Formulations

• Tablets containing 250 mg of halofantrine hydrochloride equivalent to 233 mg of halofantrine base.

• Paediatric suspension containing 100 mg of halofantrine hydrochloride, equivalent to 93.2 mg of halofantrine base, in 5 ml, i.e. 20 mg of salt per ml.

Efficacy

Halofantrine, a phenanthrene methanol, is a blood schizonticide that is active against all malaria parasites. It is active against P. falciparum infections that are resistant to chloroquine and to sulfa drug-pyrimethamine combinations. Early studies indicated that halofantrine was also active against some but not all isolates with reduced susceptibility to mefloquine.

However, recent work in experimental models and in vitro with clones or isolates from various regions indicates cross-resistance between mefloquine and halofantrine (206, 207). Halofantrine resistance is easy to produce in laboratory models and is accompanied by increased susceptibility to chloroquine and decreased susceptibility to mefloquine and quinine (208, 209). Halofantrine is not active against gametocytes or the hepatic stages of malaria parasites.

Use

Halofantrine has no place in malaria control programmes because of its high cost, its variable bioavailability, its cross-resistance to mefloquine and the fact that fatal cardiotoxicity has been reported in certain risk groups following standard therapy. It may be used on an individual basis in patients known to be free from heart disease in areas where multiple drug resistance is prevalent and no other effective antimalarial is available.

Consequently, halofantrine should only be available on a prescription basis. It is not recommended for standby treatment. Strict governmental control of its importation, distribution and utilization is recommended.

Recommended treatment

8 mg of halofantrine base per kg in three doses at 6-h intervals (for adults and children of > 10 kg).

The standard dose shown above gives a total dose of 24 mg of halofantrine base per kg, equivalent in adults to 1 500 mg of base. For non-immune patients, a second course of therapy one week after the initial treatment is recommended by the manufacturer to ensure complete cure.

Halofantrine is not recommended in children of < 10 kg since data in this weight group are limited. Data on use of the drug in over 100 children of under 2 years of age suggest, however, that the drug is well tolerated (210). Dosage schedules are shown in Table 14.

The relative absorption of halofantrine increases approximately six-fold in persons ingesting a meal with a high fat content compared with those who have not recently consumed food (211-213), and higher serum levels correlate with longer QTc intervals (214). Since an increase in absorption tends to cause prolongation of the QTc interval, the manufacturer no longer recommends administration of the drug with food.

Chemoprophylaxis

There are no data to support the use of halofantrine for malaria prophylaxis.

Use in pregnancy

Preclinical studies in rodents have demonstrated toxicity in terms of increased frequency of post-implantation embryonic death and reduced fetal body weight at doses in excess of 15 mg/kg per day (215). No teratogenic effects have been reported. Low weight gains of offspring found in animal toxicity studies suggest that halofantrine may be secreted in breast milk. Halofantrine should therefore be avoided during pregnancy and lactation.

Drug disposition

Halofantrine is a lipophilic weak base that is largely insoluble in water. Its systemic absorption from the current formulations is unpredictably variable but increases up to six-fold in the presence of fatty foods (212, 213). The elimination half life varies with the individual but is generally 24-48 h for the parent drug and twice as long for the biologically active desbutyl metabolite. The functional elimination half-life is therefore 4-5 days. The major route of elimination is the faeces (216).

Adverse effects

Adverse effects include nausea, abdominal pain, diarrhoea, pruritis and skin rashes. Prolongation of the QTc interval and rare cases of serious ventricular dysrhythmias (217-219), sometimes fatal (219), have also been reported. The latter have usually occurred in patients receiving higher than recommended doses who had also received recent or concomitant treatment with mefloquine or were known to have pre-existing prolongation of the QTc interval (185, 214, 220). Convulsive seizures (J. Horton, personal communication, 1995), intra-vascular haemolysis that compromises renal function (221), and elevation of serum transaminases have also been observed. The relation of the elevation of serum transaminases to medication is unclear since such changes are commonly seen in acute malaria. Values return to normal within one week after treatment.

Up to August 1994, 31 persons with cardiovascular events were reported to the manufacturer, of whom 13 died. Since that date and following the publication of revised guidelines on risk factors, only two additional cases have been reported to the company (J. Horton, personal communication, 1995).

Contraindications

The use of halofantrine is contraindicated in:

• persons with a history of allergy to the drug,
• persons with pre-existing cardiac disease,
• persons with a family history of sudden death or of congenital prolongation of the QTc interval,
• persons who are using other drugs or have a clinical condition known to prolong the QTc interval,
• persons who have received treatment with mefloquine in the previous 3 weeks,
• pregnant women, breastfeeding mothers and children under one year.

Overdosage

There is no experience of acute overdosage with halofantrine. Immediate emesis or gastric lavage is advised. Supportive measures should include ECG monitoring.