Adverse Drug Reactions toAnti-TB drugs

Dr M A Jalil ChowdhuryProfessor of Medicine

Bangabandhu Sheikh Mujib Medical University

Adverse Drug Reaction“Any response to a drug which is noxious and unintended, and which occurs at a doses used in man for prophylaxis, diagnosis, or treatment”-----WHO

• An exaggerated drug response

• an untoward effect on an organ system, different

from that being treated

• an allergic or hypersensitivity reaction

and idiosyncratic reaction

• a drug interaction that causes either an increased or

diminished response. contd

Adverse Drug Reactions

• Jaundice- Hepatitis

• Rash- Hypersensitivity reaction

Anti-tuberculosis drug-induced hepatotoxicity: concise up-to-date review.Tostmann A ,et al. J Gastroenterol Hepatol

2008:23;192-202

Anti-tuberculosis drug induced hepatitis

varied between 2% to 28%.

Hepatotoxicity of Anti-TB Drugs

Potentially Hepatotoxic Drugs Less Hepatotoxic

First Line ATDs INH (H) = 3 times Rifampicin (R) = 1 PZA (Z )= 10 times

First Line ATDs Aminoglycosides (AG) - SM, Ak, Km Capreomycin (Cm) Ethambutol (E)

Second Line ATDs Ethionamide (Eto) Prothionamide (Pto) PAS Rifabutin

Second Line ATDs Fluoroquinolones (FQs)

(Ofloxacin, Levofloxacin, Ciprofloxacin, Moxifloxacin)

Cycloserine (Cs)

Potential Risk Factors for Hepatotoxicity

• Increasing age• Malnutrition• Pre-existing CLD/ Elevated base line ALT• HIV infection• Pregnancy or post partum• Other hepatotoxic drugs• PZA in the regimen• Alcoholics• Slow acetylators

Drug-induced Hepatitis (DIH)

• Increase in AST/ALT > 3 times the ULN in presence of symptoms

OR

• Increase in AST/ALT > 5 times the ULN in the absence of symptoms

OR

• Serum bilirubin > 2 time the ULN or if clinically icteric

Scenario 1:

# Continue the Anti-TB drugs and Monitor

Mild or no symptom; less increase in liver enzymes (< 5 times). No clinical jaundice

Scenario 2: Developed jaundice and TB treatment can be deferred

It is very difficult to find out the cause. Anti-TB drugs

should be stopped until liver functions have returned to

normal. If liver function tests cannot be done, wait two

weeks after the jaundice has disappeared before

recommencing anti-TB treatment. It is strange, but

fortunate enough that in most cases, even in drug

induced hepatitis, the same drugs can be re-started

without return of hepatitis [TB/HIV–A Clinical Manual.

WHO 2nd ed.]. This can be done either gradually one by

one or all at once (if the hepatitis was mild). Contd.

Rechallenge schedule (ATS guideline)

• After ALT returns to less than 2 times the ULN >>> Rifampicin restarted with or without Ethambutol.>>>

• After 3 to 7 days, Isoniazid may be re-introduced, subsequently rechecking ALT.

• If symptom recurs or ALT increases, the last drug added should be stopped.

• PZA??

Scenario 3: Severely ill with Tuberculosis having mild/moderate to severe jaundice

A severely ill TB patient with drug induced

(or viral hepatitis) may die without anti-TB

drugs. In this case the patient should be

treated with a non-hepatotoxic regimen

consisting of SM, E ± fluoroquinolone(SE/SEQ) contd.

Scenario 3 contd.

• If the hepatitis has resolved the patient can then receive a continuation phase of 6-9 months of isoniazid and rifampicin (6HR).

• If hepatitis has not resolved SEQ should be continued for a total of 18-24 months.

Scenario 4: Acute Viral Hepatitis During Treatment of TB

• TB treatment should be deferred until the acute hepatitis has resolved. Re-start standard anti-TB regimen after resolution of acute hepatitis

• When it is necessary to treat during acute hepatitis: start with SM and E for 3 months

• If the hepatitis has resolved within 3 months then continue HR for 6 months (3 SE/6HR)

• If hepatitis has not fully resolved 12 SE

Scenario 5: Patient with pre-existing chronic liver disease

• Patient with established liver disease

should not receive pyrazinamide.

