US$ 0.1977, US$ 0.0233
and US$ 0.0077 for lisinopril + HCTZ 20 mg/12.5 mg, lisinopril 20 mg, and
HCTZ 12.5mg, respectively.
The Committee agreed that medicine prices should be considered
with regard to the potential cost-savings from improved hypertension control
due to improved compliance (52–54), reduced need for repeat visits to achieve
blood pressure control and with the use of FDC in settings where individuals
requiring more than one blood pressure-lowering drug may have limited access
to multiple drug classes (55, 56). A price advantage of an FDC over its component
monotherapies may be justified by a demonstrated advantage in clinical outcome
or compliance.
FDC therapy may also be associated with reduced health system costs
and out-of-pocket costs for patients. In a meta-analysis published in 2011
(57), the annual total health care costs from 44 336 patients in all included
observational studies (n = 7) were lower for patients treated with FDC compared
to individual monotherapy for hypertension (mean pooled difference US$ 1357;
95%CI US$ 778 to US$ 1935). An analysis using data from the 2004 Medical
Expenditure Panel Survey in the United States (58) demonstrated that total
monthly prescription expenditures were lower for 23 of 27 FDC medications
examined compared to the separate individual drugs (mean decrease in monthly
total costs US$ 20.89, 95%CI US$ 20.10 to US$ 21.68). Using pharmacy claims
data in Japan, a study demonstrated transitioning to FDC therapy from separate
drugs was associated with an annual saving of US$ 112 for patients (59). The cost
savings of FDC therapy for patients also translate to the larger health system. In
Canada, 60–100% of patients receiving two separate drugs transitioning to FDC
therapy has been estimated to lead to a yearly cost-saving of US$ 27 million to
US$ 45 million (60).
361
Availability
The proposed FDCs are available globally, either in the stated combinations, or
alternatives within pharmacological classes.
N/A
The Committee recommended the addition of four two-drug FDCs, each with
multiple strength formulations to the core list of the EML for use in the treatment
of hypertension. Each component of the combinations should be listed with a
square box, indicating that other medicines within the respective pharmacological
classes represent therapeutically equivalent alternatives. For the calcium channel
blocker component, the square box should be limited to dihydropyridine class of
calcium channel blockers.
The Committee accepted the efficacy of FDC antihypertensives compared
to placebo or monotherapy for reducing blood pressure and cardiovascular
events, but expressed concern that the application did not provide strong
evidence of the claimed advantages of FDC therapy versus dual component
monotherapy. However, the Committee accepted that many patients require
multiple antihypertensive treatment to achieve blood pressure targets and
recognized that FDCs may confer advantages for patients over single medicines
given concomitantly in terms of better adherence and reduced pill burden.
The Committee considered that the ongoing availability of single agent
antihypertensive medicines is critical to allow treatment modification where
necessary, and that FDCs should not displace single components at country level.
The Committee also noted that the availability of multiple FDCs
in varying strengths may be associated with significant supply chain and
affordability issues for LMICs. The Committee noted that the cost of FDCs versus
the sum of the cost of component monotherapies varies in different settings and
is not always the same (or lower) than the sum of component monotherapies.
The Committee stressed that the cost of FDCs should not be significantly higher
than the sum of the cost of their component monotherapies. In particular, in
resource-constrained settings where access is limited, the opportunity costs
associated with treating patients with FDCs must be considered.
References
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12.5 Antithrombotic medicines

12.5.2 Thrombolytic medicines
Alteplase – addition – EML
Alteplase ATC Code: B01AD02
Proposal
The application requested the inclusion of alteplase on the complementary list
of the EML as a thrombolytic agent for use in patients diagnosed with acute
ischaemic stroke (AIS) with a potentially handicapping neurological deficit at
the time of thrombolysis, and treatment within 4.5 hours after onset of stroke
symptoms (or after last proof of good health if unknown onset of symptoms).
Applicants
Patrik Michel, Michael Brainin on behalf of the World Stroke Organization

Comments on the application were received from the WHO Department
of Management of NCDs, Disability, Violence and Injury Prevention. The
technical unit advised that it supported the addition of alteplase to the EML,
stating that it is a useful and effective drug and lowers morbidity and mortality
associated with stroke when utilized correctly, and that cost-effectiveness had
been demonstrated in various settings. The technical unit also noted that use of
alteplase requires organized pre- and in-hospital care pathways in stroke-ready
facilities, clinical training in diagnosing stroke, capacity to perform and interpret
acute neuroimaging, continuous surveillance for at least 24 hours, and basic
stroke management skills.
EML/EMLc
EML
Section

Powder for injection: 10 mg, 20 mg, 50 mg
Core/Complementary
Complementary
367

Individual

Alteplase had not been previously considered for inclusion on the EML.

Globally, stroke is the second leading cause of death and disability, with the
bulk of the burden (almost 80%) residing in low- and middle-income countries
(LMICs) (1, 2). In 2016, there were almost 14 million new cases of stroke,
5.5 million deaths associated with stroke and about 81 million stroke survivors.
30% of strokes are fatal in the first year and a further 70% of survivors are left
with some level of disability. Although stroke incidence, mortality and disability
burden rates have declined since 1990, in 2016 the absolute number of people
who died from stroke, remained disabled from stroke, were affected by stroke (as
measured by incidence of new strokes), or survived stroke had almost doubled
largely due to aging of the population and population growth (2).
In well a well-developed stroke system, about 25% of all AIS patients
who arrive to a stroke centre within 24 hours of last proof of usual health are
eligible for intravenous thrombolysis (3). In Europe the current true rate is only
7.3% for all AIS patients (4), in the United States this number is probably similar
(5). Very few patients in LMICs receive intravenous thrombolysis (6, 7).

A 2014 Cochrane systematic review of 27 trials involving 10 187 participants
assessed the effectiveness and safety of thrombolytic therapy for treatment of
acute ischaemic stroke (AIS) (8). Ten trials in the review assessed alteplase in 6886
participants. Compared to control, intravenous alteplase administered within
6 hours, was associated with a significant reduction in death or dependence

(odds ratio (OR) 0.84, 95%CI 0.77 to 0.93, p=0.0006), corresponding to death
or dependence in 40 fewer participants per 1000 treated (95%CI 20 fewer to
65 fewer). When a random-effects model analysis was performed due to the
significant heterogeneity of treatment effect among the trials, the OR was 0.80
(95%CI 0.66 to 0.97, p=0.03).
For participants receiving alteplase within 3 hours (6 trials, 1779
participants), there was a significant reduction in death or dependence compared
to control (59.3% vs 68.3%; OR 0.65, 95%CI 0.54 to 0.80, p<0.0001), with no
significant heterogeneity, corresponding to death or dependence in 90 fewer
participants per 1000 treated (95%CI 46 to 135).
There was a non-significant reduction of death in the long-term follow
up of patients treated within 3 hours with an OR of 0.91 (95%CI 0.73 to 1.13,
368
p=0.39), with no statistically significant heterogeneity (p=0.22) and 14 fewer

per 1000 deaths (95%CI 26 fewer to 55 fewer). For patients treated between 3 to
6 hours, the OR for this outcome was 0.97 (95%CI 0.85 to 1.09).
A meta-analysis of individual patient data from 6756 patients in nine
randomized trials (RCTs) comparing alteplase with placebo or open control (9)
found alteplase to be associated with increased odds of a good stroke outcome
at three to six months (defined as a modified Rankin Score of 0 or 1) when
administered within 4.5 hours of stroke onset, with earlier treatment (within
3 hours) associated with greater proportional benefit, irrespective of patient age
or stroke severity.

The application presented a summary of the key safety outcomes reported in the
2014 Cochrane systematic review (8).
Alteplase was associated with a greater proportion of patients experiencing
early death (all causes, within seven to 10 days) compared to control (OR 1.44,
95%CI 1.18 to 1.76, p=0.0003; 5535 participants) corresponding to 25 more deaths
per 1000 participants treated in absolute terms (95%CI 11 more to 40 more).
Alteplase was associated with a significant increase in the rate of fatal
intracranial haemorrhage (ICH) within seven to 10 days compared to control
(OR 4.18, 95%CI 2.99 to 5.84, p<0.00001; 6683 participants) corresponding
to 30 additional ICH per 1000 treated participants in absolute terms (95%CI
20 to 40).
Early death due to causes other than fatal ICH occurred in 5.2% of
alteplase treated patients compared with 5.7% of the control group (OR 0.93,
95%CI 0.73 to 1.18, p=0.54, 5303 participants).
There was no significant effect observed on deaths from all causes
during follow-up (three to six months) between alteplase and control (OR 1.06,
95%CI 0.94 to 1.20; 7012 participants), corresponding to 7 more deaths per
1000 participants treated (95%CI 2 fewer to 25 more).
Orolingual angioedema associated with alteplase administration has
been reported in case series studies (10, 11).

N/A
WHO Guidelines
WHO does not have approved guidelines for the management of AIS.
“Treatment of acute ischaemic stroke with intravenous thrombolytic
therapy” was included as a policy option and cost-effective intervention in the
369
draft updated Appendix 3 of the Global Action Plan for the prevention and control of
non-communicable diseases 2013–2020, to assist Member States in implementing
actions to achieve targets for prevention and control of NCDs (12).
Use of IV alteplase within 4.5 hours of stroke onset is recommended in
multiple national and international guidelines (13–18).
The application reports the price for a single IV dose of 63 mg alteplase for a 70 kg
patient to range from US$ 260 (Brazil, public hospital) to US$ 6400 (average
billing amount in the United States) (19, 20).
Implementing and administering alteplase within the recommended
4.5 hours requires some initial investments in pre-hospital and intrahospital
services. Many of these investments (such as stroke unit surveillance and
care) will benefit stroke patients anyway, independently of thrombolysis being
offered or not. These additional costs have to be balanced by generally shorter
hospital stays, reduced rehabilitation needs, and reduced long-term care
(including nursing homes and home care), given the reduction of handicap from
thrombolysis (21).
The UK National Institute for Health and Care Excellence (NICE)
concluded the cost for all treatment windows up to 4.5 hours were below accepted
willingness-to-pay thresholds for alteplase (19). In another United Kingdom-
based model, the authors concluded that any strategy that increases thrombolysis
rates will result in cost savings and improved patient quality of life (22).
Studies from China and Brazil have also found alteplase treatment to be a
cost-effective intervention (23, 24).
A review of 16 studies of the cost-effectiveness of IV alteplase thrombolysis
from Australia, Canada, China, Denmark, New Zealand, Spain, the United States
and the United Kingdom, found that alteplase was a dominant or cost-effective
strategy compared with traditional treatment in all but one of the studies (25).
Availability
Alteplase has marketing approval in 104 countries globally. The 10 mg and 20 mg
strengths may not be available in all jurisdictions.
The Committee noted the use in practice of alteplase in acute myocardial
infarction (MI) and considered that it is likely that alteplase would be used for
this indication in some settings. The Committee noted that the EML currently
includes streptokinase for MI and would welcome a future application reviewing
the evidence for streptokinase and alteplase for this indication.
370
The Committee recommended the addition of alteplase on the complementary
list of the EML as a thrombolytic agent for use in patients diagnosed with
acute ischaemic stroke on the basis of the evidence presented of improved
patient outcomes in terms of reduced death or dependence when alteplase is
administered within 4.5 hours of the onset of stroke symptoms.
The Committee acknowledged the significant global burden of stroke
in terms of death and disability, and particularly in low- and middle-income
countries. The Committee noted that optimal use of alteplase would require
timely and highly organized care pathways, in facilities that are equipped and
capable of managing stroke patients.
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3. Vanacker P, Lambrou D, Eskandari A, Mosimann PJ, Maghraoui A, Michel P. Eligibility and Predictors
for Acute Revascularization Procedures in a Stroke Center. Stroke. 2016;47(7):1844–9.
4. Aguiar de Sousa D, von Martial R, Abilleira S, Gattringer T, Kobayashi A, Gallofré M et al. Access to
and delivery of acute ischaemic stroke treatments: A survey of national scientific societies and
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angioedema during thrombolysis in acute ischemic stroke. J Neurol. 2005;252(10):1167–70.
11. Hill MD, Lye T, Moss H, Barber PA, Demchuk AM, Newcommon NJ et al. Hemi-orolingual
angioedema and ACE inhibition after alteplase treatment of stroke. Neurology. 2003;60(9):
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Section 17: GASTROINTESTINAL MEDICINES

17.2 Antiemetic medicines
Aprepitant – addition – EML and EMLc
Aprepitant ATC Code: A04AD12
Proposal
The application requested the inclusion of aprepitant on the EML and EMLc
as an antiemetic medicine for the supportive care of cancer patients receiving
moderately to highly emetogenic chemotherapy.
Applicants
European Society for Medical Oncology (ESMO)

unit advised that it supported the inclusion of aprepitant on the Model Lists
as supportive care for chemotherapy-induced nausea in patients receiving
moderately to highly emetogenic antineoplastic chemotherapy.
EML/EMLc
EML and EMLc
Section

Capsule: 40 mg, 80 mg, 125 mg, 165 mg
Powder for oral suspension: 125 mg
Core/Complementary
Complementary

Individual

Aprepitant has not previously been considered for inclusion on the Model Lists.
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Chemotherapy-induced nausea and vomiting (CINV) is one of the most
represented and significant side-effects related to chemotherapy. According
to European Society of Medical Oncology (ESMO) and to the Multinational
Association of Supportive Care in Cancer (MASCC), vomiting and, especially,
nausea, continue to be two of the most distressing side-effects of cancer
chemotherapy (1). Inadequately controlled CINV and radiotherapy-induced
nausea and vomiting (RINV) can precipitate a number of medical complications,
resulting in life-threatening conditions, including severe dehydration and
electrolyte imbalance with electrocardiogram (ECG) changes or myocardial
dysfunctions and Mallory-Weiss tears of the oesophagus. These complications can
impact on the burden of care, increasing the efforts and costs of hospitalization
and reducing the overall quality of life for patients, including a poorer outcome (2).
The distress resulting from these symptoms may potentially lead to the patient’s
refusal to continue with the most effective antitumour therapy (3). According
to a temporal criterion, the chemotherapy-associated emetic symptoms are
categorized as acute or delayed: acute CINV occurs in the first 24 hours after
chemotherapy, and delayed CINV at more than 24 hours. Aprepitant is indicated
for prevention of both acute and delayed CINV.
A four-level classification of chemotherapy agents has been accepted
by registration authorities and groups producing recommendations on
antiemetics, according to the emetogenic potential: high (emetic risk >90%);
moderate (30%–90%); low (10%–30%); and minimal (<10%). To provide an
example, anthracycline-taxane containing regimens and cisplatin > 50 mg/m2
are considered highly emetogenic; carboplatin, bendamustine and doxorubicin
monotherapy are classified as moderately emetogenic; docetaxel monotherapy,
gemcitabine, 5-FU and bortezomib are considered low emetogenic medicines (4).

The application presented the findings of multiple clinical trials of aprepitant,
using the MASCC/ESMO 2016 consensus guidelines for the prevention of
chemotherapy and radiotherapy-induced nausea and vomiting (1) as a reference
source. For the prevention of highly emetogenic chemotherapy CINV, a three-
drug regimen including single doses of an anti-5-HT3, dexamethasone and anti-
NK1 given before chemotherapy is recommended (MASCC level of confidence:
high; MASCC level of consensus: high; ESMO level of evidence I; ESMO grade
of recommendation: A) in the MASCC/ESMO guidelines.
Adults:
In a multicentre, double-blind, placebo-controlled trial in 421 Chinese cancer
patients (5), addition of aprepitant to standard therapy with granisetron and
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dexamethasone resulted in an increased absolute rate of patients achieving a

complete response (no emesis and no use of rescue therapy) during the overall
phase (+12.9%, p=0.007). The benefit was mainly attributable to better control of
delayed CINV with an increase of 14.6% of patients in absolute terms. Complete
response rates for treatment groups were almost identical for acute CINV.
In a multicentre, double-blind, placebo-controlled trial in 324 Japanese
cancer patients (6), addition of aprepitant to therapy with a 5-HT3 receptor
antagonist and dexamethasone prior to chemotherapy resulted in a higher
percentage of patients with “no vomiting” in the overall phase (78.2 vs 54.8;
p<0.0001), delayed phase (80.1 vs 56.9; p<0.0001), and acute phase 96.0 vs
91.1, respectively; p=0.0495). The percentage of patients with “no significant
nausea” was higher in the aprepitant group than in the placebo group in the
overall phase (85.4 vs 74.7; p=0.0143) and in the delayed phase (85.4 vs 76.0;
p=0.0274), but there was no difference between groups in the acute phase.
Similar results have been observed in patients receiving moderately to
highly emetogenic chemotherapy in other disease-oriented clinical trials using
moderately to highly emetogenic regimens, including treatments for lung cancer
and germ-cell tumours trials in Asian and non-Asian populations (7–12).
In a clinical trial of 264 patients preparing to undergo a stem cell
transplant, patients were randomized to receive oral aprepitant or placebo in
combination with oral ondansetron and dexamethasone during and for three
days after the completion of the preparative high-dose cyclophosphamide
regimens before the transplant (13). Patients who received aprepitant had
higher complete response rates (81.9% vs 65.8%; p<0.001) compared to the
standard treatment. 48.9% of patients in the aprepitant arm were able to
maintain an intake of food >50% of normal versus only 14.6% of patients in the
placebo arm, supporting the value of aprepitant in the overall supportive care of
cancer patients.
Children:
In a randomized, double-blind, placebo-controlled trial, chemotherapy naive
children aged 5 to 18 years receiving highly emetogenic chemotherapy were
randomized to intravenous ondansetron (0.15 mg/kg) and dexamethasone
(0.15 mg/kg) prior to chemotherapy followed by oral ondansetron and
dexamethasone and either oral aprepitant (15-40 kg = days 1–3, 80 mg; 41-65 kg
= day 1, 125 mg and days 2–3, 80 mg) one hour before chemotherapy or placebo
(n=96) (14). The patients enrolled presented with both haematological and solid
tumours: 25% received the treatment for Hodgkin lymphoma and the remaining
75% for sarcoma (osteosarcoma, Ewing sarcoma, rhabdomyosarcoma) or adenoid
cystic carcinoma. Overall, 84% of patients in the placebo arm had moderate to
severe vomiting compared to 56% in the aprepitant arm (p=0.004). There was
less moderate and severe vomiting reported in the group receiving aprepitant
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compared to the placebo group (38% vs 72, p = 0.001) in the acute phase and a
non-significant difference between the two groups in the delayed phase (42% vs
56%, p= 0.18). Complete response was higher in aprepitant arm, registered in the
acute phase for 48% of patients compared to 12% in the placebo arm (p<0.001).
The use of aprepitant resulted in better food intake (normal in 48% and 28%
of the children receiving aprepitant versus placebo, p=0.04) and fluid intake
(normal in 62% and 40%, p=0.03).
In another Phase III trial, aprepitant for CINV prevention was assessed
in patients aged six months to 17 years scheduled to receive either moderately
or highly emetogenic chemotherapy (15). 307 patients were randomized to
receive aprepitant plus ondansetron on day 1, followed by aprepitant on days
2 and 3, or placebo plus ondansetron on day 1 followed by placebo on days 2
and 3; dexamethasone was incorporated in nearly one third of the patients, with
no difference between the study and control group. Patients presented with
haematological and solid tumours. 77/152 (51%) patients in the aprepitant group
and 39/150 (26%) in the control group achieved a complete response in the
delayed phase (p<0.0001), reporting an increase of 25% in absolute terms; similar
results were found in the acute phase (complete response in the acute phase for
aprepitant: 66% vs 52%, p=0.0135) and overall control (40% vs 20%, p=0.0002).
Meta-analyses:
Clinical data of aprepitant as antiemetic agent for moderately to highly emetogenic
chemotherapy have been analysed systematically, addressing the role and benefit
in cancer treatments.
A meta-analysis performed in China, of ten studies of aprepitant for
prevention of CINV, involving 4376 patients (16) found that for acute CINV,
aprepitant improved the complete response by 14.21% in the acute phase, when
combined with ondansetron and dexamethasone (83.33% vs 72.96%; p<0.001);
patients receiving cisplatin seemed to derive a greater benefit than those who
received an anthracycline plus cyclophosphamide regimen. For delayed CINV,

aprepitant could improve vomiting by 14.98% compared with ondansetron
(p=0.004).

The safety of aprepitant has been evaluated in the clinical trials.
Hu et al (5) reported similar occurrences of drug-related adverse
events (AEs) in 11.7% (24/205) of patients in the aprepitant group and 13.3%
(28/210) of patients in the placebo-controlled therapy group. One or more
AEs were reported in 40.0% (8/205) of patients in the aprepitant group and in
44.3% (93/210) of patients in the standard therapy group, representing similar
occurrences. AEs included fatigue (5.9% and 1.9% in the aprepitant and placebo-
controlled group, respectively), dizziness (2.4% and 0%), anaemia (2% and 0%),
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insomnia (2% and 5.7%), upper abdominal pain (0% and 2.9%), and non-cardiac
chest pain (0% and 1%). Overall, no severe drug-related serious AEs or laboratory
anomalies were reported during cycle 1, and there were no discontinuations due
to medication-related AEs.
In the trial of patients preparing for stem-cell transplantation (13),
incorporation of aprepitant had no effect on the engraftment and the survival,
supporting the oncological safety in terms of the cancer outcome and excluding
significant interference with the antineoplastic agents used.
Pharmacokinetic studies have shown that drug–drug interactions with
aprepitant may exist, but are not considered clinically meaningful (17).
In children, the safety profile of aprepitant appears consistent with the
reports in adult populations (15).

N/A
WHO Guidelines
None available.
The application presented two studies that evaluated the cost-effectiveness of
aprepitant regimens for CINV.
In a decision–analytic model study in Germany, an aprepitant
regimen (aprepitant/ondansetron/dexamethasone) was compared with a control
(ondansetron/dexamethasone) regimen, addressing clinical results and resource
utilization (18). Incremental drug cost per patient and cycle for antiemetic
prophylaxis was € 73.38. Expected health care utilization cost was € 154.99 in the
aprepitant group and € 178.77 in the control group. Hence, it was estimated that
42% of the aprepitant drug cost was offset by lower resource use in the aprepitant
group. Cost offsets arose mainly from lower doses of dexamethasone (€ 12.54),
reduced use of rescue medication (€ 7.38), and avoided hospitalizations (€ 15.86).
For the cost-effectiveness analysis (CEA), the range was € 26,135–31,646 per
QALY gained with aprepitant and was judged cost-effective.
The same conclusion was reached in a CEA performed in UK,
considering patients receiving chemotherapy for breast cancer (19). An average
of £ 37.11 (78%) of the cost of aprepitant was offset by the reduction in health
care resource utilization costs; use of the aprepitant was associated with an
additional cost of £ 28 for each emesis-free day gained and £ 22 for each CINV-
free day gained. The ICER with aprepitant, was £ 10 847/QALY.
Availability
Aprepitant is available globally. Generic brands are available.
377
Aprepitant should be used in combination with dexamethasone and a 5-HT3
receptor antagonist.
The Committee recognized the importance of adequate control of nausea and
vomiting in patients undergoing cancer chemotherapy, in terms quality of life
and clinical outcomes of treatment.
The Expert Committee recommended the addition of aprepitant to the
complementary list of the EML and EMLc as an antiemetic medicine for the
supportive care of cancer patients receiving moderately to highly emetogenic
chemotherapy on the basis of a favourable benefit to risk profile.
The Committee noted that aprepitant, in combination with dexamethasone
and a 5-HT3 receptor antagonist (e.g. ondansetron), is more effective than
standard antiemetic therapy at reducing both acute and delayed onset nausea
and vomiting associated with chemotherapy.
References
1. Roila F, Molassiotis A, Herrstedt J, Aapro M, Gralla RJ, Bruera E et al. 2016 MASCC and ESMO
guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and
vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27(suppl
5):v119–v33.
2. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic
control. Oncologist. 2003;8(2):187–98.
3. Doherty KM. Closing the gap in prophylactic antiemetic therapy: patient factors in calculating
the emetogenic potential of chemotherapy. Clin J Oncol Nurs. 1999;3(3):113–9.
4. Grunberg SM, Osoba D, Hesketh PJ, Gralla RJ, Borjeson S, Rapoport BL et al. Evaluation of new
antiemetic agents and definition of antineoplastic agent emetogenicity--an update. Support Care
Cancer. 2005;13(2):80–4.
5. Hu Z, Cheng Y, Zhang H, Zhou C, Han B, Zhang Y et al. Aprepitant triple therapy for the prevention
of chemotherapy-induced nausea and vomiting following high-dose cisplatin in Chinese
patients: a randomized, double-blind, placebo-controlled phase III trial. Support Care Cancer.
2014;22(4):979–87.
6. Yahata H, Kobayashi H, Sonoda K, Shimokawa M, Ohgami T, Saito T et al. Efficacy of aprepitant for
the prevention of chemotherapy-induced nausea and vomiting with a moderately emetogenic
chemotherapy regimen: a multicenter, placebo-controlled, double-blind, randomized study
in patients with gynecologic cancer receiving paclitaxel and carboplatin. Int J Clin Oncol.
2016;21(3):491–7.
7. Ito Y, Karayama M, Inui N, Kuroishi S, Nakano H, Nakamura Y et al. Aprepitant in patients with
advanced non-small-cell lung cancer receiving carboplatin-based chemotherapy. Lung Cancer.
2014;84(3):259–64.
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8. Nishimura J, Satoh T, Fukunaga M, Takemoto H, Nakata K, Ide Y et al. Combination antiemetic

therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-
based chemotherapy (SENRI trial): a multicentre, randomised, controlled phase 3 trial. Eur J
Cancer. 2015;51(10):1274–82.
9. Albany C, Brames MJ, Fausel C, Johnson CS, Picus J, Einhorn LH. Randomized, double-blind,
placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist
aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients
with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier
oncology group study. J Clin Oncol. 2012;30(32):3998–4003.
10. Olver IN, Grimison P, Chatfield M, Stockler MR, Toner GC, Gebski V et al. Results of a 7-day aprepitant
schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor
chemotherapy. Support Care Cancer. 2013;21(6):1561–8.
11. Hamada S, Hinotsu S, Kawai K, Yamada S, Narita S, Kamba T et al. Antiemetic efficacy and safety of
a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ
cell tumor receiving 5-day cisplatin-based combination chemotherapy. Support Care Cancer.
2014;22(8):2161–6.
12. Bechtel T, McBride A, Crawford B, Bullington S, Hofmeister CC, Benson DM, Jr. et al. Aprepitant for
the control of delayed nausea and vomiting associated with the use of high-dose melphalan for
autologous peripheral blood stem cell transplants in patients with multiple myeloma: a phase II
study. Support Care Cancer. 2014;22(11):2911–6.
13. Stiff PJ, Fox-Geiman MP, Kiley K, Rychlik K, Parthasarathy M, Fletcher-Gonzalez D et al. Prevention
of nausea and vomiting associated with stem cell transplant: results of a prospective, randomized
trial of aprepitant used with highly emetogenic preparative regimens. Biol Blood Marrow
Transplant. 2013;19(1):49–55.e1.
14. Bakhshi S, Batra A, Biswas B, Dhawan D, Paul R, Sreenivas V. Aprepitant as an add-on therapy
in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-
controlled trial. Support Care Cancer. 2015;23(11):3229–37.
15. Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of
chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3
trial. Lancet Oncol. 2015;16(4):385–94.
16. Fang ZW, Zhai SD. [A meta-analysis of aprepitant for prevention of chemotherapy-induced
nausea and vomiting]. Beijing da xue xue bao Yi xue ban/Journal of Peking University Health
sciences. 2010;42(6):756–63.
17. Aapro M, Carides A, Rapoport BL, Schmoll HJ, Zhang L, Warr D. Aprepitant and fosaprepitant: a
10-year review of efficacy and safety. Oncologist. 2015;20(4):450–8.
18. Lordick F, Ehlken B, Ihbe-Heffinger A, Berger K, Krobot KJ, Pellissier J et al. Health outcomes
and cost-effectiveness of aprepitant in outpatients receiving antiemetic prophylaxis for highly
emetogenic chemotherapy in Germany. Eur J Cancer. 2007;43(2):299–307.
19. Humphreys S, Pellissier J, Jones A. Cost-effectiveness of an aprepitant regimen for prevention of
chemotherapy-induced nausea and vomiting in patients with breast cancer in the UK. Cancer
Manag Res. 2013;5:215–24.
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Ondansetron – square box – EML and EMLc
Ondansetron ATC Code: A04AA01
Proposal
The application requested the addition of a square box to the listing of
ondansetron on the EML and EMLc, to correct an omission from the original
recommendation to list.
Applicants
EML Secretariat

unit advised that it supported the addition of a square box to the listings of
ondansetron as representative of the pharmacological class of 5-HT3 receptor
antagonists, stating that this class of medicines are essential medicines for the
optimal management of common treatment-related adverse events associated
with emetogenic chemotherapy.
EML/EMLc
EML and EMLc
Section
2.3 Medicines for other common symptoms in palliative care

Injection: 2 mg base/mL in 2- mL ampoule (as hydrochloride)
Oral liquid: 4 mg base/5 mL
Solid oral dosage form: Eq 4 mg base; Eq 8 mg base: Eq 24 mg base
Core/Complementary
Core

Square box
380

Ondansetron was first included on the EML and EMLc following a review of
antiemetic medicines considered by the 2009 Expert Committee (1). Listing
was recommended with a square box symbol, designating ondansetron as
representative of the pharmacological class of 5-HT3 receptor antagonists.
However, the square box was inadvertently omitted when the lists were published.
Alternative 5-HT3 receptor antagonists within the pharmacological class
are shown below:
ATC Code Medicine DDD Units RoA
A04AA01 Ondansetron 16 mg O, P, R
A04AA02 Granisetron 2 / 3 / 3.1 mg O/ P / TD
A04AA03 Tropisetron 5 mg O/P
A04AA04 Dolasetron 0.2 / 0.1 g O/P
A04AA05 Palonosetron 0.5 / 0.25 mg O/P

N/A

N/A

N/A

A 2016 systematic review of 299 studies (58 412 patients) identified during the
application review process investigated the comparative safety and effectiveness
of 5-HT3 receptor antagonists in patients undergoing chemotherapy. The review
concluded that most 5-HT3 receptor antagonists used alone, or in combination
with corticosteroids, were effective at decreasing the occurrence of nausea and/
or vomiting, and were similarly safe when compared to each other (2).
WHO Guidelines
None available.
The square box indicating therapeutic equivalence between alternative 5-HT3
receptor antagonists will allow tendering among available options or competition
in pooled procurement mechanisms at country/local level or benchmarking for
lowering prices.
381
Availability
The 5-HT3 receptor antagonists have wide market availability and are available
in generic forms.
N/A
The Committee recommended the addition of a square box to the listing of
ondansetron on the EML and EMLc, noting that the original recommendation to
list ondansetron in 2009 had included a square box.
References
(including the 16th WHO Model List of Essential Medicines and the 2nd WHO Model List of
WHO_TRS_958_eng.pdf, accessed 30 October 2019.
2. Tricco AC, Blondal E, Veroniki AA, Soobiah C, Vafaei A, Ivory J et al. Comparative safety and
effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a
systematic review and network meta-analysis. BMC Med. 2016;14(1):216.
382
17.5 Medicines used in diarrhoea

Oral rehydration salts (ORS) and zinc (co-packaged) – new formulation – EMLc
Oral rehydration salts and zinc sulfate ATC Code: A07CA,

A12CB01
Proposal
The application requested inclusion of co-packaged oral rehydration salts (ORS)
and zinc sulfate tablets on the core list of the EMLc.
Applicants
Diarrhea Innovations Group

Maternal, Newborn, Child and Adolescent Health
EML/EMLc
EMLc
Section

Powder for dilution (refer section 17.5.1) – solid oral dosage form (refer section
17.5.2) co-packaged for the treatment of acute diarrhoea.
Core/Complementary
Core

Individual

Oral rehydration salts and zinc sulfate 20 mg solid oral dosage form are
currently both listed individually on the EML and EMLc for use in the treatment
of diarrhoea.

Diarrhoea is present globally, in all regions and among all populations. However,
an inequitable proportion of diarrhoea morbidity and mortality occurs in
383
low-income countries, which in turn have fewer resources and less robust
infrastructure to manage the burden (1). The Global Burden of Disease Study 2016
(GBD) estimated diarrhoea as the eighth leading cause of death, responsible for
well more than 1.6 million deaths and the fifth leading cause of death among
children younger than 5 years (446 000 deaths). Approximately 90% (89.37%) of
diarrhoeal deaths occurred in South Asia and sub-Saharan Africa (2).

The benefits associated with ORS and zinc have been previously considered and
accepted at the time of the original listings.
The current application identified a number of studies (3–8) that provide
supporting evidence for the benefits of co-packaged ORS and zinc, including:
■■ Increased uptake and coverage of ORS and zinc (as a combination
therapy, and as individual components), reducing the risk of severe
health consequences of chronic diarrhoea and stunting, acute
diarrhoea, and zinc deficiency among children.
■■ Improved adherence to the combined therapy of ORS and zinc.
■■ Improved adherence to/preparation of individual components (e.g.
correct concentration of prepared ORS and completion of a full
course of zinc).
■■ Improved dispensing practices by health care workers.
■■ Reduced hospitalizations due to diarrhoea.
■■ Reductions in inappropriate antibiotic prescription and use.
■■ Enhanced satisfaction levels by caregivers with ORS and zinc relative
to status quo products.
■■ Enhanced opportunities for developing private sector models and
leveraging value chains to improve availability and access closer to
the household level.

Overall, ORS is safe, with few reports of adverse events. Additional adverse
events that occur with ORS administration include oedematous (puffy) eyelids,
which are a sign of over hydration, and vomiting. Zinc supplementation has
been utilized extensively with demonstrated safety in the treatment of diarrhoea.
To date, there have been no reports of severe adverse reactions from any form of
zinc treatment for diarrhoea, alone or in combination with ORS.

N/A
384
WHO Guidelines
The current WHO recommendations for ORS and zinc use in the management
of diarrhoea in children with no signs of dehydration (Plan A) are:
Low-osmolarity ORS (containing 75 mEq/L of sodium and 75 mmol/L
of glucose) after each loose motion:
■■ In a child younger than 2 years of age, provide 50 mL to 100 mL of
ORS solution.
■■ In a child 2 to 10 years of age, provide 100 mL to 200 mL of ORS
solution.
■■ In a child older than 10 years of age, provide ORS ad libitum (i.e. to
drink freely).
Zinc sulfate from the start of the diarrhoea:
■■ In a child younger than six months, provide one half of a 20 mg
tablet (i.e. 10 mg) once a day for 10 to 14 days.
■■ In a child older than six months, provide one whole 20 mg tablet
once a day for 10 to 14 days.
The current WHO recommendations for ORS and zinc use in the management of
diarrhoea in children with some dehydration (Plan B) are:
Low-osmolarity ORS (containing 75 mEq/L of sodium and 75 mmol/L
of glucose):
■■ ORS in the first four hours is administered according to the weight
of the child (or the child’s age if the weight is not known).
Zinc sulfate from the start of the diarrhoea:
■■ As per Plan A
The application presented the comparative costs of co-packaged and individually
packaged ORS and zinc from five African countries. In each case, the co-packaged
product was less expensive than the combined cost of the individual products.
Availability
Co-packaged ORS and zinc is available from multiple suppliers.
The Committee noted the multiple letters of support received in relation to this
application.
385
The Committee recommended the inclusion of co-packaged oral rehydration
salts (ORS) and zinc sulfate tablets on the core list of the EMLc. The Committee
considered that since these products are recommended to be administered
together in the management of diarrhoea, the availability of the co-packaged
product will be practical and support better adherence to treatment. Countries
may also realize cost savings with the co-packaged product.
References
1. Mills A. Health care systems in low- and middle-income countries. N Engl J Med. 2014;370(6):
552–7.
2. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a
systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):
1151–210.
3. Borapich D, Warsh M. Improving Child Health in Cambodia: Social Marketing of Diarrhea
Treatment Kit, Results of a Pilot Project. Cases in Public Health Communication & Marketing.
2010;4:4–22.
4. Gebremedhin S, Mamo G, Gezahign H, Kung’u J, Adish A. The effectiveness bundling of zinc with
Oral Rehydration Salts (ORS) for improving adherence to acute watery diarrhea treatment in
Ethiopia: cluster randomised controlled trial. BMC Public Health. 2016;16:457.
5. Roche M, Meza RG, Vossenaar M. An Intervention to Co-package Zinc and Oral Rehydration Salts
(ORS) Improves Health Provider Prescription and Maternal Adherence to WHO-recommended
Diarrhea Treatment in Western Guatemala. The FASEB Journal. 2015;29(1_supplement):902.23.
6. Habib MA, Soofi S, Sadiq K, Samejo T, Hussain M, Mirani M et al. A study to evaluate the
acceptability, feasibility and impact of packaged interventions (“Diarrhea Pack”) for prevention
and treatment of childhood diarrhea in rural Pakistan. BMC Public Health. 2013;13:922.
7. Ramchandani R. Emulating Commercial, Private-Sector Value-Chains to Improve Access to ORS
and Zinc in Rural Zambia: Evaluation of the Colalife Trial. Dissertation submitted to The Johns
Hopkins University in conformity with the requirements for the degree of Doctor of Public Health.
Available from https://jscholarship.library.jhu.edu/handle/1774.2/39229, accessed 29 September
2019.
8. Goh N, Pollak K. Progress over a Decade of Zinc and ORS Scale-up: Best Practices and Lessons
Learned. Boston MA, USA: Clinton Health Access Initiative; 2016. Available from https://
clintonhealthaccess.org/content/uploads/2016/02/Progress-over-a-Decade-of-Zinc-and-ORS-
Scale-Up.pdf, accessed 29 September 2019.
386
Section 18: MEDICINES FOR ENDOCRINE DISORDERS

18.5 Insulin and other medicines used for diabetes
Long-acting insulin analogues (including biosimilars) – addition – EML
Long-acting insulin analogues (including biosimilars)

Insulin detemir ATC Code: A10AE05
Insulin glargine ATC Code: A10AE04
Insulin degludec ATC Code: A10AE06
Proposal
The application proposed the inclusion of long-acting insulin analogues on the
core list of the EML for treatment of patients with type 1 diabetes.
Applicant
Andrea C. Tricco, Huda M. Ashoor, Jesmin Antony, Zachary Bouck, Myanca
Rodrigues, Ba’ Pham, Paul A. Khan, Vera Nincic, Nazia Darvesh, Fatemeh Yazdi,
Marco Ghassemi, John D. Ivory, Wanrudee Isaranuwatchai, Areti Angeliki
Veroniki, Catherine H. Yu, and Sharon E. Straus
Knowledge Translation Program, St Michael’s Hospital, Toronto, Canada.

unit advised that it did not support the application to add long-acting insulin
analogues (including biosimilars) to the EML, nor was the application developed
in consultation with the technical department.
EML/EMLc
EML
Section
Core

Insulin detemir: injection 100 units/mL
Insulin glargine: injection 100 units/mL
Insulin degludec: injection 100 units/mL
Core/Complementary
Core
387

Square box

Human insulin has been included on the EML since the first list in 1977 (1).
In 1985, the WHO Expert Committee on the Selection and Use of Essential
Medicines approved the inclusion of isophane neutral protamine Hagedorn
(NPH) insulin (2).
Since 1996, different insulin analogues, altered forms of human insulins,
have been introduced on markets worldwide. In recent years, additional
comparative evidence on biosimilars and reference medications in terms of
efficacy and safety became available.
In 2017, at the 21st meeting of the Expert Committee of the WHO EML,
an application for the inclusion of long-acting analogues to the EML was rejected
due to the limited magnitude of the benefits of analogues over human insulin in
terms of reduced glycated haemoglobin and reduced hypoglycaemia as compared
to the large difference in price between analogues and human insulin (3).
Since that time, additional evidence has become available encompassing
both effectiveness and increasing affordability of analogues.

Diabetes mellitus has an increasing worldwide prevalence. If current trends
continue, it is estimated that 642 adults will be living with diabetes by 2040 (4).
The incidence of type 1 diabetes mellitus (T1DM) accounts for a small proportion
of all diabetes (range: 5–10%) (5).
All people living with type 1 diabetes have an absolute need for insulin
for survival. Insulin is also required by a subset of patients with type 2 diabetes
(6). Lack of access to affordable insulin is a problem globally and contributes to
the complications of untreated or sub-optimally treated diabetes and premature
deaths (7).

The application presented the findings of a network meta-analysis (NMA) to
evaluate the comparative effectiveness and safety of long- or intermediate-acting
insulin versus biosimilar insulins in patients with T1DM, updating the results of
a previous systematic review.
The review compared basal regimens and categorizes treatments as per
class of basal insulin (i.e. intermediate acting, long-acting and ultra-long-acting),
and specific type of basal insulin, including insulin origin and insulin frequency.
The analyses were adjusted for bolus regimen.
Sixty-eight primary studies (8–75) (and 12 companion reports) involving
15 150 patients with average age ranging from 23 to 54 years were included.
388
Sixty‑two (91%) studies were randomized controlled trials (RCTs) and the
majority had an unclear/high risk of bias on random sequence generation,
allocation concealment, selective reporting, and ‘other’ bias (e.g. funding bias).
Details of the included studies are available in Appendix File 1 of the application
at: https://www.who.int/selection_medicines/committees/expert/22/applications/
s18.5_insulin-analogues.pdf?ua=1.
Primary efficacy outcomes of the network meta-analysis were A1c and
fasting plasma glucose. Secondary efficacy outcomes were mortality, any (total)
vascular complication, microvascular complications, macrovascular complications
and quality of life.
A1c
A basal insulin class NMA was conducted including 26 RCTs and 9241 patients
and three treatment nodes (long-acting, intermediate-acting and ultra-long-
acting biosimilar). Long-acting insulin was statistically superior to intermediate-
acting insulin (mean difference MD −0.14, 95%CI −0.21 to −0.07).
A specific type of insulin NMA was conducted on the A1c outcome
including 34 RCTs and 11 894 patients and nine treatment nodes. Across the 36
treatment comparisons, the following 11 showed statistically significant results:
–– Intermediate-acting (human) insulin administered four times
a day was inferior to intermediate-acting (animal and human)
insulin administered twice a day (mean difference MD 0.31,
95% CI 0.05 to 0.57).
–– Intermediate-acting (human) insulin administered qid was
inferior to intermediate-acting (human) insulin administered bid
(MD 0.43, 95%CI 0.23 to 0.63).
–– Intermediate-acting (human) insulin administered qid was
inferior to intermediate-acting (human) insulin administered
once daily (od) (MD 0.32, 95%CI 0.10 to 0.53).
–– Long-acting (biosimilar) insulin administered od was superior
to intermediate-acting (human) insulin administered qid
(MD −0.46, 95%CI −0.67 to −0.24).
–– Long-acting (human) insulin administered bid was superior
(MD −0.49, 95%CI −0.70 to −0.29).
to intermediate-acting (human) insulin administered od
(MD −0.18, 95%CI −0.30 to −0.06).
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–– Long-acting (human) insulin administered od was superior to

intermediate-acting (animal and human) insulin administered
bid (MD −0.19, 95%CI −0.37 to −0.01).
intermediate-acting (animal) insulin administered bid (MD
−1.27, 95%CI −2.54 to −0.01).
–– Long-acting (human) insulin administered od was superior
(MD −0.50, 95%CI −0.69 to −0.31).
(MD −0.18, 95%CI −0.29 to −0.08).
–– Ultra-long-acting (biosimilar) insulin administered od was
superior to intermediate-acting (human) insulin administered qid
(MD −0.44, 95%CI −0.64 to −0.23).
A sensitivity analysis to examine the impact of imputing missing standard
deviations on the results resulted in the exclusion of seven trials. The pairwise
treatment comparisons above were no longer statistically significant when the
seven trials were excluded.
When meta-regression analyses were conducted for follow-up duration,
A1c level (mild: <8%, severe: ≥8%); proportion of women; duration of diabetes;
and risk of bias associated with random sequence generation and allocation
concealment, none of the results remained statistically significant.
Statistically significant results were shown for meta-regression analyses on:
–– bolus type (rapid vs short): long-acting (human) insulin
administered od was superior to intermediate-acting (animal)
insulin administered bid (MD −1.27, 95%CI −2.54 to −0.001);
–– study design (parallel or crossover trials): long-acting (human)

insulin administered bid was superior to intermediate-acting
(animal) insulin administered bid (MD −1.27, 95%CI −2.53 to
−0.0007);
–– baseline A1c: intermediate-acting (animal and human) insulin
administered bid was superior to intermediate-acting (animal)
insulin administered bid (MD −1.32, 95%CI −2.63 to −0.02);
–– age: long-acting (human) insulin administered bid, was superior
to intermediate-acting (animal) insulin administered bid (MD
−1.31, 95%CI −2.58 to −0.04) and long-acting (human) insulin
administered od was superior to intermediate-acting (animal)
insulin administered bid (MD −1.28, 95%CI −2.54 to −0.007).
390
Fasting plasma glucose

A basal insulin class NMA was conducted on the fasting plasma glucose outcome
including 21 RCTs, 7685 patients, and three treatment nodes. Long-acting insulin
was statistically superior to intermediate-acting insulin (MD −1.03, 95%CI
−1.33 to −0.73) and ultra-long-acting insulin was superior to intermediate-acting
insulin (MD −1.45, 95%CI −2.12 to −0.79).
A specific type of insulin NMA was conducted on the fasting plasma
glucose outcome including 28 RCTs, 9773 patients, and eight treatment nodes.
Across the 28 treatment comparisons, the following nine showed statistically
significant results:
–– Long-acting (biosimilar) insulin administered od was superior
to intermediate-acting (human) insulin administered bid
(MD −1.07, 95%CI −1.98 to −0.15).
(MD −0.82, 95%CI −1.21 to −0.43).
(MD −1.26, 95%CI −1.66 to −0.85).
(MD −1.15, 95%CI −1.82 to −0.49).
long-acting (human) bid (MD −0.43, 95%CI −0.82 to −0.05).
superior to intermediate-acting (human) insulin administered qid
(MD −1.20, 95%CI −2.31 to −0.09).
superior to intermediate-acting (human) bid (MD −1.55, 95%CI
−2.24 to −0.87).
superior to intermediate-acting (human) insulin administered od
(MD −1.45, 95%CI −2.34 to −0.56).
superior to long-acting (human) insulin administered bid
(MD −0.73, 95%CI −1.38 to −0.08).
Mortality
A NMA was not possible for all-cause mortality for basal insulin classes. Two
pairwise meta-analyses were possible for long-acting versus intermediate-acting
391
insulin (four RCTs, 1682 patients), as well as ultra-long-acting versus long-acting

insulin (two RCTs, 1540 patients). None of the results were statistically significant.
A NMA was not possible for all-cause mortality for specific types of
insulin. Three pairwise meta-analyses were possible comparing long-acting
(human) insulin administered bid versus intermediate-acting (human) insulin
administered bid (two RCTs, 653 patients), long-acting (human) insulin
administered od versus long-acting (biosimilar) insulin administered od (two
RCTs, 1093 patients) and long-acting (human) insulin administered od versus
ultra-long-acting (biosimilar) insulin administered od (two RCTs, 1540 patients).
None of the results were statistically significant.
Any (total) vascular complication
A basal insulin class NMA was conducted on any vascular complication,
including 11 RCTs and 4709 patients. Across the three treatment comparisons,
none were statistically significant.
A specific type of insulin NMA was conducted on any vascular
complication including 13 RCTs and 5589 patients. Across the 10 treatment
comparisons, none were statistically significant.
Microvascular complications
A basal insulin class NMA was conducted to compare long-acting, intermediate-
acting and ultra-long acting insulins on microvascular complications including
eight RCTs and 3131 patients. The transitivity assumption was upheld but
inconsistency could not be assessed since there were no closed loops in the
network meta-analysis diagram. Across the three treatment comparisons, none
were statistically significant.
A specific type of insulin NMA was conducted on microvascular
complications including 10 RCTs and 4011 patients. Across the 10 treatment
comparisons, none were statistically significant.
Macrovascular complications
For basal insulin classes, a NMA was not possible for macrovascular
complications. Two pairwise meta-analyses were possible; long-acting insulin
versus intermediate-acting insulin (three RCTs, 998 patients) and ultra-long-
acting biosimilar insulin versus long-acting insulin (three RCTs, 2098 patients).
The results of pairwise treatment comparisons were not statistically significant.
For specific types of insulin, a NMA was not possible for macrovascular
complications. Two pairwise meta-analyses were possible for long-acting
(human) insulin administered bid versus intermediate-acting (human) insulin
administered bid (four RCTs, 1258 patients) and long-acting (human) insulin
administered od versus ultra-long-acting (biosimilar) od (two RCTs, 1540
patients). The results were not statistically significant.
392
Quality of life
A NMA or pairwise meta-analyses were not possible for health-related quality
of life for basal insulin classes or specific types of insulin. One study including
517 patients reported total quality of life and long-acting (human) insulin
administered od was not statistically significant compared with intermediate-
acting (human) insulin administered bid. The same study reported general quality
of life and long-acting (human) insulin administered od was not statistically
significant compared with intermediate-acting (human) insulin administered
bid. With respect to basal insulin classes, similar results were observed when
long-acting insulin was compared to intermediate-acting insulin.

