INSPRA film-coated tablets 11 Jul 2016 #2015-0011133

NAME OF THE MEDICINAL PRODUCT

INSPRA 25 mg
INSPRA 50 mg

1. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 25 mg or 50 mg of eplerenone.

Excipients: with known effect:

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 the full list of excipients see section 6.1.

2. PHARMACEUTICAL FORM

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.

3. CLINICAL PARTICULARS

3.1. Therapeutic indications

Inspra is indicated:

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

• in addition to standard optimal therapy, to reduce the risk of CV mortality and morbidity in adult
patients with New York Heart Association ( NYHA) class II (chronic) heart failure and left
ventricular systolic dysfunction (LVEF ≤30%) (see section 5.1).

3.2. Posology and method of administration

Posology

For the individual adjustment of dose, the strengths of 25 mg and 50 mg are available. The maximum
dose regimen is 50 mg daily.

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For post-MI heart failure patients:

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 MI.

For patients with NYHA class II (chronic) heart failure:

For chronic heart failure NYHA class II patients, treatment should be initiated at a dose of 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 and section 4.4).

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

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.

Paediatric population

The safety and efficacy of eplerenone in children and adolescents have not been established. Currently
available data are described in section 5.1 and 5.2.

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).

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Renal impairment

No initial dose adjustment is required in patients with mild renal impairment. Periodic monitoring of
serum potassium with dose adjustment according to Table 1 is recommended

Patients with moderate renal impairment (CrCl 30-60 mL /min) should be started at 25 mg every
other day, and dose should be adjusted based on the potassium level (see Table 1). Periodic
monitoring of serum potassium is recommended (see section 4.4).

There is no experience in patients with CrCl <50 mL /min with post MI heart failure. The use of
eplerenone in these patients should be done cautiously. Doses above 25 mg daily have not been
studied in patients with CrCl <50 mL/min.

Use in patients with severe renal impairment (CrCl <30 mL /min) is contraindicated (see section 4.3).
Eplerenone is not dialysable.

Hepatic impairment

No initial dose 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, erythromycin, saquinavir 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).

3.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Patients with clinically significant hyperkalemia or with conditions associated with hyperkalemia
• Patients with serum potassium level > 5.0 mmol/L at initiation
• Patients with severe renal insufficiency (eGFR <30 mL per minute per 1.73 m2)
• Patients with severe hepatic insufficiency (Child-Pugh Class C)
• Patients receiving potassium-sparing diuretics, potassium-supplements or strong inhibitors of
CYP 3A4 (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin
and nefazodone) (see section 4.5).
• The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin
receptor blocker (ARB) with eplerenone

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3.4. Special warnings and precautions for use

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: Coadministration 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.

Information for Patients: Patients receiving eplerenone should be informed not to use potassium
supplements, salt substitutes containing potassium, or contraindicated medications without consulting
the prescribing physician.
3.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

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.

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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): 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.

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.

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.

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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.

4.6 Fertility, pregnancy and lactation

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.

Breastfeeding:
: 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.

Fertility:
There are no human data available on fertility.

4.7 Effects on ability to drive and use machines

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.

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4.8 Undesirable effects

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

MedDRA system organ class Adverse reaction

Infections and infestations
Uncommon pyelonephritis, pharyngitis, infection
Blood and lymphatic system disorders
Uncommon eosinophilia
Endocrine disorders
Uncommon hypothyroidism
Metabolism and nutrition disorders
Common hyperkalaemia (see sections 4.3 and 4.4),
hypercholesterolaemia
Uncommon hyponatraemia, dehydration, hypertriglyceridaemia
Psychiatric disorders
Common insomnia
Nervous system disorders
Common dizziness, syncope, headache
Uncommon hypoaesthesia
Cardiac disorders
Common , left ventricular failure, atrial fibrillation
, tachycardia
Uncommon
Vascular disorders
Common hypotension
Uncommon arterial thrombosis limb, orthostatic hypotension
Respiratory, thoracic and mediastinal
disorders cough
Common
Gastrointestinal disorders
Common diarrhoea, nausea, constipation, vomiting
Uncommon flatulence

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Skin and subcutaneous tissue disorders

Common rash, pruritus
Uncommon hyperhidrosis, angioedema

Musculoskeletal and connective tissue

disorders
Common muscle spasms, , back pain
Uncommon , musculoskeletal pain
Renal and urinary disorders
Common renal impairment (see sections 4.4 and 4.5)
Hepatobiliary disorders
Uncommon cholecystitis
Reproductive system and breast disorders
Uncommon gynaecomastia
General disorders and administration site
conditions
Common asthenia,

Uncommon , malaise
Investigations
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 of suspected adverse reactions

Any suspected adverse events should be reported to the Ministry of Health according to the National
Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.h
ealth.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

4.9 Overdose

No cases of adverse events associated with overdose of eplerenone in humans have been reported.
The most likely manifestation of human overdose 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: aldosterone antagonists, ATC code: C03DA04

Mechanism of action

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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 CV
disease.

Pharmacodynamic effects
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 EPHESUS. EPHESUS was a double-blind, placebo-controlled study,
of 3 year duration, in 6632 subjects with acute MI, left ventricular dysfunction (as measured by left
ventricular ejection fraction [LVEF] ≤40%), and clinical signs of heart failure. Within 3to14 days
(median 7 days) after an acute MI, subjects received eplerenone or placebo in addition to standard
therapies at an initial dose of 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 subjects 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 subjects assigned to eplerenone and 16.7 % of subjects
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 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 subjects aged < 75 years old. The benefits of therapy in those subjects over the age of
75 are unclear. NYHA functional classification improved or remained stable for a statistically
significant greater proportion of subjects 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.

