ketoconazole
Nizoral

Available forms
Available by prescription only
Cream: 2%
Shampoo: 2%
Tablets: 200 mg
Available without a prescription
Shampoo: 1%

Indications and dosages
 Severe fungal infections caused by susceptible organisms. Adults: Initially, 200 mg P.O. daily as a single dose. May increase dose to 400 mg once daily in patients who don’t respond to lower dosage.
Children older than age 2: 3.3 to 6.6 mg/kg P.O. daily as a single dose.
 Topical treatment of tinea corporis, tinea cruris, tinea versicolor, and tinea pedis. Adults and children: Apply daily or b.i.d. for about 2 weeks; for tinea pedis, apply for 6 weeks.
 Seborrheic dermatitis. Adults and children: Apply b.i.d. for about 4 weeks.
 Dandruff. Adults: Apply for 1 minute, rinse, then reapply for 3 minutes. Shampoo twice weekly for 4 weeks with at least 3 days between shampoos.
 Prostatic carcinoma ◇, disseminated intravascular coagulation related to prostatic cancer ◇. Adults: 400 mg P.O. q 8 hours.

Pharmacodynamics
Antifungal action: Drug is fungicidal and fungistatic, depending on concentrations. It inhibits demethylation of lanosterol, thereby altering membrane permeability and inhibiting purine transport. The in vitro spectrum of activity includes most pathogenic fungi. However, CSF concentrations following oral administration aren’t predictable. It shouldn’t be used to treat fungal meningitis, and specimens should be obtained for susceptibility testing before therapy. Currently available tests may not accurately reflect in vivo activity, so interpret results cautiously.
Drug is used orally to treat disseminated or pulmonary coccidioidomycosis, paracoccidioidomycosis, or histoplasmosis; oral candidiasis; and candiduria (but low renal clearance may limit its usefulness).
It’s also useful in some dermatophytoses, including tinea capitis, tinea cruris, tinea pedis, tinea manus, and tinea unguium (onychomycosis) caused by Epidermophyton, Microsporum, or Trichophyton species.

Pharmacokinetics
Absorption: Converted to the hydrochloride salt before absorption. Absorption is erratic; it’s decreased by raised gastric pH and may be increased in extent and consistency by food.
Distribution: Distributed into bile, saliva, cerumen, synovial fluid, and sebum; CSF penetration is erratic and considered minimal. It is 84% to 99% bound to plasma proteins.
Metabolism: Converted into several inactive metabolites in the liver.
Excretion: More than 50% of a dose is excreted in feces within 4 days; drug and metabolites are secreted in bile. About 13% is excreted unchanged in urine. It probably appears in breast milk. Half-life is biphasic, initially 2 hours, with a terminal half-life of 8 hours.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug and in those taking oral triazolam because of risk of serious CV adverse events. Use oral form cautiously in patients with hepatic disease. Because CSF levels of ketoconazole are unpredictable after oral use, don’t use drug alone to treat fungal meningitis.

Interactions
Drug-drug. Benzodiazepines: Increases levels of these drugs, prolonging sedative effect and increasing risk of toxicity. Use together cautiously.
Buspirone, carbamazepine, donepezil, nisoldipine, protease inhibitors, quinidine, zolpidem: Increases levels of these drugs and risk of toxicity. Monitor patient closely.
Corticosteroids: May increase corticosteroid levels. Monitor patient carefully.
Cyclosporine: May raise cyclosporine levels by interfering with metabolism. Monitor patient closely.
Drugs that raise gastric pH (antacids, antimuscarinics, cimetidine, famotidine, ranitidine): Decrease ketoconazole absorption. Give these drugs 2 hours after ketoconazole.
Hepatotoxic drugs: May enhance toxicity. Monitor patient closely.
Phenytoin: May alter serum levels of both drugs. Monitor patient response to drug; monitor drug levels.
Rifampin: May decrease ketoconazole and rifampin levels to ineffective levels. Avoid use if possible.
Sulfonylureas: May intensify effects of sulfonylureas. Monitor patient closely.
Tacrolimus: Increases tacrolimus levels. Use cautiously. Monitor renal function and tacrolimus level.
Warfarin: May enhance anticoagulant effect. Monitor PT and INR.
Drug-herb. Yew preparations: Inhibit ketoconazole metabolism. Discourage use together.
Drug-lifestyle. Alcohol use: May cause a disulfiram-like reaction. Discourage alcohol use.

Adverse reactions
CNS: headache, nervousness, dizziness, somnolence, photophobia, suicidal tendencies, severe depression (with oral administration), fever.
GI: nausea, vomiting, abdominal pain, diarrhea (with oral administration).
GU: impotence (with oral administration).
Hematologic: thrombocytopenia, hemolytic anemia, leukopenia (with oral administration).
Hepatic: fatal hepatotoxicity (with oral administration).
Skin: pruritus; severe irritation, stinging (with topical administration).
Other: gynecomastia with tenderness, chills.

Effects on lab test results
• May increase lipid, alkaline phosphatase, ALT, and AST levels.
• May decrease hemoglobin and platelet and WBC counts.

Overdose and treatment
Overdose may cause dizziness, tinnitus, headache, nausea, vomiting, or diarrhea; patients with adrenal hypofunction or patients on long-term corticosteroid therapy may show signs of adrenal crisis.
 Treatment includes induced emesis and sodium bicarbonate lavage, followed by activated charcoal and a cathartic; supportive measures as needed.

Special considerations
• Identify organism, but don’t delay therapy for laboratory test results.
• Give oral form with citrus juice.
• Oral drug requires acidity for absorption; adjust administration for patients with achlorhydria.
• Watch for signs of hepatotoxicity: persistent nausea, unusual fatigue, jaundice, dark urine, and pale stools.
Pregnant patients
• Don’t give ketoconazole to pregnant women.
Breast-feeding patients
• Drug may appear in breast milk. An alternative to breast-feeding is recommended.
Pediatric patients
• Safe use in children younger than age 2 hasn’t been established. Consider use in children only when the benefits outweigh the risks.

Patient education
• Instruct achlorhydric patient to dissolve each tablet in 4 ml of 0.2 N hydrochloric acid solution or take with 200 ml of 0.1 N hydrochloric acid. Tell patient to use a glass or plastic straw to avoid damaging tooth enamel and to follow each dose with a glass of water.
• Tell patient to avoid driving or performing other hazardous activities if dizziness or drowsiness occurs; these often occur early in treatment but abate as treatment continues.
• Caution patient not to alter dose or dosage interval or to discontinue drug without medical approval; to prevent recurrence, therapy must continue until active fungal infection is completely eradicated.
• Reassure patient that nausea will subside; to minimize reaction, patient may take drug with food or may divide dosage into two doses.
• Advise patient to avoid preparations for GI distress (such as antacids); some may alter gastric pH levels and interfere with drug action.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use