Ketoconazole: Difference between revisions

{{Short description|Antifungal chemical compound}}

{{Use American English|date=April 2020}}

{{Use dmy dates|date=August 2021}}

{{cs1 config | name-list-style=vanc | display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 457114462

| image = Ketoconazole enantiomers.svg

| width = 250

| alt =

| caption = (2''R'',4''S'')-(+)-ketoconazole (top)<br />(2''S'',4''R'')-(−)-ketoconazole (bottom)

| image2 = (2R,4S)-(+)-ketoconazole-from-xtal-3D-bs-17.png

| alt2 =

| caption2 = [[Ball-and-stick model]] of (2''R'',4''S'')-(+)-ketoconazole

| chirality = [[Racemic mixture]]<ref name="AR">{{cite web|title=Assessment report: Ketoconazole HRA|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003906/WC500181493.pdf |publisher=[[European Medicines Agency]] (EMA) |access-date=26 August 2016|url-status=live|archive-url=https://web.archive.org/web/20160827011824/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003906/WC500181493.pdf|archive-date=27 August 2016}}</ref><ref name = "Arakak">{{cite journal | vauthors = Arakaki R, Welles B | title = Ketoconazole enantiomer for the treatment of diabetes mellitus | journal = Expert Opinion on Investigational Drugs | volume = 19 | issue = 2 | pages = 185–94 | date = February 2010 | pmid = 20047506 | doi = 10.1517/13543780903381411 | s2cid = 26531459 }}</ref>

<!-- Clinical data -->

| pronounce =

{{IPAc-en|ˌ|k|iː|t|oʊ|ˈ|k|oʊ|n|ə|ˌ|z|oʊ|l|,_|-|z|ɒ|l}}{{refn|{{MerriamWebsterDictionary|Ketoconazole}}

}}{{refn|{{Dictionary.com|Ketoconazole}}

}}

| tradename = Nizoral, others

| DailyMedID = Ketoconazole

| pregnancy_AU = B3

| pregnancy_AU_comment =

| pregnancy_category=

| routes_of_administration = [[Oral administration|By mouth]] ([[Tablet (pharmacy)|tablets]]), [[topical]] ([[Cream (pharmaceutical)|cream]], [[shampoo]], [[Solution (chemistry)|solution]])

| class =

| ATC_prefix = J02

| ATC_suffix = AB02

| ATC_supplemental = {{ATC|D01|AC08}}, {{ATC|G01|AF11}}, {{ATC|H02|CA03}} <!-- Oral formulations only indicated in treatment of Cushing’s -->

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled-->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = <ref>{{cite web | title=Ketoconazole HRA 200mg Tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=18 September 2017 | url=https://www.medicines.org.uk/emc/product/1767/smpc | access-date=1 April 2020 | archive-date=2 August 2020 | archive-url=https://web.archive.org/web/20200802215412/https://www.medicines.org.uk/emc/product/1767/smpc | url-status=live }}</ref><ref>{{cite web | title=Ketoconazole 2% w/w Shampoo - Summary of Product Characteristics (SmPC) | website=(emc) | date=5 October 2015 | url=https://www.medicines.org.uk/emc/product/4559/smpc | access-date=1 April 2020 | archive-date=3 August 2020 | archive-url=https://web.archive.org/web/20200803021950/https://www.medicines.org.uk/emc/product/4559/smpc | url-status=live }}</ref>

| legal_US = Rx-only

| legal_US_comment = <ref name="Ketoconazole tablet label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Ketoconazole HRA EPAR" />

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = [[Oral administration|By mouth]]: 37–97%<ref name="Millikan2016" />

| metabolism = Extensive [[liver]] (predominantly oxidation, ''O''-dealkylation)

| metabolites = ''N''-deacetyl ketoconazole

| onset =

| elimination_half-life = Biphasic

| duration_of_action =

| excretion = [[Bile duct]] (major) and [[kidney]]<ref name = "AR" />

<!-- Identifiers -->

| CAS_supplemental =

| PubChem = 3823

| PubChem2 = 47576

| IUPHAR_ligand = 2568

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChemSpiderID2 = 3691

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL2 = 157101

| NIAID_ChemDB =

| PDB_ligand = KTN

| synonyms = R-41400; KW-1414

<!-- Chemical and physical data -->

| IUPAC_name = 1-[4-[4-<nowiki>[[</nowiki>2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone

| C=26 | H=28 | Cl=2 | N=4 | O=4

| SMILES = O=C(N5CCN(c4ccc(OC[C@@H]1O[C@](OC1)(c2ccc(Cl)cc2Cl)Cn3ccnc3)cc4)CC5)C

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

[[File:Ketoconazole STADA®.jpg|thumb|150px|Stada]]

<!-- Definition and medical uses -->

'''Ketoconazole''', sold under the brand name '''Nizoral''' among others, is an [[antiandrogen]], [[antifungal drug|antifungal]], and [[antiglucocorticoid]] medication used to treat a number of [[fungal infection]]s.<ref name="AHFS2019">{{cite web |title=Ketoconazole Monograph for Professionals |url=https://www.drugs.com/monograph/ketoconazole.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=23 March 2019 |archive-date=28 December 2010 |archive-url=https://web.archive.org/web/20101228050612/https://www.drugs.com/monograph/ketoconazole.html |url-status=live }}</ref> Applied to the skin it is used for [[fungal skin infections]] such as [[tinea]], [[cutaneous candidiasis]], [[pityriasis versicolor]], [[dandruff]], and [[seborrhoeic dermatitis|seborrheic dermatitis]].<ref name="BNF76">{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=1198|edition=76}}</ref> Taken [[oral administration|by mouth]] it is a less preferred option and only recommended for severe infections when other agents cannot be used.<ref name="AHFS2019" /> Other uses include treatment of [[hirsutism|excessive male-patterned hair growth in women]] and [[Cushing's syndrome]].<ref name=AHFS2019/>

<!-- Side effects and mechanisms -->

Common [[side effect]]s when [[transdermal administration|applied to the skin]] include redness.<ref name=BNF76/> Common side effects when taken by mouth include [[nausea]], [[headache]], and [[liver problems]].<ref name=AHFS2019/> Liver problems may result in death or the need for a [[liver transplantation]].<ref name=AHFS2019/><ref name=FDA2013/> Other severe side effects when taken by mouth include [[QT prolongation]], [[adrenocortical insufficiency]], and [[anaphylaxis]].<ref name=AHFS2019/><ref name=FDA2013>{{cite news | title=FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems | newspaper=FDA Drug Safety Communication | url=https://www.fda.gov/Drugs/DrugSafety/ucm362415.htm | publisher=[[U.S. Food and Drug Administration]] | date=26 July 2013 | access-date=23 November 2013 | url-status=live | archive-url=https://web.archive.org/web/20131202231140/https://www.fda.gov/Drugs/DrugSafety/ucm362415.htm | archive-date=2 December 2013 }}</ref> It is an [[imidazole]] and works by hindering the production of [[ergosterol]] required for the fungal [[cell membrane]], thereby slowing growth.<ref name=AHFS2019/>

<!-- Society and culture -->

Ketoconazole was patented in 1977 by Belgian pharmaceutical company [[Janssen Pharmaceuticals|Janssen]], and came into medical use in 1981.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=503 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA503 }}</ref> It is available as a [[generic medication]] and formulations that are applied to the skin are [[over the counter]] in the [[United Kingdom]].<ref name=BNF76/> In 2021, it was the 161st most commonly prescribed medication in the United States, with more than 3{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Ketoconazole - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Ketoconazole | access-date = 14 January 2024 | archive-date = 8 July 2020 | archive-url = https://web.archive.org/web/20200708064013/https://clincalc.com/DrugStats/Drugs/Ketoconazole | url-status = live }}</ref> The formulation that is taken by mouth was [[withdrawn drug|withdrawn]] in the European Union and in Australia in 2013,<ref>{{cite web |title=Oral ketoconazole (Nizoral) 200 mg tablets |url=https://www.tga.gov.au/alert/oral-ketoconazole-nizoral-200-mg-tablets |website=Therapeutic Goods Administration (TGA) |access-date=23 March 2019 |date=10 October 2013 |archive-date=2 July 2015 |archive-url=https://web.archive.org/web/20150702154853/http://www.tga.gov.au/alert/oral-ketoconazole-nizoral-200-mg-tablets |url-status=live }}</ref><ref name=GuptaLyons2015/> and in China in 2015.<ref>{{cite web | url=http://www.sfda.gov.cn/WS01/CL0087/122883.html | title=国家食品药品监督管理总局关于停止生产销售使用酮康唑口服制剂的公告（2015年第85号） | publisher=[[China Food and Drug Administration]] | date=25 June 2015 | access-date=2 July 2015 | language=zh | url-status=live | archive-url=https://web.archive.org/web/20150702151102/http://www.sfda.gov.cn/WS01/CL0087/122883.html | archive-date=2 July 2015 }}</ref> In addition, its use was restricted in the United States and Canada in 2013.<ref name=GuptaLyons2015>{{cite journal | vauthors = Gupta AK, Lyons DC | title = The Rise and Fall of Oral Ketoconazole | journal = [[Journal of Cutaneous Medicine and Surgery]] | volume = 19 | issue = 4 | pages = 352–7 | year = 2015 | pmid = 25775613 | doi = 10.1177/1203475415574970 | s2cid = 206695486 }}</ref>

{{TOC limit}}

==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]].<ref name=phillips>{{cite book | vauthors = Phillips RM, Rosen T | title=Comprehensive Dermatologic Therapy | year=2013 | publisher=Saunders | location=Philadelphia | isbn=978-1-4377-2003-7 | pages=460–472 | edition=3rd | veditors = Wolverton SE | chapter=Topical Antifungal Agents}}</ref> Topical ketoconazole is also used as a treatment for [[dandruff]] (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.<ref name=phillips/><ref name=neider>{{cite book |vauthors=Neider R, Fritsch PO | title=Dermatology | year=2012 | publisher=Saunders | location=Philadelphia | isbn=9780723435716 | pages=219–221 | edition=3rd | veditors = Bolognia JL | chapter=Other Eczematous Eruptions}}</ref><ref>{{cite book |vauthors=Young BK, Brodell RT, Cooper KD | title=Comprehensive Dermatologic Therapy | year=2013 | publisher=Saunders | location=Philadelphia | isbn=978-1-4377-2003-7 | pages=562–569 | edition=3rd | veditors = Wolverton SE | chapter=Therapeutic Shampoos}}</ref>

===Systemic antifungal===

Ketoconazole has activity against many kinds of fungi that may cause human disease, such as ''[[Candida (fungus)|Candida]]'', ''[[Histoplasma]]'', ''[[Coccidioides]]'', and ''[[Blastomyces]]'' (although it is not active against ''[[Aspergillus]]''), [[Chromoblastomycosis|chromomycosis]] and [[paracoccidioidomycosis]].<ref name=finkel>{{cite book |vauthors=Finkel R, Cubeddu LX, Clark MA | title=Pharmacology | year=2009 | publisher=Lippincott Williams & Wilkins | location=Baltimore | page=411 | edition=4th}}</ref><ref name=FDA2013/> First made in 1977,<ref name=phillips/> ketoconazole was the first orally-active [[azole]] antifungal medication.<ref name=finkel/> However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by other [[azole antifungal]] agents, such as [[fluconazole]] and/or [[itraconazole]], because of ketoconazole's greater toxicity, poorer absorption, and more limited spectrum of activity.<ref name=finkel/><ref>{{cite book | vauthors=Kauffman CA | title=Cecil Textbook of Medicine | year=2004 | publisher=Saunders | location=Philadelphia | isbn=978-0-7216-9652-2 | page=[https://archive.org/details/ceciltextbookofm0000unse/page/2043 2043] | edition=22nd | veditors = Goldman L, Ausiello D | chapter=Introduction to the Mycoses | chapter-url-access=registration | chapter-url=https://archive.org/details/ceciltextbookofm0000unse/page/2043 }}</ref>

Ketoconazole is used orally in dosages of 200 to 400&nbsp;mg per day in the treatment of superficial and deep fungal infections.<ref name="Becker2001">{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1197|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=1197–}}</ref>

===Off-label uses===

====Hair loss====

[[File:Ketoconazole shampoo skin.jpg|alt=|thumb|257x257px|Ketoconazole 2% gel]]

Ketoconazole shampoo in conjunction with an oral [[5α-reductase inhibitor]] such as [[finasteride]] or [[dutasteride]] has been used off label to treat [[androgenic alopecia]]. It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.<ref name="pmid22735503">{{cite journal | vauthors = McElwee KJ, Shapiro JS | title = Promising therapies for treating and/or preventing androgenic alopecia | journal = Skin Therapy Letter | volume = 17 | issue = 6 | pages = 1–4 | date = June 2012 | pmid = 22735503 | url = http://www.skintherapyletter.com/2012/17.6/1.html | url-status = live | archive-url = https://web.archive.org/web/20151212040921/http://www.skintherapyletter.com/2012/17.6/1.html | archive-date = 12 December 2015 }}</ref>

Limited clinical studies suggest ketoconazole shampoo used either alone<ref name="pmid9669136">{{cite journal | vauthors = Piérard-Franchimont C, De Doncker P, Cauwenbergh G, Piérard GE | title = Ketoconazole shampoo: effect of long-term use in androgenic alopecia | journal = Dermatology | volume = 196 | issue = 4 | pages = 474–7 | year = 1998 | pmid = 9669136 | doi = 10.1159/000017954 | s2cid = 30635892 }}</ref><ref name="pmid18498517">{{cite journal | vauthors = Piérard-Franchimont C, Goffin V, Henry F, Uhoda I, Braham C, Piérard GE | title = Nudging hair shedding by antidandruff shampoos. A comparison of 1% ketoconazole, 1% piroctone olamine and 1% zinc pyrithione formulations | journal = International Journal of Cosmetic Science | volume = 24 | issue = 5 | pages = 249–56 | date = October 2002 | pmid = 18498517 | doi = 10.1046/j.1467-2494.2002.00145.x | hdl = 2268/11902 | url = http://orbi.ulg.ac.be/handle/2268/11902 | hdl-access = free | access-date = 4 July 2019 | archive-date = 29 August 2021 | archive-url = https://web.archive.org/web/20210829142726/https://orbi.uliege.be/handle/2268/11902 | url-status = live }}</ref> or in combination with other treatments<ref name="pmid12227482">{{cite journal | vauthors = Khandpur S, Suman M, Reddy BS | title = Comparative efficacy of various treatment regimens for androgenetic alopecia in men | journal = The Journal of Dermatology | volume = 29 | issue = 8 | pages = 489–98 | date = August 2002 | pmid = 12227482 | doi = 10.1111/j.1346-8138.2002.tb00314.x | s2cid = 20886812 }}</ref> may be useful in reducing hair loss in some cases.<ref name="pmid31832993">{{cite journal | vauthors = Marks DH, Prasad S, De Souza B, Burns LJ, Senna MM | title = Topical Antiandrogen Therapies for Androgenetic Alopecia and Acne Vulgaris | journal = Am J Clin Dermatol | volume = 21| issue = 2| pages = 245–254| date = December 2019 | pmid = 31832993 | doi = 10.1007/s40257-019-00493-z | s2cid = 209331373 }}</ref>

====Hormonal====

{{See also|Steroidogenesis inhibitor|CYP17A1 inhibitor}}

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&nbsp;mg/day), it potently inhibits the activity of several [[enzyme]]s necessary for the conversion of [[cholesterol]] to [[steroid hormone]]s such as [[testosterone]] and [[cortisol]].<ref name=finkel/><ref name="Becker2001" /> Specifically, ketoconazole has been shown to inhibit [[cholesterol side-chain cleavage enzyme]], which converts cholesterol to [[pregnenolone]], [[17α-hydroxylase]] and [[17,20-lyase]],<ref name="Becker2001" /> which convert [[pregnenolone]] into [[androgen]]s, and [[11β-hydroxylase]], which converts [[11-deoxycortisol]] to [[cortisol]].<ref name=Medscape-keto>{{cite web|title=MedScape|url=http://www.medscape.org/viewarticle/582330_3|website=Ectopic Cortisol Production Derived From Malignant Testicular Masses: Treatment and Management|publisher=Nature Publishing Group|access-date=18 April 2015|url-status=live|archive-url=https://web.archive.org/web/20180513210423/https://www.medscape.org/viewarticle/582330_3|archive-date=13 May 2018}}</ref> All of these enzymes are mitochondrial [[cytochrome p450]] enzymes.<ref name="pmid6304148">{{cite journal | vauthors = Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D | title = Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes | journal = The Journal of Clinical Investigation | volume = 71 | issue = 5 | pages = 1495–9 | date = May 1983 | pmid = 6304148 | pmc = 437014 | doi = 10.1172/JCI110903 }}</ref> Based on these [[antiandrogen]] and [[antiglucocorticoid]] effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advanced [[prostate cancer]]<ref name="Becker2001" /><ref name=zelefsky>{{cite book |vauthors=Zelefsky MJ, Eastham JA, Sartor OA, Kantoff P | title=Cancer: Principles & Practice of Oncology | year=2008 | publisher=Lippincott Williams & Wilkins | location=Philadelphia | isbn=9780781772075 | page=1443 | edition=8th |veditors=DeVita VT, Lawrence TS, Rosenberg SA }}</ref> and for the suppression of [[glucocorticoid]] synthesis in the treatment of [[Cushing's syndrome]].<ref name=Cushing>{{cite journal | vauthors = Loli P, Berselli ME, Tagliaferri M | title = Use of ketoconazole in the treatment of Cushing's syndrome | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 63 | issue = 6 | pages = 1365–71 | date = December 1986 | pmid = 3023421 | doi = 10.1210/jcem-63-6-1365 }}</ref> However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent [[adrenal insufficiency]].<ref name="Becker2001" /> Ketoconazole has additionally been used, in lower dosages, to treat [[hirsutism]] and, in combination with a [[GnRH analogue]], [[male-limited precocious puberty]].<ref name="Becker2001" /> 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.<ref name="Becker2001" />

Ketoconazole has been used to prevent the [[testosterone]] flare at the initiation of [[GnRH agonist]] therapy in men with prostate cancer.<ref name="pmid16986003">{{cite journal | vauthors = Thompson IM | title = Flare Associated with LHRH-Agonist Therapy | journal = Reviews in Urology | volume = 3 | issue = Suppl 3 | pages = S10–4 | date = 2001 | pmid = 16986003 | pmc = 1476081 }}</ref>

==Contraindications==

Oral ketoconazole has various [[contraindication]]s, such as concomitant use with certain other drugs due to known [[drug interaction]]s.<ref name="Ketoconazole tablet label" /> Other contraindications of oral ketoconazole include [[liver disease]], [[adrenal insufficiency]], and known [[hypersensitivity]] to oral ketoconazole.<ref name="Ketoconazole tablet label" />

==Side effects==

===Gastrointestinal===

Vomiting, diarrhea, nausea, constipation, abdominal pain, upper abdominal pain, dry mouth, [[dysgeusia]], [[dyspepsia]], [[flatulence]], tongue discoloration may occur.<ref name=":1" />

===Endocrine===

The drug may cause [[adrenal insufficiency]] so the level of the [[adrenocortical hormone]]s should be monitored while taking it.<ref name=FDA2013/><ref name=":1" /> Oral ketoconazole at a dosage range of 400 to 2,000&nbsp;mg/day has been found to result in a rate of [[gynecomastia]] of 21%.<ref name="DeepinderBraunstein2012">{{cite journal | vauthors = Deepinder F, Braunstein GD | title = Drug-induced gynecomastia: an evidence-based review | journal = Expert Opinion on Drug Safety | volume = 11 | issue = 5 | pages = 779–95 | date = September 2012 | pmid = 22862307 | doi = 10.1517/14740338.2012.712109 | s2cid = 22938364 }}</ref>

===Liver===

In July 2013, the US [[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.<ref name=FDA2013/> 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.<ref name=FDA2013/> As contraindication it should not be used in people with acute or chronic liver disease.<ref name=FDA2013/>

===Hypersensitivity===

[[Anaphylaxis]] after the first dose may occur.{{medcn|date=February 2024}} Other cases of hypersensitivity include [[Hives|urticaria]].<ref name="AHFS2019" /><ref name="Ketoconazole tablet label" />

===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.<ref name=FDA2013/>

===Pregnancy===

Ketoconazole is categorized as [[Pregnancy category (pharmaceutical)|pregnancy category C]] in the US.<ref name=Preg2020/> Research in animals has shown it to cause [[Teratology|teratogenesis]] when administered in high doses.<ref name=Preg2020>{{cite web |title=Ketoconazole (Nizoral) Use During Pregnancy |url=https://www.drugs.com/pregnancy/ketoconazole.html |website=Drugs.com |access-date=24 May 2020 |language=en |archive-date=10 April 2020 |archive-url=https://web.archive.org/web/20200410175858/https://www.drugs.com/pregnancy/ketoconazole.html |url-status=live }}</ref> A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.<ref name=Giant_Hungarian_Human_Birth_Defects_Study>{{cite journal | vauthors = Kazy Z, Puhó E, Czeizel AE | title = Population-based case-control study of oral ketoconazole treatment for birth outcomes | journal = Congenital Anomalies | volume = 45 | issue = 1 | pages = 5–8 | date = March 2005 | pmid = 15737124 | doi = 10.1111/j.1741-4520.2005.00053.x | s2cid = 41187361 | doi-access = free }}</ref>

==Overdose==

In the event of an [[overdose]] of oral ketoconazole, treatment should be supportive and based on [[symptom]]s.<ref name="Ketoconazole tablet label" /> [[Activated charcoal]] may be administered within the first hour following overdose of oral ketoconazole.<ref name="Ketoconazole tablet label" />

== Interactions ==

The concomitant use of the following medications is contraindicated with ketoconazole tablets:<ref name="Ketoconazole tablet label">{{cite web | title=Ketoconazole tablet | website=DailyMed | date=26 June 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6d4be760-c723-4f54-a854-12c61cf91703 | access-date=5 January 2020 | archive-date=5 August 2020 | archive-url=https://web.archive.org/web/20200805193136/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6d4be760-c723-4f54-a854-12c61cf91703 | url-status=live }}</ref><ref name=":1">{{Cite web|url=https://www.rxlist.com/nizoral-drug.htm|title=Nizoral (Ketoconazole): Side Effects, Interactions, Warning, Dosage & Uses|website=RxList|access-date=7 April 2019|archive-date=7 April 2019|archive-url=https://web.archive.org/web/20190407214804/https://www.rxlist.com/nizoral-drug.htm|url-status=live}}</ref>

* [[methadone]], [[disopyramide]], [[dronedarone]]

* [[irinotecan]], [[lurasidone]], [[colchicine]]

* [[alprazolam]], oral [[midazolam]], oral [[triazolam]]

* [[felodipine]], [[ranolazine]], [[tolvaptan]], [[eplerenone]]

* [[HMG-CoA reductase inhibitor]]s: [[lovastatin]], [[simvastatin]]

* [[ergot alkaloid]]s: [[ergotamine]], [[dihydroergotamine]], [[ergometrine]], [[methylergometrine]]

* Others: [[cisapride]], [[nisoldipine]], [[dofetilide]], [[pimozide]]

And is not recommended:<ref name="Ketoconazole tablet label" /><ref name=":1" />

* [[carbamazepine]], [[phenytoin]]

* gastric acid suppressants: [[antacid]]s, [[muscarinic antagonist|antimuscarinic]]s, [[H2 antagonist|histamine H₂ blockers]], [[proton pump inhibitor]]s

* [[sucralfate]]

* [[rifampin]], [[rifabutin]], [[isoniazid]]

* [[efavirenz]], [[nevirapine]]

[[Ritonavir]] is known for increasing activity of the ketoconazole so it is recommended to reduce dosage.<ref name="Ketoconazole tablet label" />

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.<ref name="Ketoconazole tablet label" /><ref name=":1" />

==Pharmacology==

===Pharmacodynamics===

====Antifungal activity====

{{More citations needed section|date=May 2013}}

As an antifungal, ketoconazole is structurally similar to [[imidazole]], and interferes with the fungal synthesis of [[ergosterol]], a constituent of fungal [[cell membrane]]s, as well as certain [[enzyme]]s. As with all [[azole antifungal]] agents, ketoconazole works principally by inhibiting the [[enzyme]] [[cytochrome P450]] [[14α-demethylase]] (CYP51A1).<ref name="pmid6304148"/> This enzyme participates in the [[sterol]] [[biosynthesis]] pathway that leads from [[lanosterol]] to [[ergosterol]]. Lower doses of [[fluconazole]] and [[itraconazole]] are required to kill fungi compared to ketoconazole, as they have been found to have a greater [[affinity (pharmacology)|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|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.<ref>{{cite journal | vauthors = Cartledge JD, Midgley J, Gazzard BG | title = Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis | journal = AIDS | volume = 11 | issue = 15 | pages = 1839–44 | date = December 1997 | pmid = 9412702 | doi = 10.1097/00002030-199715000-00008 | s2cid = 8440973 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sanglard D, Ischer F, Monod M, Bille J | title = Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene | journal = Microbiology | volume = 143 | issue = Pt 2 | pages = 405–16 | date = February 1997 | pmid = 9043118 | doi = 10.1099/00221287-143-2-405 | doi-access = free }}</ref>

====Antihormonal activity====

As an [[antiandrogen]], ketoconazole operates through at least two [[mechanism of action|mechanisms]] of action. First, and most notably, high oral doses of ketoconazole (e.g. 40&nbsp;mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels.<ref name="Becker2001" /><ref name="pmid2652864">{{cite journal | vauthors = Witjes FJ, Debruyne FM, Fernandez del Moral P, Geboers AD | title = Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer. Dutch South-Eastern Urological Cooperative Group | journal = Urology | volume = 33 | issue = 5 | pages = 411–5 | date = May 1989 | pmid = 2652864 | doi = 10.1016/0090-4295(89)90037-X }}</ref> 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 (biochemistry)|precursor]]s of [[testosterone]].<ref name="Becker2001" /> Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer.<ref name="pmid8603034">{{cite journal | vauthors = De Coster R, Wouters W, Bruynseels J | title = P450-dependent enzymes as targets for prostate cancer therapy | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 56 | issue = 1–6 Spec No | pages = 133–43 | date = January 1996 | pmid = 8603034 | doi = 10.1016/0960-0760(95)00230-8 | s2cid = 42845713 }}</ref> 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.<ref name="pmid1526623">{{cite journal | vauthors = Eil C | title = Ketoconazole binds to the human androgen receptor | journal = Hormone and Metabolic Research | volume = 24 | issue = 8 | pages = 367–70 | date = August 1992 | pmid = 1526623 | doi = 10.1055/s-2007-1003337 | s2cid = 33271618 | url = https://zenodo.org/record/1236018 | access-date = 4 July 2019 | archive-date = 11 February 2020 | archive-url = https://web.archive.org/web/20200211203025/https://zenodo.org/record/1236018 | url-status = live }}</ref>

Ketoconazole, along with [[miconazole]], has been found to act as an [[receptor antagonist|antagonist]] of the [[glucocorticoid receptor]].<ref name="pmid6135709">{{cite journal | vauthors = Loose DS, Stover EP, Feldman D | title = Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells | journal = The Journal of Clinical Investigation | volume = 72 | issue = 1 | pages = 404–8 | date = July 1983 | pmid = 6135709 | pmc = 1129197 | doi = 10.1172/jci110982 }}</ref><ref name="pmid16608920">{{cite journal | vauthors = Duret C, Daujat-Chavanieu M, Pascussi JM, Pichard-Garcia L, Balaguer P, Fabre JM, Vilarem MJ, Maurel P, Gerbal-Chaloin S | title = Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor | journal = Molecular Pharmacology | volume = 70 | issue = 1 | pages = 329–39 | date = July 2006 | pmid = 16608920 | doi = 10.1124/mol.105.022046 | s2cid = 21455699 }}</ref>

Ketoconazole is a [[racemic mixture]] consisting of ''cis''-(2''S'',4''R'')-(−) and ''cis''-(2''R'',4''S'')-(+) enantiomers.<ref name = "Arakak" /> The ''cis''-(2''S'',4''R'') isomer was more potent in inhibiting [[CYP17A1|progesterone 17α,20-lyase]] than its enantiomer ([[IC50|IC₅₀]] values of 0.05 and 2.38 ''μ''M, respectively) and in inhibiting [[Steroid 11-beta-hydroxylase|11β-hydroxylase]] (IC₅₀ values of 0.152 and 0.608 ''μ''M, respectively). Both isomers were relatively weak inhibitors of human placental [[aromatase]].<ref name = "AR" />

Oral ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200&nbsp;mg/day.<ref name="Shaw1996">{{cite journal | vauthors = Shaw JC | title = Antiandrogen therapy in dermatology | journal = International Journal of Dermatology | volume = 35 | issue = 11 | pages = 770–8 | date = November 1996 | pmid = 8915726 | doi = 10.1111/j.1365-4362.1996.tb02970.x | s2cid = 39334280 }}</ref><ref name="Sonino1986" /><ref name="WheelerKeye2010">{{cite book| vauthors = Wheeler CJ, Keye WR, Peterson CM |title=Reproductive Endocrinology and Infertility |chapter=Polycystic Ovary Syndrome |year=2010 |pages=147–182 |doi=10.1007/978-1-4419-1436-1_11 |isbn=978-1-4419-1435-4}}</ref> Numerous small studies have investigated the effects of oral ketoconazole on hormone levels in humans.<ref name="DrobnisNangia2017" /> 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]], and [[prolactin]] were unaffected.<ref name="DrobnisNangia2017">{{cite book | vauthors = Drobnis EZ, Nangia AK | title = Impacts of Medications on Male Fertility | chapter = Antimicrobials and Male Reproduction | series = Advances in Experimental Medicine and Biology | volume = 1034 | pages = 131–161 | year = 2017 | pmid = 29256130 | doi = 10.1007/978-3-319-69535-8_10 | isbn = 978-3-319-69534-1 }}</ref><ref name="Feldman1986">{{cite journal | vauthors = Feldman D | title = Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis | journal = Endocrine Reviews | volume = 7 | issue = 4 | pages = 409–20 | date = November 1986 | pmid = 3536461 | doi = 10.1210/edrv-7-4-409 }}</ref><ref name="Sonino1986" /> The ratio of testosterone to estradiol is also decreased during oral ketoconazole therapy in men.<ref name="Sonino1986">{{cite journal | vauthors = Sonino N | title = The endocrine effects of ketoconazole | journal = Journal of Endocrinological Investigation | volume = 9 | issue = 4 | pages = 341–7 | date = August 1986 | pmid = 3537102 | doi = 10.1007/BF03346939 | s2cid = 9148909 }}</ref> Suppression of testosterone levels by ketoconazole is generally partial and has often been found to be transient.<ref name="DrobnisNangia2017" /> 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.<ref name="Sonino1986" /> In [[premenopausal]] women with [[polycystic ovary syndrome]], ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol.<ref name="WheelerKeye2010" /><ref name="GalOrly1994">{{cite journal | vauthors = Gal M, Orly J, Barr I, Algur N, Boldes R, Diamant YZ | title = Low dose ketoconazole attenuates serum androgen levels in patients with polycystic ovary syndrome and inhibits ovarian steroidogenesis in vitro | journal = Fertility and Sterility | volume = 61 | issue = 5 | pages = 823–32 | date = May 1994 | pmid = 8174717 | doi = 10.1016/S0015-0282(16)56691-6 | doi-access = free }}</ref> 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.<ref name="Lønning2009">{{cite journal | vauthors = Lønning PE | title = New endocrine drugs for treatment of advanced breast cancer | journal = Acta Oncologica | volume = 29 | issue = 3 | pages = 379–86 | year = 2009 | pmid = 2194539 | doi = 10.3109/02841869009090018 | doi-access = free }}</ref> This indicates minimal inhibition of aromatase by ketoconazole ''[[in vivo]]'' in humans.<ref name="Lønning2009" /> Ketoconazole has also been found to decrease levels of [[endogenous]] [[corticosteroid]]s, such as [[cortisol]], [[corticosterone]], and [[aldosterone]], as well as [[vitamin D]].<ref name="TarbitRobertson1990">{{cite book | vauthors = Tarbit MH, Robertson WR, Lambert A |title= Chemotherapy of Fungal Diseases|chapter=Hepatic and Endocrine Effects of Azole Antifungal Agents |volume=96 |year=1990 |pages=205–229 |issn=0171-2004 |doi=10.1007/978-3-642-75458-6_10 |series=Handbook of Experimental Pharmacology |isbn=978-3-642-75460-9 }}</ref><ref name="Sonino1986" />

Ketoconazole has been found to displace [[dihydrotestosterone]] and estradiol from [[sex hormone-binding globulin]] ''[[in vitro]]'', but this was not found to be relevant ''[[in vivo]]''.<ref name="Sonino1986" />

====Other activities====

Ketoconazole has been found to inhibit the activity of the cation channel [[TRPM5]].<ref>{{cite journal | vauthors = Philippaert K, Kerselaers S, Voets T, Vennekens R | title = 2+-Activated Monovalent Cation-Selective Channels | journal = SLAS Discovery | volume = 23 | issue = 4 | pages = 341–352 | date = April 2018 | pmid = 29316407 | doi = 10.1177/2472555217748932 | doi-access = free }}</ref>

===Pharmacokinetics===

When administered orally, ketoconazole is best absorbed at highly [[acid]]ic levels, so [[antacid]]s 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]].<ref>{{cite journal | vauthors = Chin TW, Loeb M, Fong IW | title = Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole | journal = Antimicrobial Agents and Chemotherapy | volume = 39 | issue = 8 | pages = 1671–5 | date = August 1995 | pmid = 7486898 | pmc = 162805 | doi = 10.1128/AAC.39.8.1671 }}</ref> Ketoconazole is very [[Lipophilicity|lipophilic]] and tends to accumulate in fatty tissues.

==Chemistry==

Ketoconazole is a [[synthetic compound|synthetic]] [[imidazole]].<ref name="Elks2014" /><ref name="IndexNominum2000" /> It is a [[nonsteroidal]] compound.<ref name="Elks2014" /><ref name="IndexNominum2000" /> It is a [[racemic mixture]] of two [[enantiomer]]s, [[levoketoconazole]] ((2''S'',4''R'')-(−)-ketoconazole) and dextroketoconazole ((2''R'',4''S'')-(+)-ketoconazole).<ref name="Elks2014" /><ref name="IndexNominum2000" /> Levoketoconazole is under development for potential clinical use as a steroidogenesis inhibitor with better [[tolerability]] and less [[toxicity]] than ketoconazole. Other steroidogenesis inhibitors besides ketoconazole and levoketoconazole include the nonsteroidal compound [[aminoglutethimide]] and the [[steroid]]al compound [[abiraterone acetate]].{{cn|date=December 2022}}

Ketoconazole was discovered in 1976 at [[Janssen Pharmaceuticals]].<ref name="Heeres_1979">{{cite journal | vauthors = Heeres J, Backx LJ, Mostmans JH, Van Cutsem J | title = Antimycotic imidazoles. part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent | journal = Journal of Medicinal Chemistry | volume = 22 | issue = 8 | pages = 1003–5 | date = August 1979 | pmid = 490531 | doi = 10.1021/jm00194a023 }}</ref> It was [[patent]]ed in 1977,<ref name=Fis2006 /> followed by introduction in the [[United States]] in July 1981.<ref name="GuptaLyons2015" /><ref name="Millikan2016">{{cite book| vauthors = Millikan LE |title=Drug Therapy in Dermatology|url=https://books.google.com/books?id=3TDMBQAAQBAJ&pg=PA82|date=19 April 2016|publisher=CRC Press|isbn=978-0-203-90831-0|pages=82–}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|edition=3rd|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1997|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1997–|access-date=14 June 2019|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110131025/https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1997|url-status=live}}</ref><ref name=Fis2006 /> Following its introduction, ketoconazole was the only systemic antifungal available for almost a decade.<ref name="GuptaLyons2015" /> Ketoconazole was introduced as the prototypical medication of the imidazole group of antifungals.<ref name="Golan2008">{{cite book|vauthors=Golan DE|title=Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy|url=https://books.google.com/books?id=az8uSDkB0mgC&pg=PA624|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-8355-2|pages=624–|access-date=11 April 2017|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110131048/https://books.google.com/books?id=az8uSDkB0mgC&pg=PA624|url-status=live}}</ref> Oral ketoconazole has been replaced with oral [[fluconazole]] or [[itraconazole]] for many [[mycosis|mycose]]s.<ref name="Golan2008" />

