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Halfan (Halofantrine Hydrochloride) - Description and Clinical Pharmacology

 
 



HALFAN
(halofantrine hydrochloride)
Tablets

DESCRIPTION

HALFAN (halofantrine hydrochloride) is an antimalarial drug available as tablets containing 250 mg of halofantrine hydrochloride (equivalent to 233 mg of the free base) for oral administration.

The chemical name of halofantrine hydrochloride is 1,3-dichloro-α-[2-(dibutylamino) ethyl]-6-(trifluoromethyl)-9-phenanthrene-methanol hydrochloride.

The drug, a white to off-white crystalline compound, is practically insoluble in water. Halofantrine hydrochloride has a calculated molecular weight of 536.89. The empirical formula is C26H30Cl2F3NO•HCl and the structural formula is

Inactive Ingredients

Inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium starch glycolate, and talc.

CLINICAL PHARMACOLOGY

The interindividual variability in the pharmacokinetic parameters of halofantrine is very wide and has led to great difficulty in precisely determining the pharmacokinetic characteristics of this product.

Following administration of halofantrine hydrochloride tablets in single oral doses of 250 mg to 1,000 mg to healthy volunteers, peak plasma levels were reached in 5 to 7 hours. High variability in the peak plasma levels was observed in all studies, suggesting erratic absorption from the gastrointestinal tract. An approximately 7-fold increase in peak plasma concentration and a 3-fold increase in area under the curve (AUC) of halofantrine were obtained when a single 250-mg tablet was administered with high-fat food to healthy subjects.

Healthy volunteers who were given 3 oral doses of 500 mg of halofantrine hydrochloride (500 mg every 6 hours), when fed 2 hours before the second and third doses, had similar 3- to 5-fold increases in absorption. A mean Cmax of 3,200 ng/mL (range 1,555 to 4,920 ng/mL) with a corresponding Tmax of 9 to 17 hours was attained following this multiple-dose regimen.

Halofantrine has a relatively long distribution phase with a half-life of 16 hours and a variable terminal elimination half-life of 6 to 10 days. The half-life of halofantrine varies considerably among individuals.

The primary metabolite of halofantrine is n-desbutyl halofantrine. Cmax valuesranging from 310 to 410 ng/mL were observed to occur between 32 and 56 hours following oral administration of multiple doses of 500 mg halofantrine q6h for 3 doses. The apparent terminal elimination half-life of the metabolite is 3 to 4 days.

Based on animal studies, hepatobiliary clearance with fecal elimination of halofantrine parent compound and metabolite predominates. The extent to which halofantrine is bound to plasma proteins and the extent to which halofantrine is taken up into red blood cells are unknown.

The pharmacokinetics of halofantrine in patients with compromised renal or hepatic function has not been investigated.

The course of the anemia developed by a few malaria patients treated with halofantrine whose red blood cells were deficient in glucose-6-phosphate dehydrogenase (G6PD) was not different from that in malaria patients with normal G6PD values.

Microbiology

Halofantrine is a blood schizonticidal antimalarial agent with no apparent action on the sporozoite, gametocyte, or hepatic stages of the infection. The exact mechanism of its action is unknown. The primary metabolite, n-desbutyl halofantrine, and the parent compound are equally active in vitro .

While in vitro studies indicate that there may be cross-resistance between halofantrine and mefloquine, the clinical data do not support this view. No significant correlation between halofantrine and mefloquine resistance was observed in clinical trials.

Clinical Trials

In controlled clinical trials involving 90 non-immune patients with malaria due to Plasmodium falciparum, treatment with HALFAN (500 mg every 6 hours for 3 doses on days 0 and 7) had a cure rate of 99%. Patients were followed for 28 days or more after initiation of treatment.

In trials involving 583 acute malaria patients, the majority of whom were semi-immune, treatment with HALFAN (500 mg every 6 hours for 3 doses) produced a cure rate of 90% against Plasmodium falciparum infection (n=512), and a cure rate of 99% against Plasmodium vivax (n=71).

ANIMAL TOXICOLOGY

In a phototoxicity study, halofantrine hydrochloride was phototoxic to mice at 80 mg/kg (6/10 of the maximum recommended human dose based on mg/m2). At 40 mg/kg, the lowest dose tested, there was a slight erythematous response.

In a whole-body radioautographic study in the rat, it was demonstrated that high drug levels of halofantrine are retained in the retina and in the Harderian gland for an entire 4-week observation period. Moreover, the estimated half-lives for the radiolabeled equivalents in the retina and Harderian gland were from 91 to 778 hours for the 4-week observation period. The drug passes the blood-brain barrier and is retained for an undetermined time in the central nervous system.

Elevated cholesterol values have been reported in the rat when halofantrine hydrochloride is administered for 4 weeks at oral doses of 30 mg/kg (2/10 of the maximum recommended human dose based on mg/m2) and higher.

Increases in serum cholesterol have also been reported in dogs administered halofantrine hydrochloride for 28 days at oral doses of 25 mg/kg (1/2 of the recommended human dose based on mg/m2) and higher.

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