What is the guideline for calculating fixed-dose combination (fixcom) of anti-tuberculosis medications, including isoniazid, rifampicin, pyrazinamide, and ethambutol, for adults with pulmonary tuberculosis (PTB) based on weight?

Weight-Based Dosing of Fixed-Dose Combination Anti-Tuberculosis Medications for Pulmonary TB

For adults with pulmonary tuberculosis, fixed-dose combination tablets should be dosed based on body weight using the FDA-approved Rifater formulation during the 2-month intensive phase: patients ≤44 kg receive 4 tablets daily, 45-54 kg receive 5 tablets daily, and ≥55 kg receive 6 tablets daily, with all tablets administered as a single daily dose. 1

Available FDC Formulations and Composition

• Rifater (the 4-drug FDC) contains rifampin 120 mg + isoniazid 50 mg + pyrazinamide 300 mg per tablet 1
• Rifamate (the 2-drug FDC) contains rifampin 300 mg + isoniazid 150 mg per capsule, dosed as 2 capsules daily during the continuation phase 1
• These are the only two FDA-approved fixed-dose combinations available in the United States 1

Weight-Based Dosing Algorithm for Rifater (Intensive Phase)

The weight-based dosing for the 4-drug FDC during the initial 2-month intensive phase is:

• ≤44 kg body weight: 4 tablets daily 1
• 45-54 kg body weight: 5 tablets daily 1
• ≥55 kg body weight: 6 tablets daily 1

Critical Administration Requirements

• All tablets must be taken together as a single daily dose—never split throughout the day 1
• The intensive phase lasts for 56 doses over 8 weeks 1
• After the intensive phase, transition to Rifamate (2-drug FDC) for the 4-month continuation phase 1

Individual Drug Dosing Targets Achieved by FDC

The weight-based FDC dosing achieves the following approximate individual drug doses:

• Isoniazid: 5 mg/kg daily (maximum 300 mg) 2
• Rifampin: 10 mg/kg daily (maximum 600 mg) 3
• Pyrazinamide: 15-30 mg/kg daily (maximum 2 g) 4
• Ethambutol: Should be added separately if needed, as Rifater only contains 3 drugs 5

Common Pitfall: Ethambutol Addition

• Rifater does not contain ethambutol—if a 4-drug regimen is indicated (which is standard for new TB cases), ethambutol must be prescribed separately at 15-25 mg/kg daily 5
• Ethambutol should be included in the initial regimen until drug susceptibility is confirmed, especially in areas where isoniazid resistance exceeds 4% 2

Contraindications to FDC Use

Fixed-dose combinations should NOT be used in the following situations: 1

• Intermittent (twice or thrice weekly) dosing regimens
• Pregnancy (requires individualized dosing)
• Renal insufficiency (requires dose adjustments)
• Hepatic disease (requires modified regimens)

Advantages of FDC Over Separate Tablets

• Prevents inadvertent monotherapy, which is the primary cause of acquired drug resistance 1
• Reduces pill burden from 10-12 tablets daily to 4-6 tablets daily 1
• Improves adherence through simplified regimens 1, 6
• Minimizes medication errors in dispensing and administration 1

Quality Assurance Consideration

• Only use FDCs with proven bioavailability—many formulations achieve inadequate blood levels of component drugs 1
• The bioavailability of FDA-approved Rifater has been validated and produces clinical results equivalent to separate drug administration 5

Monitoring During Treatment

• Baseline liver function tests are required before initiating therapy 1
• Monthly clinical assessments for adverse effects throughout treatment 1
• Hepatotoxicity surveillance should be performed weekly for 2 weeks, then every 2 weeks for the first 2 months 1
• Sputum smear microscopy at 2 months (end of intensive phase), 5 months, and end of treatment 5

Directly Observed Therapy

• Directly observed therapy (DOT) is the standard of care and should be used whenever drugs are administered less than 7 days per week 1
• FDCs are particularly valuable in DOT programs as they ensure all drugs are taken together 5