Weight change
A basal insulin class NMA was conducted including 16 RCTs, 6822 patients,
and three treatment nodes. Long-acting insulin was statistically superior to
intermediate-acting insulin (MD −0.70, 95%CI −1.07 to −0.33).
A specific type of insulin NMA was conducted including 20 RCTs,
8335 patients, and seven treatment nodes. Across the 21 treatment comparisons,
the following four showed statistically significant results:
(MD −0.85, 95%CI −1.24 to −0.46).
(MD −1.18, 95%CI −2.13 to −0.24).
–– Long-acting (human) insulin administered bid was superior to
long-acting (biosimilar) insulin administered od (MD −0.96,
95%CI −1.91 to −0.01).
to ultra-long-acting (biosimilar) insulin administered od
(MD −0.69, 95%CI −1.32 to −0.06).
All-cause hypoglycaemia (defined differently across RCTs)
A basal insulin class NMA was conducted including 17 RCTs and 5949 patients.
Across the three treatment comparisons, none were statistically significant.
A specific type of insulin NMA was conducted including 22 RCTs
and 6917 patients. Across the 21 treatment comparisons, none were statistically
significant.
393
Major or serious hypoglycaemia (defined differently across RCTs)

intermediate-acting insulin (odds ratio OR 0.63, 95%CI 0.51 to 0.76).
A specific type of insulin NMA was conducted including 25 RCTs and
9300 patients. Across the 21 treatment comparisons, the following four showed
statistically significant results:
–– Long-acting (biosimilar) insulin administered od was superior to
intermediate-acting (human) insulin administered bid (OR 0.48,
95%CI 0.24 to 0.97).
95%CI 0.54 to 0.88).
95%CI 0.39 to 0.72).
intermediate-acting (human) insulin administered od (OR 0.60,
95%CI 0.42 to 0.86).
Minor or mild hypoglycaemia
For basal insulin classes, a NMA was not possible. One pairwise meta-analysis
was possible for long-acting versus intermediate-acting insulin (eight RCTs,
2949 patients) and the results were not statistically significant.
A specific type of insulin NMA was conducted including 11 RCTs
and 3926 patients. Across the 15 treatment comparisons, none were statistically
significant.
Nocturnal hypoglycaemia (defined differently across RCTs)

intermediate-acting insulin (OR 0.71, 95%CI 0.57 to 0.89) and ultra-long-acting
biosimilar insulin was statistically superior to intermediate-acting insulin (OR
0.60, 95%CI 0.42 to 0.86).
A specific type of insulin NMA was conducted including 19 RCTs and
7564 patients. Across the 15 treatment comparisons, the following two showed
statistically significant results:
–– Intermediate-acting (human) insulin administered bid was
inferior to ultra-long-acting (biosimilar) insulin administered od
(OR 1.58, 95%CI 1.11 to 2.25).
394

95%CI 0.44 to 0.79).
Incident cancers
For basal insulin classes, a NMA was not possible. One pairwise meta-analysis
was possible for long-acting versus intermediate-acting insulin (three RCTs,
1651 patients) and the results were not statistically significant.
For specific types of insulin, a NMA was not possible. One pairwise meta-
analysis was possible (two RCTs and 1204 patients), which compared long-acting
(human) insulin administered od versus intermediate-acting (human) insulin
administered bid. The results were not statistically significant.
Any (total) adverse events, serious adverse events, and dropouts due to adverse events
For basal insulin classes, NMAs were conducted on any adverse events including
16 RCTs and 5367 patients, on serious adverse events including 20 RCTs and
6840 patients, and on withdrawals due to adverse events including 14 RCTs and
5440 patients. Across the three treatment comparisons in each NMA, none were
statistically significant.
For specific types of insulin, NMAs were conducted on any adverse
events including 22 RCTs and 6830 patients, on serious adverse events including
26 RCTs and 8989 patients, and on withdrawals due to adverse events including
21 RCTs and 7795 patients. Across the 15 treatment comparisons in each NMA,
none were statistically significant.

The current application does not include data on long-acting insulin analogue
use in children. Long-acting insulin analogues have been investigated extensively
in the paediatric age-group in low- and high-resource settings and were found
to be safe and effective (76–80). They are approved in children from age two
years (glargine and detemir) or one year (degludec) (81). Long-acting analogues
have also been successfully used in infants and have shown positive effects on
glucose control and on hypoglycaemia. However, the evidence is based on case
reports (82, 83).
WHO Guidelines
The WHO 2018 Guidelines on second- and third-line medicines and type of insulin
for the control of blood glucose levels in non-pregnant adults with diabetes mellitus
(84) make the following recommendations regarding the use of insulin:
–– Use human insulin (short-acting regular human insulin and
intermediate-acting human insulin (NPH insulin)) to manage
395
blood glucose in adults with type 1 diabetes and in adults with type
2 diabetes for whom insulin is indicated (strong recommendation,
low quality evidence).
–– Consider long-acting insulin analogues to manage blood glucose
in adults with type 1 or type 2 diabetes who have frequent severe
hypoglycaemia with human insulin (weak recommendation,
moderate quality evidence for severe hypoglycaemia).
Recommendations from the 2018 WHO guidelines targeting type 1
diabetes were based on evidence from systematic reviews of randomized
controlled trials (85–87).
For patients with type 1 diabetes, the mean difference in HbA1c level
between short-acting insulin analogues and regular human insulin was −0.15%
(95%CI −0.20% to −0.10%) (low quality evidence). The difference in HbA1c level
in patients treated with short-acting insulin analogues compared with those
treated with regular human insulin was not considered clinically meaningful by
the guidelines development group. Long-acting insulin analogues and human
NPH insulin had similar effects on HbA1c level (moderate quality evidence).
Long-acting insulin analogues reduced risk for severe hypoglycaemia, but
only the reduction with detemir was statistically significant (moderate quality
evidence). The guideline panel concluded that the relatively modest overall
benefit from insulin analogues was outweighed by the large price difference
between human insulin and insulin analogues. Thus, the panel considered use
of long-acting detemir and glargine insulin analogues as alternatives to human
insulin only in specific circumstances, such as unexplained and frequent severe
hypoglycaemic events.
Ten cost-effectiveness analyses reported in three studies compared long-acting

insulin detemir once a day with intermediate-acting insulin NPH once a day
(72, 73, 75). Two studies (72, 75) found that detemir was less costly and more
effective, while the third (73) showed that detemir was more costly but also
more effective than NPH. Two cost-effectiveness analyses reported in a single
study compared long-acting insulin detemir once a day with long-acting insulin
glargine once a day (74). This study demonstrated that detemir is more cost-
effective than glargine. Finally, a single cost-effectiveness analysis in a single
study compared ultra-long-acting biosimilar insulin degludec once a day with
long-acting insulin glargine once a day (71). Degludec was shown to be the more
cost-effective treatment in comparison to glargine.
396
Availability
Three pharmaceutical companies are solely responsible for the supply of almost
all insulin on markets worldwide. Despite being available for almost 100 years,
achieving reliable, equitable and affordable access to insulin, human or analogue,
remains a public health challenge in many countries (88). The Committee
recognized the need for a wider understanding of the complexities of access to
insulin and the current insulin market and recommended WHO to prioritize
the coordination of a series of actions to address the issues of insulin access
and affordability.
The review found long-acting insulin analogues to be superior to intermediate
acting insulin with regard to major or serious hypoglycaemia, which may
represent an advantage particularly in settings where food security is not reliable.
Glucagon, used in the management of severe hypoglycaemia, has very limited
availability in many low-resource settings (89). Thus, the lower incidence of
major or serious hypoglycaemia associated with the use of (ultra) long-acting
insulin analogues may offer further advantages in such settings.
The Committee acknowledged and noted the comments received in
relation to this application from organizations and individuals expressing
concern about the potential inclusion of insulin analogues on the Model List and
associated consequences.
The Committee acknowledged that insulin is a life-saving essential medicine
for which a compelling public health need exists. Yet despite being available for
almost 100 years, achieving reliable, equitable and affordable access to insulin
remains a public health challenge in many countries.
The Committee did not recommend the addition of insulin analogues
to the EML, reiterating the conclusion of the 2017 Committee, that although
the available evidence for long-acting insulin analogues shows some efficacy
advantages and reduced hypoglycaemia compared to human insulin, the
price differential that exists between analogue and human insulin remains
disproportionately high in most settings.
The Committee remained concerned about the ongoing problems of
access and affordability of insulin worldwide, despite human insulin not being
patented. The Committee noted the long-standing domination of the insulin
market by three manufacturers, limiting broader competition and slowing the
entry of biosimilars to the market.
Recognizing the complexities of these problems and the need for a
wider understanding of the insulin market and access to insulin, the Committee
397
recommended WHO coordinate a series of actions to address the issues of

insulin access and affordability. In the absence of other coordinated actions, the
Committee considered that the inclusion of insulin analogues for adults on the
EML would be inadequate to address the underlying issues of poor access and
affordability of insulins more generally.
The Committee recommended that a WHO-led approach should be
multi-factorial and multi-disciplinary and should include:
■■ establishment of an independent WHO technical working group on
access to insulin;
■■ consultation with Member States and other stakeholders to identify/
clarify barriers to access at country level;
■■ strategies to address current regulatory barriers for biosimilar
insulins, such as the expansion of the WHO Prequalification
Programme;
■■ development of a comprehensive approach to address insulin prices,
including mechanisms for pooled procurement;
■■ identification of evidence and research gaps regarding insulin use
and supply, including setting-specific differences in clinical practice
and health systems (e.g. food insecurity, displaced populations,
emergencies).
The Committee would welcome a report that comprehensively describes
the actions that are undertaken by WHO over the next biennium and an
application that reviews in-depth the current challenges for optimal global access
and the role of insulin analogues in children.
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18.6 Medicines for hypoglycaemia

Diazoxide – addition – EMLc
Diazoxide ATC Code: V03AH01
Proposal
The application requested the inclusion of diazoxide on the EMLc for the
management of hypoglycaemia secondary to prolonged hyperinsulinism (HI).
Applicant
Global Pediatric Endocrinology and Diabetes (GPED)
Caring and Living as Neighbours (CLAN)
Congenital Hyperinsulinism International (CHI)

Comments on the applications were received from the WHO department of
unit advised that it supported the addition of diazoxide to the complementary
list of the EMLc, stating that congenital hyperinsulinism is a rare but serious
condition requiring specialist assessment and care, and that inclusion of
diazoxide on the EMLc could facilitate access to this medicine in countries where
it is currently unavailable.
EML/EMLc
EMLc
Section

Oral liquid: 50 mg/mL
Tablet: 50 mg
Core/Complementary
Complementary

Individual
405

Diazoxide had not previously been considered for inclusion on the EMLc for
hypoglycaemia secondary to prolonged HI.

Congenital hyperinsulinism (HI) disorders are a group of disorders characterized
by inappropriately persistent secretion of insulin in the context of low blood
glucose. This condition can be transient or permanent. It is responsible for
permanent neurological damage in the newborn and infant. Congenital HI has an
estimated incidence ranging from 1 in 50 000 live births, with considerably higher
incidence (up to 1 in 2500) seen in populations with high rates of consanguineous
unions (1). Recurrent episodes of hypoglycaemia produced by HI increase risk for
seizures, brain damage and intellectual disability. Management of hypoglycaemia
is critical to prevent and reduce the risk of these serious consequences (2).
Neurological damage is present in up to 50% of children with early
onset HI. Neurodevelopmental damage is observed in transient, permanent,
mild and severe forms of HI, emphasizing the need for rapid diagnosis and
prompt management (3–6).
Diazoxide is indicated for hypoglycaemia that is secondary to transient
and prolonged inappropriate insulin secretion and as a first-line treatment
in patients with permanent HI where a dietary approach alone does not
appropriately prevent hypoglycaemia.

No randomized controlled trials involving diazoxide were identified in the
application.
Case series studies from China (7), Germany (5), Turkey (8, 9), Thailand
(10) and the United Kingdom (11) have reported the clinical response to
diazoxide therapy ranging from 40% to 74% at dose ranges up to 20 mg/kg/day.

The effect of diazoxide depends on the genetic cause of hyperinsulinism.
The majority of cases of neonatal onset persistent congenital HI are caused by
defects in the KATP channel genes of the beta-cell of the pancreas, and diazoxide
is ineffective in these patients (12).

The total number of patients who have received diazoxide to date has not
been assessed. It is estimated that tens of thousands of patients have received
diazoxide since 1964. The application summarized safety findings for diazoxide
from cohort studies and case reports (5, 7, 13–24). The medicine is usually well
tolerated. Adverse effects include water retention and hyponatraemia at onset of
therapy, and hypertrichosis (in particular on back and limbs) that is reversible
406
after the treatment is discontinued. Less commonly reported adverse events

include rash, thrombocytopenia, neutropenia, heart failure, extrapyramidal
adverse events and paradoxical hypoglycaemia. Adverse events may be dose-
related and are usually reversible with dose reduction or discontinuation of
therapy. Heart failure secondary to water retention has been reported in
premature babies and associated with reopening of the ductus arteriosus.
Diazoxide is recommended to be used with caution in these patients (13).
Pulmonary hypertension has been reported to the United States Food
and Drug Administration and Health Canada in neonates and infants treated
with diazoxide.
The application noted that overall, the quality of the safety data is weak as
it comes from small series of patients and case reports. No randomized controlled
trials are available. Adverse events data was not systematically collected in the
cohort studies. The likelihood that adverse events were associated with diazoxide
was not assessed in any of the cohort studies or case reports.

A retrospective cohort study of 295 patients investigated the prevalence of
adverse events in children with congenital HI treated with diazoxide (25). 2.4%
of children developed pulmonary hypertension after initiation of diazoxide
(most of them had additional risk factors such as prematurity, structural heart
disease and respiratory failure). In addition, 15.6% developed neutropenia, 4.7%
thrombocytopenia and 5% hyperuricaemia. The authors concluded that screening
for neutropenia, thrombocytopenia and hyperuricaemia in diazoxide‑treated
patients may be of value given the relatively high prevalence of these events.
WHO Guidelines
The 2013 WHO Pocket book of Hospital Care for Children (26) recognizes the
importance of hypoglycaemia and the need to treat it as an emergency in order
to prevent neurological sequelae. It focuses on the most common causes of
hypoglycaemia and does not consider HI or make recommendations regarding
diazoxide treatment.
Clinical practice guidelines for congenital HI developed by the Japanese
Society for Pediatric Endocrinology and the Japanese Society of Pediatric
Surgeons (12) make the following recommendations for first-line treatment of
congenital HI:
■■ Maintain blood glucose above the target range by continuous glucose
infusion. [Recommendation level 1, Evidence level A].
■■ When blood glucose is successfully maintained by continuous
glucose infusion, nutritional support by frequent feeding, continuous
feeding, cornstarch (after nine months), or formula for glycogen
407
storage diseases should be attempted. [Recommendation level 1,

Evidence level A].
■■ When blood glucose is not maintained by continuous glucose
infusion, or when it is difficult to withdraw glucose infusion for an
extended period, a 5-day trial of oral diazoxide, in 2–3 divided doses,
at 5–15 mg/kg/day should be attempted, unless contraindicated
by cardiac failure or pulmonary hypertension. [Recommendation
level 1, Evidence level A].
■■ When diazoxide is effective in stabilizing blood glucose levels,
intravenous glucose infusion should be withdrawn and transfer
to nutritional support (frequent feeding, continuous feeding,
or cornstarch formula for glycogen storage diseases) should be
attempted. [Recommendation level 1, Evidence level A].
■■ While on diazoxide, the patient should be on a glucose self-
monitoring regimen to detect episodes of hypoglycaemia.
Furthermore, complete blood count (CBC), blood chemistry, and
physical examination should be performed to detect frequent
adverse events, such as hypertrichosis, tachycardia, or oedema.
[Recommendation level 1, Evidence level B].
■■ When euglycaemia is not achieved by the first-line treatment and
continuous glucose infusion cannot be withdrawn, the second-line
treatment should be initiated. [Recommendation level 1, Evidence
level A].
No information was provided in the application regarding the cost and cost-
effectiveness of diazoxide.
Preliminary results of an international survey of paediatric endocrinologists
conducted in 2018 by Congenital Hyperinsulinism International to assess the

availability and need for diazoxide reported that 53% of respondents agreed that
cost to the patient was an obstacle to accessing diazoxide.
Availability
Global availability, reliable supply and regulatory approval of diazoxide is variable.
N/A
The Committee recommended the addition of diazoxide to the complementary
list of the EMLc for the management of hypoglycaemia secondary to prolonged
408
hyperinsulinism (HI), based on evidence of favourable efficacy and tolerability,

and taking into account the serious consequences of this condition in children
not treated.
The Committee noted the variable global availability and reliability of
supply of diazoxide and considered inclusion of diazoxide on the EMLc could
help to facilitate more reliable access.
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26. Pocket book of hospital care for children: guidelines for the managment of common illnesses
with limited resources. Geneva: World Health Organization; 2013. Available from https://www.
who.int/maternal_child_adolescent/documents/9241546700/en/, accessed 30 October 2019.
410
18.7 Thyroid hormones and antithyroid medicines

Medicines for first-line treatment of primary hyperthyroidism – review – EML and EMLc
Methimazole ATC Code: H03BB01

Propylthiouracil ATC Code: H03BA02
Proposal
The application requested:
■■ inclusion on the core list of the EML and EMLc of methimazole
(INN thiamazole) with a square box for the first-line management of
Graves’ hyperthyroidism in children and non-pregnant adults;
■■ transferring the current EML listing for propylthiouracil from the
core to the complementary list, and removal of the square box.
■■ Inclusion of a note with the listing of propylthiouracil specifying use
only when alternative first-line treatments are not appropriate or
available, to reinforce its place as a second-line therapy.
Applicant
Global Pediatric Endocrinology and Diabetes (GPED)

unit advised that it did not support the requests made in the application and
considered the evidence presented in the application to be deficient.
EML/EMLc
EML and EMLc
Section

Methimazole: tablet 5 mg, 10 mg, 20 mg
Propylthiouracil: tablet 50 mg
Core/Complementary
Methimazole: core
Propylthiouracil: complementary
411

Methimazole: Square box incorporating carbimazole as a therapeutically equivalent
alternative.
Propylthiouracil: individual

Propylthiouracil (PTU) with a square box has been included on the core list
of the EML since the first list in 1977. In 2007, it was added (without a square
box) to the complementary list of the EMLc. The EMLc Subcommittee noted
that PTU was licensed for use in children aged over 6 years, although in some
settings carbimazole (CMZ) was the more commonly used drug. The EMLc
Subcommittee decided to list PTU but recommended the role of CMZ in children
be reviewed (1).

Graves’ disease is the most common cause of hyperthyroidism. Women are
affected more frequently than men at a ratio of 8:1, most commonly in the third
to fifth decade of life (2). A meta-analysis of European studies estimated a mean
prevalence rate of 0.75% for males and females combined and an incidence rate
of 51 cases per 100 000 per year with a significant influence of ethnicity and
iodine nutrition (3).
Among children, Graves’ disease represents more than 90% of the cases
of hyperthyroidism with an incidence ranging from 0.1 per 100 000 children
and 3.0 per 100 000 adolescents per year (4).

The application identified four randomized controlled trials (RCTs) that
compared the effectiveness of PTU and MMI in adults and one retrospective
study in children and adolescents.

The trials in adults found MMI to have similar or greater effectiveness
than PTU at reducing or normalizing thyroid hormone concentrations (5–8).
The paediatric study found no significant difference in the mean duration for
normalization of serum T4 concentration between MMI (1.7 ± 1.0 months) and
PTU (2.3 ± 2.4) treated patients (9).
Two RCTs evaluated the effect of MMI (10) and CMZ (11) taken once,
twice or three times daily. The results indicated that once daily dosing is as
effective as multiple daily dosing.
The application acknowledged that in general, less information was
available for CMZ but because CMZ is metabolized to MMI after absorption, it
was assumed that data that apply to MMI also apply to CMZ.
412

Overall, both PTU and MMI/CMZ all present with minor and major adverse
events in adults and in children. However, major adverse events were less
commonly reported for patients receiving MMI/CMZ. Common minor side-
effects for these medicines include pruritis, skin rash, urticaria and arthralgias.
Major adverse events are uncommon but include agranulocytosis, hepatic failure,
vasculitis and fetal malformations.
In the RCT by Nakamura et al (5), the overall incidence of adverse events
was higher in the PTU group than the MMI 30 mg/d group (51.9% vs 30%).
The percentage of patients who showed aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) higher than double the upper range of the
normal standard was significantly higher for the PTU group compared to the
MMI 30 mg/d group (26.9% vs 6.6%). Skin eruption or urticaria was similar
between groups. Leukocytopenia (less than 1000/mm3) was observed in five
patients in the PTU group only.
A retrospective cohort study of 71 379 Taiwanese patients found MMI/
CBZ to be associated in a dose-dependent manner with an increased risk for
hepatitis compared to PTU. However, no significant difference in risk was
observed between groups for acute liver failure or cholestasis (12).
In the paediatric retrospective study, minor adverse events were observed
more frequently among PTU treated patients compared to MMI treated patient
(31.9% vs 25.0%), although the difference was not significant. The incidence of
liver dysfunction was significantly higher among PTU treated patients (18.9% vs
6.3%) (9). A 2000 RCT involving 40 children found no difference in side-effects
between patients receiving PTU or MMI within the same age groups (13).
Agranulocytosis has been observed with both MMI/CMZ and PTU
(14). There have been reports of PTU-related liver failure and death in adults
and children (15), where the risk is five times higher in children than in adults.
Between 1990 and 2008, a total of 23 PTU-related liver transplants were reported,
and 30% of recipients were paediatric patients. No MMI-related liver transplants
were reported in the same time period (16). Antineutrophil cytoplasmic
antibodies (ANCA) vasculitis has been reported, more often related to PTU than
MMI (17, 18).
A high prevalence of birth defects in children exposed to anti-thyroid
drugs in early pregnancy has been reported (19). It is not clear whether MMI
and CMZ lead to a higher prevalence of fetal malformations compared to PTU.
Some studies have shown similar rates of fetal defects with both drugs (12).
However, this rate may not be higher than the rate of malformations in the
control population (20). In contrast, a recent meta-analysis showed an increased
risk of neonatal congenital malformations associated with MMI, but not PTU
when compared to no antithyroid medicines exposure (21). However, the fetal
413
malformations associated with PTU may be less severe and easier to correct
than those associated with MMI and CMZ.

N/A
WHO Guidelines
There are no WHO guidelines currently available for the management of Graves’
disease.
The 2018 European Thyroid Association guidelines for management of
Graves’ disease recommend MMI as preferred treatment for newly diagnosed
patients (both adults and children). The guidelines further recommend that
MMI-treated women should be switched to PTU when planning pregnancy and
during the first trimester (22).
The 2016 American Thyroid Association Guidelines also recommend use
of MMI in almost all patients. PTU is recommended for patients during the first
trimester of pregnancy, in the treatment of thyroid storm, and in patients with
minor reactions to MMI who refuse radioactive iodine therapy or surgery (23).
Costs of PTU, MMI and CMZ vary considerably between countries. The
application compared the calculated costs for one month of treatment with PTU,
MMI or CMZ. For the induction treatment period, costs ranged from US$ 7 to
US$ 37 per month for MMI, US$ 18 to US$ 27 per month for CMZ and from
US$ 3.50 to US$ 68 per month for PTU. For the core treatment period, costs
ranged from US$ 3.50 to US$ 18.50 per month for MMI, and from US$ 9 to 13.50
per month for CMZ and US$ 1.80 US$ 34 per month for PTU.
Availability
Usually, only one of CMZ or MMI is available in a given country reflecting

differences in regulatory approval in different jurisdictions.
PTU is available globally.
N/A
The Committee recommended the addition of methimazole with a square box
to the core list of the EML and to the complementary list of the EMLc for use
as first-line therapy for hyperthyroidism. The square box listing should specify
carbimazole as a therapeutically equivalent alternative.
414
The Committee recommended that propylthiouracil should remain on

the core list of the EML for use in patients during the first trimester of pregnancy,
and for other patients in whom alternative first-line treatment is not appropriate
or available. The square box should be removed from the listing. The Committee
also recommended that propylthiouracil should remain on the complementary
list of the EMLc for use in patients for whom alternative first-line treatment is
not appropriate or available.
The Committee considered that the available evidence indicated that
efficacy of methimazole is at least equivalent to propylthiouracil. Compared to
propylthiouracil however, methimazole demonstrated a more favourable safety
profile with fewer reported major adverse events. The Committee noted that
propylthiouracil remains the treatment of choice in some patients and therefore
should remain available.
References
1. The selection and use of essential medicines. Report of the WHO Expert Committee, October
2007 (including the Model List of Essential Medicines for Children) (WHO Technical Report Series,
No. 950). Geneva: World Health Organization; 2008. Available from https://apps.who.int/iris/
bitstream/handle/10665/43745/WHO_TRS_946_eng.pdf, accessed 30 October 2019.
2. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;388(10047):906–18.
3. Garmendia Madariaga A, Santos Palacios S, Guillen-Grima F, Galofre JC. The incidence and
prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab.
2014;99(3):923–31.
4. Lee HS, Hwang JS. The treatment of Graves’ disease in children and adolescents. Ann Pediatr
Endocrinol Metab. 2014;19(3):122–6.
5. Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and
propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol
Metab. 2007;92(6):2157–62.
6. He CT, Hsieh AT, Pei D, Hung YJ, Wu LY, Yang TC et al. Comparison of single daily dose of
methimazole and propylthiouracil in the treatment of Graves’ hyperthyroidism. Clin Endocrinol
(Oxf). 2004;60(6):676–81.
7. Homsanit M, Sriussadaporn S, Vannasaeng S, Peerapatdit T, Nitiyanant W, Vichayanrat A. Efficacy
of single daily dosage of methimazole vs. propylthiouracil in the induction of euthyroidism.
Clin Endocrinol (Oxf). 2001;54(3):385–90.
8. Nicholas WC, Fischer RG, Stevenson RA, Bass JD. Single daily dose of methimazole compared to
every 8 hours propylthiouracil in the treatment of hyperthyroidism. South Med J. 1995;88(9):
973–6.
9. Sato H, Minagawa M, Sasaki N, Sugihara S, Kazukawa I, Minamitani K et al. Comparison of
methimazole and propylthiouracil in the management of children and adolescents with Graves’
disease: efficacy and adverse reactions during initial treatment and long-term outcome. J Pediatr
Endocrinol Metab. 2011;24(5-6):257–63.
415
10. Sriussadaporn S, Pumchumpol W, Lertwattanarak R, Kunavisarut T. Efficacy of Once Daily versus

Divided Daily Administration of Low Daily Dosage (15 mg/Day) of Methimazole in the Induction
of Euthyroidism in Graves’ Hyperthyroidism: A Randomized Controlled Study. Int J Endocrinol.
2017;2017:2619695.
11. Mafauzy M, Wan Mohamad WB, Zahary MK, Mustafa BE. Comparison of the efficacy of single
and multiple regimens of carbimazole in the treatment of thyrotoxicosis. Med J Malaysia.
1993;48(1):71–5.
12. Wang MT, Lee WJ, Huang TY, Chu CL, Hsieh CH. Antithyroid drug-related hepatotoxicity in
hyperthyroidism patients: a population-based cohort study. Br J Clin Pharmacol. 2014;78(3):
619–29.
13. Lazar L, Kalter-Leibovici O, Pertzelan A, Weintrob N, Josefsberg Z, Phillip M. Thyrotoxicosis in
prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol
Metab. 2000;85(10):3678–82.
14. Marino M, Vitti P, Chiovato L. Graves’ Disease. In: Jameson JL, editor. Endinocrinology: Adult and
Pediatric. Philadelphia: Elsevier Saunders; 2016. p. 1437–64.
15. Akmal A, Kung J. Propylthiouracil, and methimazole, and carbimazole-related hepatotoxicity.
Expert Opin Drug Saf. 2014;13(10):1397–406.
16. Rivkees SA, Mattison DR. Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations
for Discontinuation of Use. Int J Pediatr Endocrinol. 2009;2009:132041.
17. Gao Y, Zhao MH, Guo XH, Xin G, Gao Y, Wang HY. The prevalence and target antigens of
antithyroid drugs induced antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with
hyperthyroidism. Endocr Res. 2004;30(2):205–13.
18. Huang CN, Hsu TC, Chou HH, Tsay GJ. Prevalence of perinuclear antineutrophil cytoplasmic
antibody in patients with Graves’ disease treated with propylthiouracil or methimazole in Taiwan.
J Formos Med Assoc. 2004;103(4):274–9.
19. Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of antithyroid
drugs: a Danish nationwide study. J Clin Endocrinol Metab. 2013;98(11):4373–81.
20. Koenig D, Spreux A, Hieronimus S, Chichmanian RM, Bastiani F, Fenichel P et al. Birth defects
observed with maternal carbimazole treatment: Six cases reported to Nice’s Pharmacovigilance
Center. Ann Endocrinol (Paris). 2010;71(6):535–42.
21. Song R, Lin H, Chen Y, Zhang X, Feng W. Effects of methimazole and propylthiouracil exposure
during pregnancy on the risk of neonatal congenital malformations: A meta-analysis. PLoS One.
2017;12(7):e0180108.
22. Kahaly GJ, Bartalena L, Hegedus L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid
Association Guideline for the Management of Graves’ Hyperthyroidism. Eur Thyroid J.
2018;7(4):167–86.
23. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL et al. 2016 American Thyroid
Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of
Thyrotoxicosis. Thyroid. 2016;26(10):1343–421.
416
Section 22: MEDICINES FOR REPRODUCTIVE HEALTH

AND PERINATAL CARE
22.3 Uterotonics
Carbetocin (heat-stable) – addition – EML
Carbetocin ATC Code: H01BB03
Proposal
The application requested the inclusion of heat-stable carbetocin on the EML for
the prevention of postpartum haemorrhage (PPH).
Applicant
WHO Department of Reproductive Health and Research

Reproductive Health and Research
EML/EMLc
EML
Section
22.3 Uterotonics

Injection (heat stable): 100 micrograms/mL
Core/Complementary
Core

Individual

Carbetocin has not previously been considered for inclusion on the EML for
prevention of PPH. Oxytocin, misoprostol and ergometrine are currently
included on the EML for the prevention of PPH.

Obstetric haemorrhage, especially PPH, is responsible for more than a quarter
of all maternal deaths worldwide (1). In most low-income countries, PPH is the
leading cause of maternal deaths.
417
PPH is commonly defined as a blood loss of 500 mL or more within

24 hours after birth, and affects about 5% of all women giving birth around the
world (2, 3). Uterine atony is the most common cause of PPH and a leading
cause of PPH-related maternal mortality worldwide (1).
PPH can be prevented if prophylactic uterotonics are administered
during the third stage of labour, and by timely and appropriate management (4).
Oxytocin is the first choice uterotonic drug recommended by WHO. However,
oxytocin is sensitive to heat exposure and must be transported and store at 2–8 °C
continuously. This represents a problem in low-resource settings where the cold
chain is difficult to maintain. Carbetocin, in its heat stable formulation, does
not require cold chain transport and storage and can stay at room temperature
for a long period of time (30 °C for three years, 40 °C for six months, 50 °C for
three months and 60 °C for one month) (5). Based on the WHO CHAMPION
trial results and on the updated WHO recommendations on uterotonics for the
prevention of PPH, carbetocin is recommended for PPH prevention, especially
in those settings where the cold storage of oxytocin is not possible.

The application presented the findings of a Cochrane systematic review and
network meta-analysis of seven uterotonic options (6), and GRADE tables
extracted from the WHO recommendations on uterotonics for prevention of
PPH (4).
Carbetocin compared with placebo or no treatment was investigated in
two randomized controlled trials (RCTs) involving 169 women in the network
meta-analysis. There was moderate certainty evidence that carbetocin was
associated with a substantial reduction in PPH ≥500 mL (relative risk (RR) 0.42,
95%CI 0.31 to 0.57), PPH ≥1000 mL (RR 0.52, 95%CI 0.38 to 0.72), blood
transfusion (RR 0.48, 95%CI 0.26 to 0.89), and use of additional uterotonics
(RR 0.19, 95%CI 0.13 to 0.27) when compared with placebo or no treatment.
Evidence on whether the prophylactic use of carbetocin during the third stage
of labour reduces maternal death when compared to placebo was of very low
certainty. It was uncertain whether carbetocin reduced maternal intensive care
unit (ICU) admissions due to the very low number of events. There was moderate
certainty evidence that the use of prophylactic carbetocin probably reduces
average blood loss compared with women receiving placebo or no treatment
(mean difference: 138.37 mL, 95%CI 193.24 mL lower to 83.50 mL lower).
There is moderate certainty evidence that carbetocin has similar effects
to oxytocin for the outcomes of maternal death, blood transfusion and ICU
admissions. Carbetocin may be superior to oxytocin for the outcomes of PPH
≥500 mL (41 few events per 1000 women – moderate certainty evidence), use of
additional uterotonics (74 fewer per 1000 women – low certainty evidence) and
blood loss after birth (82 mL less, on average – low certainty evidence). There
418
was very low certainty evidence of a difference in effect between carbetocin and
oxytocin for the outcome of PPH ≥1000 mL.

The application presented the findings of a Cochrane systematic review and
network meta-analysis of seven uterotonic options (6), and GRADE tables
extracted from the WHO recommendations on uterotonics for prevention of
PPH (4).
Compared to placebo or no treatment, carbetocin was associated with
little or no difference to the risk of experiencing adverse effects (i.e. nausea,
vomiting, headache, abdominal pain, hypertension, shivering, fever and
diarrhoea). Compared to oxytocin, there was no clear difference in terms of
adverse effects. The certainty of the evidence ranged from very low to moderate.

N/A
WHO Guidelines
The 2018 WHO recommendations for uterotonics for the prevention of
PPH (4) recommend use of an effective uterotonic during the third stage of
labour for all births. Recommended uterotonics are oxytocin, carbetocin,
misoprostol, ergometrine/methylergometrine and oxytocin + ergometrine in
fixed-dose combination.
The Guidelines Development Group made a context-specific
recommendation for carbetocin and recommended its use in contexts where
its cost is comparable to other effective uterotonics, noting that the current
cost of using carbetocin for PPH prevention was greater than the cost of using
other effective uterotonics.
Ex-factory prices of carbetocin vary globally and range from € 8 to € 40 per unit
(100 micrograms).
In 2013, WHO was approached by Merck for Mothers (a philanthropic
initiative of Merck, known outside the United States as Merck Sharpe & Dohme
(MSD)) and Ferring Pharmaceuticals to explore the potential value of heat-stable
carbetocin for reducing the incidence of maternal death. WHO convened an
international panel of stakeholders who identified the need for demonstration of
non-inferiority of heat-stable carbetocin before a change in guidance and practice
could be considered. If non-inferior to oxytocin, the heat-stable formulation of
carbetocin would be made available in public sector health care facilities in high-
burden countries at an affordable and sustainable “access price” (comparable to
419
the United Nations Population Fund (UNFPA) price of oxytocin), according to

a memorandum of understanding signed by representatives of WHO, Ferring
Pharmaceuticals and Merck (7). This price is a subsidized price of US$ 0.31 +/-
10% per ampoule of 100 µg heat-stable carbetocin (the UNFPA current price of
Oxytocin is US$ 0.27 per unit (10 I.U.)).
It was noted that the cost-effectiveness of carbetocin varies across settings
(6, 8–12). The WHO recommendations for uterotonics state that “carbetocin
would probably be cost-effective if the unit cost is comparable to other effective
uterotonics and in settings where the cost of PPH care is substantial” (4).
Availability
Carbetocin is approved in more than 80 countries worldwide, not including the
United States and Japan. In most countries carbetocin is approved for prevention
of uterine atony following delivery of the infant by caesarean section. In a few
countries, primarily in Latin America and recently in Australia, it is also approved
for prevention of uterine atony following vaginal delivery.
The currently approved product is manufactured in Germany.
The product Ferring will make available in low- and middle-income
countries (LMICs) at access price will be manufactured in China and India.
Ferring began the registration process in September 2018, where the first
application was submitted to Swissmedic, via their procedure for Marketing
Authorisation for Global Health Products (MAGHP). The approval by Swissmedic
is anticipated in 2020, whereafter Ferring will pursue registrations in LMICs and
seek WHO prequalification.
The heat-stable formulation of carbetocin does not need to be transported under
cold chain conditions, nor does it require refrigerated storage. This may make
carbetocin a preferred choice in settings where cold chain transport and storage
of oxytocin is not possible.
The Committee recommended the addition of heat-stable carbetocin injection
to the core list of the EML for the prevention of postpartum haemorrhage on the
basis of similar effects compared to oxytocin for efficacy and safety outcomes.
The Committee agreed that heat-stable carbetocin may offer advantages
over oxytocin in some settings as it does not require cold chain transport or
refrigerated storage.
The Committee noted the current higher cost of carbetocin compared
to other uterotonics and agreed with the context-specific recommendation in
WHO guidelines for the prevention of PPH, that carbetocin be used where its
cost is comparable to other effective uterotonics.
420
The Committee also recommended that WHO facilitate increased access

and affordability of carbetocin through inclusion in the WHO prequalification
programme.
References
1. Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J et al. Global causes of maternal death: a
WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323–33.
2. Souza JP, Gulmezoglu AM, Vogel J, Carroli G, Lumbiganon P, Qureshi Z et al. Moving beyond
essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on
Maternal and Newborn Health): a cross-sectional study. Lancet. 2013;381(9879):1747–55.
3. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a
systematic review. Best Pract Res Clin Obstet Gynaecol. 2008;22(6):999–1012.
4. WHO recommendations: uterotonics for the prevention of postpartum haemorrhage. Geneva:
10665/277276/9789241550420-eng.pdf?ua=1&ua=1, accessed 29 September 2019.
5. Malm M, Madsen I, Kjellstrom J. Development and stability of a heat-stable formulation of
carbetocin for the prevention of postpartum haemorrhage for use in low and middle-income
countries. J Pept Sci. 2018;24(6):e3082.
6. Gallos ID, Papadopoulou A, Man R, Athanasopoulos N, Tobias A, Price MJ et al. Uterotonic agents
for preventing postpartum haemorrhage: a network meta-analysis. Cochrane Database Syst Rev.
2018;12:CD011689.
7. Widmer M, Piaggio G, Nguyen TMH, Osoti A, Owa OO, Misra S et al. Heat-Stable Carbetocin versus
Oxytocin to Prevent Hemorrhage after Vaginal Birth. N Engl J Med. 2018;379(8):743–52.
8. Henriquez-Trujillo AR, Lucio-Romero RA, Bermudez-Gallegos K. Analysis of the cost-effectiveness
of carbetocin for the prevention of hemorrhage following cesarean delivery in Ecuador. J Comp
Eff Res. 2017;6(6):529–36.
9. Voon HY, Shafie AA, Bujang MA, Suharjono HN. Cost effectiveness analysis of carbetocin during
cesarean section in a high volume maternity unit. J Obstet Gynaecol Res. 2018;44(1):109–16.
10. van der Nelson HA, Draycott T, Siassakos D, Yau CWH, Hatswell AJ. Carbetocin versus oxytocin
for prevention of post-partum haemorrhage at caesarean section in the United Kingdom: An
economic impact analysis. Eur J Obstet Gynecol Reprod Biol. 2017;210:286–91.
11. Luni Y, Borakati A, Matah A, Skeats K, Eedarapalli P. A prospective cohort study evaluating the
cost-effectiveness of carbetocin for prevention of postpartum haemorrhage in caesarean
sections. J Obstet Gynaecol. 2017;37(5):601–4.
12. Caceda SI, Ramos RR, Saborido CM. Pharmacoeconomic study comparing carbetocin with
oxytocin for the prevention of hemorrhage following cesarean delivery in Lima, Peru. J Comp Eff
Res. 2018;7(1):49–55.
421
Mifepristone-misoprostol – change to listing – EML
Mifepristone-misoprostol ATC Code: G03XB01,

G02AD06
Proposal
The application requested the following changes to the current listing on the
EML of mifepristone-misoprostol:
■■ transfer from the complementary to the core list;
■■ removal of the note stating “Requires close medical supervision”;
■■ removal of the boxed text stating “Where permitted under national
law and where culturally acceptable”;
■■ addition of a co-packaged presentation of mifepristone and
misoprostol.
Applicant

EML/EMLc
EML
Section
22.3 Uterotonics

Tablet 200 mg – tablet 200 micrograms
Co-packaged mifepristone 200 mg tablet [1] and misoprostol 200 microgram
tablet [4]
Core/Complementary
Core

Individual
422

Mifepristone-misoprostol has been included on the EML for use in medical
abortion since 2005. The Committee recommended listing on the complementary
list with the note regarding the requirement for close medical supervision.
In reviewing the recommendation by the Committee, the Director-
General sought clarification from the Committee regarding the risks and
benefits of mifepristone-misoprostol. The Director-General subsequently made
the decision to approve listing mifepristone-misoprostol on the EML with an
additional note: “Where permitted under national law and where culturally
acceptable.”

Despite the major advances in management of abortion over the past two
decades, of the 55.7 million abortions that occurred worldwide each year
between 2010–2014, 30.6 million (54.9%) were considered safe, 17.1 million
(30.7%) are classified as less safe and 8.0 million (14.4%) were considered
least safe according to new safety classifications. 24.3 million (97%) of unsafe
abortions occur in low- and middle-income countries (LMICs) (1). In LMICs,
around 7 million women are admitted to hospitals annually as a result of unsafe
abortion (2). Globally, between 4.7% and 13% of maternal deaths have been
attributed to unsafe abortion (3).

Evidence for the clinical effectiveness of mifepristone-misoprostol was evaluated
at the time of original listing in 2005 (4). Updated evidence was considered
as part of the development process for the 2018 WHO guidelines for medical
management of abortion and continues to support the effectiveness, safety and
acceptability of mifepristone-misoprostol (5).
Support for less medicalized service delivery of mifepristone-misoprostol
exists in a number of WHO guidelines, clinical guidance and systematic reviews
(5–11). Specifically, the WHO 2015 Health worker roles in providing safe abortion
care and post-abortion contraception (7) and the 2018 Medical management of
abortion guidance (5), state that administration of mifepristone-misoprostol does
not require direct medical supervision or specialized care. WHO recommends
that pregnant persons should be provided information and access to health care
providers if they are experiencing signs of ongoing pregnancy or for any other
medical reasons (5, 7, 8, 12). One health worker can provide the entire package,
but it is equally possible for sub-tasks to be performed by different health workers
and at different locations.
The application states that specialized diagnostics or treatment are not
needed (6). Provision of care generally requires access to quality mifepristone and
423
misoprostol in the correct dosages, instructions on how to use them (including

dating of gestational age) and information about how to recognize complications
(e.g. in the event of very heavy and/or prolonged bleeding) and where to seek
help. Ultrasound scanning is not routinely required (5–8), and routine use of
antibiotics and testing for sexually transmitted infections is not recommended.
In the event of undiagnosed ectopic pregnancy, heavy, ongoing bleeding and/or
retained products of conception that may not evacuate on its own, the pregnant
person may require referral to a higher level care (6–8).
Evidence supports safe and effective provision of medical abortion for
pregnancies less than 12 weeks uterine size by the following health care cadres:
auxiliary nurses, auxiliary nurse midwives, nurses, midwives, associate and
advanced associate clinicians, non-specialist and specialist doctors (5–9, 13–17).
It is recommended that every primary care health service delivery point have
staff (regardless of their cadre) trained and competent to take a medical history,
perform a bimanual and abdominal examination and establish a referral network
with higher level facilities and/or providers who are available to manage
complications in the rare event that they may arise.
The application stated that desired benefit of co-packaged mifepristone-
misoprostol is to ensure availability of quality-assured products with consistent
and clear dosing. A recent study of the provision of medical abortion and
post-abortion contraception by mid-level health care providers in Kyrgyzstan
involved training midwives and family nurses to provide medical abortion
with co-packaged mifepristone-misoprostol (18). Results demonstrated that
trained midwives and nurses can provide medical abortion safely and effectively.
Although the study did not compare co-packaged mifepristone-misoprostol with
individually packaged drugs, the authors recommended registration and market
availability of high quality co-packaged mifepristone-misoprostol as a strategy
to facilitate the scale up of safe abortion in Kyrgyzstan.

Evidence for the safety of mifepristone-misoprostol was evaluated at the time of
original listing in 2005 (4).
Recently published safety data from the United States reported an
estimated mifepristone-associated mortality rate of 0.00063% (19). Studies
including mifepristone-misoprostol medical abortions among more than 423 000
persons globally reported very low rates (0.01 to 0.7%) of non-fatal serious
adverse events such as hospital admission, blood transfusion or serious infection
after use of mifepristone (19). In addition, a pooled analysis of serious adverse
reactions including data from 30 966 clinical study participants presenting for
mifepristone-misoprostol medical abortion through 70 days gestation found
no differences in rate or type of serious adverse reaction by geographical
424
location (20). Serious adverse reaction rates were reported in <0.5% of study
participants and include atypical presentation of infection, sepsis and prolonged
heavy bleeding/haemorrhage (20). These events were typically treatable without
permanent sequelae.
The 2015 WHO recommendations on health worker roles in providing safe
abortion care and post-abortion contraception highlight that the most commonly
experienced non-life threatening side-effects can be managed in primary care
and outpatient settings by various cadres of health care providers (7).
Evidence suggests that the provision of medical abortion by mid-level
providers has no impact on the safety or efficacy of the abortion process (21).
Self-management of medical abortion with mifepristone-misoprostol without
the direct supervision of a health care provider is recommended in specific
circumstances, in which pregnant persons have the appropriate information and
access to health services should they be wanted or required (5–7, 22).

