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HALOFANTRINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Halofantrine, a 9-phenanthrenemethanol antimalarial agent, is a blood schizontocide with no apparent activity against the sporocyte, gametocyte, or hepatic stages of the infection.

Specific Substances

    1) WR-171669
    2) SKF-102886
    3) Molecular Formula: C26-H30-CL2-F3-N-O, HCL
    4) CAS 69756-53-2 (halofantrine)
    5) CAS 36167-63-2 (halofantrine hydrochloride)
    6) CAS 66051-63-6 (+/- halofantrine)

Available Forms Sources

    A) FORMS
    1) The distribution of halofantrine has been discontinued in the United States market.
    B) USES
    1) Halofantrine is indicated for the treatment of mild to moderate falciparum and vivax malaria (equal or less than 100,000 parasites/mm(3)) (Prod Info Halfan(R), halofantrine, 1998).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Therapeutic administration of halofantrine may cause QTc interval prolongation and ventricular arrhythmias, especially in individuals with pre-existing heart disease. Nausea, vomiting, abdominal pain, diarrhea, syncope, dizziness, pruritus, and seizures may also occur.
    B) WITH POISONING/EXPOSURE
    1) Human overdose information is limited. Although not reported, overdose of halofantrine might be expected to cause cardiotoxicity (ECG abnormalities and ventricular arrhythmias) and gastrointestinal toxicity (nausea, vomiting, diarrhea, and abdominal pain).
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Ventricular arrhythmias, including torsades de pointes and ventricular fibrillation, and QTc interval prolongation have been reported following therapeutic administration of halofantrine and may occur more frequently in patients with pre-existing cardiopathy.
    2) Sudden deaths have been associated with the therapeutic administration of halofantrine.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Seizures, syncope, and headaches have been reported with therapeutic use of halofantrine.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) GI distress, including nausea, vomiting, diarrhea, and abdominal pain, are common occurrences with therapeutic halofantrine administration.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Acute intravascular hemolysis has been associated with therapeutic administration of halofantrine.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Pruritus was reported with therapeutic use of halofantrine.
    0.2.20) REPRODUCTIVE
    A) Halofantrine has been classified as FDA pregnancy category C.

Laboratory Monitoring

    A) Halofantrine levels are not clinically useful.
    B) Monitor liver enzyme levels for possible transient elevations.
    C) Monitor electrolyte concentrations if patient experiences severe vomiting and/or diarrhea or develops dysrhythmias or QTc prolongation.
    D) Obtain an ECG and institute continuous cardiac monitoring for possible QT prolongation and dysrhythmias.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) VENTRICULAR DYSRHYTHMIAS SUMMARY
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    D) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    1) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    2) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    3) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    E) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

