Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

For the individual adjustment of dose, the strengths of 25 mg and 50 mg are available.

The recommended maintenance dose of eplerenone is 50 mg once daily (OD). Treatment should be initiated at 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 1). Eplerenone therapy should usually be started within 3-14 days after an acute myocardial infarction.

Patients with a serum potassium of> 5.0 mmol/L should not be started on eplerenone.

Serum potassium should be measured before initiating eplerenone therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed as needed periodically thereafter.

After initiation, the dose should be adjusted based on the serum potassium level as shown in Table 1.

Table 1: Dose adjustment table after initiation

Serum potassium (mmol/L)	Action	Dose adjustment
< 5.0	Increase	25 mg EOD* to 25 mg OD 25 mg OD to 50 mg OD<
5.0 – 5.4	Maintain	No dose adjustment
5.5 – 5.9	Decrease	50 mg OD to 25 mg OD 25 mg OD to 25 mg EOD* 25 mg EOD* to withhold
6.0	Withhold	N/A

* EOD: Every Other Day

Following withholding eplerenone due to serum potassium 6.0 mmol/L, eplerenone can be re-started at a dose of 25 mg every other day when potassium levels have fallen below 5.0 mmol/L.

Children and adolescents

There are no data to recommend the use of eplerenone in the paediatric population, and therefore, use in this age group is not recommended.

Elderly

No initial dose adjustment is required in the elderly. Due to an age-related decline in renal function, the risk of hyperkalaemia is increased in elderly patients. This risk may be further increased when co-morbidity associated with increased systemic exposure is also present, in particular mild-to-moderate hepatic impairment. Periodic monitoring of serum potassium is recommended.

Renal impairment

No initial dose adjustment is required in patients with mild renal impairment. Periodic monitoring of serum potassium is recommended.

Eplerenone is not dialysable.

Hepatic impairment

No initial dosage adjustment is necessary for patients with mild-to-moderate hepatic impairment. Due to an increased systemic exposure to eplerenone in patients with mild-to-moderate hepatic impairment, frequent and regular monitoring of serum potassium is recommended in these patients, especially when elderly.

Concomitant treatment

In case of concomitant treatment with mild to moderate CYP3A4 inhibitors, e.g. amiodarone, diltiazem and verapamil, a starting dose of 25 mg OD may be initiated. Dosing should not exceed 25 mg OD.

Eplerenone may be administered with or without food.

Child Dosage

Elderly Dosage

Contra Indications

Hypersensitivity to eplerenone or any of the excipients.

• Patients with serum potassium level> 5.0 mmol/L at initiation

• Patients with moderate to severe renal insufficiency (creatinine clearance < 50 mL/min)

• Patients with severe hepatic insufficiency (Child-Pugh Class C)

• Patients receiving potassium-sparing diuretics, potassium-supplements or strong inhibitors of CYP 3A4 (eg itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone).

Special Precautions

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 with renal insufficiency 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.

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 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 eva luated and its use is therefore contraindicated.

CYP3A4 inducers: Coadministration of eplerenone with strong CYP3A4 inducers is not recommended.

Lithium, cyclosporin, tacromilus should be avoided during treatment with eplerenone.

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.

Interactions

Pharmacodynamic interactions

Potassium-sparing diuretics and potassium supplements: Due to increased risk of hyperkalaemia, eplerenone should not be administered to patients receiving potassium-sparing diuretics and potassium supplements. Potassium-sparing diuretics may potentiate the effect of anti-hypertensive agents and other diuretics.

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. Coadministration of eplerenone and lithium should be avoided. If this combination appears necessary, lithium plasma concentrations should be monitored.

Cyclosporin, tacrolimus: Cyclosporin and tacromilus 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.

Non-steroidal anti-inflammatory drugs (NSAIDs): 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.

Trimethroprim: The concomitant administration of trimethroprim 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.

ACE inhibitors, angiotensin-II receptors antagonists (AIIA): Eplerenone and ACE inhibitors or angiotensin-II receptors antagonists should be co-administered with caution. Combining eplerenone with these drugs may increase risk of hyperkalaemia in patients at risk for impaired renal function, e.g. the elderly. A close monitoring of serum potassium and renal function is recommended.

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.

Glucocorticoides, 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.

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. The concomitant use of eplerenone with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone, is contra-indicated.

Mild to moderate CYP3A4 inhibitors: Co-administration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, and fluconazole have led to significant pharmacokinetic interactions with rank order increases in AUC ranging from 98% to 187%. Eplerenone dosing should therefore not exceed 25 mg when mild to moderate inhibitors of CYP3A4 are co-administered with eplerenone.

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.

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

Adverse Reactions

In the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS), the overall incidence of adverse events reported with eplerenone (78.9%) was similar to placebo (79.5%). The discontinuation rate due to adverse events in these studies was 4.4% for patients receiving eplerenone and for 4.3% patients receiving placebo.

Adverse events reported below are either taken from EPHESUS and 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: common> 1/100, < 1/10; uncommon> 1/1000, < 1/100.

Infections and infestations

Uncommon: pyelonephritis

Blood and lymphatic system disorders

Uncommon: eosinophilia

Metabolism and nutrition disorders

Common: hyperkalaemia

Uncommon: hyponatraemia, dehydration, hypercholesterolaemia, hypertriglyceridaemia,

Psychiatric disorders

Uncommon: insomnia

Nervous system disorders

Common: dizziness

Uncommon: headache

Cardiac disorders

Uncommon: myocardial infarction, cardiac failure left, fibrillation atrial,

Vascular disorders

Common: hypotension

Uncommon: thrombosis arterial leg, hypotension postural,

Respiratory, thoracic and mediastinal disorders

Uncommon: pharyngitis

Gastrointestinal disorders

Common: diarrhoea, nausea

Uncommon: vomiting, flatulence,

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: pruritus, sweating increased

Not known: angioneurotic oedema

Musculoskeletal and connective tissue disorders

Uncommon: back pain, cramp legs

Renal and urinary disorders

Common: renal function abnormal

Reproductive system and breast disorders

Uncommon: gynecomastia

General disorders and administration site conditions

Uncommon: asthenia, malaise

Investigations

Uncommon: BUN increased, creatinine increase

In EPHESUS, there were numerically more cases of stroke in the elderly group (>