KETOZOLE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KETOZOLE (KETOZOLE).
Ketoconazole is an imidazole antifungal agent that inhibits fungal cytochrome P450 14α-demethylase, thereby blocking the conversion of lanosterol to ergosterol, a key component of the fungal cell membrane. This leads to increased membrane permeability and cell death.
| Metabolism | Primarily hepatic via oxidative metabolism involving CYP3A4 and to a lesser extent CYP1A2, CYP2C9, and CYP2C19. It is a potent inhibitor of CYP3A4 and CYP2C9. |
| Excretion | Primarily hepatic metabolism; renal excretion of unchanged drug <1%. Biliary/fecal excretion accounts for ~20-35% of metabolites. |
| Half-life | Terminal elimination half-life is approximately 2 hours (range 1.5–3.5 hours). Clinically, duration of antifungal effect extends beyond plasma half-life due to persistent tissue levels. |
| Protein binding | 99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Vd is approximately 3.5 L/kg (range 2–4 L/kg); indicates extensive tissue distribution with high concentrations in skin, liver, and bone. |
| Bioavailability | Oral bioavailability is approximately 75% (range 70–80%) after administration with a meal. Topical bioavailability: <5% systemically. |
| Onset of Action | Oral: Onset of antifungal effect occurs within 1–4 hours after first dose. Topical: Onset within 72 hours for dermatophyte infections. |
| Duration of Action | Oral: Clinical duration ~12–24 hours; requires daily dosing. Topical: Duration of action up to 72 hours after application. |
| Molecular Weight | 291.39 |
| Action Class | Fungal ergosterol synthesis inhibitor |
| Brand Substitutes | Ketofly 200mg Tablet, Ketoscalp Tablet, Ketozig 200mg Tablet, Candizone 200mg Tablet, Ketocop 200mg Tablet |
200 mg orally once daily with food.
| Dosage form | CREAM |
| Renal impairment | No adjustment required for GFR >30 mL/min. For GFR <30 mL/min, consider dose reduction to 200 mg every 48 hours. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B or C: reduce dose to 200 mg every 48 hours. |
| Pediatric use | Children >2 years: 3-5 mg/kg orally once daily; maximum 200 mg. |
| Geriatric use | Initiate at 200 mg once daily; monitor renal and hepatic function; consider dose reduction if impaired. |
| 1st trimester | Contraindicated due to teratogenic effects (skeletal and cardiac malformations) in animal studies and case reports. |
| 2nd trimester | Contraindicated due to risk of fetal toxicity and potential for prolonged persistence in tissues. |
| 3rd trimester | Contraindicated due to risk of prolonged persistence and potential for fetal harm; avoid near term. |
Clinical note
Comprehensive clinical and safety monograph for KETOZOLE (KETOZOLE).
| Placental transfer | Extensive; crosses placenta readily with fetal concentrations similar to maternal. |
| Breastfeeding | Excreted into breast milk in small amounts; potential for infant exposure and toxicity. Use contraindicated due to long half-life and accumulation. |
| Lactation Rating |
■ FDA Black Box Warning
Hepatotoxicity: Ketoconazole has been associated with severe hepatotoxicity, including fatal cases. Use only when other antifungal therapies are not available or tolerated. Monitor liver function tests frequently. Contraindicated in patients with acute or chronic liver disease.
| Serious Effects |
Hypersensitivity to ketoconazole or azolesPregnancyLactationSevere hepatic impairmentUse with drugs that prolong QTc interval
| Precautions | Hepatotoxicity (see black box warning), QT interval prolongation: May prolong QT interval; avoid use with other QT-prolonging drugs or in patients with electrolyte disturbances or bradycardia, Adrenal insufficiency: Inhibits adrenal steroidogenesis; may cause adrenal suppression with prolonged use, Drug interactions: Potent CYP3A4 inhibitor; contraindicated with certain drugs (e.g., ergot alkaloids, midazolam, certain statins), Gastrointestinal disturbances: Nausea, vomiting, abdominal pain |
| Food/Dietary | Grapefruit and grapefruit juice increase ketoconazole absorption and risk of toxicity. Avoid acidic drinks (e.g., cola) that may reduce absorption. Take with non-acidic food such as water or milk. Avoid alcohol due to hepatotoxicity risk. |
Loading safety data…
| L5 (Contraindicated) |
| Teratogenic Risk | First trimester: Crosses placenta; animal studies show teratogenicity at high doses; limited human data preclude risk quantification but suggest possible increased risk of congenital anomalies, particularly skeletal and craniofacial defects. Second/third trimester: Potential for fetal adrenal suppression with prolonged use; reports of preterm birth, low birth weight; avoid unless essential. |
| Fetal Monitoring | Maternal: Liver function tests, renal function, electrolyte levels, serum potassium and glucose, adrenal function tests (if prolonged use), signs of hepatotoxicity or adrenal suppression. Fetal: Ultrasound for growth assessment and amniotic fluid volume; consider fetal echocardiography for prolonged exposure. Neonatal: Monitor for adrenal insufficiency, hypoglycemia, and liver function after delivery. |
| Fertility Effects | May cause reversible inhibition of spermatogenesis in males (reduced sperm count and motility). In females, potential ovulation inhibition due to antiestrogenic effects; no controlled data in humans. Discontinue if pregnancy is planned. |
| Clinical Pearls | Ketoconazole is a potent inhibitor of CYP3A4 and CYP1A2; assess for drug interactions. Monitor liver function tests due to hepatotoxicity risk. Oral ketoconazole is contraindicated in adrenal insufficiency as it inhibits steroidogenesis. Topical forms have minimal systemic absorption. |
| Patient Advice | Take oral ketoconazole with food to improve absorption and reduce GI upset. · Avoid alcohol and hepatotoxic drugs. · Complete full course even if symptoms improve. · Report signs of liver toxicity: jaundice, dark urine, fatigue. · Topical: apply to affected area only; avoid eyes and mucous membranes. |