Itraconazole

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.

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 licenced for use in blastomycosis, histoplasmosis and onychomycosis. Itraconazole is over 99% protein bound and has virtually no penetration intocerebrospinal fluid. Therefore, it should never be used to treat meningitis or other central nervous systeminfections. 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 otherantifungal drugs are inappropriate or ineffective.

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.

Formulation
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.

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
 * Liver failure, sometimes fatal

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 is produced as blue 22 mm capsules with tiny 1.5 mm blue pellets inside. Each capsule contains 100 mg and is usually taken twice a day i.e. every twelve hours. The Sporanox the brand name of itraconazole has been developed and marketed by Janssen Pharmaceutica, a subsidiary of Johnson & Johnson. The three layer structure of these blue capsules are 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.