What are the contraindications for taking ketoconazole?

Contraindications for Ketoconazole

Ketoconazole is contraindicated in patients with acute or chronic liver disease, those with hypersensitivity to the drug, and when coadministered with numerous medications that interact via CYP3A4 metabolism or P-glycoprotein pathways. 1

Absolute Contraindications

Hepatic Disease

• Any patient with acute or chronic liver disease cannot receive ketoconazole due to the risk of serious hepatotoxicity, including fatal outcomes and cases requiring liver transplantation 1
• Hepatotoxicity occurs in 10-20% of patients, typically within the first 6 months of treatment, though serious injury can occur at any time during therapy 2
• Fatal hepatotoxicity has been reported even in patients without obvious risk factors for liver disease 1
• Liver cirrhosis can develop as a sequela of ketoconazole-induced acute hepatic injury, even after drug cessation 3

Hypersensitivity

• Patients with known hypersensitivity to ketoconazole are contraindicated from use 1
• Anaphylaxis has been reported after the first dose 1

Critical Drug-Drug Interactions

Cardiovascular medications that are absolutely contraindicated with ketoconazole include 1:

• Antiarrhythmics: dofetilide, quinidine, disopyramide, dronedarone
• Other cardiac drugs: methadone, ranolazine
• Mechanism: Elevated plasma concentrations lead to QT prolongation and potentially fatal ventricular tachyarrhythmias including torsades de pointes 1

CNS medications contraindicated with ketoconazole 1:

• Benzodiazepines: oral midazolam, oral triazolam, alprazolam (enhanced sedation with prolonged hypnotic effects)
• Antipsychotics: pimozide, lurasidone

Other critical contraindications 1:

• Ergot alkaloids (dihydroergotamine, ergotamine, ergometrine, methylergometrine) - risk of ergotism
• HMG-CoA reductase inhibitors: simvastatin, lovastatin - risk of myopathy
• GI medications: cisapride
• Oncology: irinotecan
• Other: felodipine, nisoldipine, tolvaptan, eplerenone, colchicine

Additional High-Risk Drug Interactions

Protease inhibitors and certain antifungals are contraindicated when using oral ketoconazole 2:

• Ketoconazole itself is contraindicated with protease inhibitor-based therapies due to strong CYP3A4 inhibition 2
• Concomitant use with ciclosporin, itraconazole, and tacrolimus is contraindicated 2

Novel oral anticoagulants (NOACs) require extreme caution 2:

• Ketoconazole is listed as a strong P-glycoprotein inhibitor that can significantly alter dabigatran bioavailability
• Acts as both CYP3A4 and P-gp inhibitor, causing important reduction in rivaroxaban clearance 2

Relative Contraindications and High-Risk Situations

Adrenal Insufficiency Risk

• Ketoconazole decreases adrenal corticosteroid secretion at doses ≥400 mg daily 1
• Adrenal function must be monitored in patients with borderline adrenal function or under prolonged stress (major surgery, intensive care) 1
• The recommended dose of 200-400 mg daily should not be exceeded 1

Renal Impairment

• While not an absolute contraindication, severe renal insufficiency (CrCl 15-29 mL/min) requires careful consideration as these patients were excluded from major clinical trials 2

Pregnancy and Reproductive Considerations

• Men may experience hypogonadism and gynecomastia, which can limit prolonged treatment 2
• Menstrual irregularities can occur in women 2

Clinical Monitoring Requirements

When ketoconazole must be used despite risks 1:

• Baseline laboratory tests required: SGGT, alkaline phosphatase, ALT, AST, total bilirubin, PT, INR, and viral hepatitis testing
• Weekly serum ALT monitoring for the duration of treatment
• Interrupt treatment immediately if ALT exceeds upper limit of normal or increases 30% above baseline 1
• Patients must avoid alcohol consumption during treatment 1
• Avoid other potentially hepatotoxic drugs when possible 1

Important Caveats

• Ketoconazole is not indicated for onychomycosis, cutaneous dermatophyte infections, or Candida infections due to serious adverse reaction risks 1
• Should only be used when other effective antifungal therapy is not available or tolerated 1
• The FDA and European Medicines Agency have issued warnings limiting oral ketoconazole use due to hepatotoxicity and drug interaction risks 4, 5
• Hepatotoxicity has been reported with rechallenge after restarting oral ketoconazole 1
• In clinical trials for advanced prostate cancer using high doses (1200 mg/day), eleven deaths were reported within two weeks of starting treatment 1