Inspra, 25 mg 30 pcs.

Inspra is a diuretic.

Pharmacodynamics

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

Eplerenone causes a persistent increase in plasma renin and serum aldosterone concentrations. Subsequently, renin secretion is inhibited by aldosterone through a feedback mechanism. At the same time, increase of renin activity or concentration of circulating aldosterone does not affect the effects of eplerenone.

. The efficacy of eplerenone was studied in a double-blind, placebo-controlled EMPHESUS (Eplerenone Postacute Myocardial Infarction Heart failure Efficacy and Survival Study) in 6632 patients with acute myocardial infarction (MI), left ventricular (LV) dysfunction (ejection fraction (EF)

. The EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure) clinical trial enrolled 2737 patients with NYHA (New York Heart Association) functional class II (FC) CHF and severe systolic dysfunction (mean LV EF in the study was 26.1%). The average follow-up period was 21 months. In the eplerenone active treatment group, patients were taking ACE inhibitors or angiotensin II receptor blockers (94%), β-adrenoblockers (86.6%) before inclusion. Primary end point: death from cardiovascular causes or hospitalization for heart failure. The EMPHASIS-HF clinical trial demonstrated that eplerenone at a mean dose (39.1±13.8) mg/day (25-50 mg) in patients with NYHA class II CHF reduced cardiovascular-related mortality by 37% (p

EKG

In studies examining ECG dynamics in healthy volunteers, no significant effect of eplerenone on HR, QRS interval duration, PR, or QT intervals was found.

Pharmacokinetics

Eplerenone absorption and distribution

The absolute bioavailability of eplerenone is 69% after oral administration of 100 mg of eplerenone as tablets. T_max is approximately 2 h. C_max and AUC are linearly dose-dependent between 10 and 100 mg and nonlinearly dose-dependent above 100 mg. The equilibrium state is reached within 2 days. Food intake has no effect on absorption.

Eplerenone is approximately 50% bound to plasma proteins, predominantly to the α₁-acid group of glycoproteins. The calculated V_d in equilibrium is (50±7) liters. Eplerenone does not bind to erythrocytes.

Metabolism and excretion

The metabolism of eplerenone is primarily by the CYP3A4 isoenzyme. Active metabolites of eplerenone have not been identified in blood plasma.

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

Particular groups

Age, sex and race. The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been studied in elderly patients (older than 65 years), men and women. Eplerenone pharmacokinetics was not significantly different in men and women. At equilibrium, older patientsC_max and AUC were 22% and 45% higher, respectively, than younger patients (18-45 years old).

Renal insufficiency. The pharmacokinetics of eplerenone were studied in patients with renal insufficiency of various degrees of severity and in patients on hemodialysis. Compared with patients in control group, in patients with severe renal failure equilibrium AUC and C_max were increased by 38 and 24%, respectively, and in patients on hemodialysis – their decrease by 26 and 3%. No correlation was found between eplerenone plasma clearance and creatinine clearance. Eplerenone is not eliminated by hemodialysis.

Hepatic failure. The pharmacokinetics of eplerenone at a dose of 400 mg were compared in patients with moderate hepatic impairment (Child-Pugh score 7-9) and healthy volunteers. The equilibrium C_max and AUC of eplerenone were increased by 3.6% and 42%, respectively. Eplerenone has not been studied in patients with severe hepatic impairment, so its use in this group of patients is not indicated.

Heart failure. Pharmacokinetics of eplerenone at a dose of 50 mg was studied in patients with heart failure (II-IV FC). Equilibrium AUC and C_max in patients with heart failure were 38 and 30% higher, respectively, than in healthy volunteers matched for age, body weight, and sex. The clearance of eplerenone in patients with heart failure was similar to that of healthy older adults.

Indications

Myocardial infarction – in addition to standard therapy to reduce the risk of cardiovascular mortality and morbidity in patients with stable LV dysfunction (EF ≤40%) and clinical signs of heart failure after myocardial infarction; Chronic heart failure – in addition to standard therapy to decrease risk of cardiovascular mortality and morbidity in patients with chronic heart failure II class according to NYHA classification, with LV dysfunction (FV ≤35%).

Active ingredient

Composition

Active substance:

Eplerenone 25 mg;

Associates:

Lactose monohydrate;

MCC;

croscarmellose sodium;

Hypromellose;

Sodium lauryl sulfate;

Talc;

Magnesium stearate;

Film film jacket:

Opadry Yellow YS-1-12524-A (hypromellose, titanium dioxide, macrogol, polysorbate 80, iron oxide yellow dye, iron oxide red dye)

How to take, the dosage

Ingestion. Food intake has no effect on absorption of the drug Inspra®.

