Espiro (Eplerenon)

Potassium-sparing diuretic. 

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

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

- 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 for the purpose of reducing cardiovascular mortality and morbidity in patients with chronic heart failure of NYHA II functional class with a reduced left ventricular ejection fraction.

- clinically significant hyperkalemia;

- the concentration of potassium in the blood serum at the beginning of treatment is more than 5 mmol / l;

- moderate or severe renal impairment;

- severe liver failure (more than 9 points on the Child-Pugh scale);

- concomitant use of potassium-sparing diuretics, potassium preparations or powerful inhibitors of CYP3A4, for example, 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 up to 18 years of age (there is no experience of using the drug in patients of this age group);

- hypersensitivity to eplerenone or other components of the drug.

The drug should be prescribed with caution  in type 2 diabetes mellitus and microalbuminuria; the simultaneous use of eplerenone, ACE inhibitors or angiotensin II receptor antagonists, preparations containing lithium, cyclosporine or tacrolimus, digoxin and warfarin in doses close to the maximum therapeutic; with impaired renal function (CC

The following undesirable effects are given in accordance with the following gradation of the frequency of their occurrence according to the classification of the World Health Organization: very often (≥10%); often (≥1%).

From the hematopoietic system:  infrequently - eosinophilia.

From the endocrine system:  infrequently - hypothyroidism.

From the side of metabolism and nutrition:  often - hyperkalemia, hypercholesterolemia, hypertriglyceridemia, dehydration; infrequently - hyponatremia.

Mental disorders:  infrequently - insomnia.

From the nervous system:  often - dizziness, fainting; infrequently - headache, hypesthesia.

From the side of the cardiovascular system:  frequent - a marked decrease in blood pressure, myocardial infarction; infrequently - atrial fibrillation, left ventricular failure, tachycardia, orthostatic hypotension, thrombosis of the arteries of the lower extremities.

From the respiratory system:  often - cough; infrequently - pharyngitis.

From the digestive system:  often - diarrhea, nausea, constipation; infrequently - flatulence, vomiting, cholecystitis.

From the skin and subcutaneous tissues:  often - itchy skin; infrequently - increased sweating.

From the musculoskeletal system:  often - cramps of the calf muscles, musculoskeletal pain; infrequently - back pain.

From the urinary system:  often - impaired renal function; infrequently - pyelonephritis.

Allergic reactions:  infrequently - skin rash; frequency unknown - angioedema.

Others:  infrequently - asthenia, malaise, gynecomastia.

Laboratory indicators:  infrequently - an increase in the concentration of residual urea nitrogen, creatinine, a decrease in the expression of the epidermal growth factor receptor, an increase in the concentration of glucose in the blood serum.

Pharmacodynamic interaction

Potassium-sparing diuretics and potassium supplements: Given the increased risk of hyperkalemia, eplerenone should not be given to patients receiving potassium-sparing diuretics and potassium supplements. Potassium-sparing diuretics may enhance the effects of antihypertensive drugs and other diuretics.

Lithium-containing preparations: The  interaction of eplerenone with lithium preparations has not been studied. However, in patients receiving lithium preparations in combination with diuretics and ACE inhibitors, cases of increased concentration and intoxication with lithium have been described. If such a combination is necessary, it is advisable to control the concentration of lithium in the blood plasma.

Cyclosporine, tacrolimus:  Cyclosporine and tacrolimus may impair renal function and increase the risk of hyperkalemia. Simultaneous use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus is required during treatment with eplerenone, regular monitoring of serum potassium and renal function is recommended.

NSAIDs: NSAID  treatment can lead to acute renal failure by directly suppressing glomerular filtration, especially in patients at risk (elderly patients and / or patients with dehydration). When these funds are used together, before and during treatment, it is necessary to ensure an adequate water regime and monitor renal function.

Trimethoprim: 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 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 levels should be monitored regularly. This combination may increase the risk of developing hyperkalemia, especially in patients with impaired renal function, incl. in elderly patients. A triple combination of an ACE inhibitor and ARAII with eplerenone should not be used.

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

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

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

Pharmacokinetic interaction

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

Digoxin: The  AUC of digoxin when used concomitantly with eplerenone increases by 16% (90% CI: 4-30%). Care must be taken if digoxin is used in doses close to the maximum therapeutic dose.

Warfarin: No  clinically significant pharmacokinetic interaction with warfarin has been identified. Care must be taken if warfarin is used in doses close to the maximum therapeutic dose.

CYP3A4 substrates : Specific studies have shown no evidence of pharmacokinetic interactions between eplerenone and CYP3A4 substrates such as midazolam and cisapride.

CYP3A4 inhibitors:

- potent inhibitors of CYP3A4:  when using eplerenone with drugs that inhibit CYP3A4, a significant pharmacokinetic interaction is possible. A potent inhibitor of CYP3A4 (ketoconazole 200 mg 2 times / day) caused an increase in the AUC of eplerenone by 441%. Concomitant use of eplerenone with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazadone is contraindicated;

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

CYP3A4 inducers:  simultaneous administration of drugs containing St. John's wort (a powerful inducer of CYP3A4) with eplerenone caused a 30% decrease in the latter's AUC. With the use of more powerful inducers of CYP3A4, such as rifampicin, a more pronounced decrease in AUC of eplerenone is possible. Considering the possible decrease in the effectiveness of eplerenone, the simultaneous use of powerful inducers of CYP3A4 (rifampicin, carbamazepine, phenytoin, phenobarbital, preparations containing St. John's wort) is not recommended.