In the EMPHASIS-HF trial the effect of eplerenone when added to standard therapy was investigated
on clinical outcomes in subjects with systolic heart failure and mild symptoms (NYHA functional
class II).

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Subjects were included if they were at least 55 years old, had a LVEF ≤ 30% or LVEF ≤ 35% in
addition to QRS duration of > 130 msec, and were either hospitalized for CV reasons 6 months prior
to inclusion or had a plasma level of B-type natriuretic peptide (BNP) of at least 250 pg/ mL or a
plasma level of N-terminal pro-BNP of at least 500 pg/ mL in men (750 pg/ml in women). Eplerenone
was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily if the
serum potassium level was < 5.0 mmol/L. Alternatively, if the estimated glomerular filtration rate
(GFR) was 30-49 mL/min/1.73 m2, eplerenone was started at 25 mg on alternate days, and increased
to 25 mg once daily.

In total, 2737 subjects were randomized (double-blind) to the treatment with eplerenone or placebo
including baseline therapy of diuretics (85%), ACE inhibitors (78%), angiotensin II receptor blockers
(19%), beta blockers (87%), anti thrombotic drugs (88%), lipid lowering agents (63%), and digitalis
glycosides (27%). The mean LVEF was ~26% and the mean QRS duration was ~122 msec. Most of
the subjects (83.4%) were previously hospitalized for CV reasons within 6 months of randomization,
with around 50% of them due to heart failure. Around 20% of the subjects had implantable
defibrillators or cardiac resynchronization therapy.

The primary endpoint, death from CVcauses or hospitalization for heart failure occurred in 249
(18.3%) subjects in the eplerenone group and 356 (25.9%) subjects in the placebo group (RR 0.63,
95% CI, 0.54-0.74; p<0.001). The effect of eplerenone on the primary endpoint outcomes was
consistent across all pre-specified subgroups.

The secondary endpoint of all cause mortality was met by 171 (12.5%) subjects in the eplerenone
group and 213 (15.5%) subjects in the placebo group (RR 0.76; 95% CI, 0.62-0.93; p = 0.008). Death
from CV causes was reported in 147 (10.8%) subjects in the eplerenone group and 185 (13.5%)
patients in the placebo group (RR 0.76; 95% CI, 0.61-0.94; p = 0.01).

During the study, hyperkalaemia (serum potassium level > 5.5 mmol/L) was reported in 158 (11.8%)
subjects in the eplerenone group and 96 (7.2%) subjects in the placebo group (p < 0.001).
Hypokalaemia, defined as serum potassium levels < 4.0 mmol/L, was statistically lower with
eplerenone when compared to placebo (38.9% for eplerenone compared to 48.4% for placebo,
p<0.0001).

Paediatric population:

Eplerenone has not been studied in pediatric subjects with heart failure.

In a 10 week study of paediatric subjects with hypertension (age range 4 to 17 years, n=304),
eplerenone, at doses (from 25 mg up to 100 mg per day) that produced exposure similar to that in
adults, did not lower blood pressure effectively. In this study and in a 1-year paediatric safety study in
149 subjects, the safety profile was similar to that of adults. Eplerenone has not been studied in
hypertensive subjects less than 4 years old because the study in older paediatric patients showed a
lack of efficacy (See section 4.2).

Any (long term) effect on hormonal status in paediatric subjects has not been studied

5.2 Pharmacokinetic properties

Absorption
The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet.

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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.
Distribution

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.

Biotransformation
:

Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone

have been identified in human plasma.

Elimination
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 Cmax (22%) and AUC (45%) compared with younger subjects
(18 to 45 years). At steady state, Cmax was 19% lower and AUC was 26% lower in blacks. (see
section 4.2.)

Paediatric population: A population pharmacokinetic model for eplerenone concentrations from two
studies in 51 paediatric hypertensive subjects of ages 4to16 years identified that patient body weight
had a statistically significant effect on eplerenone volume of distribution but not on its clearance.
Eplerenone volume of distribution and peak exposure in a heavier paediatric patient are predicted to
be similar to that in an adult of similar body weight; in a lighter 45 kg patient, the volume of
distribution is about 40% lower and the peak exposure is predicted to be higher than typical adults.
Eplerenone treatment was initiated at 25 mg once daily in paediatric patients and increased to 25 mg
twice daily after 2 weeks and eventually to 50 mg twice daily, if clinically indicated. At these doses,
the highest observed eplerenone concentrations in paediatric subjects were not substantially higher
than those in adults initiated at 50 mg once daily.

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

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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.

5.3 Preclinical safety data

Preclinical studies on safety pharmacology, genotoxicity, carcinogenic potential and reproductive

toxicity 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. Studies in rats and
rabbits showed no teratogenic effects, although decreased body weight in maternal rabbits and
increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered
dosage.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Hypromellose
Sodium laurilsulfate
Talc
Magnesium stearate

Tablet coating:
Opadry yellow:
Hypromellose
Titanium dioxide
Macrogol 400
Polysorbate 80
Iron oxide yellow
Iron oxide red

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INSPRA film-coated tablets 11 Jul 2016 #2015-0011133

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

6.5 Store below 25ºC Nature and contents of container

Opaque PVC/Al blisters containing 10, 20, 28, 30, 50, 100 or 200 tablets
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 Registration Holder

Pfizer PFE Pharmaceuticals Israel Ltd.

8 Shenkar St., Herzliya Pituach 46725

Manufacturer: Fareva Amboise, France

9 Registration Number

Inspra 25mg – 134-67-31192-00

Inspra 50mg – 134-68-31193-00

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