Endocrine
The drug may cause adrenal insufficiency so the level of the adrenocortical hormones should be monitored while taking it. Oral ketoconazole at a dosage range of 400 to 2,000 mg/day has 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.
As azole antifungals all act at the same point in the sterol pathway, resistant isolates are normally cross-resistant to all members of the azole family. Antihormonal activity
As an antiandrogen, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (e.g. 40 mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels. It produces this effect through inhibition of 17α-hydroxylase and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone. Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer. Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the androgen receptor. This effect is thought to be quite weak however, even with high oral doses of ketoconazole.Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers. The cis-(2S,4R) isomer was more potent in inhibiting progesterone 17α,20-lyase than its enantiomer (IC50 values of 0.05 and 2.38 μM, respectively) and in inhibiting 11β-hydroxylase (IC50 values of 0.152 and 0.608 μM, respectively). Both isomers were relatively weak inhibitors of human placental aromatase.Oral ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day.