Summary Basis of Decision for Inspra ™/MC

3.3.1 Pharmacodynamics

At doses as low as 25 mg once a day (QD), eplerenone was pharmacologically active as an antagonist of aldosterone. This was demonstrated by mean percent increases from baseline in plasma renin (total and active) and serum aldosterone, across the clinical studies. The eplerenone-related increases in active and total plasma renin, and serum aldosterone were consistent with the blockade of aldosterone at the mineralocorticoid receptor and the compensatory feedback activation of the renin-angiotensin-aldosterone system (RAAS). Eplerenone increased the activity of RAAS hormones, and the magnitude of the effects of eplerenone on blood pressure and RAAS hormones were dose-dependent. Additionally, the pharmacodynamic effects of eplerenone lasted more than 24 hours, thus permitting effective once-daily dosing.

3.3.2 Pharmacokinetics

Absorption

Eplerenone was rapidly absorbed after oral administration. The time to reach the maximum plasma concentration was <2 hours in an empty stomach. The absolute bioavailability was approximately 70%. At doses ranging from 10-100 mg/day administered as single or multiple doses, the drug exposure parameters were fairly proportional to the dose but less than proportional at doses from 100-300 mg/day. Food, including a high-fat meal, did not significantly affect absorption. Bioequivalence studies were reviewed for the purpose of confirming statements made in the proposed Product Monograph with respect to the nature of the pharmacokinetics (PK) of Inspra in the 25-100 mg dose range and the food effect.

Significant accumulation with repeat-dosing was not observed. A one-compartment model with first-order kinetics adequately characterized the PK of eplerenone when administered orally in healthy subjects, patients with HF, and hypertensive patients.

Distribution

At eplerenone plasma concentrations of 0.02-1.0 μg/mL, which is within the expected therapeutic range for doses of 25-50 mg/day, eplerenone binding to plasma proteins was approximately 50% and the binding was mainly to alpha 1-acid glycoproteins. Eplerenone did not bind to red blood cells. The volume of distribution was 43-90 L.

Metabolism

Eplerenone is extensively metabolized by the liver (<5% was excreted unchanged in the urine and faeces). Eplerenone is primarily metabolized by the CYP isozyme, CYP3A4. None of the metabolites were pharmacologically active at the relevant concentrations.

Excretion

The kidney was the major route of elimination. Approximately 67% of the dose was excreted as metabolites in urine and the rest was eliminated in the faeces. The elimination half-life of eplerenone was 4-6 hours and the plasma clearance was approximately 10 L/hour.

Drug Interactions

Clinical studies confirmed that coadministration of potent CYP3A4 inhibitors significantly increased total plasma exposure of eplerenone. The concomitant use of strong inhibitors of CYP3A4 such as ketoconazole or clarithromycin are therefore contraindicated. Weaker CYP3A4 inhibitors (for example, erythromycin, amiodarone, fluconazole) may be co-administered with an eplerenone dose no greater than 25 mg if potassium levels are monitored very closely.

An interaction is possible with non-steroidal anti-inflammatory drugs (NSAIDs) particularly in patients with impaired renal function and concomitant treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) Both of these products reduce aldosterone plasma concentration. It is known that in such patients, potassium-sparing diuretics can exacerbate potential hyperkalaemia.

Special Populations

Hepatic Impairment: In single- and multiple-dose studies administering eplerenone 400 mg QD (once a day), patients with moderate hepatic impairment (Child-Pugh Class B) had significantly higher (42%) drug exposure (AUC) levels and a 30% lower clearance (CL/F) compared to healthy subjects. The maximum plasma concentrations (Cmax) and time to reach the maximum plasma concentrations were similar. The dose of 400 mg QD is 8-fold greater than the recommended therapeutic dose. No dose adjustment is required for patients with moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. Therefore, Inspra is not recommended in these patients.

Renal Impairment: In single- and multiple-dose studies administering eplerenone 100 mg QD, there were no statistically significant differences between any of the renal impairment groups and their matched-normal groups for AUC, Cmax, or CL/F. Among the subjects with mild, moderate and severe renal impairment, changes in CL/F and AUC increased with increased degree of renal impairment; however, none of the observed changes were statistically significant.

Age and Gender: In single- and multiple-dose studies administering eplerenone 100 mg QD, at steady-state PK, the Cmax and AUC were 22% and 45% greater, respectively, for elderly subjects (≥65 years) compared to younger subjects (18-45 years). Both the elderly and the young excreted <8% of the administered dose in urine as unchanged total eplerenone. No significant differences were found in steady-state PK parameters of eplerenone between females and males.

3.3.3 Clinical Efficacy

The efficacy and safety of Inspra were evaluated in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS). EPHESUS was a double-blind, randomized, placebo-controlled, multinational, multicentre study in patients (n=6,632) clinically stable 3-14 days after an acute MI with LV dysfunction and either diabetes or clinical evidence of HF. Patients with HF of valvular or congenital etiology, patients with unstable post-infarct angina, and patients with a serum potassium >5.0 mmol/L or serum creatinine >221 μmol/L were excluded. Patients were allowed to receive standard post-MI drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft surgery. Patients who received Inspra (eplerenone) were given an initial dose of 25 mg QD, titrated to the target dose of 50 mg QD after 4 weeks if their serum potassium was <5.0 mmol/L. The mean dose of Inspra was 43 mg/day. Patients also received standard care including ACE inhibitors, beta-blockers, aspirin, nitrates, diuretics, or 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Patients were followed for an average of 16 months (range: 0-33 months).