N/A
WHO Guidelines
WHO Safe abortion: Technical and policy guidance (6) was first issued in 2003
and updated in 2012. It includes recommendations for clinical care, while
also addressing policy, programmatic and health systems considerations in the
provision of safe abortion.
WHO Clinical practice handbook for safe abortion (8) was issued in 2014. It
provides guidance to providers with requisite skills and training necessary to
provide safe abortion and/or treat complications of unsafe abortion.
WHO Health worker roles in providing safe abortion and post-abortion
contraception (7) was issued in 2015 and contains recommendations on the
roles of various health workers in the provision of abortion care, as well as self-
management of medical abortion.
WHO Medical management of abortion (5) guidelines issued in 2018 includes
the following recommendations on medical abortion regimens for management
of induced abortion:
For the medical management of induced abortion at less than 12 weeks
gestation, the 2018 WHO guidelines recommend the use of 200 mg mifepristone
administered orally, followed one to two days later by 800 micrograms
misoprostol administered vaginally, sublingually or buccally. The minimum
recommended interval between use of mifepristone and misoprostol is 24 hours
(strong recommendation, moderate certainty evidence).
425
For the medical management of induced abortion at ≥ 12 weeks of

gestation, the 2018 WHO guidelines suggest the use of 200 mg mifepristone
administered orally, followed one to two days later by repeat doses of 400
micrograms misoprostol administered vaginally, sublingually or buccally every
three hours. The minimum recommended interval between use of mifepristone
and misoprostol is 24 hours (weak, conditional, discretionary or qualified
recommendation, moderate certainty evidence).
The price of individual and co-packaged mifepristone and misoprostol varies
globally. The legal status of abortion, willing marketers and distributors and a
perceived sustainable market all impact the cost to the buyer. Market flexibility
is being regulated by the increasing number of new products in markets – both
individual and co-packaged products. It is hoped that increasing access to quality
co-packaged medicines for medical abortion will drive prices down.
The application stated that when purchased individually, the average cost
of mifepristone and misoprostol for one medical abortion ranges from US$ 4.19
to US$ 10.03, while costs for the co-packaged product range from US$ 3.75 to
US$ 11.75.
Availability
Mifepristone and misoprostol, both individually and co-packaged are available
globally.
The Committee noted the large number of letters of support received in relation
to this application.
The Expert Committee recommended moving mifepristone-misoprostol from

the complementary to the core list of the EML, and removal of the note that
states that close medical supervision is required, on the basis of the strong
evidence presented that close medical supervision is not required for its safe
and effective use.
The Committee also recommended the addition of a co-packaged
presentation of mifepristone and misoprostol to the core list of the EML.
Recalling that their role and responsibility is to provide WHO with
technical guidance in relation to the selection and use of essential medicines,
the Expert Committee noted that its mandate does not extend to providing
advice on the statement “Where permitted under national law and where
culturally acceptable”.
426
References
1. Ganatra B, Gerdts C, Rossier C, Johnson BR, Jr., Tuncalp O, Assifi A et al. Global, regional, and
subregional classification of abortions by safety, 2010-14: estimates from a Bayesian hierarchical
model. Lancet. 2017;390(10110):2372–81.
2. Singh S, Maddow-Zimet I. Facility-based treatment for medical complications resulting from
unsafe pregnancy termination in the developing world, 2012: a review of evidence from 26
countries. BJOG. 2016;123(9):1489–98.
(including the 14th Model List of Essential Medicines) (WHO Technical Report Series, No. 933).
5. Medical management of abortion. Geneva: World Health Organization; 2018. Available from
https://apps.who.int/iris/bitstream/handle/10665/278968/9789241550406-eng.pdf?ua=1,
6. Safe abortion: technical and policy guidance for health systems. 2nd edition. Geneva, World
Health Organization. 2012. Available from: https://apps.who.int/iris/bitstream/handle/10665/
70914/9789241548434_eng.pdf?sequence=1, accessed 29 September 2019.
7. Health worker roles in providing safe abortion care and post-abortion contraception. Geneva,
World Health Organization. 2015. Available from https://apps.who.int/iris/bitstream/handle/
10665/181041/9789241549264_eng.pdf?sequence=1, accessed 29 September 2019.
8. Clinical practice handbook of safe abortion. Geneva, World Health Organization. 2014.
pdf?sequence=1, accessed 29 September 2019.
9. Sjostrom S, Dragoman M, Fonhus MS, Ganatra B, Gemzell-Danielsson K. Effectiveness, safety,
and acceptability of first-trimester medical termination of pregnancy performed by non-doctor
providers: a systematic review. BJOG. 2017;124(13):1928–40.
10. Clinical updates in reproductive health. Chapel Hill: Ipas; 2019. Available from https://www.ipas.
org/resources/clinical-updates-in-reproductive-health, accessed 29 September 2019.
11. Wildschut H, Both MI, Medema S, Thomee E, Wildhagen MF, Kapp N. Medical methods for mid-
trimester termination of pregnancy. Cochrane Database Syst Rev. 2011(1):CD005216.
12. Abubeker FK, Kim CR, Lavelanet A. Medical termination of pregnancy in early first trimester
(≤ 63 days): a systematic review. [Evidence synthesis for a WHO guideline]. 2018 (unpublished).
13. Ganatra B. Health worker roles in safe abortion care and post-abortion contraception. Lancet
Glob Health. 2015;3(9):e512–3.
14. Glenton C, Sorhaindo AM, Ganatra B, Lewin S. Implementation considerations when expanding
health worker roles to include safe abortion care: a five-country case study synthesis. BMC Public
Health. 2017;17(1):730.
15. Gupta P, Iyengar SD, Ganatra B, Johnston HB, Iyengar K. Can community health workers play a
greater role in increasing access to medical abortion services? A qualitative study. BMC Womens
Health. 2017;17(1):37.
16. Barnard S, Kim C, Park MH, Ngo TD. Doctors or mid-level providers for abortion. Cochrane
427
17. Olavarrieta CD, Ganatra B, Sorhaindo A, Karver TS, Seuc A, Villalobos A et al. Nurse versus
physician-provision of early medical abortion in Mexico: a randomized controlled non-inferiority
trial. Bull World Health Organ. 2015;93(4):249–58.
18. Johnson BR, Jr., Maksutova E, Boobekova A, Davletova A, Kazakbaeva C, Kondrateva Y et al.
Provision of medical abortion by midlevel healthcare providers in Kyrgyzstan: testing an
intervention to expand safe abortion services to underserved rural and periurban areas.
Contraception. 2018;97(2):160–6.
19. Raymond EG, Blanchard K, Blumenthal PD, Cleland K, Foster AM, Gold M et al. Sixteen Years of
Overregulation: Time to Unburden Mifeprex. N Engl J Med. 2017;376(8):790–4.
20. Mifeprex product label, revised March 2016. Silver Spring: U.S. Food and Drug Administration;
2016. Available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020687s020
lbl.pdf, accessed 29 September 2019.
21. Winikoff B, Sheldon W. Use of medicines changing the face of abortion. Int Perspect Sex Reprod
Health. 2012;38(3):164–6.
22. Kapp N, Blanchard K, Coast E, Ganatra B, Harries J, Footman K et al. Developing a forward-
looking agenda and methodologies for research of self-use of medical abortion. Contraception.
2018;97(2):184–8.
428
Misoprostol – deletion of prevention of PPH indication – EML
Misoprostol ATC Code: G02AD06
Proposal
The application requested the deletion of misoprostol from the EML for the
indication of prevention of postpartum haemorrhage.
Applicant
Petra Sevcikova, Allyson Pollock

The WHO Department of Reproductive Health and Research provided comments
on the application and advised that it did not support the proposal to delete
misoprostol from EML for PPH prevention indication.
In December 2018, WHO updated its recommendations on uterotonics
based on a Cochrane systematic review and a network meta-analysis (NMA)
that included 196 trials (and 135 559 women) (1). The updating of these
recommendations followed WHO Guidelines Review Committee procedures as
well as internationally accepted guideline development methods and standards
that included not only the synthesis of evidence of effects of uterotonics but also
incorporated evidence regarding values of key stakeholders, resource use, cost
effectiveness, equity, acceptability and feasibility.
The technical department stated that the use of NMA for evidence of
effects of available uterotonics offered additional advantages over pairwise
meta-analyses used in conventional systematic reviews. It allowed a consistent
and systematic assessment of eligibility, risk of bias and outcome reporting of
all trials of uterotonic agents, including misoprostol. The evidence assessed
and synthesized for misoprostol during this update included all eligible studies
published as of May 2018. The NMA showed that when used for PPH prevention,
misoprostol is associated with a substantial reduction in PPH (≥ 500 ml), severe
PPH (≥ 1000 ml), blood transfusion and the use of additional uterotonics when
compared with placebo or no uterotonic. It is noteworthy that the evidence of
effects of misoprostol versus placebo or no uterotonics on the critical outcomes
PPH ≥1000 mL (RR 0.71, 95%CI 0.59 to 0.85) and blood transfusion (RR 0.52,
95%CI 0.35 to 0.80) were of high certainty according to GRADE assessment
(i.e. we are very confident that the true effect lies close to that of the estimate
of the effect). Based on high certainty evidence of efficacy regarding priority
PPH outcomes, which clearly outweighs the side-effects of misoprostol, and
considerations of evidence across other important domains of GRADE evidence-
to-decision framework, RHR advised that there was no scientific justification for
the removal of misoprostol for its PPH indication from the EML.
429
The WHO 2018 PPH guideline panel reaffirmed the recommendation

of misoprostol as an alternative option to oxytocin in settings where injectable
uterotonics are not available having fully considered the most up-to-date body
of scientific evidence, and implementation and regulatory issues raised in the
proposal by Dr Sevcikova and Dr Pollock.
EML/EMLc
EML
Section
22.3 Uterotonics

Tablet 200 micrograms
Core/Complementary
Core

Individual

Misoprostol was added to the EML in 2011 for prevention of PPH in settings
where parenteral uterotonics are not available or feasible. It was, and remains
listed with a conditional note specifying that its use in PPH is limited to
circumstances where oxytocin is not available or cannot be safely used.
This was the fourth application from Drs Sevcikova and Pollock
requesting deletion of misoprostol from the EML for prevention of PPH. Most
recently in 2017, the Expert Committee did not recommend deletion, noting
that very few new clinical data were included in the application. The Committee
considered that the evidence presented was insufficient to support deletion.
The Expert Committee once again acknowledged that misoprostol
is less effective than oxytocin infusion and is associated with adverse events,
particularly vomiting and shivering. The circumstances of use have not changed;
misoprostol remains an alternative for the prevention of PPH in resource-poor,
community and rural settings where intravenous oxytocin is not available or
cannot be safely administered (2).

Obstetric haemorrhage, especially PPH, is responsible for more than a quarter
of all maternal deaths worldwide (3). In most low-income countries, PPH is the
leading cause of maternal deaths.
430

The same evidence presented in the 2017 application was included in the current
application. Only evidence not previously considered by the Committee is
presented here.
To update the evidence base presented and considered in previous
applications, the current application undertook a literature search for
randomized controlled trials (RCTs) assessing misoprostol use in community
and home birth settings in low- and middle-income countries (LMICs)
published between November 2016 and November 2018. This search identified
two systematic reviews (1, 4), one of which was excluded as it included trials
conducted in hospitals (4). No additional RCTs conducted in low-resource
settings were identified.
The application presented results extracted from a sub-group analysis
from the Cochrane systematic review by Gallos et al for the comparison of
misoprostol versus placebo or no treatment from three trials conducted in the
community setting (5–7).
Efficacy outcomes Effect size Safety Effect size

Death RR 1.00 [95%CI 0.10 Nausea RR 1.12 [95%CI 0.74 to 1.70]
to 9.59]
PPH >= 1000 ml RR 0.59 [95%CI 0.39 Vomiting RR 1.27 [95%CI 0.80 to 2.01]
to 0.88]
Blood transfusion RR 0.14 [95%CI 0.02 Headache RR 0.94 [95%CI 0.32 to 2.77]
to 1.15]
Severe maternal RR 1.00 [95%CI 0.14 Shivering RR 2.71 [95%CI 2.33 to 3.15]
morbidity: to 7.05]
PPH >= 500 ml RR 0.73 [95%CI 0.56 Fever RR 2.87 [95%CI 0.90 to 9.18]
to 0.96]
Additional RR 0.50 [95%CI 0.12 Diarrhoea RR 3.11 [95%CI 1.28 to 7.51]
uterotonics to 1.98]
Blood loss MD −43.79 [95%CI
−58.09 to −29.49]
Change in MD −2.12 [95%CI
haemoglobin −3.46 to −0.77]
RR: risk ratio, MD: mean difference
Gallos et al reported no important differences were identified in the sub-

group analysis by hospital or community setting (1).
431
Commenting on the quality of available evidence, the application noted

that all community studies have important shortcomings either due to small
numbers; use of alternative uterotonics in the control arm; confounding due
to management practice and subjective assessment; and with one exception (6)
(in which the numbers were very small), exclusion of high-risk women. PPH
incidence fell in both the control and intervention groups in both the trials (5, 7)
that informed the 2011 decision to add misoprostol to the EML. This suggests
factors other than misoprostol use are crucial in determining outcomes.

No new safety data (beyond that presented above) were included in the current
application.

N/A
WHO Guidelines
The 2018 WHO recommendations for uterotonics for the prevention of PPH
(8) recommend use of an effective uterotonic during the third stage of labour
for all births. Misoprostol 400 µg or 600 µg, orally is a recommended option for
all births.
The 2018 WHO recommendations state that as misoprostol is inexpensive and
can also be used by lay health workers in community settings, it is associated with
moderate savings and is probably cost-effective, especially when implemented in
settings with a shortage of skilled health personnel (8).
Availability
N/A
N/A
The Committee did not recommend the deletion of the indication for prevention
of PPH from the listing of misoprostol from EML. The Committee considered
that the new evidence presented in this re-submission was insufficient to support
any change to the current listing.
The Committee reiterated that misoprostol remains an effective
alternative for prevention of PPH in resource-poor, community and rural
432
settings where oxytocin is unavailable or cannot be safely administered. The

listing of misoprostol on the EML supports its appropriate use in such settings
and is consistent with the 2018 WHO recommendations for uterotonics for the
prevention of PPH.
References
1. Gallos ID, Papadopoulou A, Man R, Athanasopoulos N, Tobias A, Price MJ et al. Uterotonic agents
for preventing postpartum haemorrhage: a network meta-analysis. Cochrane Database Syst Rev.
2018;12:CD011689.
4. Abd El Aziz MA, Iraqi A, Abedi P, Jahanfar S. The effect of carbetocin compared to misoprostol in
management of the third stage of labor and prevention of postpartum hemorrhage: a systematic
review. Syst Rev. 2018;7(1):170.
5. Derman RJ, Kodkany BS, Goudar SS, Geller SE, Naik VA, Bellad MB et al. Oral misoprostol in
preventing postpartum haemorrhage in resource-poor communities: a randomised controlled
trial. Lancet. 2006;368(9543):1248–53.
6. Hoj L, Cardoso P, Nielsen BB, Hvidman L, Nielsen J, Aaby P. Effect of sublingual misoprostol on
severe postpartum haemorrhage in a primary health centre in Guinea-Bissau: randomised double
blind clinical trial. BMJ. 2005;331(7519):723.
7. Mobeen N, Durocher J, Zuberi N, Jahan N, Blum J, Wasim S et al. Administration of misoprostol
by trained traditional birth attendants to prevent postpartum haemorrhage in homebirths in
Pakistan: a randomised placebo-controlled trial. BJOG. 2011;118(3):353–61.
8. WHO recommendations: uterotonics for the prevention of postpartum haemorrhage. Geneva:
10665/277276/9789241550420-eng.pdf?ua=1&ua=1, accessed 29 September 2019.
433
Tranexamic acid – new indication – EML
Tranexamic acid ATC Code: B02AA02
Proposal
The application requested inclusion of tranexamic acid (TXA) on the core list of
the EML for the new indication of treatment of postpartum haemorrhage.
Applicants

EML/EMLc
EML
Section
22.5 Other medicines administered to the mother

Injection: 100 mg/mL
Core/Complementary
Core

Individual

Tranexamic acid (TXA) had not previously been considered for inclusion on the
EML for the treatment of postpartum haemorrhage.
In 2009, an application requesting EML listing of TXA to reduce blood
loss during cardiac surgery was rejected as the indication was considered to be of
uncertain public health relevance (1).
Tranexamic acid was recommended for inclusion on the EML in 2011
for treatment of adult patients with trauma and significant risk of ongoing
haemorrhage (2).
434

Postpartum haemorrhage (PPH) is defined as blood loss of 500 mL or more
within 24 hours after birth. Globally, nearly one quarter of all maternal deaths
are associated with PPH, and in most low-income countries, it is the main cause
of maternal mortality (3). Improving health care for women during childbirth
to prevent and treat PPH is a necessary step towards achievement of the health
targets of the Sustainable Development Goals.

The application presented the findings of a Cochrane systematic review on
antifibrinolytic drugs for treating primary PPH (4) that included two trials:
WOMAN and Ducloy-Bouthors (5, 6), and GRADE tables extracted from the
WHO recommendation on tranexamic acid for the treatment of PPH (7).
For the comparison of TXA (plus standard care) versus standard care
alone, there was moderate certainty evidence that TXA was associated with
slightly reduced all cause maternal mortality (RR 0.88, 95%CI 0.74 to 1.05, not
statistically significant) and maternal mortality due to PPH (RR 0.81, 95%CI 0.65
to 1.00).
For maternal morbidity outcomes, moderate certainty evidence suggested
little or no difference between treatment groups for any outcomes reported
(respiratory failure: RR 0.87, 95%CI 0.67 to 1.12; seizure: two studies; RR 0.76,
95%CI 0.49 to 1.20; hepatic failure RR 0.96, 95%CI 0.58 to 1.60; cardiac failure:
RR 0.95, 95%CI 0.73 to 1.23; renal failure: two studies; RR 1.09, 95%CI 0.85
to 1.39).
Moderate certainty evidence suggests little or no difference between
treatment groups for transfusion of blood products, with more than half of the
women in both arms of the WOMAN trial receiving a transfusion (two studies;
RR 1.00, 95%CI 0.97 to 1.03).
Ducloy-Bouthors 2011 reported additional blood loss > 500 mL or
> 1000 mL. Low quality evidence suggests TXA probably reduces blood loss
> 500 mL (RR 0.50, 95%CI 0.27 to 0.93, 151 women). Although the direction of
effect was the same for loss > 1000 ml, the study was insufficiently powered to
demonstrate a difference between groups (4/77 women versus 8/74).
There was high certainty evidence of no difference between treatment
groups in the use of additional uterotonics (99.3% vs 99.1%, two studies; RR 1.00,
95%CI 1.0 to 1.0).
High or moderate certainty evidence suggests there is probably little
difference between treatment groups for most surgical interventions to control
bleeding (hysterectomy (all): two studies; RR 1.01, 95%CI 0.88 to 1.17; ligature:
RR 0.88, 95%CI 0.74 to 1.05; embolization: RR 0.82, 95%CI 0.42 to 1.62). High
certainty evidence suggests laparotomy to control bleeding is reduced for women
435
in the TXA group (0.8% vs 1.3%) (RR 0.64, 95%CI 0.49 to 0.85) while brace
sutures are increased (RR 1.19, 95%CI 1.01 to 1.41).
High certainty evidence suggests there is probably little or no difference
in intrauterine tamponade (one study; RR 0.96, 95%CI 0.87 to 1.06) or manual
removal of placenta: (one study; RR 0.95, 95%CI 0.87 to 1.04).
Sub-group analysis examining treatment effect by mode of birth (vaginal
or caesarean) suggests no clear difference in effect on maternal death (all causes)
and maternal death due to PPH for type of birth (moderate certainty evidence).
A sub-group analysis of the WOMAN trial investigated the effects of
timing of TXA administration. There was a reduced risk of maternal mortality
due to bleeding in women given TXA within three hours of delivery (RR 0.69,
95%CI 0.52 to 0.91; p=0.008) compared with women given TXA more than
three hours after delivery (RR 1.07, 95%CI 0.76 to 1.51; p=0.70).
Compared to the control group, women who received TXA within one
hour of delivery had a similar risk of death (any cause) (RR 0.98, 95%CI 0.72
to 1.33), as did women receiving TXA more than three hours after delivery
(RR 1.00, 95%CI 0.75 to 1.33). However, women receiving TXA between one and
three hours after delivery were at reduced risk of death from all causes (RR 0.69,
95%CI 0.49 to 0.96). There were similar findings for the composite outcome of
death or hysterectomy: within one hour (RR 1.08, 95%CI 0.91 to 1.28), more
than three hours (RR 1.01, 95%CI 0.82 to 1.25) and between one and three hours
(RR 0.80, 95%CI 0.63 to 1.00).
Compared to the control group, women receiving TXA within one hour
of delivery had reduced risk of laparotomy for bleeding (RR 0.48, 95%CI 0.29
to 0.79), as did women receiving TXA at one to three hours after birth (RR
0.54, 95%CI 0.31 to 0.95). Women receiving TXA more than three hours after
birth were not at reduced risk of laparotomy for bleeding (RR 0.89, 95%CI 0.59
to 1.35).
In summary, there is evidence that TXA is associated with benefits in
reducing maternal deaths due to bleeding and reducing the need for laparotomy
to stop bleeding. Treatment within three hours of delivery appears to optimize
benefits.

The application presented the findings of a Cochrane systematic review on
antifibrinolytic drugs for treating primary PPH (4) which included two trials –
WOMAN and Ducloy-Bouthors (5, 6), and GRADE tables extracted from the
WHO recommendation on tranexamic acid for the treatment of PPH (7).
Moderate certainty evidence suggests there is probably little or no
difference between treatment groups for thromboembolic events (any maternal
thromboembolic event: RR 0.88, 95%CI 0.54 to 1.43; deep venous thrombosis:
two studies; RR 0.62, 95%CI 0.20 to 1.88; pulmonary embolism RR 0.85, 95%CI
436
0.44 to 1.61; myocardial infarction: RR 0.66, 95%CI 0.11 to 3.97; stroke: RR 1.33,
95%CI 0.46 to 3.82).
Available neonatal outcome data were limited (data from WOMAN trial
only). There were no neonatal thromboembolic events and no clear differences
in deaths in breastfed neonates (eight deaths with TXA vs seven deaths with
placebo) in the WOMAN trial.
Available data on longer-term outcomes was limited (data from the
WOMAN trial only). Outcomes in the WOMAN trial were measured up to
hospital discharge or 42 days if still in hospital. There was no information on
longer-term outcomes in women or babies.
On balance, there does not appear to be evidence of maternal or
newborn harms, or significant side-effects. While no difference in newborn
thromboembolic events were seen, in the WOMAN trial most women and babies
were followed until discharge from the health facility, thus this evidence is more
likely representative of the first few days after birth.

N/A
WHO Guidelines
In 2012, WHO published 32 recommendations for the prevention and treatment
of PPH, including a weak recommendation on the use of TXA for treatment of
PPH if oxytocin and other uterotonics fail to stop bleeding of if it is thought
that bleeding may be partly due to trauma (8). In 2017, in response to important
new evidence, the existing WHO recommendation on the use of TXA for PPH
treatment was updated to recommend early use of intravenous TXA within three
hours of birth in addition to standard care for women with clinically diagnosed
PPH following vaginal birth or caesarean section (strong recommendation,
moderate quality of evidence) (7).
In making this updated recommendation, the Guideline Development
Group (GDG) also made the following remarks (7):
–– “Based on the dosing regimen used in the WOMAN trial, the GDG
supports the administration of tranexamic acid (TXA) at a fixed
dose of 1 g (100 mg/mL) intravenously (IV) at 1 mL per minute
(i.e. administered over 10 minutes), with a second dose of 1 g IV if
bleeding continues after 30 minutes, or if bleeding restarts within
24 hours of completing the first dose.
–– The WOMAN trial defined “clinically diagnosed postpartum
haemorrhage” as clinically estimated blood loss of more than 500 mL
after a vaginal birth or 1000 mL after caesarean section, or any
blood loss sufficient to compromise haemodynamic stability.
437
–– Based on evidence from the WOMAN trial, the reference point for
the start of the 3-hour window for starting TXA administration is
time of birth. If time of birth is unknown, the best estimate of time
of birth should be used as the reference point. As most deaths due
to PPH occur within the first 2 to 3 hours after birth, it is critical
that TXA is given as soon as possible to achieve clinical benefits.
–– Analysis of the effects of timing of administration in the WOMAN
trial, as well as an individual patient data (IPD) meta-analysis of
40 138 bleeding patients (including WOMAN trial participants),
indicates that TXA administration beyond 3 hours does not confer
any clinical benefit. Furthermore, the point estimates of effect of
TXA use beyond 3 hours on death for trauma or after PPH were
both in the direction of harm, albeit not statistically significant
for women with PPH. In view of this evidence, the GDG does not
support the use of TXA more than 3 hours after birth.
–– Administration of TXA should be considered as part of the standard
PPH treatment package. Standard care in the context of this
recommendation includes routine care for PPH treatment, including
fluid replacement, medical (uterotonics), monitoring of vital signs,
nonsurgical (e.g. bimanual compression, intrauterine balloon
tamponade, nonpneumatic antishock garment, aortic compression)
and surgical interventions (e.t., brace sutures, arterial ligation, or
hysterectomy) in accordance with WHO guidelines or adapted local
PPH treatment protocols.
–– TXA should be used in all cases of PPH, regardless of whether the
bleeding is due to genital tract trauma or other causes.
–– The use of TXA should be avoided in women with a clear
contraindication to antifibrinolytic therapy (including TXA) (e.g. a
known thromboembolic event during pregnancy).

–– This recommendation applies only to IV use. The evaluation of
benefits and potential harms of other routes of TXA administration
is a research priority.
–– Regardless of the level of health system resources, TXA should
be recognized as a life-saving intervention and be made readily
available for the management of PPH in settings where emergency
obstetric care is provided.”
Costs/cost-effectiveness:
Research evidence on cost-effectiveness of TXA can be extrapolated from cost-
effectiveness analysis of TXA for bleeding trauma patients (9). The study found
438
that administering TXA to bleeding trauma patients within three hours of

injury saved an estimated 372, 315 and 755 life-years (LYs) per 1000 trauma
patients in Tanzania, India and the United Kingdom respectively. The cost of
giving TXA to 1000 patients was US$ 17 483 in Tanzania, US$ 19 550 in India
and US$ 30 830 in the UK. The incremental cost of giving TXA versus not giving
TXA was US$ 18 025 in Tanzania, US$ 20 670 in India and US$ 48 002 in the
United Kingdom. The estimated incremental cost per LY gained of administering
TXA is US$ 48, US$ 66 and US$ 64 in Tanzania, India and the United Kingdom
respectively. Early administration of TXA to bleeding trauma patients is likely
to be highly cost effective in low-, middle- and high-income settings. The cost
of TXA varied between settings, with an approximated range of US$ 1.00 to
US$ 5.70 per gram.
The use of TXA may also reduce subsequent costs related to surgical
procedures for PPH treatment (such as laparotomy) as well as any complications
associated with surgery.
Out-of-pocket costs to individual women might be higher when TXA is
added to standard care for PPH in settings where women incur financial costs
for birth.
Availability
Tranexamic acid 100 mg/mL injection is available from multiple generic
manufacturers.
N/A
The Committee recommended listing of tranexamic acid (TXA) intravenous
injection on the core list of the EML for the new indication of treatment of
postpartum haemorrhage.
While the evidence presented in the application supporting the
effectiveness of TXA for this indication was limited and came primarily from a
single trial, the Committee considered there was benefit associated with the use
of TXA in addition to standard care, when administered within three hours of
childbirth. The Committee also considered that the use of different medicines
with different pharmacological mechanisms of action may be useful in the
management of PPH.
The Committee noted that there did not appear to be significant harms
or adverse events associated with use of TXA in mothers or newborns, but that
evidence was limited. The committee considered that further evidence of safety
would be desirable.
439
References
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WHO systematic analysis. ancet Globl Health. 2014;2(6):e323–33.
4. Shakur H, Beaumont D, Pavord S, Gayet-Ageron A, Ker K, Mousa HA. Antifibrinolytic drugs for
treating primary postpartum haemorrhage. Cochrane Database Syst Rev. 2018;2:CD012964.
5. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality,
hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an
international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):
2105–16.
6. Ducloy-Bouthors AS, Jude B, Duhamel A, Broisin F, Huissoud C, Keita-Meyer H et al. High-dose
tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care. 2011;15(2):R117.
7. WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage.
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8. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva:
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9. Guerriero C, Cairns J, Perel P, Shakur H, Roberts I. Cost-effectiveness analysis of administering
tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial. PLoS One.
2011;6(5):e18987.
440
Section 24: MEDICINES FOR MENTAL AND BEHAVIOURAL DISORDERS

Methylphenidate – addition – EML and EMLc
Methylphenidate ATC Code: N06BA04
Proposal
The application requested the inclusion of methylphenidate on the complementary
list of the EML and EMLc for the treatment of attention-deficit hyperactivity
disorder (ADHD).
Applicant
Patricia Moscibrodzki and Craig L Katz

Mental Health and Substance Abuse
EML/EMLc
EML and EMLc
Section
24 Medicines used in behavioural disorders

Tablet (immediate-release): 10 mg, 20 mg
Core/Complementary
Complementary

Individual

Methylphenidate had not previously been considered for inclusion on the Model
List.

The mental disorders that methylphenidate is approved to treat have a high
global disease burden. In 2010, mental neurological and substance use disorders
accounted for 10.4% of global disability-adjusted life years (DALYs) and 28.5%
of years of life lost due to disability, illness, or premature death (YLDs), making
441
them the leading cause of YLDs (1). The Global Burden of Disease Study 2010
(GBD 2010) is the first to include conduct disorder (CD) and attention-deficit
hyperactivity disorder (ADHD) for burden quantification (2). Globally, CD was
responsible for 5.75 million YLDs/DALYs with ADHD responsible for a further
491 500 (3). Collectively, CD and ADHD accounted for 0.80% of total global
YLDs and 0.25% of total global DALYs (3).
The prevalence of ADHD is a controversial issue with varying estimates
across populations, using different diagnostic criteria and reporting. A 2015
systematic review and meta-analysis of 175 studies reporting point prevalence
estimates of ADHD estimated the pooled prevalence to be 7.2% (95%CI 6.7%
to 7.8%) (4).
A 2007 systematic review and meta-regression analysis of 102 studies
(171 756 subjects) investigating the prevalence rates of ADHD/HD worldwide
found large variability of ADHD/HD prevalence rates worldwide resulting
mainly from methodological differences across studies. When adjusted for
methodological differences, prevalence rate variability was only detected
between studies conducted in North America and those conducted in Africa and
the Middle East (5).

A literature review undertaken by the applicants included 28 studies and review
articles as evidence for the comparative effectiveness of methylphenidate for the
treatment of ADHD versus placebo or other stimulants (6–15), versus second-
line non-stimulant therapies (16–25), and in patients with ADHD comorbid with
other conditions (26–31) in children, adolescents and adults. The large majority
of the trials and reviews were conducted in children and adolescents and were of
short duration (three months). Summaries of the findings of the included trials
were presented.
Based on this review, the applicants concluded that in the treatment of
ADHD, methylphenidate has shown similar efficacy to amphetamine-based

drugs with varying results on different psychometric scales. Some individual
studies have demonstrated superiority of methylphenidate over amphetamine-
based medicines, some have found superiority of amphetamine-based medicines
over methylphenidate, and others have shown no difference between the two
treatments. Given the currently available evidence, it has not been demonstrated
that one stimulant is more efficacious than any other at a population level. In the
comparison of methylphenidate with non-stimulant medications for treatment
of ADHD, non-stimulant medications appear to have a lower efficacy though
some studies show equivalent efficacy with atomoxetine. The application stated
that methylphenidate is effective in reducing fatigue in palliative care patients
when compared to placebo and that there is also evidence of methylphenidate
442
being effective in reducing symptoms in patients with ADHD comorbid with

oppositional defiant disorder and aggression. No assessment was made in the
application regarding the quality of the evidence or confidence in the estimates
of benefit.

A literature review undertaken by the applicants included 29 studies and review
articles as evidence for the comparative safety of methylphenidate for the
treatment of ADHD versus placebo (6, 32–34), versus other stimulants and non-
stimulants (9, 11, 12, 14, 16–19, 21, 35–38), and in patients with ADHD comorbid
with other conditions (26, 27, 30, 39–43). The large majority of the trials and
reviews were conducted in children and adolescents and were of short duration.
Summaries of the findings of the included trials were presented.
Based on this review, the applicants concluded that there is considerable
overlap in the adverse event profiles of methylphenidate- and amphetamine-
based ADHD medications. Both have been associated with insomnia and
appetite suppression as the most common adverse events. Overall, studies suggest
that the frequency and severity of adverse events may be somewhat greater
with amphetamine-based products. In comparison to other non-stimulant
medications, methylphenidate was associated with less sleeping problems and
higher tolerability. No assessment was made in the application regarding the
quality of the evidence or confidence in the estimates of harm.
As methylphenidate is a controlled Schedule II substance under the
1971 Convention on Psychotropic Substances, the application addressed the
issue of potential misuse. Methylphenidate-specific misuse data generally mimic
results of studies looking at stimulant medication misuse in general. While
there are limited data on malingering specifically for methylphenidate, studies
of malingering for stimulants in general are likely generally applicable (44).
Overall, the misuse of methylphenidate raises legitimate safety concerns for
overdose and drug interactions with other medications or nonmedical use drugs,
particularly since illicit users are generally unaware of these issues and often use
methylphenidate with other recreational drugs. However, studies suggest that
amphetamine-based drugs are being used more often than methylphenidate for
non-medical use, particularly in immediate-release formulations (45–48).

A 2014 Cochrane systematic review of immediate-release methylphenidate for
treatment of adults with ADHD was withdrawn in 2016 following failure by
the authors to satisfactorily address a number of criticisms of the methodology
used and conclusions drawn (49, 50). A commentary on the withdrawn review
summarized the criticisms, which primarily focussed on the methodological flaws
443
and “misleading conclusions that gave a false sense of certainty of the benefits
and the absence of harms, when this in fact could not be concluded” (51).
WHO Guidelines
The 2016 WHO mhGAP intervention guide for mental, neurological and
substance use disorders in non-specialized health settings (version 2.0) includes
a recommendation to refer children (aged 6 years and above with a diagnosis
of ADHD in whom other treatment approaches have failed) to a specialist for
methylphenidate treatment (52).
The median buyer price of immediate release methylphenidate 10 mg, according
to the International Medical Products Price Guide is US$ 0.067 per tablet/
capsule (53).
A literature review undertaken by the applicants included 11 articles as
evidence for the comparative cost-effectiveness of methylphenidate (54–65).
Summaries of economic evaluations of methylphenidate for ADHD were
presented, and the application concluded that the identified literature favoured
methylphenidate as cost-effective or cost-neutral relative to stimulant and non-
stimulant treatments.
The Committee considered that while methylphenidate appeared to
be low cost and affordable, no conclusions could be drawn regarding the cost-
effectiveness of the medicine given the considerable uncertainty in the estimates
of benefit and harms.
Availability
Methylphenidate immediate release tablets are available internationally in
innovator and generic brands.
Public comments on the application were received from Professor Ole Jakob
Storebø and Dr Christian Gluud, authors of a 2015 Cochrane systematic review of
methylphenidate use in children and adolescents (6) included in the application.
They expressed concern in relation to limitations in the reporting and summary
of the evidence in the application, with particular regard to the quality of
the evidence, duration of trials, misplacement of evidence, and suspected
selective biases. They stated that their assessment of the evidence supporting
methylphenidate for ADHD (and other disorders) was more critical than that
of the applicants, noting that the high risk of bias in the randomized trials likely
overestimates positive intervention effects and underestimates risk of harms.
444
The Committee did not recommend the addition of methylphenidate to the
complementary list of the EML and EMLc for the treatment of attention-deficit
hyperactivity disorder (ADHD) due to concerns regarding the quality and
interpretation of the evidence for benefits and harms.
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with ADHD alone or comorbid with ODD. Int J Psychiatry Clin Pract. 2018;22(2):109–14.
30. Masi G, Manfredi A, Nieri G, Muratori P, Pfanner C, Milone A. A Naturalistic Comparison of
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449
24.2 Medicines used in mood disorders

24.2.1 Medicines used in depressive disorders
Escitalopram – addition – EML
Fluoxetine – addition of square box – EML
Selective serotonin reuptake inhibitors

Escitalopram ATC Code: N06AB10
Fluoxetine ATC Code: N06AB03
Proposal
Two applications regarding the listing of selective serotonin reuptake inhibitors
(SSRIs) were received:
Application 1: requested the inclusion of escitalopram on the core list of the EML
for the treatment of adults with major depressive disorder.
Application 2: requested the addition of a square box symbol to the current listing
of fluoxetine on the core list of the EML for treatment of depressive disorders.
Applicant
Application 1: Dr Iona Machado, Dr Csilla Lippert, Dr Ricardo Lozano,
Dr Michael J Ostacher
Application 2: Kavitha Kolappa, Corrado Barbui

Mental Health and Substance Abuse
EML/EMLc
EML
Section

Application 1: Escitalopram: Tablet 10 mg
Application 2: Fluoxetine: Solid oral dosage form 20 mg
Core/Complementary
Core
450

Application 1: Individual
Application 2: Square box to include citalopram, escitalopram and sertraline.

Fluoxetine was added to the core list of the EML in 2007. The Committee
considered that the available evidence supported the public health need,
comparable effectiveness and generally more favourable tolerability of fluoxetine
compared to amitriptyline. A square box was not recommended as the Committee
felt there may be significant within-class differences among SSRIs in relation
to safety (1).

The public health relevance of depressive disorders is well established and has
been previously accepted by the Committee. However, the global burden of
disease due to depressive disorders is increasing over time. In 2017, depressive
disorders were estimated to affect over 260 million people globally, including
160 million with major depressive disorder. According to the Global Burden of
Disease Study 2017, depressive disorders were responsible for over 43 million
disability-adjusted life years (DALYs) annually, accounting for 1.7% of total
estimated DALYs due to any disease. Depressive disorders were also responsible
for over 43 million years lived with disability (YLD), accounting for 5.0% of the
total YLD globally (2).

Both applications presented the findings of a 2018 systematic review and network
meta-analysis (NMA) of 522 randomized controlled trials (RCTs) involving
117 477 participants, which evaluated the comparative efficacy and tolerability
of 21 antidepressant medicines compared to each other and to placebo for the
treatment of depression in adults (3).
Compared to placebo, all SSRIs were associated with statistically
significantly greater response rates. The greatest response rate seen was
for paroxetine (odds ratio (OR) 1.75, 95%CI 1.61 to 1.90). With regard to
acceptability, as measured by dropout rates, all SSRIs except for fluvoxamine
showed an advantage over placebo, however this was only statistically significant
for fluoxetine (OR 0.88, 95%CI 0.80 to 0.96).
In comparisons between SSRIs, there was moderate level GRADE
evidence of statically significant superior efficacy of escitalopram compared
to citalopram, fluoxetine, and fluvoxamine, and of paroxetine compared to
fluoxetine. Other comparisons were not statistically significant.
The findings of a 2009 Cochrane systematic review of 22 RCTs
comparing escitalopram to other antidepressants were largely consistent with
451
the 2018 NMA (4). In six studies (1823 participants) that compared response
rates between escitalopram and citalopram, there was a statistically significant
difference in favour of escitalopram (OR 0.67, 95%CI 0.50 to 0.89, p=0.006),
also found in remission rates (OR 0.57, 95%CI 0.36 to 0.90, p=0.02). Three
studies (783 participants) that directly compared escitalopram and fluoxetine
did not find a statistically significant difference in response or remission rates
but did find escitalopram to be more efficacious than fluoxetine in reduction of
depressive symptoms from baseline (SMD −0.17, 95%CI −0.32 to −0.03, p=0.02)
Two studies (784 participants) that compared escitalopram to paroxetine, and
two studies (489 participants) that compared escitalopram to sertraline, did not
find any statistically significant differences for any of the above parameters.

In the above-mentioned Cochrane review, 14 RCTs compared escitalopram to
another SSRI (4). Escitalopram did not have significantly different rates of mild
to severe adverse events than citalopram (n = 1802 in six RCTs), fluoxetine
(n = 804 in four RCTs), or paroxetine (n = 784 in two RCTs). Also, there was no
significant difference in serious adverse events for escitalopram compared to
sertraline (n = 483 in 2 RCTs); however, escitalopram had a decreased incidence
of diarrhoea. Overall, escitalopram and other SSRIs had similar rates of agitation,
anxiety, constipation, diarrhoea, dry mouth, hypotension, insomnia, nausea,
urinary complaints, drowsiness, vomiting, deaths, suicide, suicidality and other
adverse events.
With respect to acceptability as measured by dropout rates, in the above-
mentioned NMA, escitalopram was associated with moderate level GRADE
evidence of superiority compared to fluvoxamine. There were no other statistically
significant differences between SSRIs with regard to acceptability (3).
A 2006 meta-analysis using patient-level data from published and
unpublished clinical trials based on mandatory reporting by pharmaceutical

companies assessed the risk of suicidality (ideation or worse) amongst
antidepressants (5, 6). Half of the treatment indications were related to
depression, with the remaining 50% for other psychiatric or non-psychiatric
indications. Among SSRI, considering only data for adults with psychiatric
diagnoses, suicidality risk was found to be lowest for sertraline and fluoxetine
(low quality evidence). Suicidality risk was greatest for citalopram and
escitalopram although the differences did not reach statistical significance (very
low-quality evidence).
A 2014 meta-analysis examined the association between SSRI
antidepressants and QTc (corrected QT) prolongation (7). Citalopram and
escitalopram were associated with the greatest amount of QTc prolongation,
while sertraline was associated with the least. Fluvoxamine was associated
452
with shortened QTc. Results for fluoxetine and paroxetine were not statistically
significant.
With regard to sexual dysfunction, escitalopram and paroxetine have
been associated with a higher risk of sexual dysfunction than fluoxetine.
Pairwise comparisons of other SSRIs have not shown statistically significant
differences (8).
The pharmacokinetic properties of individual SSRIs differ considerably.
Considering potential for drug–drug interactions, many SSRIs are inhibitors
of cytochrome P450 enzymes and may interact with other drugs that are
metabolized by these enzymes. Fluoxetine and paroxetine are potent inhibitors
of CYP2D6, fluvoxamine is a potent inhibitor of CYP1A2. Fluoxetine and
fluvoxamine are also moderate inhibitors of CYP2C19. Citalopram, escitalopram
and sertraline are considered to have the lowest potential for CYP enzyme-
mediated interactions (9).
Fluoxetine has a half-life of one to four days and an active metabolite
(norfluoxetine) with a half-life of seven to fifteen days. The half-lives of the other
SSRIs are considerably shorter. Therefore, fluoxetine will take longer to reach
steady-state concentrations and will remain in the body for longer following
discontinuation of therapy. As a result, adverse reactions and drug-interactions
with fluoxetine may persist for some time following cessation of treatment
(10). Paroxetine has the shortest half-life among the SSRIs (one day) and has
been found to have a higher potential for withdrawal symptoms following
discontinuation (11).

N/A
WHO Guidelines
The WHO Mental Health Gap Action Programme (mhGAP) Guidelines make
the following recommendations in relation to antidepressants for treatment of
adults with depression (12):
–– Antidepressants should not be considered for the initial
treatment of adults with mild depressive episode. (Strength of
recommendation: Conditional; Quality of evidence: Low);
–– Tricyclic antidepressants or fluoxetine should be considered
in adults with moderate to severe depressive episode/disorder.
(Strength of recommendation: Conditional; Quality of evidence:
Low);
–– If drug treatment is required in older people, tricyclic
antidepressants should be avoided if possible. (Strength of
recommendation: Conditional; Quality of evidence: Low)
453
–– If drug treatment is required in women with depressive episode

who are planning a pregnancy or are pregnant or breastfeeding,
tricyclic antidepressants or fluoxetine should be considered.
(Strength of recommendation: Conditional; Quality of evidence:
Low).
SSRIs are also recommended as first-line treatment choices in numerous
international guidelines (13–17). The choice of individual SSRI should be made
after taking into consideration the differing safety and tolerability profiles,
pharmacokinetic and pharmacodynamic factors, price and individual patient
factors and patient preferences.
SSRIs vary in price globally, but are generally inexpensive, with multiple generic
brands available. Cost-effectiveness analyses in different settings have shown
SSRIs to be cost-effective interventions (18–27).
Availability
SSRIs are widely available globally, with off-patent generic formulations available.
Letter of support for escitalopram application from the Ministry for Health and
Welfare, National Centre for Mental Health, Republic of Korea: “More than
one SSRI should be considered as essential drugs. It is an important point that
patients may respond to specific SSRIs differently and it is difficult to predict
which agent will be the most effective for each patient.”
The Committee recommended the addition of a square box symbol to the
current listing of fluoxetine on the core list of the EML for treatment of
depressive disorders.
The Committee noted that medicines within the pharmacological class
of selective serotonin reuptake inhibitors all have demonstrated efficacy, but
can differ in terms of pharmacokinetics, adverse events and drug-interaction
profiles. The availability of different SSRIs as essential medicines may be
beneficial at country level to expand therapeutic alternatives for patients and
support better procurement.
As a consequence of the recommendation for the square box with
fluoxetine, the Committee did not recommend the separate addition of
escitalopram to the core list of the EML. Escitalopram, and other SSRIs should
be considered therapeutically equivalent alternatives to fluoxetine for selection
at national level.
454
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acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive
disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357–66.
4. Cipriani A, Santilli C, Furukawa TA, Signoretti A, Nakagawa A, McGuire H et al. Escitalopram versus
other antidepressive agents for depression. Cochrane Database Syst Rev. 2009(2):CD006532.
5. Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A et al. Risk of suicidality in
clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and
Drug Administration. BMJ. 2009;339:b2880.
6. Laughren TP. Memorandum: Department of Health and Human Services Public Health Service
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7. Beach SR, Kostis WJ, Celano CM, Januzzi JL, Ruskin JN, Noseworthy PA et al. Meta-analysis of
selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry. 2014;
75(5):e441–9.
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depressive disorder: results from a systematic review with network meta-analysis. Drug Saf.
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11. Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal Symptoms after Selective Serotonin
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treatment of adults with depression. mhGAP Evidence Resource Center. Geneva: World Health
Organization, 2012. Available from https://www.who.int/mental_health/mhgap/evidence/
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depression. J Manag Care Pharm. 2007;13(6 Suppl A):S8-18.

27. Kongsakon R, Bunchapattanasakda C. The treatment of major depressive disorders (MDD) in
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evaluation. J Med Assoc Thai. 2008;91(7):1117–28.
456
Section 25: MEDICINES ACTING ON THE RESPIRATORY TRACT

25.1 Antiasthmatic and medicines for chronic
obstructive pulmonary disease
Tiotropium – addition – EML
Tiotropium bromide ATC Code: R03BB04
Proposal
The application requested the inclusion of tiotropium with a square box as
representative of the pharmacological class of long-acting muscarinic agents
(LAMA) to the EML for use in the treatment of chronic obstructive pulmonary
disease (COPD).
Applicant
Forum of International Respiratory Societies

Comments on the application were received from the Department of Management
of Noncommunicable Diseases, Disability, Violence and Injury Prevention. The
technical unit supports the inclusion of tiotropium on the EML, stating that it
is an effective formulation to control COPD symptoms and the frequency and
severity of exacerbations. Its inclusion on the EML may improve equity by
making it more accessible to patients who need prolonged bronchodilator effect.
EML/EMLc
EML
Section
25.1 Antiasthmatic and medicines for COPD

Powder for inhalation in capsules 18 µg
Inhalation solution 1.25 μg per dose and 2.5 µg per dose
Core/Complementary
Core

Square box listing incorporating tiotropium bromide, glycopyrronium bromide,
aclidinium bromide and umeclidinium bromide.
457

Single agent LAMAs had not previously been considered for inclusion on the
EML.
The short-acting muscarinic agent ipratropium has been included on the
EML since 1998.

COPD affects approximately 300 million people worldwide and was responsible
for over 3 million deaths globally in 2017 (1). In 2017, it was the third leading
cause of death worldwide, after ischaemic heart disease and stroke (2).

Data were presented from systematic reviews and network meta-analyses
identified through a literature search conducted for the application.
A 2018 Cochrane systematic review and network meta-analysis of 99
studies (101 311 participants) compared the efficacy and safety of LAMA and
long-acting beta agonist (LABA) monotherapy and LABA/LAMA and LABA/
inhaled corticosteroid (ICS) dual combination therapy for COPD (3). The
quality of the included studies was considered by the authors to be generally
good. Results of the NMA suggested that the LABA/LAMA combination was
the highest ranking treatment for reducing COPD exacerbations, followed
by LAMA monotherapy in patients at both high- and low-risk for COPD
exacerbations, although there was some uncertainty in the results. The authors
also concluded that dual combination therapies appeared more effective than
LABA or LAMA monotherapy for improving symptom and quality of life scores.
For the comparison of LAMA versus LABA (six studies, 11 943 participants),
LAMAs were associated with decreased moderate to severe exacerbations
compared to LABA (odds ratio (OR) 0.86, 95%CI 0.79 to 0.93).
A 2014 Cochrane systematic review and NMA of 71 studies (73 062

participants) assessed the efficacy of long-acting therapies for COPD (beta-
agonists, anticholinergics and corticosteroids) (4). The efficacy outcomes evaluated
with St George’s Respiratory Questionnaire (SGRQ) total score, and trough forced
expiratory volume in 1 second (FEV1). Results from pairwise comparisons for
the efficacy outcome of SGRQ total score indicated LABA/ICS as the highest
ranked intervention, with a mean improvement over placebo of −3.89 units at
six months (95% credible interval (CrI) −4.70 to −2.97) and −3.60 at 12 months
(95%CrI −4.63 to −2.34). LAMAs and LABAs were ranked second and third at
six months, with mean differences of −2.63 (95%CrI −3.53 to −1.97) and −2.29
(95%CrI −3.18 to −1.53), respectively. Inhaled corticosteroids were ranked
fourth (MD −2.00, 95%CrI −3.06 to −0.87). Results from pairwise comparisons
for the outcome of FEV1 also indicated LABA/ICS to be the highest ranking
458
intervention, followed by LAMAs and LABAs with essentially equivalent results,

with ICS ranking fourth. The authors concluded that quality of life and lung
function were improved most with LABA/ICS combination therapy. LAMA and
LABA monotherapy demonstrated similar effects to each other.
A 2014 Cochrane systematic review of 12 randomized controlled trials
(9547 participants) evaluated the efficacy and safety of the LAMA aclidinium
bromide in patients with stable COPD (5). Compared to placebo, aclidinium
was associated with improvements in quality of life as measured by SGRQ total
score (mean difference −2.34, 95%CI −3.18 to −1.51). Aclidinium also reduced
the number of hospitalizations due to severe exacerbations compared to placebo
(OR 0.64; 95%CI 0.46 to 0.88; corresponding to 4 to 20 fewer per 1000 in
absolute terms). However, the authors concluded that overall, aclidinium did not
significantly reduce mortality, serious adverse events, or exacerbations requiring
oral steroids and/or antibiotics. The available data were insufficient and of very
low quality for efficacy comparisons of aclidinium versus tiotropium.
A 2018 Cochrane systematic review of seven randomized controlled trials
(5921 participants) evaluated the efficacy and safety of combination therapy with
aclidinium bromide and LABAs in patients with stable COPD (6). Compared
to individual monotherapy or placebo, aclidinium/LABA combination therapy
was associated with improved dyspnoea, lung function and quality of life. The
authors found no evidence of a difference between combination therapy and
monotherapy or placebo for exacerbations, hospital admissions, mortality, non-
fatal serious adverse event (SAEs) or adverse events.
A 2015 Cochrane systematic review of 10 trials (10 894 participants)
compared the relative effects of treatment with LABA plus tiotropium versus
tiotropium or LABA monotherapy in patients with COPD (7). The authors
concluded that LABA/tiotropium combination therapy was associated with a
small mean improvement in health-related quality of life and FEV1 compared
to either agent alone. There was no observed difference in hospital admissions or
death between treatment groups.
The application also presented the results of systematic reviews
and individual trials that compared monotherapy with aclidinium (5, 8),
glycopyrronium (9–11), tiotropium (12–18) and umeclidinium (19, 20) versus
placebo, other short- and long-acting LAMAs, and LABAs.
The findings of two network meta-analyses of LAMAs versus placebo
indicated no significant differences among medicines within the class for most
efficacy outcomes (21, 22).

