Itraconazole: Difference between revisions

Itraconazole
Clinical data
Trade names	Sporanox, Sporaz, Orungal, others
Other names	ITZ
AHFS/Drugs.com	Monograph
MedlinePlus	a692049
License data	US DailyMed: Itraconazole;
Pregnancy; category	AU: B3; ;
Routes of; administration	By mouth, solution), vaginal suppository, intravenous
ATC code	J02AC02 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: WARNINGRx-only;
Pharmacokinetic data
Bioavailability	~55%, maximal if taken with full meal
Protein binding	99.8%
Metabolism	Extensive in liver (CYP3A4)
Metabolites	Hydroxy-itraconazole, keto-itraconazole,; N-desalkyl-itraconazole
Elimination half-life	21 hours
Excretion	Kidney (35%), faeces (54%)
Identifiers
	IUPAC name (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-rel-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one;
CAS Number	84625-61-6 ;
PubChem CID	55283;
DrugBank	DB01167 ;
ChemSpider	49927 ;
UNII	304NUG5GF4;
KEGG	D00350 ;
ChEBI	CHEBI:6076 ;
ChEMBL	ChEMBL22587 ;
CompTox Dashboard (EPA)	DTXSID3023180 ;
ECHA InfoCard	100.123.596
Chemical and physical data
Formula	C35H38Cl2N8O4
Molar mass	705.64 g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
Melting point	165 °C (329 °F)
Solubility in water	7.8 ± 0.4 × 10−6 mol/L (pH 1.6) mg/mL (20 °C)
	SMILES O=C1N(/N=C\N1c2ccc(cc2)N7CCN(c6ccc(OC[C@@H]3O[C@](OC3)(c4ccc(Cl)cc4Cl)Cn5ncnc5)cc6)CC7)C(C)CC;
	InChI InChI=1S/C35H38Cl2N8O4/c1-3-25(2)45-34(46)44(24-40-45)29-7-5-27(6-8-29)41-14-16-42(17-15-41)28-9-11-30(12-10-28)47-19-31-20-48-35(49-31,21-43-23-38-22-39-43)32-13-4-26(36)18-33(32)37/h4-13,18,22-25,31H,3,14-17,19-21H2,1-2H3/t25?,31-,35-/m0/s1 ; Key:VHVPQPYKVGDNFY-ZPGVKDDISA-N ;
	(verify)

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Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections.^[7] This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis.^[7] It may be given by mouth or intravenously.^[7]

Common side effects include nausea, diarrhea, abdominal pain, rash, and headache.^[7] Severe side effects may include liver problems, heart failure, Stevens–Johnson syndrome and allergic reactions including anaphylaxis.^[7] It is unclear if use during pregnancy or breastfeeding is safe.^[1] It is in the triazole family of medications.^[7] It stops fungal growth by affecting the cell membrane or affecting their metabolism.^[7]

Itraconazole was patented in 1978 and approved for medical use in the United States in 1992.^[7]^[8] It is on the World Health Organization's List of Essential Medicines.^[9]

Recent research works suggest itraconazole (ITZ) could also be used in the treatment of cancer by inhibiting the hedgehog pathway^[10] in a similar way to sonidegib.

Medical uses

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.^[11] According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis".^[12]

It is also prescribed for systemic infections, such as aspergillosis, candidiasis, and cryptococcosis, where other antifungal drugs are inappropriate or ineffective.^{[citation needed]}

Itraconazole has been explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer.^[13] For example, in a phase II study involving men with advanced prostate cancer, high-dose itraconazole (600 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.^[14]^[15]^[16] 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.^[17]

Available forms

Itraconazole is produced as blue 22 mm (0.87 in) capsules with tiny 1.5 mm (0.059 in) blue pellets inside. Each capsule contains 100 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.^{[citation needed]} 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.^[18] The tiny blue pellets contained in the capsule are manufactured in Beerse, Belgium.^[18]^[19]

The oral solution is better absorbed. The cyclodextrin contained in the oral solution can cause an 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.^{[citation needed]} "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".^[20] 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 blocker or proton pump inhibitor.^{[citation needed]}

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:^[21]

elevated alanine aminotransferase levels are found in 4% of people taking itraconazole
"small but real risk" of developing congestive heart failure^[21]
liver failure, sometimes fatal

