Action And Clinical Pharmacology: Halofantrine is schizonticidal and exerts its action at the erythrocytic stage of the life cycle (trophozoite and schizont). It is not effective against exo-erythrocytic (hepatic) schizonts or against the sporozoite, merozoite or gametozoite stages of the life cycle of Plasmodium species investigated.
The precise mechanism of action of halofantrine is not certain. It has been hypothesized that halofantrine interferes with the neutralization of a toxic metabolite involved in the digestion of hemoglobin within the plasmodium. The toxic metabolite accumulates and breaks down internal cell membranes resulting in the death of the parasite.
In addition there is evidence to suggest that halofantrine may inhibit the energy-dependent proton pump on the external surface of the plasmodia in erythrocytes, thereby destroying the membrane integrity of the parasite.
Pharmacokinetics: After administration of single doses of halofantrine, plasma levels of halofantrine reach maximum concentrations at approximately 6 hours after dosing, while those of the equipotent metabolite desbutal halofantrine occur somewhat later, usually between 10 and 18 hours postdose. The maximum concentration of halofantrine after a single dose of 500 mg averages about 270 nmol/L (135 ng/mL) and concentrations of the metabolite reach about one-half this level. The blood profile and area under the curve (AUC) indicate that halofantrine appears in the systemic circulation within 1 hour of administration and that the absorption continues at a relatively low rate for several hours.
The elimination half-life of halofantrine from blood varies with the individual but is generally 2 to 3 days. The desbutyl metabolite has a half-life of about twice the parent compound.
The major route of elimination from the body is via the feces.
The absorption of halofantrine is known to be variable following single doses (250 mg to 2 000 mg) in healthy subjects, hence the rationale for divided dosing to ensure adequate blood concentrations.
The relative bioavailability of halofantrine is increased approximately 6-fold when taken with a fatty meal. This must not be used as a method of enhancing absorption.
Indications And Clinical Uses: In the treatment of acute uncomplicated malaria due to Plasmodium falciparum and Plasmodium vivax, including those strains resistant to chloroquine. Administration of halofantrine in the treatment of malaria caused by P. vivax should be followed up by treatment with an 8-aminoquinoline derivative to eliminate hepatic forms.
Halofantrine may be given to patients intolerant to chloroquine.
Prophylaxis: Halofantrine should not be used as a prophylactic agent.
Resistance: In vitro sensitivity studies and sentinel cases have suggested that cross resistance between halofantrine and mefloquine can occur.
Note: The safety and efficacy of halofantrine in the treatment of patients with cerebral malaria and other forms of complicated malaria are not known.
Contra-Indications: In patients with congenital or acquired QTc interval prolongation (see Warnings).
Halofantrine is contraindicated in patients with a known hypersensitivity to the drug.
Manufacturers’ Warnings In Clinical States: General: Halofantrine prolongs QTc interval at the recommended therapeutic dose. Risks of prolonged QTc interval include torsades de pointes and ventricular fibrillation. Halofantrine is not recommended in patients with known QTc prolongation, in combination with drugs or in clinical conditions known to prolong QTc interval, or in patients with ventricular dysrhythmias, AV conduction disorders, severe electrolyte abnormalities or unexplained syncopal attacks. Higher than recommended doses of halofantrine have been shown to further prolong QTc interval. The prolongation of the QTc time is reversible within 3 to 4 days.
An ECG should be performed in all patients who are being considered for treatment with halofantrine to assess whether there are conduction abnormalities or a prolonged QTc interval.
Drug Interactions: An interaction between halofantrine and mefloquine has been reported to lead to further prolongation of the QTc interval.
Pregnancy: The use of halofantrine in pregnant women is not recommended, unless the benefits are considered to outweigh the potential risk. No teratogenicity was seen in rat studies at doses up to 120 mg/kg/day (4 times the recommended human dose based on mg/kg). Studies in rabbits revealed that doses up to 60 mg/kg/day (2 times the recommended human dose based on mg/kg) did not produce harmful effects to the mother or fetus. Severe maternal toxicity was evident in a second rabbit teratology study where a slight increase in the incidence of skeletal malformations was observed in the high dose group only (120 mg/kg which is 4 times the recommended human dose based on mg/kg).
Lactation: The use of halofantrine is not recommended in breast-feeding mothers. Animal data suggest that halofantrine may be secreted in maternal milk, resulting in reduced rate of weight gain of offspring.
Precautions: General: While a phototoxic potential for halofantrine cannot be ruled out on the basis of the chemical structure of the drug and on the results of animal studies, there is no clinical evidence of this effect in humans.
Children: The use of halofantrine in children is not recommended.
Geriatrics: The use of halofantrine in elderly patients has not been studied.
Liver/Kidney Diseases: The use of halofantrine in subjects with liver or kidney diseases has not been investigated.
Adverse Reactions: Halofantrine is generally well tolerated. In clinical studies the most frequently reported adverse events were diarrhea (6.7%), vomiting (3.9%), coughing (3.5%), nausea (3.3%), pruritus (3.2%), headache (2.5%) and fever (2.4%), but the causal relationship has not been established.
Skin rash, and very rarely, convulsions, anaphylaxis and angioedema have been reported with halofantrine. Hemolytic reactions which have compromised renal function have been reported in patients with malaria.
There have been rare reports of serious ventricular dysrhythmias sometimes associated with death. These cases have occurred particularly under certain conditions which include use of doses higher than recommended, recent or concomitant treatment with mefloquine or presence of pre-existing prolongation of QTc interval. Palpitations and dizziness are often symptoms of malaria but may also be associated with cardiac arrhythmias.
Occasional elevation of serum transaminases have been reported following treatment. Their relation to medication is unclear since such changes are commonly seen in acute malaria. Values have generally returned to normal within 1 week after treatment.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: The absence of experience with acute overdosage with halofantrine precludes characterization of sequela and assessment of antidotal efficacy at this time. However, in case of accidental overdosage, immediate induction of emesis or gastric lavage is recommended, in conjunction with supportive measures which should include ECG monitoring.
Dosage And Administration: It is important that halofantrine be given on an empty stomach 1 hour before or 3 hours after meals due to the observation that absorption is increased when taken with a fatty meal. High plasma levels of the parent drug may be associated with significant QT prolongation and therefore increased potential for cardiotoxicity.
Adults: Non-immune Patients: Patients with no previous exposure or minimal exposure to malaria should be considered non-immune. These patients should receive 500 mg (2Â´250 mg tablets) every 6 hours for 3 doses (total first course dosage 1 500 mg). This course of therapy should be repeated 7 days after the first course.
Semi-immune Patients: Patients with a history of life-long residence in malaria endemic areas and who have a clear history of recent malarial infection with the same species of parasite may be considered semi-immune. These patients should receive 500 mg (2Â´250 mg tablets) every 6 hours for 3 doses (total dosage 1500 mg).
Children: The use of halofantrine is not recommended in children.
Availability And Storage: Each white to off-white, capsule-shaped tablet with a breakline on one side and inscribed HALFAN on the other side, contains: halofantrine HCl 250 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium starch glycollate and talc. Blister packs of 6 and 12. Store at room temperature (below 30°C).
HALFAN SmithKline Beecham Halofantrine HCl Antimalarial