Search Medications (Drugs):
Medications (Drugs) from A to Z:
Home > Medications (Drugs) > Itraconazole > More information about Itraconazole

More information about Itraconazole

Pronunciation

(i tra KOE na zole)


U.S. Brand Names

Sporanox®

Generic Available

No

Canadian Brand Names

Sporanox®

Use

Treatment of susceptible fungal infections in immunocompromised and immunocompetent patients including blastomycosis and histoplasmosis; indicated for aspergillosis, and onychomycosis of the toenail; treatment of onychomycosis of the fingernail without concomitant toenail infection via a pulse-type dosing regimen; has activity against Aspergillus, Candida, Coccidioides, Cryptococcus, Sporothrix, tinea unguium

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

C

Pregnancy Implications

Should not be used to treat onychomycosis during pregnancy. Effective contraception should be used during treatment and for 2 months following treatment. Congenital abnormalities have been reported during postmarketing surveillance, but a causal relationship has not been established.

Lactation

Enters breast milk/not recommended

Contraindications

Hypersensitivity to itraconazole, any component of the formulation, or to other azoles; concurrent administration with cisapride, dofetilide, ergot derivatives, levomethadyl, lovastatin, midazolam, pimozide, quinidine, simvastatin, or triazolam; treatment of onychomycosis in patients with evidence of left ventricular dysfunction, CHF, or a history of CHF

Warnings/Precautions

Discontinue if signs or symptoms of CHF or neuropathy occur during treatment. Rare cases of serious cardiovascular adverse events (including death), ventricular tachycardia, and torsade de pointes have been observed due to increased cisapride concentrations induced by itraconazole. Use with caution in patients with left ventricular dysfunction or a history of CHF. Not recommended for use in patients with active liver disease, elevated liver enzymes, or prior hepatotoxic reactions to other drugs. Itraconazole has been associated with rare cases of serious hepatotoxicity (including fatal cases and cases within the first week of treatment); treatment should be discontinued in patients who develop clinical symptoms of liver dysfunction or abnormal liver function tests during itraconazole therapy except in cases where expected benefit exceeds risk. Large differences in itraconazole pharmacokinetic parameters have been observed in cystic fibrosis patients receiving the solution; if a patient with cystic fibrosis does not respond to therapy, alternate therapies should be considered. Due to differences in bioavailability, oral capsules and oral solution cannot be used interchangeably. Intravenous formulation should be used with caution in renal impairment; consider conversion to oral therapy if renal dysfunction/toxicity is noted. Initiation of treatment with oral solution is not recommended in patients at immediate risk for systemic candidiasis (eg, patients with severe neutropenia).

Adverse Reactions

Listed incidences are for higher doses appropriate for systemic fungal infection.

>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

Overdoses are well tolerated. Treatment is supportive. Dialysis is not effective.

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP3A4 (strong)

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

Compatible:   Stable in NS

Mechanism of Action

Interferes with cytochrome P450 activity, decreasing ergosterol synthesis (principal sterol in fungal cell membrane) and inhibiting cell membrane formation

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

Note:   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.

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

Liver function in patients with pre-existing hepatic dysfunction, and in all patients being treated for longer than 1 month

Dietary Considerations

Capsule: Administer with food.

Solution: Take without food, if possible.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Use exactly as directed. Stop therapy and report any signs and symptoms that may suggest liver dysfunction (eg, unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stool) immediately so that the appropriate laboratory testing can be done. Take full course of medication, do not discontinue without consulting prescriber. Take capsule with food; solution on empty stomach, 1 hour before or 2 hours after meals. Observe good hygiene measures to prevent reinfection. If you have diabetes, test serum glucose regularly (may affect response to oral hypoglycemics). Frequent blood tests may be required with prolonged therapy. You may experience dizziness or drowsiness (use caution when driving or engaging in tasks that require alertness until response to drug is known); nausea, vomiting, or anorexia (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or skin rash or other persistent adverse reactions. Pregnancy/breast-feeding precautions:   Inform prescriber if you are or intend to become pregnant. Consult prescriber about appropriate contraceptive use - efficacy of oral contraceptives may be reduced. Breast-feeding is not recommended.

Additional Information

Due to potential toxicity, the manufacturer recommends confirmation of diagnosis testing of nail specimens prior to treatment of onychomycosis.

Cardiovascular Considerations

Itraconazole has negative inotropic properties and cases of new heart failure or exacerbation of congestive heart failure have been reported. Itraconazole is contraindicated for the treatment of onychomycosis in patients with heart failure. The benefit:risk for therapy in the treatment of other types of fungal infections should be carefully considered in each patient, particularly those with congestive heart failure and in heart transplant recipients. If indicated after cardiac, renal, or liver transplantation, itraconazole can increase cyclosporine levels by up to 50% at high doses. It also increases serum levels of lovastatin by up to 20-fold, as well as other HMG-CoA reductase inhibitors, by inhibiting CYP3A4. This is important since many post-transplantation patients are also hyperlipidemic and on HMG-CoA reductase inhibitors. Itraconazole may also increase levels of dofetilide and quinidine. The simultaneous administration of these medications is contraindicated because of increased risk of cardiotoxicity.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause sedation

Mental Health: Effects on Psychiatric Treatment

Contraindicated with oral midazolam, pimozide, and triazolam

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]

References

"1997 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected With Human Immunodeficiency Virus. USPHS/IDSA Prevention of Opportunistic Infections Working Group,"MMWR Recomm Rep, 1997, 46(RR-12):1-46.

