Halofantrine prolongs QT interval and therefore should notbe used with other drugs that can prolong QT interval because of increased risk of cardiac arrhythmias. The concurrent and sequential use of halofantrine and mefloquine markedlyincreased risk of clinically important increases in QT interval. Pyrimethamine/sulfadoxine and tetracycline have been shown toincrease halofantrine levels,and may therefore increase its toxicity. Diltiazem, erythromycin, ketoconazole, mefloquine, quinine,and quinidine might also increase toxicity of halofantrine because they have been shown to inhibit its metabolism in vitro. The manufacturer has therefore recommended caution with concurrent use of potent CYP3A4 inhibitors. Fatty food markedlyincreases halofantrine levels,consequently it is recommendedthat halofantrine is taken on an empty stomach. Grapefruit juicehas a similar effect. Note that halofantrine is no longer widelymarketed.
Clinical evidence,mechanism, importance and management
A study in animals found that ketoconazole roughly doubled AUC of halofantrine and inhibited its metabolism to equipotent metabolite, desbutylhalofantrine (See reference number 1). In in vitro studies, ketoconazole markedly inhibited metabolism of halofantrine by CYP3A4 (See reference number 2,3). It has been suggested that rise in halofantrine levels could reasonably be expected to increase toxicity (See reference number 2,3). Other CYP3A4 inhibitors, diltiazem and erythromycin, also inhibited metabolism of halofantrine in vitro, and might therefore do so clinically (See reference number 3). The manufacturer recommended caution with concurrent use of potent CYP3A4 inhibitors (See reference number 4). Further study is needed of these potential pharmacokinetic interactions. Mefloquine, quinine and quinidine may also inhibit metabolism of halofantrine by CYP3A4, see (b) below.
(b) Drugs that prolong QT interval
Halofantrine, in therapeutic doses, can prolong QT interval in majority of patients, causing ventricular arrhythmias in a very small number. The effect is increased if halofantrine is taken with fatty foods because of marked increase in absorption, see (d) below. By 1993,worldwide, 14 cases of cardiac arrhythmias associated with halofantrine had been reported, and 8 patients were known to have died. In order to reduce likelihood of arrhythmias, in 1994 UK Committee on Safety of Medicines advised that halofantrine should not be taken with meals, or with certain other drugs that may induce arrhythmias. They list chloroquine,mefloquine, quinine, tricyclic antidepressants, antipsychotics, certain antiarrhythmics, terfenadine and astemizole, as well as drugs causing electrolyte disturbances (See reference number 5). Although not listed, it would seem prudent to avoid other drugs that prolong QT interval. For a list,see table 1 below,’.
In addition to possible additive QT-prolonging effects, quinidine and quinine have been shown in vitro to inhibit metabolism of halofantrine by CYP3A4, and so may increase halofantrine levels, which could reasonably be expected to increase toxicity (See reference number 2,3). Animal studies found that although mefloquine alone did not significantly alter QTc interval, it enhanced effects of halofantrine by increasing blood levels (See reference number 6). Similarly, a study in patients with malaria found that risk of clinically relevant QT prolongation was increased twofold when halofantrine was used after mefloquine failure (7 of 10 patients) when compared with use as primary treatment (18 of 51 patients). However, authors note that their population had longer baseline QT intervals than average population, which may have made them more susceptible to effects of halofantrine(See reference number 7) The manufacturers of mefloquine(See reference number 8,9) and halofantrine,(See reference number 4) therefore contraindicated concurrent use, and use of halofantrine after mefloquine.
A study in 6 healthy subjects found that maximum plasma levels and AUC of a single 250mg dose of halofantrine were increased by about 6.6-fold and 2.9-fold,respectively, when given with a fatty meal rather than in a fasting state. The AUC of metabolite desbutylhalofantrine was also increased (See reference number 10). Animal data suggest that fats may reduce presystemic metabolism of halofantrine (See reference number 1). As this is likely to increase risk of halofantrine-induced arrhythmias, halofantrine should not be taken with meals, but should be taken on an empty stomach.
A crossover study in 12 healthy subjects given halofantrine 500mg with 250 mL of either water, orange juice or grapefruit juice (standard strength), found that grapefruit juice increased AUC and peak plasma levels of halofantrine by 2.8-fold and 3.2-fold,respectively. The QTc interval increased by 17 milliseconds with halofantrine,and by 31 milliseconds when grapefruit juice was also given. Orange juice did not affect pharmacokinetics or pharmacodynamics of halofantrine (See reference number 11). These data suggest that grapefruit juice should be avoided by patients taking halofantrine due to increased risk of arrhythmias (See reference number 11).
In a preliminary study in healthy subjects, pyrimethamine/sulfadoxine (Fansidar) raised AUC0-6 and peak plasma levels of halofantrine by about 1.6-fold, without changing overall AUC. This might lead to an increased incidence of arrhythmias,(See reference number 12) see also (b) above.