Antacids:  Based on a pharmacokinetic clinical study, a significant interaction of antacids with eplerenone is not expected when they are used simultaneously.

The drug is administered orally, regardless of food intake.

Myocardial infarction

Treatment should begin with a dose of 25 mg 1 time / day and increase it to 50 mg 1 time / day after 4 weeks, taking into account the concentration of potassium in the blood serum (see table 1). The recommended maintenance dose of Espiro is 50 mg 1 time / day.

Chronic heart failure II functional class according to NYHA classification

Treatment should start with a dose of 25 mg 1 time / day and increase it to 50 mg 1 time / day after 4 weeks, taking into account the concentration of potassium in the blood serum. The maximum daily dose is 50 mg.

After the temporary discontinuation of Espiro due to an increase in serum potassium concentration up to 6 mmol / L or more, Espiro therapy can be resumed at a dose of 25 mg every other day, when the serum potassium concentration is

The concentration of potassium in the blood serum should be determined before the appointment of the drug Espiro , during the first week and 1 month after the start of therapy or when changing the dose of the drug. In the future, it is also necessary to periodically monitor the concentration of potassium in the blood serum.

Correction of the initial dose in elderly patients is not required. Due to the age-related decrease in renal function in elderly patients, the risk of developing hyperkalemia increases, especially in the presence of concomitant diseases that contribute to an increase in serum eplerenone concentrations, in particular, with mild to moderate liver dysfunction. It is recommended to periodically determine the concentration of potassium in the blood serum (see table 1).

Correction of the initial dose in patients with mild renal impairment is not required. The degree of hyperkalemia increases with deteriorating renal function. It is recommended to periodically determine the concentration of potassium in the blood serum (see table 1). Eplerenone is not removed by hemodialysis. In patients with severe renal impairment (CC

In patients with NYHA functional class II chronic heart failure and moderate renal impairment (CC 30-60 ml / min), therapy should be started with a dose of 25 mg every other day, followed by dose adjustment depending on the concentration of potassium in the blood serum ( see table 1).

Experience of using the drug Espiro in patients with heart failure after myocardial infarction and CC

In patients with CC

Adjustment of the initial dose in patients with mild to moderate hepatic dysfunction is not required. Given the increased concentration of eplerenone in these patients, it is recommended that serum potassium levels be monitored regularly, especially in elderly patients. The use of the drug Espiro in patients with severe liver dysfunction is contraindicated.

Concomitant therapy

With the simultaneous use of drugs that have a weak or moderate inhibitory effect on CYP3A4, for example, erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole, treatment with Espiro can be started with a dose of 25 mg 1 time / day.

Cases of overdose of eplerenone in humans have not been described. The most likely manifestations of an overdose may be an excessive decrease in blood pressure and hyperkalemia.

Treatment:  with an excessive decrease in blood pressure, supportive treatment should be prescribed. If hyperkalemia develops, standard therapy is indicated. Eplerenone is not removed by hemodialysis. It has been found that eplerenone actively binds to activated carbon.

Hyperkalemia

During treatment with Espiro , hyperkalemia may develop, which is due to its mechanism of action. At the beginning of treatment and when changing the dose of the drug in all patients, the concentration of potassium in the blood serum should be monitored. In the future, periodic monitoring of the potassium content is recommended in patients with an increased risk of hyperkalemia, for example, in elderly patients, patients with renal failure and diabetes mellitus. Given the increased risk of hyperkalemia, prescribing potassium supplements after starting treatment with Espiro is not recommended. Reducing the dose of the drug Espiroleads to a decrease in the concentration of potassium in the serum. In one study, the addition of hydrochlorothiazide to eplerenone inhibited an increase in serum potassium concentration.

Impaired renal function

In patients with impaired renal function, incl. diabetic microalbuminuria, it is recommended to regularly monitor the concentration of potassium in the blood serum. The risk of developing hyperkalemia increases with decreased renal function. Although the number of patients with type 2 diabetes mellitus and microalbuminuria was limited in the studies, an increase in the incidence of hyperkalemia was noted in this small sample. In this regard, such patients should be treated with caution. Eplerenone is not removed by hemodialysis. The use of the drug Espiro is contraindicated in severe renal failure.

Liver dysfunction

In patients with mild or moderate impairment of liver function (5-6 and 7-9 points on the Child-Pugh scale), an increase in serum potassium concentration of more than 5.5 mmol / L was not detected. In such patients, electrolyte levels should be monitored. Eplerenone has not been studied in patients with severe hepatic impairment and is therefore contraindicated.

CYP3A4 inductors

The simultaneous use of the drug Espiro with powerful inducers of CYP3A4 is not recommended.

Cyclosporine, tacrolimus, lithium preparations

During treatment with Espiro , the appointment of these funds should be avoided.

Lactose

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

Influence on the ability to drive vehicles and use mechanisms

The influence of the drug Espiro on the ability to drive vehicles or use complex equipment has not been studied. However, given the possibility of the drug causing dizziness and fainting, caution should be exercised when driving or using complex equipment while taking Espiro .

Film-coated tablets, yellow, round, biconvex, with a line on one side; at the break - from white to almost white.