Ahmad SR, Singer SJ, and Leissa BG, "Congestive Heart Failure Associated With Itraconazole,"Lancet, 2001, 357(9270):1766-7.

Amichai B and Grunwald MH, "Adverse Drug Reactions of the New Oral Antifungal Agents - Terbinafine, Fluconazole, and Itraconazole,"Int J Dermatol, 1998, 37(6):410-5.

Cleary JD, Taylor JW, and Chapman SW, "Itraconazole in Antifungal Therapy,"Ann Pharmacother, 1992, 26(4):502-9.

Cowie F, Meller ST, Cushing P, et al, "Chemoprophylaxis for Pulmonary Aspergillosis During Intensive Chemotherapy,"Arch Dis Child, 1994, 70(2):136-8.

De Backer M, De Vroey C, Lesaffre E, et al, "Twelve Weeks of Continuous Oral Therapy for Toenail Onychomycosis Caused by Dermatophytes: A Double-Blind Comparative Trial of Terbinafine 250 mg/day Versus Itraconazole 200 mg/day,"J Am Acad Dermatol, 1998, 38(5 Pt 3):S57-63.

Grant SM and Clissold SP, "Itraconazole. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Superficial and Systemic Mycoses,"Drugs, 1989, 37(3):310-44.

Haria M, Bryson HM, and Goa KL, "Itraconazole: A Reappraisal of Its Pharmacological Properties and Therapeutic Use in the Management of Superficial Fungal Infections,"Drugs, 1996, 51(4):585-620.

Heymann WR and Manders SM, "Itraconazole-Induced Acute Generalized Exanthemic Pustulosis,"J Am Acad Dermatol, 1995, 33(1):130-1.

Jennings TS and Hardin TC, "Treatment of Aspergillosis With Itraconazole,"Ann Pharmacother, 1993, 27(10):1206-11.

Kauffman CA and Carver PL, "Antifungal Agents in the 1990s. Current Status and Future Developments,"Drugs, 1997, 53(4):539-49.

Kintzel PE, Rollins CJ, Yee WJ, et al, "Low Itraconazole Serum Concentrations Following Administration of Itraconazole Suspension to Critically Ill Allogenic Bone Marrow Transplant Recipients,"Ann Pharmacother, 1995, 29(2):140-3.

Lyman CA and Walsh TJ, "Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications,"Drugs, 1992, 44(1):9-35.

Mouy R, Veber F, Blanche S, et al, "Long-Term Itraconazole Prophylaxis Against Aspergillus Infections in Thirty-Two Patients With Chronic Granulomatous Disease,"J Pediatr, 1994, 125(6 Pt 1):998-1003.

Neuvonen PJ and Suhonen R, "Itraconazole Interacts With Felodipine,"J Am Acad Dermatol , 1995, 33(1):134-5.

Terrell CL, "Antifungal Agents. Part II. The Azoles,"Mayo Clin Proc, 1999, 74(1):78-100.

Tobon AM, Franco L, Espinal D, et al, "Disseminated Histoplasmosis in Children: The Role of Itraconazole Therapy,"Pediatr Infect Dis J, 1996; 15:1002-8.

Trepanier EF and Amsden GW, "Current Issues in Onchomycosis,"Ann Pharmacother, 1998, 32(2):204-14.

Tucker RM, Haq Y, Denning DW, et al, "Adverse Effects Associated With Itraconazole in 189 Patients on Chronic Therapy,"J Antimicrob Chemother, 1990, 26(4):561-6.

Varhe A, Olkkola KT, and Neuvonen PJ, "Oral Triazolam is Potentially Hazardous to Patients Receiving Systemic Antimycotics Ketoconazole or Itraconazole,"Clin Pharmacol Ther, 1994, 56(6 Pt 1):601-7.

Wheat J, Hafner R, Korzun AH, et al, "Itraconazole Treatment of Disseminated Histoplasmosis in Patients With the Acquired Immunodeficiency Syndrome,"Am J Med, 1995, 98(4):336-42.

International Brand Names

Canadiol® (ES); Candistat® (IN); Canditral® (SG, TH); Carexan® (MX); Forcanox® (ID); Fungibet® (CL); Fungitrazol® (ID); Funit® (TR); Furonok® (ID); Hongoseril® (ES); Icona® (TH); Isox® (DO, GT, HN, MX, SV); Itodal® (CL); Itrac® (HR); Itracol® (DE); Itracon® (TH); Itraflux® (AR); Itranax® (BR, MX); Itraspor® (BR, TR); Itra® (TH); Itrazol® (BR); Itzol® (ID); Kanazol® (YU); Micotenk® (AR); Mycosyst® (RU); Norspor® (TH); Nufarindo® (ID); Orungal® (BG, HR, HU, PL, RO, RU, YU); Petrazole® (ID); Salimidin® (AR); Sempera® (DE); Siros® (DE); Spazol® (TH); Sporacid® (ID); Sporal® (TH); Sporanox® (AR, AT, AU, BE, BR, CA, CH, CL, CO, CR, CY, CZ, DK, DO, EC, EG, ES, FI, FR, GB, GT, HK, HN, ID, IE, IL, IT, JO, LB, LK, LU, MT, MX, NO, NZ, PA, PT, RO, SE, SG, SI, SV, ZA); Sporex® (TR); Sporlab® (TH); Spornar® (TH); Spyrocon® (ID); Teramic® (CL); Trachon® (ID); Traconal® (BR); Tranazol® (BR); Triasporin® (IT); Trisporal® (NL); Unitrac® (ID)

Advertisement
Header