1. Adverse Drug Reactions to Anti-TB drugs Dr M A Jalil Chowdhury Professor of Medicine Bangabandhu Sheikh Mujib Medical University

2. 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

3. Adverse Drug Reactions Jaundice- Hepatitis Rash- Hypersensitivity reaction

4. 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%.

5. Hepatotoxicity of Anti-TB Drugs Potentially Hepatotoxic DrugsLess 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)

6. 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

7. 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

8. Scenario 1: # Continue the Anti-TB drugs and Monitor Mild or no symptom; less increase in liver enzymes (< 5 times). No clinical jaundice

9. 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 2 nd ed.]. This can be done either gradually one by one or all at once (if the hepatitis was mild). Contd.

10. 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??

11. 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.

12. 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.

13. 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

14. 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

15. Possible alternative Anti-TB drug regimens in liver diseases a)Two hepatotoxic drugs 9HRE 2 SHRE/6HR 6-9RZE b) One hepatotoxic drug 2SHE/10HE 9 RE c) No hepatotoxic drug 18-24SEQ

16. Management of Skin itching and rash/ Hypersensitivity reaction (regime not containing thioacetazone)

17. 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.

18. Management of Skin itching and rash/ Hypersensitivity reaction Itching –> exclude other obvious cause Antihistamine—> itching resolves Continue Anti-TB drugs Contd.

19. 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?

20. 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.

21. Re-introduction of anti-TB drugs The idea of drug challenging is to identify the drug responsible for the reaction. Contd.

22. 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

23. 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.

24. Challenging dose for detecting hypersensitivity reaction to anti-TB drugs/ Re-introduction of Anti-TB drugs following drug reaction Likelihood of causing a reactionChallenge doses DrugDay 1Day 2Day 3 Isoniazid Least likely50mg300mg Rifampicin75mg300mgFull dose Pyrazinamide250mg1gmFull dose Ethambutol100mg500mgFull dose Streptomycin Most likely125mg500mgFull dose

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.