The co-primary endpoints for EPHESUS were (a) the time to death from any cause, and (b) the time to first occurrence of either cardiovascular (CV) mortality (defined as sudden cardiac death or death due to progression of HF, stroke, or other CV causes) or CV hospitalization (defined as hospitalization for progression of HF, ventricular arrhythmias, acute MI, or stroke).

Inspra significantly reduced all-cause mortality compared to placebo. For the first primary endpoint (time to death from any cause), there were 478 deaths in the Inspra group (14.4%) compared to 554 deaths in the placebo group (16.7%). An increase in survival and decrease in mortality was seen with the use of Inspra, not only in the general population enrolled but also in the main subgroups analyzed (males and females, age groups, regions, race, New York Heart Association (NYHA) classification, Killip classification, diabetic and non-diabetic patients, history or no history of hypertension at baseline, blood pressure levels, at all baseline serum potassium levels except >5 mmol/L, and in patients receiving anti-hypertensive medications at baseline). Statistical significance was not seen in all subgroups. It was noted that a decrease in sudden death was the main contributor to a decrease in mortality (one third of the deaths from any cause were due to sudden death). There was also a significant reduction in CV deaths (largely due to decrease in sudden death) and CV hospitalizations (largely due to a decrease in the risk and number of episodes of HF).

3.3.4 Clinical Safety

The study results for the evaluation of clinical safety were primarily taken from the study EPHESUS. Compared to the placebo group, the Inspra group had a statistically significantly greater number of patients that experienced serious hyperkalaemia ≥6 mmol/L [5.5 versus (vs.) 3.9%]; increased creatinine (2.4 vs. 1.5%); increased blood urea nitrogen (1.6 vs. 1.0%); postural hypotension (0.7 vs. 0.3%); gastrointestinal reflux, pancreatitis, sepsis, and hypothyroidism (0.5 vs. 0.2% each); arterial leg thrombosis (0.4 vs. <0.1%); varicose veins (0.3 vs. <0.1%), and ketosis (0.3 vs. <0.1%). The most common treatment-emergent adverse events (AEs, >2.0%) were related to the condition of the patients and these AEs were seen with the same or greater frequency in the placebo-treated patients: HF, unstable angina, non-cardiac chest pain, MI, dyspnoea and coughing, as well as dizziness which may or may not be related to the patient condition.

Serious adverse events (SAEs) that were associated significantly more with Inspra compared to placebo included: dehydration (0.5 vs. 0.2%), arterial leg thrombosis (0.3 vs. <0.1), increased creatinine (0.3 vs. <0.1%), and pyelonephritis (0.2 vs. 0.0%).

The percentage of patients that discontinued medication due to an AE was not significantly different in the two groups. The most common reason was hyperkalaemia in the Inspra group (0.7%) and HF in the placebo group (0.8%).

Overall, there was a greater incidence of SAEs observed in the placebo-treated patients (51%) compared to the Inspra-treated patients (48.5%). Most of these SAEs were due to HF-related events which led to the authorization of Inspra for the management of patients with HF post-MI.

Two areas of interest associated with aldosterone antagonists are their effects on serum potassium and sex-related hormones.

Hyperkalaemia

A statistically significant greater percentage of Inspra-treated patients had elevated serum potassium levels compared to the placebo group (>5.5 mmol/L [15.6% vs. 11.2%], ≥6.0 mmol/L [5.5% vs. 3.9%], or >5.5 mmol/L on at least two consecutive occasions [3.0% vs. 1.7%]). More than 50% of the episodes of hyperkalaemia took place during the first 30 days of treatment but they also occurred sporadically throughout the 2-year period of therapy. The number of patients that permanently discontinued treatment due to hyperkalaemia were rather low (0.7% with Inspra and 0.3% with placebo).

Hyperkalaemia is more likely to occur in certain patients such as those with high serum potassium before the onset of treatment and with renal impairment. The use of certain agents may also increase the risk of hyperkalaemia. Such drugs or conditions include but are not necessarily limited to: (a) NSAIDs including cyclooxygenase-2 (COX-2) inhibitors, cyclosporine, sirolimus, diabetes, or advanced age, (b) agents which affect the RAAS, such as ACE inhibitors and ARBs which are all known to increase serum potassium levels, (c) adrenal disease, ketoconazole which all impair aldosterone metabolism, (d) aldosterone mineralocorticoid receptor blockers such as eplerenone and spironolactone, and (e) potassium-sparing diuretic.

The risk of hyperkalaemia increased with decreasing renal function for both placebo- and Inspra-treated patients but the increase was significantly larger for the latter at the lower creatinine clearance. The risk of hyperkalaemia also increased with patients >65 years of age and even more with patients >75 years of age which is probably a reflection of the decrease in renal function in these patients.

The risk of hyperkalaemia will likely be higher when Inspra is used in routine clinical practice rather than in a clinical trial where monitoring is more strict. For this reason, appropriate warnings and precautions have been incorporated in the Product Monograph and the labelling.

Sex Hormone-Related Adverse Events

The incidence rates of decreased libido, impotence, gynecomastia, female breast pain, and menstrual abnormalities were <1.0% in each treatment group (Inspra and placebo) with no statistically significant treatment differences observed.