Rifampicin for Tuberculosis

Rifampicin is a semisynthetic rifamycin and the most important sterilising drug in tuberculosis treatment, active against dividing and slowly dividing bacilli. It carries the 6-month regimen and is also used for latent infection. It is a potent inducer of hepatic enzymes and transporters, so drug interactions are the main practical hazard, followed by hepatotoxicity.

Class. First-line antimycobacterial; rifamycin.

Mechanism. Binds the beta subunit of bacterial DNA-dependent RNA polymerase (rpoB), blocking transcription. rpoB mutations cause resistance and are the target of rapid molecular tests.

Pharmacokinetics. Well absorbed on an empty stomach, peak at 2 to 4 hours, half life 2 to 5 hours and shorter with repeated dosing because of auto-induction. Hepatic deacetylation to an active metabolite, biliary excretion and enterohepatic circulation. Good tissue and cerebrospinal fluid penetration. Induces CYP3A4, CYP2C9, CYP2C19, UGT enzymes and P-glycoprotein.

Drug-susceptible tuberculosis (first line). - Adults: 10 mg/kg (range 8 to 12) orally once daily; usual 450 mg under 50 kg and 600 mg at 50 kg or over; maximum 600 mg daily. - Children: 15 mg/kg (range 10 to 20) once daily; maximum 600 mg. - Duration: 2 months with isoniazid, pyrazinamide and ethambutol, then 4 months with isoniazid. - Loading dose: none. Titration: none.

Latent tuberculosis infection. 10 mg/kg daily (maximum 600 mg) for 4 months, or 3 months combined with isoniazid.

Intravenous use (unable to take oral). Same dose as oral; reconstitute 600 mg in the supplied solvent, dilute in 500 mL of 5% glucose or 0.9% sodium chloride and infuse over 2 to 3 hours.

Specialist use. Doses of 15 mg/kg or more, up to 35 mg/kg, are being studied, mainly for tuberculous meningitis; not routine practice.

Interrupted treatment. After missed doses, restart daily dosing, not intermittent, to avoid flu-like and immune-mediated reactions.

Contraindications. Hypersensitivity to rifamycins, jaundice, and use with drugs whose levels cannot be safely lowered, including most boosted protease inhibitors.

Serious adverse effects. Hepatitis, thrombocytopenia, haemolytic anaemia, acute kidney injury, flu-like syndrome (mostly with intermittent dosing), severe skin reactions and haemorrhage in newborns exposed late in pregnancy.

Common adverse effects. Orange-red urine, tears, sweat and sputum (stains soft contact lenses), nausea and rash.

Interactions.

• Contraception: combined and progestogen-only pills and the levonorgestrel implant are unreliable; use a copper device, levonorgestrel intrauterine system or injectable depot progestogen.
• Antiretrovirals: efavirenz 600 mg daily acceptable; dolutegravir increased to 50 mg twice daily during treatment and for 2 weeks after; avoid nevirapine, boosted protease inhibitors, bictegravir, tenofovir alafenamide and cobicistat.
• Warfarin (large dose rises, frequent INR) and direct oral anticoagulants (avoid).
• Lowers levels of azole antifungals, tacrolimus, ciclosporin, corticosteroids, digoxin, methadone, phenytoin, sulphonylureas, statins, amlodipine, beta blockers and levothyroxine.

Common prescribing errors. Missing interaction checks, forgetting dolutegravir dose increase, using pills for contraception, and unplanned intermittent restart.

Special groups. - Pregnancy: used at usual dose; give vitamin K to the newborn if taken late in pregnancy. - Breastfeeding: compatible. - Children: higher weight-based dose; dispersible forms. - Older adults: usual dose; liver tests early. - Kidney impairment: no adjustment. - Liver impairment: use with great caution; some practice caps the dose near 8 mg/kg daily with frequent liver tests.

Formulations. Capsules or tablets 150 mg and 300 mg, fixed-dose combinations, oral suspension and intravenous powder 600 mg.

Administration. Once daily on an empty stomach, 1 hour before or 2 hours after food; with a little food if nauseated.

Baseline. Liver tests, full blood count, creatinine, HIV status, pregnancy test and a full drug and contraception history.

Monitoring. Symptoms of hepatitis at each visit; liver tests at 2 and 4 weeks in at-risk patients; full blood count if bruising, fever or pallor; INR and drug levels where relevant.

Stopping thresholds. Stop all hepatotoxic antituberculosis drugs if ALT is over three times the upper limit of normal with symptoms, or over five times without. Stop permanently for thrombocytopenia, haemolysis or kidney injury attributed to the drug.

Referral and escalation. Specialist review for rifampicin resistance, hepatitis, immune-mediated reactions or complex interactions.