Pronunciation:

(kee toe KOE na zole)

U.S. Brand Names:

Generic Available:

Canadian Brand Names:

Use:

Use - Dental:

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Lactation:

Contraindications:

Warnings/Precautions:

Adverse Reactions:

Oral:

1% to 10%:

Dermatologic: Pruritus (2%)

Gastrointestinal: Nausea/vomiting (3% to 10%), abdominal pain (1%)

<1%: Headache, dizziness, somnolence, fever, chills, bulging fontanelles, depression, gynecomastia, diarrhea, impotence, thrombocytopenia, leukopenia, hemolytic anemia, hepatotoxicity, photophobia

Cream: Severe irritation, pruritus, stinging (~5%)

Shampoo: Increases in normal hair loss, irritation (<1%), abnormal hair texture, scalp pustules, mild dryness of skin, itching, oiliness/dryness of hair

Overdosage/Toxicology:

Drug Interactions:

Benzodiazepines: Alprazolam, diazepam, temazepam, triazolam, and midazolam serum concentrations may be increased; consider a benzodiazepine not metabolized by CYP3A4 (such as lorazepam) or another antifungal that is metabolized by CYP3A4. Concurrent use is contraindicated.

Buspirone: Serum concentrations may be increased; monitor for sedation

Busulfan: Serum concentrations may be increased; avoid concurrent use

Calcium channel blockers: Serum concentrations may be increased (applies to those agents metabolized by CYP3A4, including felodipine, nifedipine, and verapamil); consider another agent instead of a calcium channel blocker, another antifungal, or reduce the dose of the calcium channel blocker; monitor blood pressure

Cisapride: Serum concentration is increased which may lead to malignant arrhythmias; concurrent use is contraindicated

CYP1A2 substrates: Ketoconazole may increase the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine.

CYP2A6 substrates: Ketoconazole may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.

CYP2C8/9 substrates: Ketoconazole may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

CYP2C19 substrates: Ketoconazole may increase the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline.

CYP2D6 substrates: Ketoconazole may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Ketoconazole may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of ketoconazole. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 substrates: Ketoconazole may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Didanosine: May decrease absorption of ketoconazole (due to buffering capacity of oral solution); applies only to oral solution formulation of didanosine

Docetaxel: Serum concentrations may be increased; avoid concurrent use

Erythromycin (and clarithromycin): May increase serum concentrations of ketoconazole.

H2 blockers: May decrease ketoconazole absorption. Ketoconazole depends on gastric acidity for absorption. Avoid concurrent use.

HMG-CoA reductase inhibitors (except pravastatin and fluvastatin): Serum concentrations may be increased. The risk of myopathy/rhabdomyolysis may be increased. Switch to pravastatin/fluvastatin or suspend treatment during course of ketoconazole therapy.

Immunosuppressants: Cyclosporine, sirolimus, and tacrolimus: Serum concentrations may be increased; monitor serum concentrations and renal function

Methylprednisolone: Serum concentrations may be increased; monitor

Nevirapine: May decrease serum concentrations of ketoconazole; monitor

Oral contraceptives: Efficacy may be reduced by ketoconazole (limited data); use barrier birth control method during concurrent use

Phenytoin: Serum concentrations may be increased; monitor phenytoin levels and adjust dose as needed

Protease inhibitors: May increase serum concentrations of ketoconazole. Includes amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir; monitor

Proton pump inhibitors: May decrease ketoconazole absorption. Ketoconazole depends on gastric acidity for absorption. Avoid concurrent use (includes omeprazole, lansoprazole).

Quinidine: Serum levels may be increased; monitor

Rifampin: Rifampin decreases ketoconazole's serum concentration to levels which are no longer effective; avoid concurrent use.

Sildenafil: Serum concentrations may be increased by ketoconazole; consider dosage reduction. A maximum sildenafil dose of 25 mg in 48 hours is recommended with other strong CYP3A4 inhibitors.

Tadalafil: Serum concentrations may be increased by ketoconazole. A maximum tadalafil dose of 10 mg in 72 hours is recommended with strong CYP3A4 inhibitors.

Trimetrexate: Serum concentrations may be increased; monitor

Vardenafil: Serum concentrations may be increased by ketoconazole. If ketoconazole dose is 200 mg/day, limit vardenafil to a maximum of 5 mg/24 hours. If ketoconazole dose is 400 mg/day, limit vardenafil dose to a maximum of 2.5 mg/24 hours.

Warfarin: Anticoagulant effects may be increased; monitor INR and adjust warfarin's dose as needed

Vinca alkaloids: Serum concentrations may be increased; avoid concurrent use

Zolpidem: Serum levels may be increased; monitor

Ethanol/Nutrition/Herb Interactions:

Food: Ketoconazole peak serum levels may be prolonged if taken with food.

Herb/Nutraceutical: St John's wort may decrease ketoconazole levels.

Mechanism of Action:

Pharmacodynamics/Kinetics:

Absorption: Oral: Rapid (~75%); Shampoo: None

Distribution: Well into inflamed joint fluid, saliva, bile, urine, breast milk, sebum, cerumen, feces, tendons, skin and soft tissues, and testes; crosses blood-brain barrier poorly; only negligible amounts reach CSF

Protein binding: 93% to 96%

Metabolism: Partially hepatic via CYP3A4 to inactive compounds

Bioavailability: Decreases as gastric pH increases

Half-life elimination: Biphasic: Initial: 2 hours; Terminal: 8 hours

Time to peak, serum: 1-2 hours

Excretion: Feces (57%); urine (13%)

Dosage:

Fungal infections:

Oral:

Children 2 years: 3.3-6.6 mg/kg/day as a single dose for 1-2 weeks for candidiasis, for at least 4 weeks in recalcitrant dermatophyte infections, and for up to 6 months for other systemic mycoses

Adults: 200-400 mg/day as a single daily dose for durations as stated above

Shampoo: Apply twice weekly for 4 weeks with at least 3 days between each shampoo

Topical: Rub gently into the affected area once daily to twice daily

Prostate cancer (unlabeled use): Oral: Adults: 400 mg 3 times/day

Dosing adjustment in hepatic impairment: Dose reductions should be considered in patients with severe liver disease

Hemodialysis: Not dialyzable (0% to 5%)

Administration:

Monitoring Parameters:

Dietary Considerations:

Patient Education:

Topical: Wash and dry area before applying medication thinly. Do not cover with occlusive dressing. Report severe skin irritation or if condition does not improve.

Shampoo: Allow 3 days between shampoos. You may experience some hair loss, scalp irritations, itching change in hair texture, or scalp pustules. Report severe side effects or if infestation persists.

Cardiovascular Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Effects on Mental Status:

Mental Health: Effects on Psychiatric Treatment:

Dosage Forms:

Cream, topical: 2% (15 g, 30 g, 60 g)

Shampoo, topical (Nizoral® A-D): 1% (6 mL, 120 mL, 210 mL)

Tablet (Nizoral®): 200 mg

Extemporaneously Prepared:

Allen LV, "Ketoconazole Oral Suspension,"US Pharm, 1993, 18(2):98-9, 101.

International Brand Names: