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Transcript
Adverse Drug Reactions to Anti-TB drugs Dr M A Jalil Chowdhury Professor 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: Mild or no symptom; less increase in liver enzymes (< 5 times). No clinical jaundice # Continue the Anti-TB drugs and Monitor 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 restarted 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). 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 reintroduced, 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 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 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 reintroducing 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 Drug Challenge doses Day 1 Day 2 Day 3 50mg 300mg 300mg Rifampicin 75mg 300mg Full dose Pyrazinamide 250mg 1gm Full dose Ethambutol 100mg 500mg Full dose 125mg 500mg Full dose Isoniazid Streptomycin Least likely Most likely 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.