Halfan

Halfan is part of the drug class:

• Other antimalarials

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).

In case of overdosage, vomiting should be induced, in conjunction with appropriate supportive measures, which should include ECG monitoring. The possibility of neurologic toxicity, especially decreased consciousness and seizures, should be evaluated. Dehydration secondary to gastrointestinal toxicity with diarrhea and vomiting may require treatment with intravenous fluid therapy.

Gastrointestinal distress with abdominal pain, vomiting, cramping, and diarrhea occurs at doses higher than the recommended therapeutic regimen. Palpitations have also been reported at these higher doses.

Halfan is available as a white to off-white, capsule-shaped tablet containing 250 mg of halofantrine hydrochloride in bottles of 60 tablets. The tablets are imprinted Halfan on 1 side.

Store at controlled room temperature between 20° to 25°C (68° to 77°F) and protect from light.

250 mg 60’s: NDC 0007-4195-18

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.

Applies to halofantrine: oral tablet

Cardiovascular

Cardiovascular side effects have included QT interval prolongation, torsades de pointes, ventricular arrhythmias, and death. Chest pain and palpitations have been reported less than 1% of patients in clinical trials, and orthostatic hypotension has been reported in less than 1% to 33% of patients. Hypertensive crisis (1/933) and cerebrovascular accident (1/933) have been reported, although causality was not clearly established. Quinidine-like electrocardiographic changes have also been reported.[Ref]

Higher risk may be associated with larger than recommended doses, previous or concurrent mefloquine treatment, preexisting QT interval prolongation, or concurrent administration of other QT interval-prolonging drugs. Prolonged QTc interval has been reported in up to 81% of adults treated with standard halofantrine doses and in 100% of patients treated with high doses (72 mg/kg). Prolonged QTc interval has been reported in 50% of children and prolonged PR interval has been reported in 38% of children (n=21). Females may have a higher risk of adverse cardiovascular effects.

It has been proposed that halofantrine prolongs repolarization by blocking HERG potassium channels.[Ref]

Gastrointestinal

Gastrointestinal (GI) side effects have included abdominal pain (8.5%), diarrhea (6%), vomiting (4.3%), and nausea (3.4%), although these symptoms may also occur with a malarial infection. Abdominal distention, anorexia, constipation, dyspepsia, and stomatitis have been reported in less than 1% of patients. GI upset has also been reported.[Ref]

Hematologic

Hematologic side effects have included decreased hematocrit, decreased or increased white blood cells, decreased platelet counts, hemolysis, and hemolytic anemia. These reactions may also occur with a malaria infection.[Ref]

Hypersensitivity

Hypersensitivity side effects have included allergic and anaphylactic reactions including facial edema and urticaria.[Ref]

Dermatologic

Dermatologic side effects have included pruritus (2.6%) and rash (less than 1%).[Ref]

Musculoskeletal

Musculoskeletal side effects have included rigors (1.7%), myalgia (1.3%), arthralgia (less than 1%), and back pain (less than 1%).[Ref]

Nervous system

Nervous system side effects have included dizziness (4.5%) and headache (3%). Asthenia, confusion, convulsions, depression, paresthesia, and sleep disorder have been reported in less than 1% of patients.[Ref]

Genitourinary

Genitourinary side effects have included urinary frequency (less than 1%).[Ref]

Ocular

Ocular side effects have included abnormal vision (less than 1%).[Ref]

Respiratory

Respiratory side effects have included cough (3%). Pulmonary edema has been reported (1/933); however, causality was not determined.[Ref]

Other

Other side effects have included fatigue, malaise, and tinnitus in less than 1% of patients.[Ref]

Hepatic

Hepatic side effects have included increased hepatic transaminases, which returned to normal within 2 to 3 weeks.[Ref]

Renal

Renal side effects have included blackwater fever (acute intravascular hemolysis with acute renal failure and hemoglobinuria) requiring hemodialysis patients taking halofantrine (the active ingredient contained in Halfan) for Plasmodium falciparum infections (n=2). Causality was not clearly established. One patient had a positive Coombs test.[Ref]

Some side effects of Halfan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.