Rimstar 4-FDC

Approved Indications:

• Pulmonary Tuberculosis (TB): First-line therapy for newly diagnosed active pulmonary TB caused by Mycobacterium tuberculosis.
• Extrapulmonary Tuberculosis: Includes TB lymphadenitis, TB meningitis, pleural TB, and disseminated/miliary TB.
• Initial Intensive Phase: Used as part of the 4-drug intensive regimen (2 months) in combination therapy before transitioning to a continuation phase (usually 2 drugs).

Important Off-Label or Clinically Accepted Uses:

• Latent TB (in certain high-risk contacts): Occasionally considered in drug-resistant latent TB regimens based on susceptibility testing.
• Empiric TB Treatment in High-Burden Settings: Used where diagnostic confirmation is delayed or unavailable, based on clinical and radiological suspicion.

Adults:

• Standard Regimen:
• Intensive phase: 2 months of daily Rifampicin 150 mg + Isoniazid 75 mg + Pyrazinamide 400 mg + Ethambutol 275 mg per tablet (4-FDC).
• Dosage by weight:
• 30–37 kg: 2 tablets daily
• 38–54 kg: 3 tablets daily
• 55–70 kg: 4 tablets daily
• 70 kg: 5 tablets daily
• Administer orally on an empty stomach, preferably in the morning.

Pediatrics:

• Weight-based dosing using pediatric formulations (dispersible tablets or syrups where available). Doses must be adjusted according to national TB program guidelines.

Elderly:

• Same as adult dosing; monitor closely for hepatotoxicity, visual changes, and peripheral neuropathy.

Renal Impairment:

• Mild to moderate: No routine adjustment needed, but monitor ethambutol accumulation.
• Severe impairment or dialysis: Reduce dose or increase dosing interval of ethambutol and pyrazinamide.

Hepatic Impairment:

• Use cautiously; hepatotoxicity is a significant concern. Monitor liver function tests frequently.

This fixed-dose combination acts synergistically against Mycobacterium tuberculosis:

• Rifampicin: Inhibits bacterial DNA-dependent RNA polymerase, preventing RNA synthesis.
• Isoniazid: Inhibits synthesis of mycolic acids, essential components of the mycobacterial cell wall.
• Pyrazinamide: Disrupts membrane energetics and transport functions in acidic environments within macrophages.
• Ethambutol: Inhibits arabinosyl transferase, impairing cell wall biosynthesis and increasing permeability to other drugs.
  This combination maximizes bactericidal activity, shortens treatment duration, and reduces resistance emergence.

• Absorption: Well absorbed orally; food delays or reduces rifampicin absorption.
• Distribution: Widely distributed, including CSF; rifampicin and isoniazid cross the blood-brain barrier.
• Metabolism:
• Rifampicin: Hepatic via deacetylation; induces CYP450 enzymes.
• Isoniazid: Acetylated in liver (rate varies by genetic phenotype).
• Pyrazinamide: Hepatically metabolized to pyrazinoic acid.
• Ethambutol: Partially hepatic metabolism.
• Elimination:
• Rifampicin, isoniazid, and pyrazinamide primarily via urine and bile.
• Ethambutol excreted unchanged in urine.
• Half-lives:
• Rifampicin: ~3–5 hours
• Isoniazid: 1–4 hours (faster in fast acetylators)
• Pyrazinamide: 9–10 hours
• Ethambutol: 3–4 hours

• Pregnancy:
• Generally used when TB treatment is necessary during pregnancy.
• Individual components are not absolute contraindications; however, careful monitoring is essential.
• Pyridoxine (Vitamin B6) supplementation is recommended to reduce neurotoxicity (esp. from isoniazid).
• Lactation:
• All four drugs are excreted in breast milk in low amounts.
• Breastfeeding is generally safe and encouraged during TB treatment.
• Monitor infants for jaundice or hepatic effects; supplement maternal pyridoxine.

• Primary Class: Antitubercular Agents (Anti-TB)
• Subclass: First-line anti-TB fixed-dose combination (FDC)
• Includes: Bactericidal and bacteriostatic agents

• Known hypersensitivity to rifampicin, isoniazid, pyrazinamide, ethambutol, or excipients
• Acute hepatic disease or severe liver impairment (relative contraindication)
• History of drug-induced hepatitis from any of the components
• Optic neuritis (contraindicates ethambutol use)
• Concurrent use with potent CYP450 substrates/inhibitors that may lead to severe interactions

• Hepatotoxicity: Monitor liver function frequently. Avoid alcohol.
• Peripheral neuropathy: Especially with isoniazid; co-administer pyridoxine.
• Optic neuritis: Ethambutol may cause visual disturbances; monitor vision regularly.
• Drug resistance: Avoid monotherapy or poor adherence to prevent resistance.
• Drug interactions: Rifampicin induces hepatic enzymes; adjust concurrent medications accordingly.
• High-risk groups: Elderly, HIV-positive, pregnant women, and those with liver or kidney disease need close supervision.

Common (by system):

• GI: Nausea, vomiting, abdominal pain, loss of appetite
• Hepatic: Transaminitis, jaundice, hepatitis
• Neurological: Peripheral neuropathy (isoniazid), headache, dizziness
• Ocular: Blurred vision, optic neuritis (ethambutol)
• Dermatological: Rash, pruritus
• Others: Orange-red discoloration of urine, sweat, and tears (rifampicin)

Serious:

• Hepatotoxicity
• Severe hypersensitivity or anaphylaxis
• Drug-induced lupus-like syndrome (isoniazid)
• Visual loss (ethambutol)
• Severe anemia, thrombocytopenia (rare)

• CYP450 Induction: Rifampicin strongly induces CYP3A4, 2C9, and others; reduces efficacy of oral contraceptives, warfarin, antiretrovirals.
• Alcohol: Increases risk of hepatotoxicity.
• Phenytoin, Carbamazepine: May require dose adjustments due to altered metabolism.
• Antacids: Reduce absorption of ethambutol; space doses by 2 hours.
• Theophylline: Isoniazid may increase serum levels.

• WHO and national TB programs: Continue to recommend this 4-drug regimen for the initial 2-month intensive phase of drug-susceptible TB.
• New formulations: Pediatric dispersible FDCs widely endorsed for weight-based dosing in children.
• Monitoring emphasis: Global focus on minimizing hepatotoxicity through baseline and periodic liver function tests.
• Digital DOTS (Directly Observed Therapy): Increasing recommendation for digital adherence technologies in TB treatment support.

• Storage Temperature: 15°C to 30°C (room temperature)
• Humidity/Light: Store in a dry place; protect from excessive humidity and light
• Handling Precautions: Keep in original blister until administration
• Pediatric Formulations: Some dispersible tablets may require reconstitution in clean water and should be used immediately after mixing