Due to incidence of serious [[liver toxicity]], the use of oral ketoconazole was suspended in France in July 2011, following review.<ref name="GuptaLyons2015"/> This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union.<ref name="GuptaLyons2015" /><ref>{{cite web | title=Ketoconazole-containing medicines | publisher=[[European Medicines Agency]] (EMA) | date=25 July 2013 | url=https://www.ema.europa.eu/en/medicines/human/referrals/ketoconazole-containing-medicines | access-date=22 February 2024 | archive-date=22 February 2024 | archive-url=https://web.archive.org/web/20240222030047/https://www.ema.europa.eu/en/medicines/human/referrals/ketoconazole-containing-medicines | url-status=live }}</ref> In 2013, oral ketoconazole was withdrawn in the European Union and Australia, and strict restrictions were placed on the use of oral ketoconazole in the United States and Canada.<ref name="GuptaLyons2015" /> Oral ketoconazole is indicated for use in these countries when the indication is a severe or life-threatening systemic infection and alternatives are unavailable.<ref name="GuptaLyons2015" /> However, topical ketoconazole, which does not distribute systemically, is safe and widely used still.<ref name="GuptaLyons2015" />

Ketoconazole HRA was approved for use in the European Union for treatment of [[Cushing's syndrome]] in November 2013.<ref name="Ketoconazole HRA EPAR">{{cite web | title=Ketoconazole HRA EPAR | publisher=[[European Medicines Agency]] (EMA) | date=23 April 2012 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ketoconazole-hra | access-date=1 April 2020 | archive-date=3 August 2020 | archive-url=https://web.archive.org/web/20200803001830/https://www.ema.europa.eu/en/medicines/human/EPAR/ketoconazole-hra | url-status=live }}</ref><ref>{{cite web | title=Ketoconazole HRA recommended for approval in Cushing's syndrome | publisher=[[European Medicines Agency]] (EMA) | date=26 September 2014 | url=https://www.ema.europa.eu/en/news/ketoconazole-hra-recommended-approval-cushings-syndrome | access-date=22 February 2024 | archive-date=22 February 2024 | archive-url=https://web.archive.org/web/20240222030047/https://www.ema.europa.eu/en/news/ketoconazole-hra-recommended-approval-cushings-syndrome | url-status=live }}</ref>

==Society and culture==

===Generic names===

Ketoconazole is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book|vauthors=Elks J|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA720|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=720–|access-date=11 April 2017|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110131052/https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA720|url-status=live}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA586|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=586–|access-date=22 July 2018|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110131022/https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA586|url-status=live}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA159|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=159–}}</ref><ref name="Drugs.com">{{Cite web | url=https://www.drugs.com/international/ketoconazole.html | title=Ketoconazole | access-date=22 July 2018 | archive-date=23 July 2018 | archive-url=https://web.archive.org/web/20180723034504/https://www.drugs.com/international/ketoconazole.html | url-status=live }}</ref>

===Brand names===

Ketoconazole has been marketed under a large number of brand names.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /><ref name="Drugs.com" />

===Availability===

Ketoconazole is available widely throughout the world.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

In 2013, the [[European Medicines Agency]]'s [[Committee for 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.<ref name="url_ema">{{cite press release | url = http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp | title = European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole | date = 26 July 2013 | publisher = [[European Medicines Agency]] (EMA) | url-status = dead | archive-url = http://archive.wikiwix.com/cache/20140114220504/http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp | archive-date = 14 January 2014 }}</ref>

== Research ==

As of March 2019, oral [[levoketoconazole]] (developmental code name COR-003, tentative brand name Recorlev) is [[Phases of clinical research#Phase III|phase III]] [[clinical trial]]s for the treatment of [[Cushing's syndrome]].<ref name="Levoketoconazole-AdisInsight">{{Cite web | url=https://adisinsight.springer.com/drugs/800037965 | title=Levoketoconazole - Strongbridge Biopharma - AdisInsight | access-date=14 June 2019 | archive-date=23 January 2020 | archive-url=https://web.archive.org/web/20200123090417/https://adisinsight.springer.com/drugs/800037965 | url-status=live }}</ref> Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole.<ref name="FleseriuCastinetti2016">{{cite journal | vauthors = Fleseriu M, Castinetti F | title = Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies | journal = Pituitary | volume = 19 | issue = 6 | pages = 643–653 | date = December 2016 | pmid = 27600150 | pmc = 5080363 | doi = 10.1007/s11102-016-0742-1 }}</ref>

==Veterinary use==

Ketoconazole is sometimes prescribed as an antifungal by [[veterinarian]]s for use in pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage.<ref name="KuKanich_2008">{{cite journal | journal = Veterinary Medicine | title = A review of selected systemic antifungal drugs for use in dogs and cats | vauthors = KuKanich B | date = January 2008 | url = http://veterinarymedicine.dvm360.com/vetmed/Medicine/ArticleStandard/Article/detail/483478 | url-status = live | archive-url = https://web.archive.org/web/20131005093333/http://veterinarymedicine.dvm360.com/vetmed/Medicine/ArticleStandard/Article/detail/483478 | archive-date = 5 October 2013 }}</ref>

== References ==

{{Other dermatological preparations}}

{{Androgens and antiandrogens}}

{{Glucocorticoids and antiglucocorticoids}}

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