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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NIZORAL (NIZORAL).
| Breastfeeding | Excreted into breast milk; M/P ratio unknown. Avoid breastfeeding due to potential for hepatic toxicity and adrenal suppression in the infant. Alternative antifungals preferred. |
| 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. |
■ 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 excipients; concomitant use with drugs metabolized by CYP3A4 that prolong QT interval; patients with QT interval prolongation; hepatic impairment; concurrent use with colchicine, fesoterodine, solifenacin, ergot alkaloids, HMG-CoA reductase inhibitors, midazolam, triazolam, felodipine, etc.; pregnancy (may cause fetal harm).
| 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). |
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| 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. |