Clofazimine

Clofazimine is a lipophilic riminophenazine dye with antimycobacterial and anti-inflammatory activity. It is a companion drug in regimens for rifampicin-resistant and multidrug-resistant tuberculosis and is also used in leprosy. It accumulates in tissue and has a half life of weeks to months. Skin discolouration is universal and QT prolongation is the main cardiac concern.

Class. Riminophenazine antimycobacterial.

Mechanism. Not fully defined; it is thought to generate reactive oxygen species through redox cycling and to disrupt membrane function. Mutations in Rv0678 raise efflux and cause cross-resistance with bedaquiline.

Pharmacokinetics. Oral absorption 45 to 70%, improved with food. Very large volume of distribution, deposition in fat, skin, macrophages and the reticuloendothelial system. Terminal half life about 70 days. Excreted mainly in faeces, with small amounts in bile and sweat.

Rifampicin-resistant and multidrug-resistant tuberculosis (adults). - 100 mg orally once daily, with food. - Duration: set by the regimen, from 6 months in short regimens to 18 to 20 months in longer individualised regimens. - Loading dose: none. Maintenance dose: 100 mg daily. Maximum: 100 mg daily in current practice.

Alternative. Some older regimens used 200 mg daily for the first 2 months, then 100 mg daily; higher doses increase discolouration and gastrointestinal toxicity.

Children (specialist). Weight-based, roughly 1 to 2 mg/kg daily; lower doses or alternate-day dosing are used under 30 kg.

Leprosy. 50 mg daily with a monthly 300 mg supervised dose.

Titration. None; reduce or stop for abdominal pain or QT prolongation.

Contraindications. Hypersensitivity, QTcF over 500 ms and uncorrected electrolyte disturbance. Avoid with severe abdominal pain of unclear cause, and in untreated severe depression where discolouration is likely to be distressing.

Serious adverse effects. QT prolongation and arrhythmia, severe abdominal pain with crystal deposition in the bowel wall, splenic infarction, bowel obstruction and gastrointestinal bleeding (all uncommon).

Common adverse effects. Reddish-brown discolouration of skin, conjunctivae, sweat and urine (resolves over months to years), dry skin, ichthyosis, photosensitivity, nausea and diarrhoea.

Interactions. Additive QT prolongation with bedaquiline, delamanid, moxifloxacin, levofloxacin, macrolides, ondansetron and antipsychotics. Few enzyme interactions.

Common prescribing errors. Omitting a baseline ECG, giving it fasting, failing to counsel on discolouration before starting, and giving it with several QT-prolonging drugs without ECG monitoring.

Special groups. - Pregnancy: crosses the placenta and causes neonatal skin discolouration; use only when no alternative exists. - Breastfeeding: excreted in milk; infant skin discolouration expected. - Children: skin discolouration; weight-based doses under specialist care. - Older adults: usual dose with ECG monitoring. - Kidney impairment: no adjustment. - Liver impairment: use with caution in severe disease; no formal adjustment.

Formulations. Soft-gel capsules 50 mg and 100 mg.

Administration. Once daily with a meal or milk. Counsel that discolouration is expected, reversible and usually slow to clear.

Baseline. ECG with QTcF, potassium, calcium, magnesium and liver tests.

Monitoring. ECG at baseline, 2, 4, 8, 12 and 24 weeks when given with other QT-prolonging drugs; electrolytes monthly; ask about abdominal pain at every visit.

Stopping thresholds. Stop for QTcF over 500 ms (confirmed), arrhythmia or persistent severe abdominal pain.

Referral and escalation. Manage within a drug-resistant tuberculosis programme; surgical review for suspected obstruction or splenic infarction.