Harrison Internal Medicine
Harrison Internal Medicine
Harrison Internal Medicine
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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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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
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Executive summary
beta-lactam and other antibacterials). The subsequent sub-sections within Section 6.2 are
re‑numbered accordingly:
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
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Executive summary
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.
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.
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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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
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.
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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:
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.
6
For European Society For Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (ESMO–MCBS),
see: https://www.esmo.org/score/cards.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
–– 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).
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:
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.
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.
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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:
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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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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,
WHO Technical Report Series, No. 1021, 2019
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
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Table 1 continued
EML – New medicines added EMLc – New medicines added
Medicine Indication Medicine Indication
Fexinidazole Human African Fluorouracil Nasopharyngeal cancer,
trypanosomiasis metastatic colorectal
cancer, early colon cancer,
early rectal cancer
Telmisartan + Hypertension
amlodipine
Telmisartan + Hypertension
hydrochlorothi
azide
Tiotropium COPD
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Executive summary
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Table 1 continued
EML - New/changed indications EMLc - New/changed indications
Medicine Indication Medicine Indication
Prednisolone Diffuse large B-cell
lymphoma
Etoposide Capsule 50 mg
WHO Technical Report Series, No. 1021, 2019
Lopinavir + Granules 40 mg + 10 mg
ritonavir
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Executive summary
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”
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Table 1 continued
Other changes to listings
Propylthiouracil Add note “for use when alternative first-line treatment EMLc
is not appropriate or available”
Iodine capsules Amend strength from 200 mg to 190 mg EML and EMLc
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Executive summary
Table 1 continued
Changes to sections and sub-sections of the Model Lists
2017 2019
6.4.4.2.2 Protease inhibitors 6.4.4.2.2 Non-pangenotypic direct-acting
antiviral combinations
8.2 Cytotoxic and adjuvant medicines 8.2 Antineoplastics and supportive medicines
8.2.3 Immunomodulators
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
18.5 Insulins and other medicines used for 18.5 Medicines for diabetes
diabetes
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Table 1 continued
Changes to sections and sub-sections of the Model Lists
2017 2019
Section 22: RENAMED - Medicines for reproductive health and perinatal care (formerly Oxytocics
and antioxytocics)
22.3 Uterotonics
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)
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Executive summary
Table 2
Applications and medicines not recommended for 2019 EML and EMLc
ADDITIONAL MEDICINES
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 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 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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Table 2 continued
NEW INDICATIONS
New indication for 5-fluorouracil for treatment of cervical cancer in the curative EML
setting.
DELETIONS
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
WHO Technical Report Series, No. 1021, 2019
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
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 Technical Report Series, No. 1021, 2019
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Technical Report Series, No. 1021, 2019
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
WHO Technical Report Series, No. 1021, 2019
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/.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
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
14
Available at: https://www.esmo.org/Guidelines/ESMO-MCBS.
5
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
Follow-up items and EML Working Groups
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
19
Available at: https://apps.who.int/iris/bitstream/handle/10665/327957/WHO-EMP-IAU-2019.11-eng.xlsx.
8
Follow-up items and EML Working Groups
Table 1
Antibiotics included on the 2019 Model Lists of Essential Medicines by AWaRe groups
9
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Table 2
Summary of AWaRe classification of antibiotics
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
Follow-up items and EML Working Groups
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.
WHO Technical Report Series, No. 1021, 2019
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.
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.
WHO Technical Report Series, No. 1021, 2019
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 27 : Multiple micronutrient powders were added to the core list of the
EMLc for the prevention of anaemia in infants and children.
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.
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 6.6 : Ivermectin was included on the core list of the EML and EMLc for
the new indication of treatment of scabies.
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.
16
Summary of changes
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.
WHO Technical Report Series, No. 1021, 2019
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
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
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).
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
24
Applications for the 21st EML and the 7th EMLc
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
Lancet Infect Dis. 2016;16(5):535–45.
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.
WHO Technical Report Series, No. 1021, 2019
26
Applications for the 21st EML and the 7th EMLc
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
20
https://www.who.int/gpsc/5may/global-surveys/en/
28
Applications for the 21st EML and the 7th EMLc
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
Applications for the 21st EML and the 7th EMLc
31
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Table continued
PROCEDURE FIRST-LINE ALTERNATIVES
(when allergic to
first-line choices)
First choice Second choice
Appendectomy Cefazolin (or cefuroxime) N/A Gentamicin plus
plus metronidazole metronidazole
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
WHO Technical Report Series, No. 1021, 2019
partial nephrectomy
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
Applications for the 21st EML and the 7th EMLc
EML listings
Antibiotics proposed for both EML and EMLc unless specified
Endorsement indicates those antibiotics currently included on EML/EMLc
33
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Committee recommendations
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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34
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antibioprophylaxis: Systematic review in ENT cancer surgery. [French]. Ann Fr Anesth Reanim.
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cardiac surgery: systematic review and meta-analysis. J Antimicrob Chemother. 2012;67(3):541–
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22. Vos RJ, Van Putte BP, Kloppenburg GTL. Prevention of deep sternal wound infection in cardiac
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23. Fischer MI, Dias C, Stein A, Meinhardt NG, Heineck I. Antibiotic prophylaxis in obese patients
submitted to bariatric surgery. A systematic review. Acta Cir Bras. 2014;29(3):209–17.
24. Nelson RL, Gladman E, Barbateskovic M. Antimicrobial prophylaxis for colorectal surgery. Cochrane
Database Syst Rev. 2014;5:CD001181.
25. Rangel SJ, Islam S, St Peter SD, Goldin AB, Abdullah F, Downard CD, et al. Prevention of infectious
complications after elective colorectal surgery in children: an American Pediatric Surgical
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2015;50(1):192–200.
26. Dahlke JD, Mendez-Figueroa H, Rouse DJ, Berghella V, Baxter JK, Chauhan SP. Evidence-
based surgery for cesarean delivery: an updated systematic review. Am J Obstet Gynecol.
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35
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
27. Morrill MY, Schimpf MO, Abed H, Carberry C, Margulies RU, White AB, et al. Antibiotic prophylaxis
for selected gynecologic surgeries. Int J Gynaecol Obstet. 2013;120(1):10–15.
28. Boonchan T, Wilasrusmee C, McEvoy M, Attia J, Thakkinstian A. Network meta-analysis of
antibiotic prophylaxis for prevention of surgical-site infection after groin hernia surgery. Br J
Surg. 2017;104(2):e106-e17.
29. Dauwe PB, Pulikkottil BJ, Scheuer JF, Stuzin JM, Rohrich RJ. Infection in face-lift surgery: an
evidence-based approach to infection prevention. Plast Reconstr Surg. 2015;135(1):58e–66e.
30. Saleh A, Khanna A, Chagin KM, Klika AK, Johnston D, Barsoum WK. Glycopeptides versus beta-
lactams for the prevention of surgical site infections in cardiovascular and orthopedic surgery: a
meta-analysis. Ann Surg. 2015;261(1):72–80.
31. Chambers D, Worthy G, Myers L, Weatherly H, Elliott R, Hawkins N, et al. Glycopeptide vs. non-
glycopeptide antibiotics for prophylaxis of surgical site infections: a systematic review. Surg
Infect (Larchmt). 2010;11(5):455–62.
32. Luo S, Lai Y, Liu C, Chen Y, Qiao X. Prophylactic use of gentamicin/flucloxacillin versus cefuroxime
in surgery: a meta analysis of clinical studies. Int J Clin Exp Med. 2015;8(10):17856–67.
33. Gurusamy KS, Koti R, Wilson P, Davidson BR. Antibiotic prophylaxis for the prevention of methicillin-
resistant Staphylococcus aureus (MRSA) related complications in surgical patients. Cochrane
Database Syst Rev.. 2013;8:CD010268.
34. Surgical site infections: prevention and treatment. Clinical guideline [CG74]; London: National
Institute for Health and Care Excellence; 2008. Available from https://www.nice.org.uk/guidance/
cg74, accessed 30 October 2019.
35. van Schalkwyk J, Van Eyk N. Antibiotic prophylaxis in obstetric procedures. J Obstet Gynaecol
Can. 2010;32(9):878–84.
36. Grabe M, Bjerklund-Johansen TE, Botto H, et al. Guidelines on urological infections. Arnhem:
European Association of Urology; 2011. (https://uroweb.org/wp-content/uploads/17_Urological-
infections_LR-II.pdf, accessed 30 October 2019).
37. Systematic review and evidence-based guidance on perioperative antibiotic prophylaxis.
Stockholm: European Centre for Disease Prevention and Control; 2013.
38. Caesarean section. Clinical guideline [CG132]: London: National Institute for Health and Care
Excellence; 2011. Available from https://www.nice.org.uk/guidance/cg132, accessed 30 October
2019.
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39. Shaffer WO, Baisden JL, Fernand R, Matz PG. An evidence-based clinical guideline for antibiotic
prophylaxis in spine surgery. Spine J. 2013;13(10):1387–92.
40. Safer Healthcare Now. Prevent Surgical Site Infections Getting Started Kit. Edmonton: Canadian
Patient Safety Institute; 2014.
41. Targeted literature review: What are the key infection prevention and control recommendations
to inform a surgical site infection (SSI) prevention quality improvement tool? Glasgow: Health
Protection Scotland; 2015.
42. Ariyan S, Martin J, Lal A, Cheng D, Borah GL, Chung KC, et al. Antibiotic prophylaxis for preventing
surgical-site infection in plastic surgery: an evidence-based consensus conference statement
from the American Association of Plastic Surgeons. Plast Reconstr Surg. 2015;135(6):1723–39.
43. Khashab MA, Chithadi KV, Acosta RD, Bruining DH, Chandrasekhara V, Eloubeidi MA, et al.
Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc. 2015;81(1):81–9.
44. Mrkobrada M, Ying I, Mokrycke S, Dresser G, Elsayed S, Bathini V, et al. CUA Guidelines on
antibiotic prophylaxis for urologic procedures. Can Urol Assoc J. 2015;9(1-2):13–22.
36
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45. Ban KA, Minei JP, Laronga C, Harbrecht BG, Jensen EH, Fry DE, et al. American College of Surgeons
and Surgical Infection Society: Surgical Site Infection Guidelines, 2016 Update. J Am Coll Surg.
2017;224(1):59–74.
46. Berrios-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Centers for Disease
Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg.
2017;152(8):784–91.
47. Antibioprophylaxie en chirurgie et médecine interventionnelle (patients adultes). Paris: Société
Française d’Anesthésie et de Réanimation; 2018.
48. Hézode C, Alric L, Brown A, Hassanein T, Rizzetto M, Buti M, et al. Daclatasvir in Combination with
Peginterferon Alfa-2a and Ribavirin for Treatment-Naive Patients with HCV Genotype 4 Infection:
Phase 3 COMMAND-4 Results. Open Forum Infect Dis. 2014;1(suppl 1):S233.
49. Broaddus E, Topham A, Singh AD. Incidence of retinoblastoma in the USA: 1975-2004. Br J
Ophthalmol. 2009;93(1):21–3.
50. Vitale MG, Riedel MD, Glotzbecker MP, Matsumoto H, Roye DP, Akbarnia BA, et al. Building
consensus: development of a Best Practice Guideline (BPG) for surgical site infection (SSI)
prevention in high-risk pediatric spine surgery. J Pediatr Orthop. 2013;33(5):471–8.
51. Anderson DJ, Podgorny K, Berríos-Torres SI, Bratzler DW, Dellinger EP, Greene L, et al. Strategies
to prevent surgical site infections in acute care hospitals: 2014 update. Infect Control Hosp
Epidemiol. 2014;35(6):605–27.
52. National Treatment Guidelines for Infectious Diseases. New Delhi: Indian National Centre for
Disease Control; 2016.
53. National Antibiotic Guidelines 2016. Colombo: Sri Lanka College of Microbiologists; 2016.
54. Yamamoto S, Shigemura K, Kiyota H, Wada K, Hayami H, Yasuda M, et al. Essential Japanese
guidelines for the prevention of perioperative infections in the urological field: 2015 edition. Int J
Urol. 2016;23(10):814–24.
55. Children’s Health Queensland: Paediatric surgical antibiotic prophylaxis 2017. Brisbane:
Government of Queensland; 2017.
56. Clinical Guideline: Surgical Antimicrobial Prophylaxis. Adelaide: Government of South Australia;
2017.
57. Haas H, Launay E, Minodier P, Cohen R, Gras-Le Guen C. Surgical and medical antibiotic
prophylaxis. Arch Pediatr. 2017;24(12, Supplement):S46–S51.
58. Treament Guidelines for Antimicrobial Prophylaxis 2017. New Delhi: Indian Council of Medical
Research; 2017.
59. ACOG Practice Bulletin No. 199: Use of Prophylactic Antibiotics in Labor and Delivery. Obstet
Gynecol. 2018;132(3):e103–e19.
60. Anderson DJ, Sexton DJ. Antimicrobial prophylaxis for prevention of surgical site infection in
adults [Internet]. Available from https://www.uptodate.com/contents/antimicrobial-prophylaxis-
for-prevention-of-surgical-site-infection-in-adults, accessed 10 September 2019.
61. Garner JS. CDC guideline for prevention of surgical wound infections, 1985. Supersedes
guideline for prevention of surgical wound infections published in 1982. (Originally published in
November 1985). Revised. Infect Control. 1986;7(3):193–200.
62. Simmons BP. Guideline for prevention of surgical wound infections. Infect Control. 1982;3:185–96.
63. Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA, et al. Itraconazole versus
fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell
transplants. Blood. 2004;103(4):1527–33.
37
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
64. WHO Model list of essential medicines, 20th list (March 2017, amended August 2017). Geneva:
World Health Organization; 2017. Available from https://apps.who.int/iris/handle/10665/273826,
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66. Tita AT, Szychowski JM, Boggess K, Saade G, Longo S, Clark E, et al. Adjunctive Azithromycin
Prophylaxis for Cesarean Delivery. N Engl J Med. 2016;375(13):1231–41.
WHO Technical Report Series, No. 1021, 2019
38
Applications for the 21st EML and the 7th EMLc
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.
(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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
EML listings
Antibiotics proposed for both EML and EMLc unless specified
Endorsement indicates those antibiotics currently included on EML/EMLc
Committee recommendations
The Expert Committee endorsed listing of amoxicillin and phenoxymethylpenicillin
on the core list of the EML and EMLc as first-choice treatment for progressive
WHO Technical Report Series, No. 1021, 2019
References
1. Dar-Odeh NS, Abu-Hammad OA, Al-Omiri MK, Khraisat AS, Shehabi AA. Antibiotic prescribing
practices by dentists: a review. Ther Clin Risk Manag. 2010;6:301–6.
2. Poveda Roda R, Bagan JV, Sanchis Bielsa JM, Carbonell Pastor E. Antibiotic use in dental practice. A
review. Med Oral Patol Oral Cir Bucal. 2007;12(3):E186–92.
3. Dailey YM, Martin MV. Are antibiotics being used appropriately for emergency dental treatment?
Br Dent J. 2001;191(7):391–3.
44
Applications for the 21st EML and the 7th EMLc
46
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML and EMLc
Section
6.2.3 Reserve group antibiotics
Core/Complementary
Complementary
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
Committee recommendations
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
WHO Technical Report Series, No. 1021, 2019
50
Applications for the 21st EML and the 7th EMLc
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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 Secretariat on behalf of the EML Antibiotics Working Group
EML/EMLc
EML
Section
6.2.3 Reserve group antibiotics
Core/Complementary
Complementary
Individual listing
groups with headache and gastrointestinal symptoms being the most frequent
AE (8, 9).
WHO Guidelines
There are no available WHO guidelines for the treatment of infections due to
MDROs.
Costs/cost-effectiveness
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.
Other considerations
N/A
WHO Technical Report Series, No. 1021, 2019
Committee recommendations
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.
The Committee agreed with the EML Antibiotic Working Group’s
recommendation that this antibiotic should be classified in the AWaRe Reserve
group.
54
Applications for the 21st EML and the 7th EMLc
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.
2. 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.
3. 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.
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.
5. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae.
Virulence. 2017;8(4):460–9.
6. 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.
7. 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.
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
56
Applications for the 21st EML and the 7th EMLc
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 Secretariat on behalf of the EML Antibiotics Working Group
EML/EMLc
EML
Section
6.2.2 Watch group antibiotics
Core/Complementary
Complementary
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
Applications for the 21st EML and the 7th EMLc
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).
Costs/cost-effectiveness
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.
Other considerations
N/A
Committee recommendations
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
5. 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.
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.
7. Global action plan on antimicrobial resistance. Geneva: World Health Organization; 2015.
Available from: https://apps.who.int/iris/handle/10665/311820, accessed 30 October 2019.
8. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae.
Virulence. 2017;8(4):460–9.
9. 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.
10. 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.
11. Lodise T, Corey R, Hooper D, Cammarata S. Safety of Delafloxacin: Focus on Adverse Events of
WHO Technical Report Series, No. 1021, 2019
60
Applications for the 21st EML and the 7th EMLc
Proposal
The application requested the inclusion of eravacycline on the complementary
list of the EML as a last-resort treatment option for infections due to multidrug-
resistant organisms (MRDOs).
Applicant
EML Secretariat on behalf of the EML Antibiotics Working Group
EML/EMLc
EML
Section
6.2.3 Reserve group antibiotics
Core/Complementary
Complementary
61
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
WHO Guidelines
There are no available WHO guidelines for the treatment of infections due to
MDROs.
Costs/cost-effectiveness
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.
Other considerations
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.
Committee recommendations
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.
The Expert Committee agreed with the EML Antibiotic Working Group’s
recommendation that eravacycline be classified in the AWaRe Reserve group.
63
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
5. 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.
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.
7. Global action plan on antimicrobial resistance. Geneva: World Health Organization; 2015.
Available from: https://apps.who.int/iris/handle/10665/311820, accessed 30 October 2019.
8. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae.
Virulence. 2017;8(4):460–9.
9. 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.
10. 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.
11. Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, et al. Assessing the Efficacy and Safety of
WHO Technical Report Series, No. 1021, 2019
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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 Secretariat on behalf of the EML Antibiotics Working Group
EML/EMLc
EML
Section
6.2.3 Reserve group antibiotics
Core/Complementary
Complementary
Individual
WHO Guidelines
There are no available WHO guidelines for the treatment of infections due to
MDROs.
67
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Costs/cost-effectiveness
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.
Other considerations
The Committee noted that there was very limited clinical trial evidence of the
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
WHO Technical Report Series, No. 1021, 2019
Committee recommendations
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.
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
68
Applications for the 21st EML and the 7th EMLc
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.
3. 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.
4. 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.
5. Global action plan on antimicrobial resistance. Geneva: World Health Organization; 2015.
Available from: https://apps.who.int/iris/handle/10665/311820, accessed 30 October 2019.
6. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae.
Virulence. 2017;8(4):460–9.
7. Prioritization of pathogens to guide discovery, research and development of new antibiotics for
drug-resistant bacterial infections, including tuberculosis. Geneva: World Health Organization;
2017.
8. 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.
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Proposal
The application requested the inclusion of omadacycline on the complementary
list of the EML 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
EML/EMLc
EML
Section
6.2.3 Reserve group antibiotic
Core/Complementary
Complementary
WHO Technical Report Series, No. 1021, 2019
71
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
The results of NCT02531438 and NCT02378480 have since been published (see
additional evidence).
was similar in both groups, with gastrointestinal side effects being the most
commonly observed AE (18.0% vs 15.8%).
WHO Guidelines
There are no available WHO guidelines for the treatment of infections due to
multidrug-resistant organisms.
Costs/cost-effectiveness
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
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Applications for the 21st EML and the 7th EMLc
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).
Other considerations
N/A
Committee recommendations
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.
The Expert Committee agreed with the EML Antibiotic Working Group’s
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.
2. 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.
3. 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.
4. 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.
5. Global action plan on antimicrobial resistance. Geneva: World Health Organization; 2015.
Available from: https://apps.who.int/iris/handle/10665/311820, accessed 30 October 2019.
6. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae.
Virulence. 2017;8(4):460–9.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
7. 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.
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.
WHO Technical Report Series, No. 1021, 2019
74
Applications for the 21st EML and the 7th EMLc
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-
resistant organisms (MDROs).
Applicant
EML Secretariat on behalf of the EML Antibiotics Working Group
EML/EMLc
EML
Section
6.2.3 Reserve group antibiotics
Core/Complementary
Complementary
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Applications for the 21st EML and the 7th EMLc
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
There are no available WHO guidelines for the treatment of infections due to
MDROs.
Costs/cost-effectiveness
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.
Other considerations
The Committee noted that there was very limited clinical trial evidence of the
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.
Committee recommendations
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.
The Committee agreed with the EML Antibiotic Working Group’s
recommendation that this antibiotic should be classified in the AWaRe Reserve
group (Section 6.2.3).
The Committee recommended further collaboration between relevant
stakeholders to design and implement strategic public health-orientated studies
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
3. 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.
4. 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.
5. Global action plan on antimicrobial resistance. Geneva: World Health Organization; 2015.
Available from: https://apps.who.int/iris/handle/10665/311820, accessed 30 October 2019.
6. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae.
Virulence. 2017;8(4):460–9.
7. Prioritization of pathogens to guide discovery, research and development of new antibiotics for
drug-resistant bacterial infections, including tuberculosis. Geneva: World Health Organization;
2017.
8. 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.
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.
WHO Technical Report Series, No. 1021, 2019
78
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML and EMLc
Section
6.2.5 Antituberculosis medicines
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Core/Complementary
Core: ethambutol, isoniazid, rifabutin
Complementary: clofazimine, cycloserine, ethionamide, levofloxacin, linezolid,
moxifloxacin
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Applications for the 21st EML and the 7th EMLc
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
Costs/cost-effectiveness
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.
Other considerations
N/A
Committee recommendations
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.
WHO Technical Report Series, No. 1021, 2019
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.
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Applications for the 21st EML and the 7th EMLc
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
EML/EMLc
EML
Section
6.2.5 Antituberculosis medicines
Core/Complementary
Core
Background
Abbreviations used for tuberculosis (TB) medicines:
H = isoniazid, R = rifampicin, Z = pyrazinamide, E = ethambutol
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Applications for the 21st EML and the 7th EMLc
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.
Costs/cost-effectiveness
N/A
Availability
N/A
Other considerations
Alternative strength fixed-dose formulations of isoniazid + pyrazinamide +
rifampicin and isoniazid + rifampicin remain available on the EML for use in
daily dosing regimens.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Committee recommendations
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.
2. 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.
WHO Technical Report Series, No. 1021, 2019
86
Applications for the 21st EML and the 7th EMLc
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
EML/EMLc
EML and EMLc
Section
6.2.5 Antituberculosis medicines
Core/Complementary
Core
88
Applications for the 21st EML and the 7th EMLc
(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.
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).
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Costs/cost-effectiveness
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.
Other considerations
N/A
Committee recommendations
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
WHO Technical Report Series, No. 1021, 2019
References
1. 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.
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).
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Applications for the 21st EML and the 7th EMLc
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.
10. 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/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/
9789241511339-eng.pdf, accessed 30 October 2019.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Global TB Programme
EML/EMLc
EMLc
Section
6.2.5 Antituberculosis medicines
Core/Complementary
Complementary
Individual
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Applications for the 21st EML and the 7th EMLc
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).
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).
Costs/cost-effectiveness
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
WHO Technical Report Series, No. 1021, 2019
Other considerations
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.
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Applications for the 21st EML and the 7th EMLc
Committee recommendations
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
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2015
(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
Organization; 2015. Available from https://apps.who.int/iris/bitstream/handle/10665/189763/
9789241209946_eng.pdf, accessed 30 October 2019.
2. 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.
3. 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.
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Global TB Programme
EML/EMLc
EML and EMLc
Section
6.2.5 Antituberculosis medicines
Core/Complementary
Complementary
WHO Technical Report Series, No. 1021, 2019
Background
N/A
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Applications for the 21st EML and the 7th EMLc
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.
Costs/cost-effectiveness
N/A
Availability
N/A
Other considerations
Amikacin and streptomycin remain available on the Model List for use in
treatment regimens for drug-resistant TB.
Committee recommendations
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
1. 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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
98
Applications for the 21st EML and the 7th EMLc
Proposal
The application requested a change to the age restriction that applies to the listing
of delamanid on the Model Lists.
Applicant
WHO Global TB Programme
EML/EMLc
EML and EMLc
Section
6.2.5 Antituberculosis medicines
Core/Complementary
Complementary
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.
WHO Guidelines
The 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment
WHO Technical Report Series, No. 1021, 2019
Costs/cost-effectiveness
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.
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Applications for the 21st EML and the 7th EMLc
Other considerations
N/A
Committee recommendations
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:
World Health Organization; 2019. Available from https://apps.who.int/iris/bitstream/handle/
10665/311390/WHO-CDS-TB-2019.3-eng.pdf, accessed 30 October 2019.
2. 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.
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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
WHO Global TB Programme
EML/EMLc
EML and EMLc
(EML only for imipenem + cilastatin)
Section
6.2.5 Antituberculosis medicines
WHO Technical Report Series, No. 1021, 2019
Core/Complementary
Complementary
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
WHO Technical Report Series, No. 1021, 2019
p-aminosalicylic acid
WHO Guidelines
The 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment
(3) include the following recommendations regarding longer treatment regimens
for MDR-/RR-TB:
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Costs/cost-effectiveness
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.
Other considerations
N/A
WHO Technical Report Series, No. 1021, 2019
Committee recommendations
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
Applications for the 21st EML and the 7th EMLc
References
1. 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.
2. Jenkins HE, Yuen CM. The burden of multidrug-resistant tuberculosis in children. Int J Tuberc
Lung Dis. 2018;22(5):3–6.
3. 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 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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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:
World Health Organization; 2019. Available from https://apps.who.int/iris/bitstream/handle/
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).
WHO Technical Report Series, No. 1021, 2019
108
Applications for the 21st EML and the 7th 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
EML/EMLc
EMLc
Section
6.2.4 Antituberculosis medicines
Core/Complementary
Core
109
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
Applications for the 21st EML and the 7th EMLc
Costs/cost-effectiveness
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.
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Other considerations
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.
Committee recommendations
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
WHO Technical Report Series, No. 1021, 2019
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.
2. 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.
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
Applications for the 21st EML and the 7th EMLc
113
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Proposal
The application requested the deletion of various antiretroviral (ARV)
formulations from the core list of the EML and EMLc.
Applicant
WHO HIV Department
EML/EMLc
EML and EMLc
Section
6.4.2 Antiretrovirals
Core/Complementary
Core
114
Applications for the 21st EML and the 7th EMLc
WHO Guidelines
The proposed deletions are in alignment with recommendations in the 2018
WHO guidelines and paediatric ARV formulary.
Costs/cost-effectiveness
N/A
Availability
N/A
115
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Other considerations
–– 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.
Committee recommendations
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
WHO Technical Report Series, No. 1021, 2019
Committee recommendations
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 for the 21st EML and the 7th EMLc
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
EML/EMLc
EML and EMLc
Section
6.4.2.3 Protease inhibitors
Core/Complementary
Core
Individual
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).
WHO Guidelines
WHO guidelines for paediatric HIV treatment recommend the approach of
WHO Technical Report Series, No. 1021, 2019
‘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).
Costs/cost-effectiveness
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.
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Applications for the 21st EML and the 7th EMLc
Other considerations
N/A
Committee recommendations
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,
accessed 26 September 2019.
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
WHO Technical Report Series, No. 1021, 2019
122
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EMLc
Section
6.4.2.3 Protease inhibitors
Core/Complementary
Core
123
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
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.
124
Applications for the 21st EML and the 7th EMLc
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.
Costs/cost-effectiveness
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.
Other considerations
N/A
Committee recommendations
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
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,
accessed 29 September 2019.
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.
6. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV
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,
accessed 29 September 2019.
7. 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
WHO Technical Report Series, No. 1021, 2019
126
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EMLc
Section
6.4.2.4 Integrase inhibitors
Core/Complementary
Core
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
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Applications for the 21st EML and the 7th EMLc
Costs/cost-effectiveness
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.
Other considerations
N/A
Committee recommendations
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
1. 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.
2. 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,
accessed 29 September 2019.
131
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
132
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML and EMLc
Section
6.4.2.4 Integrase inhibitors
Core/Complementary
Core
1.8 million children living with HIV, the vast majority in sub-Saharan Africa (1).
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).
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%
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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.
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).
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Costs/cost-effectiveness
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.
Other considerations
Raltegravir granules for oral suspension are not recommended in pre-term
neonates or in paediatric patients weighing less than 2 kg.
Committee recommendations
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
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.
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.
WHO Technical Report Series, No. 1021, 2019
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,
accessed 29 September 2019.
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.
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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.
8. 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. 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.
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Fixed-dose combinations
Dolutegravir + lamivudine + tenofovir disoproxil fumarate – addition – EML
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
EML/EMLc
EML
Section
6.4.2 Antiretrovirals – fixed-dose combinations
Core/Complementary
WHO Technical Report Series, No. 1021, 2019
Core
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).
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).
Costs/cost-effectiveness
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.
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Availability
This product is currently available for procurement from multiple suppliers
(including WHO prequalified manufacturers).
Other considerations
N/A
Committee recommendations
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.
WHO Technical Report Series, No. 1021, 2019
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.
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
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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.
12. 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. 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.
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.
14. 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 29 September 2019.
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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.
EML/EMLc
EML
Section
6.4.4.2.1 Pangenotypic direct-acting antiviral combinations
Core/Complementary
Core
WHO Technical Report Series, No. 1021, 2019
Background
Neither this fixed-dose combination (FDC) nor its individual components have
been previously considered by the Expert Committee for addition to the EML.
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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).
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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)
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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.
Costs/cost-effectiveness
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
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Other considerations
N/A
Committee recommendations
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
WHO Technical Report Series, No. 1021, 2019
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
Applications for the 21st EML and the 7th EMLc
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.
Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
EML/EMLc
EMLc
Section
6.5.3.2 Antimalarial medicines – For chemoprevention
Core/Complementary
WHO Technical Report Series, No. 1021, 2019
Core
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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).
Costs/cost-effectiveness
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.
WHO Technical Report Series, No. 1021, 2019
Other considerations
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
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Committee recommendations
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
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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.
WHO Technical Report Series, No. 1021, 2019
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Applications for the 21st EML and the 7th EMLc
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
WHO Global Malaria Programme
EML/EMLc
EML
Section
6.5.3.2 Antimalarial medicines - For chemoprevention
Core/Complementary
Core
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).
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Costs/cost-effectiveness
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).
Other considerations
WHO Technical Report Series, No. 1021, 2019
Committee recommendations
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
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for mothers and newborns, and acceptable safety, and in alignment with WHO
malaria treatment guidelines.
The Expert Committee noted the lack of evidence of the impact of the
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.
5. 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,
accessed 29 September 2019.
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.
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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.
WHO Technical Report Series, No. 1021, 2019
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Applications for the 21st EML and the 7th EMLc
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
WHO Global Malaria Programme
EML/EMLc
EMLc
Section
6.5.3.2 Antimalarial medicines - For chemoprevention
Core/Complementary
Core
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).
Costs/cost-effectiveness
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).
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
Other considerations
N/A
Committee recommendations
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.
The Expert Committee noted the lack of evidence of the impact of the
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.
WHO Technical Report Series, No. 1021, 2019
164
Applications for the 21st EML and the 7th EMLc
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.
8. 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,
accessed 29 September 2019.
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
EML/EMLc
EML and EMLc
Section
6.5.5.1 African trypanosomiasis
Tablet 600 mg
Core/Complementary
Core
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.
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
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Applications for the 21st EML and the 7th EMLc
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.
Costs/cost-effectiveness
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
WHO Technical Report Series, No. 1021, 2019
Other considerations
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
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Applications for the 21st EML and the 7th EMLc
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.
Committee recommendations
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:
1. 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). Geneva: World Health Organization; 2017. (WHO Technical
Report Series, No. 1006). Available from https://apps.who.int/iris/bitstream/handle/10665/
259481/9789241210157-eng.pdf, accessed 30 October 2019.
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
WHO Technical Report Series, No. 1021, 2019
172
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML and EMLc
Section
6.6 Medicines for ectoparasitic infections
Core/Complementary
Core
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Applications for the 21st EML and the 7th EMLc
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.
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/
WHO Technical Report Series, No. 1021, 2019
Costs/cost-effectiveness
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.
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Applications for the 21st EML and the 7th EMLc
Other considerations
N/A
Committee recommendations
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.
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2. Karimkhani C, Colombara DV, Drucker AM, Norton SA, Hay R, Engelman D et al. The global
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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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
WHO Technical Report Series, No. 1021, 2019
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
EML/EMLc
EML
Section
7.1 Antimigraine medicines – For treatment of acute attack
Core/Complementary
Core
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(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).
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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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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
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Costs/cost-effectiveness
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.
Other considerations
Sumatriptan was not proposed for inclusion in the EMLc by the applicant
because:
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Committee recommendations
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.
WHO Technical Report Series, No. 1021, 2019
References
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2007
(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
low- and middle-income countries. J Headache Pain. 2015;16:15.
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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)
EML/EMLc
EML and EMLc
Section
8.1 Immunomodulators for non-malignant disease
Core/Complementary
Complementary
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).
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Technical Report Series, No. 1021, 2019
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
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Applications for the 21st EML and the 7th EMLc
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).
(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).
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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.
Costs/cost-effectiveness
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
WHO Technical Report Series, No. 1021, 2019
Other considerations
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
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Applications for the 21st EML and the 7th EMLc
Committee recommendations
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.
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References
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2015 (including
the 19th WHO Model List of Essential Medicines and the 5th WHO Model List of Essential Medicines
for Children) (WHO Technical Report Series, No. 994). Geneva: World Health Organization; 2015.
Available from https://apps.who.int/iris/bitstream/handle/10665/189763/9789241209946_eng.
pdf, accessed 30 October 2019.
2. Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, Chandraratna D et al. ECTRIMS/
EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler.
2018;24(2):96–120.
3. Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS et al. Practice guideline
recommendations summary: Disease-modifying therapies for adults with multiple sclerosis:
Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the
American Academy of Neurology. Neurology. 2018;90(17):777–88.
4. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72 Suppl 1:1–5.
5. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M et al. The relation
between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(Pt
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TNF-alfa inhibitors for chronic inflammatory diseases – addition – EML and EMLc
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
EML/EMLc
EML and EMLc
Section
8.1 Immunomodulators for non-malignant disease
Core / Complementary
Complementary
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Applications for the 21st EML and the 7th EMLc
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
WHO Technical Report Series, No. 1021, 2019
(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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Applications for the 21st EML and the 7th EMLc
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
WHO Technical Report Series, No. 1021, 2019
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).
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Applications for the 21st EML and the 7th EMLc
WHO Guidelines
None available
Costs/cost-effectiveness
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.
Other considerations
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Committee recommendations
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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37. Watanabe T, Fukae J, Fukaya S, Sawamukai N, Isobe M, Matsuhashi M et al. Incidence and risk
factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated
with biological disease-modifying antirheumatic drugs. Int J Rheum Dis. 2019;22(4):574–82.
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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:
214
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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
EML/EMLc
EMLc
Section
8.2 Antineoplastic and supportive medicines
Core/Complementary
Complementary
215
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Applications for the 21st EML and the 7th EMLc
218
Applications for the 21st EML and the 7th EMLc
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
WHO Guidelines
None available
Costs/cost-effectiveness
Not reported in the application.
220
Applications for the 21st EML and the 7th EMLc
Availability
The proposed medicines are already included on the EML and/or EMLc.
Other considerations
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.
Committee recommendations
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.
221
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
Metastatic colorectal 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
WHO Technical Report Series, No. 1021, 2019
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WHO Technical Report Series, No. 1021, 2019
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Applications for the 21st EML and the 7th EMLc
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.
EML/EMLc
EML and EMLc
Section
8.2 Antineoplastic and supportive medicines
Core/Complementary
Complementary
227
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228
Applications for the 21st EML and the 7th EMLc
229
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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”
WHO Guidelines
None available
Costs/cost-effectiveness
N/A
Availability
N/A
Other considerations
N/A
WHO Technical Report Series, No. 1021, 2019
Committee recommendations
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.
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Applications for the 21st EML and the 7th EMLc
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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)
EML/EMLc
EML and EMLc
Section
8.2.1 Cytotoxic medicines
WHO Technical Report Series, No. 1021, 2019
Core/Complementary
Complementary
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
WHO Technical Report Series, No. 1021, 2019
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).
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Applications for the 21st EML and the 7th EMLc
WHO Guidelines
None available
Costs/cost-effectiveness
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
Other considerations
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,
WHO Technical Report Series, No. 1021, 2019
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Committee recommendations
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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240
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML
Section
8.2.1 Cytotoxic medicines
Core/Complementary
Complementary
a specific endorsement for the indication of cervical cancer, and the listing for
cisplatin is specific for use as a radiosensitizer.
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).
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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
WHO Technical Report Series, No. 1021, 2019
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
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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%
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
WHO Guidelines
None available
Costs/cost-effectiveness
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.
Other considerations
N/A
Committee recommendations
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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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chemotherapy-induced-nausea-and-vomiting-in-adults, accessed 29 September 2019).
31. Portilla D, Safar AM, Shannon ML, Penson RT. Cisplatin nephrotoxicity [website]. Waltham:
UpToDate; 2019. (https://www.uptodate.com/contents/cisplatin-nephrotoxicity, accessed 29
September 2019).
32. Castells M, Matulonis U, Horton T. Infusion reactions to systemic chemotherapy [website].
Waltham: UpToDate; 2019. (https://www.uptodate.com/contents/infusion-reactions-to-systemic-
chemotherapy, accessed 29 September 2019).
33. LaCasce A, Castells M, Burnstein H, Meyerhardt J. Infusion reactions to therapeutic monoclonal
antiboties used for cancer therapy [website]. Waltham: UpToDate; 2019. (https://www.uptodate.
com/contents/infusion-related-reactions-to-therapeutic-monoclonal-antibodies-used-for-
cancer-therapy, accessed 29 September 2019).
