Espiro, 50 mg 30 pcs.

A potassium-saving diuretic.

Eplerenone is highly selective for mineralocorticoid receptors in humans in contrast to glucocorticoid, progesterone and androgen receptors and prevents binding of mineralocorticoid receptors to aldosterone, a key PAAC hormone that is involved in BP regulation and pathogenesis of cardiovascular disease.

Eplerenone causes a persistent increase in plasma renin and serum aldosterone activity. Subsequently, renin secretion is inhibited by aldosterone through a feedback mechanism. At the same time, an increase in renin activity or circulating aldosterone concentration does not affect the effects of eplerenone. No significant effect of eplerenone on HR, duration of QRS, PR or QT intervals was found in healthy volunteers.

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 NYHA functional class II with reduced left ventricular ejection fraction.

Active ingredient

Composition

1 tablet

Eplerenone 50 mg.

Excipients:Lactose monohydrate – 77.34 mg, microcrystalline cellulose – 30.76 mg, hypromellose 15cP – 2.5 mg, sodium lauryl sulfate – 1.7 mg, croscarmellose sodium – 6 mg, magnesium stearate – 1.7 mg.

Shell contents: Opadray II 33G32578 (yellow) – 8 mg (hypromellose 6cP (E464) – 3.2 mg, titanium dioxide (E171) – 1.82 mg, lactose monohydrate – 1.68 mg, macrogol 3350 – 0.64 mg, triacetin – 0.48 mg, iron oxide yellow dye (E172) – 0.18 mg).

10 pcs. – Blisters (3) – cardboard boxes.

How to take, the dosage

The drug is administered orally, regardless of meals.

Myocardial Infarction

The treatment should be started with a dose of 25 mg once daily and increased to 50 mg once daily after 4 weeks, taking into account the serum potassium concentration (see Table 1. Table 1). The recommended maintenance dose of Espiro is 50 mg once daily.

Chronic heart failure II functional class according to NYHA classification

. Treatment should be started with a dose of 25 mg once daily and increased to 50 mg once daily after 4 weeks, taking into account the serum potassium concentration. Maximum daily dose is 50 mg.

In case of temporary discontinuation of Espiro® due to increase of serum potassium concentration to 6 mmol/l or more, therapy with Espiro® can be restarted in 25 mg dose every other day when serum potassium concentration is

Interaction

Pharmacodynamic interaction

Kalium-saving diuretics and potassium preparations: Given the increased risk of hyperkalemia, eplerenone should not be prescribed in patients receiving potassium-saving diuretics and potassium preparations. Potassium-saving diuretics may increase the effects of antihypertensive drugs and other diuretics.

Drugs containing lithium:The interaction of eplerenone with lithium preparations has not been studied. However, in patients who received lithium preparations in combination with diuretics and ACE inhibitors, there have been described cases of increased concentration and intoxication with lithium. If such a combination is necessary, it is reasonable to monitor plasma lithium concentration.

Cyclosporine, tacrolimus:Cyclosporine and tacrolimus may cause renal dysfunction and increase the risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus will be required during treatment with eplerenone, it is recommended that serum potassium concentration and renal function be monitored regularly.

NSAIDs: treatment with NSAIDs may lead to acute renal failure through direct suppression of glomerular filtration, especially in patients at risk (elderly patients and/or patients with dehydration). When concomitant use of these drugs before and during treatment it is necessary to ensure adequate water regimen and monitor renal function.

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

ACE inhibitors and angiotensin II receptor antagonists: When using eplerenone with ACE inhibitors or angiotensin II receptor antagonists, serum potassium concentrations should be monitored regularly. Such a combination may lead to an increased risk of hyperkalemia, especially in patients with impaired renal function, including elderly patients. Do not use a triple combination of ACE inhibitor and ARAII with eplerenone.

Alpha1-adrenoblockers (prazosin, alfuzosin):The simultaneous use of alpha1-adrenoblockers with eplerenone may increase antihypertensive effect and/or risk of orthostatic hypotension; therefore, it is recommended to control BP when changing body position.

Tricyclic antidepressants, neuroleptics, amifostine, baclofen:The simultaneous use of these drugs with eplerenone may increase the antihypertensive effect or the risk of orthostatic hypotension.

Glucocorticoids, tetracosactide:Concomitant use of these agents with eplerenone may lead to sodium and fluid retention.

Pharmacokinetic interaction

In vitro studies indicate that eplerenone does not inhibit the CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 isoenzymes. Eplerenone is not a substrate or inhibitor of glycoprotein P.

Digoxin:The AUC of digoxin is increased by 16% (90% CI: 4-30%) when used concomitantly with eplerenone. Caution should be exercised when digoxin is used in doses close to the maximum therapeutic dose.

Warfarin:no clinically significant pharmacokinetic interaction with warfarin has been observed. Caution should be exercised if warfarin is used in doses close to the maximum therapeutic.

CYP3A4 substrates: No evidence of pharmacokinetic interaction of eplerenone with CYP3A4 substrates such as midazolam and cisapride has been found in specific studies.

CYP3A4 inhibitors:

powerful CYP3A4 inhibitors: – There may be a significant pharmacokinetic interaction when using eplerenone with agents that inhibit CYP3A4. Powerful CYP3A4 inhibitor (ketoconazole 200 mg 2 times/day) caused 441% increase in AUC of eplerenone. Concomitant use of eplerenone with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone is contraindicated;

– weak and moderate CYP3A4 inhibitors: concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, and fluconazole was accompanied by a significant pharmacokinetic interaction (degree of AUC increase varied from 98% to 187%). When concomitant use of these agents with eplerenone, the dose of the latter should not exceed 25 mg.