Range Of Toxicity

    A) A man ingested 16.5 grams of halofantrine over an 11-day period and developed gastric pain, diarrhea, headaches, fever spikes, and slightly elevated liver enzyme levels. The patient completely recovered 48 hours after discontinuation of halofantrine.
    B) A woman, with no history of heart disease, developed QTc interval prolongation after taking 26 tablets of halofantrine (6500 mg instead of 1500 mg at the recommended dose) over a 5-day period. She did not experience other clinical manifestations or significant ECG changes.
    C) A 2-year-old boy developed bradycardia and died 4 hours after taking the second dose of halofantrine (8 mg/kg).
    D) A woman died suddenly approximately 2 hours after taking the second dose of halofantrine (500 mg)and cephalexin.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Therapeutic administration of halofantrine may cause QTc interval prolongation and ventricular arrhythmias, especially in individuals with pre-existing heart disease. Nausea, vomiting, abdominal pain, diarrhea, syncope, dizziness, pruritus, and seizures may also occur.
    B) WITH POISONING/EXPOSURE
    1) Human overdose information is limited. Although not reported, overdose of halofantrine might be expected to cause cardiotoxicity (ECG abnormalities and ventricular arrhythmias) and gastrointestinal toxicity (nausea, vomiting, diarrhea, and abdominal pain).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Ventricular arrhythmias, including torsades de pointes and ventricular fibrillation, and QTc interval prolongation have been reported following therapeutic administration of halofantrine and may occur more frequently in patients with pre-existing cardiopathy.
    2) Sudden deaths have been associated with the therapeutic administration of halofantrine.
    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) QTc interval prolongation has been commonly reported following therapeutic administration of halofantrine (Karbwang et al, 1993; Kano et al, 1995; Matson et al, 1996; Restrepo et al, 1996; Touze et al, 1996; Gundersen et al, 1997).
    b) QTc interval prolongation was greater in patients with pre-existing cardiopathy or co-ingestion of other drugs known to prolong the QTc-interval (Castot et al, 1993; Toivonen et al, 1994; Monlun et al, 1995; Nosten et al, 1993) and therefore administration of halofantrine is not recommended to patients on drugs or with clinical conditions known to prolong the QTc interval. The prolongation of the QT interval is directly proportional to the plasma concentration of halofantrine but not to its principal metabolite, desbutylhalfantrine (Giudecelli et al, 1996).
    c) CASE SERIES - Two groups of patients (11 patients with confirmed malaria and 9 patients with fever but not malaria) received two courses of halofantrine, 500 mg three times at 6 hour intervals, with a one week interval between courses (total amount of halofantrine was 3000 mg). More than 50% of patients in each group experienced QT interval prolongation at 24 to 36 hours following initiation of halofantrine treatment, which coincided with the highest halofantrine serum levels in each patient (Monlun et al, 1993).
    d) IN-VITRO STUDY - A study was conducted, using an isolated perfused feline heart model, in order to evaluate the potential cardiotoxicity caused by either halofantrine or its metabolite. It was shown that, although halofantrine had a minimal effect on the QT interval at 1 mcmol/L, there was a concentration-dependent QT interval prolongation at higher concentrations tested (10 mcmol/L). Also, halofantrine's metabolite, N-desbutylhalofantrine, had a minimal effect on QT prolongation at concentrations up to 20 mcmol/L, suggesting that N-desbutylhalofantrine may be potentially safer than halofantrine for use as an antimalarial agent (Wesche et al, 2000).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 70-year-old female, with no history of heart disease, developed QTc interval prolongation (0.62 seconds) after taking 26 tablets of halofantrine (6500 mg instead of 1500 mg at the recommended dose) over a 5-day period. Approximately 3 and 24 hours after the last intake, blood levels of halofantrine (1,050 and 400 ng/mL, respectively) and N-desbutyl-halofantrine (1,154 and 1,328 ng/mL, respectively) were high (Bouchaud et al, 2002).
    B) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) Torsade de pointes was reported in two family members, previously diagnosed with congenital long QT syndrome, following halofantrine administration (total ingestion was 1000 mg). Both patients recovered following symptomatic and supportive treatment and discontinuation of halofantrine (Toivonen et al, 1994).
    b) Bursts of torsade de pointes were documented in two young women presenting with episodes of syncope following administration of halofantrine 500 milligrams every six hours for three doses on days one and seven (abstract states 500 milligrams six hourly for three doses on days one and seven). Both women were found to have congenital long QT-interval/Romano-Ward syndrome on subsequent electrophysiological testing (Monlun et al, 1993)
    C) VENTRICULAR FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 26-year-old female contracted malaria and was given halofantrine, chloramphenicol, and metronidazole without any adverse effects. A week later, the patient was still not feeling well, and she began a second course of treatment with halofantrine. Six hours after her second halofantrine dose, the patient experienced syncope, seizures and developed respiratory arrest. On arrival to the ED, ventricular fibrillation was recorded and cardioversion was successful. The patient gradually recovered (Gunderson et al, 1997).
    D) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 37-year-old female, with malaria, ingested high-dose halofantrine after unsuccessful 21-day treatment with mefloquine. After receiving the ninth dose of halofantrine, the patient developed cardiac arrest and could not be resuscitated. The patient's past medical history included frequent syncope with rapid cardiac palpitations (Nosten et al, 1993).
    b) CASE REPORT - After taking the third dose of halofantrine (1,500 mg course), a 25-year-old woman with malaria developed cardiac arrest and could not be resuscitated. Autopsy revealed severe rheumatic mitral and aortic valve stenosis. She had a normal QTc interval prior to begining halofantrine, but QTc increased to 0.48 seconds after the second dose. Halofantrine blood concentrations were normal 6 and 30 hours after the first dose (Bouchaud et al, 2002).
    E) DEAD - SUDDEN DEATH
    1) WITH THERAPEUTIC USE
    a) Akhtar and Imran (1994) reported two cases of sudden death during halofantrine therapy.
    1) The first case was a 2-year-old boy who had initially been given amodiaquine to treat malaria but was unsuccessful. He was then switched to halofantrine, 8 mg/kg every 6 hours for 3 doses. After the second dose, the patient complained of abdominal discomfort. Four hours after the second dose the patient suddenly developed bradycardia and died. There was no evidence of seizures or aspiration.
    a) In the second case, a 36-year-old female died suddenly approximately 2 hours after taking the second dose of halofantrine, 500 mg. There was no history of seizures or heart disease.
    b) CASE REPORT - A case of sudden death occurred in a 22-year-old traveler during halofantrine therapy. The autopsy revealed a previously undiagnosed atypical asymmetric hypertrophic cardiomyopathy (Anon, 2001).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Seizures, syncope, and headaches have been reported with therapeutic use of halofantrine.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Three cases of seizures were reported by the manufacturer following therapeutic administration of halofantrine (Prod Info Halfan(R), halofantrine, 1998). It was unclear if the seizures were due to malaria or an underlying illness or due to direct toxicity of halofantrine.
    b) CASE REPORT - A 29-year-old female experienced three generalized seizures following administration of 500 mg halofantrine. Valproic acid, 100 mg daily, was administered with no recurrence of seizures (Castot et al, 1993). The patient had been previously diagnosed with an asymptomatic familial QT interval prolongation condition that may have been related to the occurrence of seizures and may have been worsened with the administration of halofantrine.
    B) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) Syncopal episodes were reported in several patients following therapeutic administration of halofantrine (total amounts ingested were 1000 mg). Syncope appeared to be related to the occurrence of QTc interval prolongation which the patients had also experienced following halofantrine ingestion (Castot et al, 1993; Nosten et al, 1993; Toivonen et al, 1994; Gundersen et al, 1997).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) INCIDENCE - Headaches occurred in 3% of patients involved in halofantrine clinical trials (n=933) (Prod Info Halfan(R), halofantrine, 1998).
    b) Headaches developed in 5% of healthy volunteers given 1000 mg to 1500 mg halofantrine in a single dosing course (Prod Info Halfan(R), halofantrine, 1998).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) INCIDENCE - Dizziness was reported in 5% of healthy volunteers given 1000 mg to 1500 mg halofantrine in a single dosing course (Prod Info Halfan(R), halofantrine, 1998) and in 4.5% of patients involved in halofantrine clinical trials (n=933).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 46-year-old male experienced throbbing headaches 3 days after taking halofantrine 1500 mg daily. The headaches resolved completely 48 hours after discontinuing halofantrine treatment (Vincent et al, 1992).
    1) The first course of halofantrine therapy, 105 mg/12 hours, was unsuccessful but there were no apparent adverse effects.

