How to reintroduce weight-wise doses of isoniazid (INH) and rifampicin (RIF) in a patient with a history of drug-induced hepatitis due to rifampicin?

Reintroduction of Isoniazid and Rifampicin After Drug-Induced Hepatitis

Direct Answer

When rifampicin is identified as the cause of drug-induced hepatitis, it should be permanently excluded from the regimen and replaced with alternative agents, as rifampicin rechallenge carries significant risk of severe recurrent hepatotoxicity. 1, 2

Understanding the Hepatotoxicity Pattern

The timing of hepatitis onset helps identify the culprit drug:

• Early hepatitis (within 15 days) typically represents rifampicin-enhanced isoniazid toxicity, where rifampicin's enzyme induction increases toxic isoniazid metabolites 2
• Late hepatitis (>1 month) is more commonly pyrazinamide-related and carries a poor prognosis 2
• Rifampicin alone rarely causes hepatitis (1.1% incidence), but when combined with isoniazid the rate increases to 2.7% 3

Sequential Reintroduction Protocol (When Rifampicin is NOT the Culprit)

If you must reintroduce drugs after hepatitis of uncertain etiology, follow this strict sequence after liver function normalizes:

Step 1: Isoniazid Reintroduction

• Start at 50 mg/day 1
• Increase to 300 mg/day after 2-3 days if no reaction occurs 1
• Continue for 2-3 more days without reaction before adding the next drug 1
• Monitor liver function daily during this period 1

Step 2: Rifampicin Reintroduction

• Start at 75 mg/day 1
• Increase to 300 mg after 2-3 days 1
• Further increase to weight-appropriate dose (10 mg/kg, maximum 600 mg) after 2-3 more days 3, 1
• Monitor liver function daily 1

Step 3: Pyrazinamide Reintroduction (if needed)

• Start at 250 mg/day 1
• Increase to 1.0 g after 2-3 days 1
• Further increase to weight-appropriate dose 1

When Rifampicin Must Be Permanently Excluded

If rifampicin is confirmed as the causative agent through rechallenge or clinical evidence, do NOT attempt reintroduction. 1, 2, 4

Alternative Regimen Without Rifampicin

• Isoniazid + ethambutol for at least 12 months 1
• Add pyrazinamide for the initial 2 months 1
• This represents a significant extension from the standard 6-month rifampicin-based regimen 1

Critical Monitoring During Reintroduction

• Daily clinical assessment for fever, malaise, vomiting, jaundice, or abdominal pain 3, 1, 5
• Daily liver function tests during the reintroduction phase 1
• Immediately stop the most recently added drug if any reaction recurs 1
• The drug causing recurrent reaction should be permanently excluded 1

Weight-Based Dosing for Maintenance Therapy

Once drugs are successfully reintroduced, use these weight-based doses:

Isoniazid

• Adults: 5 mg/kg daily (maximum 300 mg) 3, 5
• Children: 10-15 mg/kg daily (maximum 300 mg) 3, 5

Rifampicin

• Adults: 10 mg/kg daily (maximum 600 mg) 3, 5
• Children: 10-20 mg/kg daily (maximum 600 mg) 3, 5

Critical Pitfalls to Avoid

• Never use combined drug preparations during reintroduction, as you cannot identify the specific offending agent if hepatitis recurs 1
• Do not reintroduce pyrazinamide if it caused the initial hepatitis, as recurrence carries poor prognosis 2
• Avoid intermittent dosing during reintroduction, as doses >600 mg given once or twice weekly increase adverse reaction rates 6
• Do not continue a drug if hepatitis recurs, as this leads to more severe liver damage 5

Special Considerations for Rifampicin-Induced Hepatitis

• Case reports demonstrate that rifampicin can cause hepatotoxicity even when well-tolerated alone, but becomes toxic when combined with isoniazid 4
• The FDA label emphasizes that rifampicin's enzyme induction properties enhance metabolism of other drugs, including isoniazid, potentially increasing toxicity 6
• Patients with underlying liver disease should not receive pyrazinamide 2

Monitoring Thresholds

• Stop all hepatotoxic drugs if ALT/AST >5 times upper limit of normal 1
• Stop all hepatotoxic drugs if bilirubin rises 1
• Continue non-hepatotoxic drugs (streptomycin, ethambutol) if patient has infectious TB 1