Formulations

Tablets containing 20 mg of artemether plus 120 mg of lumefantrine (benflumetol).

Efficacy

Lumefantrine is an aryl amino alcohol similar to quinine, mefloquine and halofantrine. Biochemical studies suggest that its antimalarial effect involves lysosomal trapping of the drug in the intra-erythrocytic parasite, followed by binding to toxic haemin that is produced in the course of haemoglobin digestion. This binding prevents the polymerization of haemin to non-toxic malaria pigment.

A total of 16 clinical trials with more than 3 000 patients, including 600 children under 5 years of age, have been carried out in Europe, South-East Asia and Africa. In areas with low or no malaria transmission, the 28-day cure rates with a 4-dose regimen were 95.1% outside Thailand and 76.5% in Thailand, where most patients came from areas with multidrug-resistant malaria (317-319). In Thailand, a 6-dose regimen gave a 28-day cure rate of 97.3% (318). In a trial in Africa, the 28-day cure rate complemented by PCR studies to distinguish reinfections from recrudescences showed a corrected cure rate of 92.7% (319). A dose-finding trial in Thailand demonstrated the importance of the number of doses rather than the dose level for the efficacy of this combination drug. These studies also showed that the cure rate was 97% in patients receiving a total dose of > or = 50 mg/kg, regardless of the level of initial parasitaemia, but that cure rates were significantly lower with parasite densities of > or = 20 000 per ml when the total lumefantrine dose was < 50 mg/kg (320-322).

Use

Artemether-lumefantrine can be used for the treatment of uncomplicated infections with P. falciparum, including strains from multidrug-resistant areas. Although the 4-dose regimen appears to be effective in semi-immune adult patients from Africa, children should probably receive a 6-dose regimen because of their lower immunity (323; M. van Vught et al., unpublished data). To avoid confusion and ensure the highest efficacy and reliability with this drug, it may be advisable to recommend the 6-dose regimen uniformly as the standard treatment. Artemether-lumefantrine has been registered in Switzerland for use as standby emergency treatment for travellers to areas where the parasite is resistant to other drugs.

Recommended treatment

In semi-immune patients, the manufacturer recommends the 4-dose regimen, consisting of 1, 2, 3 or 4 tablets taken at 0 h, 8 h, 24 h and 48 h. The total course for an adult is 16 tablets, which gives a total dose of 320 mg of artemether plus 1920 mg of lumefantrine.

In areas with multidrug-resistant P. falciparum and in non-immune patients, an intensive 6-dose course consisting of the doses shown above at 0 h and 8 h, and twice daily doses on the next 2 days is recommended, as shown in Table 19.

Thus, the course for an adult would be 4 tablets at 0 h and 8 h and 4 tablets twice a day on the second and third days.

There is no evidence of increased toxicity with the 6-dose as compared to the 4-dose regimen and, for simplicity of implementation, it may be advantageous to use the 6-dose regimen in all areas.

Chemoprophylaxis

This drug is not recommended for chemoprophylaxis.

Use in pregnancy

This drug should not be used in pregnant women. Safety of its use in pregnancy has not yet been established.

Drug disposition

Absorption of lumefantrine is variable and is increased when the drug is taken with food. Maximum blood levels are observed 6-12 h after drug administration. The half-life is 88 h in healthy subjects and about twice as long in malaria patients. The drug is excreted via the liver and faeces. There is no evidence of pharmacokinetic interaction between artemether and lumefantrine (324).

Adverse effects

The following adverse effects have been reported (325): dizziness and fatigue, anorexia, nausea, vomiting, abdominal pain, palpitations, myalgia, sleep disorders, arthralgia, headache and rash.

In children and adults treated with this combination, the frequency and degree of QTc prolongations was lower than with chloroquine, mefloquine or halo-fantrine (324). Studies show no indication of cardiotoxicity (326).

Contraindications

Artemether-lumefantrine is contraindicated in:

• pregnant and lactating women,
  
• persons with known hypersensitivity to either of the components,
  
• persons with severe malaria.