Ipleron^® (Tablets) Instructions for Use

Marketing Authorization Holder

Aspectus Pharma LLC (Russia)

Manufactured By

Synthon Hispania, S.L. (Spain)

ATC Code

C03DA04 (Eplerenone)

Active Substance

Eplerenone (Rec.INN registered by WHO)

Dosage Forms

	Ipleron®	Film-coated tablets, 25 mg: 30 or 60 pcs.
		Film-coated tablets, 50 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light yellow to light brownish in color, round, biconvex, with an engraving “E9RN” on one side and “25” on the other side.

Excipients: lactose monohydrate – 35.7 mg, microcrystalline cellulose – 6.38 mg, microcrystalline cellulose (extragranular) – 9 mg, croscarmellose sodium – 4.25 mg, hypromellose – 2.55 mg, magnesium stearate – 0.43 mg, sodium lauryl sulfate – 0.85 mg, talc – 0.85 mg.

Film coating composition opadry yellow 15B220000 (hypromellose – 2.44 mg, polysorbate 80 – 0.04 mg, macrogol – 0.31 mg, titanium dioxide – 0.94 mg, iron oxide yellow dye – 0.1 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets from light yellow to light brownish in color, round, biconvex, with an engraving “E9RN” on one side and “50” on the other side.

Excipients: lactose monohydrate – 71.4 mg, microcrystalline cellulose – 12.75 mg, microcrystalline cellulose (extragranular) – 18 mg, croscarmellose sodium – 8.5 mg, hypromellose – 5.1 mg, magnesium stearate – 0.85 mg, sodium lauryl sulfate – 1.7 mg, talc – 1.7 mg.

Film coating composition opadry yellow 15B220000 (hypromellose – 4.88 mg, polysorbate 80 – 0.08 mg, macrogol – 0.62 mg, titanium dioxide – 0.94 mg, iron oxide yellow dye – 0.19 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Potassium-sparing diuretic

Pharmacotherapeutic Group

Potassium-sparing diuretic agent

Pharmacological Action

Potassium-sparing diuretic. Eplerenone has relative selectivity for mineralocorticoid receptors in humans compared to glucocorticoid, progesterone, and androgen receptors and prevents their binding with aldosterone, a key hormone of the RAAS involved in blood pressure regulation and the pathogenesis of cardiovascular diseases.

Eplerenone causes a sustained increase in plasma renin levels and serum aldosterone levels. Subsequently, renin secretion is suppressed by aldosterone via a feedback mechanism. However, the increase in renin activity or circulating aldosterone level does not affect the effects of eplerenone.

In patients with chronic heart failure of NYHA functional class II-IV, the addition of eplerenone to standard therapy led to a predictable dose-dependent increase in aldosterone level. A study on heart and kidney function in patients also established a significant increase in aldosterone level as a result of eplerenone therapy. These data confirm mineralocorticoid receptor blockade.

Pharmacokinetics

After oral administration of eplerenone at a dose of 100 mg, the absolute bioavailability is 69%. C_max in plasma is reached approximately 2 hours after oral administration. C_max and AUC are linearly dependent on the dose in the range from 10 to 100 mg and non-linearly at doses above 100 mg. C_ss is achieved within 2 days. Food intake does not affect absorption.

The binding of eplerenone to plasma proteins is approximately 50%, primarily with the alpha1-acid glycoprotein group. The estimated V_d at steady state is 50 (±7) L. Eplerenone does not bind to erythrocytes.

Eplerenone metabolism occurs mainly with the participation of the CYP3A4 isoenzyme. Active metabolites of eplerenone in plasma have not been identified.

The T_1/2 of eplerenone is about 3-5 hours, plasma clearance is approximately 10 L/h. Less than 5% of the eplerenone dose is excreted unchanged by the kidneys and through the intestines. After a single oral administration of labeled eplerenone, about 32% of the dose was excreted through the intestines and about 67% by the kidneys.

Indications

Myocardial infarction: in addition to standard therapy to reduce the risk of cardiovascular mortality and morbidity in patients with stable left ventricular dysfunction (ejection fraction less than 40%) and clinical signs of heart failure after myocardial infarction.

Chronic heart failure: in addition to standard therapy to reduce cardiovascular mortality and morbidity in patients with chronic heart failure of NYHA functional class II with reduced left ventricular ejection fraction (<35%).

ICD codes

Dosage Regimen

Take orally. The initial dose is 25 mg once daily. Dose increase is carried out gradually under the control of blood potassium levels. The recommended maintenance dose is 50 mg once daily.

When used concomitantly with drugs that have a weak or moderate inhibitory effect on CYP3A4, for example, amiodarone, diltiazem and verapamil, fluconazole, erythromycin, saquinavir, the dose of eplerenone should not exceed 25 mg once daily.

Adverse Reactions

Metabolism and nutrition disorders: common – hyperkalemia; uncommon – dehydration, hypercholesterolemia, hypertriglyceridemia, hyponatremia.

Nervous system disorders: common – dizziness; uncommon – headache, insomnia.

Cardiac and vascular disorders: common – decreased blood pressure; uncommon – atrial fibrillation, myocardial infarction, left ventricular failure, orthostatic hypotension, arterial thrombosis of lower extremities.

Gastrointestinal disorders: common – diarrhea, nausea; uncommon – flatulence, vomiting.

Blood and lymphatic system disorders: uncommon – eosinophilia.

Respiratory, thoracic and mediastinal disorders: uncommon – pharyngitis.

Skin and subcutaneous tissue disorders: uncommon – increased sweating, pruritus.

Musculoskeletal and connective tissue disorders: uncommon – back pain, leg muscle cramps.

Renal and urinary disorders: common – renal function impairment; uncommon – pyelonephritis.