34. Floyd J, Morgan JP. Cardiotoxicity of non-anthracycline cancer chemotherapy agents
[website]. Waltham: UpToDate; 2019. (https://www.uptodate.com/contents/cardiotoxicity-of-
non-anthracycline-cancer-chemotherapy-agents, accessed 29 September 2019).
35. McKim A, Walter AC, Sheely KM, Manahan KJ, Geisler JP. An economic analysis of cisplatin alone
versus cisplatin doublets in the treatment of women with advanced or recurrent cervical cancer.
Eur J Gynaecol Oncol. 2016;37(3):353–6.
36. Geisler JP, Swathirajan J, Wood KL, Manahan KJ. Treatment of advanced or recurrent cervical
cancer with Cisplatin or Cisplatin containing regimens: a cost effective analysis. J Cancer.
2012;3:454–8.
WHO Technical Report Series, No. 1021, 2019
250
Applications for the 21st EML and the 7th EMLc
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)
EML/EMLc
EML and EMLc
Section
8.2.1 Cytotoxic medicines
Core/Complementary
Complementary
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.
Costs/cost-effectiveness
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.
Other considerations
The risk of allergic hypersensitivity reactions to asparaginase therapy increases
WHO Technical Report Series, No. 1021, 2019
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.
Committee recommendations
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
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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–
42.
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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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
WHO Technical Report Series, No. 1021, 2019
256
Applications for the 21st EML and the 7th EMLc
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.
EML/EMLc
EML
Section
8.2.2 Targeted therapies
Core/Complementary
Complementary
+ 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).
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Applications for the 21st EML and the 7th EMLc
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
WHO Technical Report Series, No. 1021, 2019
WHO Guidelines
None available.
Costs/cost-effectiveness
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).
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Availability
As of 7 June 2018, pertuzumab has been approved in more than 100 countries
worldwide.
Other considerations
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).
Committee recommendations
The Committee endorsed the recommendations of the EML 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 of
pertuzumab.
The Committee acknowledged that pertuzumab was associated with
WHO Technical Report Series, No. 1021, 2019
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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2. Shulman LN, Willett W, Sievers A, Knaul FM. Breast cancer in developing countries: opportunities
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3. Sundaresan S, Penuel E, Sliwkowski MX. The biology of human epidermal growth factor receptor
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Clinical Oncology/College of American Pathologists guideline recommendations for human
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5. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor
and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.
Oncologist. 2009;14(4):320–68.
6. Borg A, Tandon AK, Sigurdsson H, Clark GM, Ferno M, Fuqua SA et al. HER-2/neu amplification
predicts poor survival in node-positive breast cancer. Cancer Res. 1990;50(14):4332–7.
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factor, and target for therapy. Stem Cells. 1998;16(6):413–28.
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Oncology. 2001;61 Suppl 2:67–72.
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.
10. Curigliano G, Viale G, Bagnardi V, Fumagalli L, Locatelli M, Rotmensz N et al. Clinical relevance of
HER2 overexpression/amplification in patients with small tumor size and node-negative breast
cancer. J Clin Oncol. 2009;27(34):5693–9.
11. Neven P, Van Calster B, Van den Bempt I, Van Huffel S, Van Belle V, Hendrickx W et al. Age interacts
with the expression of steroid and HER-2 receptors in operable invasive breast cancer. Breast
Cancer Res Treat. 2008;110(1):153–9.
12. Dawood S, Merajver SD, Viens P, Vermeulen PB, Swain SM, Buchholz TA et al. International expert
panel on inflammatory breast cancer: consensus statement for standardized diagnosis and
treatment. Ann Oncol. 2011;22(3):515–23.
13. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I et al. Trastuzumab
after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–72.
14. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Jr., Davidson NE et al. Trastuzumab plus
adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):
1673–84.
15. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M et al. Adjuvant trastuzumab in
HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83.
16. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive
breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2011;9(1):16–32.
17. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus
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22. Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A et al. 5-year analysis of neoadjuvant
pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage
HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.
Lancet Oncol. 2016;17(6):791–800.
23. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R et al. Pertuzumab plus trastuzumab
in combination with standard neoadjuvant anthracycline-containing and anthracycline-free
chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized
phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278–84.
24. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M et al. Long-term efficacy
analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab
and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-
free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer.
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25. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G et al. Adjuvant
Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017;377(2):
122–31.
26. Pejeta: EPAR - Product Information. Annex 1 Summary of product characteristics (Perjeta - EMEA/
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27. Rimawi M, Ferrero JM, de la Haba-Rodriguez J, Poole C, De Placido S, Osborne CK et al. First-Line
Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal
Growth Factor Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally
Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial. J Clin Oncol.
2018;36(28):2826–35.
28. Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Lang I, Tomasello G et al. Randomized Phase
III Trial of Trastuzumab Plus Capecitabine With or Without Pertuzumab in Patients With Human
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Progression During or After Trastuzumab-Based Therapy. J Clin Oncol. 2017;35(26):3030–8.
29. Ellis PA, Barrios CH, Eiermann W, Toi M, Im YH, Conte PF et al. Phase III, randomized study of
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Meeting - Abstract 507 J Clin Oncol (Meeting Abstracts). 2015;33(Suppl).
30. Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P et al. Trastuzumab Emtansine With or
Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor
Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE
Study. J Clin Oncol. 2017;35(2):141–8.
31. Pertuzumab for adjuvant treatment of HER2-positive early stage breast cancer (TA569). London:
National Institute for Health and Care Excellence (NICE); 2019. Available from https://www.nice.
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32. Pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer (TA509).
London: National Institute for Health and Care Excellence (NICE); 2018. Available from https://
www.nice.org.uk/guidance/ta509, accessed 30 October 2019.
33. Schleich W, Tournier C, Campagnoli E, Era S. 1225 Potential long-term cost savings due to
significant clinical benefit of pertuzumab in combination with trastuzumab for the neoadjuvant
treatment of patients with HER2-positive, locally advanced, inflammatory or early stage breast
cancer. Eur J Cancer. 2015;51:S180–S1.
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34. Attard CL, Pepper AN, Brown ST, Thompson MF, Thuresson PO, Yunger S et al. Cost-effectiveness
analysis of neoadjuvant pertuzumab and trastuzumab therapy for locally advanced, inflammatory,
or early HER2-positive breast cancer in Canada. J Med Econ. 2015;18(3):173–88.
35. Pradelli L, Zaniolo O, Caputo A, Roussel M, Tournier C. PCN181 - Cost-utility analysis of adjuvant
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36. ESMO-Magnitude of Clinical Benefit Scale. The ESMO-MCBS Score Card [website]. Lugano:
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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
EML/EMLc
EML
Section
8.2.2 Targeted therapies
Core/Complementary
Complementary
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)
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Applications for the 21st EML and the 7th EMLc
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.
WHO Guidelines
None available.
Costs/cost-effectiveness
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.
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Other considerations
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.
Committee recommendations
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
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2015
(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
WHO Technical Report Series, No. 1021, 2019
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.
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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
F. Hoffmann-La Roche Ltd
EML/EMLc
EML
Section
8.2.2 Targeted therapies
Core/Complementary
Complementary
276
Applications for the 21st EML and the 7th EMLc
277
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
WHO Guidelines
None available.
Costs/cost-effectiveness
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
WHO Technical Report Series, No. 1021, 2019
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
Applications for the 21st EML and the 7th EMLc
Other considerations
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.
Committee recommendations
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
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2015
(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 Organization; 2015. Available from https://apps.who.int/iris/bitstream/handle/10665/
189763/9789241209946_eng.pdf, accessed 30 October 2019.
2. Global Cancer Observatory: Cancer Today [website]. Lyon: International Agency for Research on
Cancer; 2018. (https://gco.iarc.fr/today, accessed 29 September 2019).
3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018:
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA
Cancer J Clin. 2018;68(6):394–424.
4. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ et al. American Society of
Clinical Oncology/College of American Pathologists guideline recommendations for human
epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25(1):118–45.
5. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor
and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.
Oncologist. 2009;14(4):320–68.
279
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
6. Borg A, Tandon AK, Sigurdsson H, Clark GM, Ferno M, Fuqua SA et al. HER-2/neu amplification
predicts poor survival in node-positive breast cancer. Cancer Res. 1990;50(14):4332–7.
7. Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive
factor, and target for therapy. Stem Cells. 1998;16(6):413–28.
8. Menard S, Fortis S, Castiglioni F, Agresti R, Balsari A. HER2 as a prognostic factor in breast cancer.
Oncology. 2001;61 Suppl 2:67–72.
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.
10. Curigliano G, Viale G, Bagnardi V, Fumagalli L, Locatelli M, Rotmensz N et al. Clinical relevance of
HER2 overexpression/amplification in patients with small tumor size and node-negative breast
cancer. J Clin Oncol. 2009;27(34):5693–9.
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.
WHO Technical Report Series, No. 1021, 2019
280
Applications for the 21st EML and the 7th EMLc
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
F. Hoffmann-La Roche Ltd
EML/EMLc
EML
Section
8.2.2 Targeted therapies
Core/Complementary
Complementary
281
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
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.
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
WHO Technical Report Series, No. 1021, 2019
WHO Guidelines
None available.
Costs/cost-effectiveness
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.
Other considerations
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
Committee recommendations
The Committee endorsed the recommendations of the EML 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 of
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
WHO Technical Report Series, No. 1021, 2019
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6. Borg A, Tandon AK, Sigurdsson H, Clark GM, Ferno M, Fuqua SA et al. HER-2/neu amplification
predicts poor survival in node-positive breast cancer. Cancer Res. 1990;50(14):4332–7.
7. Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive
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invasive breast cancer: the California Cancer Registry, 1999-2004. Cancer. 2008;112(4):737–47.
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pbac-meetings/psd/2014-11/files/pertuzumab-trastuzumab-psd-11-2014.pdf, accessed 29
September 2019).
37. Trastuzumab emtansine (Kadcyla) is accepted for use within NHS Scotland [website]. Glasgow:
Scottish Medicines Consortium; 2017. (https://www.scottishmedicines.org.uk/medicines-advice/
trastuzumab-emtansine-kadcyla-resubmission-99014/, accessed 29 September 2019).
38. Trastuzumab emtansine (Kadcyla) Pharmacoeconomic Evaluations [website]. Dublin: National
Centre for Pharmacoeconomics (NCPE) Ireland; 2015. (http://www.ncpe.ie/drugs/trastuzumab-
emtansine-kadcyla/, accessed 29 September 2019).
39. Kadcyla (trastuzumab emtansine), anticorps ciblant le récepteur HER 2 couplé à un cytotoxique.
Cancérologie – Nouveau Médicament et Avis d’efficience [website]. Saint-Denis La Plaine:
Haute Autorité de santé (HAS); 2014. (https://www.has-sante.fr/jcms/c_1735595/fr/kadcyla-
trastuzumab-emtansine-anticorps-ciblant-le-recepteur-her-2-couple-a-un-cytotoxique?xtmc=
&xtcr=1, accessed 29 September 2019).
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292
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML
Section
8.2.2 Targeted therapies
Core/Complementary
Complementary
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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).
WHO Guidelines
N/A
Costs/cost-effectiveness
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
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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.
Other considerations
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).
Committee recommendations
The Committee endorsed the recommendations of the EML 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 of the
tyrosine kinase inhibitors afatinib, erlotinib and gefitinib.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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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Essential Medicines for Children) (WHO Technical Report Series, No. 994). Geneva: World Health
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9789241209946_eng.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. Pearce A, Sharp L, Hanly P, Barchuk A, Bray F, de Camargo Cancela M et al. Productivity losses
due to premature mortality from cancer in Brazil, Russia, India, China, and South Africa (BRICS): A
population-based comparison. Cancer Epidemiol. 2018;53:27–34.
4. Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C, Reid ME. The International Epidemiology
of Lung Cancer: Latest Trends, Disparities, and Tumor Characteristics. J Thorac Oncol. 2016;
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11(10):1653–71.
5. Morgensztern D, Ng SH, Gao F, Govindan R. Trends in stage distribution for patients with non-
small cell lung cancer: a National Cancer Database survey. J Thorac Oncol. 2010;5(1):29–33.
6. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of
adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J
Cancer Res. 2015;5(9):2892–911.
7. Benbrahim Z, Antonia T, Mellas N. EGFR mutation frequency in Middle East and African non-small
cell lung cancer patients: a systematic review and meta-analysis. BMC Cancer. 2018;18(1):891.
8. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C et al. Screening for epidermal growth
factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):95867.
9. Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C et al. Metastatic non-small cell lung
cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.
2018;29(Supplement_4):iv192–iv237.
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10. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al. Gefitinib or carboplatin-paclitaxel
in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.
11. Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT et al. First-SIGNAL: first-line single-agent iressa
versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin
Oncol. 2012;30(10):1122–8.
12. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H et al. Gefitinib or chemotherapy
for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8.
13. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E et al. Erlotinib versus standard
chemotherapy as first-line treatment for European patients with advanced EGFR mutation-
positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3
trial. Lancet Oncol. 2012;13(3):239–46.
14. Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T et al. Phase III study of afatinib
or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR
mutations. J Clin Oncol. 2013;31(27):3327–34.
15. Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y et al. Afatinib versus cisplatin plus gemcitabine
for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring
EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;
15(2):213–22.
16. Nan X, Xie C, Yu X, Liu J. EGFR TKI as first-line treatment for patients with advanced EGFR
mutation-positive non-small-cell lung cancer. Oncotarget. 2017;8(43):75712–26.
17. Xu J, Zhang X, Yang H, Ding G, Jin B, Lou Y et al. Comparison of outcomes of tyrosine kinase
inhibitor in first- or second-line therapy for advanced non-small-cell lung cancer patients with
sensitive EGFR mutations. Oncotarget. 2016;7(42):68442–8.
18. Park K, Yu CJ, Kim SW, Lin MC, Sriuranpong V, Tsai CM et al. First-Line Erlotinib Therapy Until
and Beyond Response Evaluation Criteria in Solid Tumors Progression in Asian Patients
With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: The
ASPIRATION Study. JAMA Oncol. 2016;2(3):305–12.
19. Jiang T, Chu Q, Wang H, Zhou F, Gao G, Chen X et al. EGFR-TKIs plus local therapy demonstrated
survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC patients with oligometastatic or
oligoprogressive liver metastases. Int J Cancer. 2018; 144(10):2605–2612.
20. Mok TSK, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ et al. Gefitinib Plus Chemotherapy
Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell
Lung Cancer Resistant to First-Line Gefitinib (IMPRESS): Overall Survival and Biomarker Analyses.
J Clin Oncol. 2017;35(36):4027–34.
21. Nakamura A, Inoue A, Morita S, Hosomi Y, Kato T, Fukuhara T et al. Phase III study comparing
gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed
(GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR
mutations (NEJ009). J Clin Oncol. 2018;36(15_suppl):9005.
22. Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T et al. Afatinib versus gefitinib as first-line
treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a
phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577–89.
23. Paz-Ares L, Tan EH, O’Byrne K, Zhang L, Hirsh V, Boyer M et al. Afatinib versus gefitinib in patients
with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from
the phase IIb LUX-Lung 7 trial. Ann Oncol. 2017;28(2):270–7.
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24. Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-
based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-
Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol.
2015;16(2):141-51.
25. Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S et al. Improvement in Overall Survival
in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced
Non‑Small-Cell Lung Cancer and EGFR-Activating Mutations. J Clin Oncol. 2018;36(22):2244–50.
26. Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S et al. Dacomitinib versus gefitinib as first-
line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER
1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454–66.
27. Takeda M, Nakagawa K. Toxicity profile of epidermal growth factor receptor tyrosine kinase
inhibitors in patients with epidermal growth factor receptor gene mutation-positive lung cancer.
Mol Clin Oncol. 2017;6(1):3-6.
28. Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR
mutation-positive non-small cell lung cancer. Lung Cancer. 2015;88(1):74–9.
29. Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H et al. Quality of life
with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis
of North East Japan Study Group 002 Trial. Oncologist. 2012;17(6):863–70.
30. Metro G. EGFR targeted therapy for lung cancer: are we almost there? Transl Lung Cancer Res.
2018;7(Suppl 2):S142–s5.
31. Kohler J, Schuler M. Afatinib, erlotinib and gefitinib in the first-line therapy of EGFR mutation-
positive lung adenocarcinoma: a review. Onkologie. 2013;36(9):510–8.
32. Yang JC, Hirsh V, Schuler M, Yamamoto N, O’Byrne KJ, Mok TS et al. Symptom control and quality
of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with
advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3342–50.
33. Chen G, Feng J, Zhou C, Wu YL, Liu XQ, Wang C et al. Quality of life (QoL) analyses from
OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus
chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer
(NSCLC). Ann Oncol. 2013;24(6):1615–22.
34. Treatment options for advanced non-small cell lung cancer: Effectiveness, value and value-
based price benchmarks. Evidence Report. Boston: Institute for Clinical and Economic Review;
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38. Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive
non-small-cell lung cancer. Technology appraisal guidance [TA258]. London: National Institute
for Health and Care Excellence; 2012. Available from https://www.nice.org.uk/guidance/TA258,
accessed 29 September 2019.
39. ESMO-Magnitude of Clinical Benefit Scale. The ESMO-MCBS Score Card. Lugano: European Society
for Medical Oncology. Available from https://www.esmo.org/score/cards, accessed 29 September
2019.
40. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C et al. Erlotinib versus chemotherapy as first-
line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer
(OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol.
2011;12(8):735–42.
41. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V et al. Biomarker
analyses and final overall survival results from a phase III, randomized, open-label, first-line study
of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-
small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866–74.
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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
EML/EMLc
EML
Section
WHO Technical Report Series, No. 1021, 2019
Core/Complementary
Complementary
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).
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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.
Costs/cost-effectiveness
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,
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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,
WHO Technical Report Series, No. 1021, 2019
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).
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Applications for the 21st EML and the 7th EMLc
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.
Other considerations
N/A
Committee recommendations
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.
References
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3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018:
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9. Pawlyn C, Davies F, Cairns D, Striha A, Best P, Sigsworth R et al. Continuous treatment with
lenalidomide improves outcomes in newly diagnosed myeloma patients not eligible for
autologous stem cell transplant: results of the myeloma xi trial. Blood Conference: 59th annual
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for responders with newly diagnosed multiple myeloma in the randomized FIRST trial. Leukemia.
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12. Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA et al. Melphalan,
prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in
untreated multiple myeloma. Blood. 2015;126(11):1294–301.
13. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J et al. Continuous lenalidomide
treatment for newly diagnosed multiple myeloma.[Erratum appears in N Engl J Med. 2012 Jul
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31. Durie GM, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP et al. Bortezomib with
lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients
with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant
(SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017; 389(10068):519–527.
32. Jacobus SJ, Rajkumar SV, Weiss M, Stewart AK, Stadtmauer EA, Callander NS et al. Randomized
phase III trial of consolidation therapy with bortezomib-lenalidomide-Dexamethasone (VRd) vs
bortezomib-dexamethasone (Vd) for patients with multiple myeloma who have completed a
dexamethasone based induction regimen. Blood Cancer J. 2016;6(7):e448.
33. Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V et al. Bortezomib-
melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide
compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma:
updated follow-up and improved survival. J Clin Oncol. 2014;32(7):634–40.
34. A Randomized Study With Oral Melphalan + Prednisone (MP) Versus Melphalan, + Prednisone
+ Thalidomide (MPT) for Newly Diagnosesd Elderly Patients With Multiple Myeloma [Internet].
Bethesda: National Library of Medicine (ClinicalTrials.gov); 2011. Available from https://
clinicaltrials.gov/ct2/show/NCT01274403, accessed 29 September 2019.
35. ESMO-Magnitude of Clinical Benefit Scale. The ESMO-MCBS Score Card [website]. Lugano:
European Society for Medical Oncology. (https://www.esmo.org/score/cards, accessed 29
September 2019).
36. ESMO Magnitude of Clinical Benefit Scale v1.1. Form 2a: for therapies that are not likely to be
curative with primary endpoint of OS 2018. Lugano: European Society for Medical Oncology.
Available from https://www.esmo.org/content/download/117388/2059152/file/ESMO-MCBS-
Version-1-1-Evaluation-Form-2a-OS-24-Months.pdf, accessed 29 September 2019.
37. Sonneveld P, Goldschmidt H, Rosinol L, Blade J, Lahuerta JJ, Cavo M et al. Bortezomib-based
versus nonbortezomib-based induction treatment before autologous stem-cell transplantation
in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized,
controlled trials. J Clin Oncol. 2013;31(26):3279–87.
38. Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP et al. Bortezomib with
lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients
with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant
(SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519–27.
39. McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P et al. Lenalidomide
WHO Technical Report Series, No. 1021, 2019
43. Picot J, Cooper K, Bryant J, Clegg AJ. The clinical effectiveness and cost-effectiveness of bortezomib
and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the
first-line treatment of multiple myeloma: a systematic review and economic evaluation. Health
Technol Assess. 2011;15(41):1–204.
44. Garrison LP, Jr., Wang ST, Huang H, Ba-Mancini A, Shi H, Chen K et al. The cost-effectiveness of
initial treatment of multiple myeloma in the U.S. with bortezomib plus melphalan and prednisone
versus thalidomide plus melphalan and prednisone or lenalidomide plus melphalan and
prednisone with continuous lenalidomide maintenance treatment. Oncologist. 2013;18(1):27–36.
45. Schey S, Montero LFC, Stengel-Tosetti C, Gibson CJ, Dhanasiri S. The Cost Impact of Lenalidomide
for Newly Diagnosed Multiple Myeloma in the EU5. Oncol Ther. 2017;5(1):31–40.
46. Arikian SR, Milentijevic D, Binder G, Gibson CJ, Hu XH, Nagarwala Y et al. Patterns of total cost and
economic consequences of progression for patients with newly diagnosed multiple myeloma.
Curr Med Res Opin. 2015;31(6):1105–15.
47. Bortezomib and thalidomide for the first‑line treatment of multiple myeloma. Technology
appraisal guidance [TA228]. London: National Institute for Health and Care Excellence; 2011.
Available from https://www.nice.org.uk/guidance/ta228
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Proposal
The application requested the addition of atezolizumab, nivolumab and
pembrolizumab to the complementary list of the EML for the following
indications:
Applicant
Jean-Yves Douillard, Chief Medical Officer, European Society for Medical
Oncology (ESMO)
EML/EMLc
EML
Section
8.2.3 Immunomodulators
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Applications for the 21st EML and the 7th EMLc
Core/Complementary
Complementary
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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
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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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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
WHO Technical Report Series, No. 1021, 2019
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.
WHO Technical Report Series, No. 1021, 2019
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).
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WHO Guidelines
None available.
Costs/cost-effectiveness
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
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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.
Other considerations
WHO Technical Report Series, No. 1021, 2019
Committee recommendations
The Committee endorsed the recommendations of the EML 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 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
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ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised,
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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
037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375–84.
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-
CTLA-4 Therapy (CheckMate 037) (ClinicalTrials.gov Identifier: NCT01721746). Bethesda: U.S.
National Library of Medicine; 2017. Available from https://clinicaltrials.gov/ct2/show/results/
NCT01721746, accessed 209 September 2019
30. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L et al. Nivolumab in previously
untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.
31. Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM et al. Survival Outcomes in
Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab
Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019; 5(2):187–194.
32. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD et al. Combined Nivolumab and
Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23–34.
33. Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL et al. Nivolumab plus
ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067):
WHO Technical Report Series, No. 1021, 2019
39. Meng Y, Hertel N, Ellis J, Morais E, Johnson H, Philips Z et al. The cost-effectiveness of nivolumab
monotherapy for the treatment of advanced melanoma patients in England. Eur J Health Econ.
2018;19(8):1163–72.
40. Miguel LS, Lopes FV, Pinheiro B, Wang J, Xu R, Pellissier J et al. Cost Effectiveness of Pembrolizumab
for Advanced Melanoma Treatment in Portugal. Value Health. 2017;20(8):1065–73.
331
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
EML/EMLc
EML
Section
8.2.4 Hormones and antihormones
Enzalutamide: capsule 40 mg
Core/Complementary
Complementary
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.
Costs/cost-effectiveness
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
WHO Technical Report Series, No. 1021, 2019
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
Applications for the 21st EML and the 7th EMLc
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.
Other considerations
N/A
Committee recommendations
The Committee endorsed the recommendations of the EML 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 of
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
References
1. 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.
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018:
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA
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.
WHO Technical Report Series, No. 1021, 2019
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
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML
Section
10.2 Medicines affecting coagulation
339
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Core/Complementary
Core
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
Applications for the 21st EML and the 7th EMLc
344
Applications for the 21st EML and the 7th EMLc
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.
Costs/cost-effectiveness
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.
Application 2 – NVAF:
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Technical Report Series, No. 1021, 2019
Other considerations
N/A
Committee recommendations
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
Applications for the 21st EML and the 7th EMLc
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
EML/EMLc
EML
Section
12.3 Antihypertensive Medicines
Core/Complementary
Core
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.
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).
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Costs/cost-effectiveness
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).
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Availability
The proposed FDCs are available globally, either in the stated combinations, or
alternatives within pharmacological classes.
Other considerations
N/A
Committee recommendations
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
WHO Technical Report Series, No. 1021, 2019
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.
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bing za zhi. 2011;39(7):579–615.
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of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399–407.
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medication compliance: a meta-analysis. Am J Med. 2007;120(8):713-9.
55. Attaei MW, Khatib R, McKee M, Lear S, Dagenais G, Igumbor EU et al. Availability and affordability
of blood pressure-lowering medicines and the effect on blood pressure control in high-income,
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low-income countries: an analysis of the PURE study data. Lancet. 2016;387(10013):61–9.