Extensive use of LAMAs in a wide range of doses and clinical settings has
shown them to be acceptably safe. Common adverse effects of LAMAs relate to
their anticholinergic activity and include dry mouth, constipation and urinary
459
retention (23–26). However, inhaled anticholinergic medicines are poorly

absorbed, which limits the systemic effects observed with atropine (24). Most
safety data is available for tiotropium, but the rate of anticholinergic side-effects
for the wider class of LAMAs appears to be low and generally similar (27).
In a large, long-term clinical trial in COPD patients, tiotropium added
to other standard therapies had no effect on cardiovascular risk (24).

N/A
WHO Guidelines
There are no current WHO guidelines for the management of COPD.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD)
released an updated report on its global strategy for the diagnosis, management
and prevention of COPD in 2019 (28). LAMAs, alone or in combination with
LABAs are recommended as initial pharmacological treatment for stable COPD
in patients classified as Gold B, C and D using the “ABCD” assessment tool, which
takes into account both symptom burden and exacerbation risk.
A 2017 systematic review of 18 pharmacoeconomic analyses of COPD therapy
included six analyses of LAMA monotherapy (tiotropium, glycopyrronium and
aclidinium) (29). All studies were conducted in high-income settings and were
funded by pharmaceutical companies. Based on these and previous studies, the
authors considered that there was strong evidence that tiotropium monotherapy is
cost-effective compared to usual care but considered evidence to be inconclusive
for the relative cost-effectiveness of tiotropium, glycopyrronium and aclidinium
versus each other.
The application presented wholesale monthly costs for tiotropium from

Australia and the United States, between which, a substantial (10-fold) difference
in cost exists. No information was presented in the application regarding the
monthly treatment costs for other medicines in the class.
The United Kingdom’s March 2019 NHS Prescription Services Drug
Tariff reported similar prices (for one months’ treatment) across the four LAMAs
tiotropium, aclidinium, glycopyrronium and umeclidinium (30).
Availability
Tiotropium has wide international availability and is available in generic brands.
N/A
460
The Committee recommended the inclusion of tiotropium with a square box
as representative of the pharmacological class of long-acting muscarinic agents
(LAMA) to the core list of the EML for use in the treatment of chronic obstructive
pulmonary disease (COPD) based on the evidence presented for efficacy in
reducing COPD exacerbations, safety and cost-effectiveness.
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the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus
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obstructive pulmonary disease. Cochrane Database Syst Rev. 2012(9):CD009157.
18. Cheyne L, Irvin-Sellers MJ, White J. Tiotropium versus ipratropium bromide for chronic obstructive
pulmonary disease. Cochrane Database Syst Rev. 2013(9):CD009552.
19. Trivedi R, Richard N, Mehta R, Church A. Umeclidinium in patients with COPD: a randomised,
placebo-controlled study. Eur Respir J. 2014;43(1):72–81.
20. Feldman G, Maltais F, Khindri S, Vahdati-Bolouri M, Church A, Fahy WA et al. A randomized, blinded
study to evaluate the efficacy and safety of umeclidinium 62.5 mug compared with tiotropium
18 mug in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:719–30.
21. Oba Y, Lone NA. Comparative efficacy of long-acting muscarinic antagonists in preventing COPD
exacerbations: a network meta-analysis and meta-regression. Ther Adv Respir Dis. 2015;9(1):3–15.
22. Ismaila AS, Huisman EL, Punekar YS, Karabis A. Comparative efficacy of long-acting muscarinic
antagonist monotherapies in COPD: a systematic review and network meta-analysis. Int J Chron
Obstruct Pulmon Dis. 2015;10:2495–517.
23. Disse B, Speck GA, Rominger KL, Witek TJ, Jr., Hammer R. Tiotropium (Spiriva): mechanistical
considerations and clinical profile in obstructive lung disease. Life Sci. 1999;64(6-7):457–64.
24. Tashkin DP. Long-acting anticholinergic use in chronic obstructive pulmonary disease: efficacy
and safety. Curr Opin Pulm Med. 2010;16(2):97–105.
25. Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest.
2006;130(6):1695–703.
26. Halpin DM, Dahl R, Hallmann C, Mueller A, Tashkin D. Tiotropium HandiHaler((R)) and Respimat((R))
in COPD: a pooled safety analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:239-59.
27. Jones PW, Singh D, Bateman ED, Agusti A, Lamarca R, de Miquel G et al. Efficacy and safety of
twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012;40(4):
830–6.
28. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary
disease (2019 Report). Fontana: Global Initiative for Chronic Obstructive Lung Disease; 2019.
Available from https://goldcopd.org/, accessed 29 September 2019.
29. van der Schans S, Goossens LMA, Boland MRS, Kocks JWH, Postma MJ, van Boven JFM et al.
Systematic Review and Quality Appraisal of Cost-Effectiveness Analyses of Pharmacologic
Maintenance Treatment for Chronic Obstructive Pulmonary Disease: Methodological
Considerations and Recommendations. Pharmacoeconomics. 2017;35(1):43–63.
30. NHS Business Services Authority Electronic Drug Tariff. March 2019. Available from http://www.
drugtariff.nhsbsa.nhs.uk/#/00684922-DA/DA00684858/Home, accessed 26 March 2019.
462
Section 27: VITAMINS AND MINERALS

Iodine – change to listing – EML and EMLc
Iodine ATC Code: H03CA
Proposal
The application requested a correction to the strength of iodine capsules listed
on the EML and EMLc
Applicant
Guerbet

N/A
EML/EMLc
EML and EMLc
Section
27. Vitamin and Minerals

Capsule 190 mg
Core/Complementary
Core

Individual

Iodine capsules 200 mg and iodized oil were added to the EML in 1990 for the
prophylaxis of goitre in areas where severe iodine deficiency is endemic and
where dietary intake of iodine, including iodized salt, is inadequate (1). The
same formulations were included on the first EMLc in 2007 (2).

N/A

N/A
463

N/A

N/A
WHO Guidelines
N/A
N/A
Availability
A discrepancy exists between the listed strength of iodine capsules on the EML
and EMLc and the marketing authorization of the product.
The marketing authorization and Summary of Product Characteristics
(SmPC) for the product marketed by Guebet report the qualitative and
quantitative composition as 500 mg ethyl esters of iodised fatty acids from poppy
seed oil, corresponding to 190 mg iodine (38% w/w).
N/A
The Committee recommended that the strength of iodine capsules in the
EML and EMLc be corrected to 190 mg, to accurately reflect the quantitative
composition as described in the marketing authorization and Summary of
Product Characteristics (SmPC).
References
1. The use of essential drugs. Report of the WHO Expert Committee, 1990 (WHO Technical Report
Series, No. 796). Geneva: World Health Organization; 1990. Available from https://apps.who.int/
2. The selection and use of essential medicines. Report of the WHO Expert Committee, October
2007 (including the Model List of Essential Medicines for Children) (WHO Technical Report
Series, No. 950). Geneva: World Health Organization; 2008. Available from https://apps.who.int/
iris/bitstream/handle/10665/43745/WHO_TRS_946_eng.pdf, accessed 30 October 2019.
464
Multiple micronutrient powders – addition – EMLc
Multiple micronutrient powders ATC Code: B03AE10
Proposal
The application requested the inclusion of multiple micronutrient powders
(MNP) for the prevention of anaemia in infants and children on the core list of
the EMLc.
Applicant
Dr Stanley Zlotkin

Nutrition for Health and Development
EML/EMLc
EMLc
Section
27. Vitamins and minerals

Oral powder sachet 1 g containing:
– elemental iron 12.5 mg
– elemental zinc 5 mg
– vitamin A 300 mcg
– with or without other micronutrients at recommended daily values
Core/Complementary
Core

Individual

Multiple micronutrient powders have not previously been considered for
inclusion on the EMLc.

The global prevalence of anaemia worldwide for pre-school children in 2011
was 43% or an estimated 273 children, of which about 42% is attributable to
465
iron deficiency (1). Anaemia in early childhood reduces cognitive ability and
causes developmental delays and disability (1). Currently, epidemiological and
experimental data suggest that in order to minimize these risks, prevention of
anaemia is preferred over treatment because the physiological impairments
due to deficiency start at an early age and they may be irreversible, even after
repletion of iron stores (2). There are no direct estimates for prevalence of zinc
deficiency; however, it is believed to be as prevalent as iron deficiency affecting
approximately 293 million children under five and is responsible for 13% of
lower respiratory tract infections (primarily pneumonia and influenza) (3).
Amongst children under 5 years of age globally, an estimated 190 million
have vitamin A deficiency. The prevalence of vitamin A deficiency is about
44% amongst children in Africa and about 50% in children in South-East Asia.
Vitamin A deficiency associated with prevalence of night blindness is around 2%
in African children, and about 0.5% in children in parts of South-East Asia (3).
Deficiencies of vitamins and minerals such as iron, zinc, vitamin A
and others, often occur simultaneously in children due to factors such as poor
nutritional status (3). The effects of these deficiencies in neonates can result in
serious adverse events including mortality. Furthermore, the effects of these
deficiencies in childhood may result in long-term, life-long irreversible physical
and cognitive problems that lead to negative consequences for health and
economic opportunities. Mineral and vitamin deficiencies particularly in iron,
zinc and vitamin A, among other nutritional risk factors, are determined to be
responsible for 3.9 million deaths (35% of total deaths) in children under the
age of 5 years annually. These deficiencies are also responsible for 144 million
disability-adjusted life years in the same population (3).

Evidence for the effectiveness of MNP comes from two systematic reviews that
informed the development of the 2016 WHO Guidelines for use of multiple
micronutrient powders for point-of-use fortification of foods consumed by

infants and young children 6 to 23 months and children 2 to 12 years (4).
A 2011 Cochrane systematic review of 15 randomized and quasi-
randomized trials (12 239 participants) evaluated the effects and safety of
point‑of-use fortification of foods with MNP for infants and young children
from 6 to 23 months of age. The trials were conducted in low- and middle-
income countries (LMICs) in Asia, Africa and the Americas. Six studies were
conducted in malaria-endemic areas. Most trials were assessed as having a low
risk of bias (5).
The Guideline Development Group reported that infants and young
children from 6 to 23 months of age who consumed foods fortified at the
point-of-use with multiple micronutrients powders had a lower risk for the
critical outcome of anaemia, with a 26% reduction compared to placebo or
466
no intervention (risk ratio (RR) 0.74, 95%CI 0.66 to 0.83; 10 studies; 2802
participants, high quality evidence). They also had a lower risk for the critical
outcome of iron deficiency, with a 52% reduction (RR: 0.48, 95%CI 0.36 to 0.62;
five studies; 796 participants, moderate quality evidence). Compared to no
treatment or placebo, children receiving multiple micronutrient powders had a
5.12 g/L higher haemoglobin concentration at follow-up (mean difference (MD)
5.12 g/L, 95%CI 2.70 to 7.54; 12 studies; 3565 participants, low quality evidence).
With respect to iron status, compared to no treatment or placebo, children
receiving multiple micronutrient powders had an average increase in serum
ferritin concentration of 16.47 μg/L at follow up (MD: 16.47 μg/L, 95%CI 3.03
to 29.91; three studies; 694 participants, very low quality evidence). Regarding
weight-for-age z-score, the mean difference was minimal (MD: 0.04 in z-score,
95%CI –0.13 to 0.21; four studies; 606 participants, low quality evidence) (4).
A second Cochrane systematic review of 12 randomized and quasi-
randomized trials (5720 participants) assessed the effects and safety of point-
of-use fortification of foods with MNP for children aged from 2 to 12 years. The
trials were conducted in low- and middle-income countries in Asia, Africa and
the Americas. Most trials were assessed as having a low risk of bias (6).
The Guideline Development Group reported that children aged 2 to
12 years receiving iron-containing multiple micronutrient powders for point-of-
use fortification of foods were significantly less likely to have anaemia at follow-
up than those children receiving no intervention or a placebo (prevalence ratio
(PR) 0.66, 95%CI 0.49 to 0.88; 10 studies, 2448 participants, moderate quality
evidence). These children also had a 3.37 g/L higher haemoglobin concentration
at follow-up (MD 3.37 g/L, 95%CI 0.94 to 5.80; 11 studies; 2746 participants,
low quality evidence). Also, children receiving iron-containing multiple
micronutrient powders for point-of-use fortification of foods were significantly
less likely to have iron deficiency at follow up than those children receiving
no intervention or a placebo (PR 0.35, 95%CI 0.27 to 0.47; five studies; 1364
participants, moderate quality evidence). With respect to ferritin concentrations,
children receiving iron-containing multiple micronutrient powders had, on
average, 0.42 μg of ferritin more per litre at follow-up than those children
receiving no intervention or a placebo (standardized mean difference (SMD):
0.42 μg/L, 95%CI –4.36 to 5.19; three studies; 1066 participants, very low quality
evidence) (4).

In the systematic review on MNP in infants and young children, data on
morbidity, other indicators of vitamin and mineral status and side-effects were
scarce due to a lack of standardization; however, none of the trials reported
deaths attributable to the intervention and there was no difference regarding the
patterns of morbidity between children receiving placebo or no intervention and
467
the ones receiving MNP. Only one of the studies conducted in malaria-endemic
areas reported results related to malaria and found no difference in the presence
of positive malaria smears between the groups (RR 0.24, 95%CI 0.05 to 1.12; 194
children). None of the trials reported on the outcome of all-cause mortality (5).
In the systematic review on MNP in older children, only one trial reported
on the outcome of all-cause mortality and there were no deaths reported during
this trial (MD 0, 95%CI –0.03 to 0.03; one study; 115 participants, low quality
evidence). Finally, diarrhoea (three liquid stools or more per day) was reported
by two trials and children receiving iron-containing MNP were as likely to have
diarrhoea at follow-up as those children receiving no intervention or a placebo
(RR 0.97, 95%CI 0.53 to 1.78; two studies; 366 participants, moderate quality
evidence) (6).
A 2016 Cochrane systematic review evaluated the effects and safety of
iron supplementation (including MNP), with or without folic acid, in children
living in areas with hyperendemic or holoendemic malaria transmission. The
review found that overall, iron does not cause an excess of clinical malaria
(RR 0.93, 95%CI 0.87 to 1.00; 14 trials, 7168 children, high quality evidence).
Iron probably does not cause an excess of clinical malaria in both populations
where anaemia is common and those in which anaemia is uncommon. In areas
where there are prevention and management services for malaria, iron (with or
without folic acid) may reduce clinical malaria (RR 0.91, 95%CI 0.84 to 0.97;
seven trials, 5586 participants, low quality evidence), while in areas where
such services are unavailable, iron (with or without folic acid) may increase the
incidence of malaria, although the lower CIs indicate no difference (RR 1.16,
95%CI 1.02 to 1.31; nine trials, 19 086 participants, low quality evidence). Iron
supplementation does not cause an excess of severe malaria (RR 0.90, 95%CI
0.81 to 0.98; 6 trials, 3421 children, high quality evidence). Iron resulted in fewer
anaemic children at follow up, and the end average change in haemoglobin from
base line was higher with iron (7).

N/A
WHO Guidelines
The 2016 WHO Use of multiple micronutrient powders for point-of-use fortification
of foods consumed by infants and young children 6–23 months and children 2–12
years (4) make the following recommendations with regard to MNP:
–– In populations where anaemia is a public health problem, point-
of-use fortification of complementary foods with iron-containing
micronutrient powders in infants and young children aged 6 to
23 months is recommended, to improve iron status and reduce
468
anaemia (strong recommendation, moderate quality evidence).

–– In populations where anaemia is a public health problem, point-
of-use fortification of foods with iron containing micronutrient
powders in children aged 2 to 12 years is recommended, to
improve iron status and reduce anaemia (strong recommendation,
moderate quality evidence).
The current listed price of the MNP provided by UNICEF Supply Catalogue
website is US$ 0.62 to US$ 0.65 per pack (30 sachets) (8). The composition of
the UNICEF supplied product differs from the composition of MNP proposed
for inclusion on the EMLc with regard to the amount of iron, vitamin A and
zinc, and the inclusion of 12 additional micronutrients.
The World Bank estimated the annual cost of MNP intervention at
US$ 3.60 per child aged 12 to 23 months (9). A Copenhagen Consensus review
found that micronutrient interventions were cost-effective in general (10). It has
also been estimated that iron-containing MNP recover US$ 37 for every US$ 1
invested due to the positive effects of addressing childhood anaemia among
children aged 6 to 23 months (11).
Availability
The following manufacturers were identified in 2016 by UNICEF Supply
Division’s Multiple Micronutrient Powder Supply & Market Outlook as meeting
standards (i.e. good manufacturing practice) and having the capacity to provide
suitable, age-appropriate dose forms and strengths of multiple micronutrient
powders for administration to infants and children (12):
1. DSM Europe (Switzerland)
2. DSM (Malaysia) – formerly Fortitech
3. Renata (Bangladesh)
4. Piramal (India)
5. DSM (South Africa)
The Committee noted the information provided in the application regarding the
submission for MNP to be included in the United States Pharmacopoeia (USP),
including a draft of the approved product monograph, which will take effect in
May 2019.
469
The Committee recommended the addition of multiple micronutrient powders
to the core list of the EMLc for the prevention of anaemia in infants and
children in populations where anaemia is a public health problem. Use should
be in line with the recommendations in current WHO guidelines for point-of-
use fortification of foods.
References
1. The global prevalence of anaemia in 2011. Geneva: World Health Organization; 2015.
2. Intermittent iron supplementation in pre-school and school-age children. Geneva: World
3. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva:
World Health Organization; 2009.
4. Use of multiple micronutrient powders for point-of-use fortification of foods consumed by
infants and young children aged 6–23 months and children aged 2–12 years. Geneva: World
252540/9789241549943-eng.pdf, accessed 29 September 2019.
5. De-Regil LM, Suchdev PS, Vist GE, Walleser S, Pena-Rosas JP. Home fortification of foods with
multiple micronutrient powders for health and nutrition in children under two years of age.
6. De-Regil LM, Jefferds MED, Pena-Rosas JP. Point-of-use fortification of foods with micronutrient
powders containing iron in children of preschool and school-age. Cochrane Database Syst Rev.
2017;11:CD009666.
7. Neuberger A, Okebe J, Yahav D, Paul M. Oral iron supplements for children in malaria-endemic
areas. Cochrane Database Syst Rev. 2016;2:CD006589.
8. UNICEF Supply Catalogue [website]. New York: United Nations Children’s Fund. (https://supply.
unicef.org/, accessed 29 September 2019).
9. Horton S, Shekar M, Mcdonald C, Mahal A, Brooks J. Scaling up nutrition: what will it cost?
Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2010.
10. Horton S, Alderman H, Rivera J A. Copenhagen Consensus 2009 Challenge Paper: Hunger and
Malnutrition. [ed.] Bjorn Lomborg. In: Global Crises, Global Solutions. Cambridge: Cambridge
University Press; 2009.
11. Sharieff W, Horton SE, Zlotkin S. Economic gains of a home fortification program: evaluation of
“Sprinkles” from the provider’s perspective. Can J Public Health. 2006;97(1):20–3.
12. Multiple micronutrient powder supply & market outlook. Available from https://www.
unicef.org/supply/files/Multiple_Micronutrient_Powder_Supply_and_Market_Update.pdf.
Copenhagen: United Nations Children’s Fund; 2016.
470
Annex 1
WHO Model List of Essential Medicines (2019)
Explanatory notes
The core list presents a list of minimum medicine needs for a basic health-
care system, listing the most efficacious, safe and cost–effective medicines for
priority conditions. Priority conditions are selected on the basis of current
and estimated future public health relevance, and potential for safe and cost-
effective treatment.
Where the [c] symbol is placed next to an individual medicine or
strength of medicine on the core list it signifies that there is a specific indication
for restricting its use to children.
The complementary list presents essential medicines for priority
diseases, for which specialized diagnostic or monitoring facilities, and/or
specialist medical care, and/or specialist training are needed. In case of doubt
medicines may also be listed as complementary on the basis of consistent higher
costs or less attractive cost-effectiveness in a variety of settings.
Where the [c] symbol is placed next to an individual medicine or
strength of medicine on the complementary list it signifies that the medicine(s)
require(s) specialist diagnostic or monitoring facilities, and/or specialist medical
care, and/or specialist training for their use in children.
The square box symbol () is primarily intended to indicate similar
clinical performance within a pharmacological class. The listed medicine should
be the example of the class for which there is the best evidence for effectiveness
and safety. In some cases, this may be the first medicine that is licensed for
marketing; in other instances, subsequently licensed compounds may be safer or
more effective. Where there is no difference in terms of efficacy and safety data,
the listed medicine should be the one that is generally available at the lowest
price, based on international drug price information sources. Not all square
boxes are applicable to medicine selection for children.
Therapeutic equivalence is indicated only on the basis of reviews of
efficacy and safety and when consistent with WHO clinical guidelines. National
lists should not use a similar symbol and should be specific in their final selection,
which would depend on local availability and price.
The a symbol indicates that there is an age or weight restriction on use
of the medicine; details for each medicine can be found in Table 1.1.
The presence of an entry on the Essential Medicines List carries no
assurance as to pharmaceutical quality. It is the responsibility of the relevant
national or regional drug regulatory authority to ensure that each product is of
471
appropriate pharmaceutical quality (including stability) and that, when relevant,

different products are interchangeable.
For recommendations and advice concerning all aspects of the quality
assurance of medicines see the WHO Medicines website http://www.who.int/
medicines/areas/quality_safety/quality_assurance/en/.
Medicines and dosage forms are listed in alphabetical order within
each section and there is no implication of preference for one form over
another. Standard treatment guidelines should be consulted for information on
appropriate dosage forms.
The main terms used for dosage forms in the Essential Medicines List can
be found in Table 1.2.
Definitions of many of these terms and pharmaceutical quality
requirements applicable to the different categories are published in the current
edition of The International Pharmacopoeia http://www.who.int/medicines/
publications/pharmacopoeia.
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Annex 1: 21st WHO Model List of Essential Medicines (2019)
1. ANAESTHETICS, PREOPERATIVE MEDICINES AND MEDICAL GASES

1.1 General anaesthetics and oxygen
1.1.1 Inhalational medicines
halothane Inhalation.
isoflurane Inhalation.
nitrous oxide Inhalation.
oxygen Inhalation (medical gas).
1.1.2 Injectable medicines
ketamine Injection: 50 mg (as hydrochloride)/ mL in 10- mL vial.
propofol* Injection: 10 mg/ mL; 20 mg/ mL.
* Thiopental may be used as an alternative depending on local
availability and cost.
1.2 Local anaesthetics

 bupivacaine Injection: 0.25%; 0.5% (hydrochloride) in vial.
Injection for spinal anaesthesia: 0.5% (hydrochloride)
in 4- mL ampoule to be mixed with 7.5% glucose
solution.
 lidocaine Injection: 1%; 2% (hydrochloride) in vial.
Injection for spinal anaesthesia: 5% (hydrochloride) in
2- mL ampoule to be mixed with 7.5% glucose solution.
Topical forms: 2% to 4% (hydrochloride).
lidocaine + epinephrine Dental cartridge: 2% (hydrochloride) + epinephrine
(adrenaline) 1:80 000.
Injection: 1%; 2% (hydrochloride or sulfate) +
epinephrine 1:200 000 in vial.
Complementary List
ephedrine* Injection: 30 mg (hydrochloride)/ mL in 1- mL ampoule.
* For use in spinal anaesthesia during delivery, to prevent
hypotension.
473
1. ANAESTHETICS, PREOPERATIVE MEDICINES AND MEDICAL GASES (continued)

1.3 Preoperative medication and sedation for short-term procedures
atropine Injection: 1 mg (sulfate) in 1- mL ampoule.
 midazolam Injection: 1 mg/ mL.
Oral liquid: 2 mg/ mL [c] .
Tablet: 7.5 mg; 15 mg.
morphine Injection: 10 mg (sulfate or hydrochloride) in 1- mL
ampoule.
1.4 Medical gases
oxygen* Inhalation
For use in the management of hypoxaemia.
* No more than 30% oxygen should be used to initiate
resuscitation of neonates less than or equal to 32 weeks
of gestation.
2. MEDICINES FOR PAIN AND PALLIATIVE CARE

2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs)
acetylsalicylic acid Suppository: 50 mg to 150 mg.
Tablet: 100 mg to 500 mg.
ibuprofen a Oral liquid: 200 mg/5 mL.
Tablet: 200 mg; 400 mg; 600 mg.
a Not in children less than 3 months.
paracetamol* Oral liquid: 120 mg/5 mL; 125 mg/5 mL.
Suppository: 100 mg.
* Not recommended for anti-inflammatory use due to lack of

proven benefit to that effect.
474
2. MEDICINES FOR PAIN AND PALLIATIVE CARE (continued)

2.2 Opioid analgesics
codeine Tablet: 30 mg (phosphate).
fentanyl* Transdermal patch: 12 micrograms/hr;
25 micrograms/hr; 50 micrograms/hr; 75 micrograms/hr;
100 micrograms/hr
* For the management of cancer pain
 morphine* Granules (slow-release; to mix with water): 20 mg–

200 mg (morphine sulfate).
Injection: 10 mg (morphine hydrochloride or morphine
sulfate) in 1- mL ampoule.
Oral liquid: 10 mg (morphine hydrochloride or
morphine sulfate)/5 mL.
Tablet (slow release): 10 mg–200mg (morphine
hydrochloride or morphine sulfate).
Tablet (immediate release): 10 mg (morphine sulfate).
* Alternatives limited to hydromorphone and oxycodone
Complementary list
methadone* Tablet: 5 mg; 10 mg (as hydrochloride)
Oral liquid: 5mg/ 5mL; 10mg/ 5mL (as hydrochloride)
Concentrate for oral liquid: 5 mg/ mL; 10mg/ mL
(as hydrochloride)
* For the management of cancer pain.
2.3 Medicines for other common symptoms in palliative care

amitriptyline Tablet: 10 mg; 25 mg; 75 mg.
cyclizine [c] Injection: 50 mg/ mL.
Tablet: 50 mg.
dexamethasone Injection: 4 mg/ mL in 1- mL ampoule (as disodium
phosphate salt).
Oral liquid: 2 mg/5 mL.
Tablet: 2 mg [c] ; 4 mg.
diazepam Injection: 5 mg/ mL.
Rectal solution: 2.5 mg; 5 mg; 10 mg.
Tablet: 5 mg; 10 mg.
475

docusate sodium Capsule: 100 mg.
fluoxetine a Solid oral dosage form: 20 mg (as hydrochloride).
a >8 years.
haloperidol Injection: 5 mg in 1‐ mL ampoule.
Oral liquid: 2 mg/ mL.
Solid oral dosage form: 0.5 mg; 2mg; 5 mg.
hyoscine butylbromide Injection: 20 mg/ mL.
hyoscine hydrobromide [c] Injection: 400 micrograms/ mL; 600 micrograms/ mL.
Transdermal patches: 1 mg/72 hours.
lactulose [c] Oral liquid: 3.1–3.7 g/5 mL.
loperamide Solid oral dosage form: 2 mg.
metoclopramide Injection: 5 mg (hydrochloride)/mL in 2‐mL ampoule.
Solid oral form: 10 mg (hydrochloride).
midazolam Injection: 1 mg/ mL; 5 mg/ mL.
Solid oral dosage form: 7.5 mg; 15 mg.
Oral liquid: 2mg/ mL [c] .
 ondansetron [c] a Injection: 2 mg base/ mL in 2- mL ampoule
(as hydrochloride).
Oral liquid: 4 mg base/5 mL.
Solid oral dosage form: Eq 4 mg base; Eq 8 mg base.
a >1 month.
senna Oral liquid: 7.5 mg/5 mL.

3. ANTIALLERGICS AND MEDICINES USED IN ANAPHYLAXIS
phosphate salt).
epinephrine (adrenaline) Injection: 1 mg (as hydrochloride or hydrogen tartrate)
in 1- mL ampoule.
hydrocortisone Powder for injection: 100 mg (as sodium succinate) in
vial.
476
3. ANTIALLERGICS AND MEDICINES USED IN ANAPHYLAXIS (continued)

 loratadine* Oral liquid: 1 mg/ mL.
Tablet: 10 mg.
* There may be a role for sedating antihistamines for limited
indications (EMLc).
 prednisolone Oral liquid: 5 mg/ mL [c] .

4. ANTIDOTES AND OTHER SUBSTANCES USED IN POISONINGS
4.1 Non-specific
charcoal, activated Powder.
4.2 Specific
acetylcysteine Injection: 200 mg/ mL in 10- mL ampoule.
Oral liquid: 10% [c] ; 20% [c] .
atropine Injection: 1 mg (sulfate) in 1- mL ampoule.
calcium gluconate Injection: 100 mg/ mL in 10- mL ampoule.
methylthioninium chloride Injection: 10 mg/ mL in 10- mL ampoule.
(methylene blue)
naloxone Injection: 400 micrograms (hydrochloride) in 1- mL
ampoule.
penicillamine Solid oral dosage form: 250 mg.
potassium ferric Powder for oral administration.
hexacyano‑ferrate(II)
-2H2O(Prussian blue)
sodium nitrite Injection: 30 mg/ mL in 10- mL ampoule.
sodium thiosulfate Injection: 250 mg/ mL in 50- mL ampoule.
Complementary List
deferoxamine Powder for injection: 500 mg (mesilate) in vial.
dimercaprol Injection in oil: 50 mg/ mL in 2- mL ampoule.
fomepizole Injection: 5 mg/ mL (sulfate) in 20- mL ampoule or 1 g/ mL
(base) in 1.5- mL ampoule.
sodium calcium edetate Injection: 200 mg/ mL in 5- mL ampoule.
succimer Solid oral dosage form: 100 mg.
477
5. ANTICONVULSANTS/ANTIEPILEPTICS
carbamazepine Oral liquid: 100 mg/5 mL.
Tablet (chewable): 100 mg; 200 mg.
Tablet (scored): 100 mg; 200 mg.
diazepam Gel or rectal solution: 5 mg/ mL in 0.5 mL; 2- mL; 4- mL
tubes.
lamotrigine* Tablet: 25 mg; 50 mg; 100 mg; 200 mg.
Tablet (chewable, dispersible): 2 mg; 5 mg; 25 mg;
50 mg; 100 mg; 200 mg.
* As adjunctive therapy for treatment-resistant partial or
generalized seizures.
 lorazepam Parenteral formulation: 2 mg/ mL in 1- mL ampoule;

4 mg/ mL in 1- mL ampoule.
magnesium sulfate* Injection: 0.5g/ mL in 2- mL ampoule (equivalent to
1 g in 2 mL; 50% weight/volume); 0.5g/ mL in 10- mL
ampoule (equivalent to 5 g in 10 mL; 50% weight/
volume).
* For use in eclampsia and severe pre-eclampsia and not for
other convulsant disorders.
midazolam Solution for oromucosal administration: 5 mg/mL;

10 mg/mL.
Ampoule*: 1 mg/ mL; 10 mg/mL.
* For buccal administration when solution for oromucosal
administration is not available.
phenobarbital Injection: 200 mg/ mL (sodium).

phenytoin Injection: 50 mg/ mL in 5- mL vial (sodium salt).

Oral liquid: 25 mg to 30 mg/5 mL.*
Solid oral dosage form: 25 mg; 50 mg; 100 mg (sodium
salt).
Tablet (chewable): 50 mg.
* The presence of both 25 mg/5 mL and 30 mg/5 mL strengths
on the same market would cause confusion in prescribing and
dispensing and should be avoided.
valproic acid Oral liquid: 200 mg/5 mL.

(sodium valproate) Tablet (crushable): 100 mg.
Tablet (enteric-coated): 200 mg; 500 mg (sodium
valproate).
478
5. ANTICONVULSANTS/ANTIEPILEPTICS (continued)
Complementary List
ethosuximide Capsule: 250 mg.
valproic acid Injection: 100 mg/ mL in 4- mL ampoule; 100 mg/ mL in
(sodium valproate) 10- mL ampoule.
6. ANTI-INFECTIVE MEDICINES
6.1 Anthelminthics
6.1.1 Intestinal anthelminthics
albendazole Tablet (chewable): 400 mg.
ivermectin Tablet (scored): 3 mg.
levamisole Tablet: 50 mg; 150 mg (as hydrochloride).
mebendazole Tablet (chewable): 100 mg; 500 mg.
niclosamide Tablet (chewable): 500 mg.
praziquantel Tablet: 150 mg; 600 mg.
pyrantel Oral liquid: 50 mg (as embonate or pamoate)/ mL.
Tablet (chewable): 250 mg (as embonate or pamoate).
6.1.2 Antifilarials
diethylcarbamazine Tablet: 50 mg; 100 mg (dihydrogen citrate).
6.1.3 Antischistosomals and other antitrematode medicines
praziquantel Tablet: 600 mg.
triclabendazole Tablet: 250 mg.
Complementary List
oxamniquine* Capsule: 250 mg.
* Oxamniquine is listed for use when praziquantel treatment fails.
479
6. ANTI-INFECTIVE MEDICINES (continued)

6.2 Antibacterials
To assist in the development of tools for antibiotic stewardship at local, national and
global levels and to reduce antimicrobial resistance, the Access, Watch, Reserve
(AWaRe) classification of antibiotics was developed – where antibiotics are classified
into different groups to emphasize the importance of their appropriate use.
ACCESS GROUP ANTIBIOTICS
This group includes antibiotics that have activity against a wide range of commonly
encountered susceptible pathogens while also showing lower resistance potential than
antibiotics in the other groups. Selected Access group antibiotics are recommended
as essential first or second choice empiric treatment options for infectious syndromes
reviewed by the EML Expert Committee and are listed as individual medicines on
the Model Lists to improve access and promote appropriate use. They are essential
antibiotics that should be widely available, affordable and quality assured.
WATCH GROUP ANTIBIOTICS
This group includes antibiotic classes that have higher resistance potential and includes
most of the highest priority agents among the Critically Important Antimicrobials
for Human Medicine 1 and/or antibiotics that are at relatively high risk of selection of
bacterial resistance. These medicines should be prioritized as key targets of stewardship
programs and monitoring. Selected Watch group antibiotics are recommended as
essential first or second choice empiric treatment options for a limited number of
specific infectious syndromes and are listed as individual medicines on the Model Lists.
1
http://apps.who.int/iris/bitstream/10665/251715/1/9789241511469-eng.pdf?ua=1
RESERVE GROUP ANTIBIOTICS

This group includes antibiotics and antibiotic classes that should be reserved for
treatment of confirmed or suspected infections due to multi-drug-resistant organisms.
Reserve group antibiotics should be treated as “last resort” options. Selected Reserve
group antibiotics are listed as individual medicines on the Model Lists when they have
a favourable risk-benefit profile and proven activity against “Critical Priority” or “High
Priority” pathogens identified by the WHO Priority Pathogens List 1, notably carbapenem
resistant Enterobacteriaceae. These antibiotics should be accessible, but their use
should be tailored to highly specific patients and settings, when all alternatives have
failed or are not suitable. These medicines could be protected and prioritized as key
targets of national and international stewardship programs involving monitoring and
utilization reporting, to preserve their effectiveness.
1
https://apps.who.int/iris/handle/10665/311820
480

6.2.1 Access group antibiotics
amikacin Injection: 250 mg (as sulfate)/mL in 2- mL vial
FIRST CHOICE SECOND CHOICE
- pyelonephritis or - sepsis in neonates and
prostatitis (severe) children [c]
- high-risk febrile
neutropenia
amoxicillin Powder for oral liquid: 125 mg (as trihydrate)/5 mL;
250 mg (as trihydrate)/5 mL [c] .
Solid oral dosage form: 250 mg; 500 mg (as trihydrate).
Powder for injection: 250 mg; 500 mg; 1 g (as sodium)
in vial.
- community acquired - acute bacterial meningitis
pneumonia (mild to
moderate)
- community acquired
pneumonia (severe) [c]
- complicated severe acute
malnutrition [c]
- exacerbations of COPD
- lower urinary tract
infections
- otitis media
- pharyngitis
- sepsis in neonates and
children [c]
- sinusitis
- uncomplicated severe
acute malnutrition [c]
- progressive apical dental
abscess
481

amoxicillin + clavulanic acid Oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic
acid/5 mL AND 250 mg amoxicillin + 62.5 mg clavulanic
acid/5 mL [c] .
Tablet: 500 mg (as trihydrate) + 125 mg (as potassium
salt).
Powder for injection: 500 mg (as sodium) + 100 mg
(as potassium salt); 1000 mg (as sodium) + 200 mg
(as potassium salt) in vial.
- community acquired - bone and joint infections
pneumonia (severe) [c] - community-acquired
- complicated pneumonia (mild to
intraabdominal infections moderate)
(mild to moderate) - community acquired
- exacerbations of COPD pneumonia (severe)
- hospital acquired - otitis media
pneumonia - surgical prophylaxis
- low-risk febrile
neutropenia
infections
- sinusitis
- skin and soft tissue
infections
ampicillin Powder for injection: 500 mg; 1 g (as sodium salt) in vial.

pneumonia (severe) [c]
malnutrition [c]
children [c]
benzathine benzylpenicillin Powder for injection: 900 mg benzylpenicillin
(= 1.2 million IU) in 5- mL vial [c] ; 1.44 g benzylpenicillin
(= 2.4 million IU) in 5- mL vial.
- syphilis
482

benzylpenicillin Powder for injection: 600 mg (= 1 million IU);
3 g (= 5 million IU) (sodium or potassium salt) in vial.
- community acquired - acute bacterial
pneumonia (severe) [c] meningitis [c]
malnutrition [c]
children [c]
- syphilis
cefalexin Powder for reconstitution with water: 125 mg/5 mL;
250 mg/5 mL (anhydrous).
Solid oral dosage form: 250 mg (as monohydrate).
- pharyngitis
infections
cefazolin a Powder for injection: 1 g (as sodium salt) in vial.
a >1 month.
- surgical prophylaxis - bone and joint infections
chloramphenicol Capsule: 250 mg.
Oily suspension for injection*: 0.5 g (as sodium
succinate)/ mL in 2- mL ampoule.
* Only for the presumptive treatment of epidemic meningitis in
children older than 2 years and in adults.
Oral liquid: 150 mg (as palmitate)/5 mL.
Powder for injection: 1 g (sodium succinate) in vial.
- acute bacterial meningitis
clindamycin Capsule: 150 mg (as hydrochloride).
Injection: 150 mg (as phosphate)/ mL.
Oral liquid: 75 mg/5 mL (as palmitate) [c] .
- bone and joint infections
483

 cloxacillin* Capsule: 500 mg; 1 g (as sodium salt).
Powder for injection: 500 mg (as sodium salt) in vial.
Powder for oral liquid: 125 mg (as sodium salt)/5 mL.
* Cloxacillin, dicloxacillin and flucloxacillin are preferred for oral
administration due to better bioavailability.

- bone and joint infections - sepsis in neonates and
- skin and soft tissue children [c]
infections
doxycycline a Oral liquid: 25 mg/5 mL [c] ; 50 mg/5 mL
(anhydrous) [c] .
Solid oral dosage form: 50 mg [c] ; 100 mg (as hyclate).
Powder for injection: 100 mg in vial.
a Use in children <8 years only for life-threatening infections
when no alternative exists.

- sexually transmitted - cholera [c]
infection due to - community acquired
Chlamydia trachomatis pneumonia (mild to
- cholera moderate)
gentamicin Injection: 10 mg; 40 mg (as sulfate)/ mL in 2- mL vial.
- community acquired - gonorrhoea
pneumonia (severe) [c] - surgical prophylaxis

malnutrition [c]
children [c]
484

metronidazole Injection: 500 mg in 100- mL vial.
Oral liquid: 200 mg (as benzoate)/5 mL.
Suppository: 500 mg; 1 g.
- C. difficile infection - complicated
- complicated intraabdominal infections
intraabdominal infections (mild to moderate)
(mild to moderate)
- complicated
intraabdominal infections
(severe)
- trichomoniasis
- surgical prophylaxis
nitrofurantoin Oral liquid: 25 mg/5 mL [c] .
Tablet: 100 mg.
infections
phenoxymethylpenicillin Powder for oral liquid: 250 mg (as potassium salt)/5 mL.
Tablet: 250 mg (as potassium salt).
pneumonia (mild to
moderate)
- pharyngitis
abscess
procaine benzylpenicillin* Powder for injection: 1 g (=1 million IU); 3 g (=3 million
IU) in vial.
* Procaine benzylpenicillin is not recommended as first-line
treatment for neonatal sepsis except in settings with high
neonatal mortality, when given by trained health workers in
cases where hospital care is not achievable.

- syphilis [c] - syphilis
485

spectinomycin Powder for injection: 2 g (as hydrochloride) in vial.
- gonorrhoea
sulfamethoxazole + Injection:
trimethoprim* 80 mg + 16 mg/ mL in 5- mL ampoule;
80 mg + 16 mg/ mL in 10- mL ampoule.
Oral liquid: 200 mg + 40 mg/5 mL.
Tablet: 100 mg + 20 mg; 400 mg + 80 mg; 800 mg +
160 mg.
* Single agent trimethoprim may be an alternative for lower
urinary tract infection.

- lower urinary tract - acute invasive diarrhoea /
infections bacterial dysentery
azithromycin* Capsule: 250 mg; 500 mg (anhydrous).
* Also listed for single-dose treatment of trachoma and yaws.

- sexually transmitted - acute invasive bacterial
infection due to diarrhoea / dysentery
Chlamydia trachomatis - gonorrhoea
- cholera [c]
- gonorrhoea
- enteric fever
cefixime Capsule or tablet: 200 mg; 400 mg (as trihydrate).

Powder for oral liquid: 100 mg /5 mL [c] .
- acute invasive bacterial
diarrhoea / dysentery
- gonorrhoea
486

cefotaxime* Powder for injection: 250 mg per vial (as sodium salt).
* 3rd generation cephalosporin of choice for use in hospitalized
neonates.

- acute bacterial meningitis - bone and joint infections
- community acquired - pyelonephritis or
pneumonia (severe) prostatitis (mild to
- complicated moderate)
intraabdominal infections - sepsis in neonates and
(mild to moderate) children [c]
- complicated
(severe)
- hospital acquired
pneumonia
- pyelonephritis or
prostatitis (severe)
ceftriaxone* a Powder for injection: 250 mg; 1 g (as sodium salt) in vial.
* Do not administer with calcium and avoid in infants with
hyperbilirubinaemia.
a >41 weeks corrected gestational age.
- acute bacterial meningitis - acute invasive bacterial
- community acquired diarrhoea / dysentery
pneumonia (severe) - bone and joint infections
- complicated - pyelonephritis or prostatitis
intraabdominal infections (mild to moderate)
(mild to moderate) - sepsis in neonates and
- complicated children [c]
(severe)
- hospital acquired
pneumonia
- gonorrhoea
- pyelonephritis or
prostatitis (severe)
- enteric fever
487

cefuroxime Powder for injection: 250 mg, 750 mg, 1.5 g (as sodium
salt) in vial
ciprofloxacin Oral liquid: 250 mg/5 mL (anhydrous) [c] .
Solution for IV infusion: 2 mg/ mL (as hyclate) [c] .
Tablet: 250 mg (as hydrochloride).
- acute invasive bacterial - cholera
diarrhoea / dysentery - complicated
- low-risk febrile intraabdominal infections
neutropenia (mild to moderate)
- pyelonephritis or
prostatitis (mild to
moderate)
- enteric fever
clarithromycin*† Solid oral dosage form: 500 mg.
Powder for oral liquid: 125 mg/5 mL; 250 mg/5 mL
Powder for injection: 500 mg in vial
* Erythromycin may be an alternative.
† Clarithromycin is also listed for use in combination regimens for
eradication of H. pylori in adults.

- community acquired - pharyngitis
pneumonia (severe)
piperacillin + tazobactam Powder for injection: 2 g (as sodium salt) + 250 mg

(as sodium salt); 4 g (as sodium salt) + 500 mg (as sodium
salt) in vial
- complicated
(severe)
- high-risk febrile
neutropenia
- hospital acquired
pneumonia
488

vancomycin Capsule: 125 mg; 250 mg (as hydrochloride).
SECOND CHOICE
- C. difficile infection
Complementary List
ceftazidime Powder for injection: 250 mg or 1 g (as pentahydrate)
in vial.
meropenem* a Powder for injection: 500 mg (as trihydrate); 1 g
(as trihydrate) in vial
a >3 months.
* Imipenem + cilastatin is an alternative except for acute bacterial
meningitis where meropenem is preferred.

in neonates [c]
- complicated
(severe)
- high-risk febrile
neutropenia
vancomycin Powder for injection: 250 mg (as hydrochloride) in vial.
- high-risk febrile
neutropenia
Complementary List
ceftazidime + avibactam Powder for injection: 2 g + 0.5 g in vial
colistin Powder for injection: 1 million I.U. (as colistemethate
sodium) in vial
fosfomycin Powder for injection: 2 g; 4 g (as sodium) in vial
linezolid Injection for intravenous administration: 2 mg/ mL in
300 mL bag.
Powder for oral liquid: 100 mg/5 mL.
489

meropenem + Powder for injection: 1 g + 1 g in vial
vaborbactam
plazomicin Injection: 500 mg/10 mL
polymyxin B Powder for injection: 500,000 I.U. in vial
6.2.4 Antileprosy medicines
Medicines used in the treatment of leprosy should never be used except in combination.
Combination therapy is essential to prevent the emergence of drug resistance.
Colour-coded blister packs (MDT blister packs) containing standard two-medicine
(paucibacillary leprosy) or three-medicine (multibacillary leprosy) combinations for
adult and childhood leprosy should be used. MDT blister packs can be supplied free of
charge through WHO.
clofazimine Capsule: 50 mg; 100 mg.
dapsone Tablet: 25 mg; 50 mg; 100 mg.
rifampicin Solid oral dosage form: 150 mg; 300 mg.
490

WHO recommends and endorses the use of fixed-dose combinations and the
development of appropriate new fixed-dose combinations, including modified
dosage forms, non-refrigerated products and paediatric dosage forms of assured
pharmaceutical quality.
ethambutol Oral liquid: 25 mg/ mL [c] .
Tablet: 100 mg to 400 mg (hydrochloride).
Tablet (dispersible): 100 mg [c] .
ethambutol + isoniazid + Tablet: 275 mg + 75 mg + 400 mg + 150 mg.
pyrazinamide + rifampicin
ethambutol + isoniazid + Tablet: 275 mg + 75 mg + 150 mg.
rifampicin
isoniazid Oral liquid: 50 mg/5 mL [c] .
Tablet (scored): 50 mg.
isoniazid + pyrazinamide + Tablet: 75 mg + 400 mg + 150 mg.
rifampicin Tablet (dispersible): 50 mg + 150 mg + 75 mg [c] .
isoniazid + rifampicin Tablet: 75 mg + 150 mg; 150 mg + 300 mg.
Tablet (dispersible): 50 mg + 75 mg [c] .
pyrazinamide Oral liquid: 30 mg/ mL [c] .
Tablet: 400 mg.
Tablet (dispersible): 150 mg.
rifabutin Solid oral dosage form: 150 mg.*
* For use only in patients with HIV receiving protease inhibitors.
rifampicin Oral liquid: 20 mg/ mL [c] .

Solid oral dosage form: 150 mg; 300 mg.
rifapentine* Tablet: 150 mg
* For treatment of latent TB infection (LTBI) only.
491

Complementary List
Medicines for the treatment of multidrug-resistant tuberculosis (MDR-TB) should be
used in specialized centres adhering to WHO standards for TB control.
amikacin Powder for injection: 100 mg; 500 mg; 1 g (as sulfate) in vial.
amoxicillin + Oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic
clavulanic acid* acid/5 mL; 250 mg amoxicillin + 62.5 mg clavulanic
acid/5 mL [c] .
Tablet: 500 mg (as trihydrate) + 125 mg (as potassium salt).
* For use only in combination with meropenem or imipenem+cilastatin
bedaquiline a Tablet: 100 mg.

a ≥6 years.
clofazimine Solid oral dosage form: 50 mg; 100 mg.
cycloserine* Solid oral dosage form: 125 mg [c] ; 250 mg.
* Terizidone may be an alternative.
delamanid a Tablet: 50 mg.

a ≥6 years
ethionamide* Tablet: 125 mg; 250 mg.
* Protionamide may be an alternative.
levofloxacin Tablet: 250mg; 500 mg; 750 mg.

