Miconazole

Mechanism

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.

Symptoms

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).

Management

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).

Mechanism

Miconazole inhibits the liver enzymes CYP2C9 and CYP3A4 (miconazole labels), and these are the enzymes that break down warfarin. CYP2C9 breaks down the more potent S-enantiomer, and CYP1A2 and CYP3A4 the R-enantiomer (warfarin label, US Food and Drug Administration, FDA). According to the FDA warfarin label, inhibitors of these enzymes increase warfarin exposure and the international normalised ratio (INR). The Spanish warfarin label also lists miconazole among drugs that displace warfarin from plasma protein binding and potentiate its effect. The size of the effect depends on how much miconazole reaches the blood. A 60 mg dose of oral gel gives peak plasma levels of 31–49 ng/mL, and a 1200 mg vaginal ovule about 10–12 ng/mL. Less than 1% of a cream dose is absorbed (miconazole labels, Spanish Agency of Medicines and Medical Devices, AEMPS). The half-life of miconazole after oral gel is 20–25 hours (miconazole oral gel label, AEMPS).

Symptoms

The risk is bleeding: blood in the urine or stool, black tarry stools, heavy menstrual bleeding, petechiae, excessive bruising, prolonged bleeding from cuts, bleeding gums and nosebleeds (warfarin label, US Food and Drug Administration, FDA). Bleeding can also show as pain in the head, chest, abdomen or muscles, dizziness, shortness of breath, difficulty breathing or swallowing, unexplained swelling, weakness, low blood pressure or shock (warfarin label, Spanish Agency of Medicines and Medical Devices, AEMPS). Bleeding events, some fatal, have been reported with miconazole oral gel and warfarin (miconazole oral gel label, AEMPS). Bleeding and bruising have been reported after topical, vaginal and oral miconazole (miconazole buccal tablet label, FDA).

Management

Warfarin is contraindicated with systemic miconazole and with miconazole oral gel (warfarin label, Spanish Agency of Medicines and Medical Devices, AEMPS). The miconazole oral gel label also contraindicates the gel with warfarin (AEMPS). Miconazole skin creams, spray and vaginal ovules are not contraindicated. Use them with warfarin cautiously, monitor the anticoagulant effect closely and titrate the warfarin dose (miconazole cream and vaginal ovule labels, AEMPS). Explain the signs of bleeding to the patient and advise them to stop miconazole at once and contact a doctor if these appear (same labels). Check the international normalised ratio (INR) more often when any antifungal is started or stopped (warfarin label, US Food and Drug Administration, FDA). The Spanish warfarin label requires strict coagulation monitoring whenever any drug is added or withdrawn (warfarin label, AEMPS). If miconazole oral gel and warfarin have been combined, monitor the prothrombin time or other suitable coagulation tests closely and adjust the warfarin dose (miconazole oral gel label, AEMPS). In warfarin overdose with an INR below 6 and no bleeding, stop warfarin temporarily and restart at a lower dose guided by the INR. With an INR above 6 and no severe bleeding, give 0.5 mg of vitamin K1 by continuous infusion over 20–30 minutes, or 1 mg if the INR reaches 10 (warfarin label, AEMPS). In severe bleeding, give 10–20 mg of vitamin K1 by slow infusion over 1 hour together with fresh frozen plasma, whole blood or a factor IX complex (warfarin label, AEMPS).