Itraconazole

Itraconazole

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Systematic (IUPAC) name
(2R,4S)-rel-1-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2- (1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan- 4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one
Clinical data
Pregnancy category	C (safety unknown)
Routes of administration	Oral and i.v. (US), Oral only (UK)
Legal status
Legal status	FDA: Rx, UK: POM
Pharmacokinetic data
Bioavailability	55%, maximal if taken with full meal
Protein binding	99.8%
Metabolism	hepatic (CYP3A4)
Biological half-life	21 hours
Identifiers
CAS Number	84625-61-6
ATC code	J02AC02 (WHO)
PubChem	CID 55283
DrugBank	APRD00040
ChemSpider	49927
Chemical data
Formula	C35H38Cl2N8O4
Molar mass	705.64[[]]
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Itraconazole (marketed as Sporanox by Janssen Pharmaceutica), invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.

Pharmacology

The mechanism of action of itraconazole is the same as the other azole antifungals: it inhibits the fungal cytochrome P450 oxidase-mediated synthesis of ergosterol. Because of its ability to inhibit cytochrome P450 3A4 CC-3, caution should be used when considering interactions with other medications.

Indication

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 licenced for use in blastomycosis, histoplasmosis and onychomycosis. Itraconazole is over 99% protein bound and has virtually no penetration into cerebrospinal fluid. Therefore, it should never be used to treat meningitis or other central nervous system infections. According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis". It is also prescribed for systemic infections such as aspergillosis, candidiasis and cryptococcosis where other antifungal drugs are inappropriate or ineffective.

Dosing

Itraconazole is available as capsules or as an oral solution. The dose is 200 mg once a day, to 400 mg in severe infection. There is an intravenous preparation available in the US, but not in the UK. In the UK, if an intravenous preparation is required, then an alternative antifungal drug should be used.

Itraconazole has relatively low bioavailability after oral administration, especially when given in capsule form on an empty stomach. The capsule form is a molecular dispersion of itraconazole in amorphous HPMC polymer. The fast dissolving polymer targets a supersaturated solution of itraconazole from which enhanced absorption can be expected. Recently, it was evidenced that itraconazole contributes to the formation of nanofibers in certain simulated intestinal fluids. These nanofibers have a uniform width of 12 nm and a length up to several micrometers . 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. Itraconazole capsules should always be taken with food, as this improves absorption. 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.

Some doctors give an oral loading dose of 200 mg three times a day for three days, before dropping down to the usual dose. Because itraconazole absorption is unreliable, blood levels should be monitored at least once a week in those patients who are being treated for life-threatening (or potentially life-threatening) fungal infections.

In intravenous dosing, four doses of itraconazole 200 mg are given 12 hours apart, before changing the dose to once daily. There are no safety data for giving the intravenous preparation for more than 14 days continuously.

The following drugs should not be taken together with itraconazole:

• cisapride (Propulsid);
• dofetilide (Tikosyn);
• nisoldipine (Sular);
• pimozide (Orap);
• quinidine (Quinaglute, Quinidex, Quin-Release);
• lovastatin (Altocor, Altoprev, Mevacor) or simvastatin (Zocor);
• midazolam (Versed) or triazolam (Halcion);
• ergot medicines such as dihydroedrgotamine (D.H.E. 45, Migranal), ergonavine (Ergotrate), ergotamine (Ergomar, Cafergot, Ercaf, Migergot), or methylergonovine (Methergine).

Adverse 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.

• Elevated alanine aminotransferase levels is found in 4% of people taking itraconazole
• "Small but real risk" of developing congestive heart failure

The cyclodextrin that is used to make the syrup preparation can cause diarrhea. Side-effects that may indicate a greater problem include:

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

Production and marketing

Itraconazole can be consumed orally in blue 22 mm (⅞ in) capsules with tiny 1.5 mm blue pellets inside. Each capsule contains 100 mg and is usually taken multiple times a day such as every twelve hours. Sporanox, the brand name of itraconazole, has been developed and marketed by Janssen Pharmaceutica Products, L.P. a subsidiary of Johnson and Johnson. Apparently, the three layer structure of these blue capsules are quite 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. The contents of the capsule, the tiny blue pellets, are manufactured in Beerse, Belgium.

See also

• Fluconazole

External links

• General pharmacologic information about itraconazole
• Treatment of aseptic meningitis

de:Itraconazol zh:伊曲康唑