Ketoconazole, sold under the brand name Nizoral among others, is an
antiandrogen and
antifungal medication used to treat a number of
fungal infections.
Applied to the skin it is used for
fungal skin infections such as
tinea,
cutaneous candidiasis,
pityriasis versicolor,
dandruff
Dandruff is a skin condition that mainly affects the scalp. Symptoms include flaking and sometimes mild itchiness. It can result in social or self-esteem problems. A more severe form of the condition, which includes inflammation of the skin ...
, and
seborrheic dermatitis.
Taken
by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used.
[ Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.][
Common side effects when applied to the skin include redness.][ Common side effects when taken by mouth include ]nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
, headache, and liver problems.[ Liver problems may result in death or the need for a liver transplantation.][ Other severe side effects when taken by mouth include ]QT prolongation
Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, ...
, adrenocortical insufficiency
The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...
, and anaphylaxis
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follo ...
. It is an imidazole
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non ...
and works by hindering the production of ergosterol required for the fungal cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
, thereby slowing growth.[
Ketoconazole was patented in 1977 by Belgian pharmaceutical company Janssen, 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 in the United Kingdom
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the continental mainland. It comprises England, Scotland, Wales and ...
.[ In 2020, it was the 170th most commonly prescribed medication in the United States, with more than 3million prescriptions. The formulation that is taken by mouth was withdrawn in the European Union and in Australia in 2013,][ and in China in 2015. In addition, its use was restricted in the United States and Canada in 2013.]
Medical uses
Topical antifungal
Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch, and tinea versicolor. Topical ketoconazole is also used as a treatment for dandruff
Dandruff is a skin condition that mainly affects the scalp. Symptoms include flaking and sometimes mild itchiness. It can result in social or self-esteem problems. A more severe form of the condition, which includes inflammation of the skin ...
(seborrheic dermatitis of the scalp) and for seborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungus '' Malassezia furfur'' on the skin.
Systemic antifungal
Ketoconazole has activity against many kinds of fungi that may cause human disease, such as '' Candida'', ''Histoplasma
''Histoplasma'' is a genus of dimorphic fungi commonly found in bird and bat fecal material. ''Histoplasma'' contains a few species, including—''Histoplasma capsulatum''—the causative agent of histoplasmosis; and ''Histoplasma capsulatum var ...
'', '' Coccidioides'', and ''Blastomyces
''Chrysosporium'' is a genus of hyaline hyphomycetes fungi in the family Onygenaceae.
''Chrysosporium'' colonies are moderately fast-growing, flat, white to tan to beige in color; they often have a powdery or granular surface texture. Hyaline, ...
'' (although it is not active against '' Aspergillus''), chromomycosis and paracoccidioidomycosis
Paracoccidioidomycosis (PCM), also known as South American blastomycosis, is a fungal infection that can occur as a mouth and skin type, lymphangitic type, multi-organ involvement type (particularly lungs), or mixed type. If there are mouth ulce ...
.[ First made in 1977,][ ketoconazole was the first orally-active azole antifungal medication.][ However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by other ]azole antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryp ...
agents, such as itraconazole, because of ketoconazole's greater toxicity, poorer absorption, and more limited spectrum of activity.[
Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.]
Off-label uses
Hair loss
Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor
5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes o ...
such as finasteride or dutasteride has been used off label to treat androgenic alopecia
Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front ha ...
. It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.
Limited clinical studies suggest ketoconazole shampoo used either alone or in combination with other treatments may be useful in reducing hair loss in some cases.
Hormonal
The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions. While ketoconazole blocks the synthesis of the sterol ergosterol in fungi, in humans, at high dosages (>800 mg/day), it potently inhibits the activity of several enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s necessary for the conversion of cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
to steroid hormones such as testosterone and cortisol. Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocor ...
, 17α-hydroxylase and 17,20-lyase, which convert pregnenolone
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocor ...
into androgens, and 11β-hydoxylase, which converts 11-deoxycortisol to cortisol. All of these enzymes are mitochondrial cytochrome p450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
enzymes. Based on these antiandrogen and antiglucocorticoid
An antiglucocorticoid is a drug which reduces glucocorticoid activity in the body. They include direct glucocorticoid receptor antagonists such as mifepristone and synthesis inhibitors such as metyrapone, ketoconazole, and aminoglutethimide. They ...
effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advanced prostate cancer and for the suppression of glucocorticoid synthesis in the treatment of Cushing's syndrome. However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency. Ketoconazole has additionally been used, in lower dosages, to treat hirsutism and, in combination with a GnRH analogue, male-limited precocious puberty. In any case, the risk of hepatotoxicity with ketoconazole limits its use in all of these indications, especially in those that are benign such as hirsutism.
Ketoconazole has been used to prevent the testosterone flare at the initiation of GnRH agonist therapy in men with prostate cancer.
Contraindications
Oral ketoconazole has various contraindications, such as concomitant use with certain other drugs due to known drug interactions. Other contraindications of oral ketoconazole include liver disease, adrenal insufficiency, and known hypersensitivity
Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...
to oral ketoconazole.
Side effects
Gastrointestinal
Vomiting, diarrhea, nausea, constipation, abdominal pain, upper abdominal pain, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration may occur.
Endocrine
The drug may cause adrenal insufficiency so the level of the adrenocortical hormone In humans and other animals, the adrenocortical hormones are hormones produced by the adrenal cortex, the outer region of the adrenal gland. These polycyclic steroid hormones have a variety of roles that are crucial for the body’s response to str ...
s 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
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follo ...
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
"Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016).
Background
In an inter ...
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
Irinotecan, sold under the brand name Camptosar among others, is a medication used to treat colon cancer, and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cispl ...
, lurasidone, colchicine
* alprazolam, oral midazolam, oral triazolam
* felodipine, ranolazine
Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient. Benefits appear smaller in women than men. It ...
, tolvaptan, eplerenone
* HMG-CoA reductase inhibitors: lovastatin, simvastatin
Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of hear ...
* ergot alkaloids: ergotamine, dihydroergotamine
Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy simi ...
, ergometrine, methylergometrine
* Others: cisapride, nisoldipine
Nisoldipine is a pharmaceutical drug used for the treatment of chronic angina pectoris and hypertension. It is a calcium channel blocker of the dihydropyridine class. It is sold in the United States under the proprietary name Sular. Nisoldipine h ...
, dofetilide
Dofetilide is a class III antiarrhythmic agent. It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide. It is not available in Europe or Australia. ...
, pimozide
And is not recommended:
* carbamazepine, phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...
* gastric acid suppressants: antacids, antimuscarinics, histamine H2 blockers, proton pump inhibitors
* sucralfate
* rifampin, rifabutin
Rifabutin (Rfb) is an antibiotic used to treat tuberculosis and prevent and treat ''Mycobacterium avium'' complex. It is typically only used in those who cannot tolerate rifampin such as people with HIV/AIDS on antiretrovirals. For active tuber ...
, 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
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non ...
, and interferes with the fungal synthesis of ergosterol, a constituent of fungal cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
s, as well as certain enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s. As with all azole antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryp ...
agents, ketoconazole works principally by inhibiting the enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
14α-demethylase (CYP51A1). This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Lower doses of fluconazole
Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to prev ...
and itraconazole are required to kill fungi compared to ketoconazole, as they have been found to have a greater affinity for fungal cell membranes.
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.
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 precursor
Precursor or Precursors may refer to:
* Precursor (religion), a forerunner, predecessor
** The Precursor, John the Baptist
Science and technology
* Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of u ...
s 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
Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
(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
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
consisting of ''cis''-(2''S'',4''R'')-(−) and ''cis''-(2''R'',4''S'')-(+) enantiomers. The ''cis''-(2''S'',4''R'') isomer was more potent in inhibiting progesterone 17α,20-lyase than its enantiomer ( IC50 values of 0.05 and 2.38 ''μ''M, respectively) and in inhibiting 11β-hydroxylase (IC50 values of 0.152 and 0.608 ''μ''M, 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. Numerous small studies have investigated the effects of oral ketoconazole on hormone levels in humans. It has been found in men to significantly decrease testosterone and estradiol levels and to significantly increase luteinizing hormone, progesterone, and 17α-hydroxyprogesterone levels, whereas levels of androstenedione, follicle-stimulating hormone
Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...
, and prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pi ...
were unaffected. The ratio of testosterone to estradiol is also decreased during oral ketoconazole therapy in men. Suppression of testosterone levels by ketoconazole is generally partial and has often been found to be transient. Better effects on suppression of testosterone levels have been observed in men when ketoconazole is combined with a GnRH agonist to suppress the hypothalamic–pituitary–gonadal axis, which prevents compensatory upregulation of luteinizing hormone secretion and consequent activation of gonadal testosterone production. In premenopausal women with polycystic ovary syndrome
Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
, ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol. Studies in postmenopausal women with breast cancer have found that ketoconazole significantly decreases androstenedione levels, slightly decreases estradiol levels, and does not affect estrone levels. This indicates minimal inhibition of aromatase by ketoconazole ''in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
'' in humans. Ketoconazole has also been found to decrease levels of endogenous corticosteroids, such as cortisol, corticosterone
Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. It is of minor importance in humans, except in the very rar ...
, and aldosterone, as well as vitamin D
Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...
.
Ketoconazole has been found to displace dihydrotestosterone
Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
and estradiol from sex hormone-binding globulin ''in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
'', but this was not found to be relevant ''in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
''.
Other activities
Ketoconazole has been found to inhibit the activity of the cation channel TRPM5
Transient receptor potential cation channel subfamily M member 5 (TRPM5), also known as long transient receptor potential channel 5 is a protein that in humans is encoded by the ''TRPM5'' gene.
Function
TRPM5 is a calcium-activated non-select ...
.
Pharmacokinetics
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.
Chemistry
Ketoconazole is a synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to:
Science
* Synthetic chemical or compound, produced by the process of chemical synthesis
* Synthetic ...
imidazole
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non ...
. It is a nonsteroidal compound. It is a racemic mixture
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
of two enantiomers, levoketoconazole ((2''S'',4''R'')-(−)-ketoconazole) and dextroketoconazole ((2''R'',4''S'')-(+)-ketoconazole). Levoketoconazole is under development for potential clinical use as a steroidogenesis inhibitor with better tolerability and less toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
than ketoconazole. Other steroidogenesis inhibitors besides ketoconazole and levoketoconazole include the nonsteroidal compound aminoglutethimide and the steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
al compound abiraterone acetate.
History
Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals. It was patent
A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...
ed in 1977, followed by introduction in the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
in July 1981. Following its introduction, ketoconazole was the only systemic antifungal available for almost a decade. Ketoconazole was introduced as the prototypical medication of the imidazole group of antifungals. Oral ketoconazole has been replaced with oral itraconazole for many mycoses.
Due to incidence of serious liver toxicity, the use of oral ketoconazole was suspended in France
France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...
in July 2011 following review. This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union
The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are located primarily in Europe, Europe. The union has a total area of ...
as well. In 2013, oral ketoconazole was withdrawn in Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
and Australia
Australia, officially the Commonwealth of Australia, is a sovereign country comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands. With an area of , Australia is the largest country by ...
, and strict restrictions were placed on the use of oral ketoconazole in the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
and Canada
Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by to ...
. 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 HRA was approved for use in the European Union for treatment of Cushing's syndrome in November 2013.
As of March 2019, oral levoketoconazole (developmental code name COR-003, tentative brand name Recorlev) is phase III clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s for the treatment of Cushing's syndrome. Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole.
Society and culture
Generic names
''Ketoconazole'' is the generic name of the drug and its , , , and .
Brand names
Ketoconazole has been marketed under a large number of brand names.
Availability
Ketoconazole is available widely throughout the world.
In 2013, the European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...
'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
A liver injury, also known as liver laceration, is some form of trauma sustained to the liver. This can occur through either a blunt force such as a car accident, or a penetrating foreign object such as a knife. Liver injuries constitute 5% of ...
from systemic ketoconazole outweighs its benefits.
Veterinary use
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.
References
External links
*
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