Inspra - instructions for use, doses, side effects, contraindications

Active substanceEplerenoneEplerenone

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Inspra®

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Pfizer Inc. USA

Eplerenone-Teva

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Teva Pharmaceutical Enterprises Co., Ltd. Israel

Espiro

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Pharmaceutical factory "POLFARMA" JSC Poland

Dosage form: & nbspFilm-coated tablets.

Composition:

1 tablet contains:

active substance: eplerenone 25 mg or 50 mg;

Excipients: Lactose monohydrate 35.700 / 71.400 mg microcrystalline cellulose 15.375 / 30.750 mg Croscarmellose sodium 4.250 / 8.500 mg Hypromellose 2,550 / 5,100 mg, sodium lauryl sulfate 0.850 / 1.700 mg talc 0.850 / 1.700 mg magnesium stearate 0.425 / 0.850 mg;

film sheath: Rape yellow YS-1-12524-A 3.825 / 5.10 mg (hypromellose, titanium dioxide, macrogol, polysorbate-80, iron oxide colorant yellow, iron oxide red dye).

Description:

Tablets 25 mg: yellow, diamond-shaped tablets, film-coated, with the inscription "NSR" above the number "25" on one side and "Pfizer" on the other side;

tablets 50 mg: yellow diamond-shaped tablets, film-coated, with the inscription "NSR" of number "50" on one side and "Pfizer" on the other side.

Pharmacotherapeutic group:Diuretic potassium-sparing agent

ATX: & nbsp

C.03.D.A.04 Eplerenone

Pharmacodynamics:

Eplerenone has a high selectivity to a human mineralocorticoid receptor unlike glucocorticoid,progesterone and androgen receptors and prevents the binding of mineralocorticoid receptors with aldosterone, the key hormone of the renin-angiotensin-aldosterone system (RAAS), which is involved in the regulation of blood pressure and the pathogenesis of cardiovascular diseases.

Eplerenone causes a persistent increase in renin activity in plasma and aldosterone in the blood serum. Subsequently, renin secretion is suppressed by aldosterone by the feedback mechanism. In this case, an increase in the activity of renin or the concentration of circulating aldosterone does not affect the effects of eplerenone. The efficacy of eplerenone was studied in a double-blind, placebo-controlled study EPHESUS (Eplerenone Postacute myocardial infarction Heart failure Efficacy and SUrvival Study) the 6632 patients with acute myocardial infarction (MI), left ventricular dysfunction (LV) (ejection fraction (EF) <40%) and with clinical signs of heart failure. Within 3-14 days (an average of 7 days) after acute myocardial infarction, patients were assigned eplerenone or placebo in addition to standard therapy. Treatment started with a dose of 25 mg once a day and by the end of the 4th week it was increased to 50 mg once a day if the serum potassium content was less than 5.0 mmol / l.During the study, patients received standard therapy with acetylsalicylic acid (92%), inhibitors angiotensin converting enzyme (ACE) (90%), beta-blockers (83%), nitrates (72%), loop diuretics (66%) or inhibitors 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG CoA reductase) (60%).

The primary endpoint in the study was total mortality, and the combined endpoint was mortality or hospitalization for cardiovascular disease. As a result of eplerenone therapy, the risk of total mortality was reduced by 15% (relative risk 0.85, 95% confidence interval (CI), 0.75-0.96, p = 0.008) compared with placebo, mainly due to a decrease in mortality as a result of cardiovascular diseases. The risk of death or hospitalization for cardiovascular disease with eplerenone was reduced by 13% (relative risk 0.87, 95% CI, 0.79-0.95, p = 0.002). Reduction of absolute risk for two end points - total mortality and mortality / hospitalization for cardiovascular disease - were 2.3 and 3.3% respectively.

In a clinical trial EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure) were included 2737 patients with chronic heart failure (CHF) II functional class (FC) by classification NYHA (New York Heart Association) and severe systolic dysfunction (mean value of the left ventricular ejection fraction in the study was 26.1%). The average follow-up period is 21 months. In the active treatment with eplerenone before the inclusion, patients took ACE inhibitors or angiotensin II receptor blockers (94%), beta-blockers (86.6%). Primary endpoint: death from cardiovascular causes or hospitalization for heart failure (CH). Clinical study EMPHASIS-HF demonstrated that the use of eplerenone at an average dose of 39.1 ± 13.8 mg / day (25-50 mg) in patients with CHF II FC according to the classification NYHA reduces the mortality associated with cardiovascular disease by 37% (p <0.001). Clinical efficacy was demonstrated mainly with the use of eplerenone in patients under the age of 75 years. The effectiveness of therapy in patients over the age of 75 years has not been studied.

Electrocardiography

In studies on the dynamics of the electrocardiogram (ECG) in healthy volunteers, the significant effect of eplerenone on the heart rate (heart rate), the duration of intervals QRS, PR or QT not found.

