Ketoconazole (Apo-Ketoconazole)

1. Health Canada Product Monograph — Ketoconazole

• Ketoconazole tablets treat serious or life-threatening systemic fungal infections, including systemic candidiasis, chronic mucocutaneous candidiasis, coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, and chromomycosis, in patients for whom other antifungal therapy is unsuitable or has failed.
• It may also be used for severe, recalcitrant dermatophyte (skin) infections that have not responded to other treatments.
• Ketoconazole is not recommended for fungal infections of the central nervous system, since it penetrates poorly into the brain and spinal fluid.
• Because of its liver toxicity risk, ketoconazole tablets are reserved for serious infections and should not be used for mild or moderate fungal infections.

• Ketoconazole crosses the placenta and has caused fetal abnormalities and pregnancy loss in animal studies, so very careful consideration should be given to its use during pregnancy.
• Women of childbearing potential should use effective contraception while taking ketoconazole tablets.
• If pregnancy occurs during treatment, the prescriber should carefully weigh the risks and benefits of continuing therapy.

• Ketoconazole passes into breast milk, so breastfeeding should be stopped before starting treatment with ketoconazole tablets.

• Older adults may be more prone to the bone-thinning effects of long-term ketoconazole use, so the dose should not exceed 400 mg per day in this age group.
• Age-related decline in liver function may increase the risk of hepatotoxicity, so older adults should have liver function monitored closely.

• Ketoconazole tablets have not been systematically studied in children, and there is little information available in children under 2 years of age.
• Ketoconazole should only be used in children when the potential benefit outweighs the risk, with careful monitoring of liver function and blood counts.
• Long-term use in children requires caution because ketoconazole can interfere with steroid hormone production, vitamin D metabolism, and normal growth and puberty.
• A case of hypoparathyroidism has been reported in a child on long-term ketoconazole therapy.

• The usual adult dose of ketoconazole is 200 mg once daily, taken with a meal.
• If the response is inadequate, the dose may be increased to 400 mg once daily; the maximum recommended dose is 400 mg per day.
• Duration of treatment depends on the infection being treated, ranging from about 4 weeks for dermatophyte infections to 6 months or longer for infections such as coccidioidomycosis and chromomycosis.
• Antacids or other acid-reducing medicines should be taken at least 2 hours after ketoconazole, since ketoconazole needs stomach acid to dissolve and absorb properly.
• Patients with reduced stomach acid, including those on acid-suppressing medicines, may be advised to take ketoconazole with a cola beverage to improve absorption.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Overdose has not been extensively documented but would be expected to produce an exaggeration of ketoconazole's known adverse effects, particularly on the liver and gastrointestinal tract.
• Supportive care is the mainstay of treatment, including gastric lavage with sodium bicarbonate if performed within the first hour of ingestion.
• Activated charcoal may be given to reduce further absorption.
• Ketoconazole is not removed by hemodialysis, so dialysis is not useful in overdose management.

• Nausea and vomiting may occur.
• Indigestion (dyspepsia) may occur.
• Abdominal pain may occur.
• Diarrhea may occur.
• Itching (pruritus) may occur.
• Skin rash may occur.
• Headache may occur.
• Dizziness may occur.
• Drowsiness may occur.
• Hair loss (alopecia) may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Ketoconazole can cause serious liver injury, including liver failure and death, even at recommended doses and after short courses of treatment.
• Signs of liver problems include unusual tiredness, loss of appetite, nausea, vomiting, yellowing of the skin or eyes, dark urine, or pale stools.
• Severe allergic reactions, including anaphylaxis with swelling of the face, throat, or body, have been reported.
• Severe skin reactions, including widespread blistering or peeling skin, may occur.
• Ketoconazole can reduce adrenal gland hormone production, which may become significant during periods of stress, illness, or surgery.
• Ketoconazole can lower testosterone levels in men, potentially causing breast enlargement (gynecomastia), reduced libido, impotence, and reduced sperm counts.
• Menstrual irregularities may occur in women.
• Increased pressure inside the skull has been reported rarely.
• Blood disorders, including low platelet counts and reduced white blood cell counts, may occur.
• Seek urgent medical attention for signs of liver injury, a severe allergic reaction, a severe skin reaction, or an irregular or very fast heartbeat.