300 mL bag.

meropenem* Powder for injection: 500 mg (as trihydrate); 1 g
(as trihydrate) in vial.
* Imipenem+cilastatin may be an alternatiave.
moxifloxacin Tablet: 400 mg.

p-aminosalicylic acid Granules: 4 g in sachet.
Tablet: 500 mg.
streptomycin [c] Powder for injection: 1 g (as sulfate) in vial.
492

6.3 Antifungal medicines
amphotericin B Powder for injection: 50 mg in vial (as sodium
deoxycholate or liposomal complex).
clotrimazole Vaginal cream: 1%; 10%.
Vaginal tablet: 100 mg; 500 mg.
fluconazole Capsule: 50 mg.
Injection: 2 mg/ mL in vial.
flucytosine Capsule: 250 mg.
Infusion: 2.5 g in 250 mL.
griseofulvin Oral liquid: 125 mg/5 mL [c] .
itraconazole* Capsule: 100 mg.
Oral liquid: 10 mg/mL.
* For treatment of chronic pulmonary aspergillosis,
histoplasmosis, sporotrichosis, paracoccidiodomycosis,
mycoses caused by T. marneffei and chromoblastomycosis;
and prophylaxis of histoplasmosis and infections caused by
T. marneffei in AIDS patients.
nystatin Lozenge: 100 000 IU.

Oral liquid: 50 mg/5 mL [c] ; 100 000 IU/ mL [c] .
Pessary: 100 000 IU.
Tablet: 100 000 IU; 500 000 IU.
voriconazole* Tablet: 50 mg; 200 mg.
Powder for oral liquid: 40 mg/mL.
* For treatment of chronic pulmonary aspergillosis and acute
invasive aspergillosis.
Complementary List
potassium iodide Saturated solution.
493

6.4.1 Antiherpes medicines
 aciclovir Oral liquid: 200 mg/5 mL [c] .
Tablet: 200 mg.
Based on current evidence and experience of use, medicines in the following classes
of antiretrovirals are included as essential medicines for treatment and prevention of
HIV (prevention of mother-to-child transmission, pre-exposure prophylaxsis (where
indicated) and post-exposure prophylaxis). WHO emphasizes the importance of using
these products in accordance with global and national guidelines. WHO recommends
and endorses the use of fixed-dose combinations and the development of appropriate
new fixed-dose combinations, including modified dosage forms, non-refrigerated
products and paediatric dosage forms of assured pharmaceutical quality.
Scored tablets can be used in children and therefore can be considered for inclusion
in the listing of tablets, provided that adequate quality products are available.
6.4.2.1 Nucleoside/Nucleotide reverse transcriptase inhibitors
abacavir (ABC) Tablet: 300 mg (as sulfate).
Tablet (dispersible, scored): 60 mg (as sulfate) [c] .
lamivudine (3TC) Oral liquid: 50 mg/5 mL [c] .
Tablet: 150 mg.
tenofovir disoproxil Tablet: 300 mg (tenofovir disoproxil fumarate –
fumarate† (TDF) equivalent to 245 mg tenofovir disoproxil).
† Also indicated for pre-exposure prophylaxis.
zidovudine (ZDV or AZT) Capsule: 250 mg.

Solution for IV infusion injection: 10 mg/ mL in
20- mL vial.
Tablet: 300 mg.
6.4.2.2 Non-nucleoside reverse transcriptase inhibitors
efavirenz (EFV or EFZ) a Tablet: 200 mg (scored); 600 mg.
a >3 years or >10 kg weight.
nevirapine (NVP) a Oral liquid: 50 mg/5 mL.
Tablet: 50 mg (dispersible); 200 mg.
a >6 weeks.
494

Selection of protease inhibitor(s) from the Model List will need to be determined by
each country after consideration of international and national treatment guidelines
and experience. Ritonavir is recommended for use in combination as a pharmacological
booster, and not as an antiretroviral in its own right. All other protease inhibitors should
be used in boosted forms (e.g. with ritonavir).
atazanavir a Solid oral dosage form: 100 mg; 300 mg (as sulfate).
a >25 kg.
atazanavir + ritonavir Tablet (heat stable): 300 mg (as sulfate) + 100 mg.
darunavir a Tablet: 75 mg; 400 mg; 600 mg; 800 mg.
a >3 years.
lopinavir + ritonavir (LPV/r) Oral liquid: 400 mg + 100 mg/5 mL.
Tablet (heat stable): 100 mg + 25 mg; 200 mg + 50 mg.
Solid oral dosage form: 40 mg + 10 mg [c] .
ritonavir Oral liquid: 400 mg/5 mL.
Tablet (heat stable): 25 mg; 100 mg.
Oral powder: 100 mg in sachet [c] .
495

dolutegravir a Tablet: 50 mg.
a ≥25 kg.
raltegravir* Tablet (chewable): 25 mg; 100 mg.
Tablet: 400 mg.
Granules for oral suspension: 100 mg in sachet.
* For use in pregnant women and in second-line regimens in
accordance with WHO treatemnt guidelines.
FIXED-DOSE COMBINATIONS
abacavir + lamivudine Tablet (dispersible, scored): 120 mg (as sulfate) + 60 mg.
dolutegravir + lamivudine + Tablet: 50 mg + 300 mg + 300 mg (disoproxil fumarate
tenofovir equivalent to 245 mg tenofovir disoproxil).
efavirenz + emtricitabine* + Tablet: 600 mg + 200 mg + 300 mg (disoproxil
tenofovir fumarate equivalent to 245 mg tenofovir disoproxil).
* Emtricitabine (FTC) is an acceptable alternative to 3TC, based
on knowledge of the pharmacology, the resistance patterns
and clinical trials of antiretrovirals.
efavirenz + lamivudine + Tablet: 400 mg + 300 mg + 300 mg (disoproxil

tenofovir fumarate equivalent to 245 mg tenofovir disoproxil).
emtricitabine* + tenofovir† Tablet: 200 mg + 300 mg (disoproxil fumarate
equivalent to 245 mg tenofovir disoproxil).
* Emtricitabine (FTC) is an acceptable alternative to 3TC, based
on knowledge of the pharmacology, the resistance patterns
and clinical trials of antiretrovirals.
† Combination also indicated for pre-exposure prophylaxis.
lamivudine + nevirapine + Tablet: 30 mg + 50 mg + 60 mg [c] ; 150 mg + 200 mg +

zidovudine 300 mg.
lamivudine + zidovudine Tablet: 30 mg + 60 mg [c] ; 150 mg + 300 mg.
6.4.2.5 Medicines for prevention of HIV-related opportunistic infections
isoniazid + pyridoxine + Tablet (scored): 300 mg + 25 mg + 800 mg + 160 mg
sulfamethoxazole +
trimethoprim
496

6.4.3 Other antivirals
ribavirin* Injection for intravenous administration: 800 mg and
1 g in 10- mL phosphate buffer solution.
Solid oral dosage form: 200 mg; 400 mg; 600 mg.
* For the treatment of viral haemorrhagic fevers.
valganciclovir* Tablet: 450 mg.

* For the treatment of cytomegalovirus retinitis (CMVr).
Complementary list
oseltamivir* Capsule: 30 mg; 45 mg; 75 mg (as phosphate).
Oral powder: 12 mg/ mL.
* Severe illness due to confirmed or suspected influenza virus infection
in critically ill hospitalized patients.
valganciclovir* [c] Powder for oral solution: 50 mg/ mL.

Tablet: 450 mg.
497

6.4.4.1 Medicines for hepatitis B
6.4.4.1.1 Nucleoside/Nucleotide reverse transcriptase inhibitors
entecavir Oral liquid: 0.05 mg/ mL.
tenofovir disoproxil Tablet: 300 mg (tenofovir disoproxil fumarate –
fumarate (TDF) equivalent to 245 mg tenofovir disoproxil).
WHO guidelines recommend the use of pangenotypic direct-acting antiviral (DAA)
regimens for the treatment of persons with chronic HCV infection aged 18 years
and above.
WHO recommended treatment regimens for adolescents aged 12-17 years or weighing
at least 35 kg with chronic HCV infection are genotype-specific.
Pangenotypic DAAs should be considered as therapeutically equivalent for the
purposes of selection and procurement at national level.
6.4.4.2.1  Pangenotypic direct-acting antiviral combinations
daclatasvir* Tablet: 30 mg; 60 mg (as hydrochloride)
* Pangenotypic when used in combination with sofosbuvir.
glecaprevir + pibrentasvir Tablet: 100 mg + 40 mg

sofosbuvir* Tablet: 400 mg
* Pangenotypic when used in combination with daclatasvir.
sofosbuvir + velpatasvir Tablet: 400 mg + 100 mg

6.4.4.2.2 Non-pangenotypic direct-acting antiviral combinations

dasabuvir Tablet: 250 mg
ledipasvir + sofosbuvir Tablet: 90 mg + 400 mg.
ombitasvir + paritaprevir + Tablet: 12.5 mg + 75 mg + 50 mg
ritonavir
6.4.4.2.3 Other antivirals for hepatitis C
1 g in 10- mL phosphate buffer solution.
* For the treatment of hepatitis C, in combination with direct
acting anti-viral medicines.
498

Complementary list
pegylated interferon alfa Vial or prefilled syringe:
(2a or 2b)* 180 micrograms (peginterferon alfa-2a),
80 microgram, 100 microgram (peginterferon alfa-2b).
* To be used in combination with ribavirin.

6.5.1 Antiamoebic and antigiardiasis medicines
diloxanide a Tablet: 500 mg (furoate).
a >25 kg.
 metronidazole Injection: 500 mg in 100- mL vial.
6.5.2 Antileishmaniasis medicines
miltefosine Solid oral dosage form: 10 mg; 50 mg.
paromomycin Solution for intramuscular injection: 750 mg of
paromomycin base (as the sulfate).
sodium stibogluconate or Injection: 100 mg/ mL, 1 vial = 30 mL or 30%,
meglumine antimoniate equivalent to approximately 8.1% antimony
(pentavalent) in 5- mL ampoule.
499

6.5.3.1 For curative treatment
Medicines for the treatment of P. falciparum malaria cases should be used in
combination. The list currently recommends combinations according to treatment
guidelines. WHO recognizes that not all of the fixed dose combinations (FDCs) in the
WHO treatment guidelines exist, and encourages their development and rigorous
testing. WHO also encourages development and testing of rectal dosage formulations.
amodiaquine* Tablet: 153 mg or 200 mg (as hydrochloride).
* To be used in combination with artesunate 50 mg.
artemether* Oily injection: 80 mg/ mL in 1- mL ampoule.

* For use in the management of severe malaria.
artemether + lumefantrine* Tablet: 20 mg + 120 mg.

Tablet (dispersible): 20 mg + 120 mg [c] .
* Not recommended in the first trimester of pregnancy or in
children below 5 kg.
artesunate* ** Injection: ampoules, containing 60 mg anhydrous

artesunic acid with a separate ampoule of 5% sodium
bicarbonate solution.
Rectal dosage form: 50 mg [c] ; 100 mg [c] ; 200 mg
capsules (for pre-referral treatment of severe malaria
only; patients should be taken to an appropriate health
facility for follow-up care) [c] .
Tablet: 50 mg.
** To be used in combination with either amodiaquine,
mefloquine or sulfadoxine + pyrimethamine.
artesunate + amodiaquine* Tablet: 25 mg + 67.5 mg; 50 mg + 135 mg; 100 mg +

270 mg.
* Other combinations that deliver the target doses required such
as 153 mg or 200 mg (as hydrochloride) with 50 mg artesunate
can be alternatives.
artesunate + mefloquine Tablet: 25 mg + 55 mg; 100 mg + 220 mg.

artesunate + pyronaridine Tablet: 60 mg + 180 mg
tetraphosphate a Granules: 20 mg + 60 mg [c] .
a >5 kg.
500

chloroquine* Oral liquid: 50 mg (as phosphate or sulfate)/5 mL.
Tablet: 100 mg; 150 mg (as phosphate or sulfate).
* For use only for the treatment of P. vivax infection.
dihydroartemisinin + Tablet: 20 mg + 160 mg; 40 mg + 320 mg.

piperaquine phosphate a a >5 kg.
doxycycline* Capsule: 100 mg (as hydrochloride or hyclate).
Tablet (dispersible): 100 mg (as monohydrate).
* For use only in combination with quinine.
mefloquine* Tablet: 250 mg (as hydrochloride).

primaquine* Tablet: 7.5 mg; 15 mg (as diphosphate).

* Only for use to achieve radical cure of P. vivax and P. ovale
infections, given for 14 days.
quinine* Injection: 300 mg quinine hydrochloride/ mL in 2- mL

ampoule.
Tablet: 300 mg (quinine sulfate) or 300 mg (quinine
bisulfate).
* For use only in the management of severe malaria, and should
be used in combination with doxycycline.
sulfadoxine + Tablet: 500 mg + 25 mg.

pyrimethamine* * Only in combination with artesunate 50 mg.
501

amodiaquine – Co-packaged dispersible tablets:
sulfadoxine + amodiaquine 76.5 mg (as hydrochloride) [3] and
pyrimethamine [c] sulfadoxine + pyrimethamine 250 mg + 12.5 mg [1];
amodiaquine 153 mg (as hydrochloride) [3] and
sulfadoxine + pyrimethamine 500 mg + 25 mg [1];
Tablet: 150 mg (as phosphate or sulfate).
* For use only in central American regions, for P. vivax infections.
doxycycline a Solid oral dosage form: 100 mg (as hydrochloride or

hyclate).
a >8 years.
mefloquine a Tablet: 250 mg (as hydrochloride).
a >5 kg or >3 months.
proguanil* Tablet: 100 mg (as hydrochloride).
* For use only in combination with chloroquine.
sulfadoxine + Tablet: 250 mg + 12.5 mg [c] ; 500 mg + 25 mg.

pyrimethamine
6.5.4 Antipneumocystosis and antitoxoplasmosis medicines
pyrimethamine Tablet: 25 mg.
sulfadiazine Tablet: 500 mg.
trimethoprim 80 mg + 16 mg/ mL in 5- mL ampoule;

Oral liquid: 200 mg + 40 mg/5 mL [c] .
Tablet: 100 mg + 20 mg; 400 mg + 80 mg [c] ; 800 mg +
160 mg
Complementary List
pentamidine Tablet: 200 mg; 300 mg (as isethionate).
502

fexinidazole* Tablet: 600 mg
* For the treatment of 1st and 2 nd stage of human African
trypanosomiasis due to Trypanosoma brucei gambiense
infection.
Medicines for the treatment of 1st stage African trypanosomiasis

pentamidine* Powder for injection: 200 mg (as isetionate) in vial.
* To be used for the treatment of Trypanosoma brucei gambiense
infection.
suramin sodium* Powder for injection: 1 g in vial.

* To be used for the treatment of the initial phase of Trypanosoma
brucei rhodesiense infection.
Medicines for the treatment of 2 nd stage African trypanosomiasis

eflornithine* Injection: 200 mg (hydrochloride)/ mL in 100- mL bottle.
infection.
melarsoprol Injection: 3.6% solution, 5- mL ampoule (180 mg of

active compound).
nifurtimox* Tablet: 120 mg.
* Only to be used in combination with eflornithine, for the
treatment of Trypanosoma brucei gambiense infection.
Complementary List
melarsoprol [c] Injection: 3.6% solution in 5- mL ampoule (180 mg of
active compound).
6.5.5.2 American trypanosomiasis
benznidazole Tablet: 12.5 mg [c] ;100 mg.
nifurtimox Tablet: 30 mg; 120 mg; 250 mg.
503
7. ANTIMIGRAINE MEDICINES
acetylsalicylic acid Tablet: 300 mg to 500 mg.
ibuprofen [c] Tablet: 200 mg; 400 mg.
paracetamol Oral liquid: 120 mg/5 mL [c] ; 125 mg/5 mL [c] .
7.2 For prophylaxis
 propranolol Tablet: 20 mg; 40 mg (hydrochloride).
8. IMMUNOMODULATORS AND ANTINEOPLASTICS
Complementary List
 adalimumab* Injection: 40 mg/0.8 mL; 40 mg/0.4 mL
* Certolizumab pegol, etanercept, golimumab and infliximab are
alternatives, including quality-assured biosimilars.
azathioprine Powder for injection: 100 mg (as sodium salt) in vial.

ciclosporin* Capsule: 25 mg.
Concentrate for injection: 50 mg/ mL in 1- mL ampoule.
* For organ transplantation.
504
8. IMMUNOMODULATORS AND ANTINEOPLASTICS (continued)

8.2 Antineoplastics and supportive medicines
Medicines listed below should be used according to protocols for treatment of
the diseases.
Complementary List
arsenic trioxide Concentrate for solution for infusion: 1 mg/mL
- Acute promyelocytic leukaemia
asparaginase Powder for injection: 10 000 IU in vial
- Acute lymphoblastic leukaemia.
bendamustine Injection: 45 mg/0.5 mL; 180 mg/2 mL.
- Chronic lymphocytic leukaemia
- Follicular lymphoma
bleomycin Powder for injection: 15 mg (as sulfate) in vial.
- Hodgkin lymphoma
- Kaposi sarcoma
- Ovarian germ cell tumour
- Testicular germ cell tumour
calcium folinate Injection: 3 mg/ mL in 10- mL ampoule.
Tablet: 5 mg, 15 mg, 25 mg.
- Early stage colon cancer
- Early stage rectal cancer
- Gestational trophoblastic neoplasia
- Metastatic colorectal cancer
- Osteosarcoma
- Burkitt lymphoma
capecitabine Tablet: 150 mg; 500 mg.
- Metastatic breast cancer
505

carboplatin Injection: 50 mg/5 mL; 150 mg/15 mL; 450 mg/45 mL;
600 mg/60 mL.
- Early stage breast cancer
- Epithelial ovarian cancer
- Nasopharyngeal cancer
- Non-small cell lung cancer
- Osteosarcoma
- Retinoblastoma
- Cervical cancer
chlorambucil Tablet: 2 mg.
- Chronic lymphocytic leukaemia.
cisplatin Injection: 50 mg/50 mL; 100 mg/100 mL.
- Cervical cancer
- Head and neck cancer (as a radio-sensitizer)
- Nasopharyngeal cancer (as a radio-sensitizer)
- Osteosarcoma
cyclophosphamide Powder for injection: 500 mg in vial.
Tablet: 25 mg, 50 mg.
- Diffuse large B-cell lymphoma
- Hodgkin lymphoma
- Rhabdomyosarcoma
- Ewing sarcoma
- Acute lymphoblastic leukaemia
- Burkitt lymphoma
- Multiple myeloma.
cytarabine Powder for injection: 100 mg in vial.
- Acute myeloid leukaemia
- Burkitt lymphoma.
506

dacarbazine Powder for injection: 100 mg in vial.
- Hodgkin lymphoma
dactinomycin Powder for injection: 500 micrograms in vial.
- Rhabdomyosarcoma
- Nephroblastoma (Wilms tumour)
daunorubicin Powder for injection: 50 mg (hydrochloride) in vial.
docetaxel Injection: 20 mg/ mL; 40 mg/ mL.
- Metastatic prostate cancer
doxorubicin Powder for injection: 10 mg; 50 mg (hydrochloride) in vial.
- Hodgkin lymphoma
- Kaposi sarcoma
- Osteosarcoma
- Ewing sarcoma
- Burkitt lymphoma
- Multiple myeloma.
etoposide Capsule: 50 mg, 100 mg.
Injection: 20 mg/ mL in 5- mL ampoule.
- Hodgkin lymphoma
- Retinoblastoma
- Ewing sarcoma
- Burkitt lymphoma
507

fludarabine Powder for injection: 50 mg (phosphate) in vial.
Tablet: 10 mg
- Chronic lymphocytic leukaemia.
fluorouracil Injection: 50 mg/ mL in 5- mL ampoule.
gemcitabine Powder for injection: 200 mg in vial, 1 g in vial.
hydroxycarbamide Solid oral dosage form: 200 mg; 250 mg; 300 mg; 400 mg;
500 mg; 1 g.
- Chronic myeloid leukaemia.
ifosfamide Powder for injection: 500 mg vial; 1-g vial; 2-g vial.
- Osteosarcoma
- Rhabdomyosarcoma
- Ewing sarcoma
irinotecan Injection: 40 mg/2 mL in 2- mL vial; 100 mg/5 mL in 5- mL
vial; 500 mg/25 mL in 25- mL vial.
- Metastatic colorectal cancer.
melphalan Tablet: 2 mg
Powder for injection: 50 mg in vial

- Multiple myeloma.
mercaptopurine Tablet: 50 mg.
- Acute promyelocytic leukaemia.
508

methotrexate Powder for injection: 50 mg (as sodium salt) in vial.
Tablet: 2.5 mg (as sodium salt).
- Osteosarcoma
oxaliplatin Injection: 50 mg/10 mL in 10- mL vial; 100 mg/20 mL in
20- mL vial; 200 mg/40 mL in 40- mL vial.
Powder for injection: 50 mg, 100 mg in vial.
paclitaxel Powder for injection: 6 mg/ mL.
- Kaposi sarcoma
- Cervical cancer
pegaspargase* Injection: 3,750 units/5 mL in vial.
* Including quality-assured biosimilars.
procarbazine [c] Capsule: 50 mg (as hydrochloride).

- Hodgkin lymphoma
realgar-Indigo naturalis Tablet: 270 mg (containing tetra-arsenic tetra-sulfide
formulation 30 mg).
tioguanine [c] Solid oral dosage form: 40 mg.
vinblastine Powder for injection: 10 mg (sulfate) in vial.
- Hodgkin lymphoma
- Kaposi sarcoma
509

vincristine Powder for injection: 1 mg; 5 mg (sulfate) in vial.
- Hodgkin lymphoma
- Kaposi sarcoma
- Retinoblastoma
- Rhabdomyosarcoma
- Ewing sarcoma
- Burkitt lymphoma
vinorelbine Injection: 10 mg/mL in 1- mL vial; 50 mg/5 mL in
5- mL vial.
510

Complementary List
all-trans retinoic acid Capsule: 10 mg.
(ATRA) - Acute promyelocytic leukaemia.
bortezomib Powder for injection: 3.5 g in vial.
- Multiple myeloma
dasatinib Tablet: 20 mg; 50 mg; 70 mg; 80 mg; 100 mg; 140 mg.
- Imatinib-resistant chronic myeloid leukaemia
 erlotinib* Tablet: 100 mg, 150 mg
- EGFR mutation-positive advanced non-small cell
lung cancer
* Gefitinb and afatinb are alternatives.
imatinib Tablet: 100 mg; 400 mg.

- Chronic myeloid leukaemia
- Gastrointestinal stromal tumour
nilotinib Capsule: 150 mg; 200 mg.
rituximab* Injection (intravenous): 100 mg/10 mL in 10- mL vial;
500 mg/50 mL in 50- mL vial.
- Follicular lymphoma.
trastuzumab* Powder for injection: 60 mg; 150 mg; 440 mg in vial.

- Early stage HER2 positive breast cancer
- Metastatic HER2 positive breast cancer.
511

Complementary List
filgrastim Injection: 120 micrograms/0.2 mL;
300 micrograms/0.5 mL; 480 micrograms/0.8 mL in
pre-filled syringe 300 micrograms/mL in 1- mL vial,
480 micrograms/1.6 mL in 1.6- mL vial.
- Primary prophylaxis in patients at high risk for
developing febrile neutropenia associated with
myelotoxic chemotherapy.
- Secondary prophylaxis for patients who have
experienced neutropenia following prior myelotoxic
chemotherapy
- To facilitate administration of dose dense
chemotherapy regimens
lenalidomide Capsule: 25 mg.
- Multiple myeloma
 nivolumab* Concentrate solution for infusion: 10 mg/mL.
- Metastatic melanoma
* Pembrolizumab is an alternative.
thalidomide Capsule: 50 mg.

- Multiple myeloma
512

Complementary List
abiraterone Tablet: 250 mg; 500 mg.
- Metastatic castration-resistant prostate cancer.
 anastrozole Tablet: 1 mg.
- Metastatic breast cancer.
 bicalutamide Tablet: 50 mg.
- Metastatic prostate cancer.
phosphate salt).
Oral liquid: 2 mg/5 mL [c] .
Tablet: 2 mg [c] ; 4 mg.
- Multiple myeloma.
hydrocortisone Powder for injection: 100 mg (as sodium succinate) in vial.
 leuprorelin Injection: 7.5 mg; 22.5 mg in pre-filled syringe
- Metastatic prostate cancer.
methylprednisolone [c] Injection: 40 mg/ mL (as sodium succinate) in 1- mL
single-dose vial and 5- mL multi-dose vials; 80 mg/ mL
(as sodium succinate) in 1- mL single-dose vial.
- Acute lymphoblastic leukamia.
 prednisolone Oral liquid: 5 mg/ mL [c] .
- Hodgkin lymphoma
- Burkitt lymphoma
- Metastatic castration-resitsant prostate cancer
- Multiple myeloma.
tamoxifen Tablet: 10 mg; 20 mg (as citrate).
- Metastatic breast cancer.
513

Complementary List
allopurinol [c] Tablet: 100 mg; 300 mg.
- Tumour lysis syndrome
mesna Injection: 100 mg/ mL in 4- mL and 10- mL ampoules.
- Osteosarcoma
- Rhabdomyosarcoma
- Ewing sarcoma
zoledronic acid Concentrate solution for infusion: 4 mg/5 mL in 5- mL vial.
Solution for infusion: 4 mg/100 mL in 100- mL bottle.
- Malignancy-related bone disease
9. ANTIPARKINSONISM MEDICINES
 biperiden Injection: 5 mg (lactate) in 1- mL ampoule.
Tablet: 2 mg (hydrochloride).
levodopa +  carbidopa Tablet: 100 mg + 10 mg; 100 mg + 25 mg; 250 mg +
25 mg.
514
10. MEDICINES AFFECTING THE BLOOD

10.1 Antianaemia medicines
ferrous salt Oral liquid: equivalent to 25 mg iron (as sulfate)/ mL.
Tablet: equivalent to 60 mg iron.
ferrous salt + folic acid* Tablet: equivalent to 60 mg iron + 400 micrograms
folic acid.
* Nutritional supplement for use during pregnancy.
folic acid Tablet: 400 micrograms*; 1 mg; 5 mg.

* Periconceptual use for prevention of first occurrence of neural
tube defects.
hydroxocobalamin Injection: 1 mg (as acetate, as hydrochloride or as

sulfate) in 1- mL ampoule.
Complementary List
 erythropoiesis- Injection: pre-filled syringe
stimulating agents* 1000IU/ 0.5 mL; 2000IU/ 0.5 mL; 3000IU/ 0.3 mL; 4000IU/
0.4 mL; 5000IU/ 0.5 mL; 6000IU/ 0.6 mL; 8000IU/ 0.8mL;
10 000IU/ 1 mL; 20 000IU/ 0.5 mL; 40 000IU/ 1 mL
* The square box applies to epoetin alfa, beta and theta, darbepoetin
alfa, methoxy polyethylene glycol-epoetin beta,and their respective
biosimilars.
515
10. MEDICINES AFFECTING THE BLOOD (continued)

 dabigatran* Capsule: 110 mg; 150 mg
* Apixaban, edoxaban and rivaroxaban are alternatives.
 enoxaparin* Injection: ampoule or pre-filled syringe

20 mg/0.2 mL; 40 mg/0.4 mL; 60 mg/0.6 mL; 80 mg/
0.8 mL; 100 mg/1 mL; 120 mg/0.8 mL; 150 mg/1 mL
* Alternatives are limited to nadroparin and dalteparin.
heparin sodium Injection: 1000 IU/ mL; 5000 IU/ mL; 20 000 IU/ mL in
1- mL ampoule.
phytomenadione Injection: 1 mg/ mL [c] ; 10 mg/ mL in ampoule.
Tablet: 10 mg.
protamine sulfate Injection: 10 mg/ mL in 5- mL ampoule.
tranexamic acid Injection: 100 mg/ mL in 10- mL ampoule.
 warfarin Tablet: 1 mg; 2 mg; 5 mg (sodium salt).
Complementary List
desmopressin Injection: 4 micrograms/ mL (as acetate) in 1- mL ampoule.
Nasal spray: 10 micrograms (as acetate) per dose
heparin sodium [c] Injection: 1000 IU/ mL; 5000 IU/ mL in 1- mL ampoule.
protamine sulfate [c] Injection: 10 mg/ mL in 5- mL ampoule.
 warfarin [c] Tablet: 0.5 mg; 1 mg; 2 mg; 5 mg (sodium salt).
10.3 Other medicines for haemoglobinopathies
Complementary List
deferoxamine* Powder for injection: 500 mg (mesilate) in vial.
* Deferasirox oral form may be an alternative, depending on cost
and availability.
hydroxycarbamide Solid oral dosage form: 200 mg; 500 mg; 1 g.
516
11. BLOOD PRODUCTS OF HUMAN ORIGIN AND PLASMA SUBSTITUTES

11.1 Blood and blood components
In accordance with the World Health Assembly resolution WHA63.12, WHO recognizes
that achieving self-sufficiency, unless special circumstances preclude it, in the supply of
safe blood components based on voluntary, non-remunerated blood donation, and the
security of that supply are important national goals to prevent blood shortages and
meet the transfusion requirements of the patient population. All preparations should
comply with the WHO requirements.
fresh–frozen plasma
platelets
red blood cells
whole blood
11.2 Plasma-derived medicines
All human plasma-derived medicines should comply with the WHO requirements.
11.2.1 Human immunoglobulins
anti-D immunoglobulin Injection: 250 micrograms in single-dose vial.
Anti-rabies Injection: 150 IU/ mL in vial.
immunoglobulin
Anti-tetanus Injection: 500 IU in vial.
immunoglobulin
Complementary List
normal immunoglobulin Intramuscular administration: 16% protein solution.*
Intravenous administration: 5%; 10% protein solution.**
Subcutaneous administration: 15%; 16% protein solution.*
* Indicated for primary immune deficiency.
** Indicated for primary immune deficiency and Kawasaki disease.
11.2.2 Blood coagulation factors

Complementary List
 coagulation factor VIII Powder for injection: 500 IU/vial.
 coagulation factor IX Powder for injection: 500 IU/vial, 1000 IU/vial.
11.3 Plasma substitutes
 dextran 70* Injectable solution: 6%.
* Polygeline, injectable solution, 3.5% is considered as equivalent.
517
12. CARDIOVASCULAR MEDICINES

12.1 Antianginal medicines
 bisoprolol* Tablet: 1.25 mg; 5 mg.
* The square box includes metoprolol and carvedilol as alternatives.
glyceryl trinitrate Tablet (sublingual): 500 micrograms.

 isosorbide dinitrate Tablet (sublingual): 5 mg.
verapamil Tablet: 40 mg; 80 mg (hydrochloride).
12.2 Antiarrhythmic medicines
digoxin Injection: 250 micrograms/ mL in 2- mL ampoule.

Oral liquid: 50 micrograms/ mL.
Tablet: 62.5 micrograms; 250 micrograms.
epinephrine (adrenaline) Injection: 100 micrograms/ mL (as acid tartrate or
hydrochloride) in 10- mL ampoule.
lidocaine Injection: 20 mg (hydrochloride)/ mL in 5- mL ampoule.
verapamil Injection: 2.5 mg (hydrochloride)/ mL in 2- mL ampoule.
Tablet: 40 mg; 80 mg (hydrochloride).
Complementary List
amiodarone Injection: 50 mg/ mL in 3- mL ampoule (hydrochloride).
Tablet: 100 mg; 200 mg; 400 mg (hydrochloride).
518
12. CARDIOVASCULAR MEDICINES (continued)

 amlodipine Tablet: 5 mg (as maleate, mesylate or besylate).
* The square box includes atenolol, metoprolol and carvedilol as
alternatives. Atenolol should not be used as a first-line agent in
uncomplicated hypertension in patients >60 years.
 enalapril Tablet: 2.5 mg; 5 mg (as hydrogen maleate).

hydralazine* Powder for injection: 20 mg (hydrochloride) in ampoule.
* Hydralazine is listed for use only in the acute management of
severe pregnancy-induced hypertension. Its use in the treatment
of essential hypertension is not recommended in view of the
evidence of greater efficacy and safety of other medicines.
 hydrochlorothiazide Oral liquid: 50 mg/5 mL.

 lisinopril +  amlodipine Tablet: 10 mg + 5 mg; 20 mg + 5 mg; 20 mg + 10 mg.
 lisinopril + Tablet: 10 mg + 12.5 mg; 20 mg + 12.5 mg; 20 mg +
 hydrochlorothiazide 25 mg
 losartan Tablet: 25 mg; 50 mg; 100 mg.
methyldopa* Tablet: 250 mg.
* Methyldopa is listed for use only in the management of
pregnancy-induced hypertension. Its use in the treatment of
essential hypertension is not recommended in view of the
evidence of greater efficacy and safety of other medicines.
 telmisartan + Tablet: 40 mg + 5 mg; 80 mg + 5 mg; 80 mg + 10 mg.

 amlodipine
 telmisartan + Tablet: 40 mg + 12.5 mg; 80 mg + 12.5 mg; 80 mg +
 hydrochlorothiazide 25 mg.
Complementary List
sodium nitroprusside Powder for infusion: 50 mg in ampoule.
519
12. CARDIOVASCULAR MEDICINES (continued)

12.4 Medicines used in heart failure
digoxin Injection: 250 micrograms/ mL in 2- mL ampoule.

Oral liquid: 50 micrograms/ mL.
 furosemide Injection: 10 mg/ mL in 2- mL ampoule.
Tablet: 40 mg.
 hydrochlorothiazide Oral liquid: 50 mg/5 mL.
Solid oral dosage form: 25 mg.
 losartan Tablet: 25 mg; 50 mg; 100 mg.
spironolactone Tablet: 25 mg.
Complementary List
dopamine Injection: 40 mg/ mL (hydrochloride) in 5- mL vial.
12.5.1 Anti-platelet medicines
acetylsalicylic acid Tablet: 100 mg.
clopidogrel Tablet: 75 mg; 300 mg
Complementary List
alteplase Powder for injection: 10 mg; 20 mg; 50 mg in vial
streptokinase Powder for injection: 1.5 million IU in vial.
12.6 Lipid-lowering agents
 simvastatin* Tablet: 5 mg; 10 mg; 20 mg; 40 mg.
* For use in high-risk patients.
520
13. DERMATOLOGICAL MEDICINES (topical)

 miconazole Cream or ointment: 2% (nitrate).
selenium sulfide Detergent-based suspension: 2%.
sodium thiosulfate Solution: 15%.
terbinafine Cream: 1% or Ointment: 1% terbinafine hydrochloride.
13.2 Anti-infective medicines
mupirocin Cream (as mupirocin calcium): 2%.
Ointment: 2%.
potassium permanganate Aqueous solution: 1:10 000.
silver sulfadiazine a Cream: 1%.
a >2 months.
13.3 Anti-inflammatory and antipruritic medicines
 betamethasone a Cream or ointment: 0.1% (as valerate).
a Hydrocortisone preferred in neonates.
 calamine Lotion.
 hydrocortisone Cream or ointment: 1% (acetate).
13.4 Medicines affecting skin differentiation and proliferation
benzoyl peroxide Cream or lotion: 5%.
coal tar Solution: 5%.
fluorouracil Ointment: 5%.
 podophyllum resin Solution: 10% to 25%.
salicylic acid Solution: 5%.
urea Cream or ointment: 5%; 10%.
13.5 Scabicides and pediculicides
 benzyl benzoate a Lotion: 25%.
a >2 years.
permethrin Cream: 5%.
Lotion: 1%.
521
14. DIAGNOSTIC AGENTS

14.1 Ophthalmic medicines
fluorescein Eye drops: 1% (sodium salt).
 tropicamide Eye drops: 0.5%.
14.2 Radiocontrast media
 amidotrizoate Injection: 140 mg to 420 mg iodine (as sodium or
meglumine salt)/ mL in 20- mL ampoule.
barium sulfate Aqueous suspension.
 iohexol Injection: 140 mg to 350 mg iodine/ mL in 5- mL; 10- mL;
20- mL ampoules.
Complementary List
barium sulfate [c] Aqueous suspension.
 meglumine iotroxate Solution: 5 g to 8 g iodine in 100 mL to 250 mL.
15. DISINFECTANTS AND ANTISEPTICS
15.1 Antiseptics
 chlorhexidine Solution: 5% (digluconate).
 ethanol Solution: 70% (denatured).
 povidone iodine Solution: 10% (equivalent to 1% available iodine).
15.2 Disinfectants
alcohol based hand rub Solution: containing ethanol 80% volume /volume
Solution: containing isopropyl alcohol 75% volume/
volume.
 chlorine base compound Powder: (0.1% available chlorine) for solution.

 chloroxylenol Solution: 4.8%.
glutaral Solution: 2%.
522
16. DIURETICS
amiloride Tablet: 5 mg (hydrochloride).
 furosemide Injection: 10 mg/ mL in 2- mL ampoule.
Tablet: 10 mg [c] ; 20 mg [c] ; 40 mg.
 hydrochlorothiazide Solid oral dosage form: 25 mg.
mannitol Injectable solution: 10%; 20%.
spironolactone Tablet: 25 mg.
Complementary List
 hydrochlorothiazide Tablet (scored): 25 mg.
[c]
mannitol [c] Injectable solution: 10%; 20%.
spironolactone [c] Oral liquid: 5 mg/5 mL; 10 mg/5 mL; 25 mg/5 mL.
Tablet: 25 mg.
523
17. GASTROINTESTINAL MEDICINES

Complementary List
 pancreatic enzymes Age-appropriate formulations and doses including lipase,
[c] protease and amylase.
17.1 Antiulcer medicines

 omeprazole Powder for injection: 40 mg in vial
Powder for oral liquid: 20 mg; 40 mg sachets.
 ranitidine Injection: 25 mg/ mL (as hydrochloride) in 2- mL
ampoule.
Oral liquid: 75 mg/5 mL (as hydrochloride).
phosphate salt).
Oral liquid: 0.5 mg/5 mL; 2 mg/5 mL.
Solid oral dosage form: 0.5 mg; 0.75 mg; 1.5 mg; 4 mg.
metoclopramide a Injection: 5 mg (hydrochloride)/ mL in 2- mL ampoule.
a Not in neonates.
 ondansetron a Injection: 2 mg base/ mL in 2- mL ampoule
(as hydrochloride).
Solid oral dosage form: Eq 4 mg base; Eq 8 mg base;

Eq 24 mg base.
a >1 month.
Complementary list
aprepitant Capsule: 80 mg; 125 mg; 165 mg.
Powder for oral susupension: 125 mg in sachet.
524
17. GASTROINTESTINAL MEDICINES (continued)

17.3 Anti-inflammatory medicines
 sulfasalazine Retention enema.
Tablet: 500 mg.
Complementary List
 hydrocortisone* Retention enema.
Suppository: 25 mg (acetate).
* The square box only applies to hydrocortisone retention enema).
17.4 Laxatives
 senna Tablet: 7.5 mg (sennosides) (or traditional dosage forms).
oral rehydration salts – zinc Co-package containing:
sulfate [c] ORS powder for dilution (see Section 17.5.1) – zinc
sulfate solid oral dosage form 20 mg (see Section 17.5.2)
17.5.1 Oral rehydration
oral rehydration salts Powder for dilution in 200 mL; 500 mL; 1 L.
glucose: 75 mEq
sodium: 75 mEq or mmol/L
chloride: 65 mEq or mmol/L
potassium: 20 mEq or mmol/L
citrate: 10 mmol/L
osmolarity: 245 mOsm/L
glucose: 13.5 g/L
sodium chloride: 2.6 g/L
potassium chloride: 1.5 g/L
trisodium citrate dihydrate*: 2.9 g/L
* Trisodium citrate dihydrate may be replaced by sodium
hydrogen carbonate (sodium bicarbonate) 2.5 g/L. However, as
the stability of this latter formulation is very poor under tropical
conditions, it is recommended only when manufactured for
immediate use.
17.5.2 Medicines for diarrhoea

zinc sulfate* Solid oral dosage form: 20 mg.
* In acute diarrhoea zinc sulfate should be used as an adjunct to
oral rehydration salts.
525
18. MEDICINES FOR ENDOCRINE DISORDERS

18.1 Adrenal hormones and synthetic substitutes
fludrocortisone Tablet: 100 micrograms (acetate).
hydrocortisone Tablet: 5 mg; 10 mg; 20 mg.
18.2 Androgens
Complementary List
testosterone Injection: 200 mg (enanthate) in 1- mL ampoule.
18.3 Estrogens —
18.4 Progestogens
 medroxyprogesterone Tablet: 5 mg.
acetate
18.5 Medicines for diabetes
18.5.1 Insulins
insulin injection (soluble) Injection: 40 IU/ mL in 10- mL vial; 100 IU/ mL in
10- mL vial.
intermediate-acting insulin Injection: 40 IU/ mL in 10- mL vial; 100 IU/ mL in 10- mL
vial (as compound insulin zinc suspension or isophane
insulin).
18.5.2 Oral hypoglycaemic agents
 gliclazide* Solid oral dosage form: (controlled-release tablets)
30 mg; 60 mg; 80 mg.
* Glibenclamide not suitable above 60 years.
metformin Tablet: 500 mg (hydrochloride).

Complementary List
metformin [c] Tablet: 500 mg (hydrochloride).
glucagon Injection: 1 mg/ mL.
Complementary List
diazoxide [c] Oral liquid: 50 mg/mL
Tablet: 50 mg
526
18. MEDICINES FOR ENDOCRINE DISORDERS (continued)

levothyroxine Tablet: 25 micrograms [c] ; 50 micrograms;
100 micrograms (sodium salt).
potassium iodide Tablet: 60 mg.
 methimazole* Tablet: 5mg, 10mg, 20mg.
* Carbimazole is an alternative depending on local availability.
propylthiouracil* Tablet: 50 mg.

* For use when alternative first-line treatment is not appropriate or
available; and in patients during the first trimester of pregnancy.
Complementary List
Lugol’s solution [c] Oral liquid: about 130 mg total iodine/ mL.
 methimazole* [c] Tablet: 5mg, 10mg, 20mg.
potassium iodide [c] Tablet: 60 mg.

propylthiouracil* [c] Tablet: 50 mg.
* For use when alternative first-line treatment is not appropriate
or available.
19. IMMUNOLOGICALS
19.1 Diagnostic agents
All tuberculins should comply with the WHO requirements for tuberculins.
tuberculin, purified protein Injection.
derivative (PPD)
19.2 Sera and immunoglobulins
All plasma fractions should comply with the WHO requirements.
Anti-venom Injection.
immunoglobulin* * Exact type to be defined locally.
diphtheria antitoxin Injection: 10 000 IU; 20 000 IU in vial.
527
19. IMMUNOLOGICALS (continued)

19.3 Vaccines
WHO immunization policy recommendations are published in vaccine position papers
on the basis of recommendations made by the Strategic Advisory Group of Experts on
Immunization (SAGE).
WHO vaccine position papers are updated three to four times per year. The list
below details the vaccines for which there is a recommendation from SAGE and a
corresponding WHO position paper as at December 2018. The most recent versions of
the WHO position papers, reflecting the current evidence related to a specific vaccine
and the related recommendations, can be accessed at any time on the WHO website
at: http://www.who.int/immunization/documents/positionpapers/en/index.html.
Vaccine recommendations may be universal or conditional (e.g., in certain regions,
in some high-risk populations or as part of immunization programmes with certain
characteristics). Details are available in the relevant position papers, and in the
Summary Tables of WHO Routine Immunization Recommendations available on the
WHO website at: http://www.who.int/immunization/policy/immunization_tables/en/
index.html.
Selection of vaccines from the Model List will need to be determined by each
country after consideration of international recommendations, epidemiology and
national priorities.
All vaccines should comply with the WHO requirements for biological substances.
WHO noted the need for vaccines used in children to be polyvalent.
Recommendations for all
BCG vaccine
diphtheria vaccine
Haemophilus influenzae type b vaccine
hepatitis B vaccine
HPV vaccine
measles vaccine
pertussis vaccine
pneumococcal vaccine
poliomyelitis vaccine
rotavirus vaccine
rubella vaccine
tetanus vaccine
528

Recommendations for certain regions
Japanese encephalitis vaccine
yellow fever vaccine
tick-borne encephalitis vaccine
Recommendations for some high-risk populations
cholera vaccine
dengue vaccine
hepatitis A vaccine
meningococcal meningitis vaccine
rabies vaccine
typhoid vaccine
Recommendations for immunization programmes with certain characteristics
influenza vaccine (seasonal)
mumps vaccine
varicella vaccine
20. MUSCLE RELAXANTS (PERIPHERALLY-ACTING) AND CHOLINESTERASE
INHIBITORS
 atracurium Injection: 10 mg/ mL (besylate).
neostigmine Injection: 500 micrograms in 1- mL ampoule; 2.5 mg
(metilsulfate) in 1- mL ampoule.
Tablet: 15 mg (bromide).
suxamethonium Injection: 50 mg (chloride)/ mL in 2- mL ampoule.
Powder for injection (chloride), in vial.
 vecuronium [c] Powder for injection: 10 mg (bromide) in vial.
Complementary List
pyridostigmine Injection: 1 mg in 1- mL ampoule.
 vecuronium Powder for injection: 10 mg (bromide) in vial.
529
21. OPHTHALMOLOGICAL PREPARATIONS

21.1 Anti-infective agents
aciclovir Ointment: 3% W/W.
azithromycin Solution (eye drops): 1.5%.
erythromycin* Ointment: 0.5% [c] .
* Infections due to Chlamydia trachomatis or Neisseria gonorrhoea.
 gentamicin Solution (eye drops): 0.3% (sulfate).

natamycin Suspension: (eye drops): 5%.
 ofloxacin Solution (eye drops): 0.3%.
 tetracycline Eye ointment: 1% (hydrochloride).
21.2 Anti-inflammatory agents
 prednisolone Solution (eye drops): 0.5% (sodium phosphate).
 tetracaine a Solution (eye drops): 0.5% (hydrochloride).
a Not in preterm neonates.
21.4 Miotics and antiglaucoma medicines
acetazolamide Tablet: 250 mg.
latanoprost Solution (eye drops): latanoprost 50 micrograms/mL.
 pilocarpine Solution (eye drops): 2%; 4% (hydrochloride or nitrate).
 timolol Solution (eye drops): 0.25%; 0.5% (as hydrogen maleate).
21.5 Mydriatics
atropine* a Solution (eye drops): 0.1%; 0.5%; 1% (sulfate).

* [c] Or homatropine (hydrobromide) or cyclopentolate
(hydrochloride).
a >3 months.
Complementary List
epinephrine (adrenaline) Solution (eye drops): 2% (as hydrochloride).
21.6 Anti-vascular endothelial growth factor (VEGF) preparations
Complementary List
bevacizumab Injection: 25 mg/ mL.
530
22. MEDICINES FOR REPRODUCTIVE HEALTH AND PERINATAL CARE

22.1 Contraceptives
22.1.1 Oral hormonal contraceptives
 ethinylestradiol + Tablet: 30 micrograms + 150 micrograms.
 levonorgestrel
 ethinylestradiol + Tablet: 35 micrograms + 1 mg.
 norethisterone
levonorgestrel Tablet: 30 micrograms; 750 micrograms (pack of two);
1.5 mg.
ulipristal Tablet: 30 mg (as acetate).
22.1.2 Injectable hormonal contraceptives
estradiol cypionate + Injection: 5 mg + 25 mg.
medroxyprogesterone
acetate
medroxyprogesterone Injection (intramuscular): 150 mg/ mL in 1- mL vial.
acetate Injection (subcutaneous): 104 mg/0.65 mL in pre-filled
syringe or single-dose injection delivery system.
norethisterone enantate Oily solution: 200 mg/ mL in 1- mL ampoule.
22.1.3 Intrauterine devices
copper-containing device
levonorgestrel-releasing Intrauterine system with reservoir containing 52 mg
intrauterine system of levonorestrel.
22.1.4 Barrier methods
condoms
diaphragms
22.1.5 Implantable contraceptives
etonogestrel-releasing Single-rod etonogestrel-releasing implant, containing
implant 68 mg of etonogestrel.
levonorgestrel-releasing Two-rod levonorgestrel-releasing implant, each rod
implant containing 75 mg of levonorgestrel (150 mg total).
22.1.6 Intravaginal contraceptives
progesterone vaginal ring* Progesterone-releasing vaginal ring containing 2.074 g
of micronized progesterone.
* For use in women actively breastfeeding at least 4 times per day.
531
22. MEDICINES FOR REPRODUCTIVE HEALTH AND PERINATAL CARE (continued)

22.2 Ovulation inducers
Complementary List
clomifene Tablet: 50 mg (citrate).
22.3 Uterotonics
carbetocin Injection (heat stable): 100 micrograms/mL.
 ergometrine Injection: 200 micrograms (hydrogen maleate) in 1- mL
ampoule.
mifepristone – misoprostol Tablet 200 mg – tablet 200 micrograms.
Where permitted under Co-package containing:
national law and where mifepristone 200 mg tablet [1] and
culturally acceptable. misoprostol 200 microgram tablet [4]
misoprostol Tablet: 200 micrograms.

