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. |
| Molecular Weight | 705.63 |
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 | Animal studies show embryotoxicity and teratogenicity; human data limited. Use only if potential benefit justifies risk. |
| 2nd trimester | Avoid use unless essential; consider alternative antifungal therapy. |
| 3rd trimester | Avoid near term due to potential for neonatal hypoglycemia and adrenal suppression. |
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.
| Placental transfer | Itraconazole crosses the placenta; fetal concentrations are about 40-50% of maternal serum levels. |
| Breastfeeding | Itraconazole is excreted into breast milk in low concentrations; however, limited long-term data. Use with caution, monitor infant for adverse effects. |
■ 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 |
Concomitant use with certain HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin)Concomitant use with ergot alkaloidsConcomitant use with oral midazolam, triazolamConcomitant use with CYP3A4 substrates that prolong QT interval (e.g., pimozide, quinidine)Concomitant use with certain tyrosine kinase inhibitors (e.g., sunitinib)Hypersensitivity to itraconazole or excipients
| Precautions | 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. |
Loading safety data…
| Lactation Rating |
| L3 (Moderately Safe) |
| 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). |
| 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. |
| Food/Dietary | Itraconazole capsules must be taken with a full meal to ensure adequate absorption; oral solution should be taken on an empty stomach. Avoid grapefruit and grapefruit juice as they can decrease itraconazole absorption and increase serum levels, leading to toxicity. Avoid alcohol due to potential hepatotoxicity. No other specific dietary restrictions. |
| Clinical Pearls | Itraconazole is a triazole antifungal with potent CYP3A4 inhibition; check for drug interactions especially with statins, benzodiazepines, and calcium channel blockers. Requires acidic gastric pH for absorption; avoid concurrent antacids, H2 blockers, or PPIs. Monitor liver function tests and serum potassium levels. Use with caution in patients with ventricular dysfunction due to negative inotropic effects. Therapeutic drug monitoring recommended for serious infections; target trough levels >0.5 mg/L for prophylaxis and >1 mg/L for treatment. |
| Patient Advice | Take itraconazole capsules with a full meal to enhance absorption; the oral solution should be taken on an empty stomach. · Do not take antacids, H2 blockers (e.g., famotidine), or proton pump inhibitors (e.g., omeprazole) while on itraconazole, as they reduce its effectiveness. · Avoid grapefruit and grapefruit juice during treatment, as they may alter drug levels. · Report signs of liver problems such as dark urine, pale stools, yellowing of skin or eyes, or persistent nausea and vomiting. · Inform your doctor of all medications you take, including over-the-counter drugs and herbal supplements, due to numerous interactions. · Complete the full course of therapy even if you feel better; do not skip doses. · Store capsules at room temperature away from moisture and heat. |