Itraconazole

Itraconazole is a lipophilic triazole antifungal with activity against Candida, Aspergillus, dermatophytes, Histoplasma, Blastomyces, Sporothrix and many agents of chromoblastomycosis and eumycetoma. Absorption is variable and formulation-dependent. It is a strong CYP3A4 and P-glycoprotein inhibitor, carries a boxed warning for negative inotropic effect in heart failure, and has a large number of contraindicated drug combinations.

Class. Triazole antifungal.

Mechanism. Inhibits fungal cytochrome P450 14-alpha-demethylase (CYP51), blocking ergosterol synthesis.

Pharmacokinetics. Capsules need gastric acid and a full meal; oral solution is better absorbed on an empty stomach; the two are not interchangeable. Highly protein bound, poor cerebrospinal fluid penetration, half life 24 to 42 hours at steady state, hepatic metabolism to the active hydroxy-itraconazole.

Endemic mycoses. - Histoplasmosis, mild to moderate: 200 mg three times daily for 3 days (loading), then 200 mg once or twice daily for 6 to 12 weeks. - Severe histoplasmosis: after 1 to 2 weeks of amphotericin B, 200 mg twice daily to complete 12 weeks, then suppression if immunosuppression persists. - Blastomycosis: 200 mg three times daily for 3 days, then 200 mg once or twice daily for 6 to 12 months.

Other deep and subcutaneous mycoses. - Chronic pulmonary aspergillosis: 200 mg twice daily for 6 months or longer. - Allergic bronchopulmonary aspergillosis: 200 mg twice daily for 16 weeks with corticosteroid. - Lymphocutaneous sporotrichosis: 200 mg daily for 3 to 6 months, continued for 2 to 4 weeks after lesions heal. - Eumycetoma: 200 mg twice daily for 12 months or longer, usually with surgery; response is limited. - Maximum: 400 mg daily (600 mg daily for the 3-day load).

Superficial infections. - Oropharyngeal candidiasis (oral solution): 200 mg daily, swished and swallowed, for 1 to 2 weeks. - Onychomycosis: 200 mg daily for 12 weeks (toenails), or pulses of 200 mg twice daily for 1 week each month (2 pulses for fingernails, 3 for toenails). - Pityriasis versicolor: 200 mg daily for 7 days. Tinea corporis or cruris: 100 mg daily for 15 days. Tinea pedis: 100 mg daily for 30 days.

Children. Oral solution about 5 mg/kg daily in two divided doses; data are limited.

Therapeutic drug monitoring. Trough (itraconazole by chromatography) 1 to 2 mg/L for treatment; toxicity is likely over 4 mg/L. Check at 1 to 2 weeks.

Contraindications. Heart failure or ventricular dysfunction (except life-threatening infection), pregnancy for non-life-threatening infection, hypersensitivity, and co-prescription of simvastatin, lovastatin, oral midazolam, triazolam, pimozide, quinidine, dofetilide, methadone, ergot alkaloids, ticagrelor, felodipine and colchicine in kidney or liver impairment.

Serious adverse effects. Congestive heart failure, hepatotoxicity, hypokalaemia, hypertension and oedema (mineralocorticoid excess), peripheral neuropathy, hearing loss and severe skin reactions.

Common adverse effects. Nausea, abdominal pain, headache, rash and raised transaminases.

Interactions. Acid suppression lowers capsule absorption. Rifampicin, isoniazid, phenytoin and carbamazepine lower levels sharply and should be avoided. Raises digoxin, ciclosporin, tacrolimus, vincristine and oral anticoagulants.

Common prescribing errors. Swapping capsule and solution one for one, giving capsules without food or with a proton pump inhibitor, missing interactions, and using it in heart failure.

Special groups. - Pregnancy: avoid; effective contraception during treatment and for 2 months after. - Breastfeeding: excreted in milk; avoid. - Children: oral solution only, weight-based, with level monitoring. - Older adults: higher heart failure risk; assess cardiac function. - Kidney impairment: oral dose unchanged; intravenous cyclodextrin vehicle accumulates. - Liver impairment: use with caution and monitor liver tests; avoid if previous itraconazole hepatotoxicity.

Formulations. Capsules 100 mg; oral solution 10 mg/mL.

Administration. Capsules with a full meal and an acidic drink; oral solution 1 hour before a meal, not with food.

Baseline. Liver tests, potassium, blood pressure, cardiac assessment (symptoms, oedema, echocardiography if risk), pregnancy test, drug review.

Monitoring. Liver tests at baseline, 2 weeks and then monthly on prolonged courses; potassium and blood pressure; heart failure symptoms; trough level at 1 to 2 weeks.

Stopping thresholds. Stop for new heart failure, ALT over five times the upper limit of normal (or over three times with symptoms), severe skin reaction or neuropathy.

Referral and escalation. Specialist review for invasive mycoses, treatment failure, raised levels or any cardiac concern.