No

Antifungal Agent, Oral; Antifungal Agent, Topical

Dental: Treatment of susceptible fungal infections in the oral cavity including candidiasis, oral thrush, and chronic mucocutaneous candidiasis

Medical: Treatment of susceptible fungal infections, including candidiasis, oral thrush, blastomycosis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, chromomycosis, candiduria, chronic mucocutaneous candidiasis, as well as, certain recalcitrant cutaneous dermatophytoses; used topically for treatment of tinea corporis, tinea cruris, tinea versicolor, and cutaneous candidiasis, seborrheic dermatitis

C

Hypersensitivity to ketoconazole or any component; CNS fungal infections (due to poor CNS penetration); coadministration with terfenadine, astemizole, or cisapride is contraindicated due to risk of potentially fatal cardiac arrhythmias

Rare cases of serious cardiovascular adverse event, including death, ventricular tachycardia and torsade de pointes have been observed due to increased terfenadine concentrations induced by ketoconazole. Use with caution in patients with impaired hepatic function; has been associated with hepatotoxicity, including some fatalities; perform periodic liver function tests; high doses of ketoconazole may depress adrenocortical function.

Oral:

1% to 10%:

Dermatologic: Pruritus (1.5%)

Gastrointestinal: Nausea/vomiting (3% to 10%), abdominal pain (1.2%)

<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

Symptoms of overdose include dizziness, headache, nausea, vomiting, diarrhea; overdoses are well tolerated

Treatment includes supportive measures and gastric decontamination

CYP3A3/4 enzyme substrate; CYP1A2, 2C, 2C9, 2C18, 2C19, 3A3/4, and 3A5-7 enzyme inhibitor

Decreased ketoconazole serum levels with isoniazid and phenytoin; decreased/undetectable serum levels with rifampin - should not be administered concomitantly with rifampin; theophylline and oral hypoglycemic serum levels may be decreased

Absorption requires gastric acidity; therefore, antacids, H₂-antagonists (cimetidine and ranitidine), omeprazole, and sucralfate significantly reduce bioavailability resulting in treatment failures; should not be administered concomitantly

Increased toxicity:

May increase cyclosporine levels (by 50%) when high doses are used

Inhibits warfarin metabolism resulting in increased anticoagulant effect

Increases corticosteroid bioavailability and decreases steroid clearance

Increases amprenavir, phenytoin, digoxin, terfenadine, astemizole, indinavir and cisapride concentrations; concomitant administration with astemizole or cisapride is contraindicated; may significantly increase levels and toxicity of lovastatin and simvastatin due to CYP3A4 inhibition; a disulfiram-type reaction may occur with concomitant ethanol

Alters the permeability of the cell wall by blocking fungal cytochrome P-450; inhibits biosynthesis of triglycerides and phospholipids by fungi; inhibits several fungal enzymes that results in a build-up of toxic concentrations of hydrogen peroxide

Absorption: Oral: Rapid (~75%); no detectable absorption following use of the shampoo

Distribution: Well distributed to 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 in the liver by enzymes to inactive compounds

Bioavailability: Decreases as pH of the gastric contents increases

Half-life, biphasic: Initial: 2 hours; Terminal: 8 hours

Time to peak serum concentration: 1-2 hours

Elimination: Primarily in feces (57%) with smaller amounts excreted in urine (13%)

Oral:

Children greater than or equal to 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

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

Hemodialysis: Not dialyzable (0% to 5%)

May be taken with food or milk to decrease GI adverse effects

Liver function tests

May cause drowsiness, dizziness, or depression

May cause leukopenia; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

Oral: May take with food; at least 2 hours before any antacids. Take full course of medication as directed; some infections may require long periods of therapy. Frequent blood tests may be required with long-term therapy. Practice good hygiene measures to reduce incidence of reinfection. If diabetic, test serum glucose regularly. You may experience nausea and vomiting (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); headache (mild analgesic may be necessary); or dizziness (use caution when driving). Report unresolved headache, rash or itching, yellowing of eyes or skin, changes in color of urine or stool, chest pain or palpitations, or sense of fullness or ringing in ears. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Breast-feeding is not recommended.

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 irritation, itching, change in hair texture, or scalp pustules. Report severe side effects or if infestation persists.

Administer 2 hours prior to antacids to prevent decreased absorption due to the high pH of gastric contents

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

Shampoo: 2% (120 mL)

Tablet: 200 mg

A 20 mg/mL suspension may be made by pulverizing twelve 200 mg ketoconazole tablets to a fine powder; add 40 mL Ora-Plus® in small portions with thorough mixing; incorporate Ora-Sweet® to make a final volume of 120 mL and mix thoroughly; refrigerate (no stability information is available)

Como JA and Dismukes WE, "Oral Azole Drugs as Systemic Antifungal Therapy," N Engl J Med, 1994, 330(4):263-72.

Ginsburg AM, McCracken GH Jr, and Olsen K, "Pharmacology of Ketoconazole Suspension in Infants and Children," Antimicrob Agents Chemother, 1983, 23(5):787-9.

Gorman SE, Dela Cruz F, and Paloucek F, "Ketoconazole and Zidovudine Overdose," Am J Emerg Med, 1995, 13(1):115-6.

Greenblatt DJ, von Moltke LL, Harmatz JS, et al, "Interaction of Triazolam and Ketoconazole," Lancet, 1995, 345(8943):191.

Herrod HG, "Chronic Mucocutaneous Candidiasis in Childhood and Complications of non- Candida Infection: A Report of the Pediatric Immunodeficiency Collaborative Study Group," J Pediatr, 1990, 116(3):377-82.

Hwang WL, Gau JP, Young JH, et al, "Ketoconazole and High-Dose Methylprednisolone Predisposing to Cyclosporine-Induced Seizures: A Report of Three Cases," Acta Haematol, 1992, 88(2-3):139-41.

Janssen PA and Symoens JE, "Hepatic Reactions During Ketoconazole Treatment," Am J Med, 1983, 74(1B):80-5.

Lyman CA and Walsh TJ, "Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications," Drugs, 1992, 44(1):9-35.

Terrell CL, "Antifungal Agents. Part II. The Azoles," Mayo Clin Proc, 1999, 74(1):78-100.

Varhe A, Olkkola KT, and Neuvonen PJ, "Oral Triazolam is Potentially Hazardous to Patients Receiving Systemic Antimycotics Ketoconazole or Itraconazole," Clin Pharmacol Ther, 1994, 56(6 Pt 1):601-7.

Wynn RL, "Erythromycin and Ketoconazole (Nizoral®) Associated With Terfenadine (Seldane®)-Induced Ventricular Arrhythmias," Gen Dent, 1993, 41(1):27-9.