INSPRA 25 mg film-coated tablets.

INSPRA 50 mg film-coated tablets.

Each tablet contains 25 mg of eplerenone.

Each tablet contains 50 mg of eplerenone.

Excipients:

Each 25mg tablet contains 35.7mg of lactose monohydrate (see section 4.4).

Each 50mg tablet contains 71.4mg of lactose monohydrate (see section 4.4).

For a full list of excipients see section 6.1.

Film-coated tablet.

25 mg tablet: yellow tablet with stylized “Pfizer” on one side of tablet, “NSR” over “25”on the other side of tablet.

50 mg tablet: yellow tablet with stylized “Pfizer” on one side of tablet, “NSR” over “50”on the other side of tablet.

Eplerenone is indicated, in addition to standard therapy including beta-blockers, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (LVEF 40 %) and clinical evidence of heart failure after recent myocardial infarction.

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 (see section 4.3).

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

* 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 (see section 4.4).

Renal impairment

No initial dose adjustment is required in patients with mild renal impairment. Periodic monitoring of serum potassium is recommended (see section 4.4).

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 (see section 4.4).

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 (see section 4.5).

Eplerenone may be administered with or without food (see section 5.2).

• Hypersensitivity to eplerenone or any of the excipients (see section 6.1).

• 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) (see section 4.5).

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 (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.

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 evaluated and its use is therefore contraindicated (see section 4.3).

CYP3A4 inducers: Coadministration of eplerenone with strong CYP3A4 inducers is not recommended (see section 4.5).

Lithium, cyclosporin, tacromilus 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.

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 (see section 4.3). 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 (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 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 (see section 4.4).

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 (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, 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 (see sections 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.

Pregnancy: 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.

Lactation: 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.

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 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 (> 75 years old). There was however no statistical significant difference between the occurrence of stroke in the eplerenone (30) vs placebo (22) groups.

No cases of human overdosage with eplerenone have been reported. The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalaemia. Eplerenone cannot be removed by haemodialysis. Eplerenone has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be initiated. If hyperkalaemia develops, standard treatment should be initiated.

Pharmacotherapeutic group: aldosterone antagonists, ATC code: C03DA04

Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease.

Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone.

In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone. Similarly, in a cardiorenal substudy of EPHESUS, therapy with eplerenone led to a significant increase in aldosterone. These results confirm the blockade of the mineralocorticoid receptor in these populations.

Eplerenone was studied in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS). EPHESUS was a double-blind, placebo-controlled study, of 3 year duration, in 6632 patients with acute myocardial infarction (MI), left ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] 40%), and clinical signs of heart failure. Within 3-14 days (median 7 days) after an acute MI, patients received eplerenone or placebo in addition to standard therapies at an initial dose 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was < 5.0 mmol/L. During the study patients received standard care including acetylsalicylic acid (92%), ACE inhibitors (90%), ß-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG CoA reductase inhibitors (60%).

In EPHESUS, the co-primary endpoints were all-cause mortality and the combined endpoint of CV death or CV hospitalisation; 14.4 % of patients assigned to eplerenone and 16.7 % of patients assigned to placebo died (all causes), while 26.7 % of patients assigned to eplerenone and 30.0 % assigned to placebo met the combined endpoint of CV death or hospitalisation. Thus, in EPHESUS, eplerenone reduced the risk of death from any cause by 15% (RR 0.85; 95% CI, 0.75-0.96; p= 0.008) compared to placebo, primarily by reducing cardiovascular (CV) mortality. The risk of CV death or CV hospitalisation was reduced by 13% with eplerenone (RR 0.87; 95% CI, 0.79-0.95; p=0.002). The absolute risk reductions for the endpoints all cause mortality and CV mortality/hospitalisation were 2.3 and 3.3%, respectively. Clinical efficacy was primarily demonstrated when eplerenone therapy was initiated in patients aged < 75 years old. The benefits of therapy in those patients over the age of 75 are unclear. NYHA functional classification improved or remained stable for a statistically significantly greater proportion of patients receiving eplerenone compared to placebo. The incidence of hyperkalaemia was 3.4 % in the eplerenone group vs 2.0 % in the placebo group (p < 0.001). The incidence of hypokalaemia was 0.5 % in the eplerenone group vs 1.5 % in the placebo group (p < 0.001).

No consistent effects of eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.

Absorption and Distribution:

The absolute bioavailability of eplerenone is unknown. Maximum plasma concentrations are reached after about 2 hours. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 10 to 100 mg and less than proportional at doses above 100 mg. Steady state is reached within 2 days. Absorption is not affected by food.

The plasma protein binding of eplerenone is about 50% and is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state is estimated at 50 (±7) L. Eplerenone does not preferentially bind to red blood cells.

Metabolism and Excretion:

Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.

Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and faeces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the faeces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 3 to 5 hours. The apparent plasma clearance is approximately 10 L/hr.

Special Populations

Age, Gender, and Race: The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been investigated in the elderly (65 years), in males and females, and in blacks. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, elderly subjects had increases in C_max (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady state, C_max was 19% lower and AUC was 26% lower in blacks. (see section 4.2.)

Renal Insufficiency: The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal insufficiency and in patients undergoing haemodialysis. Compared with control subjects, steady-state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing haemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by haemodialysis (see section 4.4.).

Hepatic Insufficiency: The pharmacokinetics of eplerenone 400 mg have been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady-state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively (see section 4.2). Since the use of eplerenone has not been investigated in patients with severe hepatic impairment, eplerenone is contraindicated in this patients' group (see section 4.3).

Heart Failure: The pharmacokinetics of eplerenone 50 mg were evaluated in patients with heart failure (NYHA classification II-IV). Compared with healthy subjects matched according to age, weight and gender, steady state AUC and Cmax in heart failure patients were 38% and 30% higher, respectively. Consistent with these results, a population pharmacokinetic analysis of eplerenone based on a subset of patients from EPHESUS indicates that clearance of eplerenone in patients with heart failure was similar to that in healthy elderly subjects.

Preclinical studies on safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction revealed no special hazard for humans.

In repeated dose toxicity studies, prostate atrophy was observed in rats and dogs at exposure levels slightly above clinical exposure levels. The prostatic changes were not associated with adverse functional consequences. The clinical relevance of these findings is unknown.

Tablet core:

Lactose monohydrate

Microcrystalline cellulose (E460)

Croscarmellose sodium (E468)

Hypromellose (E464)

Sodium laurilsulfate

Talc (E553b)

Magnesium stearate (E470b)

Tablet coating:

Opadry yellow:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 400

Polysorbate 80 (E433)

Iron oxide yellow (E172)

Iron oxide red (E172)

Not applicable.

3 years.

No special precautions for storage.

Opaque PVC/Al blisters containing 10, 20, 28, 30, 50, 90, 100 or 200 tablets

Opaque PVC/Al perforated unit dose blisters containing 20 x 1, 30 x 1, 50 x 1, 90 x 1, 100 x 1 or 200 x 1 (10 packs of 20 x 1) tablets

Not all pack sizes may be marketed.

No special requirements.

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

PL 00057/0615-6

21/09/2004

October 2009

Version IN 6_0