been found to result in a rate of gynecomastia of 21%. Liver In July 2013, the U.S. Food and Drug Administration (FDA) issued a warning that taking ketoconazole by mouth can cause severe liver injuries and adrenal gland problems: adrenal insufficiency and worsening of other related to the gland conditions. It recommends oral tablets should not be a first-line treatment for any fungal infection. It should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated. As contraindication it should not be used in people with acute or chronic liver disease. Hypersensitivity Anaphylaxis after the first dose may occur. Other cases of hypersensitivity include urticaria. Topical formulations The topical formulations have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the ketoconazole tablets, which are taken by mouth. Pregnancy Ketoconazole is categorized as pregnancy category C in the US. Research in animals has shown it to cause teratogenesis when administered in high doses. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole. Overdose In the event of an overdose of oral ketoconazole, treatment should be supportive and based on symptoms. Activated charcoal may be administered within the first hour following overdose of oral ketoconazole. Interactions The concomitant use of the following medications is contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone irinotecan, lurasidone, colchicine alprazolam, oral midazolam, oral triazolam felodipine, ranolazine, tolvaptan, eplerenone HMG-CoA reductase inhibitors: lovastatin, simvastatin ergot alkaloids: ergotamine, dihydroergotamine, ergometrine, methylergometrine Others: cisapride, nisoldipine, dofetilide, pimozide And is not recommended: carbamazepine, phenytoin gastric acid suppressants: antacids, antimuscarinics, histamine H2 blockers, proton pump inhibitors sucralfate rifampin, rifabutin, isoniazid efavirenz, nevirapine Ritonavir is known for increasing activity of the ketoconazole so it is recommended to reduce dosage. There is also a list of drugs which significantly decrease systemic exposure to the ketoconazole and drugs whose systemic exposure is increased by the ketoconazole. Pharmacology Pharmacodynamics Antifungal activity As an antifungal, ketoconazole is structurally similar to imidazole, and interferes with the fungal synthesis of ergosterol, a constituent of fungal cell membranes, as well as certain enzymes. As with all azole antifungal agents, ketoconazole works principally by inhibiting the enzyme cytochrome P450 14α-demethylase (CYP51A1). This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol.