indication

For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.

pharmacology

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.

toxicity

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.

biotransformation

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.

absorption

The absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal.

half life

21 hours

route of elimination

Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4) in the liver, resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose.

drug interactions

Acenocoumarol: Itraconazole may increase the anticoagulant effect of acenocoumarol.

Alfentanil: Itraconazole may increase the effect and toxicity of alfentanil.

Alfuzosin: The antifungal increases the effect of alfuzosin

Almotriptan: This potent CYP3A4 inhibitor increases the effect and toxicity of the triptan

Alprazolam: Itraconazole may increase the effect of the benzodiazepine, alprazolam.

Aluminium: Aluminum-containing antacids may decrease the effect of itraconazole.

Anisindione: Itraconazole may increase the anticoagulant effect of anisindione.

Aprepitant: This CYP3A4 inhibitor, itraconazole, may increase the effect and toxicity of aprepitant.

Aripiprazole: Itraconazole may increase the effect of aripiprazole.

Astemizole: Increased risk of cardiotoxicity and arrhythmias

Atorvastatin: Increased risk of myopathy/rhabdomyolysis

Bosentan: Itraconazole may increase the effect and toxicity of bosentan.

Bromazepam: Itraconazole may increase the serum concentration of bromazepam by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bromazepam if itraconazole is initiated, discontinued or dose changed.

Budesonide: Itraconazole may increase levels/effect of budesonide.

Calcium: Calcium-containing antacids may decrease the effect of itraconazole.

Calcium carbonate: The antacid, calcium carbonate, may decrease the effect of itraconazole by decreasing its absorption.

Carbamazepine: Itraconazole may increase the effect of carbamazepine.

Cerivastatin: Increased risk of myopathy/rhabdomyolysis

Chlordiazepoxide: Itraconazole may increase the effect of the benzodiazepine, chlordiazepoxide.

Ciclesonide: Increased effects/toxicity of ciclesonide

Cilostazol: Itraconazole may increase the effect of cilostazol.

Cimetidine: The H2-receptor antagonist, cimetidine, may decrease the absorption of itraconazole.

Cinacalcet: Itraconazole may increase the effect and toxicity of cinacalcet.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clarithromycin: The macrolide, clarithromycin, may increase the effect and toxicity of itraconazole.

Clonazepam: Itraconazole may increase the effect of the benzodiazepine, clonazepam.

Clorazepate: Itraconazole may increase the effect of the benzodiazepine, clorazepate.

Conivaptan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Conivaptan. Concomitant use of conivaptan with strong CYP3A4 inhibitors (e.g., azole antifungals) is contraindicated.

Cyclosporine: Itraconazole may increase the effect of cyclosporine.

Dantrolene: Itraconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if itraconazole is initiated, discontinued or dose changed.

Darifenacin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Diazepam: Itraconazole may increase the effect of the benzodiazepine, diazepam.

Dicumarol: Itraconazole may increase the anticoagulant effect of dicumarol.

Digoxin: Itraconazole increases the effect of digoxin

Dihydroergotamine: Possible ergotism and severe ischemia with this combination

Dofetilide: This strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide

Eletriptan: This potent CYP3A4 inhibitor increases the effect and toxicity of the triptan

Eplerenone: Itraconazole may increase the effect and toxicity of eplerenone.

Ergotamine: Possible ergotism and severe ischemia with this combination

Erlotinib: Itraconazole may decrease the metabolism of erlotinib. Monitor for changes in the therapeutic and adverse effects of erlotinib if itraconazole is initiated, discontinued or dose changed.

Erythromycin: The macrolide, erythromycin, may increase the effect and toxicity of itraconazole.

Esomeprazole: The proton pump inhibitor, esomeprazole, may decrease the absorption of itraconazole.

Estazolam: Itraconazole may increase the effect of the benzodiazepine, estazolam.

Ethotoin: Phenytoin decreases the effect of itraconazole

Everolimus: Itraconazole may increase everolimus levels/toxicity.

Famotidine: The H2-receptor antagonist, famotidine, may decrease the absorption of itraconazole.

Felodipine: Itraconazole may increase the therapeutic and adverse effects of felodipine.

Fentanyl: Itraconazole may increase levels/toxicity of fentanyl.

Flurazepam: Itraconazole may increase the effect of the benzodiazepine, flurazepam.

Fosphenytoin: Phenytoin decreases the effect of itraconazole

Gefitinib: Itraconazole, a strong CYP3A4 inhibitor, may decrease the metabolism of gefitinib. Monitor for changes in the therapeutic and adverse effects of gefitinib if itraconazole is initiated, discontinued or dose changed.

Halazepam: Itraconazole may increase the effect of the benzodiazepine, halazepam.

Haloperidol: Itraconazole may increase the effect and toxicity of haloperidol.

Imatinib: Itraconazole may increase the levels of imatinib.

Josamycin: The macrolide, josamycin, may increase the effect and toxicity of itraconazole.

Lansoprazole: The proton pump inhibitor, lansoprazole, may decrease the absorption of itraconazole.

