Quinidine Halofantrine

Use of a hERG blocker in a patient also taking CYP3A4 inhibitors (e.g. antibacterial macrolides, azole antifungals, HIV protease inhibitors) or CYP2D6 inhibitors (quinidine, halofantrine, fluoxetine, paroxetine, thioridazine, terbinafine) the hERG blocker, if mostly metabolized by these CYP isoforms, may accumulate because... 

Peytavin et al. [17] have reported on the chiral resolution of mefloquine, halofantrine, enpiroline, quinine, quinidine, chloroquine, and primaquine by subcritical fluid chromatography on a (S) naphthylurea column (250 X 4.6 mm ID). The mobile phase consisted of carbon dioxide, methanol, and triethylamine at a 3-ml/min flow rate. Except for primaquine and... 

The loading dose shovild not be given if the patient has received quinine, quinidine or mefloquine in the previous 24 h see also warnings about halofantrine (below). 

There is an increased risk of dysrhythmias, including torsade de pointes, when halofantrine is combined with qui-nine/quinidine or chloroquine and any other drug that prolongs the QT interval (52). 

Clinically important, potentially hazardous interactions with amiodarone, astemizole, bepridil, carbamazepine, chloroquine, cisapride, clarithromycin, dihydroergotamine, disopyramide, ergotamine, grapefruit juice, halofantrine, haloperidol, itraconazole, ketoconazole, methadone, moxifloxacin, phenobarbital, phenytoin, pimozide, procainamide, quinidine, rifampicin, ritonavir, sotalol, St John s wort, telithromycin, terfenadine, voriconazole... 

Clinically important, potentially hazardous interactions with alcohol, amiodarone, amphotericin B, cisapride, clonidine, digitalis, diltiazem, disopyramide, erythromycin, glucocorticoids, halofantrine, haloperidol, hypokalemic diruretics, imipramine antidepressants, levodopa, lithium, pentamidine, pimozide, quinidine, sotalol, stimulant laxatives, tetracosactides, thioridazine... 

Pyrimethamine/sulfadoxine and tetracycline have been shown to increase halofantrine levels, and may therefore increase its toxicity. Diltiazem, erythromycin, ketoconazole, mefloquine, quinine, and quinidine might also increase the toxicity of halofantrine because they have been shown to inhibit its metabolism in vitro. The manufacturer has therefore recommended caution with the concurrent use of potent CYP3A4 inhibitors. Fatty food markedly increases halofantrine levels, consequently it is recommended that halofantrine is taken on an empty stomach. Grapefruit juice has a similar effect Note that halofantrine is no longer widely marketed. 

A study in animals found that ketoconazole roughly doubled the AUC of halofantrine and inhibited its metabolism to the equipotent metabolite, desbutylhalofantrine. In in vitro studies, ketoconazole markedly inhibited the metabolism of halofantrine by CYP3A4. It has been suggested that the rise in halofantrine levels could reasonably be expected to increase toxicity. Other CYP3A4 inhibitors, diltiazem and erythromycin, also inhibited the metabolism of halofantrine in vitro, and might therefore do so clinically. The manufacturer recommended caution with the concurrent use of potent CYP3A4 inhibitors. Further study is needed of these potential pharmacokinetic interactions. Mefloquine, quinine and quinidine may also inhibit the metabolism of halofantrine by CYP3A4, see (b) below. 

In addition to possible additive QT-prolonging effects, quinidine and quinine have been shown in vitro to inhibit the metabolism of halofantrine by CYP3A4, and so may increase halofantrine levels, which could reasonably be expected to increase XoxxcxXy Animal studies found that although mefloquine alone did not significantly alter the QTc interval, it enhanced the effects of halofantrine by increasing blood levels. Similarly, a study in patients with malaria found that the 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... 

---