Clarithromycin × Eplerenone

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). The clarithromycin SmPC itself calls clarithromycin a strong inhibitor of this enzyme (Klacid SmPC, AEMPS, section 4.3). According to the same SmPC, clarithromycin can raise the levels of drugs broken down by CYP3A enzymes and increase or prolong both their therapeutic and adverse effects (Klacid SmPC, AEMPS, section 4.5). The labels give no eplerenone data with clarithromycin itself. 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). Eplerenone does not affect clarithromycin: it inhibits neither the main cytochrome P450 (CYP) enzymes nor P-glycoprotein (Inspra SmPC, AEMPS, section 4.5).

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 clarithromycin 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).

The combination is contraindicated. The Inspra summary of product characteristics (SmPC) and prescribing information bar eplerenone in patients taking strong inhibitors of the enzyme CYP3A4 and name clarithromycin explicitly (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 clarithromycin labels do not name eplerenone and ask only for caution with drugs broken down by CYP3A enzymes (AEMPS, section 4.5; FDA, section 7). This does not lift the contraindication in the eplerenone labels. The eplerenone ceiling of 25 mg daily applies only to weak and moderate CYP3A4 inhibitors, and among macrolides this group includes erythromycin (Inspra SmPC, AEMPS, sections 4.2 and 4.5; FDA, sections 2.4 and 7.1). The ceiling does not apply to clarithromycin, and a lower dose does not make the combination acceptable. 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).