Eplerenone × Ketoconazole

CYP3A4 is the main route of eplerenone clearance, and oral ketoconazole is one of the strongest inhibitors of this enzyme. With ketoconazole 200 mg twice daily, eplerenone AUC rose by 441% (5.4-fold) and Cmax 1.7-fold (Inspra SmPC, AEMPS, section 4.5; Inspra prescribing information, FDA, section 12.3). Eplerenone blocks mineralocorticoid receptors, so this rise in exposure strengthens potassium retention and the fall in blood pressure. Eplerenone does not affect ketoconazole: it inhibits no CYP enzymes and is neither a substrate nor an inhibitor of P-glycoprotein (Inspra SmPC, AEMPS, section 4.5).

The main danger is hyperkalemia: the FDA ketoconazole tablets label names the risk of hyperkalemia and hypotension when eplerenone concentrations rise. High potassium shows as muscle weakness, bradycardia and arrhythmias up to cardiac arrest, with peaked T waves and a widened QRS on the ECG. Hypotension brings dizziness, weakness and fainting, especially on standing. The risk of hyperkalemia is higher in older patients, in patients with reduced renal function or diabetes, and with concurrent ACE inhibitors or angiotensin receptor blockers (Inspra SmPC, AEMPS, section 4.4).

The combination is contraindicated. The eplerenone SmPC bars it in patients receiving strong CYP3A4 inhibitors and names ketoconazole explicitly (Inspra SmPC, AEMPS, sections 4.3 and 4.5). The FDA Inspra label says the same (section 4), as does the FDA ketoconazole tablets label (Contraindications). The ban also covers the week after stopping ketoconazole (ketoconazole tablets, FDA, Precautions). This concerns oral ketoconazole: after a cream or gel, ketoconazole is not measurable in plasma, and the label expects no systemic effects from topical forms (ketoconazole cream SmPC, AEMPS, section 5.2). If a systemic azole is needed, the eplerenone SmPC classes fluconazole as a weak-to-moderate CYP3A4 inhibitor and allows it with an eplerenone ceiling of 25 mg daily (Inspra SmPC, AEMPS, section 4.5; FDA, sections 2.4 and 7.1). Itraconazole, like ketoconazole, is contraindicated. If the patient has already taken the two drugs together, stop one of them and check potassium and creatinine at once. The eplerenone label requires potassium monitoring at any change of regimen and within 3–7 days of adding even a moderate CYP3A4 inhibitor (Inspra SmPC, AEMPS, section 4.4; FDA, section 2.3).