- Management of incomplete abortion and
miscarriage;
- Prevention and treatment of postpartum
haemorrhage where oxytocin is not available or
cannot be safely used
Vaginal tablet: 25 micrograms.*
* Only for use for induction of labour where appropriate facilities
are available.
oxytocin Injection: 10 IU in 1- mL.

nifedipine Immediate-release capsule: 10 mg.

dexamethasone Injection: 4 mg/ mL dexamethasone phosphate
(as disodium salt).
tranexamic acid Injection: 100 mg/mL in 10-mL ampoule.
532
22. MEDICINES FOR REPRODUCTIVE HEALTH AND PERINATAL CARE (continued)

22.6 Medicines administered to the neonate [c]
caffeine citrate [c] Injection: 20 mg/ mL (equivalent to 10 mg caffeine
base/ mL).
Oral liquid: 20 mg/ mL (equivalent to 10 mg caffeine
base/ mL).
chlorhexidine* [c] Solution or gel: 7.1% (digluconate) delivering 4%
chlorhexidine.
* For umbilical cord care.
Complementary List
 ibuprofen [c] Solution for injection: 5 mg/ mL.
 prostaglandin E [c] Solution for injection:
Prostaglandin E1: 0.5 mg/ mL in alcohol.
Prostaglandin E 2: 1 mg/ mL.
surfactant [c] Suspension for intratracheal instillation: 25 mg/ mL or
80 mg/ mL
23. PERITONEAL DIALYSIS SOLUTION
Complementary List
intraperitoneal dialysis Parenteral solution.
solution (of appropriate
composition)
533
24. MEDICINES FOR MENTAL AND BEHAVIOURAL DISORDERS

24.1 Medicines used in psychotic disorders
 chlorpromazine Injection: 25 mg (hydrochloride)/ mL in 2- mL ampoule.
Oral liquid: 25 mg (hydrochloride)/5 mL.
 fluphenazine Injection: 25 mg (decanoate or enantate) in 1- mL
ampoule.
 haloperidol Injection: 5 mg in 1- mL ampoule.
Tablet: 2 mg; 5 mg.
risperidone Solid oral dosage form: 0.25 mg to 6.0 mg.
Complementary List
chlorpromazine [c] Injection: 25 mg (hydrochloride)/ mL in 2- mL ampoule.
Tablet: 10 mg; 25 mg; 50 mg; 100 mg (hydrochloride).
clozapine Solid oral dosage form: 25 to 200 mg.
haloperidol [c] Injection: 5 mg in 1- mL ampoule.
Oral liquid: 2 mg/ mL.
Solid oral dosage form: 0.5 mg; 2 mg; 5 mg.
 amitriptyline Tablet: 25 mg; 75mg. (hydrochloride).
 fluoxetine Solid oral dosage form: 20 mg (as hydrochloride).
Complementary List
fluoxetine a [c] Solid oral dosage form: 20 mg (as hydrochloride).
a >8 years.
24.2.2 Medicines used in bipolar disorders
carbamazepine Tablet (scored): 100 mg; 200 mg.
lithium carbonate Solid oral dosage form: 300 mg.
valproic acid (sodium Tablet (enteric-coated): 200 mg; 500 mg (sodium
valproate) valproate).
24.3 Medicines for anxiety disorders
 diazepam Tablet (scored): 2 mg; 5 mg.
534
24. MEDICINES FOR MENTAL AND BEHAVIOURAL DISORDERS (continued)

24.4 Medicines used for obsessive compulsive disorders
clomipramine Capsule: 10 mg; 25 mg (hydrochloride).
24.5 Medicines for disorders due to psychoactive substance use
nicotine replacement Chewing gum: 2 mg; 4 mg (as polacrilex).
therapy (NRT) Transdermal patch: 5 mg to 30 mg/16 hrs; 7 mg to
21 mg/24 hrs.
Complementary List
 methadone* Concentrate for oral liquid: 5 mg/ mL; 10 mg/ mL
(hydrochloride).
Oral liquid: 5 mg/5 mL; 10 mg/5 mL (hydrochloride).
* The square box is added to include buprenorphine. The medicines
should only be used within an established support programme.
535
25. MEDICINES ACTING ON THE RESPIRATORY TRACT

25.1 Antiasthmatic medicines and medicines for chronic obstructive
pulmonary disease
 beclometasone Inhalation (aerosol): 50 micrograms (dipropionate) per
dose; 100 micrograms (dipropionate) per dose (as CFC
free forms).
 budesonide [c] Inhalation (aerosol): 100 micrograms per dose;
200 micrograms per dose.
 budesonide + formoterol Dry powder inhaler: 100 micrograms + 6 micrograms
per dose; 200 micrograms + 6 micrograms per dose
in 1- mL ampoule.
ipratropium bromide Inhalation (aerosol): 20 micrograms/metered dose.
 salbutamol Inhalation (aerosol): 100 micrograms (as sulfate)
per dose.
Injection: 50 micrograms (as sulfate)/ mL in 5- mL
ampoule.
Metered dose inhaler (aerosol): 100 micrograms
(as sulfate) per dose.
Respirator solution for use in nebulizers: 5 mg
(as sulfate)/ mL.
 tiotropium Powder for inhalaton, capsule: 18 micrograms.
Inhalation solution: 1.25 micrograms; 2.5 micrograms
per actuation.
536
26. SOLUTIONS CORRECTING WATER, ELECTROLYTE AND ACID–BASE

DISTURBANCES
26.1 Oral
oral rehydration salts See section 17.5.1.
potassium chloride Powder for solution.
26.2 Parenteral
glucose Injectable solution: 5% (isotonic); 10% (hypertonic);
50% (hypertonic).
glucose with sodium Injectable solution: 4% glucose, 0.18% sodium
chloride chloride (equivalent to Na+ 30 mmol/L, Cl- 30 mmol/L).
Injectable solution: 5% glucose, 0.9% sodium chloride
(equivalent to Na+ 150 mmol/L and Cl- 150 mmol/L);
5% glucose, 0.45% sodium chloride (equivalent to
Na+ 75 mmol/L and Cl- 75 mmol/L) [c] .
potassium chloride Solution: 11.2% in 20- mL ampoule
(equivalent to K+ 1.5 mmol/ mL, Cl- 1.5 mmol/ mL).
Solution for dilution: 7.5% (equivalent to K 1 mmol/ mL
and Cl 1 mmol/ mL [c] ; 15% (equivalent to
K 2 mmol/ mL and Cl 2 mmol/ mL) [c] .
sodium chloride Injectable solution: 0.9% isotonic (equivalent to
Na+ 154 mmol/L, Cl- 154 mmol/L).
sodium hydrogen Injectable solution: 1.4% isotonic (equivalent to
carbonate Na+ 167 mmol/L, HCO3- 167 mmol/L).
Solution: 8.4% in 10- mL ampoule (equivalent to
Na+ 1000 mmol/L, HCO3-1000 mmol/L).
 sodium lactate, Injectable solution.
compound solution
26.3 Miscellaneous
water for injection 2- mL; 5- mL; 10- mL ampoules.
537
27. VITAMINS AND MINERALS

ascorbic acid Tablet: 50 mg.
calcium Tablet: 500 mg (elemental).
colecalciferol* [c] Oral liquid: 400 IU/ mL.
Solid oral dosage form: 400 IU; 1000 IU.
* Ergocalciferol can be used as an alternative.
 ergocalciferol Oral liquid: 250 micrograms/ mL (10 000 IU/ mL).

Solid oral dosage form: 1.25 mg (50 000 IU).
iodine Capsule: 190 mg.
Iodized oil: 1 mL (480 mg iodine); 0.5 mL (240 mg
iodine) in ampoule (oral or injectable); 0.57 mL (308 mg
iodine) in dispenser bottle.
multiple micronutrient Sachets containing:
powder [c] - iron (elemental) 12.5 mg (as coated ferrous
fumarate)
- zinc (elemental) 5 mg
- vitamin A 300 micrograms
- with or without other micronutrients at
recommended daily values
 nicotinamide Tablet: 50 mg.
pyridoxine Tablet: 25 mg (hydrochloride).
retinol Capsule: 50 000 IU; 100 000 IU; 200 000 IU (as palmitate).
Oral oily solution: 100 000 IU (as palmitate)/ mL in
multidose dispenser.
Tablet (sugar-coated): 10 000 IU (as palmitate).
Water-miscible injection: 100 000 IU (as palmitate) in

2- mL ampoule.
riboflavin Tablet: 5 mg.
sodium fluoride In any appropriate topical formulation.
thiamine Tablet: 50 mg (hydrochloride).
Complementary List
calcium gluconate Injection: 100 mg/ mL in 10- mL ampoule.
538
28. EAR, NOSE AND THROAT MEDICINES

acetic acid [c] Topical: 2%, in alcohol.
 budesonide [c] Nasal spray: 100 micrograms per dose.
 ciprofloxacin [c] Topical: 0.3% drops (as hydrochloride).
 xylometazoline a [c] Nasal spray: 0.05%.
29. MEDICINES FOR DISEASES OF JOINTS
29.1 Medicines used to treat gout
allopurinol Tablet: 100 mg.
29.2 Disease-modifying agents used in rheumatoid disorders (DMARDs)
chloroquine Tablet: 100 mg; 150 mg (as phosphate or sulfate).
Complementary List
azathioprine Tablet: 50 mg.
hydroxychloroquine [c] Solid oral dosage form: 200 mg (as sulfate).
methotrexate Tablet: 2.5 mg (as sodium salt).
penicillamine Solid oral dosage form: 250 mg.
sulfasalazine Tablet: 500 mg.
acetylsalicylic acid* (acute Suppository: 50 mg to 150 mg.
or chronic use) Tablet: 100 mg to 500 mg.
* For use for rheumatic fever, juvenile arthritis, Kawasaki disease.
539
Table 1.1: Medicines with age or weight restrictions
artesunate + pyronaridine >5 kg

tetraphosphate
atazanavir >25 kg
atropine >3 months
bedaquiline ≥6 years
benzyl benzoate >2 years
betamethasone topical hydrocortisone preferred in neonates
preparations
cefazolin >1 month
ceftriaxone >41 weeks corrected gestational age
darunavir >3 years
delamanid ≥6 years
dihydroartemisinin + >5 kg
piperaquine phosphate
diloxanide >25 kg
dolutegravir ≥25 kg
doxycycline >8 years (except for serious infections e.g. cholera)
efavirenz >3 years or >10 kg
fluoxetine >8 years
ibuprofen >3 months (except IV form for patent ductus

arteriosus)
mefloquine >5 kg or >3 months
metoclopramide Not in neonates
nevirapine >6 weeks
ondansetron >1 month
silver sulfadiazine >2 months
tetracaine Not in preterm neonates
xylometazoline >3 months
540
Table 1.2: Explanation of dosage forms

A. Principal dosage forms used in EML – oral administration
Term Definition
Solid oral Refers to tablets or capsules or other solid dosage forms
dosage form such as ‘melts’ that are immediate-release preparations.
It implies that there is no difference in clinical efficacy or
safety between the available dosage forms, and countries
should therefore choose the form(s) to be listed depending
on quality and availability.
The term ‘solid oral dosage form’ is never intended to allow
any type of modified-release tablet.
Tablets Refers to:
• uncoated or coated (film-coated or sugar-coated) tablets
that are intended to be swallowed whole;
• unscored and scored*;
• tablets that are intended to be chewed before being
swallowed;
• tablets that are intended to be dispersed or dissolved in
water or another suitable liquid before being swallowed;
• tablets that are intended to be crushed before being
swallowed.
The term ‘tablet’ without qualification is never intended to
allow any type of modified-release tablet.
Tablets (qualified) Refers to a specific type of tablet:
chewable - tablets that are intended to be chewed before
being swallowed;
dispersible - tablets that are intended to be dispersed in
water or another suitable liquid before being swallowed;
soluble - tablets that are intended to be dissolved in water
or another suitable liquid before being swallowed;
crushable - tablets that are intended to be crushed before
being swallowed;
scored - tablets bearing a break mark or marks where sub-
division is intended in order to provide doses of less than
one tablet;
sublingual - tablets that are intended to be placed beneath
the tongue.
* Scored tablets may be divided for ease of swallowing, provided that dose is a whole number of tablets.
541
Table 1.2 continued

Term Definition
The term ‘tablet’ is always qualified with an additional term
(in parentheses) in entries where one of the following
types of tablet is intended: gastro-resistant (such tablets
may sometimes be described as enteric-coated or as
delayed-release), prolonged-release or another modified-
release form.
Capsules Refers to hard or soft capsules.
The term ‘capsule’ without qualification is never intended to
allow any type of modified-release capsule.
Capsules (qualified) The term ‘capsule’ with qualification refers to gastro-
resistant (such capsules may sometimes be described as
enteric-coated or as delayed-release), prolonged-release
or another modified-release form.
Granules Preparations that are issued to patient as granules to be
swallowed without further preparation, to be chewed, or to
be taken in or with water or another suitable liquid.
The term ‘granules’ without further qualification is never
intended to allow any type of modified-release granules.
Oral powder Preparations that are issued to patient as powder (usually
as single-dose) to be taken in or with water or another
suitable liquid.
Oral liquid Liquid preparations intended to be swallowed i.e. oral
solutions, suspensions, emulsions and oral drops, including
those constituted from powders or granules, but not those
preparations intended for oromucosal administration e.g.
gargles and mouthwashes.
Oral liquids presented as powders or granules may offer

benefits in the form of better stability and lower transport
costs. If more than one type of oral liquid is available on
the same market (e.g. solution, suspension, granules for
reconstitution), they may be interchanged and in such cases
should be bioequivalent. It is preferable that oral liquids
do not contain sugar and that solutions for children do not
contain alcohol.
542
B. Principal dosage forms used in EML – parenteral administration
Term Definition
Injection Refers to solutions, suspensions and emulsions including
those constituted from powders or concentrated
solutions.
Injection (qualified) Route of administration is indicated in parentheses
where relevant.
Injection (oily) The term ‘injection’ is qualified by ’(oily)’ in relevant
entries.
Intravenous infusion Refers to solutions and emulsions including those
constituted from powders or concentrated solutions.
C. Other dosage forms
Mode of administration Term to be used

To the eye Eye drops, eye ointments.
Topical For liquids: lotions, paints.
For semi-solids: cream, ointment.
Rectal Suppositories, gel or solution.
Vaginal Pessaries or vaginal tablets.
Inhalation Powder for inhalation, pressurized inhalation, nebulizer.
543
Annex 2
WHO Model List of Essential Medicines for Children (2019)
Explanatory notes
This Model List is intended for use for children up to 12 years of age
The core list presents a list of minimum medicine needs for a basic health-
care system, listing the most efficacious, safe and cost-effective medicines for
priority conditions. Priority conditions are selected on the basis of current
and estimated future public health relevance, and potential for safe and cost-
effective treatment.
The complementary list presents essential medicines for priority
diseases, for which specialized diagnostic or monitoring facilities, and/or
specialist medical care, and/or specialist training are needed. In case of doubt
medicines may also be listed as complementary on the basis of consistent higher
costs or less attractive cost–effectiveness in a variety of settings.
The square box symbol () is primarily intended to indicate similar
clinical performance within a pharmacological class. The listed medicine should
be the example of the class for which there is the best evidence for effectiveness
and safety. In some cases, this may be the first medicine that is licensed for
marketing; in other instances, subsequently licensed compounds may be safer or
more effective. Where there is no difference in terms of efficacy and safety data,
the listed medicine should be the one that is generally available at the lowest
price, based on international drug price information sources.
Therapeutic equivalence is indicated only on the basis of reviews of
efficacy and safety and when consistent with WHO clinical guidelines. National
lists should not use a similar symbol and should be specific in their final selection,
which would depend on local availability and price.
The format and numbering of the 21st WHO Model List of Essential
Medicines is used for the 7th WHO Model Essential List for Children. Some
sections have been deleted because they contain medicines that are not relevant
for children.
The a symbol indicates that there is an age or weight restriction on use
of the medicine; details for each medicine are in Table 1.1 of Annex 1.
The presence of an entry on the Essential Medicines List carries no
assurance as to pharmaceutical quality. It is the responsibility of the relevant
national or regional drug regulatory authority to ensure that each product is of
appropriate pharmaceutical quality (including stability) and that when relevant,
different products are interchangeable.
545
For recommendations and advice concerning all aspects of the quality

assurance of medicines see the WHO Medicines website http://www.who.int/
medicines/areas/quality_safety/quality_assurance/en/.
Medicines and dosage forms are listed in alphabetical order within
each section and there is no implication of preference for one form over
another. Standard treatment guidelines should be consulted for information on
appropriate dosage forms.
The main terms used for dosage forms in the Essential Medicines List can
be found in Table 1.2 of Annex 1.
Definitions of many of these terms and pharmaceutical quality
requirements applicable to the different categories are published in the current
edition of The International Pharmacopoeia http://www.who.int/medicines/
publications/pharmacopoeia.
546
Annex 2: 7th WHO Model List of Essential Medicines for Children (2019)
1. ANAESTHETICS, PREOPERATIVE MEDICINES AND MEDICAL GASES

1.1 General anaesthetics and oxygen
1.1.1 Inhalational medicines
halothane Inhalation.
isoflurane Inhalation.
nitrous oxide Inhalation.
oxygen Inhalation (medical gas).
1.1.2 Injectable medicines
ketamine Injection: 50 mg (as hydrochloride)/mL in 10-mL vial.
propofol* Injection: 10 mg/mL; 20 mg/mL.
* Thiopental may be used as an alternative depending on local
availability and cost.

 bupivacaine Injection: 0.25%; 0.5% (hydrochloride) in vial.
Injection for spinal anaesthesia: 0.5% (hydrochloride) in
4-mL ampoule to be mixed with 7.5% glucose solution.
 lidocaine Injection: 1%; 2% (hydrochloride) in vial.
Injection for spinal anaesthesia: 5% (hydrochloride) in
2-mL ampoule to be mixed with 7.5% glucose solution.
Topical forms: 2% to 4% (hydrochloride).
lidocaine + epinephrine Dental cartridge: 2% (hydrochloride) + epinephrine
(adrenaline) 1:80 000.
Injection: 1%; 2% (hydrochloride or sulfate) +
epinephrine 1:200 000 in vial.
1.3 Preoperative medication and sedation for short-term procedures
atropine Injection: 1 mg (sulfate) in 1-mL ampoule.
 midazolam Injection: 1 mg/mL.
morphine Injection: 10 mg (sulfate or hydrochloride) in 1-mL
ampoule.
547
1. ANAESTHETICS, PREOPERATIVE MEDICINES AND MEDICAL GASES (continued)

1.4 Medical gases
oxygen* Inhalation
For use in the management of hypoxaemia.
* No more than 30% oxygen should be used to initiate resuscitation
of neonates less than or equal to 32 weeks of gestation.
2. MEDICINES FOR PAIN AND PALLIATIVE CARE

2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs)
ibuprofen a Oral liquid: 200 mg/5 mL.
Tablet: 200 mg; 400 mg; 600 mg.
paracetamol* Oral liquid: 120 mg/5 mL; 125 mg/5 mL.
* Not recommended for anti-inflammatory use due to lack of
proven benefit to that effect.
2.2 Opioid analgesics

 morphine* Granules (slow release; to mix with water): 20 mg to
200 mg (morphine sulfate).
Injection: 10 mg (morphine hydrochloride or morphine
sulfate) in 1-mL ampoule.
Oral liquid: 10 mg (morphine hydrochloride or morphine
sulfate)/5 mL.
Tablet (slow release): 10 mg – 200mg (morphine
hydrochloride or morphine sulfate).
Tablet (immediate release): 10 mg (morphine sulfate).

* Alternatives limited to hydromorphone and oxycodone.
Complementary list
methadone* Tablet: 5 mg; 10 mg (as hydrochloride).
Oral liquid: 5mg/ 5mL; 10mg/ 5mL (as hydrochloride).
Concentrate for oral liquid: 5 mg/ mL; 10mg/ mL
(as hydrochloride).
* For the management of cancer pain.
548

2.3 Medicines for other symptoms common in palliative care
amitriptyline Tablet: 10 mg; 25 mg.
cyclizine Injection: 50 mg/mL.
Tablet: 50 mg.
dexamethasone Injection: 4 mg/mL in 1-mL ampoule (as disodium
phosphate salt).
Tablet: 2 mg.
diazepam Injection: 5 mg/mL.
Rectal solution: 2.5 mg; 5 mg; 10 mg.
docusate sodium Capsule: 100 mg.
a >8 years.
hyoscine hydrobromide Injection: 400 micrograms/mL; 600 micrograms/mL.
Transdermal patches: 1 mg/72 hours.
lactulose Oral liquid: 3.1–3.7 g/5 mL.
midazolam Injection: 1 mg/mL; 5 mg/mL.
Oral liquid: 2mg/mL.
 ondansetron a Injection: 2 mg base/mL in 2-mL ampoule
(as hydrochloride).
a >1 month.
senna Oral liquid: 7.5 mg/5 mL.
549
3. ANTIALLERGICS AND MEDICINES USED IN ANAPHYLAXIS

phosphate salt).
in 1-mL ampoule.
hydrocortisone Powder for injection: 100 mg (as sodium succinate) in
vial.
 loratadine* Oral liquid: 1 mg/mL.
Tablet: 10 mg.
* There may be a role for sedating antihistamines for limited
indications.
 prednisolone Oral liquid: 5 mg/mL.

4. ANTIDOTES AND OTHER SUBSTANCES USED IN POISONINGS
4.1 Non-specific
charcoal, activated Powder.
4.2 Specific
acetylcysteine Injection: 200 mg/mL in 10-mL ampoule.
Oral liquid: 10%; 20%.
atropine Injection: 1 mg (sulfate) in 1-mL ampoule.
calcium gluconate Injection: 100 mg/mL in 10-mL ampoule.
naloxone Injection: 400 micrograms (hydrochloride) in 1-mL
ampoule.
Complementary List
deferoxamine Powder for injection: 500 mg (mesilate) in vial.
dimercaprol Injection in oil: 50 mg/mL in 2-mL ampoule.
fomepizole Injection: 5 mg/mL (sulfate) in 20-mL ampoule or 1 g/mL
(base) in 1.5-mL ampoule.
sodium calcium edetate Injection: 200 mg/mL in 5-mL ampoule.
succimer Solid oral dosage form: 100 mg.
550
5. ANTICONVULSANTS/ANTIEPILEPTICS
carbamazepine Oral liquid: 100 mg/5 mL.
Tablet (chewable): 100 mg; 200 mg.
Tablet (scored): 100 mg; 200 mg.
diazepam Gel or rectal solution: 5 mg/mL in 0.5 mL; 2-mL; 4-mL
tubes.
lamotrigine* Tablet: 25 mg; 50 mg; 100 mg; 200 mg.
Tablet (chewable, dispersible): 2 mg; 5 mg; 25 mg;
50 mg; 100 mg; 200 mg.
* As adjunctive therapy for treatment-resistant partial or
generalized seizures.
 lorazepam Parenteral formulation: 2 mg/mL in 1-mL ampoule;

4 mg/mL in 1-mL ampoule.
midazolam Solution for oromucosal administration: 5 mg/mL;
10 mg/mL.
Ampoule*: 1 mg/ mL; 10 mg/mL.
* For buccal administration when solution for oromucosal
administration is not available.
phenobarbital Injection: 200 mg/mL (sodium).

phenytoin Injection: 50 mg/mL in 5-mL vial (sodium salt).
Oral liquid: 25 mg to 30 mg/5 mL.*
Solid oral dosage form: 25 mg; 50 mg; 100 mg (sodium
salt).
Tablet (chewable): 50 mg.
* The presence of both 25 mg/5 mL and 30 mg/5 mL strengths
on the same market would cause confusion in prescribing and
dispensing and should be avoided.
valproic acid Oral liquid: 200 mg/5 mL.

(sodium valproate) Tablet (crushable): 100 mg.
Tablet (enteric-coated): 200 mg; 500 mg (sodium
valproate).
Complementary List
ethosuximide Capsule: 250 mg.
valproic acid Injection: 100 mg/ mL in 4- mL ampoule; 100 mg/ mL in
(sodium valproate) 10- mL ampoule.
551
6. ANTI-INFECTIVE MEDICINES
6.1 Anthelminthics
6.1.1 Intestinal anthelminthics
levamisole Tablet: 50 mg; 150 mg (as hydrochloride).
mebendazole Tablet (chewable): 100 mg; 500 mg.
niclosamide Tablet (chewable): 500 mg.
praziquantel Tablet: 150 mg; 600 mg.
pyrantel Oral liquid: 50 mg (as embonate or pamoate)/mL.
Tablet (chewable): 250 mg (as embonate or pamoate).
6.1.2 Antifilarials
diethylcarbamazine Tablet: 50 mg; 100 mg (dihydrogen citrate).
6.1.3 Antischistosomals and other antitrematode medicines
praziquantel Tablet: 600 mg.
triclabendazole Tablet: 250 mg.
Complementary List
oxamniquine* Capsule: 250 mg.
* Oxamniquine is listed for use when praziquantel treatment fails.
552

6.2 Antibacterials
To assist in the development of tools for antibiotic stewardship at local, national and
global levels and to reduce antimicrobial resistance, the Access, Watch, Reserve
(AWaRe) classification of antibiotics was developed – where antibiotics are classified
into different groups to emphasize the importance of their appropriate use.
ACCESS GROUP ANTIBIOTICS
This group includes antibiotics that have activity against a wide range of commonly
encountered susceptible pathogens while also showing lower resistance potential than
antibiotics in the other groups. Selected Access group antibiotics are recommended
as essential first or second choice empiric treatment options for infectious syndromes
reviewed by the EML Expert Committee and are listed as individual medicines on
the Model Lists to improve access and promote appropriate use. They are essential
antibiotics that should be widely available, affordable and quality assured.
WATCH GROUP ANTIBIOTICS
This group includes antibiotic classes that have higher resistance potential and includes
most of the highest priority agents among the Critically Important Antimicrobials
for Human Medicine 1 and/or antibiotics that are at relatively high risk of selection of
bacterial resistance. These medicines should be prioritized as key targets of stewardship
programs and monitoring. Selected Watch group antibiotics are recommended as
essential first or second choice empiric treatment options for a limited number of
specific infectious syndromes and are listed as individual medicines on the Model Lists.
1
http://apps.who.int/iris/bitstream/10665/251715/1/9789241511469-eng.pdf?ua=1
RESERVE GROUP ANTIBIOTICS

This group includes antibiotics and antibiotic classes that should be reserved for
treatment of confirmed or suspected infections due to multi-drug-resistant organisms.
Reserve group antibiotics should be treated as “last resort” options. Selected Reserve
group antibiotics are listed as individual medicines on the Model Lists when they have
a favourable risk-benefit profile and proven activity against “Critical Priority” or “High
Priority” pathogens identified by the WHO Priority Pathogens List 1, notably carbapenem
resistant Enterobacteriaceae. These antibiotics should be accessible, but their use
should be tailored to highly specific patients and settings, when all alternatives have
failed or are not suitable. These medicines could be protected and prioritized as key
targets of national and international stewardship programs involving monitoring and
utilization reporting, to preserve their effectiveness.
1
https://apps.who.int/iris/handle/10665/311820
553

6.2.1 Access group antibiotics
amikacin Injection: 250 mg (as sulfate)/mL in 2- mL vial.
- pyelonephritis (severe) - sepsis in neonates and
- high-risk febrile children
neutropenia
amoxicillin Powder for oral liquid: 125 mg (as trihydrate)/5 mL;
250 mg (as trihydrate)/5 mL.
Solid oral dosage form: 250 mg; 500 mg (as trihydrate).
Powder for injection: 250 mg; 500 mg; 1 g (as sodium)
in vial.
pneumonia (mild to
moderate)
pneumonia (severe)
malnutrition
infections
- otitis media
- pharyngitis
children
- sinusitis
- uncomplicated severe
acute malnutrition
abscess
554

amoxicillin + clavulanic acid Oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic
acid/5 mL AND 250 mg amoxicillin + 62.5 mg clavulanic
acid/5 mL.
Tablet: 500 mg (as trihydrate) + 125 mg (as potassium
salt).
Powder for injection: 500 mg (as sodium) + 100 mg
(as potassium salt); 1000 mg (as sodium) + 200 mg
(as potassium salt) in vial.
- community acquired - bone and joint infections
pneumonia (severe) - community acquired
- complicated pneumonia (mild to
intraabdominal infections moderate)
(mild to moderate) - community acquired
- hospital acquired pneumonia (severe)
pneumonia - otitis media
- low-risk febrile - surgical prophylaxis
neutropenia
infections
- sinusitis
infections
ampicillin Powder for injection: 500 mg; 1 g (as sodium salt) in vial.
pneumonia (severe)
malnutrition
children
benzathine benzylpenicillin Powder for injection: 900 mg benzylpenicillin
(= 1.2 million IU) in 5- mL vial; 1.44 g benzylpenicillin
(= 2.4 million IU) in 5- mL vial.
- syphilis (congenital)
555

benzylpenicillin Powder for injection: 600 mg (= 1 million IU);
3 g (= 5 million IU) (sodium or potassium salt) in vial.
pneumonia (severe)
malnutrition
children
cefalexin Powder for reconstitution with water: 125 mg/5 mL;
250 mg/5 mL (anhydrous).
Solid oral dosage form: 250 mg (as monohydrate).
- pharyngitis
infections
cefazolin a Powder for injection: 1 g (as sodium salt) in vial.
a >1 month.
- surgical prophylaxis - bone and joint infections
chloramphenicol Capsule: 250 mg.
Oily suspension for injection*: 0.5 g (as sodium
succinate)/ mL in 2- mL ampoule.
* Only for the presumptive treatment of epidemic meningitis in
children older than 2 years.

Oral liquid: 150 mg (as palmitate)/5 mL.
Powder for injection: 1 g (sodium succinate) in vial.
clindamycin Capsule: 150 mg (as hydrochloride).
Injection: 150 mg (as phosphate)/ mL.
Oral liquid: 75 mg/5 mL (as palmitate).
- bone and joint infections
556

 cloxacillin* Capsule: 500 mg; 1 g (as sodium salt).
Powder for oral liquid: 125 mg (as sodium salt)/5 mL.
* Cloxacillin, dicloxacillin and flucloxacillin are preferred for oral
administration due to better bioavailability.

- bone and joint infections - sepsis in neonates and
- skin and soft tissue children
infections
doxycycline a Oral liquid: 25 mg/5 mL; 50 mg/5 mL (anhydrous).
Solid oral dosage form: 50 mg; 100 mg (as hyclate).
a Use in children <8 years only for life-threatening infections
when no alternative exists.

- cholera
pneumonia (mild to
moderate)
gentamicin Injection: 10 mg; 40 mg (as sulfate)/ mL in 2- mL vial.
- community acquired - surgical prophylaxis
pneumonia (severe)
malnutrition
children
557

metronidazole Injection: 500 mg in 100- mL vial.
- C. difficile infection - complicated intra-
- complicated intraabdominal infections
abdominal infections (mild to moderate)
(mild to moderate)
- complicated intra-
abdominal infections
(severe)
nitrofurantoin Oral liquid: 25 mg/5 mL.
Tablet: 100 mg.
infections
phenoxymethylpenicillin Powder for oral liquid: 250 mg (as potassium
salt)/5 mL.
Tablet: 250 mg (as potassium salt).
pneumonia (mild to
moderate)
- pharyngitis

abscess
procaine benzylpenicillin* Powder for injection: 1 g (=1 million IU); 3 g (=3 million
IU) in vial.
* Procaine benzylpenicillin is not recommended as first-line
treatment for neonatal sepsis / sepsis except in settings with
high neonatal mortality, when given by trained health workers
in cases where hospital care is not achievable.

558

trimethoprim* 80 mg + 16 mg/ mL in 5- mL ampoule;
Tablet: 100 mg + 20 mg; 400 mg + 80 mg.
* Single agent trimethoprim may be an alternative for lower
urinary tract infection.

- lower urinary tract - acute invasive bacterial
infections diarrhoea / dysentery
azithromycin* Capsule: 250 mg; 500 mg (anhydrous).
* Also listed for single-dose treatment of trachoma and yaws.

- cholera - acute invasive bacterial
- enteric fever diarrhoea / dysentery
cefixime Capsules or tablets: 200 mg; 400 mg (as trihydrate).

Powder for oral liquid: 100 mg /5 mL.
- acute invasive bacterial
diarrhoea / dysentery
559

cefotaxime* Powder for injection: 250 mg per vial (as sodium salt).
* 3rd generation cephalosporin of choice for use in hospitalized
neonates.

- acute bacterial meningitis - bone and joint infections
- community acquired - pyelonephritis (mild to
pneumonia (severe) moderate)
- complicated - sepsis in neonates and
intraabdominal infections children
(mild to moderate)
- complicated
(severe)
- hospital acquired
pneumonia
- pyelonephritis (severe)
ceftriaxone* a Powder for injection: 250 mg; 1 g (as sodium salt) in vial.
* Do not administer with calcium and avoid in infants with
hyperbilirubinaemia.
a >41 weeks corrected gestational age.
- acute bacterial meningitis - acute invasive bacterial
- community acquired diarrhoea / dysentery
pneumonia (severe) - bone and joint infections
- complicated - pyelohepnritis or
intraabdominal infections prostatitis (mild to
(mild to moderate) moderate)
- complicated - sepsis in neonates and

intraabdominal infections children
(severe)
- hospital acquired
pneumonia
- pyelonephritis (severe)
- enteric fever
560

cefuroxime Powder for injection: 250 mg, 750 mg, 1.5 g (as sodium
salt) in vial
ciprofloxacin Oral liquid: 250 mg/5 mL (anhydrous) .
Solution for IV infusion: 2 mg/ mL (as hyclate).
- acute invasive bacterial - cholera
diarrhoea / dysentery - complicated
- low-risk febrile intraabdominal infections
neutropenia (mild to moderate)
- pyelonephritis (mild to
moderate)
- enteric fever
clarithromycin* Solid oral dosage form: 500 mg.
Powder for oral liquid: 125 mg/5 mL; 250 mg/5 mL.
* Erythromycin may be an alternative.

- pharyngitis
piperacillin + tazobactam Powder for injection: 2 g (as sodium salt) + 250 mg
(as sodium salt); 4 g (as sodium salt) + 500 mg (as sodium
salt) in vial.
- complicated
(severe)
- high-risk febrile
neutropenia
- hospital acquired
pneumonia
vancomycin Capsule: 125 mg; 250 mg (as hydrochloride).
SECOND CHOICE
- C. difficile infection
561

Complementary List
ceftazidime Powder for injection: 250 mg or 1 g (as pentahydrate)
in vial.
meropenem* a Powder for injection: 500 mg (as trihydrate);
1 g (as trihydrate) in vial.
a >3 months.
* Imipenem + cilastatin is an alternative except for acute bacterial
meningitis where meropenen is preferred.

in neonates
- complicated
(severe)
- high-risk febrile
neutropenia
vancomycin Powder for injection: 250 mg (as hydrochloride) in vial.
- high-risk febrile
neutropenia
Complementary List
ceftazidime + avibactam Powder for injection: 2 g + 0.5 g in vial.
colistin Powder for injection: 1 million I.U. (as colistemethate
sodium) in vial
fosfomycin Powder for injection: 2 g; 4 g (as sodium) in vial.
300 mL bag.
polymyxin B Powder for injection: 500,000 I.U. in vial.
562

6.2.4 Antileprosy medicines
Medicines used in the treatment of leprosy should never be used except in combination.
Combination therapy is essential to prevent the emergence of drug resistance.
Colour-coded blister packs (MDT blister packs) containing standard two-medicine
(paucibacillary leprosy) or three-medicine (multibacillary leprosy) combinations for
adult and childhood leprosy should be used. MDT blister packs can be supplied free of
charge through WHO.
clofazimine Capsule: 50 mg; 100 mg.
dapsone Tablet: 25 mg; 50 mg; 100 mg.
rifampicin Solid oral dosage form: 150 mg; 300 mg.
WHO recommends and endorses the use of fixed-dose combinations and the
development of appropriate new fixed-dose combinations, including modified
dosage forms, non-refrigerated products and paediatric dosage forms of assured
pharmaceutical quality.
ethambutol Oral liquid: 25 mg/mL.
isoniazid Oral liquid: 50 mg/5 mL.
isoniazid + pyrazinamide + Tablet (dispersible): 50 mg + 150 mg + 75 mg.
rifampicin
isoniazid + rifampicin Tablet (dispersible): 50 mg + 75 mg.
pyrazinamide Oral liquid: 30 mg/mL.
Tablet: 400 mg.
rifampicin Oral liquid: 20 mg/mL.
rifapentine* Tablet: 150 mg
* For treatment of latent TB infection (LTBI) only.
563

Complementary List
Medicines for the treatment of multidrug-resistant tuberculosis (MDR-TB) should be
used in specialized centres adhering to WHO standards for TB control.
amikacin Powder for injection: 100 mg; 500 mg; 1 g (as sulfate) in vial.
amoxicillin + Oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic
clavulanic acid* acid/5 mL; 250 mg amoxicillin + 62.5 mg clavulanic
acid/5 mL.
Tablet: 500 mg (as trihydrate) + 125 mg (as potassium salt).
* For use only in combination with meropenem.
bedaquiline a Tablet: 100 mg.

a ≥6 years.
clofazimine Solid oral dosage form: 50 mg; 100 mg.
cycloserine Solid oral dosage form: 125 mg; 250 mg.
delamanid a Tablet: 50 mg.
a ≥6 years
ethionamide* Tablet: 125 mg; 250 mg.
* Protionamide may be used as an alternative.
levofloxacin Tablet: 250 mg: 500 mg.

300 mL bag.

meropenem Powder for injection: 500 mg (as trihydrate);
1 g (as trihydrate) in vial.
moxifloxacin Tablet: 400 mg.
p-aminosalicylic acid Granules: 4 g in sachet.
Tablet: 500 mg.
streptomycin Powder for injection: 1 g (as sulfate) in vial.
564

fluconazole Capsule: 50 mg.
Injection: 2 mg/mL in vial.
flucytosine Capsule: 250 mg.
Infusion: 2.5 g in 250 mL.
griseofulvin Oral liquid: 125 mg/5 mL.
itraconazole* Capsule: 100 mg.
* For treatment of chronic pulmonary aspergillosis, acute
invasive aspergillosis, histoplasmosis, sporotrichosis,
paracoccidiodomycosis, mycoses caused by T. marneffei and
chromoblastomycosis; and prophylaxis of histoplasmosis and
infections caused by T. marneffei in AIDS patients.
nystatin Lozenge: 100 000 IU.

Oral liquid: 50 mg/5 mL; 100 000 IU/mL.
Tablet: 100 000 IU; 500 000 IU.
voriconazole* Tablet: 50 mg; 200 mg.
Powder for oral liquid: 40 mg/mL.
* For treatment of chronic pulmonary aspergillosis and acute
invasive aspergillosis.
Complementary List
potassium iodide Saturated solution.
565

6.4.1 Antiherpes medicines
aciclovir Oral liquid: 200 mg/5 mL.
Tablet: 200 mg.
Based on current evidence and experience of use, medicines in the following classes
of antiretrovirals are included as essential medicines for treatment and prevention of
HIV (prevention of mother-to-child transmission and post-exposure prophylaxis).
WHO emphasizes the importance of using these products in accordance with global
and national guidelines. WHO recommends and endorses the use of fixed-dose
combinations and the development of appropriate new fixed-dose combinations,
including modified dosage forms, non-refrigerated products and paediatric dosage
forms of assured pharmaceutical quality.
Scored tablets can be used in children and therefore can be considered for inclusion
in the listing of tablets, provided that adequate quality products are available.
6.4.2.1 Nucleoside/Nucleotide reverse transcriptase inhibitors
abacavir (ABC) Tablet (dispersible, scored): 60 mg (as sulfate).
lamivudine (3TC) Oral liquid: 50 mg/5 mL.
Tablet: 150 mg.
zidovudine (ZDV or AZT) Oral liquid: 50 mg/5 mL.
6.4.2.2 Non-nucleoside reverse transcriptase inhibitors
efavirenz (EFV or EFZ) a Tablet: 200 mg (scored).
a >3 years or >10 kg weight.

nevirapine (NVP) a Oral liquid: 50 mg/5 mL.
Tablet: 50 mg (dispersible).
a >6 weeks
566

Selection of protease inhibitor(s) from the Model List will need to be determined by
each country after consideration of international and national treatment guidelines
and experience. Ritonavir is recommended for use in combination as a pharmacological
booster, and not as an antiretroviral in its own right. All other protease inhibitors should
be used in boosted forms (e.g. with ritonavir).
atazanavir a Solid oral dosage form: 100 mg; (as sulfate).
a >25 kg.
darunavir a Tablet: 75 mg.
a >3 years.
lopinavir + ritonavir (LPV/r) Oral liquid: 400 mg + 100 mg/5 mL.
Tablet (heat stable): 100 mg + 25 mg.
Solid oral dosage form: 40 mg + 10 mg.
ritonavir Oral liquid: 400 mg/5 mL.
Tablet (heat stable): 25 mg; 100 mg.
Oral powder: 100 mg in sachet.
dolutegravir a Tablet: 50 mg.
a ≥25 kg
raltegravir* Tablet (chewable): 25 mg; 100 mg.
Tablet: 400 mg.
Granules for oral suspension: 100 mg in sachet.
* For use in second-line regimens in accordance with WHO
treatment guidelines.
FIXED-DOSE COMBINATIONS
abacavir + lamivudine Tablet (dispersible, scored): 120 mg (as sulfate) + 60 mg.
lamivudine + nevirapine + Tablet: 30 mg + 50 mg + 60 mg.
zidovudine
lamivudine + zidovudine Tablet: 30 mg + 60 mg.
6.4.2.5 Medicines for prevention of HIV-related opportunistic infections
isoniazid + pyridoxine + Tablet (scored): 300 mg + 25 mg + 800 mg + 160 mg.
sulfamethoxazole +
trimethoprim
567

6.4.3 Other antivirals
1 g in 10-mL phosphate buffer solution.
* For the treatment of viral haemorrhagic fevers only.
Complementary List
oseltamivir* Capsule: 30 mg; 45 mg; 75 mg (as phosphate).
Oral powder: 12 mg/ mL.
* Severe illness due to confirmed or suspected influenza virus infection
in critically ill hospitalized patients.
valganciclovir* Powder for oral solution: 50 mg/mL.

Tablet: 450 mg.

6.4.4.1 Medicines for hepatitis B
6.4.4.1.1 Nucleoside/Nucleotide reverse transcriptase inhibitors
entecavir Oral liquid: 0.05 mg/ mL.
6.5.1 Antiamoebic and antigiardiasis medicines
diloxanide a Tablet: 500 mg (furoate).
a >25 kg.
 metronidazole Injection: 500 mg in 100-mL vial.
568

6.5.2 Antileishmaniasis medicines
amphotericin B Powder for injection: 50 mg in vial.
As sodium deoxycholate or liposomal complex.
miltefosine Solid oral dosage form: 10 mg; 50 mg.
paromomycin Solution for intramuscular injection: 750 mg of
paromomycin base (as the sulfate).
sodium stibogluconate or Injection: 100 mg/mL, 1 vial = 30 mL or 30%,
meglumine antimoniate equivalent to approximately 8.1% antimony
(pentavalent) in 5-mL ampoule.
6.5.3.1 For curative treatment
Medicines for the treatment of P. falciparum malaria cases should be used in
combination. The list currently recommends combinations according to treatment
guidelines. WHO recognizes that not all of the fixed dose combinations (FDCs in the
WHO treatment guidelines exist, and encourages their development and rigorous
testing. WHO also encourages development and testing of rectal dosage formulations.
amodiaquine* Tablet: 153 mg or 200 mg (as hydrochloride).
artemether* Oily injection: 80 mg/mL in 1-mL ampoule.

artemether + lumefantrine* Tablet: 20 mg + 120 mg.

Tablet (dispersible): 20 mg + 120 mg.
* Not recommended in the first trimester of pregnancy or in
children below 5 kg.
artesunate* ** Injection: ampoules, containing 60 mg anhydrous

artesunic acid with a separate ampoule of 5% sodium
bicarbonate solution.
Rectal dosage form: 50 mg; 100 mg; 200 mg capsules
(for pre-referral treatment of severe malaria only;
patients should be taken to an appropriate health
facility for follow-up care).
Tablet: 50 mg.
** To be used in combination with either amodiaquine,
mefloquine or sulfadoxine + pyrimethamine.
569

artesunate + amodiaquine* Tablet: 25 mg + 67.5 mg; 50 mg + 135 mg; 100 mg +
270 mg.
* Other combinations that deliver the target doses required such
as 153 mg or 200 mg (as hydrochloride) with 50 mg artesunate
can be alternatives.
artesunate + mefloquine Tablet: 25 mg + 55 mg; 100 mg + 220 mg.

artesunate + pyronaridine Tablet: 60 mg + 180 mg.
tetraphosphate a Granules: 20 mg + 60 mg.
a >5 kg
Tablet: 100 mg; 150 mg (as phosphate or sulfate).
dihydroartemisinin + Tablet: 20 mg + 160 mg; 40 mg + 320 mg

piperaquine phosphate a a >5 kg.
doxycycline* Capsule: 100 mg (as hydrochloride or hyclate).
Tablet (dispersible): 100 mg (as monohydrate).
* For use only in combination with quinine.
mefloquine* Tablet: 250 mg (as hydrochloride).

primaquine* Tablet: 7.5 mg; 15 mg (as diphosphate).

* Only for use to achieve radical cure of P. vivax and P. ovale
infections, given for 14 days.
quinine* Injection: 300 mg quinine hydrochloride/mL in 2-mL

ampoule.
Tablet: 300 mg (quinine sulfate) or 300 mg (quinine

bisulfate).
* For use only in the management of severe malaria, and should
be used in combination with doxycycline.
sulfadoxine + Tablet: 500 mg + 25 mg.

pyrimethamine* * Only in combination with artesunate 50 mg.
570

amodiaquine – Co-packaged dispersible tablets:
sulfadoxine + amodiaquine 76.5 mg (as hydrochloride [3] and
pyrimethamine sulfadoxine + pyrimethamine 250 mg + 12.5 mg [1];
amodiaquine 153 mg (as hydrochloride) [3] and
sulfadoxine + pyrimethamine 500 mg + 25 mg [1];
Tablet: 150 mg (as phosphate or sulfate).
doxycycline a Solid oral dosage form: 100 mg (as hydrochloride or

hyclate).
a >8 years.
mefloquine a Tablet: 250 mg (as hydrochloride).
a >5 kg or >3 months.
proguanil* Tablet: 100 mg (as hydrochloride).
* For use only in combination with chloroquine.
sulfadoxine + Tablet: 250 mg + 12.5 mg.

pyrimethamine
6.5.4 Antipneumocystosis and antitoxoplasmosis medicines
pyrimethamine Tablet: 25 mg.
sulfadiazine Tablet: 500 mg.
trimethoprim 80 mg + 16 mg/mL in 5-mL ampoule;
80 mg + 16 mg/mL in 10-mL ampoule.
Tablet: 100 mg + 20 mg; 400 mg + 80 mg.
571

fexinidazole* Tablet: 600 mg
* For the treatment of 1st and 2 nd stage of human African
trypanosomiasis due to Trypanosoma brucei gambiense
infection.
Medicines for the treatment of 1st stage African trypanosomiasis

pentamidine* Powder for injection: 200 mg (as isetionate) in vial.
infection.
suramin sodium* Powder for injection: 1 g in vial.

* To be used for the treatment of the initial phase of Trypanosoma
brucei rhodesiense infection.
Medicines for the treatment of 2 nd stage African trypanosomiasis

eflornithine* Injection: 200 mg (hydrochloride)/mL in 100-mL bottle.
infection.
nifurtimox* Tablet: 120 mg.

