KETOCONAZOLE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Inhibits fungal cytochrome P450 14α-demethylase, impairing ergosterol synthesis and disrupting fungal cell membrane integrity.
| Metabolism | Hepatic via CYP3A4; major metabolites include N-deacetyl ketoconazole and others; also substrate of CYP1A2 and CYP2C9. |
| Excretion | Primarily metabolized in the liver; about 70% of the dose is excreted in feces via bile as metabolites, approximately 20-30% in urine (mostly as inactive metabolites), and less than 5% unchanged. |
| Half-life | Biphasic elimination: initial half-life 2-4 hours, terminal half-life 6-10 hours in adults. In severe hepatic impairment, half-life may be prolonged up to 12-20 hours. |
| Protein binding | Extensively bound to plasma proteins (99%), primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent Vd approximately 2-4 L/kg, indicating extensive tissue distribution, including skin, liver, and adipose tissue. |
| Bioavailability | Oral bioavailability is variable and dose-dependent, ranging from 30-75% due to incomplete absorption and first-pass metabolism. Absorption is enhanced by acidic gastric pH; thus, bioavailability decreases with concurrent antacids, H2 blockers, or proton pump inhibitors. |
| Onset of Action | Oral administration: time to peak plasma concentration 1-4 hours; clinical antifungal effect may take several days. Topical: antifungal effect begins within minutes to hours of application. |
| Duration of Action | After oral dosing, therapeutic concentrations persist for 24-36 hours. For topical use, duration depends on formulation and frequency; usually twice daily application recommended. |
200-400 mg orally once daily for superficial fungal infections; 400 mg orally once daily for systemic mycoses. Duration varies by indication.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR >10 mL/min. For GFR <10 mL/min, reduce dose to 50% of normal or administer every 48 hours. Not significantly removed by hemodialysis. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: contraindicated or use with extreme caution; consider alternative therapy. |
| Pediatric use | >2 years: 3.3-6.6 mg/kg orally once daily; maximum 400 mg/day. For systemic mycoses, up to 10 mg/kg/day in divided doses. Not recommended for children <2 years. |
| Geriatric use | Start at lower end of dosing range (200 mg orally once daily) due to age-related decline in hepatic and renal function. Monitor liver function tests and drug interactions. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inhibitor that can significantly increase levels of many drugs (eg statins) Contraindicated due to risk of hepatotoxicity and adrenal insufficiency.
| Breastfeeding | Ketoconazole is excreted into human breast milk; M/P ratio unknown. Systemic absorption from topical use is minimal, but oral use should be avoided due to potential neonatal hepatic toxicity. Consider alternative antifungal therapy during breastfeeding. |
| Teratogenic Risk | Ketoconazole is teratogenic in animal studies at high doses. In human pregnancy, systemic use is contraindicated, especially in the first trimester, due to potential embryotoxic and teratogenic effects (e.g., skeletal abnormalities). Topical use is considered low risk but limited data. FDA Pregnancy Category C. |
■ FDA Black Box Warning
Severe hepatotoxicity, including fatal hepatic failure, especially with oral use. Oral ketoconazole is contraindicated in patients with acute or chronic liver disease.
| Common Effects | Nausea |
| Serious Effects |
Acute or chronic liver disease; concomitant use with drugs that increase QT interval; hypersensitivity; pregnancy (oral); lactation; use with CYP3A4 substrates with narrow therapeutic index (e.g., midazolam, quinidine).
| Precautions | Hepatotoxicity (monitor liver enzymes); adrenal suppression due to inhibition of adrenal corticosteroid synthesis; QT prolongation; drug interactions (strong CYP3A4 inhibitor); avoid alcohol; topical use may cause skin reactions. |
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| Fetal Monitoring | Monitor maternal liver function tests (LFTs) due to hepatotoxicity; adrenal function if long-term therapy; fetal growth and development via ultrasound if systemic exposure occurs. For high-dose or prolonged use, monitor for signs of adrenal insufficiency in the mother. |
| Fertility Effects | Reversible reduction in testosterone levels and sperm motility in males after high-dose systemic use, potentially impairing fertility. In females, interference with ovarian steroidogenesis may affect ovulation. Effects are dose-dependent and reversible upon discontinuation. |