Inspra, pills 50mg, 30pcs

Composition

Active ingredient:

eplerenone 50 mg;

Auxiliary substances:

lactose monohydrate;

MCC;

croscarmellose sodium;

hypromellose;

sodium lauryl sulfate;

talc;

magnesium stearate;

Film shell:

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

Pharmacological action

Inspra-diuretic.

Pharmacodynamics

Eplerenone is highly selective for mineralocorticoid receptors in humans, in contrast to glucocorticoid, progesterone and androgen receptors, and interferes with the binding of mineralocorticoid receptors to aldosterone — a key hormone of the RAAS that is involved in regulation Blood pressure and pathogenesis of cardiovascular diseases.

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

The efficacy of eplerenone was studied in the double-blind placebo-controlled Jesus study (Eplerenone Postacute myocardial infarction Heart failure Efficiency and Survival Study) in 6632 patients with acute myocardial infarction (MI), left ventricular dysfunction (LV) (ejection fraction (EF)

In the clinical study EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure) The study included 2,737 patients with CHF of NYHA (New York Heart Association) functional class II (FC) and severe systolic dysfunction (mean LVEF in the study was 26.1%). The average follow — up period was 21 months. In the active eplerenone treatment group, patients received ACE inhibitors or angiotensin II receptor blockers (94%) and beta-blockers (86.6%) before admission. Primary endpoint: death from cardiovascular causes or hospitalization for heart failure. The clinical study EMPHASIS-HF demonstrated that the use of eplerenone at an average dose (39.1±13.8) mg / day (25-50 mg) in patients with NYHA FC II CHF reduces mortality associated with cardiovascular diseases by 37% (r

ECG

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

Pharmacokinetics

Suction and distribution

The absolute bioavailability of eplerenone is 69% after taking 100 mg of eplerenone orally in tablet form. T_max is approximately 2 h. Cmax and AUC depend linearly on the dose in the range from 10 to 100 mg and non-linearly – at a dose of more than 100 mg. The equilibrium state is reached within 2 days. Food intake does not affect absorption.

Eplerenone binds approximately 50% to plasma proteins, mainly to_{the α1}-acid group of glycoproteins. _{The estimated} Vd at steady state is (50±7) L. Eplerenone does not bind to red blood cells.

Metabolism and elimination

Eplerenone is mainly metabolized by the CYP3A4 isoenzyme. Active metabolites of eplerenone in blood plasma have not been identified.

Less than 5% of the eplerenone dose is excreted unchanged through the kidneys and intestines. After a single oral dose 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 hours, the clearance from blood plasma is about 10 l/h.

Special groups

Age, gender, and race. The pharmacokinetics of eplerenone at a dose of 100 mg once a day was studied in elderly patients (older than 65 years), men and women. The pharmacokinetics of eplerenone did not differ significantly in men and women. At steady state in elderly_{patients, max} and AUC were 22 and 45% higher, respectively, than in young patients (18-45 years).

Kidney failure. The pharmacokinetics of eplerenone were studied in patients with renal insufficiency of varying severity and in patients undergoing hemodialysis. In comparison with the control group, patients with severe renal insufficiency showed an increase in steady — state AUC and_cmax by 38 and 24%, respectively, and in patients on hemodialysis, their decrease by 26 and 3%. No correlation was found between plasma eplerenone clearance and creatinine clearance. Eplerenone is not removed during hemodialysis.

Liver failure. The pharmacokinetics of eplerenone 400 mg were compared in patients with moderate hepatic impairment (Child-Pugh score 7-9) and healthy volunteers. The steady_{-state cmax} and AUC of eplerenone were increased by 3.6 and 42%, respectively. Eplerenone has not been studied in patients with severe hepatic insufficiency, so its use in this group of patients is not indicated.

Heart failure. The pharmacokinetics of eplerenone at a dose of 50 mg were studied in patients with heart failure (FC II–IV). Steady-state AUC and_cmax in patients with heart failure were 38 and 30% higher, respectively, than in healthy volunteers matched by age, body weight, and gender. The clearance of eplerenone in patients with heart failure is similar to that in healthy elderly people.

Indications

Myocardial infarction-in addition to standard therapy, in order to reduce the risk of cardiovascular mortality and morbidity in patients with stable LV dysfunction (EF < 40%) and clinical signs of heart failure after a previous myocardial infarction; chronic heart failure-in addition to standard therapy, in order to reduce the risk of cardiovascular mortality and morbidity in patients with chronic heart failure FC II according to NYHA classification, with LV dysfunction (EF < 35%).

Contraindications

• hypersensitivity to eplerenone or other components of the drug;
• clinically significant hyperkalemia;
• the potassium content in the blood serum at the beginning of treatment more than 5 mmol/l;
• moderate or severe renal insufficiency (Cl creatinine NYHA;
• severe liver failure (more than 9 points classification child-Pugh);
• rare hereditary diseases, such as lactose intolerance, lactase deficiency and malabsorption syndrome of glucose-galactose (see “Special instructions”);
• concomitant use of potassium-sparing diuretics, potassium supplements or strong inhibitors of CYP3 AND 4, such as Itraconazole, ketoconazole, ritonavir, and nelfinavir, clarithromycin, telithromycin and nefazodone (see “Interaction”);
• the concentration of creatinine in the blood plasma of >2 mg/DL (>177 mmol/l) in men or >1.8 mg / dl (>>159 mmol/l) in women;
• there is no experience of using the drug in children under the age of 18, so its use in patients of this age group is not recommended.

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

Side effects

Hematopoietic and lymphatic system disorders:  infrequently — eosinophilia.

Metabolic and nutritional disorders:  often — hyperkalemia, dehydration, hypercholesterolemia, hypertriglyceridemia; infrequently-hyponatremia, hypothyroidism.

Mental disorders:  infrequently — insomnia.

Neurological disorders:  often — dizziness, fainting; infrequently-headache, hypesthesia.

From the side of the heart:  often — myocardial infarction; infrequently-atrial fibrillation, left ventricular failure, tachycardia.

Vascular disorders:  often — a marked decrease Blood pressure; infrequently-orthostatic hypotension, arterial thrombosis of the lower extremities.

Respiratory, thoracic and mediastinal disorders:  often-cough; infrequently-pharyngitis.

From the gastrointestinal tract:  often — diarrhea, nausea, constipation; infrequently-flatulence, vomiting.

Liver and biliary tract disorders:  infrequently — cholecystitis.

From the side of the skin and subcutaneous fat:  often-pruritus of the skin; infrequently-increased sweating, rash; frequency unknown-angioedema.

Musculoskeletal and connective tissue disorders:  often-cramps in the calf muscles of the legs, musculoskeletal pain; infrequently-back pain.

From the side of the kidneys and urinary tract:  often-impaired renal function.

General and local services:  infrequently-asthenia, malaise.

Laboratory parameters:  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.

Infections:  infrequently — pyelonephritis, gynecomastia.

FD interaction

Potassium-sparing diuretics and potassium preparations. Given the increased risk of hyperkalemia, eplerenone should not be prescribed to patients receiving potassium-sparing diuretics and potassium preparations (see “Contraindications”). Potassium-sparing diuretics may increase the effects of antihypertensive agents and other diuretics.

Preparations containing lithium. The interaction of eplerenone with lithium preparations has not been studied. However, increased concentrations and lithium intoxication have been reported in patients treated with lithium preparations in combination with diuretics and ACE inhibitors. If such a combination is necessary, it is advisable to monitor the concentration of lithium in the blood plasma (see “Special instructions”).

Cyclosporine, tacrolimus. These medications may cause impaired renal function 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, careful monitoring of serum potassium and renal function is recommended (see “Special Instructions”).

NSAIDs. Treatment with NSAIDs can lead to acute renal failure due to direct suppression of glomerular filtration, especially in patients at risk (elderly patients and / or patients with dehydration). With the combined use of these drugs before and during treatment, it is necessary to ensure an adequate water regime and monitor kidney 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, the concentration of potassium in the blood serum should be carefully monitored. This 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 an ACE inhibitor and angiotensin II receptor antagonists with eplerenone.

alpha_-1-adrenoblockers (prazosin, alfuzosin). Concomitant use_{of α1}-blockers with eplerenone may increase the hypotensive effect and / or increase the risk of orthostatic hypotension, and therefore it is recommended to monitor blood pressure when changing body position.

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

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

FQF

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 the glycoprotein P.

Digoxin. The AUC of digoxin when co-administered with eplerenone increases by 16% (90% CI-4-30%). Caution should be exercised if digoxin is used in doses close to the maximum therapeutic value.

Warfarin. There was no clinically significant pharmacokinetic interaction with warfarin. Caution should be exercised if warfarin is used at doses close to the maximum therapeutic value.

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

CYP3A4 substrates. No pharmacokinetic interactions of eplerenone with CYP3A4 substrates, such as midazolam and cisapride, have been identified in specific studies.

CYP3A4 inhibitors

Strong inhibitors of CYP3A4. When using eplerenone with agents that inhibit CYP3A4, significant EQF may occur. A strong CYP3A4 inhibitor (ketoconazole 200 mg twice daily) caused a 441% increase in the AUC of eplerenone. Concomitant use of eplerenone with strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone, is contraindicated (see “Contraindications”).

Mild to moderate inhibitors of CYP3A4. Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by significant PKV (the degree of increase in AUC ranged from 98 to 187%). With the simultaneous use of these drugs with eplerenone, the dose of the latter should not exceed 25 mg (see “Method of use and doses”).

CYP3A4 inducers

Concomitant use of drugs containing St. John’s wort (St John’s Wort, a strong inducer of the CYP3A4 isoenzyme) with eplerenone caused a decrease in the AUC of the latter by 30%. When using stronger 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 strong inducers of CYP3A4 (rifampicin, carbamazepine, phenytoin, phenobarbital, preparations containing St. John’s wort) is not recommended

How to take, course of use and dosage

Inside. Food intake does not affect the absorption of Inspra®.

For individual dose selection, dosages of 25 and 50 mg can be used.

TO THEM

Treatment should start with a dose of 25 mg once a day and increase it to 50 mg once a day for 4 weeks, taking into account the concentration of potassium in the blood serum (see Table 1). The recommended maintenance dose of the drug is 50 mg once a day.

CHF II FC according to NYHA classification

Treatment should start with a dose of 25 mg once a day and increase it to 50 mg once a day for 4 weeks, taking into account the concentration of potassium in the blood serum (see Table 1). The maximum daily dose is 50 mg. After temporary discontinuation of the drug due to an increase in the concentration of potassium in the blood serum to or more than 6 mmol/l, therapy with the drug can be resumed at a dose of 25 mg every other day, when the concentration of potassium in the blood serum is

General recommendations

Serum potassium concentrations should be determined prior to use of Inspra®, within 1 week and 1 month after the start of therapy, or when the dose of the drug is changed. In the future, it is also necessary to periodically monitor the concentration of potassium in the blood serum.

Elderly patients. No adjustment of the starting dose is required in elderly patients. Due to the age-related decline in renal function in elderly patients, the risk of hyperkalemia increases, especially in the presence of concomitant diseases that contribute to an increase in eplerenone concentrations in the blood serum, in particular with mild to moderate hepatic impairment. It is recommended to periodically determine the concentration of potassium in the blood serum (see Table 1, as well as “Special instructions” and “Contraindications”)., With caution).

Impaired renal function. No initial dose adjustment is required in patients with mild renal impairment. The degree of hyperkalemia increases with deterioration of renal function. It is recommended to periodically determine the content of potassium in the blood serum (see Table 1, as well as”Special instructions”). The drug Inspra® it is not removed during hemodialysis. In patients with NYHA FC CHF and moderate renal impairment (creatinine clearance 30-60 ml / min), therapy should begin 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). In patients with severe hepatic insufficiency (Cl creatinine ® in patients with heart failure after MI and Cl creatinine ® in such patients (see “Contraindications”, With caution). In patients with Cl, creatinine® at a dose higher than 25 mg once a day has not been studied (see “Special instructions”).

Impaired liver function. No initial dose adjustment is required in patients with mild to moderate hepatic impairment. Given the increase in the concentration of eplerenone in such patients, it is recommended to regularly monitor the concentration of potassium in the blood serum, especially in elderly patients (see “Special instructions”). The use of Inspra® in patients with severe hepatic impairment is contraindicated.

Concomitant therapy. With concomitant use of drugs that have a weak or moderate inhibitory effect on CYP3A4, for example, erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole, treatment with Inspra® can begin with a dose of 25 mg once a day, while the dose of the latter should not exceed 25 mg once a day

Overdose

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

Treatment: with the development of a pronounced decrease in BP maintenance treatment should be prescribed. In case of hyperkalemia, standard therapy is indicated. Eplerenone is not removed during hemodialysis. It was found that eplerenone actively binds to activated carbon.

Special instructions

Hyperkalemia. Hyperkalemia may occur during treatment with Inspra, which is caused by 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 potassium concentration is recommended for patients with an increased risk of hyperkalemia, for example, elderly patients with renal insufficiency (see “Dosage and use”) and diabetes mellitus. Given the increased risk of hyperkalemia, the use of potassium supplements after starting treatment with eplerenone is not recommended. Reducing the dose of Inspra® leads to a decrease in the concentration of potassium in the blood serum. In one study, the addition of hydrochlorothiazide to eplerenone prevented an increase in serum potassium concentrations.

Impaired renal function. In patients with impaired renal function, including diabetic microalbuminuria, it is recommended to regularly monitor the concentration of potassium in the blood serum. The risk of hyperkalemia increases with reduced renal function. Although the number of patients with type 2 diabetes mellitus and microalbuminuria in studies was limited, however, an increase in the incidence of hyperkalemia was noted in this small sample. In this regard, such patients should be treated with caution. The drug Inspra® it is not removed during hemodialysis. The use of Inspra® is contraindicated in patients with severe renal insufficiency (see “Contraindications”).

Impaired liver function. In patients with mild or moderate hepatic impairment (Child-Pugh scores 5-6 and 7-9), an increase in serum potassium concentration of more than 5.5 mmol/l was not detected. In such patients, the concentration of electrolytes should be monitored. Eplerenone has not been studied in patients with severe hepatic impairment, so its use is contraindicated (see “Contraindications”).

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

Cyclosporine, tacrolimus, lithium-containing drugs. During treatment with eplerenone, you should avoid prescribing these drugs (see “Interaction”).

Lactose. 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 work with mechanisms. Effects of Inspra® the ability to drive vehicles or use machinery was not studied. However, given the potential of the drug to cause dizziness and fainting, caution should be exercised when driving vehicles or using equipment while taking Inspra®.

Composition

Tablet Form of production

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Eplerenone

Conditions of release from pharmacies

By prescription

Dosage form

Tablets