Levomethadyl Acetate: Itraconazole increases the effect/toxicity of levomethadyl

Lovastatin: Increased risk of myopathy/rhabdomyolysis

Magnesium oxide: The antacid, magnesium oxide, may decrease the effect of itraconazole by decreasing its absorption.

Mephenytoin: Phenytoin decreases the effect of itraconazole

Mestranol: This anti-infectious agent could decrease the effect of the oral contraceptive

Methylprednisolone: The imidazole, itraconazole, may increase the effect and toxicity of the corticosteroid, methylprednisolone.

Midazolam: Itraconazole may increase the effect of the benzodiazepine, midazolam.

Nizatidine: The H2-receptor antagonist, nizatidine, may decrease the absorption of itraconazole.

Omeprazole: The proton pump inhibitor, omeprazole, may decrease the absorption of itraconazole.

Pantoprazole: The proton pump inhibitor, pantoprazole, may decrease the absorption of itraconazole.

Phenobarbital: The barbiturate, phenobarbital, decreases the effect of itraconazole.

Phenytoin: Phenytoin decreases the effect of itraconazole

Pimozide: Increased risk of cardiotoxicity and arrhythmias

Prednisolone: The imidazole, itraconazole, may increase the effect and toxicity of the corticosteroid, prednisolone.

Prednisone: The imidazole, itraconazole, may increase the effect and toxicity of the corticosteroid, prednisone.

Quazepam: Itraconazole may increase the effect of the benzodiazepine, quazepam.

Quinidine: Itraconazole may increase the effect and toxicity of quinidine.

Quinidine barbiturate: Itraconazole may increase the effect and toxicity of quinidine barbiturate.

Rabeprazole: The proton pump inhibitor, rabeprazole, may decrease the absorption of itraconazole.

Ranitidine: The H2-receptor antagonist, ranitidine, may decrease the absorption of itraconazole.

Ranolazine: Increased levels of ranolazine - risk of toxicity

Rifabutin: Rifabutin decreases the effect of itraconazole

Rifampin: Rifampin may decrease the effect of itraconazole.

Risperidone: Increases the level of risperidone

Ritonavir: Itraconazole may increase the effect and toxicity of ritonavir.

Rivaroxaban: Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.

Sildenafil: Itraconazole may increase the effect and toxicity of sildenafil.

Simvastatin: Increased risk of myopathy/rhabdomyolysis

Sirolimus: Itraconazole may increase the effect and toxicity of sirolimus.

Solifenacin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Sucralfate: Sucralfate may decrease the absorption of itraconazole.

Sunitinib: Possible increase in sunitinib levels

Tacrolimus: The antifungal, Itraconazole, may increase serum concentrations of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Itraconazole therapy is initiated, discontinued or altered.

Tadalafil: Itraconazole may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamoxifen: Itraconazole may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Tamsulosin: Itraconazole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Itraconazole is initiated, discontinued, or dose changed.

Telithromycin: Itraconazole may increase the plasma concentration of Telithromycin. Consider alternate therapy or monitor therapeutic/adverse effects.

Temsirolimus: Itraconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Teniposide: The strong CYP3A4 inhibitor, Itraconazole, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Itraconazole is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Tiagabine: The strong CYP3A4 inhibitor, Itraconazole, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Itraconazole is initiated, discontinued or dose changed.

Tipranavir: Tipranavir may increase the serum concentration of Itraconazole.

Tolterodine: Itraconazole may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Topotecan: The p-glycoprotein inhibitor, Itraconazole, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Tramadol: Itraconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inhibitor, Itraconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Itraconazole is initiated, discontinued or dose changed.

Triazolam: Itraconazole may increase the effect of the benzodiazepine, triazolam.

Trimipramine: The strong CYP3A4 inhibitor, Itraconazole, may decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Itraconazole is initiated, discontinued or dose changed.

Vardenafil: Itraconazole, a potent CYP3A4 inhibitor, may decrease the metabolism and clearance of Vardenafil. Concomitant therapy is contraindicated.

Venlafaxine: Itraconaole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Itraconazole is initiated, discontinued, or dose changed.

Verapamil: Itraconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Itraconazole is initiated, discontinued or dose changed.

Vinblastine: Itraconazole, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Itraconazole is initiated, discontinued or dose changed.

Vincristine: Itraconazole, a strong CYP3A4 and p-glycoprotein inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism and/or increasing efflux. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Itraconazole is initiated, discontinued or dose changed.

Vinorelbine: Itraconazole, a strong CYP3A4 and p-glycoprotein inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism and/or increasing its efflux. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Itraconazole is initiated, discontinued or dose changed.

Warfarin: Itraconazole may increase the anticoagulant effect of warfarin by decreasing its metabolism.

Zolpidem: Itraconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if itraconazole is initiated, discontinued or dose changed.

Zonisamide: Itraconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if itraconazole is initiated, discontinued or dose changed.

Zopiclone: Itraconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if itraconzole is initiated, discontinued or dose changed.