Dosages of 25 and 50 mg may be used for individual dosing.

IM

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

The treatment should be started with a dose of 25 mg once daily and increased to 50 mg once daily for 4 weeks, taking into account serum potassium concentrations (see Table 1). The maximum daily dose is 50 mg. After temporary discontinuation of therapy due to increase of serum potassium concentration to 6 mmol/l or more it can be restarted in 25 mg dose in one day when serum potassium concentration reaches 100 mg./p>

General guidelines

The serum potassium concentration should be determined before administration of Inspra®, during the 1st week and 1 month after the therapy start or when changing the drug dose. Thereafter, serum potassium concentration should also be periodically monitored.

Elderly patients. Adjustment of the starting dose in elderly patients is not required. Due to age-related decrease of renal function in elderly patients the risk of hyperkalemia increases, especially in presence of concomitant diseases that contribute to increased serum concentrations of eplerenone, in particular in mild to moderate hepatic dysfunction. Periodic determination of serum potassium concentrations is recommended (see Table 1 as well as “Special Indications” and “Contraindications”, Caution).

Renal dysfunction. Adjustment of the initial dose in patients with mild renal impairment is not required. The degree of hyperkalemia increases with worsening of renal function. It is recommended to determine serum potassium content periodically (see table 1 as well as “Special indications”). The drug Inspra® is not eliminated by hemodialysis. In patients with chronic cardiac insufficiency of II class according to NYHA classification and renal function disorders of moderate degree of severity (30-60 ml/min) the therapy should be started with 25 mg dose every other day with subsequent dose adjustment depending on serum potassium concentration (see table 1). In patients with severe insufficient nocicular function (creatinine Cl® in patients with heart failure after a previous MI and creatinine Cl® in such patients (see Contraindications, Caution). In patients with Cl creatinine® at a dose greater than 25 mg once daily has not been investigated (see “Cautionary Note”).

Hepatic impairment. Correction of initial dose in patients with liver dysfunction of mild to moderate degree of severity is not required. Taking into account increased concentration of eplerenone in such patients it is recommended to monitor potassium concentration in serum regularly, especially in elderly patients (see “Cautionary notes”). The use of Inspra® in patients with severe liver dysfunction is contraindicated.

Companion therapy. When concomitant use of drugs with mild to moderate CYP3A4 inhibitory effects, such as erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole, treatment with Insprasup>® can be started at a dose of 25 mg once daily, with the latter dose not to exceed 25 mg once daily

Interaction

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Potassium-saving diuretics and potassium preparations. Taking into account the increased risk of hyperkalemia, eplerenone should not be administered in patients receiving potassium-saving diuretics and potassium preparations (see “Contraindications”). Potassium-saving diuretics may increase the effects of antihypertensive agents 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 increasing concentrations and intoxication with lithium. If such a combination is necessary, it is reasonable to monitor plasma lithium concentrations (see “Special indications”).

Cyclosporine, tacrolimus. These drugs 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 is required during treatment with eplerenone, it is recommended that serum potassium concentration and renal function be carefully monitored (see “Cautionary Note”).

The NSAIDs. Treatment with NSAIDs may lead to acute renal failure due to direct suppression of glomerular filtration, especially in patients in the risk group (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 elderly patients.

ACE inhibitors and angiotensin II receptor antagonists. When using eplerenone with ACE inhibitors or angiotensin II receptor antagonists, serum potassium concentration should be carefully monitored. 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 angiotensin II receptor antagonists with eplerenone.

α1 adrenoblockers (prazosin, alfuzosin). Concomitant use of α1-adrenoblockers with eplerenone may increase the hypotensive effect and/or the risk of orthostatic hypotension; therefore, it is recommended to monitor BP with body position changes.

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

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

FKV

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 if digoxin is used in doses close to the maximum therapeutic.

Warfarin. No clinically significant pharmacokinetic interaction with warfarin has been found. Caution must be exercised if warfarin is used in doses close to the maximum therapeutic.

Antacids. Based on the pharmacokinetic clinical study, no significant interaction of antacids with eplerenone is expected when used concomitantly.

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

CYP3A4 inhibitors

Strong CYP3A4 inhibitors. When using eplerenone with agents that inhibit CYP3A4, there may be significant FKV. Strong CYP3A4 inhibitor (ketoconazole in dose 200 mg 2 times per day) caused 441% AUC increase of eplerenone. Concomitant use of eplerenone with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone is contraindicated (see “Contraindications”).

Weak and moderate CYP3A4 inhibitors. Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by significant PFC (degree of increase in AUC ranged from 98 to 187%). When concomitant use of these agents with eplerenone, the dose of the latter should not exceed 25 mg (see “Dosage and administration”).

