You are on page 1of 53

TB Adverse Reaction & Management

Dr Syazatul Syakirin Sirol Aflah


Physician
Institut Perubatan Respiratori

TB course 26th August 2015


I will talk about .

Introduction
Anti TB medication
Management of common adverse reaction
Conclusion
Why do we need to treat?

Cure patients of TB by the shortest duration of drug administration with


minimum interference with their living
Prevent relapse of TB
Prevent emergence of drug resistance
Reduce transmission of disease to others
QUICK + EFFECTIVE - COMPLICATIONS = BEST THERAPY
Anti TB drugs

First line drugs

Streptomycin

Ethambutol

Isoniazid

Rifampicin

Pyrazinamide
Regimen
Rationale for combination therapy

Resistant strain emerges rapidly when single drug is used


Combination of 3 or 4 drugs delays or prevents emergence of
resistant strain
Enhances antimicrobial efficacy
Problem

Combination therapy means increasing risk of adverse drug reaction


ANTI TB MEDICATIONS
Isoniazid
Bacteriocidal against replicating bacilli
Inhibits cell wall synthesis
Metabolised in the liver by acetylation
High frequency of spontaneous resistance
Inhibits p450 system
Dosing: 5mg/kg/day (max: 300mg/day)
Available tablets: 100mg and 400mg
Side effects of Isoniazid
Common Uncommon Rare
Hepatitis Fever
Asymptomatic
elevation of liver Cutaneous Giddiness
enzymes hypersensitivity Convulsion

Peripheral Optic neuritis


neuropathy Mental symptoms
Haemolytic anaemia
Aplastic anaemia
Lupoid reactions
Arthralgia
Gynaecomastia
Rifampicin
Bacteriocidal
Inhibits DNA-dependent RNA polymerase
Lipophilic
Resistance develops quickly, must be used in combination
Food consumption, reduce absorption from GI tract
Cytochrome p450 inducer
Dosing: 10mg/kg/day (max: 600mg/day)
Available capsules: 150mg and 300 mg
Rifampicin drug interactions
Rifampicin drug interactions
Side effect of Rifampicin

Common Uncommon Rare


Pruritus Hepatitis Shortness of breath
Orange coloured Cutaneous
Shock
urine hypersensitivity
Gastrointestinal
Haemolytic anaemia
reactions
Thrombocytopenia Acute renal failure
Thrombotic
Febrile reactions thrombocytopaenic
purpura
"Flu syndrome"
Cholestatic jaundice
Pyrazinamide

Bacteriostatic drugs but bacteriocidal to replicating bacilli


Pyramidase
Pyrazinamide pyrazinoic acid
Pyrazinoic acid disrupts membrane potential and interferes with
energy production
Pyrazinoic acid binds to ribosomal protein S1 and inhibits translation
which explains the ability to kill dormant bacilli
Dosage: 25mg/kg/day (max: 1500mg/day)
Available tablets: 500mg
Side effect of Pyrazinamide

Common Uncommon Rare

Anorexia Hepatitis Sideroblastic anaemia

Nausea Vomiting Gout

Flushing Arthralgia

Photosensitisation Cutaneous reaction


Ethambutol
Bacteriostatic
Obstructing the formation of cell wall thus increasing its permeability
50% excreted unchanged in the urine
Dosage: 15 mg/kg/ day (max: 1200mg/day)
Available tablets: 400mg
Side effect of Ethambutol

Common Uncommon Rare


Retrobulbar Peripheral
neuritis neuropathy
Cutaneous
reaction
Arthralgia
Red green
colour blindness
Streptomycin

Aminoglycoside
Acts at RNA level inhibiting protein synthesis
Injectable drug
Dosage: 15mg/kg/day (max: 1000mg/day)
Available vial: 1000mg/ml
Side effect of Streptomycin

Common Uncommon Rare


Cutaneous Clinical renal
Vertigo
hypersensitivity failure

Giddiness Ataxia Aplastic anaemia

Numbness Deafness
Tinnitus
Fixed dose combination
Combinations of multiple drugs in one tablet
AKuriT-4:
rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg
AKuriT-2
rifampicin 150mg + isoniazid 75mg

Weight (kg) AKuriT-4 (tablets) AKuriT (tablets)

30-39 2 2

40-54 3 3

55-70 4 4

>70 5 5
Rimcure 3-FDC:
rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg

Weight (kg) Tablets

30-37 2

38-54 3

55-70 4

>70 5
Management of common adverse events
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
Most common reactions are gastrointestinal or cutaneous in nature
Mostly occur within first three months of treatment
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

25
CLASSIFICATION OF ADR FOR ANTITB

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

Severe skin reaction (Steven-Johnson


Syndrome, Toxic Epidermal Necrolysis & Drug
Need IMMEDIATE Rash with Eosinophilia & Systemic Symptoms)
DISCONTINUATION Hepatitis
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 twice
upper limit of normal Hepatitis C virus infection
Baseline aspartate Concomitant use of other
aminotransferase more than hepatotoxic drugs
twice upper limit of normal
1Chung-Delgado K et al., PLoS ONE, 2011
2Vilarica
AS et al., Rev Port Pneumol, 2010
3Khalili H et al., Factors DARU, 2009
4Marzuki OA et al., Singapore Med J, 2008

