Itraconazole: Difference between revisions

{{Short description|Medication used to treat fungal infections}}

{{Use dmy dates|date=March 2024}}

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 459522522

| image = Itraconazole.svg

| width =

| alt =

| chirality = [[Racemic mixture]]

<!-- Clinical data -->

| tradename = Sporanox, Sporaz, Orungal, others

| DailyMedID = Itraconazole

| pregnancy_AU = B3

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Itraconazole Use During Pregnancy | website=Drugs.com | date=20 March 2019 | url=https://www.drugs.com/pregnancy/itraconazole.html | access-date=15 May 2020}}</ref>

| routes_of_administration = [[Oral administration|By mouth]], [[Solution (chemistry)|solution]]), [[vaginal administration|vaginal]] [[suppository]], [[Intravenous therapy|intravenous]]

| ATC_prefix = J02

| ATC_suffix = AC02

| legal_AU = S4

| legal_CA = Rx-only

| legal_UK_comment = <ref>{{cite web | title=Sporanox 10 mg/mL Oral Solution - Summary of Product Characteristics (SmPC) | website=(emc) | date=1 February 2018 | url=https://www.medicines.org.uk/emc/product/1522/smpc | access-date=15 May 2020}}</ref>

<!-- Pharmacokinetic data -->

| bioavailability = ~55%, maximal if taken with full meal

| metabolism = Extensive in [[liver]] ([[CYP3A4]])

| metabolites = Hydroxy-itraconazole, keto-itraconazole,<br />''N''-desalkyl-itraconazole<ref>{{cite journal | vauthors = Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE | title = Role of itraconazole metabolites in CYP3A4 inhibition | journal = Drug Metabolism and Disposition | volume = 32 | issue = 10 | pages = 1121–1131 | date = October 2004 | pmid = 15242978 | doi = 10.1124/dmd.104.000315 | s2cid = 6941636 }}</ref>

| excretion = [[Kidney]] (35%), faeces (54%)<ref name="Sporanox PI">{{cite web|title=Sporanox (itraconazole) Capsules. Full Prescribing Information|url=http://www.janssen.com/us/sites/www_janssen_com_usa/files/products-documents/pi-sporanoxcapsules.pdf|publisher=Janssen Pharmaceuticals, Inc.|access-date=28 August 2016|archive-date=17 May 2018|archive-url=https://web.archive.org/web/20180517073659/http://www.janssen.com/us/sites/www_janssen_com_usa/files/products-documents/pi-sporanoxcapsules.pdf|url-status=dead}}</ref>

| synonyms = ITZ

| IUPAC_name = (±)-1-[(''RS'')-''sec''-butyl]-4-[''p''-[4-[''p''-<nowiki>[[</nowiki>(2''R'',4''S'')-''rel''-2-(2,4-dichlorophenyl)-2-(1''H''-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ²-1,2,4-triazolin-5-one

| C=35 | H=38 | Cl=2 | N=8 | O=4

| melting_point = 165 <ref name="NikitaVas">{{cite journal | vauthors = Vasilev NA, Surov AO, Voronin AP, Drozd KV, Perlovich GL | title = Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility | journal = International Journal of Pharmaceutics | volume = 599 | pages = 120441 | date = April 2021 | pmid = 33675927 | doi = 10.1016/j.ijpharm.2021.120441 | s2cid = 232135660 }}</ref>

| solubility = 7.8 ± 0.4 × 10⁻⁶ mol/L (pH 1.6)<ref name="NikitaVas"/>

<!-- Definition and medical uses -->

'''Itraconazole''', sometimes abbreviated '''ITZ''', is an [[antifungal medication]] used to treat a number of [[fungal infections]].<ref name=AHFS2017/> This includes [[aspergillosis]], [[blastomycosis]], [[coccidioidomycosis]], [[histoplasmosis]], and [[paracoccidioidomycosis]].<ref name=AHFS2017/> It may be given [[oral administration|by mouth]] or [[Intravenous therapy|intravenously]].<ref name=AHFS2017/>

<!-- Side effects and mechanism -->

Common [[side effect]]s include nausea, diarrhea, abdominal pain, rash, and headache.<ref name=AHFS2017/> Severe side effects may include [[liver problems]], [[heart failure]], [[Stevens–Johnson syndrome]] and [[allergic reactions]] including [[anaphylaxis]].<ref name=AHFS2017/> It is unclear if use during [[pregnancy]] or [[breastfeeding]] is safe.<ref name="Drugs.com pregnancy" /> It is in the [[triazole]] family of medications.<ref name=AHFS2017/> It [[fungistatic|stops fungal growth]] by affecting the [[cell membrane]] or affecting their [[metabolism]].<ref name=AHFS2017/>

<!-- History and culture -->

Itraconazole was patented in 1978 and approved for medical use in the United States in 1992.<ref name=AHFS2017>{{cite web|title=Itraconazole|url=https://www.drugs.com/monograph/itraconazole.html|publisher=The American Society of Health-System Pharmacists|access-date= 8 December 2017}}</ref><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 |language=en}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref>

Recent research works suggest itraconazole (ITZ) could also be used in the treatment of cancer by inhibiting the [[hedgehog pathway]]<ref name="LiFang2019">{{cite journal | vauthors = Li K, Fang D, Xiong Z, Luo R | title = Inhibition of the hedgehog pathway for the treatment of cancer using Itraconazole | journal = OncoTargets and Therapy | volume = 12 | pages = 6875–6886 | year = 2019 | pmid = 31692536 | pmc = 6711563 | doi = 10.2147/OTT.S223119 | doi-access = free }}</ref> in a similar way to [[sonidegib]].

Itraconazole has a broader spectrum of activity than [[fluconazole]] (but not as broad as [[voriconazole]] or [[posaconazole]]). In particular, it is active against ''[[Aspergillus]]'', which fluconazole is not. It is also licensed for use in [[blastomycosis]], [[sporotrichosis]], [[histoplasmosis]], and [[onychomycosis]]. Itraconazole is over 99% protein-bound and has virtually no penetration into [[cerebrospinal fluid]]. Therefore, it should not be used to treat [[meningitis]] or other [[central nervous system]] infections.<ref name="Sanford">{{cite book | vauthors = Gilbert DN, Moellering, RC, Eliopoulos GM, Sande MA |title=The Sanford Guide to antimicrobial therapy |year=2006 |publisher=Antimicrobial Therapy, Incorporated |isbn=978-1-930808-30-0 |url-access=registration |url=https://archive.org/details/sanfordguidetoan00davi }}{{page needed|date=November 2011}}</ref> According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis".<ref>{{cite web | vauthors = Pham P, Bartlett JG |title=Itraconazole |publisher=Johns Hopkins |url=http://www.hopkins-abxguide.org/terminals/antibiotics_more.cfm?id=81&fc=p |date=24 July 2007 |url-status=dead |archive-url=https://web.archive.org/web/20071128072213/http://www.hopkins-abxguide.org/terminals/antibiotics_more.cfm?id=81&fc=p |archive-date=28 November 2007 }}</ref>

It is also prescribed for systemic infections, such as [[aspergillosis]], [[candidiasis]], and [[cryptococcosis]], where other [[Antifungal medication|antifungal]] drugs are inappropriate or ineffective.{{cn|date=December 2022}}

Itraconazole has been explored as an anticancer agent for patients with [[basal cell carcinoma]], [[non-small cell lung cancer]], and [[prostate cancer]].<ref>{{cite web |url=http://clinicaltrials.gov/ct2/results?term=itraconazole |title=Search results for Itraconazole |work=ClinicalTrials.gov |publisher=[[U.S. National Institutes of Health]]}}</ref> For example, in a phase II study involving men with advanced prostate cancer, high-dose itraconazole (600&nbsp;mg/day) was associated with significant PSA responses and a delay in tumor progression. Itraconazole also showed activity in a phase II trial in men with non-small cell lung cancer when it was combined with the chemotherapy agent, pemetrexed.<ref>{{cite journal |vauthors=Aftab BT, Dobromilskaya I, Liu JO, Rudin CM | title = Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer | journal = Cancer Research | volume = 71 | issue = 21 | pages = 6764–6772 | pmid = 21896639 | pmc = 3206167 | doi = 10.1158/0008-5472.CAN-11-0691 | year = 2011 }}</ref><ref>{{cite journal |vauthors=Antonarakis ES, Heath EI, Smith DC, Rathkopf D, Blackford AL, Danila DC, King S, Frost A, Ajiboye AS, Zhao M, Mendonca J, Kachhap SK, Rudek MA, Carducci MA | title = Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer | journal = The Oncologist | volume = 18 | issue = 2 | pages = 163–173 | year = 2013 | pmid = 23340005 | doi = 10.1634/theoncologist.2012-314 | pmc=3579600}}</ref><ref>{{cite journal |vauthors=Rudin CM, Brahmer JR, Juergens RA, Hann CL, Ettinger DS, Sebree R, Smith R, Aftab BT, Huang P, Liu JO | title = Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer | journal = Journal of Thoracic Oncology | volume = 8 | issue = 5 | pages = 619–623 | date = May 2013 | pmid = 23546045 | doi = 10.1097/JTO.0b013e31828c3950 | pmc=3636564}}</ref> A recent review also highlights its use topically and orally in conjunction with other chemotherapeutic agents for advanced and metastatic basal cell carcinomas that cannot be treated surgically.<ref>{{cite journal|vauthors=Ip KH, McKerrow K | title = Itraconazole in the treatment of basal cell carcinoma: A case-based review of the literature | journal = Australasian Journal of Dermatology | pmid =34160824 | doi = 10.1111/ajd.13655 | year = 2021| volume = 62 | issue = 3 | pages = 394–397 | s2cid = 235608763 }}</ref>

===Available forms===

Itraconazole is produced as blue {{convert|22|mm|in|abbr=on|adj=on}} capsules with tiny {{convert|1.5|mm|in|abbr=on|adj=on}} blue pellets inside. Each capsule contains 100&nbsp;mg and is usually taken twice a day at twelve-hour intervals. The Sporanox brand of itraconazole has been developed and marketed by [[Janssen Pharmaceutica]], a subsidiary of [[Johnson & Johnson]].{{cn|date=July 2021}} The three-layer structure of these blue capsules is complex because itraconazole is insoluble and is sensitive to pH. The complicated procedure not only requires a specialized machine to create it, but also the method used has manufacturing problems. Also, the pill is quite large, making it difficult for many patients to swallow. Parts of the processes of creating Sporanox were discovered by the Korean Patent Laid-open No. 10-2001-2590.<ref name = "Patent">{{cite patent | country = US | number = 20050226924 | url = https://patents.google.com/patent/US20050226924 | title = Composition comprising Itraconazole for oral administration | inventor = Lee KH, Park ES, Chi SC | assign1 = FDL Inc | pubdate = 13 October 2005 | postscript = . }}</ref> The tiny blue pellets contained in the capsule are manufactured in [[Beerse, Belgium]].<ref name = "Patent" /><ref name="sporanoxdotcom">{{cite web | url = http://www.sporanox.com/active/janus/en_US/assets/common/company/pi/sporanox.pdf | title = Sporanox (Itraconazole Capsules) | archive-url = https://web.archive.org/web/20080705033545/http://www.sporanox.com/active/janus/en_US/assets/common/company/pi/sporanox.pdf | archive-date=5 July 2008 | date = June 2006 | work = Janssen }}</ref>