CYP3A4 inducers

Continuous use of preparations containing St John’s Wort (a strong inducer of CYP3A4 isoenzyme) with eplerenone caused 30% AUC decrease of the latter. When using stronger CYP3A4 inducers, such as rifampicin, a more pronounced reduction in AUC of eplerenone is possible. Taking into account possible decrease of efficacy of eplerenone, concomitant use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, preparations containing St. John’s wort) is not recommended.

Special Instructions

Hyperkalemia. When treating with Inspra®, hyperkalemia may develop due to its mechanism of action. At the beginning of treatment and when changing the drug dose serum potassium concentration should be controlled in all patients. Further, periodic monitoring of potassium concentration is recommended in patients with increased risk of hyperkalemia, such as elderly patients with renal insufficiency (see “Dosage and administration”) and diabetics. Taking into account the increased risk of hyperkalemia, prescription of potassium preparations after the beginning of treatment with eplerenone is not recommended. Decrease of Inspra® dose leads to decrease of serum potassium concentration. In one study, the addition of hydrochlorothiazide to eplerenone prevented an increase in serum potassium concentration.

Renal dysfunction. In patients with impaired renal function, including diabetic microalbuminuria, it is recommended to monitor serum potassium concentration regularly. The risk of hyperkalemia increases with decreased renal function. Although the number of patients with type 2 diabetes and microalbuminuria in the studies was limited, nevertheless, in this small sample there was an increase in the frequency of hyperkalemia. Therefore, treatment should be used with caution in such patients. The drug Inspra® is not eliminated by hemodialysis. The use of the drug Inspra ® is contraindicated in severe renal failure (see “Contraindications”).

Hepatic impairment. In patients with mild to moderate hepatic dysfunction (5-6 and 7-9 points according to Child-Pugh classification) an increase in serum potassium concentration over 5.5 mmol/l has not been found. Electrolyte concentrations should be monitored in such patients. Eplerenone has not been studied in patients with severe liver dysfunction, therefore its use is contraindicated (see “Contraindications”).

CYP3A4 inducers. Concomitant use of eplerenone with strong CYP3A4 inducers is not recommended (see “Interactions”).

Cyclosporine, tacrolimus, drugs containing lithium. Prescribing of these drugs should be avoided during treatment with eplerenone (see “Interactions”).

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.

The effects of the drug Inspra® on the ability to drive vehicles or operate machinery have not been studied. However, taking into account the possibility of the drug causing dizziness and fainting, caution should be exercised when driving motor transport or operating machinery while taking Inspra® .

Contraindications

With caution: type 2 diabetes mellitus and microalbuminuria (see “Special Indications”). ” Cautions: elderly age; impaired renal function (creatinine Cl less than 50 ml/min); simultaneous use of eplerenone and ACE inhibitors or angiotensin II receptor antagonists, strong CYP3A4 isoenzyme inducers, drugs containing lithium, cyclosporine or tacrolimus, digoxin and warfarin in doses close to maximum therapeutic (see “Cautionary Instructions” and “Interactions”). Do not use a triple combination of an ACE inhibitor and angiotensin II receptor antagonists with eplerenone.

Side effects

Blood and lymphatic system disorders: infrequent – eosinophilia.

Metabolism and nutrition disorders: frequently – hyperkalemia, dehydration, hypercholesterolemia, hypertriglyceridemia; rarely – hyponatremia, hypothyroidism.

Mental disorders: infrequent – insomnia.

Neurological disorders: often – dizziness, fainting; infrequent – headache, hypoesthesia.

Cardiac disorders: common – myocardial infarction; infrequent – atrial fibrillation, left ventricular failure, tachycardia.

vascular disorders: often – marked decrease of BP; infrequent – orthostatic hypotension, lower limb arterial thrombosis.

Respiratory system, chest and mediastinum: often – cough; infrequently – pharyngitis.

Gastrointestinal system: frequently – diarrhea, nausea, constipation; infrequently – flatulence, vomiting.

Liver and biliary tract: infrequent – cholecystitis.

The skin and subcutaneous fatty tissue: frequently – skin itching; infrequently – increased sweating, rash; frequency unknown – angioedema.

Musculoskeletal and connective tissue disorders: frequent – cramps in the calf muscles of the legs, musculoskeletal pain; infrequent – back pain.

Renal and urinary tract: often – renal dysfunction.

General and local: infrequent – asthenia, malaise.

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

Infections: infrequent – pyelonephritis, gynecomastia.

Overdose

Symptoms: the most likely manifestations of overdose may be a pronounced decrease in BP and hyperkalemia.

Treatment: if pronounced BP decrease develops, 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 carbon.

Similarities