Eplerenone × Itraconazole

According to the Inspra summary of product characteristics (SmPC) from the Spanish Agency of Medicines and Medical Devices (AEMPS), eplerenone is cleared mainly through the enzyme CYP3A4 (section 5.2). Itraconazole strongly inhibits this enzyme (Sporanox SmPC, AEMPS, section 4.5). The pair has not been studied directly, but the itraconazole SmPC expects eplerenone levels to rise (section 4.5). The closest guide is ketoconazole, another strong CYP3A4 inhibitor. At 200 mg twice daily, it raised the eplerenone area under the curve (AUC) by 441%, or 5.4-fold (Inspra SmPC, AEMPS, section 4.5; Inspra prescribing information, US Food and Drug Administration, FDA, section 12.3). Eplerenone blocks mineralocorticoid receptors, so excess drug increases potassium retention and lowers blood pressure further. The SmPC names hypotension and hyperkalaemia as the most likely signs of overdose (Inspra SmPC, AEMPS, section 4.9). Itraconazole leaves the blood slowly. After it is stopped, its plasma levels take 7–14 days to become almost undetectable, depending on dose and treatment length (Sporanox SmPC, AEMPS, section 4.5). Itraconazole itself has a negative inotropic effect and has been linked to cases of congestive heart failure (Sporanox SmPC, AEMPS, section 4.4).

The main danger is hyperkalaemia. The eplerenone label of the US Food and Drug Administration (FDA) says the risk is higher even with moderate inhibitors of the enzyme CYP3A4. The same label lists itraconazole among the strong ones (sections 4 and 5.1). High potassium causes muscle weakness, bradycardia and arrhythmias up to cardiac arrest, with peaked T waves and a widened QRS complex on the electrocardiogram (ECG). Low blood pressure causes dizziness and fainting, especially on standing (Inspra summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS, sections 4.8 and 4.9). The risk of hyperkalaemia is higher in older people, in reduced kidney function or diabetes, and with concurrent angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (Inspra SmPC, AEMPS, section 4.4). Itraconazole has been linked to cases of congestive heart failure (Sporanox SmPC, AEMPS, section 4.4). Signs include shortness of breath, swelling of the feet, ankles or legs, sudden weight gain, increased tiredness, coughing up white or pink mucus, a fast heartbeat and waking up at night more than usual (Sporanox label, FDA, Medication Guide).

The labels of both drugs contraindicate the combination. The Inspra summary of product characteristics (SmPC) and prescribing information bar eplerenone with strong inhibitors of the enzyme CYP3A4 and name itraconazole in that list (Inspra SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS, sections 4.3 and 4.5; Inspra prescribing information, US Food and Drug Administration, FDA, section 4). The itraconazole labels list eplerenone among contraindicated drugs (AEMPS, sections 4.3 and 4.5; FDA, Contraindications). The ban also covers the two weeks after itraconazole is stopped (Sporanox SmPC, AEMPS, section 4.5; FDA, Drug Interactions table). In Spain, eplerenone is indicated only for heart failure (Inspra SmPC, AEMPS, section 4.1). In heart failure, itraconazole is given only for life-threatening or other serious infections and is stopped if signs of heart failure appear (Sporanox SmPC, AEMPS, sections 4.3 and 4.4). If a systemic azole is needed, note that the eplerenone SmPC classes fluconazole as a weak-to-moderate CYP3A4 inhibitor and limits eplerenone to 25 mg daily with it (Inspra SmPC, AEMPS, sections 4.2 and 4.5; FDA, sections 2.4 and 7.1). Ketoconazole, like itraconazole, is contraindicated. If the two drugs have already been taken together, stop one of them and check potassium and creatinine at once. The eplerenone labels require a potassium check at any dose change, and a potassium and creatinine check within 3–7 days of adding even a moderate CYP3A4 inhibitor (Inspra SmPC, AEMPS, section 4.4; FDA, section 2.3). Stop eplerenone if serum potassium reaches 6.0 mmol/L or higher (Inspra SmPC, AEMPS, section 4.2).