Ketoconazole was patented in 1977 and came into medical use in 1981. It is available as a generic medication and formulations that are applied to the skin are over the counter. A 30-gram tube in the United Kingdom costs the NHS less than £5 as of 2019. In the United States the wholesale cost of this amount is about US$6.30. In 2016 it was the 205th most prescribed medication in the United States with more than 2 million prescriptions. The formulation that is taken by mouth was withdrawn in Europe and Australia in 2013 and in China in 2015. In addition, its use was restricted in the United States and Canada in 2013.
On 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.
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 Nizoral tablets, which are taken by mouth.
Ketoconazole is likely miscategorized as pregnancy category C drug in the US. Research has shown it to cause teratogenesis when administered in high doses. Recently, the administration of systemic ketoconazole to two pregnant women for treatment of Cushing's syndrome was reported to have no adverse effects,[non-primary source needed] but this small sample precludes drawing any meaningful conclusions. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.
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.
The concomitant use of the following medications is contraindicated:
Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including Candida albicans. Experimentally, resistance usually arises as a result of mutations in the sterol biosynthesis pathway. Defects in the sterol 5-6 desaturase enzyme reduce the toxic effects of azole inhibition of the 14-alpha demethylation step. Multidrug-resistance (MDR) genes can also play a role in reducing cellular levels of the drug. 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.
As an antiandrogen, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (e.g. 400 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 receptorantagonist, 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 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.
Ketoconazole has been found to inhibit the activity of the cation channel TRPM5.
When administered orally, ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption. Absorption can be increased by taking it with an acidic beverage, such as cola. Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.
Due to incidence of serious liver toxicity, the use of oral ketoconazole was suspended in France in July 2011 following review. This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union as well. In 2013, oral ketoconazole was withdrawn in Europe and Australia, and strict restrictions were placed on the use of oral ketoconazole in the United States and Canada. Oral ketoconazole is now only indicated for use in these countries when the indication is a severe or life-threatening systemic infection and alternatives are unavailable. However, topical ketoconazole, which does not distribute systemically, is safe and widely used still.
Ketoconazole has been marketed under a large number of brand names.
Ketoconazole is available widely throughout the world.
In 2013 the European Medicines Agency's Committee on Medicinal Products for Human Use (CHMP) recommended that a ban be imposed on the use of oral ketoconazole for systemic use in humans throughout the European Union, after concluding that the risk of serious liver injury from systemic ketoconazole outweighs its benefits.
Ketoconazole is sometimes prescribed as an antifungal by veterinarians for use in pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage.
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