Managing Adverse Drug

Reaction

Dr Tan Sze Ming

IPR
 DEFINITION OF
ADVERSE DRUG REACTION (ADR)
• A response to a medicine which is unintended
or harm which occurs at a normal dosage during
normal use.

ONSET OF ADR FOR ANTITB

• ADRs occur within early stage of the
treatment compared to the later stage.
Kishore PV et al., Pa J Pharm Sci, 2008

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 RECOMMENDED ANTITB DRUGS
RECOMMENDED DOSES

DRUG Daily
Dose (range) in Maximum in mg
mg/kg
body weight

Isoniazid (H) 5 (4 - 6) 300

Rifampicin (R) 10 (8 - 12) 600
Pyrazinamide (Z) 25 (20 - 30) 2000

Ethambutol (E) 15 (15 - 20) 1600

Streptomycin (S) 15 (12 - 18) 1000

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 NEW CASES

• 6-month regimen consisting of 2 months of

EHRZ (2EHRZ) followed by 4 months of HR
(4HR) is recommended for newly-diagnosed
PTB.

To diagnose & treat an uncomplicated TB infection is

not difficult, but to treat the complication and adverse
effect that arise from it can be challenging.

The most important thing is to educate patient

regarding the disease & treatment plan.

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Anti-Tuberculosis Common Side Effects
Isoniazid Hepatitis/Jaundince, numbness and tingling sensation in the
hands/feet
Anorexia, nausea, vomiting,Abdominal pain
Skin rashes

Rifampicin Orange / red urine

Jaundice/hepatitis
Anorexia, nausea, abdominal pain
Flu symptoms (fever, chills, malaise, headache, bone pain)
Skin Rashes

Pyrazinamide Hepatitis/Jaundice, joint pain,

anorexia, nausea, abdominal pain,
skin rashes

Ethambutol Visual impairtment

Streptomycin Deafness/hearing impairment, dizziness, AKI
Skin rashes
FLOW CHART FOR 6 MONTHS
TREATMENT OF PTB

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 Epidemiology of anti TB adverse reaction

• More than 25% reported reactions to anti TB drugs

• Only less than 10% required termination or prolonged
suspension of treatment
• Mostly occur within first three months of treatment
 Timing of Adverse Event
• For antiTB treatment, most of ADRs occur
within early stage of the treatment compared
to the later stage (52.5% experience ADRs
within 20 days, 7.5% in 21 - 40 days, 22.5%
within 41 - 60 days & 17.5% in >60 days after
starting treatment).
Kishore PV et al., Pa J Pharm Sci., 2008

It is uncommon for ADR to happen after 2 months of anti TB, hence late presentation
of symptoms will prompt the treating physician to look for other causes of the
symptoms

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 SYSTEMS MOST AFFECTED BY
ANTITB DRUGS

• Hepatobiliary (57.1%)
• Gastrointestinal tract (14.3%)
• Skeletal system (9.5%)
• Skin (7.1%)
• Renal (4.8%)

Shang P et al., PLoS ONE, 2011

1

2
Teleman MD et al., Int J Tuberc Lung Dis, 2002

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 RISK FACTORS OF ADR FOR ANTITB
• Age >40 years • EPTB
• Overweight/obesity • MDR-TB medication
• Smoking • HIV infection
• Alcoholism • CD4 count <350 cells/mm3
• Anaemia • Hepatitis B virus infection
• Baseline ALT more than • Hepatitis C virus infection
twice upper limit of normal • Concomitant use of other
• Baseline aspartate hepatotoxic drugs
aminotransferase more than
twice upper limit of normal

Chung-Delgado K et al., PLoS ONE, 2011

1

2
Vilarica AS et al., Rev Port Pneumol, 2010
3
Khalili H et al., Factors DARU, 2009
4
Marzuki OA et al., Singapore Med J, 2008
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 CLASSIFICATION OF ADR FOR ANTITB

• Nausea Treat
• Tiredness symptomatically
Troublesome but WITHOUT
NOT SERIOUS • Pruritus
treatment
• Minor rashes interruption

• Severe skin reaction (Steven-

Johnson Syndrome, Toxic
Need IMMEDIATE Epidermal Necrolysis & Drug
DISCONTINUATION Rash with Eosinophilia &
Systemic Symptoms)
• Hepatitis
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 Cutaneous drug reaction
Morbiliform rash (72.3%)

Erythema multiforme syndrome

(8.5%)

Urticaria (8.5%)
Exfoliative dermatitis
Lichenoid eruption
Urticar
ia
Exfoliative dermatitis
 Steven Johnson
Lichenoid eruption syndrome
 Cutaneous drug reaction
Steven Johnson Syndrome (<10% BSA)

SJS/TEN overlap syndrome (10-20%)

Toxic epidermal necrolysis (>30%)

*SCORTEN

Drug reaction with eosinophilia and

systemic symptoms (DRESS)
 DRUG-INDUCED RASHES
Pyrazinamide (MOST)
Drug-Induced

Algorithm
Severe Cutaneous ADRs

Discontinue antiTB until the rashes subside

Reintroduce individual drug sequentially to identify the offending drug

Provide suitable regimen when an offending drug is identified

(If possible, regimen should include 2 most potent drugs namely
isoniazid & rifampicin )

Yee D et al., Am J Respir Crit Care Med, 2003

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Management cutaneous drug reaction

• ALL drugs must be withheld

• Drug timeline must be established
• The cutaneous eruption must be managed
• Dermatology referral if necessary
• Reintroduction should only be done once the eruption has
settled
Management cutaneous drug reaction
Questions?
• Polypharmacy
• Underlying hypersensitivity reaction
• Severity of cutaneous reaction

Never start bridging therapy for

cutaneous reaction
 Management Rechallenged
Reintroduce loose drug every 3-7 days
 Begin the re-challenge with introducing low dose anti TB

 If reaction does not occur after the day 1 dose, increase

to maximum dose on day 2
 If a reaction does not occur after the day 2 dose,
continue maximum dose.
 Continue to add new drugs every 3-7 days
 RECHALLANGED
• If the original reaction was severe, begin the rechallenged with 1/10 of the
maximum dose for the patient.
• If the day 2 dose is less than the normal recommended dose based on the
patient’s weight, increase to the appropriate dose on day 3
• Example for ethambutol dosing in a 70kg person
Ethambutol Ethambutol
Day 1 100mg 200mg
Day2 500mg 400mg
Day3 1000mg 1000mg

• If a reaction occurs during drug re-challange and the causative drug cannot be
discontinued, drug desensitization will be necessary.
Management cutaneous drug reaction- Re challenge
Drugs Day Dose

Isoniazid 1 50mg 100mg

2 300mg 300mg

3 Full dose Full dose

Rifampicin 75mg
4 150mg
INH Full dose
300mg
5 300mg
Full dose
Full dose
6 600mg
Full dose
Pyrazinamide 250mg
7 250mg
RIF + INH Full dose
1000mg
8 1000mg
Full dose
Full dose
9 Full dose
Full dose
Ethambutol 100mg
10 200mg
RIF + INH + PZA Full dose
500mg
11 400mg
Full dose
Full dose
DAY 1 OF TB TREATMENT 12
Full dose
Full dose

Girling DJ. Adverse effect of anti tuberculosis drugs. Drugs 1981;23. 56-74
 Problems during re-challenge
• Stop the last drug introduced
• Continue with the other drugs that were well tolerated
• Manage the rash
• Once rash has subside, continue to challenge with the rest of
the drugs
• If the drug in question is essential, it needs to be desensitized
 DRUG-INDUCED RASHES (cont.)
Desensitisation?
 If the offending drugs are both isoniazid & rifampicin
 If a suitable drug combination is available, it is not necessary to
perform desensitisation
 It is done by careful administration of increasing doses of the
drug under close supervision
 The patient should be receiving > 2 other TB medications before
undergoing drug desensitization.
 Second-line drug like fluoroquinolones, aminoglycosides,
cycloserine, clofazamine, are not encouraged as alternative
therapy for patient with drug allergy to first-line TB drugs as
they are usually reserved for MDR-TB
 Complex Cutaneous ADRs requires specialists consultation
Desensitization should not be attempt in severe skin reaction24
 Desensitization Protocols
• Re-challenge with the lower dose of anti-TB
• If reaction occurred, begin Desensitization with 1/10 of the lowest dose of
re-challenge

