What is the recommended administration of Fixed-Dose Combination (FDC) of anti-tubercular medicine, including dosage and treatment duration, for patients with tuberculosis?

Administration of Fixed-Dose Combination (FDC) Anti-Tubercular Medicines

Fixed-dose combination tablets should be administered as a single daily dose with all drugs taken together, never split throughout the day, using weight-based dosing for the specific FDC formulation. 1

Available FDC Formulations in the United States

Two FDA-approved fixed-dose combinations are available: 1

• Rifamate®: Contains rifampin 300 mg + isoniazid 150 mg per capsule

  • Standard dose: 2 capsules daily (600 mg rifampin + 300 mg isoniazid) 1

• Rifater®: Contains rifampin 120 mg + isoniazid 50 mg + pyrazinamide 300 mg per tablet

  • Weight-based dosing: 1
    • ≤44 kg: 4 tablets daily
    • 45-54 kg: 5 tablets daily
    • ≥55 kg: 6 tablets daily
  • Critical caveat: Patients >90 kg require additional pyrazinamide tablets beyond the FDC to achieve adequate dosing 1

Timing and Method of Administration

All anti-tuberculosis medications must be administered together as a single daily dose; split dosing should be avoided. 1

• Administer once daily, preferably at the same time each day 1, 2
• If gastrointestinal upset occurs, administration with food is acceptable despite modest decreases in absorption—this is clinically insignificant and preferable to splitting doses or discontinuing therapy 1
• Changing the hour of dosing (e.g., bedtime administration) may help with tolerability 1

Treatment Phases and Duration

Intensive Phase (First 2 Months)

• Rifater® is used for daily therapy during the intensive phase 1, 3
• Duration: 56 doses over 8 weeks (or 40 doses if given 5 days/week under directly observed therapy) 1

Continuation Phase (Months 3-6)

• Rifamate® is used for the continuation phase 1
• Duration: 126 doses over 18 weeks (or 90 doses if given 5 days/week) 1
• Total treatment: 6 months for drug-susceptible pulmonary TB 1, 4

Critical Advantages of FDC Use

FDCs provide several key benefits: 1

• Prevent inadvertent monotherapy, thereby reducing risk of acquired drug resistance 1, 5, 6
• Reduce pill burden and simplify prescription 1
• Improve adherence, especially when directly observed therapy (DOT) is not feasible 1
• Minimize medication errors 1

Important Limitations and Contraindications

When NOT to Use FDCs

Do not use FDCs in the following situations: 1

• Intermittent dosing regimens (twice or three times weekly)—FDCs are formulated only for daily administration 1
• Pregnancy: Rifater® should not be used because it contains pyrazinamide; Rifamate® may be used 1
• Renal insufficiency: Rifater® should not be used due to need for pyrazinamide dose adjustment; Rifamate® is acceptable 1
• Hepatic disease: Use single-drug formulations initially until safety is established in the individual patient 1
• Drug reintroduction after hepatotoxicity: Must use single drugs to identify the offending agent 7

Monitoring Requirements

Baseline Assessment

• Liver function tests (AST, ALT, bilirubin) before starting treatment 7
• Body weight for accurate FDC dosing 1

Ongoing Monitoring

• Monthly clinical assessment for adverse effects 1
• Hepatotoxicity surveillance: weekly for 2 weeks, then every 2 weeks for first 2 months 7
• Stop all hepatotoxic drugs immediately if AST/ALT >5× upper limit of normal (asymptomatic) or >3× upper limit of normal (with symptoms) 1, 7

Directly Observed Therapy (DOT) Considerations

DOT is the standard of care and should be used whenever drugs are administered less than 7 days per week. 1, 2

• FDCs are especially useful for DOT given daily 1
• When DOT is given 5 days/week, adjust total dose count accordingly (e.g., 130 doses for 6-month regimen instead of 182) 1
• Patients may be given medications for self-administration on weekends when DOT is 5 days/week 1

Common Pitfalls to Avoid

• Never split the daily dose throughout the day—all drugs must be taken together 1
• Never discontinue rifampin for minor gastrointestinal side effects—adjust timing or give with food instead 1
• Never use Rifater® in patients >90 kg without supplemental pyrazinamide tablets 1
• Never confuse Rifamate with rifampin alone—this can result in inadvertent monotherapy 5
• Never use FDCs for intermittent (twice or three times weekly) regimens—they are not formulated for this purpose 1
• Never add a single drug to a failing regimen—this promotes drug resistance 7

Quality Assurance

Only FDCs with proven bioavailability should be used, as many formulations (particularly in developing countries) achieve inadequate blood levels of component drugs, especially rifampin. 1, 5, 6