Halofantrine (Systemic)

VA CLASSIFICATION
Primary: AP101

Commonly used brand name(s): Halfan.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antimalarial—

Indications

General considerations
Malaria transmission occurs in large areas of Central and South America, Hispaniola, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania ^{01}. The estimated risk of a traveler acquiring malaria varies markedly from area to area ^{01}. Country-specific information on malaria risk can be obtained from the Centers for Disease Control and Prevention (CDC) or from the CDC's web site at http://www.cdc.gov/travel/yellowbk ^{{01} {02} {12}}.

Drug resistance to chloroquine has been confirmed or is probable in all countries with Plasmodium falciparum malaria except the Dominican Republic, Haiti, Central America west of the Panama Canal Zone, Egypt, and most countries in the Middle East ^{01}. In addition, resistance to both chloroquine and the sulfadoxine and pyrimethamine combination is widespread in Thailand, Myanmar, Cambodia, and the Amazon basin area of South America, and also has been reported sporadically in sub-Saharan Africa ^{01}. Resistance to mefloquine has been confirmed in those areas of Thailand with malaria transmission ^{01}.

Travelers to malarious areas should be advised to use an appropriate drug regimen and personal protection measures to prevent malaria ^{01}. Because of the nocturnal feeding habits of Anopheles mosquitoes, malaria transmission occurs primarily between dusk and dawn ^{01}. Therefore, travelers should take protective measures to reduce contact with mosquitoes, especially during these hours (see Patient Consultation ) ^{01}. However, travelers should be informed that regardless of methods employed, malaria still may be contracted ^{01}.

The appropriate chemoprophylactic regimen is determined by the traveler's risk of acquiring malaria in the area to be visited and by the risk of exposure to chloroquine-resistant P. falciparum ^{{01} {03}}. Indications for prophylaxis for children are identical to those for adults ^{{01} {03}}. Chemoprophylaxis should begin 1 to 2 weeks before arrival in the endemic area, allowing time for development of adequate blood concentration of the chemoprophylactic agent and evaluation of any adverse reactions ^{{02} {01}}. However, the efficacy of halofantrine in the prophylaxis of malaria has not been established ^{{04} {08}}. Halofantrine should be prescribed only by those physicians who have special competence in the diagnosis and treatment of malaria, and who are experienced in the use of antimalarial therapeutic agents (see General Dosing Information ) ^{{04} {08}}.

Halofantrine is not recommended for self-treatment of malaria because potentially serious electrocardiogram changes have been documented following therapeutic doses of halofantrine ^{01}. In many of these reports halofantrine was administered in the presence of other antimalarial agents such as mefloquine ^{01}. The safety of halofantrine for self-treatment of persons on mefloquine prophylaxis has not been established and, since halofantrine is widely available in many countries, health care professionals should caution travelers to avoid the use of halofantrine if they are taking mefloquine (see Medical considerations/Contraindications ) ^{01}.

Accepted

[Malaria (treatment)]¹—Halofantrine is indicated for the treatment of malaria in patients who can tolerate oral medication and who have mild to moderate malaria, equal to or less than 100,000 parasites/mm ³, caused by P. falciparum or Plasmodium vivax ^{{04} {08}}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Halofantrine hydrochloride: 536.89 ^{{04} {08}}

Mechanism of action/Effect:

Halofantrine acts against the asexual erythrocytic form of the parasite, but the mechanism of action remains uncertain ^{05}. The lack of gametocytocidal activity of halofantrine has been demonstrated in vitro ^{05}. It has been suggested that the mechanism of action of halofantrine may be similar to that of quinine, chloroquine, and mefloquine, i.e., halofantrine forms a complex with heme (ferriprotoporphyrin IX), which then damages the cell membrane, causing lysis and death of the parasite ^{05}. However, there is strong contradictory evidence suggesting that halofantrine does not form a complex with heme ^{05}. Other investigations suggested that halofantrine has effects on mitochondria and hematozon vesicles of the parasite ^{05}.

Absorption:

There is wide interindividual variation in halofantrine absorption, suggesting erratic absorption from the gastrointestinal tract ^{{04} {05} {06} {08}}. The rate of absorption can be greatly increased by administration of halofantrine with food, and especially with food with high fat content ^{{04} {05} {06} {08}}. However, halofantrine should not be given with food because cardiac toxicity may result ^{{04} {08}}.

Biotransformation:

Hepatic; rapidly metabolized to N-desbutyl halofantrine ^{05}. Plasma concentrations of N-desbutyl halofantrine are observed soon after administration of halofantrine, but in much lower concentrations ^{05}.

Half-life:

The half-life of halofantrine varies considerably among individuals ^{{04} {08}}.


Distribution half-life:

Approximately 16 hours ^{{04} {08}}.



Elimination half-life:

Variable; 6 to 10 days ^{{04} {08}}.


Time to peak concentration:

5 to 7 hours following a single oral dose of 250 to 1000 mg ^{{04} {08}}.

Peak serum concentration:

High variability in the peak plasma levels was observed in all studies, suggesting erratic absorption from the gastrointestinal tract ^{{04} {08}}. An approximately sevenfold increase in plasma concentration and a three-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 persons ^{{04} {08}}.

Elimination:
    Based on animal studies, halofantrine and its metabolite N-desbutyl halofantrine are eliminated in the feces ^{05}.


Precautions to Consider

Mutagenicity

Halofantrine has not been shown to be mutagenic either in animals or in in vitro tests utilizing the following assay techniques: Ames test, HGPRT gene mutation assay, CHO chromosome aberration test, mouse micronucleus test, and dominant lethal assays in rats ^{{04} {05} {08}}. There were no adverse effects observed at the proposed clinical doses in the animal tests ^{{04} {08}}.

Pregnancy/Reproduction
Fertility—
Studies in male rats given halofantrine hydrochloride at doses of 15 to 30 mg per kg of body weight (mg/kg) per day for 16 weeks have not shown that halofantrine causes adverse effects on fertility ^{{04} {08}}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Halofantrine is not recommended for use during pregnancy since it has been found to be embryocidal in rats ^{{04} {08}}.

Studies in animals have shown that halofantrine is not teratogenic at doses below 45 mg/kg of body weight per day (halofantrine base) in rats and 120 mg/kg per day (halofantrine base) in rabbits ^{{04} {08}}. However, halofantrine base was found to be embryotoxic at doses of 30 mg/kg per day in rats and 60 mg/kg per day in rabbits ^{{04} {08}}. In addition to the increased frequency of post-implantation embryonic death, reduced fetal body weight was observed at doses in excess of 15 mg/kg given for 5 days ^{{04} {08}}.

Breast-feeding

It is not known whether halofantrine is distributed into breast milk ^{{04} {08}}. However, in studies performed in lactating rats, dose-related decreases in offspring body weight were observed at doses of 25 mg/kg per day and above ^{{04} {08}}. Control pups fed by high-dosed mothers had significant decreases in body weight and survival at doses of 50 to 100 mg/kg per day ^{{04} {08}}. Therefore, because of the potential for serious adverse reactions in nursing infants from halofantrine, a decision should be made whether to discontinue nursing or to discontinue treatment with halofantrine, taking into account the importance of halofantrine to the mother ^{{04} {08}}.

Pediatrics

Appropriate studies on the relationship of age to the effects of halofantrine have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.


Geriatrics


Appropriate studies on the relationship of age to the effects of halofantrine have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Mefloquine    (recent or concomitant treatment with mefloquine further prolongs the QTc interval and may potentiate the risk of adverse cardiac effects; the prolongation may be significant and potentially fatal; therefore, halofantrine should not be given simultaneously with or subsequent to mefloquine ^{{04} {08}})

    (although no drug interaction studies have been conducted, halofantrine should not be administered with other agents known to prolong the QTc interval ^{{04} {08}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum and
Aspartate aminotransferase (AST [SGOT]), serum    (values may be increased transiently; however, their relation to medication is not clear since such enzymic changes also commonly are seen in acute malaria; values return to normal usually within 1 week after treatment ^{{04} {08}})


Electrocardiogram (ECG) changes, such as prolongation of QTc interval    (occur at both the recommended therapeutic dose and higher doses ^{{04} {08}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Atrioventricular (AV) conduction disorders or
» Syncope, unexplained, or
» Thiamine deficiency or
» Ventricular dysrhythmias    (these conditions prolong the QTc interval, which may cause an increased risk of arrhythmia ^{{04} {08}})


» Known congenital QTc prolongation, or family history of    (risk of ventricular dysrhythmias sometimes associated with death, which may be sudden ^{{04} {08} {11}})


» Hypersensitivity to halofantrine^{04}{08}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Electrocardiogram (ECG)    (may be performed prior to initiation of treatment with halofantrine to reduce the likelihood of prolongation of the QTc interval ^{{04} {08} {09}})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Pulmonary edema ^{04}{08}(coughing; noisy, rattling, or troubled breathing)

Incidence rare
    
Anaphylactic reaction ^{04}{08}(difficulty in breathing or swallowing; hives; itching, especially of feet or hands; reddening of skin, especially around ears; swelling of eyes, face, or inside of nose; unusual tiredness or weakness, sudden and severe)
    
asthenia ^{04}(unusual tiredness or weakness)
    
chest pain^{04}{08}
    
confusion^{04}{08}
    
convulsions ^{04}{08}(seizures)
    
gastrointestinal disturbances ^{04}{08}(abdominal pain; diarrhea; nausea; vomiting)
    
hypotension ^{04}{08}(unusual tiredness or weakness, severe)
    
palpitations and/or cardiovascular toxicity, specifically, prolonged QTc interval ^{04}{08}{11}(pounding heartbeat)

