ITRACONAZOLE
Clinical safety rating: avoid
Contraindicated (not allowed)
Inhibits fungal cytochrome P450-dependent 14α-demethylase, thereby blocking the conversion of lanosterol to ergosterol, disrupting fungal cell membrane synthesis.
| Metabolism | Extensively metabolized in the liver primarily by CYP3A4; major metabolite is hydroxyitraconazole (active). Inhibits CYP3A4. |
| Excretion | Itraconazole is extensively metabolized in the liver; the primary route of elimination is fecal (approximately 54% as metabolites, 18% as unchanged drug). Renal excretion accounts for about 35% of the dose, with <1% as unchanged drug. Bilary excretion also contributes. |
| Half-life | Terminal elimination half-life of itraconazole is approximately 24-36 hours after a single dose, but upon chronic dosing, the half-life increases to 34-42 hours due to saturable metabolism. For the active metabolite hydroxyitraconazole, half-life is similar. This prolonged half-life supports once- or twice-daily dosing. |
| Protein binding | Itraconazole is highly protein-bound: 99.8% bound to plasma proteins, primarily to albumin. |
| Volume of Distribution | Volume of distribution (Vd) is large, approximately 10-30 L/kg after intravenous administration, indicating extensive tissue distribution. Itraconazole concentrates in adipose tissue, skin, nails, and lungs, with tissue levels exceeding plasma levels by several-fold. |
| Bioavailability | Oral bioavailability is variable but approximately 55% under fed conditions; absorption is enhanced by acidic gastric pH and food. Capsules should be taken with a full meal. Oral solution has higher bioavailability (approximately 70%). Intravenous administration yields 100% bioavailability. |
| Onset of Action | Oral: Clinical effect (antifungal) typically begins within 1-2 weeks for dermatophyte infections. For invasive aspergillosis, detectable levels achieved within 2-4 hours, but clinical response may take days to weeks. Intravenous: Onset of antifungal action is immediate after infusion, but clinical effect evident within a few days. |
| Duration of Action | Duration of antifungal action is dose-dependent; with standard dosing (200 mg daily), effective concentrations persist for 24 hours, supporting once-daily dosing. For pulse therapy (e.g., onychomycosis), drug remains in keratinized tissue for weeks after cessation. Clinical duration may extend for months in some tissues due to accumulation. |
200 mg orally once daily; for life-threatening infections, can be increased to 200 mg three times daily for first 3 days then twice daily. IV: 200 mg IV every 12 hours for 2 days, then 200 mg IV once daily.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild-moderate renal impairment. For severe renal impairment (CrCl <30 mL/min): contraindicated due to accumulation of excipient hydroxypropyl-beta-cyclodextrin (IV formulation) or limited data for oral. Oral use should be avoided if CrCl <30 mL/min unless benefit outweighs risk. |
| Liver impairment | Child-Pugh Class A: Use with caution, no specific dose adjustment. Child-Pugh Class B: Reduce dose to 100 mg once daily or 200 mg every other day; monitor liver function. Child-Pugh Class C: Contraindicated due to risk of hepatotoxicity. |
| Pediatric use | Safety and efficacy not established for most indications. Doses for systemic fungal infections: 5 mg/kg/day orally once daily (max 400 mg) or 2.5 mg/kg IV every 12 hours (max 200 mg per dose). IV not approved in children <18 years in some regions. |
| Geriatric use | Start at lower end of dosing range (100-200 mg once daily) due to decreased hepatic or renal function; monitor for adverse effects and drug interactions. No specific dose adjustment required but caution in those with renal impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Inhibits CYP3A4 increasing levels of many drugs (eg statins) Contraindicated with drugs that prolong QT interval and can cause negative inotropy and heart failure.
| Breastfeeding | Itraconazole is excreted into human breast milk in low amounts (M/P ratio not established; estimated <0.1% of maternal weight-adjusted dose). No adverse effects reported in breastfed infants. Caution recommended for preterm or low-birth-weight infants. Consider alternative therapy for superficial infections during breastfeeding due to long half-life and accumulation. |
| Teratogenic Risk | FDA Pregnancy Category C. In animal studies, itraconazole was embryotoxic and teratogenic at high doses. Human data are limited. First trimester: increased risk of spontaneous abortion and major congenital malformations (e.g., skeletal, cardiovascular) based on retrospective studies; risk appears dose-related. Second and third trimesters: limited data, but no clear pattern of specific defects; risk-benefit should be carefully assessed due to potential fetal exposure. Avoid in pregnancy unless essential (e.g., systemic fungal infection unresponsive to safer alternatives). |
■ FDA Black Box Warning
WARNING: Congestive heart failure (CHF) has been observed. Itraconazole is contraindicated for treatment of onychomycosis in patients with evidence of ventricular dysfunction, such as CHF or a history of CHF. Do not administer for other indications in patients with ventricular dysfunction unless benefit clearly outweighs risk. Discontinue if signs or symptoms of CHF occur.
| Common Effects | Nausea Abdominal pain Constipation Dizziness Headache Indigestion Vomiting |
| Serious Effects |
["Concurrent administration with CYP3A4 substrates that prolong QT interval or cause serious arrhythmias (e.g., dofetilide, quinidine, pimozide, lurasidone, methadone, disopyramide, dronedarone, ranolazine, ergot alkaloids, certain statins like simvastatin/lovastatin, certain benzodiazepines like oral midazolam/triazolam, and certain calcium channel blockers like felodipine/nifedipine)","Hypersensitivity to itraconazole or any excipients","Documented ventricular dysfunction (including CHF or history of CHF) for onychomycosis treatment","Co-administration with colchicine, fesoterodine, naloxegol, and other drugs with narrow therapeutic index that are CYP3A4 substrates"]
| Precautions |
Loading safety data…
| Fetal Monitoring | Maternal: Monitor hepatic function (ALT, AST, bilirubin) at baseline and monthly due to risk of hepatotoxicity; assess for signs of heart failure (itraconazole has negative inotropic effects); monitor serum potassium, magnesium, and calcium during prolonged therapy to prevent hypokalemia/hypomagnesemia which can exacerbate QT prolongation. Fetal: Ultrasound for structural anomalies if first-trimester exposure; consider fetal echocardiography if high-dose or prolonged therapy due to potential cardiotoxicity. |
| Fertility Effects | In animal studies, high doses caused impaired fertility and testicular atrophy. Human data: Reversible decreases in sperm count and motility reported in men; oligospermia may persist after discontinuation. No definitive evidence of female infertility; however, hormonal disturbances (e.g., adrenal suppression) could theoretically affect ovulation. Use with caution in couples attempting conception. |
| ["Hepatotoxicity: Rare severe liver injury, including fatal cases; monitor liver function.","Cardiac effects: Negative inotropic effects; contraindicated in CHF; avoid in ventricular dysfunction.","Neuropathy: Cases of peripheral neuropathy; discontinue if symptoms develop.","Drug interactions: Potent CYP3A4 inhibitor; numerous contraindicated combinations (e.g., certain statins, benzodiazepines, ergot alkaloids, etc.).","Hearing loss: Transient or permanent hearing loss reported.","Hypersensitivity: Anaphylactic reactions; discontinue if rash or allergic symptoms.","Renal impairment: Caution in severe renal impairment (limited data).","Pediatric use: Safety not established for systemic fungal infections.","Pregnancy: Use only if benefit outweighs risk; embryotoxic and teratogenic in animals."] |