RIFATER

Clinical safety rating: caution

Comprehensive clinical and safety monograph for RIFATER (RIFATER).

How it works

Rifater is a fixed-dose combination of rifampin, isoniazid, and pyrazinamide. Rifampin inhibits bacterial DNA-dependent RNA polymerase, blocking RNA synthesis. Isoniazid inhibits mycolic acid synthesis, disrupting bacterial cell wall. Pyrazinamide is converted to pyrazinoic acid, which disrupts membrane transport and energy metabolism.

What the body does with it

Metabolism	Rifampin is metabolized via deacetylation to desacetylrifampin (active); induces CYP3A4, CYP2C9, CYP2C19, CYP2D6. Isoniazid is metabolized by N-acetyltransferase 2 (NAT2) and CYP2E1. Pyrazinamide is metabolized by hepatic microsomal enzymes to pyrazinoic acid.
Excretion	Rifampicin: primarily hepatic (biliary) excretion, ~60% fecal, ~30% renal (unchanged and metabolites). Isoniazid: hepatic metabolism, renal excretion of metabolites (75-95% as isoniazid metabolites, <10% unchanged). Pyrazinamide: hepatic metabolism, renal excretion of metabolites (70% excreted in urine, 4-14% unchanged).
Half-life	Rifampicin: 2-5 hours initially, prolonged to 5-7 hours after repeated dosing due to autoinduction. Isoniazid: 0.5-2 hours (fast acetylators), 2-5 hours (slow acetylators). Pyrazinamide: 9-10 hours.
Protein binding	Rifampicin: 80-90% bound, primarily to albumin. Isoniazid: 0-10% bound. Pyrazinamide: 10-20% bound.
Volume of Distribution	Rifampicin: 0.7 L/kg, distributes widely into tissues and body fluids. Isoniazid: 0.6-0.7 L/kg (fast acetylators), 0.4-0.6 L/kg (slow acetylators). Pyrazinamide: 0.6-0.8 L/kg, penetrates well into cells and CNS.
Bioavailability	Oral bioavailability: Rifampicin ~90-95% (reduced with food), Isoniazid ~80-90% (reduced with food), Pyrazinamide >90% (minimal food effect).
Onset of Action	Oral administration: clinical effect (bactericidal activity) typically observed within 24-48 hours for susceptible organisms.
Duration of Action	Duration of bactericidal effect: up to 24 hours, supporting daily dosing. Rifampicin exhibits post-antibiotic effect against M. tuberculosis lasting several hours.

Classification & Brands

Brand Substitutes

Rip 120 mg/80 mg/250 mg Tablet

Dosing & administration

RIFATER (rifampin/isoniazid/pyrazinamide) fixed-dose combination: 4 tablets (each tablet contains rifampin 120 mg, isoniazid 50 mg, pyrazinamide 300 mg) orally once daily for patients weighing ≥50 kg; for patients 40-49 kg, 3 tablets orally once daily; for 30-39 kg, 2 tablets orally once daily; for 20-29 kg, 1.5 tablets orally once daily. Administer on an empty stomach, 1 hour before or 2 hours after meals.

Dosage form	TABLET
Renal impairment	For GFR 30-50 mL/min: no adjustment needed. For GFR <30 mL/min: avoid pyrazinamide-containing combinations; use individual drugs with dose adjustment. Isoniazid: reduce dose to 5 mg/kg/day (max 300 mg/day) for GFR <10 mL/min or if on dialysis. Rifampin: no adjustment for renal impairment, but caution in severe impairment with concurrent liver disease. Hemodialysis: administer after dialysis; no supplemental dose.
Liver impairment	Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce isoniazid dose by 50% and monitor liver function; rifampin and pyrazinamide are contraindicated. Child-Pugh Class C: contraindicated due to risk of hepatotoxicity. Use individual drugs with close monitoring.
Pediatric use	Weight-based dosing: 10-20 kg: 1 tablet (rifampin 120 mg/isoniazid 50 mg/pyrazinamide 300 mg) orally once daily; 20-30 kg: 1.5 tablets; 30-40 kg: 2 tablets; 40-50 kg: 3 tablets; ≥50 kg: 4 tablets. Administer on empty stomach. Not recommended for children <3 years due to lack of data.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for RIFATER (RIFATER).

Breastfeeding	Excreted into breast milk; rifampin M/P ratio 0.2-0.6. Isoniazid M/P ratio ~1.0. Pyrazinamide present. Consider risk of neonatal hepatotoxicity and peripheral neuropathy. Use with caution, monitor infant for jaundice and CNS effects.
Teratogenic Risk	FDA Pregnancy Category C. First trimester: Rifampin and isoniazid are known teratogens in animals; human data limited but potential for neural tube defects. Second and third trimesters: No increased risk of major malformations, but monitor for neonatal hepatotoxicity and hemorrhage (vitamin K deficiency due to rifampin).

