Drug reference

Isoniazid + Rifampicin + Pyrazinamide + Ethambutol

Antimycobacterial · Anti-tuberculosis

Also known as Akurit-4, Forecox-4, R-Cinex E4, Myrin-P Forte, Combutol-E4

AntimycobacterialAnti-tuberculosisATC J04AM06

CDSCO approvedSchedule HATC J04AM06

EXCRETION

—

not curated

INTERACTIONS

—

none in our sources

PREGNANCY

Isoniazid, Rifampicin, Pyrazinamide are generally considered Category C, and Ethambutol is Category B. While there are potential risks, active tuberculosis poses a significant risk to both mother and fetus. Therefore, this FDC is often used in pregnancy when the benefits of treating active TB outweigh the potential fetal risks. Pyridoxine supplementation is strongly recommended to prevent Isoniazid-induced neuropathy in both mother and neonate.

FDA category + note

Mechanism

This FDC combines four potent anti-tubercular agents, each targeting different aspects of Mycobacterium tuberculosis. Isoniazid inhibits mycolic acid synthesis, disrupting the bacterial cell wall. Rifampicin inhibits bacterial DNA-dependent RNA polymerase, blocking RNA synthesis. Pyrazinamide, a prodrug, is converted to pyrazinoic acid in acidic environments within macrophages, disrupting membrane function and energy metabolism. Ethambutol interferes with arabinogalactan synthesis, an essential component of the mycobacterial cell wall, leading to cell wall disruption. Combination rationale: This four-drug FDC is a cornerstone of tuberculosis treatment, leveraging the synergistic bactericidal and sterilizing activities of its components to rapidly reduce bacterial load, prevent the emergence of drug resistance, and shorten treatment duration. The FDC significantly improves patient adherence by reducing the pill burden and simplifies drug management, which is crucial for the long and complex regimen required for TB eradication, especially in resource-limited settings like India.

Indications

Treatment of new and previously treated pulmonary and extrapulmonary tuberculosis (TB) as per national guidelines (e.g., RNTCP in India).

Dosing

Adult: Dosing is weight-band based, typically administered orally once daily. Common strengths available in India include combinations like: 75mg Isoniazid / 150mg Rifampicin / 400mg Pyrazinamide / 275mg Ethambutol (for 30-39 kg body weight); 150mg Isoniazid / 300mg Rifampicin / 800mg Pyrazinamide / 550mg Ethambutol (for 40-54 kg body weight); 225mg Isoniazid / 450mg Rifampicin / 1200mg Pyrazinamide / 82…
Pediatric: Generally not recommended for young children or infants due to fixed-dose components and difficulty in precise weight-based dosing. Specific pediatric formulations or separate drugs are preferred for children under 25 kg.
Renal adjustment: Significant dose adjustment is required for patients with severe renal impairment (CrCl <30 mL/min), especially for Pyrazinamide and Ethambutol, which are primarily renally excreted. The FDC may not be suitable in such cases, and individual agents with adjusted doses are often preferred. Typically, doses are reduced to 2-3 times weekly.
Hepatic adjustment: Contraindicated in acute liver disease or severe hepatic impairment. In mild to moderate impairment, use with extreme caution and close monitoring of liver function tests. Dose adjustments for individual components may be necessary if used off-label.
Geriatric: Use with caution. Elderly patients may have reduced renal/hepatic function, requiring dose adjustment and closer monitoring for adverse effects, especially hepatotoxicity and optic toxicity. Vitamin B6 supplementation is recommended to prevent peripheral neuropathy.
Max dose: The maximum daily dose is determined by the specific FDC strength for the highest weight band (e.g., 300mg Isoniazid, 600mg Rifampicin, 1600mg Pyrazinamide, 1100mg Ethambutol for >70 kg body weight). Individual component maximums should not be exceeded.

Pharmacokinetics

Onset

The anti-tubercular effect is not immediate; clinical efficacy is observed over weeks of consistent therapy. Bactericidal activity against M. tuberculosis begins within hours to days for individual components.

Peak effect

Isoniazid: 1-2 hours. Rifampicin: 2-4 hours. Pyrazinamide: 2 hours. Ethambutol: 2-4 hours.

Duration

Duration of anti-tubercular effect is cumulative over weeks to months, consistent with the treatment course for TB. Pharmacodynamic effects for each component are sustained for 24 hours allowing once-daily dosing.

Half-life

Isoniazid: 1-4 hours (genetically determined by N-acetyltransferase 2 activity). Rifampicin: 3-5 hours (decreases with autoinduction). Pyrazinamide: 9-10 hours. Ethambutol: 3-4 hours.

Bioavailability

Isoniazid: ~90% (variable due to first-pass metabolism). Rifampicin: 90-95%. Pyrazinamide: >90%. Ethambutol: ~80%.

Protein binding

Isoniazid: 0-10%. Rifampicin: 80-90%. Pyrazinamide: 10-20%. Ethambutol: 20-30%.

Metabolism

Isoniazid: Hepatic metabolism via N-acetylation (by NAT2) and hydrolysis. Rifampicin: Hepatic deacetylation via esterases; potent inducer of CYP3A4. Pyrazinamide: Hepatic hydrolysis to pyrazinoic acid, then further hydroxylation. Ethambutol: Partially metabolized in the liver to aldehyde and dicarboxylic acid derivatives.

Excretion

Isoniazid: Primarily renal (as metabolites). Rifampicin: Primarily biliary excretion (metabolites), with some renal excretion. Pyrazinamide: Primarily renal (as metabolites). Ethambutol: Primarily renal (unchanged and metabolites).

Contraindications

Hypersensitivity to any component of the FDC
Acute liver disease or a history of drug-induced hepatitis
Severe renal impairment
Porphyria
Optic neuritis (due to Ethambutol)
Peripheral neuropathy (relative contraindication for Isoniazid)
Gout (due to Pyrazinamide)

Side effects

Common

Nausea, vomiting, abdominal painAnorexiaRash, pruritusOrange-red discoloration of urine, sweat, tears, and other body fluids (Rifampicin)Arthralgia (Pyrazinamide)Hyperuricemia (Pyrazinamide)Peripheral neuropathy (Isoniazid, preventable with pyridoxine)HeadacheDizziness

Serious

Hepatotoxicity (severe hepatitis, jaundice - all components, especially Isoniazid, Rifampicin, Pyrazinamide)
Optic neuritis (Ethambutol, dose-related, presenting as blurred vision, red-green color blindness, visual field defects)
Hypersensitivity reactions (fever, chills, skin reactions, eosinophilia, DRESS syndrome)
Thrombocytopenia, leukopenia, hemolytic anemia (Rifampicin)
Acute renal failure (Rifampicin)
Drug-induced lupus erythematosus (Isoniazid)
Gouty arthritis (Pyrazinamide)

Pregnancy & lactation

Pregnancy

Lactation

All components pass into breast milk. While concentrations are generally low and adverse effects on infants are rare, potential risks should be considered. The benefits of treatment for the mother's active TB generally outweigh the theoretical risks to the infant. Infant monitoring for adverse effects (e.g., jaundice, lethargy) is recommended. Pyridoxine supplementation is advised for breastfeeding mothers on Isoniazid.