Dosing and uses of Nizoral (ketoconazole)
Adult dosage forms and strengths
tablet
- 200mg
Fungal Infections
Indicated for the treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis
200-400 mg/day PO
Dosage modifications
Renal impairment: No dosage modifications provided in manufacturer’s labeling
Hepatic impairment
- No dosage modifications provided in manufacturer’s labeling
- If hepatotoxicity occurs during treatment (ALT levels above UNL or ALT 30% above baseline): Interrupt dosing and order a full set of liver tests
Dosing Considerations
Do not use tablets as first-line treatment; should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential of hepatotoxicity
Avoid prescribing tablets to treat skin and nail fungal infections owing to risk of serious liver damage, adrenal gland problems, and harmful interactions with other medicines that outweigh its benefit in treating these conditions, which are not approved uses of the drug (these indications were removed from labeling by the FDA in 2013)
Do not use for fungal meningitis because of poor penetration into the CSF
Cushing Syndrome (Off-label)
Used off-label to inhibit steroidogenesis in patients with Cushing syndrome
600-800 mg/day PO
Used rarely and often toxic at doses required to reduce cortisol secretion
Recurrent Tinea Versicolor (Off-label)
400 mg PO monthly
Pediatric dosage forms and strengths
tablet
- 200mg
Fungal Infections
Indicated for the treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis
<2 years old: Safety and efficacy not established
≥2 years old: 3.3-6.6 mg/kg/day PO
Dosage modifications
Renal impairment: No dosage modifications provided in manufacturer’s labeling
Hepatic impairment
- No dosage modifications provided in manufacturer’s labeling
- If hepatotoxicity occurs during treatment (ALT levels above UNL or ALT 30% above baseline): Interrupt dosing and order a full set of liver tests
Dosing Considerations
Do not use tablets as first-line treatment; should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential of hepatotoxicity
Avoid prescribing tablets to treat skin and nail fungal infections owing to risk of serious liver damage, adrenal gland problems, and harmful interactions with other medicines that outweigh its benefit in treating these conditions, which are not approved uses of the drug (these indications were removed from labeling by the FDA in 2013)
Do not use for fungal meningitis because of poor penetration into the CSF
Nizoral (ketoconazole) adverse (side) effects
1-10%
Nausea and vomiting (3-10%)
Pruritus (2%)
Abdominal pain (1%)
<1%
Alopecia
Headache
Dizziness
Hyperlipidemia
Somnolence
Fever
Chills
Bulging fontanelles
Depression
Gynecomastia
Diarrhea
Impotence
Thrombocytopenia
Leukopenia
Hemolytic anemia
Erythema multiforme
Orthostatic hypotension
Jaundice
Dyspepsia
Dysgeusia
Hepatotoxicity
Decreased platelet count
Xeroderma
Photophobia
Warnings
Black box warnings
Tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks
Hepatotoxicity has occurred with oral use, including some fatalities or requiring liver transplantation; reported with oral administration of drug; some patients had no obvious risk factors for liver disease
May cause QT prolongation; coadministration with dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, and ranolazine is contraindicated; ketoconazole can cause elevated plasma concentrations of these drugs (by CYP3A4 inhibition) and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes
Contraindications
Hypersensitivity
Contraindicated with dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, and ranolazine; can cause elevated plasma concentrations of these drugs and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias (eg, torsades de pointes)
Concurrent therapy with cisapride, ergot derivatives, or triazolam (fatal cardiac arrhythmias may occur)
Acute or chronic liver disease
CYP3A4 metabolized HMG-CoA reductase inhibitors (eg, simvastatin, lovastatin); ketoconazole inhibits CYP3A4 and may increase risk of myopathy associated with statins
Cautions
Do not use tablets as first-line treatment; should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential of hepatotoxicity (see Black box warnings)
Avoid prescribing tablets to treat skin and nail fungal infections owing to risk of serious liver damage, adrenal gland problems, and harmful interactions with other medicines that outweigh its benefit in treating these conditions, which are not approved uses of the drug (these indications were removed from labeling by the FDA in 2013)
Hypersensitivity to other azoles
Hepatotoxicity reported, including fatalities or liver transplantation (see Black box warnings)
Ketoconazole decreases metabolism of midazolam PO, triazolam PO, or alprazolam and may result in prolonged hypnotic and sedative effects
Coadministration of CYP3A4 metabolized HMG-CoA reductase inhibitors (eg, simvastatin, lovastatin) increases risk for myopathy (see Contraindications)
Potential for gynecomastia (drug has antiandrogenic activity)
Adrenal insufficiency
- Decreases adrenal corticosteroid secretion at doses ≥400 mg
- This effect is not shared with other azoles
- Do not exceed recommended dose of 200-400 mg/day
- Monitor adrenal function in patients with adrenal insufficiency or with borderline adrenal function, and in patients under prolonged periods of stress (eg, major surgery, intensive care)
Pregnancy and lactation
Pregnancy category: C
Lactation: Drug enters breast milk
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Nizoral (ketoconazole)
Mechanism of action
Inhibits cytochrome P450-dependent synthesis of ergosterol, which in turn inhibits cell-membrane formation
Cushing syndrome (off-label): Inhibition of P450 enzymes includes the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisoL
Absorption
Rapid (~75%)
Bioavailability: Decreases as gastric pH increases
Peak plasma time: 1-2 hr
Distribution
Well distributed into inflamed joint fluid, saliva, bile, urine, breast milk, sebum, cerumen, feces, tendons, skin and soft tissue, testes; crosses blood-brain barrier poorly, with only negligible amounts reaching CSF
Protein bound: 93-96%
Metabolism
Partially metabolized in liver via CYP3A4 to inactive compounds
Elimination
Half-life: Biphasic: initial, 2 hr; terminal, 8 hr
Excretion: Feces (57%), urine (13%)