The oral solution is better absorbed. The [[cyclodextrin]] contained in the oral solution can cause an [[Diarrhea#Osmotic|osmotic diarrhea]], and if this is a problem, then half the dose can be given as oral solution and half as capsule to reduce the amount of cyclodextrin given.{{cn|date=July 2021}} "Sporanox" itraconazole capsules should always be taken with food, as this improves absorption, however the manufacturers of "Lozanoc" assert that it may be taken "without regard to meals".<ref name="urlMayne Pharma: SUBA Bioavailability Technology">{{cite web | url = http://maynepharma.com/drug-delivery/suba-bioavailability-technology/suba-bioavailability-technology | title = SUBA Bioavailability Technology | publisher = Mayne Pharma Group }}</ref> Itraconazole oral solution should be taken an hour before food, or two hours after food (and likewise if a combination of capsules and oral solution are used). Itraconazole may be taken with orange juice or [[cola]], as absorption is also improved by acid. Absorption of itraconazole is impaired when taken with an antacid, [[H2 antagonist|H₂ blocker]] or [[proton pump inhibitor]].{{citation needed|date=November 2011}}

==Side effects==

Itraconazole is a relatively well-tolerated drug (although not as well tolerated as [[fluconazole]] or [[voriconazole]]) and the range of adverse effects it produces is similar to the other azole antifungals:<ref name="FDA">{{cite web | title=The Safety of Sporanox Capsules and Lamisil Tablets for the Treatment of Onychomycosis | url=https://www.fda.gov/CDER/drug/advisory/sporanox-lamisil/advisory.htm | publisher=FDA Public Health Advisory | date=9 May 2001 | access-date=10 August 2006 | archive-url = https://web.archive.org/web/20090528160344/https://www.fda.gov/cder/drug/advisory/sporanox-lamisil/advisory.htm | archive-date=28 May 2009}}</ref>

* elevated [[alanine aminotransferase]] levels are found in 4% of people taking itraconazole

* "small but real risk" of developing [[congestive heart failure]]<ref name="FDA"/>

* liver failure, sometimes fatal

The [[cyclodextrin]] used to make the syrup preparation can cause diarrhea. Side effects that may indicate a greater problem include:{{cn|date=December 2022}}

{{div col|colwidth=18em}}

* [[nausea]]

* [[vomiting]]

* abdominal pain

* [[Fatigue (physical)|fatigue]]

* [[loss of appetite]]

* yellow skin ([[jaundice]])

* yellow eyes

* [[itching]]

* dark [[urine]]

* pale stool

* headache

{{div col end}}

==Interactions==

The following drugs should not be taken with itraconazole:<ref name="urlSporanox (Itraconazole) Capsules">{{cite web | url = https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm303524.htm | title = Sporanox (Itraconazole) Capsules | work = Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research | publisher = U.S. [[Food and Drug Administration]] (FDA) | access-date = 16 December 2019 | archive-date = 26 October 2016 | archive-url = https://web.archive.org/web/20161026050954/http://www.fda.gov/safety/medwatch/safetyinformation/ucm303524.htm | url-status = dead }}</ref>

{{div col|colwidth=22em}}

* [[amiodarone]] (Cordarone);<ref name="urlCardiac arrest provoked by itraconazole and amiodarone interaction: a case report">{{cite journal | vauthors = Tsimogianni AM, Andrianakis I, Betrosian A, Douzinas E | title = Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report | journal = Journal of Medical Case Reports | volume = 5 | pages = 333 | date = July 2011 | pmid = 21801420 | pmc = 3161953 | doi = 10.1186/1752-1947-5-333 | doi-access = free }}</ref>

* [[cisapride]]

* [[dofetilide]]

* [[nisoldipine]]

* [[Alcohol (chemistry)|alcohol]]

* [[pimozide]]

* [[quinidine]]

* [[lurasidone]]

* [[lovastatin]] or [[simvastatin]]

* [[midazolam]] or [[triazolam]]

* [[ergot]] medicines such as

** [[dihydroergotamine]]

** [[ergometrine]]

** [[ergotamine]]

** [[methylergonovine]]

{{div col end}}

===Pharmacodynamics===

The mechanism of action of itraconazole is the same as the other [[azole]] antifungals: it inhibits the fungal-mediated synthesis of [[ergosterol]], via inhibition of [[Lanosterol 14 alpha-demethylase|lanosterol 14α-demethylase]]. Because of its ability to inhibit [[CYP3A4|cytochrome P450 3A4]] CC-3, caution should be used when considering interactions with other medications.<ref>{{cite book | vauthors = Trevor AJ, Katzung BG, Kruidering-Hall M |title=Katzung & Trevor's Pharmacology: Examination & Board Review |date=2015 |publisher=McGraw Hill Medical |location=New York |isbn=978-0-07-182635-8 |edition=Eleventh |pages=397}}</ref>