The cyclodextrin used to make the syrup preparation can cause diarrhea. Side effects that may indicate a greater problem include:^{[citation needed]}

nausea
vomiting
abdominal pain
fatigue
loss of appetite
yellow skin (jaundice)
yellow eyes
itching
dark urine
pale stool
headache

Interactions

The following drugs should not be taken with itraconazole:^[22]

Pharmacology

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 14α-demethylase. Because of its ability to inhibit cytochrome P450 3A4 CC-3, caution should be used when considering interactions with other medications.^[24]

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^[25]^[26] and angiogenesis.^[27]^[28] 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, VEGFR2 phosphorylation,^[28] trafficking,^[29] and cholesterol biosynthesis pathways.^[27] Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity.^[30]

Pharmacokinetics

Itraconazole, like cyclosporine, quinidine, and clarithromycin, can inhibit P-glycoprotein, causing drug interactions 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.^[31] It has therefore been conventionally advised that patients take itraconazole after a fatty meal rather than prior to eating.^[32]^[33]

A product (Lozanoc) licensed through the European union decentralised procedure^[34] has increased bioavailability, decreased sensitivity to co ingestion of food, and hence decreased variability of serum levels.

Chemistry

The itraconazole molecule has three chiral carbons. 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 to each other. The clinical formulation is a 1:1:1:1 mixture of four stereoisomers (two enantiomeric pairs).^[35]^[36]

History

Itraconazole was approved for medical use in the United States in 1992.^[37]

It was designated an orphan drug by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).^[38]^[39]^[40]^[41]^[42]

References

^ ^a ^b "Itraconazole Use During Pregnancy". Drugs.com. 20 March 2019. Retrieved 15 May 2020.
^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
^ "Sporanox 10 mg/mL Oral Solution - Summary of Product Characteristics (SmPC)". (emc). 1 February 2018. Retrieved 15 May 2020.
^ Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE (October 2004). "Role of itraconazole metabolites in CYP3A4 inhibition". Drug Metabolism and Disposition. 32 (10): 1121–1131. doi:10.1124/dmd.104.000315. PMID 15242978. S2CID 6941636.
^ "Sporanox (itraconazole) Capsules. Full Prescribing Information" (PDF). Janssen Pharmaceuticals, Inc. Archived from the original (PDF) on 17 May 2018. Retrieved 28 August 2016.
^ ^a ^b Vasilev NA, Surov AO, Voronin AP, Drozd KV, Perlovich GL (April 2021). "Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility". International Journal of Pharmaceutics. 599: 120441. doi:10.1016/j.ijpharm.2021.120441. PMID 33675927. S2CID 232135660.
^ ^a ^b ^c ^d ^e ^f ^g ^h "Itraconazole". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 503. ISBN 9783527607495.
^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ Li K, Fang D, Xiong Z, Luo R (2019). "Inhibition of the hedgehog pathway for the treatment of cancer using Itraconazole". OncoTargets and Therapy. 12: 6875–6886. doi:10.2147/OTT.S223119. PMC 6711563. PMID 31692536.
^ Gilbert DN, Moellering, RC, Eliopoulos GM, Sande MA (2006). The Sanford Guide to antimicrobial therapy. Antimicrobial Therapy, Incorporated. ISBN 978-1-930808-30-0.^{[page needed]}
^ Pham P, Bartlett JG (24 July 2007). "Itraconazole". Johns Hopkins. Archived from the original on 28 November 2007.
^ "Search results for Itraconazole". ClinicalTrials.gov. U.S. National Institutes of Health.
^ Aftab BT, Dobromilskaya I, Liu JO, Rudin CM (2011). "Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer". Cancer Research. 71 (21): 6764–6772. doi:10.1158/0008-5472.CAN-11-0691. PMC 3206167. PMID 21896639.
^ 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 (2013). "Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer". The Oncologist. 18 (2): 163–173. doi:10.1634/theoncologist.2012-314. PMC 3579600. PMID 23340005.
^ Rudin CM, Brahmer JR, Juergens RA, Hann CL, Ettinger DS, Sebree R, Smith R, Aftab BT, Huang P, Liu JO (May 2013). "Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer". Journal of Thoracic Oncology. 8 (5): 619–623. doi:10.1097/JTO.0b013e31828c3950. PMC 3636564. PMID 23546045.
^ Ip KH, McKerrow K (2021). "Itraconazole in the treatment of basal cell carcinoma: A case-based review of the literature". Australasian Journal of Dermatology. 62 (3): 394–397. doi:10.1111/ajd.13655. PMID 34160824. S2CID 235608763.
^ ^a ^b US 20050226924, Lee KH, Park ES, Chi SC, "Composition comprising Itraconazole for oral administration", published 13 October 2005, assigned to FDL Inc.
^ "Sporanox (Itraconazole Capsules)" (PDF). Janssen. June 2006. Archived from the original (PDF) on 5 July 2008.
^ "SUBA Bioavailability Technology". Mayne Pharma Group.
^ ^a ^b "The Safety of Sporanox Capsules and Lamisil Tablets for the Treatment of Onychomycosis". FDA Public Health Advisory. 9 May 2001. Archived from the original on 28 May 2009. Retrieved 10 August 2006.
^ "Sporanox (Itraconazole) Capsules". Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research. U.S. Food and Drug Administration (FDA). Archived from the original on 26 October 2016. Retrieved 16 December 2019.
^ Tsimogianni AM, Andrianakis I, Betrosian A, Douzinas E (July 2011). "Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report". Journal of Medical Case Reports. 5: 333. doi:10.1186/1752-1947-5-333. PMC 3161953. PMID 21801420.
^ Trevor AJ, Katzung BG, Kruidering-Hall M (2015). Katzung & Trevor's Pharmacology: Examination & Board Review (Eleventh ed.). New York: McGraw Hill Medical. p. 397. ISBN 978-0-07-182635-8.
^ 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 (2010). "Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth". Cancer Cell. 17 (4): 388–99. doi:10.1016/j.ccr.2010.02.027. PMC 4039177. PMID 20385363.
^ 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 (2013). "Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists". Cancer Cell. 23 (1): 23–34. doi:10.1016/j.ccr.2012.11.017. PMC 3548977. PMID 23291299.
^ ^a ^b Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Liu JO (2007). "Inhibition of Angiogenesis by the Antifungal Drug Itraconazole". ACS Chemical Biology. 2 (4): 263–70. doi:10.1021/cb600362d. PMID 17432820.
^ ^a ^b Aftab BT, Dobromilskaya I, Liu JO, Rudin CM (2011). "Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer". Cancer Research. 71 (21): 6764–72. doi:10.1158/0008-5472.CAN-11-0691. PMC 3206167. PMID 21896639.
^ Xu J, Dang Y, Ren YR, Liu JO (2010). "Cholesterol trafficking is required for mTOR activation in endothelial cells". Proceedings of the National Academy of Sciences. 107 (10): 4764–9. Bibcode:2010PNAS..107.4764X. doi:10.1073/pnas.0910872107. PMC 2842052. PMID 20176935.
^ Shi W, Nacev BA, Aftab BT, Head S, Rudin CM, Liu JO (2011). "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 of Medicinal Chemistry. 54 (20): 7363–74. doi:10.1021/jm200944b. PMC 3307530. PMID 21936514.
^ Patterson TF, Peters J, Levine SM, Anzueto A, Bryan CL, Sako EY, Miller OL, Calhoon JH, Rinaldi MG (1996). "Systemic availability of itraconazole in lung transplantation". Antimicrob. Agents Chemother. 40 (9): 2217–20. doi:10.1128/AAC.40.9.2217. PMC 163504. PMID 8878612.
^ Fraga Fuentes MD, García Díaz B, de Juana Velasco P, Bermejo Vicedo MT (1997). "[Influence of foods on the absorption of antimicrobial agents]". Nutr Hosp (in Spanish). 12 (6): 277–88. PMID 9477653.
^ Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V (1993). "Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers". Antimicrob. Agents Chemother. 37 (4): 778–84. doi:10.1128/aac.37.4.778. PMC 187759. PMID 8388198.
^ "Lozanoc 50 Mg Hard Capsules (Itraconazole)" (PDF). Public Assessment Report Decentralised Procedure. UK Medicines and Health Care Products Regulatory Agency.
^ Kunze KL, Nelson WL, Kharasch ED, Thummel KE, Isoherranen N (April 2006). "Stereochemical aspects of itraconazole metabolism in vitro and in vivo". Drug Metabolism and Disposition. 34 (4): 583–590. doi:10.1124/dmd.105.008508. PMID 16415110. S2CID 189994.
^ "Itraconazole on Drugs.com". Drugs.com. Retrieved 28 August 2016.
^ "Itraconazole: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 15 May 2020.
^ "Itraconazole Orphan Drug Designation". U.S. Food and Drug Administration (FDA). 19 May 2016. Retrieved 15 May 2020.
^ "Itraconazole Orphan Drug Designation". U.S. Food and Drug Administration (FDA). 16 August 2016. Retrieved 15 May 2020.
^ "Itraconazole Orphan Drug Designation". U.S. Food and Drug Administration (FDA). 30 October 2008. Retrieved 15 May 2020.
^ "EU/3/17/1901". European Medicines Agency (EMA). 23 August 2017. Retrieved 15 May 2020.
^ "EU/3/18/2024". European Medicines Agency (EMA). 25 May 2018. Retrieved 15 May 2020.

