Rifapentine

Rifapentine is a long-acting rifamycin used in short-course tuberculosis treatment and in once-weekly or daily preventive regimens for latent tuberculosis. Its long half-life allows weekly dosing, and its use requires careful interaction review.

Classification. Rifamycin.

Mechanism. Binds the beta subunit of bacterial RNA polymerase; bactericidal.

Spectrum. Mycobacterium tuberculosis (drug-susceptible); cross-resistance with rifampicin is complete.

Pharmacokinetics. Absorption improves with a fatty meal. Half-life about 14 to 18 hours (active metabolite 25-desacetyl rifapentine similar). Protein binding about 97%. Hepatic metabolism with faecal excretion. Colours body fluids orange.

Maximum 1200 mg daily (adults) in the daily regimen; 900 mg once weekly in the weekly regimen.

Adults and adolescents, oral, with food. - Four-month drug-susceptible pulmonary tuberculosis regimen (12 years and over): rifapentine 1200 mg once daily with isoniazid 300 mg, pyrazinamide and ethambutol (dosed by weight) for 8 weeks, then rifapentine 1200 mg with isoniazid 300 mg daily for 9 weeks.

Doses are given daily, 7 days a week, with pyridoxine. - Latent tuberculosis, 3-month weekly regimen (3HP): rifapentine 900 mg (50 kg or more; weight-banded in children) with isoniazid 900 mg, once weekly for 12 weeks (12 doses), with pyridoxine.

Directly observed therapy or self-administration with monitoring is acceptable. - Latent tuberculosis, 1-month daily regimen (1HP) in people with HIV (13 years and over): rifapentine 600 mg with isoniazid 300 mg once daily for 28 days.

Children (3HP, aged 2 years and over), weight-banded rifapentine once weekly: 10 to 14 kg 300 mg; 14.1 to 25 kg 450 mg; 25.1 to 32 kg 600 mg; 32.1 to 49.9 kg 750 mg; 50 kg or more 900 mg, with isoniazid 25 mg/kg (maximum 900 mg). Four-month regimen from 12 years.

Alternatives. Rifampicin (4 months, or 3 months with isoniazid), isoniazid (6 to 9 months).

Contraindications. Rifamycin hypersensitivity; active liver disease; concurrent drugs that cannot be adjusted.

Adverse effects. Orange body fluids, nausea, headache, rash, dizziness. Serious: hepatotoxicity (with isoniazid), systemic drug reaction after weekly doses (flu-like syndrome with fever, hypotension, syncope; more frequent with the weekly regimen), thrombocytopenia, neutropenia, hypersensitivity, hyperuricaemia.

Interactions. Strong inducer like rifampicin: avoid or adjust protease inhibitors, nevirapine, hormonal contraception, warfarin, direct oral anticoagulants, antiepileptics, azoles, methadone, immunosuppressants, corticosteroids. Dolutegravir 50 mg once daily is acceptable with once-weekly 3HP and with 1HP in specialist use (increase to 50 mg every 12 hours with the daily four-month regimen); efavirenz is acceptable.

Common prescribing errors. Missed dose timing, skipping pyridoxine, giving without food, and not counselling about contraception.

Special groups. - Pregnancy: avoid unless essential (limited data); weekly 3HP is generally deferred until after delivery. Breastfeeding: acceptable with infant monitoring. - Older adults: monitor liver tests. - Kidney impairment: no adjustment. - Liver impairment: avoid in active hepatitis. - Region: used in high-burden tuberculosis programmes in East Africa for short-course and preventive treatment, with supply through national programmes.

Administration. Take with a meal (fat improves absorption). Tablets may be crushed and mixed with soft food.

Baseline and monitoring. - Baseline: liver tests, full blood count, HIV status, pregnancy test, medication review. - During treatment: monthly clinical review and liver tests if baseline abnormal, if symptoms appear or in the four-month regimen at 2, 4 and 8 weeks; adherence and adverse-reaction review at each dose.

Stop rules. Stop for jaundice, transaminases over 3 times the upper limit with symptoms (over 5 times without), severe systemic reaction or rash, or severe cytopenia.

Referral and escalation. Refer for liver injury, systemic drug reactions, treatment failure and drug-resistant tuberculosis.