CYP3A4 inducers: Simultaneous use of drugs containing St. John’s wort (a potent CYP3A4 inducer) with eplerenone caused 30% reduction in AUC of the latter. When using more potent CYP3A4 inducers, such as rifampicin, a more pronounced decrease in AUC of eplerenone is possible. Concomitant use of potent CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, preparations containing St. John’s wort) is not recommended taking into account possible decrease of eplerenone effectiveness.

Antacids: Based on a pharmacokinetic clinical study, no significant interaction of antacids with eplerenone is expected with their concomitant use.

Special Instructions

Hyperkalemia

Hyperkalemia may occur during treatment with Espiro due to its mechanism of action. Serum potassium concentration should be monitored at the beginning of treatment and when changing the drug dose in all patients. Further, periodic monitoring of potassium content is recommended in patients with increased risk of hyperkalemia, such as elderly patients, patients with renal insufficiency and diabetes mellitus. Taking into account the increased risk of hyperkalemia, the prescription of potassium preparations after the start of treatment with Espiro is not recommended. Decreasing the dose of Espiro leads to a decrease in serum potassium concentration. In one study, adding hydrochlorothiazide to eplerenone prevented an increase in serum potassium concentration.

Renal dysfunction

In patients with impaired renal function, including diabetic microalbuminuria, regular monitoring of serum potassium concentration is recommended. The risk of hyperkalemia increases with decreased renal function. Although the number of patients with type 2 diabetes mellitus and microalbuminuria in the studies was limited, nevertheless, in this small sample there was an increased incidence of hyperkalemia. Therefore, treatment should be used with caution in these patients. Eplerenone is not eliminated by hemodialysis. The use of the drug Espiro is contraindicated in severe renal failure.

Hepatic dysfunction

In patients with mild to moderate hepatic dysfunction (5-6 and 7-9 points on the Child-Pugh scale) no increase in serum potassium concentration over 5.5 mmol/L has been found. Electrolytes should be monitored in such patients. Eplerenone has not been studied in patients with severe hepatic impairment, therefore its use is contraindicated.

CYP3A4 inducers

The concomitant use of Espiro with potent CYP3A4 inducers is not recommended.

Cyclosporine, tacrolimus, drugs containing lithium

Prescribing these drugs should be avoided during treatment with Espiro.

Lactose

The tablets contain lactose, so they should not be prescribed for patients with rare hereditary conditions such as lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.

Influence on driving and operating machinery

The effect of the drug Espiro on the ability to drive vehicles or operate complex machinery has not been studied. However, taking into account the possibility of the drug causing dizziness and fainting, caution should be exercised when driving motor vehicles or using machinery while taking Espiro.

Contraindications

– clinically significant hyperkalemia;

– serum potassium concentration at the start of treatment greater than 5 mmol/L;

– moderate or severe renal impairment;

– severe hepatic impairment (greater than 9 points on the Child-Pugh score);

– concomitant use of potassium-saving diuretics, potassium preparations, or potent CYP3A4 inhibitors, such as itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone;

Plasma creatinine concentration >2 mg/dL (or >177 mmol/L) in men or >1.8 mg/dL (or >159 mmol/L) in women;

– lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome;

– Children and adolescents under 18 years of age (no experience of using the drug in patients in this age group);

– hypersensitivity to eplerenone or other components of the drug.

Cautions should be taken in patients with type 2 diabetes mellitus and microalbuminuria; concomitant use of eplerenone, ACE inhibitors or angiotensin II receptor antagonists, drugs containing lithium, cyclosporine or tacrolimus, digoxin and warfarin at doses close to maximum therapeutic; in impaired renal function (CKD

Side effects

The following adverse effects are listed according to the following World Health Organization frequency of occurrence: very common (≥10%); common (≥1%).

Hematopoietic system disorders: infrequent – eosinophilia.

From the endocrine system: infrequent – hypothyroidism.

Metabolism and nutrition disorders:often – hyperkalemia, hypercholesterolemia, hypertriglyceridemia, dehydration; infrequently – hyponatremia.

Psychiatric disorders: infrequent – insomnia.

Nervous system disorders:often – dizziness, fainting; infrequently – headache, hypoesthesia.

Cardiovascular system disorders:frequent – marked decrease in BP, myocardial infarction; infrequent – atrial fibrillation, left ventricular failure, tachycardia, orthostatic hypotension, lower limb artery thrombosis.

In the respiratory system:often – cough; infrequently – pharyngitis.

The digestive system:often – diarrhea, nausea, constipation; infrequently – flatulence, vomiting, cholecystitis.

Skin and subcutaneous tissue: frequent – skin itching; infrequent – increased sweating.

Muscular system disorders:often – calf cramps, musculoskeletal pain; infrequently – back pain.

Since the urinary system:often – renal dysfunction; infrequent – pyelonephritis.

Allergic reactions: infrequent – skin rash; frequency unknown – angioedema.

Others: infrequent – asthenia, malaise, gynecomastia.

Laboratory findings: infrequent – increased residual urea nitrogen concentration, creatinine, decreased epidermal growth factor receptor expression, increased serum glucose concentration.

Overdose

There have been no cases of overdose of eplerenone in humans. The most likely manifestations of overdose may be excessive BP reduction and hyperkalemia.

Treatment: In case of excessive BP decrease, maintenance treatment should be prescribed. If hyperkalemia develops, standard therapy is indicated. Eplerenone is not eliminated by hemodialysis. It has been found that eplerenone is actively bound to activated charcoal.

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