Warnings & precautions

■ FDA Black Box Warning

Rifampin can cause severe and fatal hepatotoxicity, especially with pre-existing liver disease or concurrent use of hepatotoxic drugs. Isoniazid is associated with severe and sometimes fatal hepatitis. Monitor liver function closely.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to any component, severe hepatic disease, acute liver disease, history of isoniazid-associated hepatotoxicity, rifampin-associated hepatotoxicity, or pyrazinamide-associated hepatotoxicity, concurrent use of atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir, or other protease inhibitors boosted by ritonavir or cobicistat (rifampin reduces levels).

Clinical Precautions

Precautions

Hepatotoxicity (monitor LFTs; discontinue if signs of hepatitis), peripheral neuropathy (isoniazid; prevent with pyridoxine), optic neuritis (isoniazid), hypersensitivity reactions (rifampin), hyperuricemia and gout (pyrazinamide), hematologic reactions (rifampin; monitor CBC), drug interactions (rifampin induces many CYP enzymes; reduce efficacy of oral contraceptives, anticoagulants, etc.).

Clinical Tips & Counseling

Drug interactions

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RIFATER

Clinical safety rating: caution

Comprehensive clinical and safety monograph for RIFATER (RIFATER).

How it works

What the body does with it

Metabolism	Rifampin is metabolized via deacetylation to desacetylrifampin (active); induces CYP3A4, CYP2C9, CYP2C19, CYP2D6. Isoniazid is metabolized by N-acetyltransferase 2 (NAT2) and CYP2E1. Pyrazinamide is metabolized by hepatic microsomal enzymes to pyrazinoic acid.
Excretion	Rifampicin: primarily hepatic (biliary) excretion, ~60% fecal, ~30% renal (unchanged and metabolites). Isoniazid: hepatic metabolism, renal excretion of metabolites (75-95% as isoniazid metabolites, <10% unchanged). Pyrazinamide: hepatic metabolism, renal excretion of metabolites (70% excreted in urine, 4-14% unchanged).
Half-life	Rifampicin: 2-5 hours initially, prolonged to 5-7 hours after repeated dosing due to autoinduction. Isoniazid: 0.5-2 hours (fast acetylators), 2-5 hours (slow acetylators). Pyrazinamide: 9-10 hours.
Protein binding	Rifampicin: 80-90% bound, primarily to albumin. Isoniazid: 0-10% bound. Pyrazinamide: 10-20% bound.
Volume of Distribution	Rifampicin: 0.7 L/kg, distributes widely into tissues and body fluids. Isoniazid: 0.6-0.7 L/kg (fast acetylators), 0.4-0.6 L/kg (slow acetylators). Pyrazinamide: 0.6-0.8 L/kg, penetrates well into cells and CNS.
Bioavailability	Oral bioavailability: Rifampicin ~90-95% (reduced with food), Isoniazid ~80-90% (reduced with food), Pyrazinamide >90% (minimal food effect).
Onset of Action	Oral administration: clinical effect (bactericidal activity) typically observed within 24-48 hours for susceptible organisms.
Duration of Action	Duration of bactericidal effect: up to 24 hours, supporting daily dosing. Rifampicin exhibits post-antibiotic effect against M. tuberculosis lasting several hours.

Classification & Brands

Brand Substitutes

Rip 120 mg/80 mg/250 mg Tablet

Dosing & administration

Dosage form	TABLET
Renal impairment	For GFR 30-50 mL/min: no adjustment needed. For GFR <30 mL/min: avoid pyrazinamide-containing combinations; use individual drugs with dose adjustment. Isoniazid: reduce dose to 5 mg/kg/day (max 300 mg/day) for GFR <10 mL/min or if on dialysis. Rifampin: no adjustment for renal impairment, but caution in severe impairment with concurrent liver disease. Hemodialysis: administer after dialysis; no supplemental dose.
Liver impairment	Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce isoniazid dose by 50% and monitor liver function; rifampin and pyrazinamide are contraindicated. Child-Pugh Class C: contraindicated due to risk of hepatotoxicity. Use individual drugs with close monitoring.
Pediatric use	Weight-based dosing: 10-20 kg: 1 tablet (rifampin 120 mg/isoniazid 50 mg/pyrazinamide 300 mg) orally once daily; 20-30 kg: 1.5 tablets; 30-40 kg: 2 tablets; 40-50 kg: 3 tablets; ≥50 kg: 4 tablets. Administer on empty stomach. Not recommended for children <3 years due to lack of data.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for RIFATER (RIFATER).

Breastfeeding	Excreted into breast milk; rifampin M/P ratio 0.2-0.6. Isoniazid M/P ratio ~1.0. Pyrazinamide present. Consider risk of neonatal hepatotoxicity and peripheral neuropathy. Use with caution, monitor infant for jaundice and CNS effects.
Teratogenic Risk	FDA Pregnancy Category C. First trimester: Rifampin and isoniazid are known teratogens in animals; human data limited but potential for neural tube defects. Second and third trimesters: No increased risk of major malformations, but monitor for neonatal hepatotoxicity and hemorrhage (vitamin K deficiency due to rifampin).