RIFAMATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for RIFAMATE (RIFAMATE).
Rifamate is a combination of rifampin and isoniazid. Rifampin inhibits bacterial RNA polymerase, blocking transcription. Isoniazid inhibits mycolic acid synthesis in the mycobacterial cell wall.
| Metabolism | Rifampin is metabolized by hepatic microsomal enzymes (CYP450) to 25-O-desacetylrifampin; isoniazid is metabolized by N-acetyltransferase 2 (NAT2). |
| Excretion | Renal: 30% (rifampin unchanged), 15% (isoniazid unchanged); Biliary/Fecal: 60% (rifampin as metabolite), 5% (isoniazid); Additional: isoniazid metabolites (acetylisoniazid, isonicotinic acid) excreted renally. |
| Half-life | Rifampin: 3-4 hours (initial), 2-3 hours (after autoinduction); Isoniazid: 1-4 hours (fast acetylators), 0.5-1.5 hours (slow acetylators); Clinical context: Reduced in hepatic impairment; autoinduction decreases rifampin half-life after repeated dosing. |
| Protein binding | Rifampin: 80-90% bound (albumin, alpha-1-acid glycoprotein); Isoniazid: 10-38% bound (albumin); Note: Binding is concentration-dependent for rifampin. |
| Volume of Distribution | Rifampin: 0.6-1.6 L/kg (widespread, including lungs, CSF with inflammation); Isoniazid: 0.6-0.8 L/kg (total body water, crosses BBB); Clinical meaning: Indicates extensive tissue distribution. |
| Bioavailability | Oral: Rifampin 70-90% (reduced with food); Isoniazid 80-100% (reduced with food; first-pass metabolism significant for isoniazid). |
| Onset of Action | Oral: Rifampin peaks at 2-4 hours; Isoniazid peaks at 1-2 hours; Time to bactericidal effect: 24-48 hours (first bacterial killing). |
| Duration of Action | Rifampin: Antimycobacterial effect persists 24 hours; Isoniazid: 24 hours (dosing interval); Clinical notes: Both drugs penetrate tissues; rifampin induces its own metabolism over weeks, reducing duration. |
2 capsules orally twice daily for 2 months followed by 1 capsule orally twice daily for 4 months. Each capsule contains rifampin 300 mg and isoniazid 150 mg.
| Dosage form | CAPSULE |
| Renal impairment | For CrCl <30 mL/min: reduce rifampin dose by 50% and administer isoniazid at 5 mg/kg/day (max 300 mg) with careful monitoring; avoid if severe renal impairment. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce isoniazid dose to 3 mg/kg/day (max 150 mg) and rifampin to 10 mg/kg/day (max 600 mg). Child-Pugh C: contraindicated. |
| Pediatric use | Weight-based: 10-20 kg: 1 capsule twice daily; 20-40 kg: 1.5 capsules twice daily; >40 kg: adult dose. Duration as per adult regimen. |
| Geriatric use | Monitor liver function and renal function; start at lower end of dosing (1 capsule twice daily) for 2 months then 1 capsule twice daily for 4 months; adjust for CrCl <30 mL/min as per renal adjustment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for RIFAMATE (RIFAMATE).
| Breastfeeding | Both rifampin and isoniazid are excreted in breast milk. M/P ratio: rifampin ~0.2; isoniazid ~0.6. Estimated infant dose: rifampin <1% of therapeutic dose; isoniazid ~1% of therapeutic dose. Considered compatible with breastfeeding by the AAP; however, monitor infant for jaundice and peripheral neuropathy. The benefits of breastfeeding generally outweigh risks with appropriate monitoring. |
| Teratogenic Risk | Rifamate (rifampin/isoniazid) is pregnancy category C. Rifampin crosses the placenta; isoniazid also crosses. First trimester: potential for congenital malformations (neural tube defects, cardiovascular) based on animal data and limited human reports (risk ratio ~2). Second/third trimester: increased risk of hepatotoxicity in mother and fetus; may cause hemorrhagic disease of the newborn due to vitamin K deficiency; monitoring for neonatal jaundice and coagulation defects is recommended. |
■ FDA Black Box Warning
Severe and sometimes fatal hepatitis has been reported with isoniazid therapy; risk is increased in patients with liver disease, alcohol use, or concurrent hepatotoxic drugs.
| Serious Effects |
Hypersensitivity to rifampin or isoniazid; acute liver disease; history of isoniazid-induced liver injury.
| Precautions | Hepatotoxicity; peripheral neuropathy (due to isoniazid); severe hypersensitivity reactions (including drug reaction with eosinophilia and systemic symptoms [DRESS]); rifampin may cause reddish-orange discoloration of urine, sweat, sputum, and tears. |
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| Fetal Monitoring | Maternal: baseline and periodic LFTs (ALT, AST, bilirubin), serum creatinine, CBC with platelets; monthly liver function tests due to isoniazid hepatotoxicity; monitor for signs of optic neuritis (isoniazid) and peripheral neuropathy. Fetal/neonatal: ultrasound for growth and anomalies if exposure in first trimester; neonatal monitoring for jaundice, coagulation abnormalities (vitamin K prophylaxis), and signs of hepatotoxicity. |
| Fertility Effects | No significant effects on fertility reported in humans. Animal studies show no impairment of fertility. Isoniazid may cause pyridoxine deficiency which could theoretically affect hormonal balance, but significant fertility impact is not documented. |