27
SYSTEMS MOST AFFECTED BY ANTITB DRUGS

Hepatobiliary
Skin
Gastrointestinal tract
Skeletal system
Renal

1Shang P et al., PLoS ONE, 2011


2Teleman MD et al., Int J Tuberc Lung Dis, 200

28
Cutaneous drug reaction

Types
Morbiliform rash
Erythema multiforme syndrome
Urticaria
Exfoliative dermatitis
Lichenoid eruption
Steven Johnson syndrome
Toxic epidermal necrolysis
Occurs within 2 months of initiation
Morbiliform eruption Erythema multiforme
Urticaria

Exfoliative dermatitis
Lichenoid eruption Steven Johnson syndrome
Toxic epidermal necrolysis
Cutaneous drug reaction
Pyrazinamide (MOST)
Drug-Induced

Algorithm
Severe Cutaneous ADRs

Discontinue ALL 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


35
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?
FDC
Polypharmacy
Underlying hypersensitivity reaction
Carrier or active ingredient?
Severity of cutaneous reaction
Never start bridging therapy for cutaneous reaction
Management cutaneous drug reaction- Re challenge
Drugs Day Dose

Isoniazid 1 50mg

2 300mg

3 Full dose

Rifampicin 75mg
4
INH Full dose
300mg
5
Full dose
Full dose
6
Full dose
Pyrazinamide 250mg
7
RIF + INH Full dose
1000mg
8
Full dose
Full dose
9
Full dose
Ethambutol 100mg
10
RIF + INH + PZA Full dose
500mg
11
Full dose
Full dose
DAY 1 OF TB TREATMENT 12
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 desensitised
Desensitisation should not be attempt in severe skin reaction
Cutaneous drug reaction
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
Attempted in HIV patients*
Complex Cutaneous ADRs requires specialists consultation

40
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 Monitoring
infections At least for the first 2 - 4 weeks is recommended
among all patients with antiTB treatment as DIH
Pregnancy until 90 days usually occurs within the initial 2 months of
postpartum treatment.
HIV
Organ transplant recipients 2Blumberg
1Yew WW et al., Respirology, 2006
HM et al., Am J Respir Crit Care Med,412003
DRUG-INDUCED HEPATITIS
Restarting?
Depends on whether hepatotoxicity sets in during the initial or the
continuation phase of treatment & the amount of treatment received
prior to the onset of such toxicity.

42
DRUG-INDUCED
DRUG-INDUCED HEPATITIS
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.
43
DRUG-INDUCED HEPATITIS

Degree of
Rise in transaminases Symptoms Management
hepatotoxicity

Mild 1-3x ULN No Monitoring


Mild 3x ULN No Monitoring

Moderate 3x ULN Yes Stop treatment

Moderate 5x ULN No Stop treatment

Severe 10x ULN Acute liver failure Stop treatment


DRUG-INDUCED HEPATITIS Bridging therapy

Ensure patient to still be on treatment while their DILI resolves


In severely ill and sputum positive patients
Does not count as doses of treatment
Options: streptomycin, ethambutol and ofloxacin (not hepatotoxic) -
SEO
DRUG-INDUCED HEPATITIS Re challenge

After ALT has reduced to less than 2 times ULN and patient is
asymptomatic
Bridging therapy should be continued while patient is being
rechallenged
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
Full dose
8
500mg
Full dose
9
Full dose
Day 1 of treatment SO E+H+R+Z 11 Full dose
DRUG-INDUCED HEPATITIS Alternative regimes

Two hepatotoxic drugs:


Isoniazid and rifampicin plus ethambutol for 9 months
Isoniazid, rifampicin, streptomycin and ethambutol for 2 months followed by isoniazid
and rifampicin for 6 months
Rifampicin, pyrazinamide and ethambutol for 6 to 9 months
One hepatotoxic drugs:
Streptomycin, isoniazid and ethambutol for 2 months followed by isoniazid and
ethambutol for 10 months
No hepatotoxic drug:
Streptomycin, ethambutol plus a fluoroquinolone for 18 to 24 months
Symptoms based approach

Adverse effect Drug Management

Anorexia, nausea, Small meal or last thing at


RIF, PZA
abdominal pain night

Arthralgia PZA, (INH, ETH), OFL NSAIDs or PCM

Peripheral neuropathy INH Pyridoxine 100mg

Orange or red urine RIF Reassurance


Symptoms based approach
Adverse effect Drug Management

Deafness SM Use ETH

Dizziness SM Use ETH

SM, INH, RIF, PZA,


Itching Antihistamine
ETH

Visual impairment ETH Visual examination

Use different
Acute renal failure SM, RIF
combination
NSAIDs
Gouty arthritis PZA
Colchicine
Conclusion

Adverse effects of anti TB drugs

Occur during the first few months of initiation


Unless recognized on time and managed appropriately, side
effects can lead to treatment interruption, and even life-
threatening
Proper monitoring has to be done throughout treatment
course
Conclusion

Adverse events are manageable provided appropriate management


approach is applied

Altering doses when appropriate


Ancillary drugs to treat adverse events
Discontinuation of drugs if necessary
Training of staff on adverse events
Standard protocols for registration

You might also like