NIZORAL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NIZORAL (NIZORAL).
Inhibits fungal CYP51 (lanosterol 14α-demethylase), blocking ergosterol synthesis and disrupting fungal cell membrane integrity.
| Metabolism | Primarily hepatic via CYP3A4; major metabolite inactive. Inhibits CYP3A4, CYP2C9, CYP2C19, and CYP1A2. |
| Excretion | Approximately 70% of the dose is excreted unchanged in feces via biliary elimination, and about 20–35% is excreted in urine, with less than 1% as unchanged drug in urine. |
| Half-life | Biphasic elimination: initial half-life ~2 hours, terminal half-life 6–10 hours in adults with normal hepatic function; prolonged in hepatic impairment. |
| Protein binding | 99% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 3.5 L/kg, indicating extensive tissue distribution including skin, nails, and sebaceous glands. |
| Bioavailability | Oral: ~75% under fed conditions (enhanced by acidic pH), reduced with achlorhydria or antacids; topical: negligible systemic absorption (<1% of applied dose). |
| Onset of Action | Oral: clinical response (e.g., reduction in fungal symptoms) begins within 24–48 hours; topical: antifungal effect within 1–2 hours, symptomatic relief within 24 hours. |
| Duration of Action | Oral: duration follows half-life (6–10 hours), requiring once-daily dosing; topical: sustained antifungal effect for 12–24 hours after single application. |
| Molecular Weight | 531.43 |
Ketoconazole 200 mg orally once daily with food. For severe infections, increase to 400 mg once daily. Duration depends on indication.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for renal impairment. Not significantly removed by hemodialysis. |
| Liver impairment | Contraindicated in acute or chronic liver disease. For Child-Pugh A, use only if benefit outweighs risk; reduce dose by 50% and monitor liver enzymes. Child-Pugh B or C: contraindicated. |
| Pediatric use | Children >2 years: 3.3-6.6 mg/kg orally once daily, maximum 400 mg/day. For systemic fungal infections, use only if no safer alternative. |
| Geriatric use | No specific dose adjustment. Use caution due to increased risk of hepatotoxicity and adrenal suppression; monitor liver function and adrenal status. |
| 1st trimester | Avoid: Topical use has low systemic absorption but oral use is teratogenic in animal studies; associated with increased risk of congenital anomalies (skeletal, cardiac). |
| 2nd trimester | Avoid: Limited data; potential for fetal harm based on oral ketoconazole's antiandrogenic effects and risk of fetal adrenal insufficiency. |
| 3rd trimester | Avoid: Risk of adrenal suppression in neonate if used near term; may cause prolonged gestation or dystocia due to hormonal effects. |
Clinical note
Comprehensive clinical and safety monograph for NIZORAL (NIZORAL).
| Placental transfer | Ketoconazole crosses the placenta in animal studies; in humans, fetal plasma levels are approximately 10-15% of maternal levels after oral dosing. Transfer is evident. |
| Breastfeeding | Ketoconazole is excreted into breast milk in small amounts after oral administration; topical use likely minimal systemic absorption. However, given potential for hepatic toxicity and endocrine disruption, caution is advised. Monitor infant for diarrhea, rash, or hepatic adverse effects. |
■ FDA Black Box Warning
Concomitant administration with certain drugs: terfenadine, astemizole, cisapride, quinidine, pimozide, dofetilide, methadone, ergot alkaloids, HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin), midazolam, triazolam, and felodipine is contraindicated due to risk of life-threatening arrhythmias (e.g., QT prolongation, torsades de pointes). Also contraindicated with colchicine, fesoterodine, solifenacin, and various others.
| Serious Effects |
Hypersensitivity to ketoconazole or any excipientAcute or chronic liver diseaseConcomitant use with drugs metabolized by CYP3A4 that prolong QT interval (e.g., cisapride, dofetilide, quinidine, pimozide, ergot alkaloids, simvastatin, lovastatin, methadone)Concomitant use with colchicine in patients with renal or hepatic impairment
| Precautions | Hepatotoxicity (potential fatal), QT prolongation (risk of torsades de pointes), adrenal suppression (due to cortisol inhibition), anaphylaxis, photosensitivity, drug interactions (CYP3A4 inhibition), increased intracranial pressure (with intrathecal use). |
| Food/Dietary |
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| Lactation Rating | L3 (Moderately Safe) for topical; L4 (Possibly Hazardous) for oral use |
| Teratogenic Risk | Ketoconazole (NIZORAL) is contraindicated in pregnancy (FDA Category C). First trimester: Increased risk of spontaneous abortion and congenital anomalies (limb defects, craniofacial abnormalities) based on animal studies and limited human data. Second/Third trimester: Potential for oligohydramnios, fetal growth restriction, and neonatal adrenal insufficiency due to inhibition of steroidogenesis. Use only if benefit outweighs risk. |
| Fetal Monitoring | Monitor maternal liver function tests, adrenal function (cortisol levels), and electrocardiogram (QTc prolongation risk). Fetal monitoring includes ultrasound for growth and amniotic fluid volume, and fetal heart rate monitoring if used near term. |
| Fertility Effects | Ketoconazole inhibits testosterone synthesis and may cause reversible oligospermia, decreased libido, and gynecomastia in males. In females, may disrupt ovulation due to hormonal effects. Fertility may be impaired during therapy. |
| Avoid alcohol and alcohol-containing products (disulfiram-like reaction). Grapefruit juice may increase ketoconazole absorption; avoid concurrent intake. Food increases absorption of oral formulation, so take with a meal. No specific restrictions for topical use. |
| Clinical Pearls | Nizoral (ketoconazole) is a broad-spectrum antifungal; oral use is reserved for serious infections due to hepatotoxicity risk. Topical formulations are first-line for seborrheic dermatitis and tinea versicolor. Avoid concurrent use with CYP3A4 substrates (e.g., statins, benzodiazepines) as ketoconazole is a potent inhibitor. Monitor liver function tests (LFTs) in patients on oral therapy. QT prolongation possible; avoid with other QT-prolonging drugs. |
| Patient Advice | Take oral ketoconazole with food to improve absorption and reduce GI upset. · Complete the full course of treatment even if symptoms improve. · Avoid alcohol during treatment and for at least 48 hours after last dose due to disulfiram-like reaction. · Report signs of liver problems: dark urine, pale stools, yellowing skin/eyes, persistent nausea. · Topical forms: apply to affected area and surrounding skin; avoid eyes and mucous membranes. · Do not use occlusive dressings over topical ketoconazole unless directed. |