Eplerenone Mylan 25 mg film-coated tablets

4.2 Posology and method of administration

Hepatic impairment
No initial dosage 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 and verapamil, a starting the dose of 25 mg OD may be initiated. Dosing should not exceed 25 mg OD (see section 4.5).

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- 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)

4.5 Interaction with other medicinal products and other forms of interaction

CYP3A4 inhibitors:
- 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, 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 daily when mild to moderate inhibitors of CYP3A4 are co-administered with eplerenone (see sections 4.2).

4.8 Undesirable effects

In two studies (Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (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. The most frequent adverse event reported in the EMPHASIS-HF study was hyperkalaemia with an incidence rate of 8.7% and 4% for eplerenone and placebo respectively.

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: Common (= 1/100 to < 1/10); Uncommon (= 1/1,000 to < 1/100); not known (cannot be estimated from the available data).

ADR Frequency in Eplerenone Placebo Controlled Studies:

4.9 Overdose

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

5.1  Pharmacodynamic properties

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 ventriPaediatric population:

Eplerenone has not been studied in paediatric patients with heart failure.

In a 10 week study of paediatric patients with hypertension (age range 4 to 17 16 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 patients (age range 5 to 17 years), the safety profile was similar to that of adults. Eplerenone has not been studied in hypertensive patients less than 4 years old because the study in older paediatric patients showed a lack of efficacy (See section 4.2).
cular dysfunction (as measured by left ventricular ejection fraction [LVEF] = 40%), and clinical signs of heart failure. Within 3 -to 14 days (median

5.2 Pharmacokinetic properties

Absorption
The absolute bioavailability of eplerenone is 69% following administration of a 100mg oral tablet
. Maximum plasma concentrations are reached after approximately 1.5 to about 2 hours. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 10 mg 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 to be 42- 90 at 50 (±7) L. Eplerenone does not preferentially bind to red blood cells.

 

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 6 hours. The apparent plasma clearance is approximately 10 L/hr.

 

Section 4.4:
[...]
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.

Section 4.8:
[...]

Metabolism and nutrition disorders
Common: hyperkalaemia (see sections 4.3 and 4.4), hypercholesterolaemia
Uncommon: hyponatraemia, dehydration, hypercholesterolaemia, hypertriglyceridaemia,

Psychiatric disorders
UncommonCommon: insomnia

Nervous system disorders
Common: dizziness, syncope, headache
Uncommon: headache, hypoaesthesia

Cardiac disorders
Common: myocardial infarction, left ventricular failure, atrial fibrillation
Uncommon: left ventricular failure, atrial fibrillation, tachycardia

[...]

Gastrointestinal disorders
Common: diarrhoea, nausea, constipation, vomiting
Uncommon: vomiting, flatulence

Hepatobiliary disorders
Uncommon: cholecystitis

Skin and subcutaneous tissue disorders
Common: rash, pruritus
Uncommon: hyperhidrosis, angioedema
Not known: angioedema

Musculoskeletal and connective tissue disorders
Common: muscle spasms, musculoskeletal pain, back pain
Uncommon: back pain

Hepatobiliary disorders
Uncommon: cholecystitis

[...]

General disorders and administration site conditions

Common: asthenia

Uncommon: asthenia, malaise

Investigations
Common: blood urea increased, blood creatinine increase
Uncommon: blood creatinine increase, epidermal growth factor receptor decreased, blood glucose increased

[...]


Section 5.2:

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

None provided