Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Hyperkalaemia:
Consistent with its mechanism of action, hyperkalaemia may occur with eplerenone. Serum potassium levels should be monitored in all patients at initiation of treatment and with a change in dosage. Thereafter, periodic monitoring is recommended especially in patients at risk for the development of hyperkalaemia, such as elderly patients, patients with renal insufficiency (see section 4.2) and patients with diabetes. The use of potassium supplements after initiation of eplerenone therapy is not recommended, due to an increased risk of hyperkalaemia. Dose reduction of eplerenone has been shown to decrease serum potassium levels. In one study, the addition of hydrochlorothiazide to eplerenone therapy has been shown to offset increases in serum potassium.
The risk of hyperkalaemia may increase when eplerenone is used in combination with an ACE inhibitor and/or an ARB. The combination of an ACE inhibitor and an ARB with eplerenone should not be used (see sections 4.3 and 4.5).
Impaired renal function:
Potassium levels should be monitored regularly in patients with impaired renal function, including diabetic microalbuminuria. The risk of hyperkalaemia increases with decreasing renal function. While the data from Eplerenone Post-acute Myocardial Infarction Heart failure Efficacy and Survival Study (EPHESUS) in patients with Type 2 diabetes and microalbuminuria is limited, an increased occurrence of hyperkalaemia was observed in this small number of patients. Therefore, these patients should be treated with caution. Eplerenone is not removed by haemodialysis.
Impaired hepatic function:
No elevations of serum potassium above 5.5 mmol/L were observed in patients with mild to moderate hepatic impairment (Child Pugh class A and B). Electrolyte levels should be monitored in patients with mild to moderate hepatic impairment. The use of eplerenone in patients with severe hepatic impairment has not been evaluated and its use is therefore contraindicated (see sections 4.2 and 4.3).
CYP3A4 inducers:
Co-administration of eplerenone with strong CYP3A4 inducers is not recommended (see section 4.5).
Lithium, cyclosporin, tacrolimus should be avoided during treatment with eplerenone (see section 4.5).
Lactose:
The tablets contain lactose and should not be administered in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
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.
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).
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). Co-administration of eplerenone and lithium should be avoided. If this combination appears necessary, lithium plasma concentrations should be monitored (see section 4.4).
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).
Treatment with NSAIDs may lead to acute renal failure by acting directly on glomerular filtration, especially in at-risk patients (elderly and/or dehydrated patients). Patients receiving eplerenone and NSAIDs should be adequately hydrated and be monitored for renal function prior to initiating treatment.
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.
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.
Co-administration of these drugs with eplerenone may potentially increase antihypertensive effects and risk of postural hypotension.
Co-administration of these drugs with eplerenone may potentially decrease antihypertensive effects (sodium and fluid retention).
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.
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.
No clinically significant pharmacokinetic interactions have been observed with warfarin. Caution is warranted when warfarin is dosed near the upper limit of therapeutic range.
Results of pharmacokinetic studies with CYP3A4 probe-substrates, i.e. midazolam and cisapride, showed no significant pharmacokinetic interactions when these drugs were co-administered with eplerenone.
Strong CYP3A4 inhibitors: Significant pharmacokinetic interactions may occur when eplerenone is co-administered 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).
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).
Based on the results of a pharmacokinetic clinical study, no significant interaction is expected when antacids are co-administered with eplerenone.
There are no adequate data on the use of eplerenone in pregnant women. Animal studies did not indicate direct or indirect adverse effects with respect to pregnancy, embryofoetal development, parturition and postnatal development (see section 5.3). Caution should be exercised prescribing eplerenone to pregnant women.
It is unknown if eplerenone is excreted in human breast milk after oral administration. However, preclinical data show that eplerenone and/or metabolites are present in rat breast milk and that rat pups exposed by this route developed normally. Because of the unknown potential for adverse effects on the breast fed infant, a decision should be made whether to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother.
There are no human data available on fertility.
No studies on the effect of eplerenone on the ability to drive or use machines have been performed. Eplerenone does not cause drowsiness or impairment of cognitive function but when driving vehicles or operating machines it should be taken into account that dizziness may occur during treatment.
In two studies (EPHESUS and Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure [EMPHASIS-HF]), the overall incidence of adverse events reported with eplerenone was similar to placebo.
Adverse events reported below are those with suspected relationship to treatment and in excess of placebo or are serious and significantly in excess of placebo, or have been observed during post marketing surveillance.
Adverse events are listed by body system and absolute frequency. Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Table 2. ADR Frequency in Eplerenone Placebo Controlled Studies:
Uncommon: pyelonephritis, infection, pharyngitis
Uncommon: eosinophilia
Uncommon: hypothyroidism
Common: hyperkalaemia (see sections 4.3 and 4.4), hypercholesterolaemia
Uncommon: hyponatraemia, dehydration, hypertriglyceridaemia
Common: insomnia
Common: syncope, dizziness, headache
Uncommon: hypoaesthesia
Common: left ventricular failure, atrial fibrillation
Uncommon: tachycardia
Common: hypotension
Uncommon: arterial thrombosis limb, orthostatic hypotension
Common: cough
Common: diarrhoea, nausea, constipation, vomiting
Uncommon: flatulence
Common: rash, pruritus
Uncommon: angioedema, hyperhidrosis
Common: muscle spasms, back pain
Uncommon: musculoskeletal pain
Common: renal impairment (see sections 4.4 and 4.5)
Uncommon: cholecystitis
Uncommon: gynaecomastia
Common: asthenia
Uncommon: malaise
Common: blood urea increased, blood creatinine increased
Uncommon: epidermal growth factor receptor decreased, blood glucose increased
In EPHESUS, there were numerically more cases of stroke in the very elderly group (≥75 years old). There was however no statistical significant difference between the occurrence of stroke in the eplerenone (30) vs placebo (22) groups. In EMPHASIS-HF, the number of cases of stroke in the very elderly (≥75 years old) was 9 in the eplerenone group and 8 in the placebo group.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
Not applicable.
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