• Double each dose and administer twice daily until the recommended daily
dose has been achieved

• Then switch to once daily dosing

• If a reaction develops during desensitization, decrease the dose to the

highest previous dose that did not cause a reaction and begin increasing
the doses in smaller increments.
 steroids may be utilized if drug
desensitization is urgent
• Severe TB
• Severe Drug reaction
• Hypersensitivity to > 1 drug
 DRUG-INDUCED HEPATITIS

Risk Factors1,2 Drug-Induced

• Slow acetylators Pyrazinamide (MOST)
• Old age
Isoniazid
• Extensive TB disease
• Malnutrition Rifampicin (LEAST)
• Alcoholism
• Chronic viral hepatitis B & C
infections Monitoring
• Pregnancy until 90 days At least for the first 2 - 4 weeks is
recommended among all patients with
postpartum
antiTB treatment as DIH usually occurs
• HIV within the initial 2 months of treatment.
• Organ transplant recipients
1
Yew WW et al., Respirology, 2006
2
Blumberg HM et al., Am J Respir Crit Care Med, 2003
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 DRUG-INDUCED HEPATITIS (cont.)

When to Stop AntiTB?

• Serum transaminase level reaches 3
x ULN for patients with symptoms
suggestive of hepatitis
• Serum transaminase level reaches 5
x ULN for those without symptoms

Restarting
The patient can then be retreated with a
regimen containing fewer potentially
hepatotoxic drugs such as streptomycin,
ethambutol, isoniazid & fluoroquinolones.
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Drug-induced hepatitis is a diagnosis of exclusion. Other potential causes
of abnormal liver function tests should be assessed, such as alcohol,
acetaminophen, viral hepatitis, gallstones, and biliary obstruction.
 Drug-induced hepatitis – Bridging therapy
• Ensure patient to still be on treatment while their
DILI resolves
• In general, in cases where there should be no
interruption in therapy (such as severe disease with
progressive loss of pulmonary function or current
smear-positive disease), three drugs (SEO/L) could
be started until the transaminase concentration
returns to less than two to three times the upper
limit of normal
• Does not count as doses of treatment
• Options: streptomycin, ethambutol and
ofloxacin/Levofloxacin (not hepatotoxic) – SEO/L
DRUG-INDUCED HEPATITIS (cont.)

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 Drug-induced hepatitis – re challenge
Drug Day Dose

SEO Full dose

1
Rifampicin 75mg
Full dose
2
300mg
Full dose
3
Full dose
SEO+R Full dose
4
Isoniazid 50mg
Full dose
5
300mg
Full dose
6
Full dose
S EO+H+R Full dose
7
Pyrazinamide 250mg
For those who have experienced prolonged or severe hepatotoxicity but tolerate
reintroduction with rifampin and isoniazid, rechallenge with Full dose
pyrazinamide may be
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500mg
hazardous. In this circumstance, pyrazinamide may be permanently discontinued with
extension of treatment to nine months. Full dose
9
Full dose
Day 1 of treatment SO E+H+R+Z 11 Full dose
 WHEN TO REFER
The following conditions should be referred to
specialists with experience in TB management:
•Unsure of TB diagnosis
•Retreatment of TB
•Adverse events following antiTB drugs
•MDR- & XDR-TB
•EPTB except TB lymphadenitis

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 WHEN TO REFER
• Renal &/or liver impairment with TB
• HIV-TB co-infection
• Smear negative TB
• Smear positive TB after 2 months of antiTB
treatment
• All children diagnosed as TB
• Maternal TB
• Complex TB cases requiring surgical
intervention
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• Thank you