COMPOSITION: Each coated tablet of Micosin® contains: 200 mg of ketoconazole and excipients q.s. 1 tablet.

INDICATIONS: Treatment of systemic fungal infections such as blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Its use is restricted to cases where safer and more effective alternatives are not available, or when, after evaluating the patient, the benefits outweigh potential risks. Treatment of Cushing’s syndrome in cases where no other alternatives exist, under strict medical supervision.

DOSAGE: Administered orally, 200 mg once daily, taken with food to increase absorption and reduce gastrointestinal discomfort. The dose may be increased to 400 mg daily if an adequate response is not achieved.

Pediatric Patients: Children over 2 years: recommended 3 mg per kg of body weight per day.

CONTRAINDICATIONS: Micosin® is contraindicated in patients hypersensitive to this medication. Co-administration of ketoconazole with astemizole, cisapride, corticosteroids, triazolam, cyclosporine, oral anticoagulants, and terfenadine is contraindicated. Its use is not recommended during pregnancy and lactation.

PRECAUTIONS: Liver function tests are recommended before starting treatment and periodically during therapy. Concomitant use with hepatotoxic substances such as alcohol and paracetamol should be avoided. A disulfiram-like reaction may occur in patients taking ketoconazole after consuming alcohol. The effectiveness of oral contraceptives may be reduced.

INTERACTIONS: Ketoconazole inhibits the metabolism of a number of drugs by acting on the CYP3A4 isoenzyme of the hepatic microsomal P450 system. This leads to increased plasma levels of terfenadine, prolonging the QT interval. Similarly, it reduces the clearance of astemizole, which may cause arrhythmias, tachycardia, cardiac arrest, and death. Astemizole should be discontinued at least one week before starting ketoconazole therapy. Ketoconazole reduces the clearance of cisapride; concomitant use has been associated with QT prolongation and torsades de pointes. Ketoconazole can induce disulfiram-like reactions; alcohol should be avoided during treatment and for at least 48 hours after discontinuation. Concomitant administration of ketoconazole and indinavir increases the antiviral’s AUC by 68%. Ketoconazole dramatically inhibits the hepatic metabolism of triazolam and midazolam; simultaneous use should be avoided. Other benzodiazepines affected include alprazolam and estazolam. Ketoconazole requires an acidic gastric pH for absorption; drugs that reduce gastric acid secretion or alkalinize the stomach significantly reduce its bioavailability, including antacids, antimuscarinics, H2 antihistamines, and proton pump inhibitors. Sucralfate also reduces ketoconazole absorption by 20%. Ketoconazole may decrease the clearance of corticosteroids such as prednisolone and methylprednisolone, increasing plasma concentrations. It also increases cyclosporine plasma levels. Ketoconazole can reduce the clearance of calcium channel blockers (e.g., diltiazem, felodipine, verapamil) by inhibiting CYP3A4 metabolism. Concomitant use with tacrolimus may increase tacrolimus blood levels. Co-administration with ritonavir results in 3–4 fold increases in ketoconazole concentrations; therefore, doses >200 mg/day are not recommended with ritonavir.

PREGNANCY AND LACTATION: Preclinical data indicate that ketoconazole crosses the placenta and is teratogenic. It should only be used during pregnancy when the therapeutic need for the mother outweighs the risk to the fetus. As ketoconazole is excreted in breast milk, breastfeeding should be discontinued during treatment.

ADVERSE REACTIONS: Nausea, vomiting, and abdominal pain have been reported; these are usually mild and can be minimized if the drug is taken with food, which also improves bioavailability. Rarely, hepatotoxicity occurs. These effects are reversible upon discontinuation of treatment.