Pronunciation:

(i tra KOE na zole)

U.S. Brand Names:

Generic Available:

Canadian Brand Names:

Use:

Oral: Useful in superficial mycoses including dermatophytoses (eg, tinea capitis), pityriasis versicolor, sebopsoriasis, vaginal and chronic mucocutaneous candidiases; systemic mycoses including candidiasis, meningeal and disseminated cryptococcal infections, paracoccidioidomycosis, coccidioidomycoses; miscellaneous mycoses such as sporotrichosis, chromomycosis, leishmaniasis, fungal keratitis, alternariosis, zygomycosis

Oral solution: Treatment of oral and esophageal candidiasis

Intravenous solution: Indicated in the treatment of blastomycosis, histoplasmosis (nonmeningeal), and aspergillosis (in patients intolerant or refractory to amphotericin B therapy); empiric therapy of febrile neutropenic fever

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

Adverse Reactions:

>10%: Gastrointestinal: Nausea (11%)

1% to 10%:

Cardiovascular: Edema (4%), hypertension (3%)

Central nervous system: Headache (4%), fatigue (2% to 3%), malaise (1%), fever (3%), dizziness (2%)

Dermatologic: Rash (9%), pruritus (3%)

Endocrine & metabolic: Decreased libido (1%), hypertriglyceridemia, hypokalemia (2%)

Gastrointestinal: Abdominal pain (2%), anorexia (1%), vomiting (5%), diarrhea (3%)

Hepatic: Abnormal LFTs (3%), hepatitis

Renal: Albuminuria (1%)

<1%: Adrenal suppression, constipation, gastritis, gynecomastia, impotence, somnolence, tinnitus

Postmarketing and/or case reports: Allergic reactions (urticaria, angioedema); alopecia, anaphylactoid reactions, anaphylaxis, arrhythmia, CHF, hepatic failure, menstrual disorders, neutropenia, peripheral neuropathy, photosensitivity, pulmonary edema, Stevens-Johnson syndrome

Overdosage/Toxicology:

Drug Interactions:

Antacids: May decrease serum concentration of itraconazole. Administer antacids 1 hour before or 2 hours after itraconazole capsules.

Alfentanil: Serum concentrations may be increased; monitor.

Anticonvulsants: Itraconazole may increase the serum concentration of carbamazepine; carbamazepine, phenobarbital, and phenytoin may decrease the serum concentration of itraconazole.

Benzodiazepines: Alprazolam, diazepam, temazepam, triazolam, and midazolam serum concentrations may be increased; consider a benzodiazepine not metabolized by CYP3A4 (such as lorazepam) or another antifungal that is metabolized by CYP3A4

Buspirone: Serum concentrations may be increased; monitor for sedation

Busulfan: Serum concentrations may be increased; avoid concurrent use

Calcium channel blockers: Serum concentrations may be increased (applies to those agents metabolized by CYP3A4, including felodipine, nifedipine, and verapamil); consider another agent instead of a calcium channel blocker, another antifungal, or reduce the dose of the calcium channel blocker; monitor blood pressure

Cisapride; Serum concentration is increased which may lead to malignant arrhythmias; concurrent use is contraindicated

Corticosteroids: Serum levels/effects of the corticosteroid may be increased; use caution.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of itraconazole. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 substrates: Itraconazole may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Didanosine: May decrease absorption of itraconazole (due to buffering capacity of oral solution); applies only to oral solution formulation of didanosine

Digoxin: Serum concentrations may be increased; monitor.

Disopyramide: Serum levels/effects (including QTc prolongation) may be increased; use caution.

Docetaxel: Serum concentrations may be increased; avoid concurrent use

Dofetilide: Serum levels/toxicity may be increased; concurrent use is contraindicated.

Eletriptan: Serum level/toxicity of eletriptan may be increased; use caution.

Ergot alkaloids: Toxicity (vasospasm, ischemia) may be significantly increased by itraconazole; concurrent use is contraindicated.

Erythromycin (and clarithromycin): May increase serum concentrations of itraconazole.

H2 blockers: May decrease itraconazole absorption. Itraconazole depends on gastric acidity for absorption. Avoid concurrent use.

