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. |
| Molecular Weight | 531.44 |
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 | Avoid. Teratogenic in animal studies. Use only if benefit outweighs risk. No adequate human studies. |
| 2nd trimester | Avoid. High doses may cause fetal harm. Limited human data. |
| 3rd trimester | Avoid near term. Potential for neonatal hypoglycemia and adrenal suppression if used systemically; topical use likely low risk but avoid prolonged use. |
Clinical note
Strong CYP3A4 inhibitor that can significantly increase levels of many drugs (eg statins) Contraindicated due to risk of hepatotoxicity and adrenal insufficiency.
| Placental transfer | Low molecular weight and high lipophilicity suggest placental transfer. Demonstrated in animal studies; limited human data but expected to cross. |
| Breastfeeding | Unknown if excreted in milk. Potential for infant adrenal suppression and hepatotoxicity with systemic use. Topical use is likely safe but avoid applying to breast area. Consider alternative antifungal during lactation. |
■ 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 |
Hypersensitivity to ketoconazole or any excipientAcute or chronic liver diseaseConcomitant use with CYP3A4 substrates that prolong QT interval (e.g., terfenadine, astemizole, cisapride, pimozide, quinidine, dofetilide)Concomitant use with HMG-CoA reductase inhibitors metabolized by CYP3A4 (e.g., simvastatin, lovastatin)Concomitant use with ergot alkaloids (e.g., dihydroergotamine, ergotamine)
| 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. |
| Food/Dietary |
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| Lactation Rating | L4 |
| 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. |
| 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. |
| Take with food to improve absorption. Avoid grapefruit juice (increases bioavailability). Avoid alcohol (increases hepatotoxicity risk). Acidic beverages (e.g., cola, orange juice) may enhance absorption when gastric acidity is low. Avoid high-antacid foods (e.g., milk, calcium-fortified products) within 2 hours of dose. |
| Clinical Pearls | Ketoconazole is a potent inhibitor of CYP3A4 and CYP2C9, leading to numerous drug interactions. It requires acidic gastric pH for absorption; avoid concurrent use of antacids, H2 blockers, or proton pump inhibitors. Monitor liver function tests due to risk of hepatotoxicity. QT prolongation risk; avoid with other QT-prolonging drugs. Classic indication: treatment of Cushing's syndrome (off-label) due to adrenal steroidogenesis inhibition. Topical formulations are preferred for dermatophyte infections; systemic use reserved for severe cases due to toxicity. |
| Patient Advice | Take with food and an acidic beverage (e.g., cola) if achlorhydria is a concern; avoid antacids or acid-reducing medications within 2 hours. · Report signs of liver toxicity: dark urine, pale stools, jaundice, right upper quadrant pain, or persistent fatigue. · Complete full course even if symptoms improve; do not share medication. · Avoid grapefruit juice as it may alter drug levels; limit alcohol to reduce hepatotoxicity risk. · For topical use, apply to affected area as directed; avoid contact with eyes and mucous membranes. |