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antihypertensives and their components. Am J Hypertens. 2008;21(5):509–13.
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improving hypertension management. Can J Clin Pharmacol. 2009;16(1):e151–5.
366
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML
Section
12.5.2 Thrombolytic medicines
Core/Complementary
Complementary
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
Costs/cost-effectiveness
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
WHO Technical Report Series, No. 1021, 2019
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.
Other considerations
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.
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Applications for the 21st EML and the 7th EMLc
Committee recommendations
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.
References
1. Feigin VL, Roth GA, Naghavi M, Parmar P, Krishnamurthi R, Chugh S et al. Global burden of stroke
and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of
Disease Study 2013. Lancet Neurol. 2016;15(9):913–24.
2. Global Burden of Disease compare data visualization. Seattle: Institute for Health Metrics and
Evaluation, University of Washington; 2016. Available from https://vizhub.Healthdata.Org/gbd-
compare/, accessed 29 September 2019.
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
stroke experts in 44 European countries. Eur Stroke J. 2019;4(1):13-28.
5. Schwamm LH, Ali SF, Reeves MJ, Smith EE, Saver JL, Messe S et al. Temporal trends in patient
characteristics and treatment with intravenous thrombolysis among acute ischemic stroke
patients at Get With The Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;
6(5):543–9.
6. Urimubenshi G, Cadilhac DA, Kagwiza JN, Wu O, Langhorne P. Stroke care in Africa: A systematic
review of the literature. Int J Stroke. 2018;13(8):797–805.
7. Pandian JD, William AG, Kate MP, Norrving B, Mensah GA, Davis S et al. Strategies to Improve Stroke
Care Services in Low- and Middle-Income Countries: A Systematic Review. Neuroepidemiology.
2017;49(1-2):4561.
8. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane
Database Syst Rev. 2014(7):CD000213.
9. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E et al. Effect of treatment delay,
age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute
ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet.
2014;384(9958):1929–35.
10. Engelter ST, Fluri F, Buitrago-Tellez C, Marsch S, Steck AJ, Ruegg S et al. Life-threatening orolingual
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):
1525–7.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
12. Preparation for the third High-level Meeting of the General Assembly on the Prevention and
Control of Non-communicable Diseases, to be held in 2018 - Report by the Director-General.
Geneva: World Health Organization; 2018. Available from http://apps.who.int/gb/ebwha/pdf_
files/WHA70/A70_27-en.pdf, 29 September 2019.
13. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K et al. 2018
Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for
Healthcare Professionals From the American Heart Association/American Stroke Association.
Stroke. 2018;49(3):e46–e110.
14. Boulanger JM, Lindsay MP, Gubitz G, Smith EE, Stotts G, Foley N et al. Canadian Stroke Best Practice
Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and
Acute Inpatient Stroke Care, 6th Edition, Update 2018. Int J Stroke. 2018;13(9):949–84.
15. Bryer A, Connor M, Haug P, Cheyip B, Staub H, Tipping B et al. South African guideline for
management of ischaemic stroke and transient ischaemic attack 2010: a guideline from the
South African Stroke Society (SASS) and the SASS Writing Committee. S Afr Med J. 2010;100(11 Pt
2):747–78.
16. Dong Q, Dong Y, Liu L, Xu A, Zhang Y, Zheng H et al. The Chinese Stroke Association scientific
statement: intravenous thrombolysis in acute ischaemic stroke. Stroke Vasc Neurol. 2017;2(3):
147–59.
17. Michel P, Engelter S, Arnold M, Hungerbühler HJ, Nedeltchev K, Georgiadis D et al. Thrombolyse
de l’attaque cérébrale ischémique : Recommandations actualisées. Swiss Medical Forum.
2009;9(49):982–4.
18. Cho KH, Ko SB, Kim DH, Park HK, Cho AH, Hong KS et al. Focused Update of Korean Clinical Practice
Guidelines for the Thrombolysis in Acute Stroke Management. Korean J Stroke. 2012;14:95–105.
19. Holmes M, Davis S, Simpson E. Alteplase for the treatment of acute ischaemic stroke: a NICE
single technology appraisal; an evidence review group perspective. Pharmacoeconomics.
2015;33(3):225–33.
20. Kleindorfer D, Broderick J, Demaerschalk B, Saver J. Cost of Alteplase Has More Than Doubled
Over the Past Decade. Stroke. 2017;48(7):2000–2.
21. Dirks M, Baeten SA, Dippel DW, van Exel NJ, van Wijngaarden JD, Huijsman R et al. Real-life
costs and effects of an implementation program to increase thrombolysis in stroke. Neurology.
2012;79(6):508–14.
WHO Technical Report Series, No. 1021, 2019
22. Penaloza-Ramos MC, Sheppard JP, Jowett S, Barton P, Mant J, Quinn T et al. Cost-effectiveness of
optimizing acute stroke care services for thrombolysis. Stroke. 2014;45(2):553–62.
23. Pan Y, Chen Q, Zhao X, Liao X, Wang C, Du W et al. Cost-effectiveness of thrombolysis within
4.5 hours of acute ischemic stroke in China. PLoS One. 2014;9(10):e110525.
24. Araujo DV, Teich V, Passos RB, Martins SC. Analysis of the cost-effectiveness of thrombolysis with
alteplase in stroke. Arq Bras Cardiol. 2010;95(1):12–20.
25. Joo H, Wang G, George MG. A literature review of cost-effectiveness of intravenous recombinant
tissue plasminogen activator for treating acute ischemic stroke. Stroke Vasc Neurol. 2017;2(2):
73–83.
372
Applications for the 21st EML and the 7th EMLc
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)
EML/EMLc
EML and EMLc
Section
17.2 Antiemetic medicines
Core/Complementary
Complementary
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Technical Report Series, No. 1021, 2019
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).
WHO Guidelines
None available.
Costs/cost-effectiveness
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Other considerations
Aprepitant should be used in combination with dexamethasone and a 5-HT3
receptor antagonist.
Committee recommendations
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.
WHO Technical Report Series, No. 1021, 2019
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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Applications for the 21st EML and the 7th EMLc
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
EML/EMLc
EML and EMLc
Section
2.3 Medicines for other common symptoms in palliative care
17.2 Antiemetic medicines
WHO Technical Report Series, No. 1021, 2019
Core/Complementary
Core
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Applications for the 21st EML and the 7th EMLc
WHO Guidelines
None available.
Costs/cost-effectiveness
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Availability
The 5-HT3 receptor antagonists have wide market availability and are available
in generic forms.
Other considerations
N/A
Committee recommendations
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
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2009
(including the 16th WHO Model List of Essential Medicines and the 2nd WHO Model List of
Essential Medicines for Children) (WHO Technical Report Series, No. 958). Geneva: World Health
Organization; 2009. Available from https://apps.who.int/iris/bitstream/handle/10665/44287/
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.
WHO Technical Report Series, No. 1021, 2019
382
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EMLc
Section
17.5 Medicines used in diarrhoea
Core/Complementary
Core
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
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Applications for the 21st EML and the 7th EMLc
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
Costs/cost-effectiveness
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.
Other considerations
The Committee noted the multiple letters of support received in relation to this
application.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Committee recommendations
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
WHO Technical Report Series, No. 1021, 2019
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
Applications for the 21st EML and the 7th EMLc
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.
EML/EMLc
EML
Section
Core
Core/Complementary
Core
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
deaths (7).
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
to intermediate-acting (human) insulin administered qid
(MD −0.49, 95%CI −0.70 to −0.29).
–– Long-acting (human) insulin administered bid was superior
to intermediate-acting (human) insulin administered od
(MD −0.18, 95%CI −0.30 to −0.06).
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
Applications for the 21st EML and the 7th EMLc
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
Costs/cost-effectiveness
WHO Technical Report Series, No. 1021, 2019
396
Applications for the 21st EML and the 7th EMLc
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.
Other considerations
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.
Committee recommendations
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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2004;6(5):579–88.
402
Applications for the 21st EML and the 7th EMLc
64. Tunbridge FK, Newens A, Home PD, Davis SN, Murphy M, Burrin JM et al. Double-blind crossover
trial of isophane (NPH)- and lente-based insulin regimens. Diabetes Care. 1989;12(2):115–9.
65. Vague P, Selam JL, Skeie S, De Leeuw I, Elte JW, Haahr H et al. Insulin detemir is associated
with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in
patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes
Care. 2003;26(3):590–6.
66. van Golen LW, Veltman DJ, RG IJ, Deijen JB, Heijboer AC, Barkhof F et al. Effects of insulin detemir
and NPH insulin on body weight and appetite-regulating brain regions in human type 1 diabetes:
a randomized controlled trial. PLoS One. 2014;9(4):e94483.
67. Vaughan K. An Open-Label, Randomized, Multi-center, Parallel-Group Clinical Trial Comparing
the Efficacy and Safety of Mylan’s Insulin Glargine with Lantus in Type 1 Diabetes Mellitus
Patients. Amsterdam: European Medicines Agency/EU Clinical Trials Register; 2017. Available
from https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000747-32/results, accessed 29
September 2019.
68. Verma M, Hazra P, Iyer H, Arun A, Akundi S, Dixit MN et al. Basalog® is similar to Lantus® in
producing glycemic control in patients with type 1 diabetes mellitus on multiple daily insulin
regimens. Int J Diabetes Dev Ctries. 2011;31(1):26–31.
69. Witthaus E, Stewart J, Bradley C. Treatment satisfaction and psychological well-being with insulin
glargine compared with NPH in patients with Type 1 diabetes. Diabet Med. 2001;18(8):619–25.
70. Zachariah S, Sheldon B, Shojaee-Moradie F, Jackson NC, Backhouse K, Johnsen S et al. Insulin
detemir reduces weight gain as a result of reduced food intake in patients with type 1 diabetes.
Diabetes Care. 2011;34(7):1487–91.
71. Evans M, Wolden M, Gundgaard J, Chubb B, Christensen T. Cost-effectiveness of insulin degludec
compared with insulin glargine in a basal-bolus regimen in patients with type 1 diabetes
mellitus in the UK. J Med Econ. 2015;18(1):56–68.
72. Gschwend MH, Aagren M, Valentine WJ. Cost-effectiveness of insulin detemir compared with
neutral protamine Hagedorn insulin in patients with type 1 diabetes using a basal-bolus regimen
in five European countries. J Med Econ. 2009;12(2):114–23.
73. Tunis SL, Minshall ME, Conner C, McCormick JI, Kapor J, Yale JF et al. Cost-effectiveness of insulin
detemir compared to NPH insulin for type 1 and type 2 diabetes mellitus in the Canadian payer
setting: modeling analysis. Curr Med Res Opin. 2009;25(5):1273–84.
74. Valentine WJ, Palmer AJ, Erny-Albrecht KM, Ray JA, Cobden D, Foos V et al. Cost-effectiveness of
basal insulin from a US health system perspective: comparative analyses of detemir, glargine,
and NPH. Adv Ther. 2006;23(2):191–207.
75. Valentine WJ, Aagren M, Haglund M, Ericsson A, Gschwend MH. Evaluation of the long-term
cost-effectiveness of insulin detemir compared with neutral protamine hagedorn insulin in
patients with type 1 diabetes using a basal-bolus regimen in Sweden. Scand J Public Health.
2011;39(1):79–87.
76. Karges B, Kapellen T, Neu A, Hofer SE, Rohrer T, Rosenbauer J et al. Long-acting insulin analogs
and the risk of diabetic ketoacidosis in children and adolescents with type 1 diabetes: a
prospective study of 10,682 patients from 271 institutions. Diabetes Care. 2010;33(5):1031–3.
77. Thalange N, Deeb L, Iotova V, Kawamura T, Klingensmith G, Philotheou A et al. Insulin degludec
in combination with bolus insulin aspart is safe and effective in children and adolescents with
type 1 diabetes. Pediatr Diabetes. 2015;16(3):164–76.
78. Mona HM, Maha AM, Hend SM, Hanan NM. Effect of insulin glargine on glycemic control in
adolescents with type 1-diabetes. Egyptian Pediatric Association Gazette. 2015;63(2):35–8.
403
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
79. Sharef SW, Ullah I, Al-Shidhani A, Al-Farsi T, Al-Yaarubi S. Switching to multiple daily insulin
injections in children and adolescents with type 1 diabetes: revisiting benefits from oman.
Oman Med J. 2015;30(2):83–9.
80. Biester T, Blaesig S, Remus K, Aschemeier B, Kordonouri O, Granhall C et al. Insulin degludec’s ultra-
long pharmacokinetic properties observed in adults are retained in children and adolescents
with type 1 diabetes. Pediatr Diabetes. 2014;15(1):27–33.
81. Danne T, Phillip M, Buckingham BA, Jarosz-Chobot P, Saboo B, Urakami T et al. ISPAD Clinical
Practice Consensus Guidelines 2018: Insulin treatment in children and adolescents with diabetes.
Pediatr Diabetes. 2018;19 Suppl 27:115–35.
82. Passanisi S, Timpanaro T, Lo Presti D, Mammi C, Caruso-Nicoletti M. Treatment of transient
neonatal diabetes mellitus: insulin pump or insulin glargine? Our experience. Diabetes Technol
Ther. 2014;16(12):880–4.
83. Park JH, Shin SY, Shim YJ, Choi JH, Kim HS. Multiple daily injection of insulin regimen for a
10-month-old infant with type 1 diabetes mellitus and diabetic ketoacidosis. Ann Pediatr
Endocrinol Metab. 2016;21(2):96–8.
84. 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. Geneva: World Health Organization;
2018. Available from https://apps.who.int/iris/bitstream/handle/10665/272433/9789241550284-
eng.pdf?ua=1, accessed 29 September 2019.
85. Tricco AC, Ashoor HM, Antony J, Beyene J, Veroniki AA, Isaranuwatchai W et al. Safety, effectiveness,
and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1
diabetes: systematic review and network meta-analysis. BMJ. 2014;349:g5459.
86. Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J et al. Long-acting insulin
analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane
Database Syst Rev. 2007(2):CD005613.
87. Fullerton B, Siebenhofer A, Jeitler K, Horvath K, Semlitsch T, Berghold A et al. Short-acting insulin
analogues versus regular human insulin for adults with type 1 diabetes mellitus. Cochrane
Database Syst Rev. 2016(6):CD012161.
88. Beran D, Ewen M, Laing R. Constraints and challenges in access to insulin: a global perspective.
Lancet Diabetes Endocrinol. 2016;4(3):275–85.
89. Ogle GD, Middlehurst AC, Silink M. The IDF Life for a Child Program Index of diabetes care for
WHO Technical Report Series, No. 1021, 2019
404
Applications for the 21st EML and the 7th EMLc
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)
EML/EMLc
EMLc
Section
18.6 Medicines for hypoglycaemia
Core/Complementary
Complementary
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Costs/cost-effectiveness
No information was provided in the application regarding the cost and cost-
effectiveness of diazoxide.
Preliminary results of an international survey of paediatric endocrinologists
WHO Technical Report Series, No. 1021, 2019
Availability
Global availability, reliable supply and regulatory approval of diazoxide is variable.
Other considerations
N/A
Committee recommendations
The Committee recommended the addition of diazoxide to the complementary
list of the EMLc for the management of hypoglycaemia secondary to prolonged
408
Applications for the 21st EML and the 7th EMLc
References
1. Arnoux JB, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V et al. Congenital
hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63.
2. Hussain K, Blankenstein O, De Lonlay P, Christesen HT. Hyperinsulinaemic hypoglycaemia:
biochemical basis and the importance of maintaining normoglycaemia during management.
Arch Dis Child. 2007;92(7):568–70.
3. Avatapalle HB, Banerjee I, Shah S, Pryce M, Nicholson J, Rigby L et al. Abnormal Neurodevelopmental
Outcomes are Common in Children with Transient Congenital Hyperinsulinism. Front Endocrinol
(Lausanne). 2013;4:60.
4. Ludwig A, Ziegenhorn K, Empting S, Meissner T, Marquard J, Holl R et al. Glucose metabolism and
neurological outcome in congenital hyperinsulinism. Semin Pediatr Surg. 2011;20(1):45–9.
5. Meissner T, Wendel U, Burgard P, Schaetzle S, Mayatepek E. Long-term follow-up of 114 patients
with congenital hyperinsulinism. Eur J Endocrinol. 2003;149(1):43–51.
6. Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V et al. Neurologic outcomes of 90 neonates
and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics. 2001;107(3):476–9.
7. Gong C, Huang S, Su C, Qi Z, Liu F, Wu D et al. Congenital hyperinsulinism in Chinese patients:
5-yr treatment outcome of 95 clinical cases with genetic analysis of 55 cases. Pediatr Diabetes.
2016;17(3):227–34.
8. Guven A, Cebeci AN, Ellard S, Flanagan SE. Clinical and Genetic Characteristics, Management
and Long-Term Follow-Up of Turkish Patients with Congenital Hyperinsulinism. J Clin Res Pediatr
Endocrinol. 2016;8(2):197–204.
9. Demirbilek H, Arya VB, Ozbek MN, Akinci A, Dogan M, Demirel F et al. Clinical characteristics and
phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance
of recessive KATP channel mutations. Eur J Endocrinol. 2014;170(6):885–92.
10. Sawathiparnich P, Likitmaskul S, Angsusingha K, Nimkarn S, Chaichanwatanakul K, Laohapansang
M et al. Persistent hyperinsulinemic hypoglycemia of infancy: experience at Siriraj Hospital. J Med
Assoc Thai. 2002;85 Suppl 2:S506–12.
11. Banerjee I, Skae M, Flanagan SE, Rigby L, Patel L, Didi M et al. The contribution of rapid KATP
channel gene mutation analysis to the clinical management of children with congenital
hyperinsulinism. Eur J Endocrinol. 2011;164(5):733–40.
12. Yorifuji T, Horikawa R, Hasegawa T, Adachi M, Soneda S, Minagawa M et al. Clinical practice
guidelines for congenital hyperinsulinism. Clin Paediatr Endocrinol. 2017;26(3):127–52.
13. Yoshida K, Kawai M, Marumo C, Kanazawa H, Matsukura T, Kusuda S et al. High prevalence of severe
circulatory complications with diazoxide in premature infants. Neonatology. 2014;105(3):166–71.
14. Hu S, Xu Z, Yan J, Liu M, Sun B, Li W et al. The treatment effect of diazoxide on 44 patients with
congenital hyperinsulinism. J Pediatr Endocrinol Metab. 2012;25(11–12):1119–22.
409
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
15. Touati G, Poggi-Travert F, Ogier de Baulny H, Rahier J, Brunelle F, Nihoul-Fekete C et al. Long-
term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide:
a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr.
1998;157(8):628–33.
16. Abu-Osba YK, Manasra KB, Mathew PM. Complications of diazoxide treatment in persistent
neonatal hyperinsulinism. Arch Dis Child. 1989;64(10):1496–500.
17. Goode PN, Farndon JR, Anderson J, Johnston ID, Morte JA. Diazoxide in the management of
patients with insulinoma. World J Surg. 1986;10(4):586–92.
18. Silvani P, Camporesi A, Mandelli A, Wolfler A, Salvo I. A case of severe diazoxide toxicity. Paediatr
Anaesth. 2004;14(7):607–9.
19. Parker JJ, Allen DB. Hypertrophic cardiomyopathy after prolonged diazoxide therapy for
hyperinsulinemic hypoglycemia. J Pediatr. 1991;118(6):906–9.
20. Combs JT, Grunt JA, Brandt IK. Hematologic reactions to diazoxide. Pediatrics. 1967;40(1):90-2.
21. McGraw ME, Price DA. Complications of diazoxide in the treatment of nesidioblastosis. Arch Dis
Child. 1985;60(1):62–4.
22. Ponmani C, Gannon H, Hussain K, Senniappan S. Paradoxical hypoglycaemia associated with
diazoxide therapy for hyperinsulinaemic hypoglycaemia. Horm Res Paediatr. 2013;80(2):129–33.
23. Darendeliler F, Bundak R, Bas F, Saka N, Gunoz H. Long-term diazoxide treatment in persistent
hyperinsulinemic hypoglycemia of infancy: a patient report. J Pediatr Endocrinol Metab.
1997;10(1):79–81.
24. Tas E, Mahmood B, Garibaldi L, Sperling M. Liver injury may increase the risk of diazoxide toxicity:
a case report. Eur J Pediatr. 2015;174(3):403–6.
25. Herrera A, Vajravelu ME, Givler S, Mitteer L, Avitabile CM, Lord K et al. Prevalence of Adverse
Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. J Clin Endocrinol
Metab. 2018;103(12):4365–72.
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.
WHO Technical Report Series, No. 1021, 2019
410
Applications for the 21st EML and the 7th EMLc
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)
EML/EMLc
EML and EMLc
Section
18.8 Thyroid hormones and antithyroid medicines
Core/Complementary
Methimazole: core
Propylthiouracil: complementary
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
412
Applications for the 21st EML and the 7th EMLc
malformations associated with PTU may be less severe and easier to correct
than those associated with MMI and CMZ.
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/cost-effectiveness
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
WHO Technical Report Series, No. 1021, 2019
Other considerations
N/A
Committee recommendations
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.
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Applications for the 21st EML and the 7th EMLc
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML
Section
22.3 Uterotonics
Core/Complementary
Core
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
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Applications for the 21st EML and the 7th EMLc
was very low certainty evidence of a difference in effect between carbetocin and
oxytocin for the outcome of PPH ≥1000 mL.
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.
Costs/cost-effectiveness
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
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
Other considerations
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
WHO Technical Report Series, No. 1021, 2019
Committee recommendations
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.
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Applications for the 21st EML and the 7th EMLc
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:
World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Department of Reproductive Health and Research
EML/EMLc
EML
Section
22.3 Uterotonics
WHO Technical Report Series, No. 1021, 2019
Core/Complementary
Core
422
Applications for the 21st EML and the 7th EMLc
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).
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Costs/cost-effectiveness
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.
Other considerations
The Committee noted the large number of letters of support received in relation
to this application.
Committee recommendations
WHO Technical Report Series, No. 1021, 2019
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.
3. 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.
4. The selection and use of essential medicines. Report of the WHO Expert Committee, 2005
(including the 14th Model List of Essential Medicines) (WHO Technical Report Series, No. 933).
Geneva: World Health Organization; 2005.
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,
accessed 29 September 2019.
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.
Available from https://apps.who.int/iris/bitstream/handle/10665/97415/9789241548717_eng.
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
Database Syst Rev. 2015(7):CD011242.
427
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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.
WHO Technical Report Series, No. 1021, 2019
428
Applications for the 21st EML and the 7th EMLc
Proposal
The application requested the deletion of misoprostol from the EML for the
indication of prevention of postpartum haemorrhage.
Applicant
Petra Sevcikova, Allyson Pollock
EML/EMLc
EML
Section
22.3 Uterotonics
Core/Complementary
Core
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).
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.
Costs/cost-effectiveness
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
WHO Technical Report Series, No. 1021, 2019
N/A
Other considerations
N/A
Committee recommendations
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
Applications for the 21st EML and the 7th EMLc
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.
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. 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.
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:
World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/
10665/277276/9789241550420-eng.pdf?ua=1&ua=1, accessed 29 September 2019.
433
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Department of Reproductive Health and Research
EML/EMLc
EML
Section
22.5 Other medicines administered to the mother
Core/Complementary
Core
434
Applications for the 21st EML and the 7th EMLc
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
WHO Technical Report Series, No. 1021, 2019
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.
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.
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.
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
–– 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
WHO Technical Report Series, No. 1021, 2019
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
Applications for the 21st EML and the 7th EMLc
Availability
Tranexamic acid 100 mg/mL injection is available from multiple generic
manufacturers.
Other considerations
N/A
Committee recommendations
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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
References
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2009
(including the 16th WHO Model List of Essential Medicines and the 2nd WHO Model List of
Essential Medicines for Children) (WHO Technical Report Series, No. 958). Geneva: World Health
Organization; 2009. Available from https://apps.who.int/iris/bitstream/handle/10665/44287/
WHO_TRS_958_eng.pdf, accessed 30 October 2019.
2. The selection and use of essential medicines. Report of the WHO Expert Committee, 2011
(including the 17th WHO Model List of Essential Medicines and the 3rd WHO Model List of
Essential Medicines for Children) (WHO Technical Report Series, No. 965). Geneva: World Health
Organization; 2012. Available from https://apps.who.int/iris/bitstream/handle/10665/44771/
WHO_TRS_965_eng.pdf, accessed 30 October 2019.
3. Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J et al. Global causes of maternal death: a
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.
Geneva: World Health Organization; 2017. Available from https://www.who.int/reproductive
health/publications/tranexamic-acid-pph-treatment/en/, accessed 30 October 2019.
8. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva:
World Health Organization; 2012. Available from https://www.who.int/reproductivehealth/
publications/maternal_perinatal_health/9789241548502/en/, accessed 30 October 2019.
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.
WHO Technical Report Series, No. 1021, 2019
440
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML and EMLc
Section
24 Medicines used in behavioural disorders
Core/Complementary
Complementary
441
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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).
442
Applications for the 21st EML and the 7th EMLc
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).
Costs/cost-effectiveness
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.
WHO Technical Report Series, No. 1021, 2019
Other considerations
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
Applications for the 21st EML and the 7th EMLc
Committee recommendations
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.
References
1. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE et al. Global burden of
disease attributable to mental and substance use disorders: findings from the Global Burden of
Disease Study 2010. Lancet. 2013;382(9904):1575–86.
2. Erskine HE, Ferrari AJ, Nelson P, Polanczyk GV, Flaxman AD, Vos T et al. Epidemiological modelling
of attention-deficit/hyperactivity disorder and conduct disorder for the Global Burden of Disease
Study 2010. J Child Psychol Psychiatry. 2013;54(12):1263–74.
3. Erskine HE, Ferrari AJ, Polanczyk GV, Moffitt TE, Murray CJ, Vos T et al. The global burden of
conduct disorder and attention-deficit/hyperactivity disorder in 2010. J Child Psychol Psychiatry.
2014;55(4):328–36.
4. Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity
disorder: a systematic review and meta-analysis. Pediatrics. 2015;135(4):e994–1001.
5. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD:
a systematic review and metaregression analysis. Am J Psychiatry. 2007;164(6):942–8.
6. Storebo OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M et al. Methylphenidate
for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane
Database Syst Rev. 2015(11):CD009885.
7. Bental B, Tirosh E. The effects of methylphenidate on word decoding accuracy in boys with
attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2008;28(1):89–92.
8. Flintoff MM, Barron RW, Swanson JM, Ledlow A, Kinsbourne M. Methylphenidate increases
selectivity of visual scanning in children referred for hyperactivity. J Abnorm Child Psychol.
1982;10(2):145–61.
9. Arnold LE, Christopher J, Huestis R, Smeltzer DJ. Methylphenidate vs dextroamphetamine vs
caffeine in minimal brain dysfunction: controlled comparison by placebo washout design with
Bayes' analysis. Arch Gen Psychiatry. 1978;35(4):463–73.
10. Weiss G, Minde K, Douglas V, Werry J, Sykes D. Comparison of the effects of chlorpromazine,
dextroamphetamine and methylphenidate on the behaviour and intellectual functioning of
hyperactive children. Can Med Assoc J. 1971;104(1):20–5.
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Pediatrics. 1999;104(6):1300–11.
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449
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
EML/EMLc
EML
WHO Technical Report Series, No. 1021, 2019
Section
24.2.1 Medicines used in depressive disorders
Core/Complementary
Core
450
Applications for the 21st EML and the 7th EMLc
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.
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).
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)
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
Costs/cost-effectiveness
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.
Other considerations
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.”
Committee recommendations
The Committee recommended the addition of a square box symbol to the
WHO Technical Report Series, No. 1021, 2019
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
Applications for the 21st EML and the 7th EMLc
References
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Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of
Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Can J Psychiatry.
2016;61(9):540–60.
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15. Gelenberg AJ, Marlene Freeman CP, Markowitz JC et al. Practice guideline for the treatment
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21. Mencacci C, Di Sciascio G, Katz P, Ripellino C. Cost-effectiveness evaluation of escitalopram in
major depressive disorder in Italy. ClinicoEconomics and outcomes research : CEOR. 2013;5:87–99.
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24. Sorensen J, Stage KB, Damsbo N, Le Lay A, Hemels ME. A Danish cost-effectiveness model of
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depressive disorder in primary care. Nord J Psychiatry. 2007;61(2):100–8.
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WHO Technical Report Series, No. 1021, 2019
456
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EML
Section
25.1 Antiasthmatic and medicines for COPD
Core/Complementary
Core
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.
Costs/cost-effectiveness
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.
WHO Technical Report Series, No. 1021, 2019
Availability
Tiotropium has wide international availability and is available in generic brands.
Other considerations
N/A
460
Applications for the 21st EML and the 7th EMLc
Committee recommendations
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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in COPD: a pooled safety analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:239-59.
WHO Technical Report Series, No. 1021, 2019
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
Applications for the 21st EML and the 7th EMLc
Proposal
The application requested a correction to the strength of iodine capsules listed
on the EML and EMLc
Applicant
Guerbet
EML/EMLc
EML and EMLc
Section
27. Vitamin and Minerals
Core/Complementary
Core
WHO Guidelines
N/A
Costs/cost-effectiveness
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).
Other considerations
N/A
Committee recommendations
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).
WHO Technical Report Series, No. 1021, 2019
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/
iris/bitstream/handle/10665/39338/WHO_TRS_796.pdf, accessed 30 October 2019.
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
Applications for the 21st EML and the 7th EMLc
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
EML/EMLc
EMLc
Section
27. Vitamins and minerals
Core/Complementary
Core
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).
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).
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).
WHO Technical Report Series, No. 1021, 2019
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
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Applications for the 21st EML and the 7th EMLc
Costs/cost-effectiveness
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)
Other considerations
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.
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Committee recommendations
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.
Available from https://apps.who.int/iris/bitstream/handle/10665/177094/9789241564960_eng.
pdf, accessed 30 October 2019.
2. Intermittent iron supplementation in pre-school and school-age children. Geneva: World
Health Organization; 2011. Available from https://apps.who.int/iris/bitstream/handle/10665/
44648/9789241502009_eng.pdf, accessed 30 October 2019.
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
Health Organization; 2016. Available from https://apps.who.int/iris/bitstream/handle/10665/
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.
Cochrane Database Syst Rev. 2011(9):CD008959.
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).
WHO Technical Report Series, No. 1021, 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.
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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
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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.
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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.
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5. ANTICONVULSANTS/ANTIEPILEPTICS (continued)
Complementary List
ethosuximide Capsule: 250 mg.
Oral liquid: 250 mg/5 mL.
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
albendazole Tablet (chewable): 400 mg.
diethylcarbamazine Tablet: 50 mg; 100 mg (dihydrogen citrate).
ivermectin Tablet (scored): 3 mg.
6.1.3 Antischistosomals and other antitrematode medicines
praziquantel Tablet: 600 mg.
triclabendazole Tablet: 250 mg.
Complementary List
oxamniquine* Capsule: 250 mg.
Oral liquid: 250 mg/5 mL.
* Oxamniquine is listed for use when praziquantel treatment fails.
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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
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Complementary List
potassium iodide Saturated solution.
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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.
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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.
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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.
Tablet (scored): 50 mg.
nifurtimox Tablet: 30 mg; 120 mg; 250 mg.
6.6 Medicines for ectoparasitic infections
ivermectin Tablet (scored): 3 mg.
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7. ANTIMIGRAINE MEDICINES
7.1 For treatment of acute attack
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] .
Tablet: 300 mg to 500 mg.
7.2 For prophylaxis
propranolol Tablet: 20 mg; 40 mg (hydrochloride).
8. IMMUNOMODULATORS AND ANTINEOPLASTICS
8.1 Immunomodulators for non-malignant disease
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.
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- Rhabdomyosarcoma
- Ewing sarcoma
- Acute lymphoblastic leukaemia
- Burkitt lymphoma
- Metastatic breast cancer
- Multiple myeloma.
cytarabine Powder for injection: 100 mg in vial.
- Acute myeloid leukaemia
- Acute lymphoblastic leukaemia
- Acute promyelocytic leukaemia
- Burkitt lymphoma.
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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
WHO Technical Report Series, No. 1021, 2019
Complementary List
deferoxamine* Powder for injection: 500 mg (mesilate) in vial.
* Deferasirox oral form may be an alternative, depending on cost
and availability.
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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.
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16. DIURETICS
amiloride Tablet: 5 mg (hydrochloride).
furosemide Injection: 10 mg/ mL in 2- mL ampoule.
Oral liquid: 20 mg/5 mL [c] .
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.
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17.4 Laxatives
senna Tablet: 7.5 mg (sennosides) (or traditional dosage forms).
17.5 Medicines used in diarrhoea
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.
525
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Complementary List
Lugol’s solution [c] Oral liquid: about 130 mg total iodine/ mL.
methimazole* [c] Tablet: 5mg, 10mg, 20mg.
* Carbimazole is an alternative depending on local availability.
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.
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HPV vaccine
measles vaccine
pertussis vaccine
pneumococcal vaccine
poliomyelitis vaccine
rotavirus vaccine
rubella vaccine
tetanus vaccine
528
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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)
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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
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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.
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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.
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.
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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
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549
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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
Annex 2: 7th WHO Model List of Essential Medicines for Children (2019)
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.
551
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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
albendazole Tablet (chewable): 400 mg.
diethylcarbamazine Tablet: 50 mg; 100 mg (dihydrogen citrate).
ivermectin Tablet (scored): 3 mg.
6.1.3 Antischistosomals and other antitrematode medicines
praziquantel Tablet: 600 mg.
triclabendazole Tablet: 250 mg.
Complementary List
oxamniquine* Capsule: 250 mg.
Oral liquid: 250 mg/5 mL.
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- uncomplicated severe
acute malnutrition
- progressive apical dental
abscess
554
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555
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557
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558
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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.
Tablet: 400 mg; 600 mg.
polymyxin B Powder for injection: 500,000 I.U. in vial.
562
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Complementary List
potassium iodide Saturated solution.
565
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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
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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.
a >25 kg.
metronidazole Injection: 500 mg in 100-mL vial.
Oral liquid: 200 mg (as benzoate)/5 mL.
Tablet: 200 mg to 500 mg.
568
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Complementary List
melarsoprol Injection: 3.6% solution in 5-mL ampoule (180 mg of
active compound).
6.5.5.2 American trypanosomiasis
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7. ANTIMIGRAINE MEDICINES
7.1 For treatment of acute attack
ibuprofen Tablet: 200 mg; 400 mg.
paracetamol Oral liquid: 120 mg/5 mL; 125 mg/5 mL.
Tablet: 300 mg to 500 mg.
7.2 For prophylaxis
propranolol Tablet: 20 mg; 40 mg (hydrochloride).
8. IMMUNOMODULATORS AND ANTINEOPLASTICS
8.1 Immunomodulators for non-malignant disease
Complementary List
adalimumab* Injection: 40 mg/0.8 mL; 40 mg/0.4 mL.
* Etanercept and infliximab are alternatives, including quality-
assured biosimilars.
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- Osteosarcoma
- Testicular germ cell tumours
- Ovarian germ cell tumours
- Nasopharyngeal cancer
cyclophosphamide Powder for injection: 500 mg in vial.
Tablet: 25 mg; 50 mg.
- Rhabdomyosarcoma
- Ewing sarcoma
- Acute lymphoblastic leukaemia
- Burkitt lymphoma
- Hodgkin lymphoma
- Diffuse large B-cell lymphoma
574
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8.2.3 Immunomodulators
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
WHO Technical Report Series, No. 1021, 2019
myelotoxic chemotherapy.
- Secondary prophylaxis for patients who have
experienced neutropenia following prior myelotoxic
chemotherapy
- To facilitate administration of dose dense
chemotherapy regimens
578
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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.
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
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589
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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
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594
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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.
597
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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
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B02 Antihemorrhagics
B02A Antifibrinolytics
B02AA Amino acids
B02AA02 tranexamic acid 10.2, 22.5
B02B Vitamin K and other hemostatics
B02BA Vitamin K
WHO Technical Report Series, No. 1021, 2019
600
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
601
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
C02 Antihypertensives
C02A Antiadrenergic agents, centrally acting
WHO Technical Report Series, No. 1021, 2019
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
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
603
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
D DERMATOLOGICALS
D05 Antipsoriatics
D05A Antipsoriatics for topical use
D05AA Tars* 13.4
604
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
605
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
607
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
608
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
609
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
611
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
612
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
613
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614
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
615
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
L02BB Anti-androgens
L02BB03 bicalutamide 8.2.4
L03 Immunostimulants
L03A Immunostimulants
L03AA Colony stimulating factors
L03AA02 filgrastim 8.2.3
WHO Technical Report Series, No. 1021, 2019
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
616
Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
M MUSCULO-SKELETAL SYSTEM
N NERVOUS SYSTEM
N01 Anesthetics
N01A Anesthetics, general
N01AB Halogenated hydrocarbons
N01AB01 halothane 1.1.1
N01AB06 isoflurane 1.1.1
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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
WHO Technical Report Series, No. 1021, 2019
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
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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
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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
WHO Technical Report Series, No. 1021, 2019
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
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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
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R RESPIRATORY SYSTEM
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Annex 3: The Anatomical Therapeutic Chemical (ATC) Classification System
S SENSORY ORGANS
S01 Ophthalmologicals
S01A Antiinfectives
S01AA Antibiotics
S01AA09 tetracycline 21.1
S01AA10 natamycin 21.1
S01AA11 gentamicin 21.1
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S02 Otologicals
S02A Antiinfectives
S02AA Antiinfectives
S02AA10 acetic acid 28
S02AA15 ciprofloxacin 28
624
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625
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628
Annex 4: Alphabetical list of essential medicines (with ATC classification code numbers)
629
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Annex 4: Alphabetical list of essential medicines (with ATC classification code numbers)
631
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633
The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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Annex 4: Alphabetical list of essential medicines (with ATC classification code numbers)
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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Annex 4: Alphabetical list of essential medicines (with ATC classification code numbers)
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The Selection and Use of Essential Medicines Report of the 22nd WHO Expert Committee
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Annex 4: Alphabetical list of essential medicines (with ATC classification code numbers)
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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)
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