Halofantrine: Serum levels/effects (including QTc prolongation) may be increased; use caution.

HMG-CoA reductase inhibitors (except pravastatin and fluvastatin): Serum concentrations may be increased. The risk of myopathy/rhabdomyolysis may be increased. Switch to pravastatin/fluvastatin or suspend treatment during course of itraconazole therapy.

Hypoglycemic agents, oral: Serum concentrations may be increased; monitor.

Immunosuppressants: Cyclosporine, sirolimus, and tacrolimus: Serum concentrations may be increased; monitor serum concentrations and renal function.

Levomethadyl: Serum levels/effects may be increased by itraconazole, potentially resulting in malignant arrhythmia; concurrent use is contraindicated.

Nevirapine: May decrease serum concentrations of itraconazole; monitor

Oral contraceptives: Efficacy may be reduced by itraconazole (limited data); use barrier birth control method during concurrent use

Pimozide: Serum levels/toxicity may be increased; concurrent use is contraindicated.

Protease inhibitors: May increase serum concentrations of itraconazole. Includes amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir; monitor. Serum concentrations of indinavir, ritonavir, or saquinavir may be increased by itraconazole.

Proton pump inhibitors: May decrease itraconazole absorption. Itraconazole depends on gastric acidity for absorption. Avoid concurrent use (includes omeprazole, lansoprazole).

Quinidine: Serum levels may be increased. Concurrent use is contraindicated.

Rifabutin: Serum concentrations may be increased; monitor.

Sildenafil: Serum concentrations may be increased by itraconazole; consider dosage reduction. A maximum sildenafil dose of 25 mg in 48 hours is recommended with other strong CYP3A4 inhibitors.

Tadalafil: Serum concentrations may be increased by itraconazole. A maximum tadalafil dose of 10 mg in 72 hours is recommended with strong CYP3A4 inhibitors.

Trimetrexate: Serum concentrations may be increased; monitor

Vardenafil: Serum concentrations may be increased by itraconazole. If itraconazole dose is 200 mg/day, limit vardenafil dose to a maximum of 5 mg/24 hours. If itraconazole dose is 400 mg/day, limit vardenafil dose to a maximum of 2.5 mg/24 hours.

Warfarin: Anticoagulant effects may be increased; monitor INR and adjust warfarin's dose as needed

Vinca alkaloids: Serum concentrations may be increased; avoid concurrent use

Zolpidem: Serum levels may be increased; monitor

Ethanol/Nutrition/Herb Interactions:

Food:

Capsules: Enhanced by food and possibly by gastric acidity. cola drinks have been shown to increase the absorption of the capsules in patients with achlorhydria or those taking H2-receptor antagonists or other gastric acid suppressors. Avoid grapefruit juice.

Solution: Decreased by food, time to peak concentration prolonged by food.

Herb/Nutraceutical: St John's wort may decrease itraconazole levels.

Stability:

Capsule: Store at room temperature, 15°C to 25°C (59°F to 77°F); protect from light and moisture

Oral solution: Store at 25°C (77°F); do not freeze

Solution for injection: Store at 25°C (77°F); protect from light; do not freeze. Dilute with 0.9% sodium chloride only. Do not use dextrose or lactated Ringer's. Stable for 48 hours at room temperature or under refrigeration. A precise mixing ratio is required to maintain stability (3.33:1) and avoid precipitate formation. Add 25 mL (1 ampul) to 50 mL 0.9% sodium chloride. Mix and withdraw 15 mL of solution before infusing.

Compatibility:

Mechanism of Action:

Pharmacodynamics/Kinetics:

Absorption: Requires gastric acidity; capsule better absorbed with food, solution better absorbed on empty stomach; hypochlorhydria has been reported in HIV-infected patients; therefore, oral absorption in these patients may be decreased

Distribution: Vd (average): 796 ± 185 L or 10 L/kg; highly lipophilic and tissue concentrations are higher than plasma concentrations. The highest concentrations: adipose, omentum, endometrium, cervical and vaginal mucus, and skin/nails. Aqueous fluids (eg, CSF and urine) contain negligible amounts.