Itraconazole is pharmacologically distinct from other [[azole]] antifungal agents in that it is the only inhibitor in this class that has been shown to inhibit both the [[hedgehog signaling pathway]]<ref>{{cite journal |vauthors=Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, Stevens DA, Beachy PA | title = Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth | journal = Cancer Cell | volume = 17 | issue = 4 | pages = 388–99 | year = 2010 | pmid = 20385363 | doi = 10.1016/j.ccr.2010.02.027 | pmc = 4039177 }}</ref><ref name="Kim, Aftab">{{cite journal |vauthors=Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, Kim J, Chen B, King EM, Borodovsky A, Riggins GJ, Epstein EH, Beachy PA, Rudin CM | title = Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists | journal = Cancer Cell | volume = 23 | issue = 1 | pages = 23–34 | year = 2013 | pmid = 23291299 | pmc = 3548977 | doi = 10.1016/j.ccr.2012.11.017 }}</ref> and [[angiogenesis]].<ref name="Chong">{{cite journal |vauthors=Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Liu JO | title = Inhibition of Angiogenesis by the Antifungal Drug Itraconazole | journal = ACS Chemical Biology | volume = 2 | issue = 4 | pages = 263–70 | year = 2007 | pmid = 17432820 | doi = 10.1021/cb600362d }}</ref><ref name="Aftab">{{cite journal |vauthors=Aftab BT, Dobromilskaya I, Liu JO, Rudin CM | title = Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer | journal = Cancer Research | volume = 71 | issue = 21 | pages = 6764–72 | year = 2011 | pmid = 21896639 | pmc = 3206167 | doi = 10.1158/0008-5472.CAN-11-0691 }}</ref> These distinct activities are unrelated to inhibition of the [[cytochrome P450]] [[lanosterol 14 alpha-demethylase]] and the exact molecular targets responsible remain unidentified. Functionally, the antiangiogenic activity of itraconazole has been shown to be linked to inhibition of glycosylation, [[VEGFR]]2 phosphorylation,<ref name="Aftab" /> trafficking,<ref>{{cite journal |vauthors=Xu J, Dang Y, Ren YR, Liu JO | title = Cholesterol trafficking is required for mTOR activation in endothelial cells | journal = Proceedings of the National Academy of Sciences | volume = 107 | issue = 10 | pages = 4764–9 | year = 2010 | pmid = 20176935 | pmc = 2842052 | doi = 10.1073/pnas.0910872107 | bibcode = 2010PNAS..107.4764X | doi-access = free }}</ref> and cholesterol biosynthesis pathways.<ref name="Chong" /> Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity.<ref>{{cite journal |vauthors=Shi W, Nacev BA, Aftab BT, Head S, Rudin CM, Liu JO | title = Itraconazole Side Chain Analogues: Structure–Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling | journal = Journal of Medicinal Chemistry | volume = 54 | issue = 20 | pages = 7363–74 | year = 2011 | pmid = 21936514 | pmc = 3307530 | doi = 10.1021/jm200944b }}</ref>