* Only to be used in combination with eflornithine, for the
treatment of Trypanosoma brucei gambiense infection.
Complementary List
melarsoprol Injection: 3.6% solution in 5-mL ampoule (180 mg of
active compound).
6.5.5.2 American trypanosomiasis
benznidazole Tablet: 12.5 mg; 100 mg.

nifurtimox Tablet: 30 mg; 120 mg; 250 mg.
572
7. ANTIMIGRAINE MEDICINES
ibuprofen Tablet: 200 mg; 400 mg.
paracetamol Oral liquid: 120 mg/5 mL; 125 mg/5 mL.
7.2 For prophylaxis
propranolol Tablet: 20 mg; 40 mg (hydrochloride).
8. IMMUNOMODULATORS AND ANTINEOPLASTICS
Complementary List
 adalimumab* Injection: 40 mg/0.8 mL; 40 mg/0.4 mL.
* Etanercept and infliximab are alternatives, including quality-
assured biosimilars.
azathioprine Powder for injection: 100 mg (as sodium salt) in vial.

ciclosporin Capsule: 25 mg.
Concentrate for injection: 50 mg/mL in 1-mL ampoule.
* For organ transplantation.
573

Medicines listed below should be used according to protocols for treatment of
the diseases.
Complementary List
arsenic trioxide Concentrate for solution for infusion: 1 mg/mL.
asparaginase Powder for injection: 10 000 IU in vial.
bleomycin Powder for injection: 15 mg (as sulfate) in vial.
- Hodgkin lymphoma
- Testicular germ cell tumours
- Ovarian germ cell tumours
- Kaposi sarcoma
calcium folinate Injection: 3 mg/ mL in 10- mL ampoule.
Tablet: 5 mg; 15 mg; 25 mg.
- Osteosarcoma
- Burkitt lymphoma
carboplatin Injection: 50 mg/5 mL; 150 mg/15 mL; 450 mg/45 mL;
600 mg/60 mL.
- Osteosarcoma
- Retinoblastoma
cisplatin Injection: 50 mg/50 mL; 100 mg/100 mL.
- Osteosarcoma
cyclophosphamide Powder for injection: 500 mg in vial.
- Rhabdomyosarcoma
- Ewing sarcoma
- Burkitt lymphoma
- Hodgkin lymphoma
574

cytarabine Powder for injection: 100 mg in vial.
- Burkitt lymphoma.
dacarbazine Powder for injection: 100 mg in vial.
- Hodgkin lymphoma
dactinomycin Powder for injection: 500 micrograms in vial.
- Rhabdomyosarcoma
daunorubicin Powder for injection: 50 mg (hydrochloride) in vial.
doxorubicin Powder for injection: 10 mg; 50 mg (hydrochloride) in vial.
- Osteosarcoma
- Ewing sarcoma
- Burkitt lymphoma
- Hodgkin lymphoma
- Kaposi sarcoma
etoposide Capsule: 50 mg; 100 mg.
Injection: 20 mg/ mL in 5- mL ampoule.
- Retinoblastoma
- Ewing sarcoma
- Burkitt lymphoma
- Hodgkin lymphoma
fluorouracil Injection: 50 mg/ mL in 5- mL ampoule.
575

hydroxycarbamide Solid oral dosage form: 200 mg; 250 mg; 300 mg; 400 mg;
500 mg; 1 g.
ifosfamide Powder for injection: 500 mg vial 1-g vial; 2-g vial.
- Osteosarcoma
- Rhabdomyosarcoma
- Ewing sarcoma
irinotecan Injection: 40 mg/2 mL in 2- mL vial; 100 mg/5 mL in 5- mL
vial; 500 mg/25 mL in 25- mL vial.
mercaptopurine Tablet: 50 mg.
methotrexate Powder for injection: 50 mg (as sodium salt) in vial.
Tablet: 2.5 mg (as sodium salt).
- Osteosarcoma
oxaliplatin Injection: 50 mg/10 mL in 10- mL vial; 100 mg/20 mL in
20- mL vial; 200 mg/40 mL in 40- mL vial.
Powder for injection: 50 mg, 100 mg in vial.
paclitaxel Powder for injection: 6 mg/ mL.

pegaspargase* Injection: 3,750 units/5 mL in vial.
procarbazine Capsule: 50 mg (as hydrochloride).

- Hodgkin lymphoma
realgar-Indigo naturalis Tablet: 270 mg (containing tetra-arsenic tetra-sulfide
formulation 30 mg).
576

tioguanine Solid oral dosage form: 40 mg.
vinblastine Powder for injection: 10 mg (sulfate) in vial.
- Hodgkin lymphoma
vincristine Powder for injection: 1 mg; 5 mg (sulfate) in vial.
- Retinoblastoma
- Rhabdomyosarcoma
- Ewing sarcoma
- Burkitt lymphoma
- Hodgkin lymphoma
- Kaposi sarcoma
577

Complementary List
all-trans retinoic acid Capsule: 10 mg.
(ATRA) - Acute promyelocytic leukaemia
dasatinib Tablet: 20 mg; 50 mg; 70 mg; 80 mg; 100 mg; 140 mg.
imatinib Tablet: 100 mg; 400 mg.
- Gastrointestinal stromal tumour
nilotinib Capsule: 150 mg; 200 mg.
rituximab* Injection (intravenous): 100 mg/10 mL in 10- mL vial;
500 mg/50 mL in 50- mL vial.
Complementary List
filgrastim Injection: 120 micrograms/0.2 mL; 300 micrograms/0.5 mL;
480 micrograms/0.8 mL in pre-filled syringe
300 micrograms/mL in 1- mL vial, 480 micrograms/1.6 mL
in 1.6- mL vial.
- Primary prophylaxis in patients at high risk for
developing febrile neutropenia associated with
myelotoxic chemotherapy.
- Secondary prophylaxis for patients who have
experienced neutropenia following prior myelotoxic
chemotherapy
- To facilitate administration of dose dense
chemotherapy regimens
578

Complementary List
phosphate salt).
Tablet: 2 mg; 4 mg.
hydrocortisone Powder for injection: 100 mg (as sodium succinate) in vial.
methylprednisolone Injection: 40 mg/ mL (as sodium succinate) in 1- mL
single-dose vial and 5- mL multi-dose vials; 80 mg/ mL (as
sodium succinate) in 1- mL single-dose vial.
- Acute lymphoblastic leukamia
 prednisolone Oral liquid: 5 mg/ mL.
- Burkitt lymphoma
- Hodgkin lymphoma
Complementary List
allopurinol Tablet: 100 mg; 300 mg.
- Tumour lysis syndrome
mesna Injection: 100 mg/ mL in 4- mL and 10- mL ampoules.
- Osteosarcoma
- Rhabdomyosarcoma
- Ewing sarcoma
9. ANTIPARKINSONISM MEDICINES
579
10. MEDICINES AFFECTING THE BLOOD

10.1 Antianaemia medicines
ferrous salt Oral liquid: equivalent to 25 mg iron (as sulfate)/mL.
Tablet: equivalent to 60 mg iron.
folic acid Tablet: 1 mg; 5 mg.
hydroxocobalamin Injection: 1 mg (as acetate, as hydrochloride or as
sulfate) in 1-mL ampoule.
Complementary List
 erythropoiesis- Injection: pre-filled syringe
stimulating agents* 1000IU/ 0.5 mL; 2000IU/ 0.5 mL; 3000IU/ 0.3 mL; 4000IU/
0.4 mL; 5000IU/ 0.5 mL; 6000IU/ 0.6 mL; 8000IU/ 0.8mL;
10 000IU/ 1 mL; 20 000IU/ 0.5 mL; 40 000IU/ 1 mL
* The square box applies to epoetin alfa, beta and theta, darbepoetin
alfa, and their respective biosimilars.

 enoxaparin* Injection: ampoule or pre-filled syringe
20 mg/0.2 mL; 40 mg/0.4 mL; 60 mg/0.6 mL; 80 mg/
0.8 mL; 100 mg/1 mL; 120 mg/0.8 mL; 150 mg/1 mL
* Alternatives are limited to nadroparin and dalteparin.
phytomenadione Injection: 1 mg/mL; 10 mg/mL in ampoule.

Tablet: 10 mg.
Complementary List
desmopressin Injection: 4 micrograms/ mL (as acetate) in 1- mL ampoule.
Nasal spray: 10 micrograms (as acetate) per dose.
heparin sodium Injection: 1000 IU/mL; 5000 IU/mL in 1-mL ampoule.

protamine sulfate Injection: 10 mg/mL in 5-mL ampoule.
 warfarin Tablet: 0.5 mg; 1 mg; 2 mg; 5 mg (sodium salt).
10.3 Other medicines for haemoglobinopathies
Complementary list
deferoxamine* Powder for injection: 500 mg (mesilate) in vial.
* Deferasirox oral form may be an alternative, depending on cost
and availability.
hydroxycarbamide Solid oral dosage form: 200 mg; 500 mg; 1 g.
580
11. BLOOD PRODUCTS OF HUMAN ORIGIN AND PLASMA SUBSTITUTES

11.1 Blood and blood components
In accordance with the World Health Assembly resolution WHA63.12, WHO recognizes
that achieving self-sufficiency, unless special circumstances preclude it, in the supply of
safe blood components based on voluntary, non-remunerated blood donation, and the
security of that supply are important national goals to prevent blood shortages and
meet the transfusion requirements of the patient population. All preparations should
comply with the WHO requirements.
fresh–frozen plasma
platelets
red blood cells
whole blood
11.2 Plasma-derived medicines
All human plasma-derived medicines should comply with the WHO requirements.
11.2.1 Human immunoglobulins
anti-rabies Injection: 150 IU/ mL in vial.
immunoglobulin
anti-tetanus Injection: 500 IU in vial.
immunoglobulin
Complementary List
normal immunoglobulin Intramuscular administration: 16% protein solution.*
Intravenous administration: 5%; 10% protein solution.**
Subcutaneous administration: 15%; 16% protein solution.*
* Indicated for primary immune deficiency.
** Indicated for primary immune deficiency and Kawasaki disease.
11.2.2 Blood coagulation factors

Complementary List
 coagulation factor VIII Powder for injection: 500 IU/vial.
 coagulation factor IX Powder for injection: 500 IU/vial, 1000 IU/vial.
11.3 Plasma substitutes
 dextran 70* Injectable solution: 6%.
* Polygeline, injectable solution, 3.5% is considered as equivalent.
581
12. CARDIOVASCULAR MEDICINES

12.1 Antianginal medicines
12.2 Antiarrhythmic medicines
12.4 Medicines used in heart failure
digoxin Injection: 250 micrograms/mL in 2-mL ampoule.
Oral liquid: 50 micrograms/mL.
furosemide Injection: 10 mg/mL in 2-mL ampoule.
Tablet: 40 mg.
Complementary List
dopamine Injection: 40 mg (hydrochloride) in 5-mL vial.
12.6 Lipid-lowering agents
582
13. DERMATOLOGICAL MEDICINES (topical)

 miconazole Cream or ointment: 2% (nitrate).
terbinafine Cream: 1% or Ointment: 1% terbinafine hydrochloride.
13.2 Anti-infective medicines
mupirocin Cream (as mupirocin calcium): 2%.
Ointment: 2%.
potassium permanganate Aqueous solution: 1:10 000.
silver sulfadiazine a Cream: 1%.
a >2 months.
13.3 Anti-inflammatory and antipruritic medicines
 betamethasone a Cream or ointment: 0.1% (as valerate).
a Hydrocortisone preferred in neonates.
calamine Lotion.
hydrocortisone Cream or ointment: 1% (acetate).
13.4 Medicines affecting skin differentiation and proliferation
benzoyl peroxide Cream or lotion: 5%.
coal tar Solution: 5%.
 podophyllum resin Solution: 10% to 25%.
salicylic acid Solution: 5%.
urea Cream or ointment: 5%; 10%.
13.5 Scabicides and pediculicides
 benzyl benzoate a Lotion: 25%.
a >2 years.
permethrin Cream: 5%.
Lotion: 1%.
583
14. DIAGNOSTIC AGENTS

14.1 Ophthalmic medicines
fluorescein Eye drops: 1% (sodium salt).
 tropicamide Eye drops: 0.5%.
14.2 Radiocontrast media
Complementary List
barium sulfate Aqueous suspension.
15. DISINFECTANTS AND ANTISEPTICS
15.1 Antiseptics
 chlorhexidine Solution: 5% (digluconate).
Gel: 4%.
 ethanol Solution: 70% (denatured).
 povidone iodine Solution: 10% (equivalent to 1% available iodine).
15.2 Disinfectants
alcohol based hand rub Solution containing ethanol 80% volume /volume
Solution containing isopropyl alcohol 75% volume/
volume
 chlorine base compound Powder: (0.1% available chlorine) for solution.
 chloroxylenol Solution: 4.8%.
glutaral Solution: 2%.
16. DIURETICS
furosemide Injection: 10 mg/mL in 2-mL ampoule.

Tablet: 10 mg; 20 mg; 40 mg.
Complementary List
 hydrochlorothiazide Tablet (scored): 25 mg.
mannitol Injectable solution: 10%; 20%.
spironolactone Oral liquid: 5 mg/5 mL; 10 mg/5 mL; 25 mg/5 mL.
Tablet: 25 mg.
584
17. GASTROINTESTINAL MEDICINES

Complementary List
 pancreatic enzymes Age-appropriate formulations and doses including lipase,
protease and amylase.
17.1 Antiulcer medicines
 omeprazole Powder for oral liquid: 20-mg; 40-mg sachets.
 ranitidine Injection: 25 mg/mL (as hydrochloride) in 2-mL
ampoule.
Oral liquid: 75 mg/5 mL (as hydrochloride).
phosphate salt).
Oral liquid: 0.5 mg/5 mL; 2 mg/5 mL.
Solid oral dosage form: 0.5 mg; 0.75 mg; 1.5 mg; 4 mg.
metoclopramide a Injection: 5 mg (hydrochloride)/mL in 2-mL ampoule.
a Not in neonates.
 ondansetron a Injection: 2 mg base/mL in 2-mL ampoule
(as hydrochloride).
a >1 month.
Complementary list
aprepitant Capsule: 80 mg; 125 mg; 165 mg.
Powder for oral susupension: 125 mg in sachet.
585
17. GASTROINTESTINAL MEDICINES (continued)

17.3 Anti-inflammatory medicines
17.4 Laxatives
oral rehydration salts – zinc Co-package containing:
sulfate ORS powder for dilution (see Section 17.5.1) – zinc
sulfate solid oral dosage form 20 mg (see Section
17.5.2)
17.5.1 Oral rehydration
oral rehydration salts Powder for dilution in 200 mL; 500 mL; 1 L.
glucose: 75 mEq
sodium: 75 mEq or mmol/L
chloride: 65 mEq or mmol/L
potassium: 20 mEq or mmol/L
citrate: 10 mmol/L
osmolarity: 245 mOsm/L
glucose: 13.5 g/L
sodium chloride: 2.6 g/L
potassium chloride: 1.5 g/L
trisodium citrate dihydrate*: 2.9 g/L
* Trisodium citrate dihydrate may be replaced by sodium
hydrogen carbonate (sodium bicarbonate) 2.5 g/L. However, as
the stability of this latter formulation is very poor under tropical
conditions, it is recommended only when manufactured for
immediate use.
17.5.2 Medicines for diarrhoea

zinc sulfate* Solid oral dosage form: 20 mg.
* In acute diarrhoea, zinc sulfate should be used as an adjunct to

oral rehydration salts.
586
18. MEDICINES FOR ENDOCRINE DISORDERS

18.1 Adrenal hormones and synthetic substitutes
fludrocortisone Tablet: 100 micrograms (acetate).
hydrocortisone Tablet: 5 mg; 10 mg; 20 mg.
18.2 Androgens
18.3 Estrogens
18.4 Progestogens
18.5 Medicines for diabetes
18.5.1 Insulins
insulin injection (soluble) Injection: 100 IU/mL in 10-mL vial.
intermediate-acting insulin Injection: 100 IU/mL in 10-mL vial (as compound insulin
zinc suspension or isophane insulin).
18.5.2 Oral hypoglycaemic agents
Complementary List
metformin Tablet: 500 mg (hydrochloride).
glucagon Injection: 1 mg/mL.
Complementary List
diazoxide Oral liquid: 50 mg/mL
Tablet: 50 mg
levothyroxine Tablet: 25 micrograms; 50 micrograms;
100 micrograms (sodium salt).
Complementary List
Lugol’s solution Oral liquid: about 130 mg total iodine/mL.
 methimazole* Tablet: 5mg, 10mg, 20mg.
potassium iodide Tablet: 60 mg.

propylthiouracil* Tablet: 50 mg.
* For use in patients for whom alternative first-line treatment is not
appropriate or available.
587
19. IMMUNOLOGICALS
19.1 Diagnostic agents
All tuberculins should comply with the WHO requirements for tuberculins.
tuberculin, purified protein Injection.
derivative (PPD)
19.2 Sera and immunoglobulins
All plasma fractions should comply with the WHO requirements.
anti-venom Injection.
immunoglobulin* * Exact type to be defined locally.
diphtheria antitoxin Injection: 10 000 IU; 20 000 IU in vial.

19.3 Vaccines
WHO immunization policy recommendations are published in vaccine position papers
on the basis of recommendations made by the Strategic Advisory Group of Experts on
Immunization (SAGE).
WHO vaccine position papers are updated three to four times per year. The list
below details the vaccines for which there is a recommendation from SAGE and a
corresponding WHO position paper as at December 2018. The most recent versions of
the WHO position papers, reflecting the current evidence related to a specific vaccine
and the related recommendations, can be accessed at any time on the WHO website
at: http://www.who.int/immunization/documents/positionpapers/en/index.html.
Vaccine recommendations may be universal or conditional (e.g., in certain regions,
in some high-risk populations or as part of immunization programmes with certain
characteristics). Details are available in the relevant position papers, and in the
Summary Tables of WHO Routine Immunization Recommendations available on the
WHO website at: http://www.who.int/immunization/policy/immunization_tables/en/
index.html.
Selection of vaccines from the Model List will need to be determined by each
country after consideration of international recommendations, epidemiology and
national priorities.
All vaccines should comply with the WHO requirements for biological substances.
WHO noted the need for vaccines used in children to be polyvalent.
Recommendations for all
BCG vaccine
diphtheria vaccine
Haemophilus influenzae type b vaccine
hepatitis B vaccine
588

HPV vaccine
measles vaccine
pertussis vaccine
pneumococcal vaccine
poliomyelitis vaccine
rotavirus vaccine
rubella vaccine
tetanus vaccine
Recommendations for certain regions
Japanese encephalitis vaccine
yellow fever vaccine
tick-borne encephalitis vaccine
Recommendations for some high-risk populations
cholera vaccine
dengue vaccine
hepatitis A vaccine
meningococcal meningitis vaccine
rabies vaccine
typhoid vaccine
Recommendations for immunization programmes with certain characteristics
influenza vaccine (seasonal)
mumps vaccine
varicella vaccine
589
20. MUSCLE RELAXANTS (PERIPHERALLY-ACTING) AND CHOLINESTERASE

INHIBITORS
neostigmine Injection: 500 micrograms in 1-mL ampoule; 2.5 mg
(metilsulfate) in 1-mL ampoule.
suxamethonium Injection: 50 mg (chloride)/mL in 2-mL ampoule.
Powder for injection: (chloride), in vial.
 vecuronium Powder for injection: 10 mg (bromide) in vial.
Complementary List
pyridostigmine Injection: 1 mg in 1-mL ampoule.
21. OPHTHALMOLOGICAL PREPARATIONS
21.1 Anti-infective agents
aciclovir Ointment: 3% W/W.
azithromycin Solution (eye drops): 1.5%
erythromycin* Ointment: 0.5%
* Infections due to Chlamydia trachomatis or Neisseria gonorrhoeae.
 gentamicin Solution (eye drops): 0.3% (sulfate).

natamycin Suspension: (eye drops): 5%.
 ofloxacin Solution (eye drops): 0.3%.
 tetracycline Eye ointment: 1% (hydrochloride).
21.2 Anti-inflammatory agents
 prednisolone Solution (eye drops): 0.5% (sodium phosphate).

 tetracaine a Solution (eye drops): 0.5% (hydrochloride).
a Not in preterm neonates.
21.4 Miotics and antiglaucoma medicines
590
21. OPHTHALMOLOGICAL PREPARATIONS (continued)

21.5 Mydriatics
atropine* a Solution (eye drops): 0.1%; 0.5%; 1% (sulfate).
* Or homatropine (hydrobromide) or cyclopentolate
(hydrochloride).
a >3 months.
Complementary List
epinephrine (adrenaline) Solution (eye drops): 2% (as hydrochloride).
21.6 Anti-vascular endothelial growth factor (VEGF) preparations
22. MEDICINES FOR REPRODUCTIVE HEALTH AND PERINATAL CARE
22.1 Contraceptives
22.2 Ovulation inducers
22.3 Uterotonics
22.6 Medicines administered to the neonate
caffeine citrate Injection: 20 mg/mL (equivalent to 10 mg caffeine
base/mL).
Oral liquid: 20 mg/mL (equivalent to 10 mg caffeine
base/mL).
chlorhexidine* Solution or gel: 7.1% (digluconate) delivering 4%
chlorhexidine.
* For umbilical cord care.
Complementary List
 ibuprofen Solution for injection: 5 mg/mL.
 prostaglandin E Solution for injection:
Prostaglandin E1: 0.5 mg/mL in alcohol.
Prostaglandin E2: 1 mg/mL.
surfactant Suspension for intratracheal instillation: 25 mg/mL or
80 mg/mL.
591
23. PERITONEAL DIALYSIS SOLUTION

Complementary List
intraperitoneal dialysis Parenteral solution.
solution (of appropriate
composition)
24. MEDICINES FOR MENTAL AND BEHAVIOURAL DISORDERS
24.1 Medicines used in psychotic disorders
Complementary List
chlorpromazine Injection: 25 mg (hydrochloride)/mL in 2-mL ampoule.
Tablet: 10 mg; 25 mg; 50 mg; 100 mg (hydrochloride).
haloperidol Injection: 5 mg in 1-mL ampoule.
Solid oral dosage form: 0.5 mg; 2 mg; 5 mg.
Complementary List
a >8 years.
24.2.2 Medicines used in bipolar disorders
24.3 Medicines for anxiety disorders
24.4 Medicines used for obsessive compulsive disorders
24.5 Medicines for disorders due to psychoactive substance use
592
25. MEDICINES ACTING ON THE RESPIRATORY TRACT

25.1 Antiasthmatic medicines
 budesonide Inhalation (aerosol): 100 micrograms per dose;
200 micrograms per dose.
in 1-mL ampoule.
 salbutamol Injection: 50 micrograms (as sulfate)/mL in 5-mL
ampoule.
Metered dose inhaler (aerosol): 100 micrograms
(as sulfate) per dose.
Respirator solution for use in nebulizers: 5 mg
(as sulfate)/mL.
DISTURBANCES
26.1 Oral
oral rehydration salts See section 17.5.1.
potassium chloride Powder for solution.
26.2 Parenteral
glucose Injectable solution: 5% (isotonic); 10% (hypertonic);
50% (hypertonic).
glucose with sodium Injectable solution: 5% glucose, 0.9% sodium chloride
chloride (equivalent to Na+ 150 mmol/L and Cl- 150 mmol/L);
5% glucose, 0.45% sodium chloride (equivalent to
Na+ 75 mmol/L and Cl- 75 mmol/L).
potassium chloride Solution for dilution: 7.5% (equivalent to K+ 1 mmol/mL
and Cl- 1 mmol/mL); 15% (equivalent to K+ 2 mmol/mL
and Cl- 2 mmol/mL).
sodium chloride Injectable solution: 0.9% isotonic (equivalent to
Na+ 154 mmol/L, Cl- 154 mmol/L).
sodium hydrogen Injectable solution: 1.4% isotonic (equivalent to
carbonate Na+ 167 mmol/L, HCO3- 167 mmol/L).
Solution: 8.4% in 10-mL ampoule (equivalent to
Na+ 1000 mmol/L, HCO3-1000 mmol/L).
 sodium lactate, Injectable solution.
compound solution
593

DISTURBANCES (continued)
26.3 Miscellaneous
water for injection 2-mL; 5-mL; 10-mL ampoules.
27. VITAMINS AND MINERALS
ascorbic acid Tablet: 50 mg.
colecalciferol* Oral liquid: 400 IU/mL.
Solid oral dosage form: 400 IU; 1000 IU.
* Ergocalciferol can be used as an alternative.
iodine Capsule: 190 mg.

Iodized oil: 1 mL (480 mg iodine); 0.5 mL (240 mg
iodine) in ampoule (oral or injectable); 0.57 mL (308 mg
iodine) in dispenser bottle.
multiple micronutrient Sachets containing:
powder - iron (elemental) 12.5 mg (as coated ferrous
fumarate)
- zinc (elemental) 5 mg
- vitamin A 300 micrograms
- with or without other micronutrients at
recommended daily values
pyridoxine Tablet: 25 mg (hydrochloride).
retinol Capsule: 100 000 IU; 200 000 IU (as palmitate).
Oral oily solution: 100 000 IU (as palmitate)/mL in
multidose dispenser.
Tablet (sugar-coated): 10 000 IU (as palmitate).
Water-miscible injection: 100 000 IU (as palmitate) in

2-mL ampoule.
riboflavin Tablet: 5 mg.
sodium fluoride In any appropriate topical formulation.
thiamine Tablet: 50 mg (hydrochloride).
Complementary List
calcium gluconate Injection: 100 mg/mL in 10-mL ampoule.
594
28. EAR, NOSE AND THROAT MEDICINES

acetic acid Topical: 2%, in alcohol.
 budesonide Nasal spray: 100 micrograms per dose.
 ciprofloxacin Topical: 0.3% drops (as hydrochloride).
 xylometazoline a Nasal spray: 0.05%.
29. MEDICINES FOR DISEASES OF JOINTS
29.1 Medicines used to treat gout
29.2 Disease-modifying agents used in rheumatoid disorders (DMARDs)
Complementary List
hydroxychloroquine Solid oral dosage form: 200 mg (as sulfate).
methotrexate Tablet: 2.5 mg (as sodium salt).
acetylsalicylic acid* (acute Suppository: 50 mg to 150 mg.
or chronic use) Tablet: 100 mg to 500 mg.
* For use for rheumatic fever, juvenile arthritis, Kawasaki disease.
595
Annex 3
The Anatomical Therapeutic Chemical (ATC)
Classification System
The following list provides the corresponding Anatomical Therapeutic Chemical
(ATC) classification codes for all items on the 21st WHO Model List of Essential
Medicines and the 7th WHO Model List of Essential Medicines for Children,
sorted by ATC code number.
ATC code ATC group/medicine or item Section

A ALIMENTARY TRACT AND METABOLISM
A02 Drugs for acid related disorders

A02B Drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD)
A02BA H2-receptor antagonists
A02BA02 ranitidine 17.1
A02BC Proton pump inhibitors
A02BC01 omeprazole 17.1
A03 Drugs for functional gastrointestinal disorders

A03B Belladonna and derivatives, plain
A03BA Belladonna alkaloids, tertiary amines
A03BA01 atropine 1.3; 4.2
A03BB Belladonna alkaloids, semisynthetic, quaternary ammonium compounds
A03BB01 hyoscine butylbromide* 2.3
A03F Propulsives
A03FA Propulsives
A03FA01 metoclopramide 2.3; 17.2
A04 Antiemetics and antinauseants

A04A Antiemetics and antinauseants
A04AA Serotonin (5HT3) antagonists
A04AA01 ondansetron 2.3; 17.2
A04AD Other antiemetics
A04AD01 hyoscine hydrobromide* 2.3
A04AD12 aprepitant 17.2
597

A06 Drugs for constipation
A06A Laxatives
A06AA Softeners, emollients
A06AA02 docusate sodium 2.3
A06AB Contact laxatives
A06AB06 senna glycosides* 2.3; 17.4
A06AD Osmotically acting laxatives
A06AD11 lactulose 2.3
A07 Antidiarrheals, intestinal antiinflammatory/antiinfective agents

A07A Intestinal antiinfectives
A07AA Antibiotics
A07AA06 paromomycin 6.5.2
A07B Intestinal adsorbents
A07BA Charcoal preparations
A07BA01 medicinal charcoal* 4.1
A07C Electrolytes with carbohydrates
A07CA Oral rehydration salt formulations* 17.5; 17.5.1; 26.1
A07DA Antipropulsives
A07DA03 loperamide 2.3
A07E Intestinal antiinflammatory agents
A07EA Corticosteroids for local use
A07EA02 hydrocortisone 17.3
A07EC Aminosalicylic acid and similar agents

A07EC01 sulfasalazine 17.3; 29.2
A09 Digestives, incl. enzymes

A09A Digestives, incl. enzymes
A09AA Enzyme preparations
A09AA02 multienzymes (lipase, protease, etc.)* 17
A10 Drugs used in diabetes

A10A Insulins and analogues
A10AB Insulins and analogues for injection, fast-acting
A10AB01 insulin (human)* 18.5.1
598
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System

A10AC Insulins and analogues for injection, intermediate-acting
A10AC01 insulin (human)* 18.5.1
A10B Blood glucose lowering drugs, excl. insulins
A10BA Biguanides
A10BA02 metformin 18.5.2
A10BB Sulfonamides, urea derivatives
A10BB09 gliclazide 18.5.2
A11 Vitamins
A11C Vitamin A and D, incl. combinations of the two
A11CA Vitamin A, plain
A11CA01 retinol 27
A11CC Vitamin D and analogues
A11CC01 ergocalciferol 27
A11CC05 colecalciferol 27
A11D Vitamin B1, plain and in combination with vitamin B6 and B12
A11DA Vitamin B1, plain
A11DA01 thiamine 27
A11G Ascorbic acid (vitamin C), incl. combinations
A11GA Ascorbic acid (vitamin C), plain
A11GA01 ascorbic acid 27
A11H Other plain vitamin preparations
A11HA Other plain vitamin preparations
A11HA01 nicotinamide 27
A11HA02 pyridoxine 27
A11HA04 riboflavin 27
A12 Mineral supplements

A12A Calcium
A12AA Calcium
A12AA03 calcium gluconate 4.2; 27
A12C Other mineral supplements
A12CB Zinc
A12CB01 zinc sulfate 17.5; 17.5.2
A12CD Fluoride
A12CD01 sodium fluoride 27
599

B BLOOD AND BLOOD FORMING ORGANS
B01 Antithrombotic agents

B01A Antithrombotic agents
B01AA Vitamin K antagonists
B01AA03 warfarin 10.2
B01AB Heparin group
B01AB01 heparin 10.2
B01AB05 enoxaparin 10.2
B01AC Platelet aggregation inhibitors excl. heparin
B01AC04 clopidogrel 12.5.1
B01AC06 acetylsalicylic acid 12.5.1
B01AD Enzymes
B01AD01 streptokinase 12.5.2
B01AD02 alteplase 12.5.2
B01AE Direct thrombin inhibitors
B01AE07 dabigatran etexilate 10.2
B02 Antihemorrhagics
B02A Antifibrinolytics
B02AA Amino acids
B02AA02 tranexamic acid 10.2, 22.5
B02B Vitamin K and other hemostatics
B02BA Vitamin K
B02BA01 phytomenadione 10.2

B02BD Blood coagulation factors
B02BD01 coagulation factor IX, II, VII and X in combination* 11.2.2
B02BD02 coagulation factor VIII* 11.2.2
B03 Antianemic preparations

B03A Iron preparations 10.1
B03AA Iron bivalent, oral preparations* 10.1
B03AB Iron trivalent, oral preparations* 10.1
B03AD Iron in combination with folic acid* 10.1
B03AE Iron in other combinations*
B03AE10 various combinations* 27
600

B03B Vitamin B12 and folic acid
B03BA Vitamin B12 (cyanocobalamin and analogues)
B03BA03 hydroxocobalamin 10.1
B03BB Folic acid and derivatives
B03BB01 folic acid 10.1
B03X Other antianemic preparations
B03XA Other antianemic preparations
B03XA01 erythropoietin 10.1
B03XA02 darbepoetin alfa 10.1
B03XA03 methoxy polyethylene glycol-epoetin beta 10.1
B05 Blood substitutes and perfusion solutions

B05A Blood and related products
B05A platelet concentrates 11.1
B05A whole blood* 11.1
B05AA Blood substitutes and plasma protein fractions
B05AA05 dextran* 11.3
B05AX Other blood products
B05AX01 red blood cells* 11.1
B05AX03 fresh frozen plasma* 11.1
B05B I.V. solutions
B05BA Solutions for parenteral nutrition
B05BA03 carbohydrates* 26.2
B05BB Solutions affecting the electrolyte balance
B05BB01 electrolytes* 26.2
B05BB02 electrolytes with carbohydrates* 26.2
B05BC Solutions producing osmotic diuresis
B05BC01 mannitol 16
B05D Peritoneal dialytics
B05DA Isotonic solutions* 23
B05X I.V. solution additives
B05XA Electrolyte solutions
B05XA01 potassium chloride 26.1; 26.2
B05XA02 sodium bicarbonate* 26.2
B05XA03 sodium chloride 26.2
B05XA05 magnesium sulfate 5
601

C CARDIOVASCULAR SYSTEM
C01 Cardiac therapy

C01A Cardiac glycosides
C01AA Digitalis glycosides
C01AA05 digoxin 12.2; 12.4
C01B Antiarrhythmics, class I and III
C01BB Antiarrhythmics, class Ib
C01BB01 lidocaine 12.2
C01BD Antiarrhythmics, class III
C01BD01 amiodarone 12.2
C01C Cardiac stimulants excl. cardiac glycosides
C01CA Adrenergic and dopaminergic agents
C01CA04 dopamine 12.4
C01CA24 epinephrine (adrenaline) 3; 12.2; 25.1
C01CA26 ephedrine 1.2
C01D Vasodilators used in cardiac diseases
C01DA Organic nitrates
C01DA02 glyceryl trinitrate 12.1
C01DA08 isosorbide dinitrate 12.1
C01E Other cardiac preparations
C01EA Prostaglandins 22.6
C02 Antihypertensives
C02A Antiadrenergic agents, centrally acting
C02AB Methyldopa
C02AB01 methyldopa (levorotatory)* 12.3
C02D Arteriolar smooth muscle, agents acting on
C02DB Hydrazinophthalazine derivatives
C02DB02 hydrazaline 12.3
C02DD Nitroferricyanide derivatives
C02DD01 nitroprusside* 12.3
C03 Diuretics
C03A Low-ceiling diuretics, thiazides
C03AA Thiazides, plain
C03AA03 hydrochlorothiazide 12.3; 12.4; 16
602

C03C High-ceiling diuretics
C03CA Sulfonamides, plain
C03CA01 furosemide 12.4; 16
C03D Potassium-sparing agents
C03DA Aldosterone antagonists
C03DA01 spironolactone 12.4; 16
C03DB Other potassium-sparing agents
C03DB01 amiloride 16
C07 Beta blocking agents

C07A Beta blocking agents
C07AA Beta blocking agents, non-selective
C07AA05 propranolol 7.2
C07AB Beta blocking agents, selective
C07AB07 bisoprolol 12.1; 12.2; 12.3;
12.4
C08 Calcium channel blockers

C08C Selective calcium channel blockers with mainly vascular effects
C08CA Dihydropyridine derivatives
C08CA01 amlodipine 12.3
C08CA05 nifedipine 22.4
C08D Selective calcium channel blockers with direct cardiac effects
C08DA Phenylalkylamine derivatives
C08DA01 verapamil 12.1; 12.2
C09 Agents acting on the renin-angiotensin system

C09A ACE inhibitors, plain
C09AA ACE inhibitors, plain
C09AA02 enalapril 12.3; 12.4
C09B ACE inhibitors, combinations
C09BA ACE inhibitors and diuretics
C09BA03 lisinopril and diuretics* 12.3
C09BB ACE inhibitors and calcium channel blockers
C09BB03 lisinopril and amlodipine 12.3
603

C09C Antiotensin II receptor blockers (ARBs), plain
C09CA Antiotensin II receptor blockers (ARBs), plain
C09CA01 losartan 12.3; 12.4
C09D Antiotensin II receptor blockers (ARBs), combinations
C09DA Antiotensin II receptor blockers (ARBs) and diuretics
C09DA07 telmisartan and diuretics* 12.3
C09DB Antiotensin II receptor blockers (ARBs) and calcium channel blockers
C09DB04 telmisartan and amlodipine 12.3
C10 Lipid modifying agents

C10A Lipid modifying agents, plain
C10AA HMG CoA reductase inhibitors
C10AA01 simvastatin 12.6
D DERMATOLOGICALS
D01 Antifungals for dermatological use

D01A Antifungals for topical use
D01AA Antibiotics
D01AA01 nystatin 6.3
D01AC Imidazole and triazole derivatives
D01AC02 miconazole 13.1
D01AE Other antifungals for topical use
D01AE12 salicylic acid 13.4
D01AE13 selenium sulfide 13.1
D01B Antifungals for systemic use
D01BA Antifungals for systemic use

D01BA01 griseofulvin 6.3
D01BA02 terbinafine 13.1
D02 Emollients and protectives

D02A Emollients and protectives
D02AB Zinc products* 13.3
D02AE Carbamide products
D02AE01 carbamide* 13.4
D05 Antipsoriatics
D05A Antipsoriatics for topical use
D05AA Tars* 13.4
604

D06 Antibiotics and chemotherapeutics for dermatological use
D06A Antibiotics for topical use
D06AX Other antibiotics for topical use
D06AX09 mupirocin 13.2
D06B Chemotherapeutics for topical use
D06BA Sulfonamides
D06BA01 silver sulfadiazine 13.2
D06BB Antivirals
D06BB04 podophyllotoxin* 13.4
D07 Corticosteroids, dermatological preparations

D07A Corticosteroids, plain
D07AA Corticosteroids, weak (group I)
D07AA02 hydrocortisone 13.3
D07AC Corticosteroids, potent (group III)
D07AC01 betamethasone 13.3
D08 Antiseptics and disinfectants

D08A Antiseptics and disinfectants
D08AC Biguanides and amidines
D08AC02 chlorhexidine 15.1; 22.6
D08AE Phenol and derivatives
D08AE05 chloroxylenol 15.2
D08AG Iodine products
D08AG02 povidone-iodine 15.1
D08AG03 iodine* 6.3
D08AX Other antiseptics and disinfectants* 15
D08AX05 isopropanol* 15.2
D08AX06 potassium permanganate 13.2
D08AX08 ethanol 15.1; 15.2
D10 Anti-acne preparations

D10A Anti-acne preparations for topical use
D10AE Peroxides
D10AE01 benzoyl peroxide 13.4
605

G GENITO URINARY SYSTEM AND SEX HORMONES
G01 Gynecological antiinfectives and antiseptics

G01A Antiinfectives and antiseptics, excl. combinations with corticosteroids
G01AF Imidazole derivatives
G01AF02 clotrimazole 6.3
G02 Other gynecologicals

G02A Oxytocics
G02AB Ergot alkaloids
G02AB03 ergometrine 22.3
G02AD Prostaglandins
G02AD06 misoprostol 22.3
G02B Contraceptives for topical use
G02BA Intrauterine contraceptives
G02BA02 plastic IUD with copper* 22.1.3
G02BA03 plastic IUD with progestogen* 22.1.3
G02BB Intravaginal contraceptives
G02BB02 vaginal ring with progestogen* 22.1.6
G03 Sex hormones and modulators of the genital system

G03A Hormonal contraceptives for systemic use
G03AA Progestogens and estrogens, fixed combinations
G03AA05 norethisterone and ethinylestradiol 22.1.1
G03AA07 levonorgestrel and ethinylestradiol 22.1.1
G03AA08 medroxyprogesterone and estrogen* 22.1.2
G03AC Progestogens
G03AC01 norethisterone* 22.1.2
G03AC03 levonorgestrel 22.1.1; 22.1.5
G03AC06 medroxyprogesterone* 18.4; 22.1.2
G03AC08 etonorgestrel 22.1.5
G03AD Emergency contraceptives
G03AD01 levonorgestrel 22.1.1
G03AD02 ulipristal 22.1.1
G03B Androgens
G03BA 3-oxoandrosten (4) derivatives
G03BA03 testosterone 18.2
606

G03G Gonadotropins and other ovulation stimulants
G03GB Ovulation stimulants, synthetic
G03GB02 clomifene 22.2
G03X Other sex hormones and modulators of the genital system
G03XB Antiprogesterons
G03XB01 mifepristone 22.3
H SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX

HORMONES AND INSULINS
H01 Pituitary, hypothalamic hormones and analogues

H01B Posterior pituitary lobe hormones
H01BA Vasopressin and analogues
H01BA02 desmopressin 10.2
H01BB Oxytocin and analogues
H01BB02 oxytocin 22.3
H01BB03 carbetocin 22.3
H02 Corticosteroids for systemic use

H02A Corticosteroids for systemic use, plain
H02AA Mineralocorticoids
H02AA02 fludrocortisone 18.1
H02AB Glucocorticoids
H02AB02 dexamethasone 2.3; 3; 8.2.4;
17.2; 22.5
H02AB04 methylprednisolone 8.2.4
H02AB06 prednisolone 3; 8.2.4
H02AB09 hydrocortisone 3; 8.2.4; 18.1
H03 Thyroid therapy

H03A Thyroid preparations
H03AA Thyroid hormones
H03AA01 levothyroxine sodium* 18.7
H03B Antithyroid preparations
H03BA Thiouracils
H03BA02 propylthiouracil 18.7
H03BB Sulfur-containine imidazole derivatives
H03BB01 carbimazole* 18.7
607

H03C Iodine therapy
H03CA Iodine therapy* 18.7; 27
H04 Pancreatic hormones

H04A Glycogenolytic hormones
H04AA Glycogenolytic hormones
H04AA01 glucagon 18.6
J ANTIINFECTIVES FOR SYSTEMIC USE
J01 Antibacterials for systemic use

J01A Tetracyclines
J01AA Tetracyclines
J01AA02 doxycycline 6.2.1; 6.5.3.1;
6.5.3.2
J01B Amphenicols
J01BA Amphenicols
J01BA01 chloramphenicol 6.2.1
J01C Beta-lactam antibacterials, penicillins
J01CA Penicillins with extended spectrum
J01CA01 ampicillin 6.2.1
J01CA04 amoxicillin 6.2.1
J01CE Beta-lactamase sensitive penicillins
J01CE01 benzylpenicillin 6.2.1
J01CE02 phenoxymethylpenicillin 6.2.1
J01CE08 benzathine benzylpenicillin 6.2.1

J01CE09 procaine benzylpenicillin 6.2.1
J01CF Beta-lactamase resistant penicillins
J01CF02 cloxacillin 6.2.1
J01CR Combinations of penicillins, incl. beta-lactamase inhibitors
J01CR02 amoxicillin and beta-lactamase inhibitor* 6.2.1; 6.2.5
J01CR05 piperacillin and beta-lactamase inhibitor* 6.2.2
J01D Other beta-lactam antibacterials
J01DB First-generation cephalosporins
J01DB01 cefalexin 6.2.1
J01DB04 cefazolin 6.2.1
608

J01DC Second-generation cephalosporins
J01DC02 cefuroxime 6.2.2
J01DD Third-generation cephalosporins
J01DD01 cefotaxime 6.2.2
J01DD02 ceftazidime 6.2.2
J01DD04 ceftriaxone 6.2.2
J01DD08 cefixime 6.2.2
J01DD52 ceftazidime and beta-lactamase inhibitor* 6.2.3
J01DH Carbapenems
J01DH02 meropenem 6.2.2
J01DH52 meropenem + vaborbactam 6.2.3
J01E Sulfonamides and trimethoprim
J01EC Intermediate-acting sulfonamides
J01EC02 sulfadiazine 6.5.4
J01EE Combinations of sulfonamides and trimethoprim, incl. derivatives
J01EE01 sulfamethoxazole + trimethoprim 6.2.1; 6.5.4
J01F Macrolides, lincosamides and streptogramins
J01FA Macrolides
J01FA09 clarithromycin 6.2.2
J01FA10 azithromycin 6.2.2
J01FF Lincosamides
J01FF01 clindamycin 6.2.1
J01G Aminoglycoside antibacterials
J01GA Streptomycins
J01GA01 streptomycin 6.2.5
J01GB Other aminoglycosides
J01GB03 gentamicin 6.2.1
J01GB06 amikacin 6.2.1; 6.2.5
TBA plazomicin 6.2.3
J01M Quinolone antibacterials
J01MA Fluoroquinolones
J01MA02 ciprofloxacin 6.2.2
J01MA12 levofloxacin 6.2.5
J01MA14 moxifloxacin 6.2.5
609

J01X Other antibacterials
J01XA Glycopeptide antibacterials
J01XA01 vancomycin 6.2.2
J01XB Polymyxins
J01XB01 colistin 6.2.3
J01XB02 polymyxin B 6.2.3
J01XD Imidazole derivatives
J01XD01 metronidazole 6.2.1; 6.5.1
J01XE Nitrofuran derivatives
J01XE01 nitrofurantoin 6.2.1
J01XX Other antibacterials
J01XX01 fosfomycin 6.2.3
J01XX04 spectinomycin 6.2.1
J01XX08 linezolid 6.2.3; 6.2.5
J02 Antimycotics for systemic use

J02A Antimycotics for systemic use
J02AA Antibiotics
J02AA01 amphotericin B 6.3; 6.5.2
J02AC Triazole derivatives
J02AC01 fluconazole 6.3
J02AC02 itraconazole 6.3
J02AC03 voriconazole 6.3
J02AX Other antimycotics for systemic use
J02AX01 flucytosine 6.3
J04 Antimycobacterials
J04A Drugs for treatment of tuberculosis
J04AA Aminosalicylic acid and derivatives
J04AA01 p-aminosalicylic acid* 6.2.5
J04AB Antibiotics
J04AB01 cycloserine 6.2.5
J04AB02 rifampicin 6.2.4; 6.2.5
J04AB04 rifabutin 6.2.5
J04AB05 rifapentine 6.2.5
J04AC Hydrazides
J04AC01 isoniazid 6.2.5
610

J04AD Thiocarbamide derivatives
J04AD03 ethionamide 6.2.5
J04AD01 protionamide 6.2.5
J04AK Other drugs for treatment of tuberculosis
J04AK01 pyrazinamide 6.2.5
J04AK02 ethambutol 6.2.5
J04AK05 bedaquiline 6.2.5
J04AK06 delamanid 6.2.5
J04AM Combinations of drugs for treatment of tuberculosis*
J04AM02 rifampicin and isoniazid* 6.2.5
J04AM05 rifampicin, pyrazinamide and isoniazid* 6.2.5
J04AM06 rifampicin, pyrazinamide, ethambutol and isoniazid* 6.2.5
J04AM08 isoniazid, sulfamethoxazole, trimethoprim and pyridoxine* 6.4.2.5
J04B Drugs for treatment of lepra
J04BA Drugs for treatment of lepra
J04BA01 clofazimine 6.2.4; 6.2.5
J04BA02 dapsone 6.2.4
J05 Antivirals for systemic use

J05A Direct acting antivirals
J05AB Nucleosides and nucleotides excl. reverse transcriptase inhibitors
J05AB01 aciclovir 6.4.1
J05AB14 valganciclovir 6.4.3
J05AE Protease inhibitors
J05AE03 ritonavir 6.4.2.3
J05AE08 atazanavir 6.4.2.3
J05AE10 darunavir 6.4.2.3
J05AF Nucleoside and nucleotide reverse transcriptase inhibitors
J05AF01 zidovudine (ZDV or AZT) 6.4.2.1
J05AF05 lamivudine (3TC) 6.4.2.1
J05AF06 abacavir (ABC) 6.4.2.1
J05AF07 tenofovir disoproxil 6.4.2.1; 6.4.4.1.1
J05AF10 entecavir 6.4.4.1.1
J05AG Non-nucleoside reverse transcriptase inhibitors
J05AG01 nevirapine (NVP) 6.4.2.2
J05AG03 efavirenz (EFV or EFZ) 6.4.2.2
611

J05AH Neuraminidase inhibitors
J05AH02 oseltamivir 6.4.3
J05AP Antivirals for treatment of HCV infections
J05AP01 ribavirin 6.4.3; 6.4.4.2.3
J05AP07 daclatasvir 6.4.4.2.1
J05AP08 sofosbuvir 6.4.4.2.1
J05AP09 dasabuvir 6.4.4.2.2
J05AP51 ledipasvir + sofosbuvir 6.4.4.2.2
J05AP53 ombitasvir + paritaprevir + ritonavir 6.4.4.2.2
J05AP55 sofosbuvir + velpatasvir 6.4.4.2.1
J05AP57 glecaprevir + pibrentasvir 6.4.4.2.1
J05AR Antivirals for treatment of HIV infections, combinations
J05AR01 lamivudine + zidovudine (ZDV or AZT) 6.4.2
J05AR02 abacavir + lamivudine 6.4.2
J05AR03 tenofovir disoproxil + emtricitabine 6.4.2
J05AR05 lamivudine + nevirapine + zidovudine 6.4.2
J05AR06 emtricitabine + tenofovir disoproxil + efavirenz 6.4.2
J05AR10 lopinavir + ritonavir (LPV/r)* 6.4.2.3
J05AR11 lamivudine + tenofovir disoproxil + efavirenz 6.4.2
J05AR23 atazanavir + ritonavir 6.4.2.3
TBA dolutegravir + lamivudine + tenofovir 6.4.2
J05AX Other antivirals
J05AX08 raltegravir 6.4.2.4
J05AX12 dolutegravir 6.4.2.4
J06 Immune sera and immunoglobulins

J06A Immune sera

J06AA Immune sera
J06AA01 diphtheria antitoxin 19.2
J06AA03 snake venom antiserum* 19.2
J06B Immunoglobulins
J06BA Immunoglobulins, normal human
J06BA01 immunoglobulins, normal human, for extravascular admin* 11.2.1
J06BA02 immunoglobulins, normal human, for intravascular admin* 11.2.1
J06BB Specific immunoglobulins
J06BB01 anti-D immunoglobulin 11.2.1
J06BB02 tetanus immunoglobulin* 11.2.1
J06BB05 rabies immunoglobulin* 11.2.1
612

J07 Vaccines
J07A Bacterial vaccines
J07AE Cholera vaccines* 19.3
J07AF Diphtheria vaccines
J07AF01 diphtheria toxoid* 19.3
J07AG Hemophilus influenzae B vaccines
J07AG01 hemophilus influenzae B, purified antigen conjugated* 19.3
J07AH Meningococcal vaccines* 19.3
J07AJ Pertussis vaccines
J07AJ01 pertussis vaccine 19.3
J07AL Pneumococcal vaccines
J07AL01 pneumococcus, purified polysaccharides antigen* 19.3
J07AM Tetanus vaccines
J07AM01 tetanus toxoid* 19.3
J07AN Tuberculosis vaccines
J07AN01 tuberculosis, live attenuated* 19.3
J07AP Typhoid vaccines* 19.3
J07B Viral vaccines
J07BA Encephalitis vaccines
J07BA01 encephalitis, tick-borne, inactivated, whole virus 19.3
J07BA02 encephalitis, Japanese, inactivated, whole virus 19.3
J07BB Influenza vaccines* 19.3
J07BC Hepatitis vaccines
J07BC01 hepatitis B vaccine 19.3
J07BC02 hepatitis A vaccine 19.3
J07BD Measles vaccine*
J07BD01 measles vaccine, live attenuated* 19.3
J07BE Mumps vaccines
J07BE01 mumps vaccine, live attenuated* 19.3
J07BF Poliomyelitis vaccine 19.3
J07BG Rabies vaccine 19.3
J07BH Rota virus diarrhea vaccines* 19.3
J07BJ Rubella vaccines 19.3
J07BK Varicella zoster vaccines* 19.3
613

J07BL Yellow fever vaccines 19.3
J07BM Papillomavirus vaccines
J07BM01 papillomavirus (human types 6, 11, 16, 18)* 19.3
J07BM02 papillomavirus (human types 16, 18)* 19.3
J07BX Other viral vaccines* 19.3
J07C Bacterial and viral vaccines, combined
J07CA Bacterial and viral vaccines, combined* 19.3
L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
L01 Antineoplastic agents

L01A Alkylating agents
L01AA Nitrogen mustard analogues
L01AA01 cyclophosphamide 8.2.1
L01AA02 chlorambucil 8.2.1
L01AA03 melphalan 8.2.1
L01AA06 ifosfamide 8.2.1
L01AA09 bendamustine 8.2.1
L01AX Other alkylating agents
L01AX04 dacarbazine 8.2.1
L01B Antimetabolites
L01BA Folic acid analogues
L01BA01 methotrexate 8.2.1
L01BB Purine analogues
L01BB02 mercaptopurine 8.2.1
L01BB03 tioguanine 8.2.1

L01BB05 fludarabine 8.2.1
L01BC Pyrimidine analogues
L01BC01 cytarabine 8.2.1
L01BC02 fluorouracil 8.2.1; 13.4
L01BC05 gemcitabine 8.2.1
L01BC06 capecitabine 8.2.1
L01C Plant alkaloids and other natural products
L01CA Vinca alkaloids and analogues
L01CA01 vinblastine 8.2.1
L01CA02 vincristine 8.2.1
L01CA04 vinorelbine 8.2.1
614

L01CB Podophyllotoxin derivatives
L01CB01 etoposide 8.2.1
L01CD Taxanes
L01CD01 paclitaxel 8.2.1
L01CD02 docetaxel 8.2.1
L01D Cytotoxic antibiotics and related substances
L01DA Actinomycines
L01DA01 dactinomycin 8.2.1
L01DB Anthracyclines and related substances
L01DB01 doxorubicin 8.2.1
L01DB02 daunorubicin 8.2.1
L01DC Other cytotoxic antibiotics
L01DC01 bleomycin 8.2.1
L01X Other antineoplastic agents
L01XA Platinum compounds
L01XA01 cisplatin 8.2.1
L01XA02 carboplatin 8.2.1
L01XA03 oxaliplatin 8.2.1
L01XB Methylhydrazines
L01XB01 procarbazine 8.2.1
L01X Other antineoplastic agents
L01XC Monoclonal antibodies
L01XC02 rituximab 8.2.2
L01XC03 trastuzumab 8.2.2
L01XC07 bevacizumab 21.6
L01XC17 nivolumab 8.2.3
L01XE Protein kinase inhibitors
L01XE01 imatinib 8.2.2
L01XE03 erlotinib 8.2.2
L01XE06 dasatinib 8.2.2
L01XE08 nilotinib 8.2.2
L01XX Other antineoplastic agents
L01XX02 asparaginase 8.2.1
L01XX05 hydroxycarbamide 8.2.1; 10.3
L01XX09 miltefosine 6.5.2
L01XX14 tretinoin* 8.2.2
615

L01XX19 irinotecan 8.2.1
L01XX24 pegaspargase 8.2.1
L01XX27 arsenic trioxide 8.2.1
L01XX32 bortezomib 8.2.2
TBA realgar-Indigo naturalis formula 8.2.1
L02 Endocrine therapy

L02A Hormones and related agents
L02AE Gonadotrophin releasing hormone analogues
L02AE02 leuprorelin 8.2.4
L02B Hormone antagonists and related agents

L02BA Anti-estrogens
L02BA01 tamoxifen 8.2.4
L02BB Anti-androgens
L02BB03 bicalutamide 8.2.4
L02BG Aromatase inhibitors

L02BG03 anastrozole 8.2.4
L02BX Other hormone antagonists and related agents

L02BX03 abiraterone 8.2.4
L03 Immunostimulants
L03A Immunostimulants
L03AA Colony stimulating factors
L03AA02 filgrastim 8.2.3
L03AB Interferons
L03AB10 peginterferon alfa-2b* 6.4.4.2.3
L03AB11 peginterferon alfa-2a* 6.4.4.2.3
L04 Immunosuppressants
L04A Immunosuppressants
L04AB Tumor necrosis factor alfa (TNF-a) inhibitors
L04AB04 adalimumab 8.1
L04AD Calcineurin inhibitors

L04AD01 ciclosporin 8.1
L04AX Other immunosuppressants

L04AX01 azathioprine 8.1; 29.2
616

L04AX02 thalidomide 8.2.3
L04AX03 methotrexate 29.2
L04AX04 lenalidomide 8.2.3
M MUSCULO-SKELETAL SYSTEM
M01 Antiinflammatory and antirheumatic products

M01A Antiinflammatory and antirheumatic products, non-steroids
M01AE Propionic acid derivatives
M01AE01 ibuprofen 2.1; 7.1; 22.6
M01C Specific antirheumatic agents
M01CC Penicillamine and similar agents
M01CC01 penicillamine 4.2; 29.2
M03 Muscle relaxants

M03A Muscle relaxants, peripherally acting agents
M03AB Choline derivatives
M03AB01 suxamethonium 20
M03AC Other quaternary ammonium compounds
M03AC03 vecuronium 20
M03AC04 atracurium 20
M04 Antigout preparations

M04A Antigout preparations
M04AA Preparations inhibiting uric acid production
M04AA01 allopurinol 8.2.5; 29.1
M05 Drugs for treatment of bone diseases

M05B Drugs affecting bone structure and mineralization
M05BA Bisphosphonates
M05BA08 zoledronic acid 8.2.5
N NERVOUS SYSTEM
N01 Anesthetics
N01A Anesthetics, general
N01AB Halogenated hydrocarbons
N01AB01 halothane 1.1.1
N01AB06 isoflurane 1.1.1
617

N01AX Other general anesthetics
N01AX03 ketamine 1.1.2
N01AX10 propofol 1.1.2
N01AX13 nitrous oxide 1.1.1
N01B Anesthetics, local
N01BB Amides
N01BB01 bupivacaine 1.2
N01BB02 lidocaine 1.2
N01BB52 lidocaine, combinations* 1.2
N02 Analgesics
N02A Opioids
N02AA Natural opium alkaloids
N02AA01 morphine 1.3; 2.2
N02AB Phenylpiperidine derivatives
N02AB03 fentanyl 2.2
N02B Other analgesics and antipyretics
N02BA Salicylic acid and derivatives
N02BA01 acetylsalicylic acid 2.1; 7.1; 29.3
N02BE Anilides
N02BE01 paracetamol 2.1; 7.1
N03 Antiepileptics
N03A Antiepileptics
N03AA Barbiturates and derivatives
N03AA02 phenobarbital 5
N03AB Hydantoin derivatives
N03AB02 phenytoin 5
N03AD Succinimide derivatives
N03AD01 ethosuximide 5
N03AF Carboxamide derivatives
N03AF01 carbamazepine 5; 24.2.2
N03AG Fatty acid derivatives
N03AG01 valproic acid 5; 24.2.2
N03AX Other antiepileptics
N03AX09 lamotrigine 5
618

N04 Anti-parkinson drugs
N04A Anticholinergic agents
N04AA Tertiary amines
N04AA02 biperiden 9
N04B Dopaminergic agents
N04BA Dopa and dopa derivatives
N04BA02 levodopa and decarboxylase inhibitor* 9
N05 Psycholeptics
N05A Antipsychotics
N05AA Phenothiazines with aliphatic side-chain
N05AA01 chlorpromazine 24.1
N05AB Phenothiazines with piperazine structure
N05AB02 fluphenazine 24.1
N05AH Diazepines, oxazepines, thiazepines and oxepines
N05AH02 clozapine 24.1
N05AD Butyrophenone derivatives
N05AD01 haloperidol 2.3; 24.1
N05AN Lithium
N05AN01 lithium* 24.2.2
N05AX Other antipsychotics
N05AX08 risperidone 24.1
N05B Anxiolytics
N05BA Benzodiazepine derivatives
N05BA01 diazepam 2.3; 5; 24.3
N05BA06 lorazepam 5
N05C Hypnotics and sedatives
N05CD Benzodiazepine derivatives
N05CD08 midazolam 1.3; 2.3; 5
N06 Psychoanaleptics
N06A Antidepressants
N06AA Non-selective monoamine reuptake inhibitors
N06AA04 clomipramine 24.4
N06AA09 amitriptyline 2.3; 24.2.1
619

N06AB Selective serotonin reuptake inhibitors
N06AB03 fluoxetine 2.3; 24.2.1
N06B Psychostimulants, agents used for ADHD and nootropics
N06BC Xanthine derivatives
N06BC01 caffeine citrate 22.6
N07 Other nervous system drugs

N07A Parasympathomimetics
N07AA Anticholinesterases
N07AA01 neostigmine 20
N07AA02 pyridostigmine 20
N07B Drugs used in addictive disorders
N07BA Drugs used in nicotine dependence
N07BA01 nicotine* 24.5
N07BC Drugs used in opioid dependence
N07BC02 methadone 2.2; 24.5
P ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS
P01 Antiprotozoals
P01A Agents against amoebiasis and other protozoal diseases
P01AB Nitroimidazole derivatives
P01AB01 metronidazole 6.5.1
P01AC Dichloroacetamide derivatives
P01AC01 diloxanide 6.5.1
P01B Antimalarials
P01BA Aminoquinolines
P01BA01 chloroquine 6.5.3.1; 6.5.3.2;
29.2
P01BA02 hydroxychloroquine 29.2
P01BA03 primaquine 6.5.3.1
P01BA06 amodiaquine 6.5.3.1
P01BB Biguanides
P01BB01 proguanil 6.5.3.2
P01BC Methanolquinolines
P01BC01 quinine 6.5.3.1
P01BC02 mefloquine 6.5.3.1; 6.5.3.2
620

P01BD Diaminopyrimidines
P01BD01 pyrimethamine 6.5.4
P01BD51 pyrimethamine, combinations* 6.5.3.1; 6.5.3.2
P01BE Artemisinin and derivatives
P01BE02 artemether 6.5.3.1
P01BE03 artesunate 6.5.3.1
P01BF01 artemether and lumefantrine 6.5.3.1
P01BF02 artesunate and mefloquine 6.5.3.1
P01BF03 artesunate and amodiaquine 6.5.3.1
P01BF05 artenimol and piperaquine 6.5.3.1
P01BF06 artesunate and pyronaridine 6.5.3.1
P01C Agents against leishmaniasis and trypanosomiasis
P01CA Nitroimidazole derivatives
P01CA02 benznidazole 6.5.5.2
P01CA03 fexinidazole 6.5.5.1
P01CB Antimony compounds
P01CB01 meglumine antimoniate 6.5.2
P01CB02 sodium stibogluconate 6.5.2
P01CC Nitrofuran derivatives
P01CC01 nifurtimox 6.5.5.1;
6.5.5.2
P01CD Arsenic compounds
P01CD01 melarsoprol 6.5.5.1
P01CX Other agents against leishmaniasis and trypanosomiasis
P01CX01 pentamidine isethionate* 6.5.4; 6.5.5.1
P01CX02 suramin sodium 6.5.5.1
P01CX03 eflornithine 6.5.5.1
P02 Anthelmintics
P02B Antitrematodals
P02BA Quinoline derivatives and related substances
P02BA01 praziquantel 6.1.1; 6.1.3
P02BA02 oxamniquine 6.1.3
P02BX Other antitrematodal agents
P02BX04 triclabendazole 6.1.3
621

P02C Antinematodal agents
P02CA Benzimidazole derivatives
P02CA01 mebendazole 6.1.1
P02CA03 albendazole 6.1.1; 6.1.2
P02CB Piperazine and derivatives
P02CB02 diethylcarbamazine 6.1.2
P02CC Tetrahydropyrimidine derivatives
P02CC01 pyrantel 6.1.1
P02CE Imidazothiazole derivatives
P02CE01 levamisole 6.1.1
P02CF Avermectines
P02CF01 ivermectin 6.1.1; 6.1.2; 6.6
P02D Anticestodals
P02DA Salicylic acid derivatives
P02DA01 niclosamide 6.1.1
P03 Ectoparasiticides, incl. scabicides, insecticides and repellents

P03A Ectoparasiticides, incl. scabicides
P03AC Pyrethrines, incl. synthetic compounds
P03AC04 permethrin 13.5
P03AX Other ectoparasiticides, incl. scabicides
P03AX01 benzyl benzoate 13.5
R RESPIRATORY SYSTEM
R01 Nasal preparations

R01A Decongestants and other nasal preparations for topical use
R01AA Sympathomimetics, plain
R01AA07 xylometazoline 28
R01AD Corticosteroids
R01AD05 budesonide 28
R03 Drugs for obstructive airway diseases

R03A Adrenergics, inhalants
R03AC Selective beta-2-adrenoreceptor agonists
R03AC02 salbutamol 25.1
622

R03AK Adrenergics in combination with corticosteroids or other drugs,
excl. anticholinergics
R03AK07 formoterol and budesonide 25.1
R03B Other drugs for obstructive airway diseases, inhalants
R03BA Glucocorticoids
R03BA01 beclometasone 25.1
R03BA02 budesonide 25.1
R03BB Anticholinergics
R03BB01 ipratropium bromide 25.1
R03BB04 tiotropium 25.1
R03C Adrenergics for systemic use
R03CC Selective beta-2-adrenoreceptor agonists
R03CC02 salbutamol 25.1
R05 Cough and cold preparations

R05D Cough suppressants, excl. combinations with expectorants
R05DA Opium alkaloids and derivatives
R05DA04 codeine 2.2
R06 Antihistamines for systemic use

R06A Antihistamines for systemic use
R06AE Piperazine derivatives
R06AE3 cyclizine 2.3
R06AX Other antihistamines for systemic use
R06AX13 loratadine 3
R07 Other respiratory system products

R07A Other respiratory system products
R07AA Lung surfactants 22.6
S SENSORY ORGANS
S01 Ophthalmologicals
S01A Antiinfectives
S01AA Antibiotics
S01AA09 tetracycline 21.1
S01AA10 natamycin 21.1
S01AA11 gentamicin 21.1
623

S01AA17 erythromycin 21.1
S01AA26 azithromycin 21.1
S01AD Antivirals
S01AD03 aciclovir 21.1
S01AE Fluoroquinolones
S01AE01 ofloxacin 21.1
S01B Antiinflammatory agents
S01BA Corticosteroids, plain
S01BA04 prednisolone 21.2
S01E Antiglaucoma preparations and miotics
S01EA Sympathomimetics in glaucoma therapy
S01EA01 epinephrine 21.5
S01EB Parasympathomimetics
S01EB01 pilocarpine 21.4
S01EC Carbonic anhydrase inhibitors
S01EC01 acetazolamide 21.4
S01ED Beta blocking agents
S01ED01 timolol 21.4
S01EE Prostaglandin analogues
S01EE01 latanoprost 21.4
S01F Mydriatics and cycloplegics
S01FA Anticholinergics
S01FA01 atropine 21.5
S01FA06 tropicamide 14.1
S01H Local anesthetics

S01HA Local anesthetics
S01HA03 tetracaine 21.3
S01J Diagnostic agents
S01JA Colouring agents
S01JA01 fluorescein 14.1
S02 Otologicals
S02A Antiinfectives
S02AA Antiinfectives
S02AA10 acetic acid 28
S02AA15 ciprofloxacin 28
624

V VARIOUS
V03 All other therapeutic products

V03A All other therapeutic products
V03AB Antidotes
V03AB03 edetates* 4.2
V03AB06 thiosulfate* 4.2; 13.1
V03AB08 sodium nitrite 4.2
V03AB09 dimercaprol 4.2
V03AB14 protamine* 10.2
V03AB15 naloxone 4.2
V03AB17 methylthioninium chloride (methylene blue) 4.2
V03AB23 acetylcysteine 4.2
V03AB31 potassium ferric hexacyanoferrate (II) ·2H2O (Prussian blue) 4.2
V03AB34 fomepizole 4.2
V03AC Iron chelating agents
V03AC01 deferoxamine 4.2; 10.3
V03AF Detoxifying agents for antineoplastic treatment
V03AF01 mesna 8.2.5
V03AF03 calcium folinate 8.2.1
V03AH Drugs for treatment of hypoglycaemia
V03AH01 diazoxide 18.6
V03AN Medical gases
V03AN01 oxygen 1.1.1; 1.4
V04 Diagnostic agents

V04C Other diagnostic agents
V04CF Tuberculosis diagnostics
V04CF01 tuberculin, purified protein derivative (PPD) - BCG* 19.1
V07 All other non-therapeutic products

V07A All other non-therapeutic products
V07AB Solvents and diluting agents, incl. irrigating solutions* 26.3
V07AB Water for Injection 26.3
V07AV Technical disinfectants* 15.2
V08 Contrast media
V08A X-ray contrast media, iodinated
V08AA Watersoluble, nephrotropic, high osmolar X-ray contrast media
V08AA01 diatrizoic acid* 14.2
625

V08AB Watersoluble, nephrotropic, low osmolar X-ray contrast media
V08AB02 iohexol 14.2
V08AC Watersoluble, hepatotropic X-ray contrast media
V08AC02 iotroxic acid* 14.2
V08B X-ray contrast media, non-iodinated
V08BA Barium sulfate containing X-ray contrast media
V08BA01 barium sulfate with suspending agents* 14.2
* Medicine or item name differs slightly from the name used.

626
Annex 4
Alphabetical list of essential medicines (with ATC
classification code numbers)
Medicine or item as in EML ATC code Section

abacavir (ABC) J05AF06 6.4.2.1
abacavir + lamivudine J05AR02 6.4.2
abiraterone L02BX03 8.2.4
acetazolamide S01EC01 21.4
acetic acid S02AA10 28
acetylcysteine V03AB23 4.2
acetylsalicylic acid B01AC06 12.5.1
acetylsalicylic acid N02BA01 2.1; 7.1; 29.3
aciclovir J05AB01 6.4.1
aciclovir S01AD03 21.1
adalimumab L04AB04 8.1
albendazole P02CA03 6.1.1; 6.1.2
allopurinol M04AA01 8.2.5; 29.1
alteplase B01AD02 12.5.2
amikacin J01GB06 6.2.1; 6.2.5
amiloride C03DB01 16
amiodarone C01BD01 12.2
amitriptyline N06AA09 2.3; 24.2.1
amlodipine C08CA01 12.3
amodiaquine P01BA06 6.5.3.1
amoxicillin J01CA04 6.2.1
amoxicillin and enzyme inhibitor* J01CR02 6.2.1; 6.2.5
amphotericin B J02AA01 6.3; 6.5.2
ampicillin J01CA01 6.2.1
anastrozole L02BG03 8.2.4
anti-D immunoglobulin J06BB01 11.2.1
aprepitant A04AD12 17.2
arsenic trioxide L01XX27 8.2.1
artemether P01BE02 6.5.3.1
artemether and lumefantrine P01BF01 6.5.3.1
artenimol and piperaquine P01BF05 6.5.3.1
artesunate P01BE03 6.5.3.1
artesunate and amodiaquine P01BF03 6.5.3.1
627

artesunate and mefloquine P01BF02 6.5.3.1
artesunate and pyronaridine P01BF06 6.5.3.1
ascorbic acid A11GA01 27
asparaginase L01XX02 8.2.1
atazanavir J05AE08 6.4.2.3
atazanavir + ritonavir J05AR23 6.4.2.3
atracurium M03AC04 20
atropine A03BA01 1.3; 4.2
atropine S01FA01 21.5
azathioprine L04AX01 8.1; 29.2
azithromycin J01FA10 6.2.2; 21.1
bacterial and viral vaccines, combined* J07CA 19.3

barium sulfate with suspending agents* V08BA01 14.2
beclometasone R03BA01 25.1
bedaquiline J04AK05 6.2.5
bendamustine L01AA09 8.2.1
benzathine benzylpenicillin J01CE08 6.2.1
benznidazole P01CA02 6.5.5.2
benzoyl peroxide D10AE01 13.4
benzyl benzoate P03AX01 13.5
benzylpenicillin J01CE01 6.2.1
betamethasone D07AC01 13.3
bevacizumab L01XC07 21.6
bicalutamide L02BB03 8.2.4
biperiden N04AA02 9
bisoprolol C07AB07 12.1; 12.2; 12.3; 12.4
bleomycin L01DC01 8.2.1

bortezomib L01XX32 8.2.2
budesonide R03BA02 25.1
budesonide R01AD05 28
budesonide and formoterol R03AK07 25.1
bupivacaine N01BB01 1.2
caffeine citrate N06BC01 22.6

calcium folinate V03AF03 8.2.1
calcium gluconate A12AA03 4.2; 27
capecitabine L01BC06 8.2.1
carbamazepine N03AF01 5; 24.2.2
carbamide* D02AE01 13.4
628
Annex 4: Alphabetical list of essential medicines (with ATC classification code numbers)

carbetocin H01BB03 22.3
carbimazole* H03BB01 18.7
carbohydrates* B05BA03 26.2
carboplatin L01XA02 8.2.1
cefalexin J01DB01 6.2.1
cefazolin J01DB04 6.2.1
cefixime J01DD08 6.2.2
cefotaxime J01DD01 6.2.2
ceftazidime J01DD02 6.2.2
ceftazidime and beta-lactamase inhibitor* J01DD52 6.2.3
ceftriaxone J01DD04 6.2.2
cefuroxime J01DC02 6.2.2
chlorambucil L01AA02 8.2.1
chloramphenicol J01BA01 6.2.1
chlorhexidine D08AC02 15.1; 22.6
chloroquine P01BA01 6.5.3.1; 6.5.3.2; 29.2
chloroxylenol D08AE05 15.2
chlorpromazine N05AA01 24.1
cholera vaccines* J07AE 19.3
ciclosporin L04AD01 8.1
ciprofloxacin J01MA02 6.2.2
ciprofloxacin S02AA15 28
cisplatin L01XA01 8.2.1
clarithromycin J01FA09 6.2.2
clindamycin J01FF01 6.2.1
clofazimine J04BA01 6.2.4; 6.2.5
clomifene G03GB02 22.2
clomipramine N06AA04 24.4
clopidogrel B01AC04 12.5.1
clotrimazole G01AF02 6.3
cloxacillin J01CF02 6.2.1
clozapine N05AH02 24.1
coagulation factor IX, II, VII and X in B02BD01 11.2.2
combination*
coagulation factor VIII* B02BD02 11.2.2
codeine R05DA04 2.2
colecalciferol A11CC05 27
colistin J01XB01 6.2.3
Combinations of drugs for treatment of J04AM 6.2.5
tuberculosis*
629

cyclizine R06AE3 2.3
cyclophosphamide L01AA01 8.2.1
cycloserine J04AB01 6.2.5
cytarabine L01BC01 8.2.1
dabigatran etexilate* B01AE07 10.2

dacarbazine L01AX04 8.2.1
daclatasvir J05AX14 6.4.4.2.1
dactinomycin L01DA01 8.2.1
dapsone J04BA02 6.2.4
darbepoetin alfa B03XA02 10.1
darunavir J05AE10 6.4.2.3
dasabuvir J05AX16 6.4.4.2.2
dasatinib L01XE06 8.2.2
daunorubicin L01DB02 8.2.1
deferoxamine V03AC01 4.2; 10.3
delamanid J04AK06 6.2.5
desmopressin H01BA02 10.2
dexamethasone H02AB02 2.3; 3; 8.2.4; 17.2;
22.5
dextran* B05AA05 11.3
diatrizoic acid* V08AA01 14.2
diazepam N05BA01 2.3; 5; 24.3
diazoxide V03AH01 18.6
diethylcarbamazine P02CB02 6.1.2
digoxin C01AA05 12.2; 12.4
diloxanide P01AC01 6.5.1
dimercaprol V03AB09 4.2

diphtheria antitoxin J06AA01 19.2
diphtheria toxoid* J07AF01 19.3
docetaxel L01CD02 8.2.1
docusate sodium A06AA02 2.3
dolutegravir J05AX12 6.4.2.4
dolutegravir + lamivudine + tenofovir TBA 6.4.2
dopamine C01CA04 12.4
doxorubicin L01DB01 8.2.1
doxycycline J01AA02 6.2.1; 6.5.3.1; 6.5.3.2
edetates* V03AB03 4.2

efavirenz (EFV or EFZ) J05AG03 6.4.2.2
630

efavirenz + emtricitabine + tenofovir J05AR06 6.4.2
disoproxil
efavirenz + lamivudine + tenofovir disoproxil J05AR11 6.4.2
eflornithine P01CX03 6.5.5.1
electrolytes with carbohydrates* B05BB02 26.2
electrolytes* B05BB01 26.2
emtricitabine + tenofovir disoproxil J05AR03 6.4.2
enalapril C09AA02 12.3; 12.4
encephalitis, Japanese, inactivated, J07BA02 19.3
whole virus*
encephalitis, tick-borne, inactivated, J07BA01 19.3
whole virus*
enoxaparin B01AB05 10.2
entecavir J05AF10 6.4.4.1.1
ephedrine C01CA26 1.2
epinephrine S01EA01 21.5
epinephrine (adrenaline) C01CA24 3; 12.2; 25.1
ergocalciferol A11CC01 27
ergometrine G02AB03 22.3
erlotinib L01XE03 8.2.2
erythromycin S01AA17 21.1
erythropoietin* B03SA01 10.1
ethambutol J04AK02 6.2.5
ethanol D08AX08 15.1; 15.2
ethionamide J04AD03 6.2.5
ethosuximide N03AD01 5
etonorgestrel G03AC08 22.1.5
etoposide L01CB01 8.2.1
fentanyl N02AB03 2.2

fexinidazole P01CA03 6.5.5.1
filgrastim L03AA02 8.2.3
fluconazole J02AC01 6.3
flucytosine J02AX01 6.3
fludarabine L01BB05 8.2.1
fludrocortisone H02AA02 18.1
fluorescein S01JA01 14.1
fluorouracil L01BC02 8.2.1; 13.4
fluoxetine N06AB03 2.3; 24.2.1
fluphenazine N05AB02 24.1
631

folic acid B03BB01 10.1
fomepizole V03AB34 4.2
fosfomycin J01XX01 6.2.3
fresh frozen plasma* B05AX03 11.1
furosemide C03CA01 12.4; 16
gemcitabine L01BC05 8.2.1

gentamicin J01GB03 6.2.1
gentamicin S01AA11 21.1
glecaprevir + pibrentasvir J05AP57 6.4.4.2.1
gliclazide A10BB09 18.5.2
glucagon H04AA01 18.6
glucose* B05BA03 26.2
glyceryl trinitrate C01DA02 12.1
griseofulvin D01BA01 6.3
haloperidol N05AD01 2.3; 24.1

halothane N01AB01 1.1.1
hemophilus influenzae B, purified antigen J07AG01 19.3
conjugated*
heparin* B01AB01 10.2
hepatitis A vaccine J07BC02 19.3
hepatitis B vaccine J07BC01 19.3
hydrazaline C02DB02 12.3
hydrochlorothiazide C03AA03 12.3; 12.4; 16
hydrocortisone A07EA02 17.3
hydrocortisone D07AA02 13.3
hydrocortisone H02AB09 3; 8.2.4; 18.1
hydroxocobalamin B03BA03 10.1

hydroxycarbamide L01XX05 8.2.1; 10.3
hydroxychloroquine P01BA02 29.2
hyoscine butylbromide* A03BB01 2.3
hyoscine hydrobromide* A04AD01 2.3
ibuprofen M01AE01 2.1; 7.1; 22.6

ifosfamide L01AA06 8.2.1
imatinib L01XE01 8.2.2
immunoglobulins, normal human, for J06BA01 11.2.1
extravascular admin*
immunoglobulins, normal human, for J06BA02 11.2.1
intravascular admin*
632

influenza vaccine J07BB 19.3
insulin (human)* A10AB01 18.5.1
insulin (human)* A10AC01 18.5.1
Iodine therapy* H03CA 18.7; 27
iodine* D08AG03 6.3
iohexol V08AB02 14.2
iotroxic acid* V08AC02 14.2
ipratropium bromide R03BB01 25.1
irinotecan L01XX19 8.2.1
Iron in combination with folic acid* B03AD 10.1
Iron preparations* B03A 10.1
isoflurane N01AB06 1.1.1
isoniazid J04AC01 6.2.5
isoniazid, sulfamethoxazole, trimethoprim J04AM08 6.4.2.5
and pyridoxine*
isopropanol* D08AX05 15.2
isosorbide dinitrate C01DA08 12.1
Isotonic solutions* B05DA 23
itraconazole J02AC02 6.3
ivermectin P02CF01 6.1.1; 6.1.2; 6.6
ketamine N01AX03 1.1.2
lactulose A06AD11 2.3

lamivudine (3TC) J05AF05 6.4.2.1
lamivudine + nevirapine + zidovudine J05AR05 6.4.2
lamivudine + zidovudine (ZDV or AZT) J05AR01 6.4.2
lamotrigine N03AX09 5
latanoprost S01EE01 21.4
ledipasvir + sofosbuvir J05AX65 6.4.4.2.2
lenalidomide L04AX04 8.2.3
leuprorelin L02AE02 8.2.4
levamisole P02CE01 6.1.1
levodopa and decarboxylase inhibitor* N04BA02 9
levofloxacin J01MA12 6.2.5
levonorgestrel G03AC03 22.1.1; 22.1.5
levonorgestrel G03AD01 22.1.1
levonorgestrel and ethinylestradiol G03AA07 22.1.1
levothyroxine sodium* H03AA01 18.7
lidocaine C01BB01 12.2
633

lidocaine N01BB02 1.2
lidocaine, combinations* N01BB52 1.2
linezolid J01XX08 6.2.3; 6.2.5
lisinopril and amodipine C09BB03 12.3
lisinopril and diuretics* C09BA03 12.3
lithium* N05AN01 24.2.2
loperamide A07DA03 2.3
lopinavir + ritonavir (LPV/r)* J05AR10 6.4.2.3
loratadine R06AX13 3
lorazepam N05BA06 5
losartan C09CA01 12.3; 12.4
Lung surfactants R07AA 22.6
magnesium sulfate B05XA05 5

mannitol B05BC01 16
measles vaccine, live attenuated* J07BD01 19.3
mebendazole P02CA01 6.1.1
medicinal charcoal* A07BA01 4.1
medroxyprogesterone and estrogen* G03AA08 22.1.2
medroxyprogesterone* G03AC06 18.4; 22.1.2
mefloquine P01BC02 6.5.3.1; 6.5.3.2
meglumine antimoniate P01CB01 6.5.2
melarsoprol P01CD01 6.5.5.1
melphalan L01AA03 8.2.1
meningococcal vaccines* J07AH 19.3
mercaptopurine L01BB02 8.2.1
meropenem J01DH02 6.2.2; 6.2.5
meropenem + vaborbactam J01DH52 6.2.3

mesna V03AF01 8.2.5
metformin A10BA02 18.5.2
methadone N07BC02 2.2; 24.5
methotrexate L01BA01 8.2.1; 29.2
methoxy polyethylene glycol-epoetin beta B03AX03 10.1
methyldopa (levorotatory)* C02AB01 12.3
methylprednisolone H02AB04 8.2.4
methylthioninium chloride (methylene blue) V03AB17 4.2
metoclopramide A03FA01 2.3; 17.2
metronidazole J01XD01 6.2.1
metronidazole P01AB01 6.5.1
miconazole D01AC02 13.1
634

midazolam N05CD08 1.3; 2.3; 5
mifepristone G03XB01 22.3
miltefosine L01XX09 6.5.2
misoprostol G02AD06 22.3
morphine N02AA01 1.3; 2.2
moxifloxacin J01MA14 6.2.5
multienzymes (lipase, protease, etc.)* A09AA02 17
multiple micronutrient powders B03AE10 27
mumps vaccine, live attenuated* J07BE01 19.3
mupirocin D06AX09 13.2
naloxone V03AB15 4.2

natamycin S01AA10 21.1
neostigmine N07AA01 20
nevirapine (NVP) J05AG01 6.4.2.2
niclosamide P02DA01 6.1.1
nicotinamide A11HA01 27
nicotine* N07BA01 24.5
nifedipine C08CA05 22.4
nifurtimox P01CC01 6.5.5.1; 6.5.5.2
nilotinib L01XE08 8.2.2
nitrofurantoin J01XE01 6.2.1
nitroprusside* C02DD01 12.3
nitrous oxide N01AX13 1.1.1
nivolumab L01XC17 8.2.3
norethisterone and ethinylestradiol G03AA05 22.1.1
norethisterone* G03AC01 22.1.2
nystatin D01AA01 6.3
ofloxacin S01AE01 21.1

ombitasvir + paritaprevir + ritonavir J05AX66 6.4.4.2.2
omeprazole A02BC01 17.1
ondansetron A04AA01 2.3; 17.2
oral rehydration salt formulations* A07CA 17.5.1; 26.1
oseltamivir J05AH02 6.4.3
oxaliplatin L01XA03 8.2.1
oxamniquine P02BA02 6.1.3
oxygen V03AN01 1.1.1; 1.4
oxytocin H01BB02 22.3
p-aminosalicylic acid* J04AA01 6.2.5

paclitaxel L01CD01 8.2.1
635

paracetamol N02BE01 2.1; 7.1
paromomycin A07AA06 6.5.2
pegaspargase L01XX24 8.2.1
peginterferon alfa-2a* L03AB11 6.4.4.2.3
peginterferon alfa-2b* L03AB10 6.4.4.2.3
penicillamine M01CC01 4.2; 29.2
pentamidine isethionate* P01CX01 6.5.4; 6.5.5.1
permethrin P03AC04 13.5
pertussis vaccine J07AJ01 19.3
phenobarbital N03AA02 5
phenoxymethylpenicillin J01CE02 6.2.1
phenytoin N03AB02 5
phytomenadione B02BA01 10.2
pilocarpine S01EB01 21.4
piperacillin and enzyme inhibitor* J01CR05 6.2.2
plastic IUD with copper* G02BA02 22.1.3
plastic IUD with progestogen* G02BA03 22.1.3
platelet concentrates B05A 11.1
plazomicin TBA 6.2.3
pneumococcus, purified polysaccharides J07AL01 19.3
antigen*
podophyllotoxin* D06BB04 13.4
poliomyelitis vaccine J07BF 19.3
polymyxin B J01XB02 6.2.3
potassium chloride B05XA01 26.1; 26.2
potassium ferric hexacyanoferrate (II) ·2H2O V03AB31 4.2
(Prussian blue)
potassium permanganate D08AX06 13.2

povidone-iodine* D08AG02 15.1
praziquantel P02BA01 6.1.1; 6.1.3
prednisolone H02AB06 3; 8.2.4
prednisolone S01BA04 21.2
primaquine P01BA03 6.5.3.1
procaine benzylpenicillin J01CE09 6.2.1
procarbazine L01XB01 8.2.1
proguanil P01BB01 6.5.3.2
propofol N01AX10 1.1.2
propranolol C07AA05 7.2
propylthiouracil H03BA02 18.7
prostaglandins* C01EA 22.6
636

protamine* V03AB14 10.2
pyrantel P02CC01 6.1.1
pyrazinamide J04AK01 6.2.5
pyridostigmine N07AA02 20
pyridoxine A11HA02 27
pyrimethamine P01BD01 6.5.4
pyrimethamine, combinations* P01BD51 6.5.3.1; 6.5.3.2
quinine P01BC01 6.5.3.1
rabies immunoglobulin J06BB05 11.2.1

rabies vaccine J07BG 19.3
raltegravir J05AX08 6.4.2.4
ranitidine A02BA02 17.1
realgar-Indigo naturalis formula TBA 8.2.1
red blood cells* B05AX01 11.1
retinol A11CA01 27
ribavirin J05AB04 6.4.3; 6.4.4.2.3
riboflavin A11HA04 27
rifabutin J04AB04 6.2.5
rifampicin J04AB02 6.2.4; 6.2.5
rifampicin and isoniazid* J04AM02 6.2.5
rifampicin, pyrazinamide and isoniazid* J04AM05 6.2.5
rifampicin, pyrazinamide, ethambutol and J04AM06 6.2.5
isoniazid*
rifapentine J04AB05 6.2.5
risperidone N05AX08 24.1
ritonavir (r) J05AE03 6.4.2.3
rituximab L01XC02 8.2.2
rota virus diarrhea vaccines* J07BH 19.3
rubella vaccines J07BJ 19.3
salbutamol R03CC02 25.1

salicylic acid D01AE12 13.4
selenium sulfide D01AE13 13.1
senna glycosides* A06AB06 2.3; 17.4
silver sulfadiazine D06BA01 13.2
simvastatin C10AA01 12.6
snake venom antiserum* J06AA03 19.2
sodium bicarbonate* B05XA02 26.2
sodium chloride B05XA03 26.2
637

sodium fluoride A12CD01 27
sodium nitrite V03AB08 4.2
sodium stibogluconate P01CB02 6.5.2
sofosbuvir J05AX15 6.4.4.2.1
sofosbuvir + velpatasvir J05AX69 6.4.4.2.1
Solvents and diluting agents, incl. irrigating V07AB 26.3
solutions*
spectinomycin J01XX04 6.2.1
spironolactone C03DA01 12.4; 16
streptokinase B01AD01 12.5.2
streptomycin J01GA01 6.2.5
sulfadiazine J01EC02 6.5.4
sulfamethoxazole + trimethoprim J01EE01 6.2.1; 6.5.4
sulfasalazine A07EC01 17.3; 29.2
suramin sodium P01CX02 6.5.5.1
suxamethonium M03AB01 20
tamoxifen L02BA01 8.2.4

tars* D05AA 13.4
Technical disinfectants* V07AV 15.2
telmisartan and amlodipine C09DB04 12.3
telmisartan and diuretics* C09DA07 12.3
tenofovir disoproxil fumarate J05AF07 6.4.2.1; 6.4.4.1.1
terbinafine D01BA02 13.1
testosterone G03BA03 18.2
tetanus immunoglobulin* J06BB02 11.2.1
tetanus toxoid* J07AM01 19.3
tetracaine S01HA03 21.3

tetracycline S01AA09 21.1
thalidomide L04AX02 8.2.3
thiamine A11DA01 27
thiosulfate* V03AB06 4.2; 13.1
timolol S01ED01 21.4
tioguanine L01BB03 8.2.1
tiotropium R03BB04 25.1
tranexamic acid B02AA02 10.2; 22.5
trastuzumab L01XC03 8.2.2
tretinoin* L01XX14 8.2.2
triclabendazole P02BX04 6.1.3
tropicamide S01FA06 14.1
638

tuberculin, purified protein derivative V04CF01 19.1
(PPD) - BCG*
tuberculosis, live attenuated* J07AN01 19.3
typhoid vaccine J07AP 19.3
ulipristal G03AD02 22.1.1
vaginal ring with progestogen* G02BB02 22.1.6

valganciclovir J05AB14 6.4.3
valproic acid N03AG01 5; 24.2.2
vancomycin J01XA01 6.2.2
varicella zoster vaccines* J07BK 19.3
vecuronium M03AC03 20
verapamil C08DA01 12.1; 12.2
vinblastine L01CA01 8.2.1
vincristine L01CA02 8.2.1
vinorelbine L01CA04 8.2.1
voriconazole J02AC03 6.3
warfarin B01AA03 10.2

Water for Injection V07AB 26.3
whole blood* B05A 11.1
xylometazoline R01AA07 28
yellow fever vaccines J07BL 19.3
zidovudine (ZDV or AZT) J05AF01 6.4.2.1

Zinc products* D02AB 13.3
zinc sulfate A12CB01 17.5.2
zoledronic acid M05BA08 8.2.5
* Medicine or item name differs slightly from the name used.

639
SELECTED WHO PUBLICATIONS OF RELATED INTEREST
The World Health Organization was established in 1948 as a specialized agency of the Selection of essential medicines at country level. Using the WHO Model List of
United Nations serving as the directing and coordinating authority for international Essential Medicines to update a national essential medicines list (2019)
health matters and public health. One of WHO’s constitutional functions is to ISBN 9789241515443
provide objective and reliable information and advice in the field of human health, a Prioritization of pathogens to guide discovery, research and development of new
responsibility that it fulfils in part through its extensive programme of publications. antibiotics for drug-resistant bacterial infections, including tuberculosis (2017)
The Organization seeks through its publications to support national health strategies WHO/EMP/IAU/2017.12
and address the most pressing public health concerns of populations around the world. WHO guidelines on use of medically important antimicrobials in food-producing
animals (2017)
To respond to the needs of Member States at all levels of development, WHO publishes ISBN 9789241550130
practical manuals, handbooks and training material for specific categories of health
workers; internationally applicable guidelines and standards; reviews and analyses of WHO consolidated guidelines on drug-resistant tuberculosis treatment (2019)
health policies, programmes and research; and state-of-the-art consensus reports that ISBN 9789241550529
offer technical advice and recommendations for decision-makers. These books are Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017
closely tied to the Organization’s priority activities, encompassing disease prevention update (2017)
and control, the development of equitable health systems based on primary health ISBN 9789241550000
care, and health promotion for individuals and communities. Progress towards better Guidelines for the treatment of malaria, 3rd edition (2015)
health for all also demands the global dissemination and exchange of information ISBN 9789241549127
that draws on the knowledge and experience of all WHO’s Member countries and the
collaboration of world leaders in public health and the biomedical sciences. Updated recommendations on first-line and second-line antiretroviral regimens
and post-exposure prophylaxis and recommendations on early infant diagnosis of
To ensure the widest possible availability of authoritative information and guidance on HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the
health matters, WHO secures the broad international distribution of its publications use of antiretroviral drugs for treating and preventing HIV infection (2018)
and encourages their translation and adaption. By helping to promote and protect WHO/CDS/HIV/18.51
health and prevent and control disease throughout the world, WHO’s books contribute Guidelines for the care and treatment of persons diagnosed with chronic
to achieving the Organization’s principal objective – the attainment by all people of the hepatitis C virus infection (2018)
highest possible level of health. ISBN 9789241550345
The WHO Technical Report Series makes available the findings of various international Medical management of abortion (2018)
groups of experts that provide WHO with the latest scientific and technical advice on ISBN 9789241550406
a broad range of medical and public health subjects. Members of such expert groups Technical report: pricing of cancer medicines and its impacts: a comprehensive
serve without remuneration in their personal capacities rather than as representatives technical report for the World Health Assembly Resolution 70.12: operative
of governments or other bodies; their views do not necessarily reflect the decisions or paragraph 2.9 on pricing approaches and their impacts on availability and
the stated policy of WHO. affordability of medicines for the prevention and treatment of cancer (2018)
To purchase WHO publications, please contact: WHO Press, World Health ISBN 9789241515115
Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264;
fax: +41 22 791 4857; email: [email protected]; order on line: http://www.who.int/
bookorders ).
Further information on these and other WHO publications can be obtained from
WHO Press, World Health Organization, 1211 Geneva 27, Switzerland
(tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected];
order online: http://www.who.int/bookorders).
1021
1021
The Selection and Use of Essential Medicines

This report presents the recommendations of the WHO
Expert Committee responsible for updating the WHO
Model List of Essential Medicines and WHO Model List of
Essential Medicines for Children. It contains a summary of
the evidence presented and the Committee’s consideration,
justifications and recommendations for additions, deletions
and changes to medicines on the Model Lists.
Annexes to the main report include the 2019 WHO Model

List of Essential Medicines (21st edition) and the 2019 WHO
Model List of Essential Medicines for Children (7th edition).
In addition, all medicines on the Model Lists are presented
according to their Anatomical Therapeutic Chemical (ATC)
classification codes.
WHO Technical Report Series

ISBN 978 92 4 121030 0

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1021

The Selection and Use of Essential Medicines

Annexes to the main report include the 2019 WHO Model

WHO Technical Report Series

ISBN 978 92 4 121030 0

The Selection and Use

This report contains the views of an international group of experts, and

© World Health Organization 2019

Section 6: Anti-infective medicines

Antibiotics not classified as Access, Watch or Reserve

Antibiotics in this group are not included on the Model Lists.

–– 6.2.1: Access group antibiotics

Additions, changes and deletions

Section 6.2.1: Access group antibiotics

Access group antibiotics included on the 2019 Model Lists

Section 6.2.2: Watch group antibiotics

Watch group antibiotics included on the 2019 Model Lists

Section 6.2.3: Reserve group antibiotics

Reserve group antibiotics included on the 2019 Model Lists

EML Antibiotics/AWaRe Working Group

Section 6.2.4: Antituberculosis medicines

Section 6.4.2: Antiretrovirals

Section 6.4.4.2: Medicines for hepatitis C

Section 6.4.4.2.1: Pangenotypic direct-acting antiviral combinations

Section 6.4.4.2.2: Non-pangenotypic direct-acting antiviral combinations

Section 6.5.3.2: (Antimalarial medicines) for chemoprevention

Section 6.5.5.1: African trypanosomiasis

Section 6.6: Medicines for ectoparasitic infections (New)

Section 7: Antimigraine medicines

Section 8: Immunomodulators and antineoplastics (Re-named)

Section 8.2: Antineoplastic and supportive medicines (Re-named)

–– 8.2.1: Cytotoxic medicines

–– nivolumab, pembrolizumab and atezolizumab for the treatment of non-small

demonstrates a relevant survival benefit, its use as second-line treatment of

EML Cancer Medicines Working Group

Section 10: Medicines affecting the blood

Section 12: Cardiovascular medicines

Section 12.5.2: Thrombolytic medicines

Section 17: Gastrointestinal medicines

Section 17.5: Medicines used in diarrhoea

Section 18: Medicines for endocrine disorders (Re-named)

–– 18.1: Adrenal hormones and synthetic substitutes

Section 18.5: Medicines for diabetes

–– establishment of a WHO technical working group on access to insulin;

Section 18.6: Medicines for hypoglycaemia

Section 18.7: Thyroid hormones and antithyroid medicines

Section 19: Immunologicals

Section 22: Medicines for reproductive health and perinatal care

Section 22.3: Uterotonics

Section 22.6: Other medicines administered to the mother

Section 24: Medicines for mental and behavioural disorders

Section 24.2.1: Medicines used in depressive disorders

Section 25: Medicines acting on the respiratory tract

Section 27: Vitamins and minerals

Section 29: Medicines for diseases of joints

Follow up decisions from the 2017 Expert Committee meeting

Ready-to-use therapeutic food

Working Group on Transparency and Access to Clinical Trial Data

Improving access to and affordability of essential medicines

Phenoxymethyl Dental abscess Mercaptopurine Acute promyelocytic

Phenoxymethyl Dental abscess