Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions
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Potassium-sparing diuretics and potassium supplements: Due to increased risk of hyperkalaemia, eplerenone should not be administered to patients receiving other potassium-sparing diuretics and potassium supplements (see section 4.3). Potassium-sparing diuretics may also potentiate the effect of anti-hypertensive agents and other diuretics.

ACE inhibitors, ARBs:The risk of hyperkalaemia may increase when eplerenone is used in combination with an ACE inhibitor and/or an ARB. A close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly.
The triple combination of an ACE inhibitor and an ARB with eplerenone should not be used (see sections 4.3 and 4.4).


Lithium: Drug interaction studies of eplerenone have not been conducted with lithium. However, lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors (see section 4.4). Coadministration of eplerenone and lithium should be avoided. If this combination appears necessary, lithium plasma concentrations should be monitored (see section 4.4).

Cyclosporin, tacrolimus: Cyclosporin and tacrolimus may lead to impaired renal function and increase the risk of hyperkalaemia. The concomitant use of eplerenone and cyclosporin or tacrolimus should be avoided. If needed, close monitoring of serum potassium and renal function are recommended when cyclosporine and tacrolimus are to be administered during treatment with eplerenone (see section 4.4).

Non-steroidal anti-inflammatory drugs (NSAIDs): Acute renal failure may occur in at risk patients (elderly, dehydrated subjects, using diuretics, with impaired renal function) due to decreased glomerular filtration (inhibition of vasodilatory prostaglandins due to non-steroidal anti-inflammatory drugs). These effects are generally reversible. Furthermore, there may be a reduction of the antihypertensive effect. Hydrate the patient and monitor renal function at the beginning of treatment and regularly during the combination (see sections 4.2 and 4.4.).

Trimethoprim: The concomitant administration of trimethoprim with eplerenone increases the risk of hyperkalaemia. Monitoring of serum potassium and renal function should be made, particularly in patients with renal impairment and in the elderly.

Alpha-1-blockers (e.g. prazosin, alfuzosine): When alpha-1-blockers are combined with eplerenone, there is the potential for increased hypotensive effect and/or postural hypotension. Clinical monitoring for postural hypotension is recommended during alpha-1-blocker co-administration.

Tricyclic anti-depressants, neuroleptics, amifostine, baclofene : Co-administration of these drugs with eplerenone may potentially increase antihypertensive effects and risk of postural hypotension.

Glucocorticoids, tetracosactide: Co-administration of these drugs with eplerenone may potentially decrease antihypertensive effects (sodium and fluid retention).

Pharmacokinetic interactions

In vitro studies indicate that eplerenone is not an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4 isozymes. Eplerenone is not a substrate or an inhibitor of P-Glycoprotein.

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

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Warfarin: No clinically significant pharmacokinetic interactions have been observed with warfarin.
Caution is warranted when warfarin is dosed near the upper limit of therapeutic range.

CYP3A4 substrates: Results of pharmacokinetic studies with CYP3A4 probe-substrates, i.e.
midazolam and cisapride, showed no significant pharmacokinetic interactions when these drugs were coadministered with eplerenone.

CYP3A4 inhibitors:
- Strong CYP3A4 inhibitors: Significant pharmacokinetic interactions may occur when eplerenone is coadministered with drugs that inhibit the CYP3A4 enzyme. A strong inhibitor of CYP3A4 ( ketoconazole 200 mg BID) led to a 441% increase in AUC of eplerenone (see section 4.3). The concomitant use of eplerenone with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone, is contra-indicated (see section 4.3).
- Mild to moderate CYP3A4 inhibitors: Co-administration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole has led to significant pharmacokinetic interactions with rank order increases in AUC ranging from 98% to 187%. Eplerenone dosing should therefore not exceed 25 mg daily when mild to moderate inhibitors of CYP3A4 are co-administered with eplerenone (see section 4.2).

CYP3A4 inducers: Co-administration of St John’s wort (a strong CYP3A4 inducer) with eplerenone caused a 30 % decrease in eplerenone AUC. A more pronounced decrease in eplerenone AUC may occur with stronger CYP3A4 inducers such as rifampicin. Due to the risk of decreased eplerenone efficacy, the concomitant use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s wort) with eplerenone is not recommended (see section 4.4).

Antacids: Based on the results of a pharmacokinetic clinical study, no significant interaction is expected when antacids are coadministered with eplerenone.