Eplerenone

Mechanism

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).

Symptoms

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).

Management

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).

Mechanism

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).

Symptoms

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).

Management

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).

Mechanism

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).

Symptoms

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).

Management

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).

Mechanism

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).

Symptoms

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).

Management

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).

Mechanism

Both drugs are mineralocorticoid receptor antagonists. Concurrent use produces dual aldosterone blockade; renal potassium excretion stops. Severe hyperkalaemia (K+ above 6.5 mmol/L) develops with risk of fatal arrhythmia.

Symptoms

Muscle weakness, paresthesia, bradycardia. ECG shows peaked T waves, QRS widening; in severe cases asystole.

Management

Combination contraindicated. For resistant heart failure choose one: spironolactone if renal function is preserved, or eplerenone if gynaecomastia developed on spironolactone. Check potassium at weeks 1, 2 and 4, then monthly.