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) GI distress, including nausea, vomiting, diarrhea, and abdominal pain, are common occurrences with therapeutic halofantrine administration.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) INCIDENCE - Nausea and vomiting were reported in 10% of healthy volunteers given 1000 mg to 1500 mg of halofantrine in a single dosing course (Prod Info Halfan(R), halofantrine, 1998).
    b) INCIDENCE - Diarrhea was reported in 5% of healthy volunteers given 1000 mg to 1500 mg of halofantrine in a single dosing course (Prod Info Halfan(R), halofantrine, 1998).
    c) Diarrhea occurred in 3 of 152 patients given micronized halofantrine to treat malarial symptoms. The diarrhea was mild and resolved quickly (Fadat et al, 1993; Ramsay et al, 1996).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain was reported as a frequent adverse effect of halofantrine administration (Prod Info Halfan(R), halofantrine, 1998; Ramsay et al, 1996; Restrepo et al, 1996). Abdominal pain resolved with supportive care.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 46-year-old male developed gastric pain with diarrhea, throbbing headaches, and intermittent fever spikes after taking halofantrine (six 250 mg tablets) for 11 days. The patient's symptoms resolved 48 hours after discontinuation of therapy(Vincent et al, 1992).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Mild (less than 2 times the upper limit of normal) transient elevated ALT and AST levels were reported in 5 patients following therapeutic administration of halofantrine. An increased alkaline phosphatase level was also reported in one patient (Fadat et al, 1993).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 46-year-old male developed slightly elevated ALT and GGTP levels after ingesting a total of 16.5 grams halofantrine over an 11-day period. HPLC testing determined normal plasma levels of halofantrine and its metabolite, desbutylhalofantrine. The liver enzyme levels returned to normal 48 hours after discontinuation of halofantrine (Vincent et al, 1992).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Acute intravascular hemolysis has been associated with therapeutic administration of halofantrine.
    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) WITH THERAPEUTIC USE
    a) Acute intravascular hemolysis has been reported following halofantrine therapeutic ingestions and is characterized by black urine, black stools, gastrointestinal distress, jaundice, and hemoglobinemia (Vachon et al, 1992; Mojon et al, 1994; Orlando et al, 1996).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Pruritus was reported with therapeutic use of halofantrine.
    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus was reported in several patients following therapeutic administration of halofantrine. In the majority of patients, pruritus was mild and resolved spontaneously (Hallwood et al, 1989; Salako et al, 1990; Ezeamuzie et al, 1991; Fadat et al, 1993; Ramsay et al, 1996; Prod Info Halfan(R), halofantrine, 1998).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) INCIDENCE - Myalgias and rigors were reported in 1.3% and 1.7% of patients (n=933), respectively, who were involved in halofantrine clinical trials (Prod Info Halfan(R), halofantrine, 1998).
    b) Myalgia and joint pains were reported in 2 patients involved in micronized halofantrine clinical trials (Ramsay et al, 1996).