External links

Media related to Itraconazole at Wikimedia Commons

[Drugs.com_pregnancy-1] "Itraconazole Use During Pregnancy". Drugs.com. 20 March 2019. Retrieved 15 May 2020.

[FDA-AllBoxedWarnings-2] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.

[3] "Sporanox 10 mg/mL Oral Solution - Summary of Product Characteristics (SmPC)". (emc). 1 February 2018. Retrieved 15 May 2020.

[4] Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE (October 2004). "Role of itraconazole metabolites in CYP3A4 inhibition". Drug Metabolism and Disposition. 32 (10): 1121–1131. doi:10.1124/dmd.104.000315. PMID 15242978. S2CID 6941636.

[Sporanox_PI-5] "Sporanox (itraconazole) Capsules. Full Prescribing Information" (PDF). Janssen Pharmaceuticals, Inc. Archived from the original (PDF) on 17 May 2018. Retrieved 28 August 2016.

[NikitaVas-6] Vasilev NA, Surov AO, Voronin AP, Drozd KV, Perlovich GL (April 2021). "Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility". International Journal of Pharmaceutics. 599: 120441. doi:10.1016/j.ijpharm.2021.120441. PMID 33675927. S2CID 232135660.

[AHFS2017-7] ^ ^a ^b ^c ^d ^e ^f ^g ^h "Itraconazole". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.

[Fis2006-8] Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 503. ISBN 9783527607495.

[WHO21st-9] World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.

[LiFang2019-10] Li K, Fang D, Xiong Z, Luo R (2019). "Inhibition of the hedgehog pathway for the treatment of cancer using Itraconazole". OncoTargets and Therapy. 12: 6875–6886. doi:10.2147/OTT.S223119. PMC 6711563. PMID 31692536.

[Sanford-11] Gilbert DN, Moellering, RC, Eliopoulos GM, Sande MA (2006). The Sanford Guide to antimicrobial therapy. Antimicrobial Therapy, Incorporated. ISBN 978-1-930808-30-0.^{[page needed]}

[12] Pham P, Bartlett JG (24 July 2007). "Itraconazole". Johns Hopkins. Archived from the original on 28 November 2007.

[13] "Search results for Itraconazole". ClinicalTrials.gov. U.S. National Institutes of Health.

[14] Aftab BT, Dobromilskaya I, Liu JO, Rudin CM (2011). "Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer". Cancer Research. 71 (21): 6764–6772. doi:10.1158/0008-5472.CAN-11-0691. PMC 3206167. PMID 21896639.

[15] 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 (2013). "Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer". The Oncologist. 18 (2): 163–173. doi:10.1634/theoncologist.2012-314. PMC 3579600. PMID 23340005.

[16] Rudin CM, Brahmer JR, Juergens RA, Hann CL, Ettinger DS, Sebree R, Smith R, Aftab BT, Huang P, Liu JO (May 2013). "Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer". Journal of Thoracic Oncology. 8 (5): 619–623. doi:10.1097/JTO.0b013e31828c3950. PMC 3636564. PMID 23546045.

[17] Ip KH, McKerrow K (2021). "Itraconazole in the treatment of basal cell carcinoma: A case-based review of the literature". Australasian Journal of Dermatology. 62 (3): 394–397. doi:10.1111/ajd.13655. PMID 34160824. S2CID 235608763.

[Patent-18] US 20050226924, Lee KH, Park ES, Chi SC, "Composition comprising Itraconazole for oral administration", published 13 October 2005, assigned to FDL Inc.

[sporanoxdotcom-19] "Sporanox (Itraconazole Capsules)" (PDF). Janssen. June 2006. Archived from the original (PDF) on 5 July 2008.

[urlMayne_Pharma:_SUBA_Bioavailability_Technology-20] "SUBA Bioavailability Technology". Mayne Pharma Group.

[FDA-21] "The Safety of Sporanox Capsules and Lamisil Tablets for the Treatment of Onychomycosis". FDA Public Health Advisory. 9 May 2001. Archived from the original on 28 May 2009. Retrieved 10 August 2006.

[urlSporanox_(Itraconazole)_Capsules-22] "Sporanox (Itraconazole) Capsules". Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research. U.S. Food and Drug Administration (FDA). Archived from the original on 26 October 2016. Retrieved 16 December 2019.

[urlCardiac_arrest_provoked_by_itraconazole_and_amiodarone_interaction:_a_case_report-23] Tsimogianni AM, Andrianakis I, Betrosian A, Douzinas E (July 2011). "Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report". Journal of Medical Case Reports. 5: 333. doi:10.1186/1752-1947-5-333. PMC 3161953. PMID 21801420.

[24] Trevor AJ, Katzung BG, Kruidering-Hall M (2015). Katzung & Trevor's Pharmacology: Examination & Board Review (Eleventh ed.). New York: McGraw Hill Medical. p. 397. ISBN 978-0-07-182635-8.

[25] 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 (2010). "Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth". Cancer Cell. 17 (4): 388–99. doi:10.1016/j.ccr.2010.02.027. PMC 4039177. PMID 20385363.

[Kim,_Aftab-26] 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 (2013). "Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists". Cancer Cell. 23 (1): 23–34. doi:10.1016/j.ccr.2012.11.017. PMC 3548977. PMID 23291299.

[Chong-27] Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Liu JO (2007). "Inhibition of Angiogenesis by the Antifungal Drug Itraconazole". ACS Chemical Biology. 2 (4): 263–70. doi:10.1021/cb600362d. PMID 17432820.

[Aftab-28] Aftab BT, Dobromilskaya I, Liu JO, Rudin CM (2011). "Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer". Cancer Research. 71 (21): 6764–72. doi:10.1158/0008-5472.CAN-11-0691. PMC 3206167. PMID 21896639.

[29] Xu J, Dang Y, Ren YR, Liu JO (2010). "Cholesterol trafficking is required for mTOR activation in endothelial cells". Proceedings of the National Academy of Sciences. 107 (10): 4764–9. Bibcode:2010PNAS..107.4764X. doi:10.1073/pnas.0910872107. PMC 2842052. PMID 20176935.

[30] Shi W, Nacev BA, Aftab BT, Head S, Rudin CM, Liu JO (2011). "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 of Medicinal Chemistry. 54 (20): 7363–74. doi:10.1021/jm200944b. PMC 3307530. PMID 21936514.

[pmid8878612-31] Patterson TF, Peters J, Levine SM, Anzueto A, Bryan CL, Sako EY, Miller OL, Calhoon JH, Rinaldi MG (1996). "Systemic availability of itraconazole in lung transplantation". Antimicrob. Agents Chemother. 40 (9): 2217–20. doi:10.1128/AAC.40.9.2217. PMC 163504. PMID 8878612.

[pmid9477653-32] Fraga Fuentes MD, García Díaz B, de Juana Velasco P, Bermejo Vicedo MT (1997). "[Influence of foods on the absorption of antimicrobial agents]". Nutr Hosp (in Spanish). 12 (6): 277–88. PMID 9477653.

[pmid8388198-33] Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V (1993). "Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers". Antimicrob. Agents Chemother. 37 (4): 778–84. doi:10.1128/aac.37.4.778. PMC 187759. PMID 8388198.

[urlwww.mhra.gov.uk-34] "Lozanoc 50 Mg Hard Capsules (Itraconazole)" (PDF). Public Assessment Report Decentralised Procedure. UK Medicines and Health Care Products Regulatory Agency.

[35] Kunze KL, Nelson WL, Kharasch ED, Thummel KE, Isoherranen N (April 2006). "Stereochemical aspects of itraconazole metabolism in vitro and in vivo". Drug Metabolism and Disposition. 34 (4): 583–590. doi:10.1124/dmd.105.008508. PMID 16415110. S2CID 189994.

[36] "Itraconazole on Drugs.com". Drugs.com. Retrieved 28 August 2016.

[37] "Itraconazole: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 15 May 2020.

[38] "Itraconazole Orphan Drug Designation". U.S. Food and Drug Administration (FDA). 19 May 2016. Retrieved 15 May 2020.

[39] "Itraconazole Orphan Drug Designation". U.S. Food and Drug Administration (FDA). 16 August 2016. Retrieved 15 May 2020.

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[20]

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@@ Line 1: / Line 1: @@
-{{short description|Chemical compound used as medication to treat fungal infections}}
+{{Short description|Medication used to treat fungal infections}}
+{{Use dmy dates|date=March 2024}}
 {{Drugbox
 | Watchedfields = changed
 | verifiedrevid = 459522522
-| 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]-Δ<sup>2</sup>-1,2,4-triazolin-5-one
 | image = Itraconazole.svg
 | width =
+| alt =
 | chirality = [[Racemic mixture]]
-<!--Clinical data-->
+<!-- Clinical data -->
 | tradename = Sporanox, Sporaz, Orungal, others
 | Drugs.com = {{drugs.com|monograph|itraconazole}}
@@ Line 15: / Line 16: @@
 | 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]]
-| pregnancy_US = C
+| ATC_prefix = J02
-| pregnancy_US_comment = <ref name="Drugs.com pregnancy" />
+| ATC_suffix = AC02
 | legal_AU = S4
 | legal_CA = Rx-only
 | legal_UK = POM
-| 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>
+| 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>
 | legal_US = Rx-only
-| routes_of_administration = [[Oral administration|By mouth]] ([[Capsule (pharmacy)|capsules]], [[Solution (chemistry)|solution]]), local ([[vaginal administration|vaginal]] [[suppository]]), [[Intravenous therapy|intravenous]] (IV)
-<!--Pharmacokinetic data-->
+<!-- Pharmacokinetic data -->
 | bioavailability = ~55%, maximal if taken with full meal
 | protein_bound = 99.8%
 | metabolism = Extensive in [[liver]] ([[CYP3A4]])
-| metabolites = Hydroxy-itraconazole, keto-itraconazole,<br />''N''-desalkyl-itraconazole<ref>{{cite journal|last1=Isoherranen|first1=N|last2=Kunze|first2=KL|last3=Allen|first3=KE|last4=Nelson|first4=WL|last5=Thummel|first5=KE|title=Role of Itraconazole Metabolites in CYP3A4 Inhibition|journal=Drug Metabolism and Disposition|date=October 2004|volume=32|issue=10|pages=1121–31|doi=10.1124/dmd.104.000315|pmid=15242978|s2cid=6941636}}</ref>
+| 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>
 | elimination_half-life = 21 hours
-| excretion = Urine (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}}</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>
 <!--Identifiers-->
 | CAS_number_Ref = {{cascite|correct|??}}
 | CAS_number = 84625-61-6
-| ATC_prefix = J02
-| ATC_suffix = AC02
 | PubChem = 55283
 | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
@@ Line 50: / Line 50: @@
 | ChEMBL_Ref = {{ebicite|correct|EBI}}
 | ChEMBL = 22587
-| synonyms =
+| synonyms = ITZ
 <!--Chemical data-->
+| 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]-Δ<sup>2</sup>-1,2,4-triazolin-5-one
 | C=35 | H=38 | Cl=2 | N=8 | O=4
-| molecular_weight = 705.64
 | smiles = O=C1N(/N=C\N1c2ccc(cc2)N7CCN(c6ccc(OC[C@@H]3O[C@](OC3)(c4ccc(Cl)cc4Cl)Cn5ncnc5)cc6)CC7)C(C)CC
 | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
@@ Line 60: / Line 60: @@
 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
 | StdInChIKey = VHVPQPYKVGDNFY-ZPGVKDDISA-N
+| 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<sup>−6</sup> 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/>
+'''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 -->
@@ Line 68: / Line 70: @@
 <!-- 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 |last1=Fischer |first1=Jnos |last2=Ganellin |first2=C. Robin |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>
+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|last1=Li|first1=Ke|last2=Fang|first2=Dengyang|last3=Xiong|first3=Zuming|last4=Luo|first4=Runlan|title=<p>Inhibition of the hedgehog pathway for the treatment of cancer using Itraconazole</p>|journal=OncoTargets and Therapy|volume=12|year=2019|pages=6875–6886|issn=1178-6930|doi=10.2147/OTT.S223119|pmid=31692536|pmc=6711563|doi-access=free}}</ref> in a similar way to [[Sonidegib]]
+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]].
 ==Medical uses==
-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 |author=Gilbert DN, Moellering, RC, Eliopoulos GM, Sande MA |title=The Sanford Guide to antimicrobial therapy |year=2006 |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 |last1=Pham |first1=P |last2=Bartlett |first2=JG |title=Itraconazole |publisher=Johns Hopkins |url=http://www.hopkins-abxguide.org/terminals/antibiotics_more.cfm?id=81&fc=p |date=2007-07-24 |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=2007-11-28 }}</ref>
+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.
+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}}
-In the past decade, 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 has 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>
+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">[http://www.freshpatents.com/Composition-comprising-itraconazole-for-oral-administration-dt20051013ptan20050226924.php Composition comprising Itraconazole for oral administration]. 2004. Fresh Patents.com. 26 October 2006.</ref> The tiny blue pellets contained in the capsule are manufactured in [[Beerse, Belgium]].<ref name = "Patent" /><ref name="sporanoxdotcom">[http://www.sporanox.com/active/janus/en_US/assets/common/company/pi/sporanox.pdf Sporanox (Itraconazole Capsules)] {{Webarchive|url=https://web.archive.org/web/20080705033545/http://www.sporanox.com/active/janus/en_US/assets/common/company/pi/sporanox.pdf |date=2008-07-05 }}. June 2006. Janssen. 26 October 2006</ref>
+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|H<sub>2</sub> 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=May 9, 2001 | access-date=2006-08-10 | archive-url = https://web.archive.org/web/20090528160344/https://www.fda.gov/cder/drug/advisory/sporanox-lamisil/advisory.htm | archive-date=2009-05-28}}</ref>
+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:
+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}}
@@ Line 108: / Line 109: @@
 ==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) }}{{dead link|date=May 2020}}</ref>
+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 web | url = http://www.jmedicalcasereports.com/content/5/1/333 | title = Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report}}</ref>
+* [[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]]
+* [[Alcohol (chemistry)|alcohol]]
 * [[pimozide]]
 * [[quinidine]]
@@ Line 121: / Line 122: @@
 * [[lovastatin]] or [[simvastatin]]
 * [[midazolam]] or [[triazolam]]
 * [[ergot]] medicines such as
 ** [[dihydroergotamine]]
 ** [[ergometrine]]
 ** [[ergotamine]]
 ** [[methylergonovine]]
@@ Line 131: / Line 132: @@
 ===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|title=Pharmacology Examination & Board Review|last=Katzung & Trevor's|publisher=McGraw Hill|year=2015|pages=397}}</ref>
+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>
@@ Line 138: / Line 139: @@
 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.
+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|last1=Kunze|first1=KL|last2=Nelson|first2=WL|last3=Kharasch|first3=ED|last4=Thummel|first4=KE|last5=Isoherranen|first5=N|title=Stereochemical Aspects of Itraconazole Metabolism ''in vitro'' and ''in vivo''|journal=Drug Metabolism and Disposition|date=April 2006|volume=34|issue=4|pages=583–90|doi=10.1124/dmd.105.008508|pmid=16415110|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>
+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]]
@@ Line 150: / Line 151: @@
 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 the both the U.S. [[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>
+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>
 {{clear right}}
@@ Line 159: / Line 160: @@
 ==External links==
 * {{commonscatinline}}
-* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/itraconazole | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Itraconazole }}
 {{Antifungals}}
@@ Line 165: / Line 165: @@
 {{Portal bar|Medicine}}
-[[Category:1,2,4-triazol-3-ones]]
+[[Category:1,2,4-Triazol-3-ones]]
 [[Category:Belgian inventions]]
 [[Category:Chloroarenes]]
+[[Category:CYP3A4 inhibitors]]
 [[Category:Dioxolanes]]
-[[Category:Johnson & Johnson brands]]
+[[Category:Drugs developed by Johnson & Johnson]]
 [[Category:Janssen Pharmaceutica]]
 [[Category:Lanosterol 14α-demethylase inhibitors]]
 [[Category:Orphan drugs]]
-[[Category:Para-Methoxyphenylpiperazines]]
+[[Category:Piperazines]]
 [[Category:Wikipedia medicine articles ready to translate]]
 [[Category:Triazole antifungals]]
 [[Category:World Health Organization essential medicines]]
+[[Category:Phenylethanolamine ethers]]
+[[Category:Sec-Butyl compounds]]

v t e Piperazines
Simple piperazines (no additional rings)	Aminoethylpiperazine Diethylcarbamazine HEPPS Midafotel Piperazine PIPES
Phenylpiperazines	2C-B-PP 3,4-CFP Acaprazine Antrafenine Aripiprazole Batoprazine Bifeprunox BRL-15,572 Ciprofloxacin CSP-2503 Dapiprazole DCPP DMPP Diphenylpiperazine Dropropizine EGIS-12,233 Elopiprazole Eltoprazine Enpiprazole Ensaculin Etoperidone Flesinoxan Fluanisone Flibanserin Fluprazine Itraconazole Ketoconazole Levodropropizine Lorpiprazole mCPP Mefway MeOPP Mepiprazole Naftopidil Naluzotan Naphthylpiperazine Nefazodone Niaprazine Oxypertine Pardoprunox pCPP pFPP Posaconazole S-14,506 S-14,671 S-15,535 SB-258,585 SB-271,046 SB-357,134 SB-399,885 Sonepiprazole TFMPP Tolpiprazole Trazodone Urapidil Vesnarinone Vilazodone Vortioxetine WAY-100,135 WAY-100,635
Benzylpiperazines	2C-B-BZP 3-Methylbenzylpiperazine Befuraline Bifeprunox Buclizine BZP Chlorbenzoxamine DBZP Fipexide Imatinib MBZP MDBZP Meclozine Methoxypiperamide NSI-189 Piberaline Piribedil RN-1747 Sunifiram Trimetazidine Vesnarinone
Diphenylalkylpiperazines (benzhydrylalkylpiperazines)	AD-1211 Almitrine Amperozide BRL-15,572 Buclizine BW373U86 Cetirizine Chlorbenzoxamine Chlorcyclizine Cinnarizine Clocinizine Cyclizine DBL-583 Diphenpipenol Diphenylmethylpiperazine Dotarizine DPI-221 DPI-287 DPI-3290 GBR-12,783 GBR-12,935 GBR-13,069 GBR-13,098 GBR-13,119 Hydroxyzine JJC8-088 Lidoflazine Manidipine Meclozine MT-45 Oxatomide SNC-80 Vanoxerine
Pyrimidinylpiperazines	Buspirone Dasatinib Eptapirone Gepirone Ipsapirone Piribedil Pyrimidinylpiperazine Revospirone Tandospirone Tirilazad Trimazosin Umespirone Zalospirone
Pyridinylpiperazines	Atevirdine Azaperone Delavirdine Mirtazapine ORG-12962 Pyridinylpiperazine
Benzo(iso)thiazolyl piperazines	Lurasidone Perospirone Revospirone Tiospirone Ziprasidone
Tricyclics (piperazine attached via side chain)	Amoxapine Clopenthixol Clorotepine Clozapine Cyanothepin Doclothepin Docloxythepin Flupentixol Fluphenazine Isofloxythepin Loxapine Meperathiepin Metitepine Octomethothepin Olanzapine Opipramol Oxyclothepin Oxyprothepin Peradithiepin Perathiepin Perazine Perphenazine Pirenzepine Prochlorperazine Thiethylperazine Thiothixene Trifluoperazine Trifluthepin Zuclopenthixol
Others/Uncategorized	6-Nitroquipazine AP-238 Azimilide Bucinnazine Cinepazet Cinepazic acid Cinepazide CPD-1 Cyclohexylpiperazine EGIS-7625 Hexocyclium Indinavir JNJ-7777120 Lodenafil MK-212 Mirodenafil PB-28 Quipazine Ranolazine SA-4503 Sildenafil Tadalafil Vardenafil VUF-6002 WY-46824 Zipeprol