Brands, Medical Use, Clinical Data
- Capsules (100 mg)
- Liquid solution
Brands / Synonyms
ITC; ITCZ; ITR; Itraconazol [Spanish]; Itraconazole & Bovine Lactoferrin; Itraconazole [Usan:Ban:Inn:Jan]; Itraconazolum [Latin]; Itrizole; ITZ; Onmel; Oriconazole; Sporal; Sporanos; Sporanox; Sporonox; Triasporn
For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.
Itraconazole is an imidazole/triazole type antifungal agent. Itraconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 α-demethylation via the inhibition of the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell wall synthesis. The subsequent loss of normal sterols correlates with the accumulation of 14 α-methyl sterols in fungi and may be partly responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Itraconazole exhibits in vitro activity against Cryptococcus neoformans and Candida spp. Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans.
Mechanism of Action
Itraconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Itraconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.
The absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal.
No significant lethality was observed when itraconazole was administered orally to mice and rats at dosage levels of 320 mg/kg or to dogs at 200 mg/kg.
Biotrnasformation / Drug Metabolism
Itraconazole is extensively metabolized by the liver into a large number of metabolites, including hydroxyitraconazole, the major metabolite. The main metabolic pathways are oxidative scission of the dioxolane ring, aliphatic oxidation at the 1-methylpropyl substituent, N-dealkylation of this 1-methylpropyl substituent, oxidative degradation of the piperazine ring and triazolone scission.
Coadministration of terfenadine, astemizole or cisapride with Sporanox (itraconazole capsules) is
Concomitant administration of Sporanox with oral triazolam or with oral midazolam is contraindicated. .
Sporanox should not be administered for the treatment of onychomycosis to pregnant patients or to women
Sporanox is contraindicated in patients who have shown hypersensitivity to the drug or its excipients. There is no
information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should
be used in prescribing Sporanox to patients with hypersensitivity to other azoles.
Both itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of the cytochrome P450 3A4 enzyme system. Coadministration of Itraconazole and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and adverse effects. Therefore, unless otherwise specified, appropriate dosage adjustments may be necessary.
Coadministration of terfenadine with Itraconazole has led to elevated plasma concentrations of terfenadine, resulting in rare instances of life- threatening cardiac dysrhythmias and one death.
Another oral azole antifungal, ketoconazole, inhibits the metabolism of astemizole, resulting in elevated plasma concentrations of astemizole and its active metabolite desmethylastermizole which may prolong QT intervals. In vitro data suggest that itraconazole, when compared to ketoconazole, has a less pronounced effect on the biotransformation system responsible for the metabolism of astemizole. Based on the chemical resemblance of itraconazole and ketoconazole, coadministration of astemizole with itraconazole is contraindicated.
Human pharmacokinetics data indicate that oral ketoconazole potently inhibits the metabolism of cisapride resulting in an eight-fold increase in the mean AUC of cisapride. Data suggest that coadministration of oral ketoconazole and cisapride can result in prolongation of the QT interval on the ECG. In vitro data suggest that itraconazole also markedly inhibits the biotransformation system mainly responsible for the metabolism of cisapride; therefore concomitant administration of Itraconazole with cisapride is contraindicated.
Coadministration of Itraconazole with oral midazolam or triazolam has resulted in elevated plasma concentrations of the latter two drugs. This may potentiate and prolong hypnotic and sedative effects. These agents should not be used in patients treated with Itraconazole. If midazolam is administered parenterally, special precaution is required since the sedative effect may be prolonged.
Coadministration of Itraconazole and cyclosporine, tacrolimus or digoxin has led to increased plasma concentrations of the latter three drugs. Cyclosporine, tacrolimus and digoxin concentrations should be monitored at the initiation of Itraconazole therapy and frequently thereafter, and the dose of these three drug products adjusted appropriately.
There have been rare reports of rhabdomyolysis involving renal transplant patients receiving the combination of Itraconazole, cyclosporine, and the HMG-CoA reductase inhibitors lovastatin or simvastatin. Rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors administered alone (at recommended dosages) or concomitantly with immunosuppressive drugs including cyclosporine.
When Itraconazole was coadministered with phenytoin, rifampin, or H2antagonists, reduced plasma concentrations of itraconazole were reported. The physician is advised to monitor the plasma concentrations of itraconazole when any of these drugs is taken concurrently, and to increase the dose of Itraconazole if necessary. Although no studies have been conducted, concomitant administration of Itraconazole and phenytoin may alter the metabolism of phenytoin; therefore, plasma concentrations of phenytoin should also be monitored when it is given concurrently with Itraconazole.
It has been reported that Itraconazole enhances the anticoagulant effect of coumarin-like drugs. Therefore, prothrombin time should be carefully monitored in patients receiving Itraconazole and coumarin-like drugs simultaneously.
Plasma concentrations of azole antifungal agents are reduced when given concurrently with isoniazid. Itraconazole plasma concentrations should be monitored when Itraconazole and isoniazid are coadministered.
Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when Itraconazole and oral hypoglycemic agents are coadministered.
Tinnitus and decreased hearing have been reported in patients concomitantly receiving Itraconazole and quinidine. Edema has been reported in patients concomitantly receiving Itraconazole and dihydropyridine calcium channel blockers. Appropriate dosage adjustments may be necessary.
The results from a study in which eight HIV-infected individuals were treated with zidovudine, 8 +/- 0.4 mg/kg/day, showed that the pharmacokinetics of zidovudine were not affected during concomitant administration of Itraconazole, 100 mg b.i.d.