Protein binding, plasma: 99.9%; metabolite hydroxy-itraconazole: 99.5%

Metabolism: Extensively hepatic via CYP3A4 into >30 metabolites including hydroxy-itraconazole (major metabolite); appears to have in vitro antifungal activity. Main metabolic pathway is oxidation; may undergo saturation metabolism with multiple dosing.

Bioavailability: Variable, ~ 55% (oral solution) in 1 small study; Note: Oral solution has a higher degree of bioavailability (149% ± 68%) relative to oral capsules; should not be interchanged

Half-life elimination: Oral: After single 200 mg dose: 21 ± 5 hours; 64 hours at steady-state; I.V.: steady-state: 35 hours; steady-state concentrations are achieved in 13 days with multiple administration of itraconazole 100-400 mg/day.

Excretion: Feces (~3% to 18%); urine (~0.03% as parent drug, 40% as metabolites)

Dosage:

Children: Efficacy and safety have not been established; a small number of patients 3-16 years of age have been treated with 100 mg/day for systemic fungal infections with no serious adverse effects reported. A dose of 5 mg/kg once daily was used in a pharmacokinetic study using the oral solution in patients 6 months-12 years; duration of study was 2 weeks.

Adults:

Oral:

Blastomycosis/histoplasmosis: 200 mg once daily, if no obvious improvement or there is evidence of progressive fungal disease, increase the dose in 100 mg increments to a maximum of 400 mg/day; doses >200 mg/day are given in 2 divided doses; length of therapy varies from 1 day to >6 months depending on the condition and mycological response

Aspergillosis: 200-400 mg/day

Onychomycosis: 200 mg once daily for 12 consecutive weeks

Life-threatening infections: Loading dose: 200 mg 3 times/day (600 mg/day) should be given for the first 3 days of therapy

Oropharyngeal candidiasis: Oral solution: 200 mg once daily for 1-2 weeks; in patients unresponsive or refractory to fluconazole: 100 mg twice daily (clinical response expected in 1-2 weeks)

Esophageal candidiasis: Oral solution: 100-200 mg once daily for a minimum of 3 weeks; continue dosing for 2 weeks after resolution of symptoms

I.V.: 200 mg twice daily for 4 doses, followed by 200 mg daily

Dosing adjustment in renal impairment: Not necessary; itraconazole injection is not recommended in patients with Clcr<30 mL/minute; hydroxypropyl--cyclodextrin (the excipient) is eliminated primarily by the kidneys.

Hemodialysis: Not dialyzable

Dosing adjustment in hepatic impairment: May be necessary, but specific guidelines are not available. Risk-to-benefit evaluation should be undertaken in patients who develop liver function abnormalities during treatment.

Administration:

Oral: Doses >200 mg/day are given in 2 divided doses; do not administer with antacids. Capsule absorption is best if taken with food, therefore, it is best to administer itraconazole after meals; solution should be taken on an empty stomach. When treating oropharyngeal and esophageal candidiasis, solution should be swished vigorously in mouth, then swallowed.

I.V.: Using a flow control device, infuse 60 mL of the dilute solution (3.33 mg/mL = 200 mg itraconazole, pH ~4.8) intravenously over 60 minutes, using an extension line and the infusion set provided. After administration, flush the infusion set with 15-20 mL of 0.9% sodium chloride over 30 seconds to 15 minutes, via the two-way stopcock. Do not use bacteriostatic sodium chloride injection, USP. The compatibility of Sporanox® injection with flush solutions other than 0.9% sodium chloride (normal saline) is not known. Discard the entire infusion line.

Monitoring Parameters:

Dietary Considerations:

Capsule: Administer with food.

Solution: Take without food, if possible.

Patient Education:

Additional Information:

Cardiovascular Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Effects on Mental Status:

Mental Health: Effects on Psychiatric Treatment:

Dosage Forms:

Capsule: 100 mg

Injection, solution: 10 mg/mL (25 mL) [packaged in a kit containing sodium chloride 0.9% (50 mL); filtered infusion set (1)]

Solution, oral: 100 mg/10 mL (150 mL) [cherry flavor]

International Brand Names: