Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth or intravenously.
Common side effects include nausea, diarrhea, abdominal pain, rash, and headache. Severe side effects may include liver problems, heart failure, Stevens–Johnson syndrome and allergic reactions including anaphylaxis. It is unclear if use during pregnancy or breastfeeding is safe.[1] It is in the triazole family of medications. It stops fungal growth by affecting the cell membrane or affecting their metabolism.
Itraconazole was patented in 1978 and approved for medical use in the United States in 1992.[6][7] It is on the World Health Organization's List of Essential Medicines.[8]
Recent research works suggest itraconazole (ITZ) could also be used in the treatment of cancer by inhibiting the hedgehog pathway[9] 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.[10] According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis".[11]
It is also prescribed for systemic infections, such as aspergillosis, candidiasis, and cryptococcosis, where other antifungal drugs are inappropriate or ineffective.
Itraconazole has been explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, glioblastoma and prostate cancer
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:[22]
The cyclodextrin used to make the syrup preparation can cause diarrhea. Side effects that may indicate a greater problem include:
- elevated alanine aminotransferase levels are found in 4% of people taking itraconazole
- "small but real risk" of developing congestive heart failure[22]
- liver failure, sometimes fatal
- nausea
- vomiting
- abdominal pain
Interactions
The following drugs should not be taken with itraconazole:[23]
- amiodarone (Cordarone);[24]
- cisapride
- dofetilide
- nisoldipine
- alcohol
- pimozide
- quinidine
- lurasidone
- lovastatin or simvastatin
- midazolam or triazolam
- ergot medicines such as
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.[25]
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[26][27] and angiogenesis.[28][29]
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).[36][37]
History
Itraconazole was approved for medical use in the United States in 1992.[38]
It was designated an orphan drug by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).[39][40][41][42][43]
External links
References
- Itraconazole Use During Pregnancy Drugs.com, 20 March 2019, retrieved 15 May 2020^
- Sporanox 10 mg/mL Oral Solution - Summary of Product Characteristics (SmPC) (emc), 1 February 2018, retrieved 15 May 2020^
- Role of itraconazole metabolites in CYP3A4 inhibition Drug Metabolism and Disposition, October 2004^