Eplerenone × Ritonavir

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). Ritonavir strongly inhibits this enzyme (Norvir SmPC, European Medicines Agency, EMA, section 4.3). The labels give no eplerenone data with ritonavir 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). The Paxlovid labels, where ritonavir 100 mg is combined with nirmatrelvir, contraindicate eplerenone because of the potential for hyperkalaemia (EMA, section 4.5; FDA, section 7.3). Eplerenone does not affect ritonavir: it inhibits neither the main cytochrome P450 (CYP) enzymes nor P-glycoprotein (Inspra SmPC, AEMPS, section 4.5).

The main danger is hyperkalaemia. The Paxlovid labels, where ritonavir is combined with nirmatrelvir, contraindicate eplerenone for exactly this reason (European Medicines Agency, EMA; US Food and Drug Administration, FDA). 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 ritonavir 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). These documents set no dose condition, so the ban also covers the low ritonavir doses added to other antiviral drugs to raise their blood levels. Paxlovid is ritonavir 100 mg taken with nirmatrelvir every 12 hours for 5 days. Its labels contraindicate eplerenone because of the risk of hyperkalaemia (Paxlovid SmPC, European Medicines Agency, EMA, sections 4.2, 4.3 and 4.5; FDA, section 4). The eplerenone ceiling of 25 mg daily applies only to weak and moderate CYP3A4 inhibitors, so a lower dose does not make the combination with ritonavir acceptable (Inspra SmPC, AEMPS, sections 4.2 and 4.5). 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).