How do I use ketoconazole?

How to Use Ketoconazole

Ketoconazole should be taken orally at 400-800 mg once daily with a meal or acidic beverage to maximize absorption, though it has largely been replaced by safer alternatives like itraconazole for most fungal infections due to significant hepatotoxicity risks. 1

Dosing by Indication

For Systemic Fungal Infections (Blastomycosis, Histoplasmosis, Coccidioidomycosis)

• Dose: 400-800 mg once daily 1
• Duration: Minimum 6 months, with careful follow-up for 1-2 years due to 10-14% relapse rates 1
• Efficacy: 70% cure rate at 400 mg/day; 82-85% cure rate at doses >400 mg/day 1
• Important caveat: Itraconazole has replaced ketoconazole as the preferred first-line azole due to better absorption, enhanced antimycotic activity, and superior tolerability 1

For Cushing's Disease (Off-Label)

• Initial dose: 400-600 mg per day in 2-3 divided doses 1
• Titration: Increase to 800-1,200 mg per day until cortisol levels normalize 1
• Maintenance: 400-800 mg per day in 2-3 divided doses 1
• Monitoring: Liver function must be monitored closely due to hepatotoxicity risk 1

For Cutaneous Leishmaniasis (Off-Label)

• Dose: 600 mg daily for 28 days in adults 1
• Administration: Take with acidic drink (e.g., cola or citric juice) to enhance absorption 1

Critical Administration Requirements

Optimize Absorption

• Take with food: Ketoconazole requires gastric acidity for dissolution and absorption; oral bioavailability is maximal when tablets are taken with a meal 2
• Avoid acid-suppressing medications: Proton pump inhibitors reduce bioavailability to only 17% of normal; H2-receptor antagonists and antacids similarly impair absorption 2
• Alternative for patients on acid suppressors: Administer with acidic beverage (non-diet cola) to partially restore absorption, or preferably switch to fluconazole which does not require gastric acidity 3, 2
• Timing with antacids: If antacids must be used, administer at least 1 hour before or 2 hours after ketoconazole 2

Dosing Schedule

• Once daily administration: Take the entire daily dose at one time 2
• Peak concentrations: Occur 1-2 hours after dosing, with mean peak plasma levels of approximately 3.5 mcg/mL after a 200 mg dose 2

Mandatory Monitoring

Hepatotoxicity Surveillance

• Baseline: Liver function tests before initiating therapy 1
• During treatment: Weekly monitoring for the first 6 months (when hepatotoxicity most commonly appears), then periodically thereafter 1, 2
• Warning signs: Instruct patients to immediately report unusual fatigue, anorexia, nausea/vomiting, abdominal pain, jaundice, dark urine, pale stools, fever, or rash 2
• Hepatotoxicity incidence: Occurs in 10-20% of patients, typically with mild-moderate transaminase elevations (≤5× ULN), but serious hepatotoxicity requiring liver transplant or causing death has been reported 1, 2

Cardiac Monitoring

• QT prolongation risk: Ketoconazole inhibits cardiac delayed rectifier potassium current and can prolong QTc interval 2
• Contraindicated combinations: Never use with dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, or ranolazine due to life-threatening arrhythmia risk 2
• Warning symptoms: Instruct patients to report feeling faint, lightheaded, dizzy, or irregular/fast heartbeat 2

Endocrine Monitoring

• Testosterone suppression: Doses of 800 mg/day impair testosterone; 1600 mg/day abolish it 2
• Clinical manifestations: Gynecomastia, impotence, oligospermia in men; hirsutism in women 1, 2
• Adrenal insufficiency: High doses may suppress adrenal function; monitor for tiredness, weakness, dizziness, nausea, vomiting 2

Critical Drug Interactions

Contraindicated Combinations

• HMG-CoA reductase inhibitors: Never combine with simvastatin or lovastatin due to severe muscle toxicity risk 2
• Benzodiazepines: Contraindicated with triazolam, midazolam, or alprazolam (excessive sedation) 2
• Other contraindications: Eplerenone, ergot alkaloids (dihydroergotamine, ergotamine, ergometrine, methylergometrine), nisoldipine 2

Drugs Reducing Ketoconazole Efficacy

• CYP3A4 inducers: Rifampin, rifabutin, isoniazid, carbamazepine, phenytoin, efavirenz, nevirapine significantly reduce ketoconazole bioavailability 2
• Management: Avoid these drugs from 2 weeks before through the end of ketoconazole treatment; if unavoidable, monitor antifungal activity and increase ketoconazole dose as needed 2

Drugs with Increased Toxicity Risk

• CYP3A4 substrates: Ketoconazole is a potent CYP3A4 inhibitor and can dramatically increase plasma concentrations of drugs metabolized by this pathway 2
• P-glycoprotein substrates: Ketoconazole also inhibits this transporter, further increasing drug levels 2

Special Populations

Pediatric Patients

• Limited data available: Measurable concentrations achieved in infants ≥5 months with 3-13 mg/kg/day 2
• Safety concern: Should only be used if prescriber determines benefits outweigh risks 2
• Absorption considerations: Better absorbed as suspension than crushed tablet; gastric pH-altering conditions impair absorption 2

Pregnancy and Breastfeeding

• Pregnancy: Unknown fetal harm risk; use only if clearly needed 2
• Breastfeeding: Ketoconazole passes into breast milk; patient must choose between breastfeeding and treatment 2

Hepatic or Renal Impairment

• Contraindication: Do not use in patients with pre-existing liver problems 2
• Renal impairment: Pharmacokinetics not significantly altered, but use with extreme caution 2

Common Pitfalls to Avoid

1. Using as first-line therapy: The FDA has issued a black box warning restricting ketoconazole to situations where other antifungals are not appropriate due to hepatotoxicity risk 2

2. Inadequate monitoring: Failure to perform weekly liver function tests during the first 6 months can miss early hepatotoxicity 1, 2

3. Concurrent acid suppression: Prescribing ketoconazole to patients on proton pump inhibitors without switching to fluconazole or adding acidic beverages results in treatment failure 3, 2

4. Premature discontinuation: Stopping before 6 months increases relapse risk (10-14%) 1

5. Ignoring drug interactions: Failing to review the patient's complete medication list before prescribing can result in life-threatening interactions 2

6. Using for fungal nail infections: Ketoconazole tablets are not indicated for onychomycosis despite older literature suggesting efficacy 2, 4

7. Alcohol consumption: Patients must avoid alcohol during treatment 2