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INSPRA (eplerenone) Drug Interactions

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Drug Interactions


Inhibitors of CYP3A4

INSPRA (eplerenone) metabolism is predominantly mediated via CYP3A4 and therefore, INSPRA should not be used with drugs described as strong inhibitors of CYP3A4 in their labeling (see CONTRAINDICATIONS, Drug-Drug Interactions – Table 15, and DOSAGE AND ADMINISTRATION).

Caution should be used in patients treated with mild to moderate CYP3A4 inhibitors; dosing should not exceed 25mg QD in patients with an eGFR ≥ 50 ml/min/1.73m2. For patients with moderate renal impairment (eGFR 30-49 ml/min/1.73 m2), INSPRA is not recommended because a lower dose than 25 mg once daily has not been studied.

Inducers of CYP3A4

St. John’s Wort was found to decrease exposure and to increase clearance of INSPRA significantly indicating that concomitant use of strong inducers of CYP3A4 such as phenobarbital, phenytoin, rifampicin, carbamazepine should be avoided.

ACE Inhibitors and Angiotensin II Receptor Antagonists

In EPHESUS and EMPHASIS-HF, 3020 (91%) and 1282 (94%) patients, respectively, receiving INSPRA 25 to 50 mg, also received ACE inhibitors or angiotensin II receptor antagonists (ACEI/ARB). Rates of patients with maximum potassium levels >5.5 mmol/L were similar regardless of the use of ACEI/ARB. However, as ACEI/ARB can also increase serum potassium levels in some patients, concomitant use with INSPRA dictates that greater caution should be exercised.


A drug interaction study of INSPRA with lithium has not been conducted.  However, lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors and concomitant administration of INSPRA may worsen lithium toxicity. Serum lithium levels should be monitored frequently if INSPRA is administered concomitantly with lithium, as excretion may be altered as a result of modifications in sodium balance induced by the aldosterone antagonist. Lithium has also been reported to increase plasma renin activity and aldosterone levels.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

A drug interaction study of INSPRA with an NSAID has not been conducted. The administration of potassium-sparing antihypertensive drugs with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function. Therefore, when INSPRA and NSAIDs including COX-2 Inhibitors, are used concomitantly, blood pressure, renal function and serum potassium should be closely monitored.

Herbal Preparations and Salt Substitutes

The full consequence of using INSPRA in patients taking herbal preparations and/or salt substitutes has not been established, and caution should be exercised. Theoretically, patients who are taking herbal preparations that affect blood pressure or contain high levels of potassium may be at risk of hypotension/hypertension or hyperkalemia (see WARNINGS and PRECAUTIONS). Clinicians should consider discontinuing the herbal preparation or salt substitute or closely monitoring patients using such a combination. Such preparations may include (but not limited to): dandelion, potassium iodine, laminaria, morinda, oleander, phosphate salts and potassium preparations, cat’s claw, cod liver oil, and licorice.

Drug-Drug Interactions

Drug-drug interaction studies were conducted with a 100 mg dose of INSPRA and the outcomes are summarized in Table 15.

Table 15. Established or Potential Drug-Drug Interactions
Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Proper name



Clinical comment



no clinically significant interactions

Systemic Exposure (AUC) to digoxin increases by 16% (90% CI: 4-30%) when co-administered with INSPRA. Caution is warranted when digoxin is dosed near the upper limit of the therapeutic range.



no clinically significant interactions


CYP3A4 substrates (e.g. midazolam, cisapride)

T and CT

no clinically significant interactions


Potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, nefazodone)

T and CT

significant increases in eplerenone AUC

Concomitant use is contraindicated (see CONTRAINDICATIONS)

Mild to Moderate CYP3A4 inhibitors (erythromycin, saquinavir, amiodarone, diltiazem, verapamil, fluconazole)

T and CT

significant increases in eplerenone AUC

Eplerenone dosing should not exceed 25 mg daily when mild to moderate inhibitors of CYP3A4 are co-administered (see DOSAGE AND ADMINISTRATION). For patients with moderate renal impairment (eGFR 30-49 ml/min/1.73 m2) INSPRA is not recommended.

For hypertension, reduce the dose to 25 mg once daily when used with mild to moderate CYP3A4 inhibitors (e.g.,verapamil, erythromycin, saquinavir, fluconazole).

Potent CYP3A4 Inducers (e.g. carbamazepine, phenytoin, Phenobarbital, St John’s Wort, rifampicin)

T andCT

decreases eplerenone AUC

Due to the risk of decreased eplerenone efficacy, concomitant use of strong CYP3A4 inducers with INSPRA is not recommended because a lower dose than 25 mg once daily has not been studied.

Aluminum and magnesium-containing antacids


No significant changes in eplerenone pharmacokinetics


Drug-Food Interactions

INSPRA may be administered with or without food.

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