• Can receive the standard regimen

(2HRZE/4HR) provided no s/s or

laboratory evidence of active disease.

contd

Possible alternative Anti-TB drug regimens in liver

diseasesa) Two hepatotoxic drugs

• 9HRE

• 2 SHRE/6HR

• 6-9RZE

b) One hepatotoxic drug

• 2SHE/10HE

• 9 RE

c) No hepatotoxic drug

• 18-24SEQ

Management of Skin itching and rash/ Hypersensitivity reaction

(regime not containing thioacetazone)

They are commonest in the second to fourth week of treatment and rarely in the first week. Common with streptomycin ( & Th), less common with isoniazid, rifampicin, and ethambutol.

Management of Skin itching and rash/ Hypersensitivity reaction

• Itching –> exclude other obvious cause

• Antihistamine—> itching resolves

Continue Anti-TB drugs

Contd.

Management of Skin itching and rash/ Hypersensitivity reaction

• Itching not resolved+/ rash develops &/ fever—>STOP anti-TB drugs

• Wait for rash &/ fever to resolve

• Severe reaction –> supportive treatment

What next?

Management of Skin itching and rash/ Hypersensitivity reaction

The problem now is re-introducing TB treatment when we don’t know which anti-TB drug was responsible for the reaction. The table shows the standard approach to re-introducing anti-TB drugs one by one after a drug reaction.

Re-introduction of anti-TB drugs

The idea of drug challenging is to identify the drug responsible for the reaction.

Contd.

Re-introduction of anti-TB drugs

Give 2 anti-TB drugs which the patient has

not previously received.

Drug challenge starts with the anti-TB least

likely to be responsible for the reaction i.e.,

isoniazid. Thiacetazone and streptomycin

are the most likely to produce the reaction,

so test them last.

contd

Re-introduction of anti-TB drugs

Start with a small challenge dose/test dose as shown in table….If a reaction occurs to a small dose, it will not be such a bad reaction as to a full dose. There is usually a slight skin rash or fever within 2-3 hours. You can therefore test two doses a day, at 12-hour intervals, if the patient is in hospital. Gradually increase the dose over 3 days.

contd.

Challenging dose for detecting hypersensitivity reaction to anti-TB drugs/ Re-introduction of Anti-TB

drugs following drug reaction

Likelihood of causing a reaction

Challenge doses

Drug Day 1 Day 2 Day 3

Isoniazid Least likely 50mg 300mg 300mg

Rifampicin 75mg 300mg Full dose

Pyrazinamide 250mg 1gm Full dose

Ethambutol 100mg 500mg Full dose

Streptomycin Most likely 125mg 500mg Full dose

Re-introduction of anti-TB drugs

Repeat the procedure, adding in one drug at

a time. A reaction after adding a particular

drug identifies that drug as the one

responsible for the reaction.contd.

Re-introduction of anti-TB drugs

If the drug responsible for the reaction is pyrazinamide, Ethambutol, or streptomycin, resume anti-TB treatment without the offending drug. If possible, replace the offending drug with another drug. It may be necessary to extend the treatment regimen as a new start of treatment. This prolongs the total time if treatment, but decreases the risk of recurrence.

contd.

DESENSITIZATION

Rarely, patients develop hypersensitivity reactions to the 2 most potent ant-TB drugs, isoniazid and rifampicin. These drugs form the corner-stone of SCC. If an HIV-negative patient has had a reaction (but not a sever reaction) to isoniazid or rifampicin, it may be possible to desensitize the patient to the drug. However, never attempt desensitization in TB/HIV patients because of the high risk of serious toxicity. contd.

DESENSITIZATION• When starting to desensitize it is usually safer to

begin with a tenth of the normal dose. Then increase the dose b y a tenth each day, until the patient has the full dose on the tenth day. If the patient has a mild reaction to a dose, give the same dose instead of higher dose next day. If there is no reaction, go on increasing by a tenth each day. If the reaction is severe (which is unusual) go back to a lower dose and increase the doses more gradually.

• If the patient is in hospital, which should be, you can give the doses twice a day and save time.

contd.

DESENSITIZATION

• Once drug sensitization is over, give the drug as apart of the usual treatment regimen. If possible, while carrying out desensitization, give the patient 2 anti-TB drugs which the patient has not had before so as to prevent drug resistance.

• There is no evidence that challenge process gives rise to drug resistance. But desensitization process does give rise to the risk of resistance.