Miconazole × Pimozide

The liver breaks down pimozide mainly through the enzymes CYP3A4 and CYP2D6, and to a lesser extent CYP1A2 (pimozide label). Miconazole inhibits CYP3A4 and the enzyme CYP2C9. The oral gel label calls it a clinically potent inhibitor of CYP3A4 substrates: the gel is held in the mouth and then swallowed, and miconazole reaches the blood. The Spanish pimozide label lists miconazole among the azole antifungals that, according to in vitro data, may markedly raise pimozide levels. High pimozide levels can prolong the QT interval and cause life-threatening torsade de pointes (pimozide and miconazole oral gel labels). Cream and vaginal forms put far less miconazole into the blood. Less than 1% of a skin dose is absorbed. After a 1200 mg vaginal dose, peak plasma levels are more than 100 times lower than after oral or intravenous use (miconazole cream and vaginal ovule labels). The labels give no study of pimozide levels with miconazole.

QT interval prolongation itself causes no symptoms and shows only on the electrocardiogram (ECG). The danger is ventricular arrhythmia: torsade de pointes, ventricular tachycardia and ventricular fibrillation, up to cardiac arrest and sudden death (pimozide label). An episode presents as palpitations, dizziness or fainting. Excess pimozide also strengthens its usual effects, above all extrapyramidal ones: tremor, muscle rigidity and akathisia, an inability to sit still (pimozide label). The risk of arrhythmia is higher with low potassium or magnesium and with a slow heart rate (pimozide label).

The combination is contraindicated. The miconazole oral gel summary of product characteristics (SmPC) lists pimozide among the drugs that prolong the QT interval and must not be combined with oral miconazole (miconazole oral gel SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The Spanish pimozide SmPC contraindicates azole antifungals and other inhibitors of the enzyme CYP3A4 and names miconazole among the azoles (pimozide SmPC, AEMPS). The US pimozide label contraindicates itraconazole and ketoconazole by name and says pimozide should not be given with azole antifungals in general (pimozide label, US Food and Drug Administration, FDA). The ban also applies when the gel is used for oral or oesophageal candidiasis. The gel is held in the mouth and then swallowed, and miconazole reaches the blood (miconazole oral gel SmPC). For a patient taking pimozide, choose an antifungal outside the azole group. The pimozide SmPC also names ketoconazole, itraconazole and fluconazole among the azoles (pimozide SmPC, AEMPS). If a patient already takes pimozide and oral miconazole, stop one of them. The cream and vaginal ovule labels do not mention pimozide. They state that little miconazole reaches the blood and that clinically relevant interactions are rare. They ask for caution with warfarin and other vitamin K antagonists, oral antidiabetic drugs and phenytoin (miconazole cream and vaginal ovule SmPCs, AEMPS). The Spanish pimozide SmPC does not separate azoles by dosage form, and the documents give no separate rule for topical forms in patients taking pimozide. For any pimozide treatment, record an electrocardiogram (ECG) before the start and repeat it during treatment. Keep potassium and magnesium in the normal range, and stop pimozide if the QT or corrected QT (QTc) interval exceeds 500 ms (pimozide labels, AEMPS and FDA).