RIFAMPIN AND ISONIAZID
Clinical safety rating: safe
A strong inducer of CYP450 enzymes decreasing levels of many drugs Can cause hepatotoxicity and orange discoloration of bodily fluids.
Rifampin inhibits bacterial DNA-dependent RNA polymerase, blocking RNA synthesis. Isoniazid inhibits mycolic acid synthesis in Mycobacterium tuberculosis cell wall.
| Metabolism | Rifampin: hepatic via deacetylation; induces CYP3A4, CYP2C9, CYP2C19, CYP2D6. Isoniazid: hepatic via N-acetyltransferase 2 (NAT2); inhibits CYP2C9, CYP2E1, CYP3A4. |
| Excretion | Rifampin: primarily hepatic (biliary) excretion (60-65% as unchanged drug), with 30% renal (15% unchanged). Isoniazid: renal excretion (75-95% as metabolites, 5-27% unchanged); acetylation phenotype-dependent; 70% renal in fast acetylators, 90% in slow. |
| Half-life | Rifampin: 2-5 hours (terminal); decreases with repeated dosing due to autoinduction. Isoniazid: 0.5-1.5 hours (fast acetylators), 2-5 hours (slow acetylators); clinical context: dosing interval adjustment based on acetylator status. |
| Protein binding | Rifampin: 80-90% (albumin). Isoniazid: 0-10% (low); primarily unbound. |
| Volume of Distribution | Rifampin: 1.6 L/kg (wide distribution, penetrates CSF, tissues). Isoniazid: 0.6-0.7 L/kg (distributes into all body fluids and tissues, including CSF). |
| Bioavailability | Rifampin oral: 90-95% (reduced by food). Isoniazid oral: 90% (fasted); absorption reduced with food. |
| Onset of Action | Oral: bactericidal effect within 24 hours (tuberculosis); peak concentrations 1-4 hours post-dose. |
| Duration of Action | Rifampin: 24 hours (bactericidal for 12-24h). Isoniazid: 24 hours (but requires multiple doses for eradication); clinical notes: combination therapy prevents resistance. |
2 tablets (rifampin 300 mg/isoniazid 150 mg) or 2 tablets (rifampin 600 mg/isoniazid 300 mg) orally once daily depending on formulation. Each dose should be taken on an empty stomach at least 30 minutes before or 2 hours after a meal.
| Dosage form | CAPSULE |
| Renal impairment | For GFR <30 mL/min: reduce rifampin dose by 50% (to 300 mg/day) or prolong interval; isoniazid may require dose reduction (e.g., 200 mg/day) or extended interval (e.g., every 36 hours) to avoid accumulation. For GFR <10 mL/min: consider alternative regimen. No adjustment for GFR 30-89 mL/min. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce isoniazid dose by 50% (e.g., 300 mg/day) to avoid hepatotoxicity; rifampin may also require reduction (e.g., 450 mg/day). Child-Pugh C: contraindicated due to risk of severe hepatotoxicity; use alternative non-hepatotoxic agents. |
| Pediatric use | Daily dose: rifampin 10-20 mg/kg/day (max 600 mg/day) plus isoniazid 10-15 mg/kg/day (max 300 mg/day) orally once daily. Twice-weekly directly observed therapy: rifampin 10-20 mg/kg (max 600 mg) plus isoniazid 20-30 mg/kg (max 900 mg) per dose. |
| Geriatric use | Start at lower end of adult dose (e.g., rifampin 300 mg/isoniazid 150 mg daily) due to age-related decreased hepatic and renal function. Monitor liver function tests and serum creatinine more frequently. Avoid in patients with severe hepatic impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
A strong inducer of CYP450 enzymes decreasing levels of many drugs Can cause hepatotoxicity and orange discoloration of bodily fluids.
| FDA category | Human |
| Breastfeeding | Both rifampin and isoniazid are excreted into breast milk. Milk-to-plasma ratio for rifampin is approximately 0.2; for isoniazid, M/P ratio ranges from 0.6 to 1.5. Amounts ingested by the infant are subtherapeutic and generally considered compatible with breastfeeding. However, isoniazid may be associated with pyridoxine deficiency in the infant; monitor for seizures. Monitor infant for jaundice, liver enzymes elevation, and signs of peripheral neuropathy. The American Academy of Pediatrics considers rifampin and isoniazid compatible with breastfeeding. |
■ FDA Black Box Warning
Severe and fatal hepatotoxicity may occur; monitor liver function closely. Isoniazid can cause severe hepatitis, especially in patients with pre-existing liver disease or alcohol use.
| Common Effects | Hepatotoxicity |
| Serious Effects |
["Hypersensitivity to rifampin or isoniazid","Severe hepatic impairment","Acute liver disease","History of isoniazid-associated hepatotoxicity","Concurrent use of hepatotoxic drugs (relative)","Rifampin contraindicated with HIV protease inhibitors"]
| Precautions | ["Hepatotoxicity: monitor LFTs; discontinue if signs of hepatitis","Peripheral neuropathy with isoniazid: prevent with pyridoxine","Rifampin hepatotoxicity: rare but severe","Drug interactions: rifampin induces many CYP enzymes and P-glycoprotein","Hypersensitivity reactions","Hemolytic anemia, thrombocytopenia with rifampin","Antibiotic resistance: use in combination therapy"] |
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| Teratogenic Risk | First trimester: Isoniazid is associated with an increased risk of neural tube defects and major malformations; rifampin is not a major teratogen but risk cannot be excluded. Second and third trimesters: No increased risk of structural anomalies. Both drugs may cause hepatotoxicity in the mother, which can indirectly affect the fetus. Isoniazid increases risk of perinatal vitamin K deficiency and hemorrhagic disease of the newborn due to inhibition of vitamin K synthesis; maternal prophylaxis with vitamin K 10 mg/day orally from 36 weeks gestation is recommended. |
| Fetal Monitoring | Maternal: Baseline and monthly liver function tests (AST, ALT, bilirubin); baseline and periodic renal function; complete blood count; vision screening (for ethambutol if part of regimen, but not required for rifampin/isoniazid alone). Fetal: Obstetric ultrasound at 18-20 weeks to assess anatomy; serial growth scans if maternal toxicity or poor weight gain. Neonatal: Assess for jaundice, hepatomegaly; administer vitamin K 1 mg intramuscularly at birth; monitor for signs of peripheral neuropathy (irritability, feeding difficulties). |
| Fertility Effects | Rifampin may induce hepatic microsomal enzymes, reducing efficacy of oral contraceptives; advise alternative contraception. Isoniazid may cause gynecomastia and decreased libido in males, but reversible. No direct evidence of impaired fertility in either sex with standard doses. No adverse effects on spermatogenesis or ovulation. |