===Pharmacokinetics===

Itraconazole, like [[cyclosporine]], [[quinidine]], and [[clarithromycin]], can inhibit [[P-glycoprotein]], causing [[drug interaction]]s by reducing elimination and increasing absorption of organic cation drugs. With conventional itraconazole preparations serum levels can vary greatly between patients, often resulting in serum concentrations lower than the therapeutic index.<ref name="pmid8878612">{{cite journal |vauthors=Patterson TF, Peters J, Levine SM, Anzueto A, Bryan CL, Sako EY, Miller OL, Calhoon JH, Rinaldi MG | title = Systemic availability of itraconazole in lung transplantation | journal = Antimicrob. Agents Chemother. | volume = 40 | issue = 9 | pages = 2217–20 | year = 1996 | pmid = 8878612 | pmc = 163504 | doi = 10.1128/AAC.40.9.2217}}</ref> It has therefore been conventionally advised that patients take itraconazole after a fatty meal rather than prior to eating.<ref name="pmid9477653">{{cite journal |vauthors=Fraga Fuentes MD, García Díaz B, de Juana Velasco P, Bermejo Vicedo MT | title = [Influence of foods on the absorption of antimicrobial agents] | language = es| journal = Nutr Hosp | volume = 12 | issue = 6 | pages = 277–88 | year = 1997 | pmid = 9477653 }}</ref><ref name="pmid8388198">{{cite journal |vauthors=Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V | title = Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers | journal = Antimicrob. Agents Chemother. | volume = 37 | issue = 4 | pages = 778–84 | year = 1993 | pmid = 8388198 | pmc = 187759 | doi = 10.1128/aac.37.4.778}}</ref>

A product (Lozanoc) licensed through the European union decentralised procedure<ref name="urlwww.mhra.gov.uk">{{cite web | url = http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con249676.pdf | title = Lozanoc 50 Mg Hard Capsules (Itraconazole) | work = Public Assessment Report Decentralised Procedure | publisher = UK Medicines and Health Care Products Regulatory Agency }}</ref> has increased [[bioavailability]], decreased sensitivity to co ingestion of food, and hence decreased variability of serum levels.

==Chemistry==

[[File:Itraconazole chiral carbons.svg|thumb|right|300px|Chiral centers are marked by asterisks]]

The itraconazole molecule has three [[Asymmetric carbon|chiral carbon]]s. The two chiral centers in the dioxolane ring are fixed in relation to one another, and the triazolomethylene and aryloxymethylene dioxolane-ring substituents are always [[Cis–trans isomerism|''cis'']] to each other. The clinical formulation is a 1:1:1:1 mixture of four stereoisomers (two enantiomeric pairs).<ref>{{cite journal | vauthors = Kunze KL, Nelson WL, Kharasch ED, Thummel KE, Isoherranen N | title = Stereochemical aspects of itraconazole metabolism in vitro and in vivo | journal = Drug Metabolism and Disposition | volume = 34 | issue = 4 | pages = 583–590 | date = April 2006 | pmid = 16415110 | doi = 10.1124/dmd.105.008508 | s2cid = 189994 }}</ref><ref>{{cite web|title=Itraconazole on Drugs.com|url=https://www.drugs.com/pro/itraconazole.html|website=Drugs.com|access-date=28 August 2016}}</ref>

[[File:Itraconazole enantiomers.svg|thumb|right|300px|Four diastereomers of itraconazole]]

== History ==

Itraconazole was approved for medical use in the United States in 1992.<ref>{{cite web | title=Itraconazole: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020083 | access-date=15 May 2020}}</ref>

It was designated an [[orphan drug]] by both the US [[Food and Drug Administration]] (FDA) and the [[European Medicines Agency]] (EMA).<ref>{{cite web | title=Itraconazole Orphan Drug Designation | website=U.S. [[Food and Drug Administration]] (FDA) | date=19 May 2016 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=473715 | access-date=15 May 2020}}</ref><ref>{{cite web | title=Itraconazole Orphan Drug Designation | website=U.S. [[Food and Drug Administration]] (FDA) | date=16 August 2016 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=509515 | access-date=15 May 2020}}</ref><ref>{{cite web | title=Itraconazole Orphan Drug Designation | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 October 2008 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=257308 | access-date=15 May 2020}}</ref><ref>{{cite web | title=EU/3/17/1901 | website=[[European Medicines Agency]] (EMA) | date=23 August 2017 | url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3171901 | access-date=15 May 2020}}</ref><ref>{{cite web | title=EU/3/18/2024 | website=[[European Medicines Agency]] (EMA) | date=25 May 2018 | url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3182024 | access-date=15 May 2020}}</ref>

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==References==

{{Reflist}}

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