Halofantrine warnings and precautions

Halofantrine
HALFAN® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Overdosage
Dosage and Administration
How Supplied

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Warnings

WARNING HALFAN HAS BEEN SHOWN TO PROLONG QTc INTERVAL AT THE RECOMMENDED THERAPEUTIC DOSE. THERE HAVE BEEN RARE REPORTS OF SERIOUS VENTRICULAR DYSRHYTHMIAS SOMETIMES ASSOCIATED WITH DEATH, WHICH MAY BE SUDDEN. HALFAN IS THEREFORE NOT RECOMMENDED FOR USE IN COMBINATION WITH DRUGS OR CLINICAL CONDITIONS KNOWN TO PROLONG QTc INTERVAL, OR IN PATIENTS WHO HAVE PREVIOUSLY RECEIVED MEFLOQUINE, OR IN PATIENTS WITH KNOWN OR SUSPECTED VENTRICULAR DYSRHYTHMIAS, A-V CONDUCTION DISORDERS OR UNEXPLAINED SYNCOPAL ATTACKS. HALFAN SHOULD BE PRESCRIBED ONLY BY PHYSICIANS WHO HAVE SPECIAL COMPETENCE IN THE DIAGNOSIS AND TREATMENT OF MALARIA, AND WHO ARE EXPERIENCED IN THE USE OF ANTIMALARIAL DRUGS. PHYSICIANS SHOULD THOROUGHLY FAMILIARIZE THEMSELVES WITH THE COMPLETE CONTENTS OF THIS LEAFLET BEFORE PRESCRIBING HALFAN.

In life-threatening, severe, or overwhelming malarial infections, patients should be treated immediately with an appropriate parenteral antimalarial drug. The safety and efficacy of Halfan in the treatment of patients with cerebral malaria or other forms of complicated malaria have not been established.

Halfan has been shown to prolong QTc interval at the recommended therapeutic dose. There have been rare reports of serious ventricular dysrhythmias sometimes associated with death, which may be sudden. Halfan is therefore not recommended in combination with drugs, or clinical conditions, known to prolong QTc interval, or in patients with known or suspected ventricular dysrhythmias, A-V conduction disorders or unexplained syncopal attacks. Physicians should perform an ECG prior to dosing to ensure that the patient’s baseline QTc interval is within normal limits. Cardiac rhythm should be monitored during and for 8-12 hours following completion of therapy.

Caution should be used with concomitant intake of drugs which are known to significantly inhibit cytochrome P450IIIA4.

Halfan should be taken on an empty stomach as increased absorption and, thus, increased toxicity may result from dosing in association with food. Do not exceed recommended doses, as higher than recommended doses of Halfan have been shown to further prolong QTc interval.

Data on the use of Halfan subsequent to administration of mefloquine suggest a significant, potentially fatal, prolongation of the QTc interval.1 Therefore, Halfan should not be given simultaneously with or subsequent to mefloquine. (See PRECAUTIONS—Drug Interactions.) Halofantrine has been shown to be embryotoxic in animal tests. Use in women of childbearing potential only with due caution regarding the potential effect on the fetus if the patient is pregnant. (See PRECAUTIONS—Pregnancy subsection.)

Precautions

General

A phototoxic potential cannot be ruled out on the basis of the chemical moiety of halofantrine and the results of animal tests. (See ANIMAL TOXICOLOGY.) However, there is no evidence for this effect in humans.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies of halofantrine hydrochloride in animals have not been performed to evaluate carcinogenic potential.

Genotoxicity of halofantrine hydrochloride was evaluated in five assay test systems including an Ames test, a gene mutation test in Chinese hamster ovary cells, a chromosomal aberration analysis in Chinese hamster ovary cells, a micronucleus test in mice, and a dominant lethal assay. No mutagenic potential was demonstrated in any of these test systems.

Halofantrine hydrochloride did not adversely affect male or female fertility in the rat at an oral dose of 30 mg/kg (1/6 of the maximum recommended human dose based on mg/m2).

Pregnancy Category: C

Teratogenic Effects

In pregnant rabbits, maternal-lethal doses (decremental dose schedule of 360 to 120 mg/kg, equivalent to 3.6 times to 1.2 times the maximum recommended human dose, respectively, based on mg/m2) were associated with abortion and an increased incidence of skeletal malformations, but oral doses up to 60 mg/kg (6/10 of the maximum recommended human dose based on mg/m2) did not produce maternal or fetal developmental toxicity.

Non-teratogenic Effects

In reproduction teratology studies in the rat, oral doses >30 mg/kg (1/6 of the maximum recommended human dose based on mg/m2) produced postimplantation embryonic death and reduced fetal weight and viability. Halofantrine hydrochloride at doses of 15 mg/kg/day (1/10 of the maximum recommended human dose based on mg/m2) had no embryotoxicity or teratogenicity. These effects occurred at and below doses that produced overt maternal toxicity in the rats.

Halofantrine has been shown to be embryocidal in rats. There are no adequate and well- controlled studies in pregnant women. Halfan (halofantrine hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

In lactation studies performed in rats, dose-related decreases in offspring body weight were observed at a dose of 25 mg/kg/day and above (1/8 of the maximum recommended human dose based on mg/m2). Control pups breast-fed by high-dosed mothers had significant decreases in body weight and survival at doses of 50 and 100 mg/kg/day (1/4 to 1/2 of the maximum recommended human dose based on mg/m2).

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from halofantrine hydrochloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of halofantrine hydrochloride tablets in the pediatric population have not been established.

Geriatric Use

There are no studies on the use of halofantrine hydrochloride in elderly individuals.

References

Adapted from the FDA Package Insert.