• Use with caution in patients with reduced stomach acid, such as those on acid-suppressing medicines, since ketoconazole absorption depends on adequate stomach acidity.
• Use with caution in women of childbearing potential, who should use effective contraception during treatment.
• Use with caution in children requiring long-term therapy, due to potential effects on growth, puberty, and bone or calcium metabolism.
• Use with caution in postmenopausal women and older adults, who are more susceptible to bone fragility with prolonged use; the dose should not exceed 400 mg daily.
• Use with caution in patients with a history of significant alcohol use or those taking other medicines that can harm the liver.
• Use with caution in patients with known sensitivity to miconazole or other imidazole antifungals, since cross-sensitivity may occur.
• Use with caution in patients predisposed to adrenal insufficiency or under significant physical stress, since ketoconazole can blunt the adrenal stress response.

• Contraindicated in patients with known hypersensitivity to ketoconazole.
• Contraindicated in patients with liver dysfunction.
• Contraindicated for use with oral midazolam or triazolam, since ketoconazole can dangerously increase their sedative effects.
• Contraindicated for use with lovastatin or simvastatin, since ketoconazole can raise their blood levels enough to increase the risk of muscle breakdown (rhabdomyolysis).
• Contraindicated for use with pimozide, due to the risk of dangerous heart rhythm disturbances.

• Ketoconazole strongly inhibits the CYP3A4 liver enzyme and can raise blood levels of many drugs metabolized by this pathway.
• Levels of certain heart rhythm medicines, including digoxin, quinidine, and disopyramide, may rise with concurrent ketoconazole use, requiring closer monitoring.
• Levels of calcium channel blockers, including verapamil and dihydropyridines such as nisoldipine, may increase, raising the risk of low blood pressure.
• Levels of certain benzodiazepines, including alprazolam and diazepam, may increase, enhancing sedation.
• Levels of cyclosporine, tacrolimus, and sirolimus may rise, requiring dose adjustment and monitoring in transplant patients.
• Levels of certain corticosteroids, including budesonide, dexamethasone, methylprednisolone, and fluticasone, may increase.
• Levels of protease inhibitors used for HIV, such as indinavir, ritonavir, and saquinavir, may be affected.
• Levels of ergot alkaloids, such as ergotamine and dihydroergotamine, may rise, increasing the risk of ergotism.
• Warfarin's blood-thinning effect may be enhanced, requiring closer monitoring of clotting times.
• Insulin requirements may decrease during ketoconazole therapy, so blood sugar should be monitored closely in patients with diabetes.
• Rifampin, rifabutin, isoniazid, phenytoin, carbamazepine, and phenobarbital can reduce ketoconazole's effectiveness by lowering its blood levels.
• Antacids, H2-blockers, and proton pump inhibitors reduce ketoconazole absorption by lowering stomach acidity.
• Clarithromycin and erythromycin may raise ketoconazole blood levels.
• A disulfiram-like reaction, with flushing, rash, and nausea, has rarely occurred when ketoconazole is combined with alcohol.
• Loratadine blood levels may increase with concurrent ketoconazole use, though this has not been linked to significant side effects.

• Ketoconazole should be taken with a meal, since food helps stimulate the stomach acid needed to dissolve and absorb the tablet.
• Antacids and other acid-reducing medicines should be taken at least 2 hours after ketoconazole to avoid reducing its absorption.
• Patients with low stomach acid may be advised to take ketoconazole with a cola beverage to improve absorption.

• Ketoconazole should be taken once daily with a meal, at the same time each day, to support consistent absorption and reduce stomach upset.

• Store ketoconazole tablets at room temperature (15°C to 30°C) in a tightly closed container, away from children.

• Ketoconazole is a tablet-form antifungal reserved for serious fungal infections that require whole-body treatment.
• Take it with food and complete the full course as directed, even if symptoms improve early.
• Report any signs of liver problems, such as yellowing skin or eyes, dark urine, or unusual fatigue, right away.
• Tell your pharmacist about all other medicines you take, since ketoconazole interacts with many common drugs.
• Women who could become pregnant should use effective birth control while on this medicine.