Note: Gastrointestinal disturbances with abdominal pain, vomiting, cramping, and diarrhea occur at doses higher than the recommended therapeutic dose regimen, and might be symptoms of overdosage ^{04}. Palpitations have been reported also at higher doses (see Overdose ) ^{04}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Cough ^{04}{08}
    
headache ^{04}{08}

Incidence less frequent
    
Anorexia ^{04}{08}(loss of appetite)
    
arthralgia ^{04}(aches and pain in joints)
    
constipation ^{04}{08}
    
dyspepsia ^{04}{08}(indigestion)
    
frequent urination ^{04}{08}
    
hypersensitivity (skin itching or rash)^{04}{08}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (See Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Gastrointestinal disturbances ^{04}{08}(abdominal pain; diarrhea; nausea; vomiting)
    
palpitations ^{04}{08}(pounding heartbeat)


Treatment of overdose
Recommended treatment consists of the following:


To decrease absorption:
Immediate induction of emesis and/or gastric lavage may be performed ^{{04} {08}}.



Specific treatment:
Symptomatic treatment may be given ^{{04} {08}}.



Monitoring:
ECG monitoring should be done ^{{04} {08}}.



Supportive care:
Supportive measures such as maintaining an open airway, respiration, and circulation may be administered. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Halofantrine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to halofantrine

Pregnancy—Not recommended for use during pregnancy because of its embryotoxic effects in animals





Breast-feeding—May be distributed into breast milk, resulting in reduced rate of weight gain, growth, and survival of nursing offspring as shown in animals; breast-feeding is not recommended while the patient is taking halofantrine
Other medications, especially mefloquine
Other medical problems, especially, atrioventricular conduction disorders, known congenital QTc prolongation, or family history of, thiamine deficiency, unexplained syncope, or ventricular dysrhythmias

Proper use of this medication
» Taking on an empty stomach to avoid cardiotoxicity

» Compliance with full course of therapy

» Repeating treatment after 1 week

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress

Checking with physician if symptoms persist or if they become worse after the full course of treatment

Self-protection measures against mosquitoes to help prevent infection or reinfection
Avoiding exposure to mosquitoes, especially at peak feeding times (between dusk and dawn)

Wearing suitable clothing (long-sleeved shirt and long trousers) to protect arms and legs when mosquitoes are out

Applying insect repellant (containing diethyltoluamide [DEET]) sparingly to exposed skin

Sleeping in screened or air-conditioned room

Using bed netting impregnated with repellant or permethrin

Using mosquito coils or sprays


Side/adverse effects
Signs of potential side effects, especially pulmonary edema, anaphylactic reaction, asthenia, chest pain, confusion, convulsions, gastrointestinal disturbances, hypotension, and palpitations and/or cardiovascular toxicity, specifically, prolonged QTc interval


General Dosing Information
Halofantrine has been shown to cause cardiotoxicity, and to prolong the QTc interval at the recommended therapeutic dose ^{{04} {07} {08} {04} {08}}. There have been rare reports of serious ventricular dysrhythmias sometimes associated with death, which may be sudden ^{{04} {08}}. Therefore, halofantrine is not recommended for use in combination with other therapeutic agents or clinical conditions known to prolong the QTc interval, or in patients who previously have received mefloquine, or in patients with known or suspected ventricular dysrhythmias, A-V conduction disorders, or unexplained syncopal attacks ^{{04} {08}}.

Due to its cardiotoxic effects, it is recommended that halofantrine be taken on an empty stomach, because food enhances its absorption ^{{04} {08}}. Higher-than-recommended doses of halofantrine have been shown to further prolong the QTc interval; therefore, recommended doses should not be exceeded ^{{04} {08}}.

In severe, overwhelming, or life-threatening malarial infections, patients should immediately be treated with an appropriate parenteral antimalarial agent ^{{04} {08}}. The safety and efficacy of halofantrine in the treatment of patients with cerebral malaria or other forms of complicated malaria have not been established ^{{04} {08}}.

Halofantrine is a viable option in the treatment of malaria, particularly in areas where resistance to first-line antimalarial agents continues to pose a threat to the successful treatment of malaria ^{07}. However, halofantrine should be prescribed only by those physicians who have special competence in the diagnosis and treatment of malaria, and who are experienced in the use of antimalarial therapeutic agents ^{{04} {08}}.

A second course of treatment with halofantrine is recommended 1 week after the first course to prevent recrudescence ^{{04} {08}}.

Patients with acute Plasmodium vivax malaria treated with halofantrine are at risk of relapse because halofantrine does not eliminate the exoerythrocytic (hepatic phase) parasites ^{{04} {08} {10}}. To avoid relapse after initial treatment of the acute P. vivax infection with halofantrine, patients subsequently should be treated with an 8-aminoquinoline derivative such as primaquine to eradicate the exoerythrocytic parasites ^{{04} {08} {10}}.

Primaquine in an adult dose of 30 mg per day (2 tablets daily) has been shown to provide excellent protection against Plasmodium falciparum and P. vivax malaria in Indonesia, Kenya, and Colombia ^{13}. If primaquine is considered for treatment, glucose-6-phosphate dehydrogenase (G6PD) level should be determined before primaquine is administered ^{13}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

HALOFANTRINE HYDROCHLORIDE ORAL SUSPENSION

Usual adult and adolescent dose
[Malaria, (treatment)]¹
Oral, 500 mg taken on an empty stomach every six hours three times a day for one day ^{{04} {06}}. Treatment should be repeated after one week ^{{04} {06}}.


Note: Patients with a history of lifelong residence in endemic areas and a clear history of recent previous malaria caused by the same Plasmodium species may be considered semi-immune ^{04}. In these patients, omitting the second course of therapy may be considered ^{04}. Clinical trials in semi-immune patients have utilized this one-course regimen with satisfactory safety and effectiveness ^{04}.


Usual pediatric dose
[Malaria, (treatment)]¹
Infants and children up to 23 kg of body weight: Dosage has not been established ^{06}.

Children 23 to 31 kg of body weight: Oral, 250 mg taken on an empty stomach every six hours three times a day for one day ^{06}. Treatment should be repeated after one week ^{06}.

Children 32 to 37 kg of body weight: Oral, 375 mg taken on an empty stomach every six hours three times a day for one day ^{06}. Treatment should be repeated after one week.

Children 37 kg of body weight and over: See Usual adult and adolescent dose ^{06}.


Note: Dosage for children is based on 24 mg per kg of body weight divided into three doses ^{06}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Other (United Kingdom)—


100 mg (93 mg base) per 5 mL (Rx) [Halfan]

Packaging and storage:
Store at controlled room temperature between 20 and 25 °C (68 and 77 °F) in a tight container ^{04}. Protect from light ^{04}.

Auxiliary labeling:
   • Shake well.


HALOFANTRINE HYDROCHLORIDE TABLETS

Usual adult and adolescent dose
[Malaria, (treatment)]¹
See Halofantrine Hydrochloride Oral Suspension ^{06}.


Usual pediatric dose
[Malaria, (treatment)]¹
See Halofantrine Hydrochloride Oral Suspension ^{06}.


Strength(s) usually available
U.S.—


250 mg (233 mg base) (Rx) [Halfan]^{04}

Canada—
Not commercially available.

Other (United Kingdom)—


250 mg (233 mg base) (Rx) [Halfan]

Packaging and storage:
Store at controlled room temperature between 20 and 25 °C (68 and 77 °F) in a tight container ^{{04} {08}}. Protect from light ^{{04} {08}}.

Revised: 09/14/2000

References

1. Centers for Disease Control and Prevention (CDC). Malaria. In: CDC, Health information for international travel 1996–7. U.S. Department of Health and Human Services, Atlanta, GA; 1997. p. 128-37.
   

2. Lobel HO, Kozarsky PE. Update on prevention of malaria for travelers. JAMA 1997; 278(21): 1767-71.
   

3. American Academy of Pediatrics. Malaria. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 335-42.
   

4. Halfan package insert (SmithKline Beecham—US), Rev 8/97, Rec 11/97.
   

5. Karbwang J, Bangchang KN. Clinical pharmacokinetics of halofantrine. Clin Pharmacokinet 1994; 27(2): 104-19.
   

6. Halofantrine hydrochloride. In: Reynolds JEF, editor. Martindale: the extra pharmacopeia. 31st ed. London: The Pharmaceutical Press; 1996. p. 466–7.
   

7. Mbori-Ngacha DA, Onyango FE, Chunge C, et al. Efficacy of halofantrine in the treatment of uncomplicated falciparum malaria. East Afr Med J 1995; 72(12): 796-9.
   

8. Halfan (SmithKline Beecham). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 689-70.
   

9. Monlun E, Le Metayer P, Szwandt S, et al. Cardiac complications of halofantrine: a prospective study of 20 patients. Trans R Soc Trop Med Hyg 1995; 89: 430-3.
   

10. Fryauff DJ, Barid JK, Basri H, et al. Halofantrine and primaquine for radical cure of malaria in Irian Jaya, Indonesia. Ann Trop Med Parasitol 1997; 1: 7-16.
    

11. Matson PA, Luby SP, Redd SC, et al. Cardiac effects of standard-dose halofantrine therapy. Am J Trop Med Hyg 1996; 54(3): 229-31.
    

12. Panel comment, 2/99.
    

13. Panel comment, 2/99.