Miltefosine

Miltefosine is an oral alkylphosphocholine, the only oral drug for leishmaniasis. It is used for visceral and cutaneous leishmaniasis and as part of combination treatment in HIV co-infection. It is teratogenic and needs reliable contraception. Gastrointestinal effects, liver and kidney toxicity are the main concerns.

Class. Antileishmanial; alkylphosphocholine.

Mechanism. Interferes with phospholipid metabolism and cell signalling in the parasite membrane and may induce apoptosis. It also modulates host immune responses.

Pharmacokinetics. Well absorbed orally. Very long half life (about 7 days, terminal 150 to 200 hours) so drug remains for months. Slowly eliminated.

Visceral leishmaniasis. 2.5 mg/kg orally daily for 28 days. - Adults and children 12 years and over: 30 to 44 kg 50 mg twice daily; 45 kg or more 50 mg three times daily. - Children 2 to 11 years: 2.5 mg/kg daily, in one or two doses.

HIV co-infected visceral leishmaniasis (East Africa). Liposomal amphotericin B with miltefosine 100 mg daily (or 2.5 mg/kg daily in children) for 28 days.

Cutaneous and mucosal leishmaniasis. Same daily dose for 28 days, specialist care.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 150 mg daily.

Main alternatives. Liposomal amphotericin B, sodium stibogluconate with paromomycin.

Contraindications. Pregnancy; women of childbearing age not using effective contraception; Sjogren-Larsson syndrome; hypersensitivity.

Serious adverse effects. Teratogenicity and embryo-foetal toxicity, hepatotoxicity, nephrotoxicity, severe vomiting and diarrhoea with dehydration, thrombocytopenia, Stevens-Johnson syndrome, and testicular toxicity in animals.

Common adverse effects. Vomiting, nausea, diarrhoea, abdominal pain, raised liver enzymes and creatinine, and motion sickness.

Interactions. Few documented; avoid combination with other nephrotoxins; reduced effect possible with drugs that lower absorption (vomiting).

Common prescribing errors. Prescribing without a pregnancy test and contraception, stopping early, and giving without food.

Special groups. - Pregnancy: contraindicated; effective contraception during treatment and for 5 months after. - Breastfeeding: avoid. - Children: weight-based dosing from 2 years. - Older adults: usual dose; monitor kidney function. - Kidney impairment: avoid in severe impairment. - Liver impairment: avoid in severe impairment.

Regional points. Efficacy of miltefosine alone is lower in East Africa than in South Asia, so it is combined with liposomal amphotericin B or sodium stibogluconate; long-lasting levels favour resistance if used alone.

Formulations. Capsules 10 mg and 50 mg.

Administration. With food, divided doses, to reduce vomiting.

Baseline. Pregnancy test, creatinine, liver tests, full blood count, HIV test, contraception counselling.

Monitoring. Creatinine and liver tests weekly; weight and hydration; monthly pregnancy tests.

Stopping thresholds. Stop for pregnancy, ALT over 3 times the upper limit of normal with symptoms, or over 5 times without; creatinine rise of more than 50%; Stevens-Johnson syndrome.

Referral and escalation. Specialist care for all patients; admission for dehydration and renal or hepatic toxicity.