General disorders and administration site conditions: uncommon – asthenia, malaise.

Investigations: uncommon – increased blood urea nitrogen, creatinine.

Contraindications

Clinically significant hyperkalemia; serum potassium concentration at the start of treatment greater than 5 mmol/L; moderate or severe renal impairment (creatinine clearance <30 mL/min in patients with chronic heart failure of NYHA functional class II); severe hepatic impairment (more than 9 points on the Child-Pugh scale); concomitant use of potassium-sparing diuretics, potassium preparations, or potent inhibitors of CYP3A4, for example, itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone; plasma creatinine concentration >2 mg/dL (or >177 µmol/L) in men or >1.8 mg/dL (or >159 µmol/L) in women; children and adolescents under 18 years of age; hypersensitivity to eplerenone.

Use in Pregnancy and Lactation

There is no information on use during pregnancy. Use with caution and only in cases where the expected benefit to the mother significantly outweighs the possible risk to the fetus/child.

It is unknown whether Eplerenone is excreted in human breast milk. If use during lactation is necessary, breastfeeding should be discontinued.

Special Precautions

Use with caution in patients with type 2 diabetes and microalbuminuria; concomitantly with ACE inhibitors or angiotensin II receptor antagonists, digoxin and warfarin in doses close to the maximum therapeutic doses, with lithium preparations, cyclosporine, tacrolimus; in patients with impaired renal function (creatinine clearance <50 mL/min); in elderly patients.

Hyperkalemia may develop during treatment with eplerenone, which is due to its mechanism of action. At the start of treatment and when changing the drug dose, serum potassium concentration should be monitored in all patients. Subsequently, periodic monitoring of potassium concentration is recommended for patients at increased risk of developing hyperkalemia, for example, elderly patients with renal impairment and diabetes. Given the increased risk of hyperkalemia, the prescription of potassium preparations after starting treatment with eplerenone is not recommended. Reducing the dose of eplerenone leads to a decrease in serum potassium concentration.

In patients with impaired renal function, including diabetic microalbuminuria, it is recommended to regularly monitor serum potassium concentration. The risk of hyperkalemia increases with decreasing renal function. Eplerenone is not removed by hemodialysis.

In patients with mild or moderate hepatic impairment (Child-Pugh class A and B), an increase in serum potassium concentration above 5.5 mmol/L was not detected. In such patients, electrolyte levels should be monitored.

Concomitant use of eplerenone with potent inducers of CYP3A4 is not recommended.

During treatment with eplerenone, the use of cyclosporine, tacrolimus, and preparations containing lithium should be avoided.

Effect on ability to drive vehicles and operate machinery

Eplerenone does not cause drowsiness or impaired cognitive function, but the possibility of dizziness should be considered.

Drug Interactions

Given the increased risk of hyperkalemia, Eplerenone should not be prescribed to patients receiving potassium-sparing diuretics and potassium preparations. Potassium-sparing diuretics may enhance the effects of antihypertensive agents and other diuretics.

Cases of lithium intoxication have been described in patients receiving lithium in combination with diuretics and ACE inhibitors. Concomitant use of eplerenone and lithium should be avoided.

Cyclosporine and tacrolimus may cause impaired renal function and increase the risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided.

Treatment with NSAIDs may lead to acute renal failure due to direct suppression of glomerular filtration, especially in at-risk patients (elderly patients and/or patients with dehydration). When using these agents concomitantly, adequate hydration should be ensured and renal function monitored before and during treatment.

Concomitant use of trimethoprim with eplerenone increases the risk of hyperkalemia. It is recommended to monitor serum potassium concentration and renal function, especially in patients with renal impairment and in elderly patients.

Eplerenone should be used with caution with ACE inhibitors or angiotensin II receptor antagonists. Such a combination may lead to an increased risk of hyperkalemia, especially in patients with impaired renal function, including the elderly. It is recommended to carefully monitor renal function and serum potassium concentration.

When alpha₁-adrenergic blockers are used concomitantly with eplerenone, the hypotensive effect may be enhanced and/or the risk of orthostatic hypotension may increase, therefore it is recommended to monitor blood pressure when changing body position.

When tricyclic antidepressants, antipsychotics, amifostine, baclofen are used concomitantly with eplerenone, the antihypertensive effect may be enhanced or the risk of orthostatic hypotension may increase.

Concomitant use with glucocorticoids, tetracosactide may lead to a weakening of the antihypertensive effect (sodium and fluid retention).

The AUC of digoxin when used concomitantly with eplerenone increases by 16%. Caution should be exercised if digoxin is used in doses close to the maximum therapeutic doses.

No clinically significant pharmacokinetic interaction with warfarin was identified. Caution should be exercised if warfarin is used in doses close to the maximum therapeutic doses.

When eplerenone is used with agents that inhibit CYP3A4, a significant pharmacokinetic interaction is possible. A potent inhibitor of CYP3A4 (ketoconazole 200 mg twice daily) caused an increase in the AUC of eplerenone by 441%. Concomitant use of eplerenone with potent inhibitors of CYP3A4, such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone, is contraindicated.

Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, and fluconazole was accompanied by a significant pharmacokinetic interaction (the degree of AUC increase varied from 98% to 187%). When these agents are used concomitantly with eplerenone, the dose of the latter should not exceed 25 mg.

Concomitant intake of St. John’s wort tincture (a potent inducer of CYP3A4) with eplerenone caused a decrease in the AUC of the latter by 30%. When using more potent inducers of CYP3A4, such as rifampicin, a more pronounced decrease in the AUC of eplerenone is possible. Given the possible decrease in the effectiveness of eplerenone, concomitant use of potent inducers of CYP3A4 (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort tincture) is not recommended.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.