A study in 8 healthy subjects found that tetracycline 500mg twice daily for 7 days increased maximum plasma levels, AUC and elimination half-life of a single 500mg dose of halofantrine by 146%, 99%, and 73%, respectively. Increases in major metabolite of halofantrine also occurred in presence of tetracycline (See reference number 13). As both halofantrine and tetracycline are excreted into bile, competition for this elimination route may result in increased plasma levels. There may be an increased risk of halofantrine toxicity if it is used with higher doses of tetracycline (See reference number 13). In contrast, in vitro studies found that doxycycline does not inhibit metabolism of halofantrine (See reference number 2).
1.
Khoo S-M,Porter CJH, Edwards GA, Charman WN. Metabolism of halofantrine to its equipotent metabolite, desbutylhalofantrine, is decreased when orally administered with ketoconazole. J Pharm Sci (1998) 87, 1538–41.
2.
Baune B,Furlan V, Taburet AM, Farinotti R. Effect of selected antimalarial drugs and inhibitors of cytochrome P-450 3A4 on halofantrine metabolism by human liver microsomes.Drug Metab Dispos (1999) 27, 565–8.
3.
Baune B,Flinois JP, Furlan V, Gimenez F, Taburet AM, Becquemont L, Farinotti R. Halofantrine metabolism in microsomes in man: major role of CYP 3A4 and CYP 3A5. J Pharm Pharmacol (1999) 51, 419–26.
4.
Halfan (Halofantrine). SmithKline Beecham Pharmaceuticals. US Prescribing information,October 2001.
5.
Committee on Safety of Medicines/Medicines Control Agency. Cardiac arrhythmias withhalofantrine (Halfan). Current Problems (1994) 20,6.
6.
Lightbown ID,Lambert JP, Edwards G, Coker SJ. Potentiation of halofantrine-induced QTcprolongation by mefloquine: correlation with blood concentrations of halofantrine. Br J Pharmacol (2001) 132, 197–204.
7.
Nosten F,ter Kuile FO, Luxemburger C, Woodrow C, Kyle DE, Chongsuphajaisiddhi T,White NJ. Cardiac effects of antimalarial treatment with halofantrine. Lancet (1993) 341, 1054–6.
8.
Lariam (Mefloquine hydrochloride). Roche Products Ltd. UK Summary of product characteristics,September 2005.
9.
Lariam (Mefloquine hydrochloride). Roche Pharmaceuticals. US Prescribing information,May 2004.
Milton K,Edwards G, Ward SA, Orme ML’E, Breckenridge AM. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br J Clin Pharmacol (1989) 28, 71–7.
Charbit B,Becquemont L, Lepère B, Peytavin G, Funck-Brentano C. Pharmacokinetic andpharmacodynamic interaction between grapefruit juice and halofantrine. Clin Pharmacol Ther (2002) 72, 514–23.
Hombhanje FW. Effect of a single dose of Fansidar(See reference number TM) on the pharmacokinetics of halofantrine in healthy volunteers: a preliminary report. Br J Clin Pharmacol (2000) 49,283–4.
Bassi PU,Onyeji CO, Ukponmwan OE. Effects of tetracycline on the pharmacokinetics ofhalofantrine in healthy volunteers. Br J Clin Pharmacol (2004) 58, 52–5.
| Table 1 Drugs causing QT prolongation and torsade de pointes | |
| High risk | Some risk |
| Amisulpride | Clarithromycin (increase in QTc interval less than 5 milliseconds; rare case reports of torsade de pointes) |
| Antiarrhythmics, class Ia (ajmaline, cibenzoline, disopyramide, hydroquinidine, procainamide, quinidine) | Chlorpromazine (rare case reports of torsade de pointes) |
| Antiarrhythmics, class III (amiodarone, azimilide, cibenzoline, dofetilide,† ibutilide,† sotalol†) | Erythromycin oral (see also high risk) |
| Arsenic trioxide (40% of patients had a QTc interval greater than 500 milliseconds) | Gatifloxacin (increase in QTc interval less than 10 milliseconds) |
| Artemisinin derivatives (artemisinin, artemether/lumefantrine -5% of patients had an asymptomatic prolongation of QTc intervals by greater than 30 milliseconds, with an actual QTc of greater than 450 milliseconds in males and greater than 470 milliseconds in females) | Levofloxacin (rare case reports of torsade de pointes) |
| Astemizole† (if metabolism inhibited) | Lithium (greater risk if levels raised) |
| Cisapride† (if metabolism inhibited) | Methadone (in doses greater than 100 mg) |
| Droperidol† | Moxifloxacin (increase in QTc interval less than 10 milliseconds) |
| Erythromycin intravenous (see also some risk) | Pentamidine intravenous (case reports of torsade de pointes) |
| Halofantrine† | Quinine (greater risk with higher doses and intravenous use) |
| Haloperidol (also increased in high doses and with intravenous use) | Spiramycin |
| Ketanserin (30% of patients had an increase of greater than 30 milliseconds in a clinical trial) | Tricyclics (prolongation of QTc interval greater than 10 milliseconds, most notable risk occurs with clomipramine, risk with other tricyclics largely seems to be in overdose) |
| Mesoridazine† | |
| Pimozide† | |
| Ranolazine (dose-related QTc interval prolonged by up to 15 milliseconds, or more if metabolism inhibited) | |
| Sertindole† | |
| Sparfloxacin (10 millisecond increase in clinical trials) | |
| Terfenadine† (if metabolism inhibited) | |
| Thioridazine† |