Reproductive

    3.20.1) SUMMARY
    A) Halofantrine has been classified as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS - A decremental halofantrine dose schedule of 360 to 120 mg/kg (equivalent to 3.6 times to 1.2 times the maximum recommended human dose), administered to pregnant rabbits, was associated with abortion and increased incidence of fetal skeletal malformations (Prod Info Halfan(R), halofantrine, 1998).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Halofantrine has been classified as FDA pregnancy category C (Prod Info Halfan(R), halofantrine, 1998).
    B) ANIMAL STUDIES
    1) RATS - Oral halofantrine doses of 30 mg/kg or greater (1/6 of the maximum recommended human dose), administered to pregnant rats, has produced post- implantation embryonic death and decreased fetal weight and viability (Prod Info Halfan(R), halofantrine, 1998).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS - Halofantrine, administered orally to rats at a dose of 30 mg/kg (1/6 of the maximum recommended human dose), did not adversely affect male or female fertility (Prod Info Halfan(R), halofantrine, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Halofantrine levels are not clinically useful.
    B) Monitor liver enzyme levels for possible transient elevations.
    C) Monitor electrolyte concentrations if patient experiences severe vomiting and/or diarrhea or develops dysrhythmias or QTc prolongation.
    D) Obtain an ECG and institute continuous cardiac monitoring for possible QT prolongation and dysrhythmias.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum levels of halofantrine are not clinically useful.
    2) Monitor electrolyte levels if patient experiences severe vomiting and/or diarrhea, or develops dysrhythmias or QTc prolongation.
    3) Monitor liver function tests in symptomatic patients.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring. Halofantrine causes dose dependant QTc prolongation and may cause dysrhythmias, including Torsade de Pointes, ventricular fibrillation and sudden death. Patients with congenital prolonged QT syndromes and those taking other drugs which prolong the QTc interval may be at increased risk for these complications.

Methods

    A) CHROMATOGRAPHY
    1) A high-performance liquid chromatographic method with fluorometric detection was described for the quantification of halofantrine (HAL) and its metabolite, monodesbutylhalofantrine (MDBH), in human blood and plasma. In plasma, the limits of detection for HAL and MDBH were 6.1 micrograms/liter and 5.0 micrograms/liter, respectively. In whole blood, the limits of detection for HAL and MDBH were 10.8 micrograms/liter and 32.6 micrograms/liter, respectively (Gaillard et al, 1995).
    2) An ion-pair reversed-phase high-performance liquid chromatographic method, described by Onyeji & Aideloje (1997), was used to determine the presence of halofantrine and desbutylhalofantrine in human plasma. The limits of detection for halofantrine and desbutylhalofantrine were 2.5 and 2.0 nanograms/milliliter, respectively.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Halofantrine levels are not clinically useful.
    B) Monitor liver enzyme levels for possible transient elevations.
    C) Monitor electrolyte concentrations if patient experiences severe vomiting and/or diarrhea or develops dysrhythmias or QTc prolongation.
    D) Obtain an ECG and institute continuous cardiac monitoring for possible QT prolongation and dysrhythmias.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment of halofantrine overdoses is SYMPTOMATIC and SUPPORTIVE.
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolytes in cases of severe vomiting and diarrhea.
    2) Liver function tests should be monitored in symptomatic patients.
    3) Monitor ECG for ventricular dysrhythmias and ECG abnormalities.
    C) VENTRICULAR ARRHYTHMIA
    1) Therapeutic doses of halofantrine may cause prolongation of the QTc interval which may lead to ventricular dysrhythmias, including torsades de pointes.
    2) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    3) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    4) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    D) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    E) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Abstracts

Case Reports

    A) ADULT
    1) A 26-year-old female, with no history of pre-existing cardiopathy, was given a first course of halofantrine therapy, 500 mg every 6 hours for 3 doses, to treat malaria. There were no adverse effects resulting from her first course of halofantrine therapy. Eleven days later, the patient still felt unwell and began a second course of halofantrine therapy, 500 mg every 6 hours for 3 doses. Six hours after the second dose (just prior to taking the third dose), the patient experienced seizures with syncope and subsequent respiratory arrest.
    a) Upon presentation to the ED, ventricular fibrillation was recorded and cardioversion was performed successfully. After admission to the hospital, the patient was comatose and mechanical ventilation was started. An ECG showed QTc interval prolongation. The patient gradually recovered, although she continued to have partial memory loss (Gunderson et al, 1997).
    b) Nine months after the first hospital admission, the patient was found dead. There was no autopsy and the reason for death was not established.

Range Of Toxicity

Summary

    A) A man ingested 16.5 grams of halofantrine over an 11-day period and developed gastric pain, diarrhea, headaches, fever spikes, and slightly elevated liver enzyme levels. The patient completely recovered 48 hours after discontinuation of halofantrine.
    B) A woman, with no history of heart disease, developed QTc interval prolongation after taking 26 tablets of halofantrine (6500 mg instead of 1500 mg at the recommended dose) over a 5-day period. She did not experience other clinical manifestations or significant ECG changes.
    C) A 2-year-old boy developed bradycardia and died 4 hours after taking the second dose of halofantrine (8 mg/kg).
    D) A woman died suddenly approximately 2 hours after taking the second dose of halofantrine (500 mg)and cephalexin.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) NON-IMMUNE PATIENTS - Patients with no previous exposure or minimal exposure to malaria should receive 500 milligrams of halofantrine every 6 hours for three doses. This course of therapy should be repeated 7 days after the first course (Prod Info Halfan(R), halofantrine, 1998).
    2) SEMI-IMMUNE PATIENTS - Patients that have a history of life-long residence in endemic areas and have a clear history of recent previous malaria caused by the same plasmodium species should receive a one-course therapy of halofantrine, 500 milligrams every 6 hours for three doses (Prod Info Halfan(R), halofantrine, 1998).
    3) CONTRAINDICATIONS - Halofantrine should NOT be administered to patients with a personal or family history of heart disease that may result in QT interval prolongation, and halofantrine should NOT be given concurrently with other medications that may lengthen the QT interval (Prod Info Halfan(R), halofantrine, 1998).
    4) WARNING - Halofantrine should be taken on an empty stomach. Food, especially food high in fat content, increases the absorption of halofantrine which may increase halofantrine toxicity (Prod Info Halfan(R), halofantrine, 1998).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) The safety and efficacy of halofantrine administration in children has not been established (Prod Info Halfan(R), halofantrine, 1998).

Minimum Lethal Exposure

    A) PEDIATRIC
    1) CASE REPORT - A 2-year-old boy, diagnosed with malaria refractory to amodiaquine therapy, began halofantrine therapy, 8 milligrams/kilogram every 6 hours for three doses. After the first dose, the patient developed vocal hoarseness. After the second dose, the patient complained of abdominal pain. The patient's condition suddenly deteriorated and approximately four hours after the administration of the second dose the patient developed bradycardia and died. There was no evidence of seizures or aspiration (Akhtar & Imran, 1994).
    B) ADULT
    1) CASE REPORT - A 38-year-old female was prescribed halofantrine, 500 milligrams every 8 hours for three doses, and cephalexin. The patient died suddenly approximately 2 hours after taking the second dose of halofantrine. There was no history of seizures or heart disease (Akhtar & Imran, 1994).
    2) CASE REPORT - After taking the third dose of halofantrine (1,500 mg course) a 25-year-old woman with malaria developed cardiac arrest and could not be resuscitated. Autopsy revealed severe rheumatic mitral and aortic valve stenosis. She had a normal baseline QTc interval and normal blood concentration of the drug (Bouchaud et al, 2002).

Maximum Tolerated Exposure

    A) ADULT
    1) CASE REPORT - A 46-year-old male ingested 16.5 grams of halofantrine over an 11-day period and developed gastric pain, diarrhea, headaches, fever spikes, and slightly elevated liver enzyme levels. HPLC testing showed normal plasma levels of halofantrine and its metabolite, desbutyl-halofantrine (Vincent et al, 1992). The patient completely recovered 48 hours after discontinuation of halofantrine.
    2) CASE REPORT - A 70-year-old female, with no history of heart disease, developed QTc interval prolongation (0.62 seconds) after taking 26 tablets of halofantrine (6500 mg instead of 1500 mg at the recommended dose) over a 5-day period. Approximately 3 and 24 hours after the last intake, blood levels of halofantrine (1,050 and 400 ng/mL, respectively) and N-desbutyl-halofantrine (1,154 and 1,328 ng/mL, respectively) were high. She did not experience other clinical manifestations or significant ECG changes (Bouchaud et al, 2002).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) CASE REPORT - A 26-year-old female developed syncope, seizures, respiratory arrest, and ventricular fibrillation (cardioversion was successful) after ingesting two doses (total amount 1000 milligrams) of halofantrine. Sixty hours after ingestion of the first dose of halofantrine, HPLC testing showed serum concentrations of halofantrine and its metabolite, desbutylhalofantrine, to be 53 and 324 micrograms/liter, respectively (Gundersen et al, 1997).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 2050 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)RAT:
    a) 3400 mg/kg (RTECS, 2000)

Physicochemical

Physical Characteristics

    A) Halofantrine is a white to off-white crystalline compound that is practically insoluble in water (Prod Info Halfan(R), halofantrine, 1998).

Molecular Weight

    A) 536.89 (Prod Info Halfan(R), halofantrine, 1998)

References

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