Pharmacokinetics:

Suction and distribution

Absolute bioavailability of eplerenone is 69% after taking 100 mg of eplerenone orally in the form of tablets. The maximum concentration in the blood plasma (C_m_Oh) is reached after about 2 hours. Maximum concentration and the area under the "concentration-time" curve (AUC) linearly depend on the dose in the range from 10 to 100 mg and non-linearly - in a dose of more than 100 mg. The equilibrium state is reached within 2 days. Eating does not affect absorption.

Eplerenone approximately 50% binds to blood plasma proteins, mainly with the alpha-1-acid group of glycoproteins. The calculated volume of the distribution in the equilibrium state is 50 (± 7) l. Eplerenone does not bind to erythrocytes.

Metabolism and excretion

The metabolism of eplerenone is carried out, mainly, under the action of the isoenzyme CYP3A4. Active metabolites of eplerenone in the blood plasma are not identified.

In an unchanged form, less than 5% of the dose of eplerenone is excreted through the kidneys and intestine. After a single ingestion of labeled eplerenone, about 32% of the dose was excreted through the intestine and about 67% through the kidneys. The half-life of eplerenone is about 3-5 hours, the clearance from the 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 (over 65 years), men and women. The pharmacokinetics of eplerenone did not differ significantly between men and women. In the equilibrium state in elderly patients, the maximum concentration and area under the curve "concentration-time" were respectively 22% and 45% higher than in young patients (18-45 years).

Renal insufficiency

The pharmacokinetics of eplerenone have been studied in patients with renal insufficiency of varying severity and in patients on hemodialysis. In comparison with the patients of the control group, in patients with severe renal insufficiency, an increase in the equilibrium area under the curve "concentration-time" and maximum concentration by 38% and 24%, respectively, and in patients on hemodialysis - their decrease by 26% and 3%. Correlations between the clearance of eplerenone from plasma and the clearance of creatinine were not detected. Eplerenone not removed during hemodialysis.

Liver failure

The pharmacokinetics of eplerenone at a dose of 400 mg were compared in patients with moderate impaired hepatic function (7-9 points according to the Child-Pugh classification) and healthy volunteers. The equilibrium maximum concentration and AUC eplerenone were increased by 3.6% and 42%, respectively.In patients with severe hepatic insufficiency eplerenone was not studied, therefore its use in this group of patients is not shown.

Heart failure

The pharmacokinetics of eplerenone in a dose of 50 mg were studied in patients with heart failure (II-IV FC). Equilibrium area under the curve "concentration-time" and the maximum concentration in patients with heart failure were respectively 38% and 30% higher than in healthy volunteers, matched for age, body weight and sex. The eplerenone clearance in patients with heart failure is similar to that of 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 left ventricular dysfunction (ejection fraction <40%) and clinical signs of heart failure after 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 cardiac insufficiency II functional class by classification NYHA, with left ventricular dysfunction (ejection fraction <35%).

Contraindications:

- hypersensitivity to eplerenone or other components of the drug;

- clinically significant hyperkalemia;

- the content of potassium in the serum at the beginning of treatment more than 5.0 mmol / l;

- moderate or severe renal insufficiency (creatinine clearance (CK) <30 ml / min) in patients with CHF II functional class NYHA:

- severe hepatic insufficiency (more than 9 points on the Child-Pugh scale);

- simultaneous reception potassium-sparing diuretics, potassium or powerful inhibitors of isoenzyme CYP3A4, for example, itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone (see section "Interaction with other drugs");

- rare hereditary diseases, such as lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome (see section "Special instructions");

- the experience of using the drug in children under the age of 18 years is not, therefore, its appointment to patients of this age group is not recommended.

Carefully:

- Type 2 diabetes mellitus and microalbuminuria.section "Special instructions");

- elderly age;

- impaired renal function (creatinine clearance less than 50 ml / min);

- simultaneous use of eplerenone and ACE inhibitors or angiotensin II receptor antagonists; strong inductors of the isoenzyme CYP3A4; preparations containing lithium; cyclosporin or tacrolimus; digoxin and warfarin in doses close to the maximum therapeutic (see sections "Special instructions" and "Interaction with other drugs").

Do not use a triple combination of an ACE inhibitor and angiotensin receptor antagonists II with eplerenone.

Pregnancy and lactation:

There is no information on the use of the drug in pregnant women. The drug should be used with caution and only in those cases where the expected benefit to the mother significantly exceeds the possible risk to the fetus / child.

Information on the removal of eplerenone after ingestion with breast milk is not. Possible adverse effects of eplerenone on newborns who are breastfed are unknown, so it is advisable either to stop breastfeeding or to cancel the drug, depending on its importance for the mother.

Dosing and Administration:

Inside.

The ingestion of food does not affect the absorption of Inspra®. For individual dose selection, dosages of 25 mg and 50 mg can be used.

Myocardial infarction

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

Chronic heart failure II functional class by classification NYHA

Treatment should also begin with a dose of 25 mg once a day and increase it to 50 mg once a day after 4 weeks, taking into account the potassium content in the blood serum (see Table 1).

The maximum daily dose is 50 mg. After a temporary discontinuation of the drug due to an increase in serum potassium in the blood serum up to or above 6.0 mmol / l, the drug therapy can be resumed at a dose of 25 mg every other day, when the serum potassium content is <5.0 mmol / l.

General recommendations

The serum potassium content should be determined prior to the administration of Inspra®, during the first week and 1 month after the initiation of therapy, or when the dose of the drug is changed. In the future, it is also necessary to periodically monitor the potassium content in the blood serum.

Elderly patients

Correction of the initial dose in elderly patients is not required. In connection with the age-related decrease in renal function in elderly patients, the risk of hyperkalemia increases, especially in the presence of concomitant diseases that increase the concentration of eplerenone in the blood serum, in particular, in the violation of liver function from mild to moderate severity. It is recommended to periodically determine the potassium content in the blood serum (see Table No. 1, and also the sections "Special instructions", "With caution").

Impaired renal function

Correction of the initial dose in patients with mild renal impairment is not required. The degree of hyperkalemia increases with impaired renal function. It is recommended to periodically determine the potassium content in the blood serum (see Table No. 1, and also the section "Special instructions"). The drug Inspra® is not removed during hemodialysis. In patients with CHF II functional class by classification NYHA and violations of the function of the kidneys of moderate severity (creatinine clearance 30-60 ml / min) should be started with a dose of 25 mg every other day, followed by dose adjustment depending on the potassium content in the blood serum (see Table 1).

In patients with severe renal function impairment (creatinine clearance <30 ml / min), the use of the drug is contraindicated (see the section "Contraindications"),

The experience of using Inspra® in patients with heart failure after myocardial infarction and creatinine clearance <50 ml / min is not. Use with caution the preparation of Inspra® in such patients (see the section "With caution").

In patients with creatinine clearance <50 ml / min, the use of the preparation Inspra® at a dose above 25 mg was not examined once a day (also see the section "Special instructions").

Impaired liver function

Correction of the initial dose in patients with violations of liver function from mild to moderate severity is not required. Given the increased concentration of eplerenone in these patients, it is recommended to regularly monitor the potassium content in the blood serum, especially in elderly patients (see section "Special instructions"). Application of the preparation Inspr® in patients with severe impairment of liver function is contraindicated (see section "Contraindications").

Concomitant therapy

With the simultaneous use of drugs that have a weak or moderately expressed inhibitory effect on the isoenzyme CYP3A4, for example erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole, treatment with Inspra® can be started at a dose of 25 mg once a day, with the dose of the latter not exceeding 25 mg once a day (see "Interaction with other medicinal products ").

Table 1. Selection of dose after treatment

The content of potassium in the blood serum (mmol / l)	Act	Dose change
< 5,0	Increase in dose	From 25 mg every other day to 25 mg once a day; with 25 mg once a day to 50 mg once a day
5,0-5,4	Maintenance dose	The dose remains the same
5,5-5,9	Dose reduction	From 50 mg once a day to 25 mg once a day; with 25 mg once a day to 25 mg every other day; with 25 mg every other day - temporary withdrawal of the drug
> 6,0	Abolition of the drug	Not applicable

Side effects:

The following are undesirable phenomena that could be associated with treatment, as well as serious adverse events, the frequency of which is comparable to the frequency of unwanted and serious adverse events in the placebo group. Undesirable phenomena are distributed according to the body systems and frequency: often> 1/100, <1/10; infrequently> 1/1000, <1/100; frequency is unknown (can not be calculated from available data).

On the part of the hematopoiesis and lymphatic system

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, hypoesthesia.

From the heart

Often: myocardial infarction.

Infrequently: atrial fibrillation, left ventricular failure, tachycardia.

Vascular disorders

Often: marked decrease in blood pressure.

Infrequently: Orthostatic hypotension, thrombosis of lower limb arteries.

On the part of the respiratory system, thorax and mediastinum

Often: cough.

Infrequently: pharyngitis.

From the gastrointestinal tract

Often: diarrhea, nausea, constipation.

Infrequently: flatulence, vomiting.

From the liver and biliary tract

Infrequently: cholecystitis.

From the skin and subcutaneous fat

Often: itching.

Infrequently: increased sweating, rash.

Frequency unknown: angioedema.

From the side of the musculoskeletal system and connective tissue

Often: cramps in the calf muscles of the legs, musculoskeletal pain.

Infrequently: backache.

From the side of the kidneys and urinary tract

Often: impaired renal function.

General and local

Infrequently: asthenia, malaise.

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 serum glucose concentration.

Infections

Infrequently: pyelonephritis, gynecomastia.

Overdose:

The cases of an eplerenone overdose in humans are not described.

Symptoms: the most likely manifestations of an overdose may be a marked decrease in blood pressure and hyperkalemia.

Treatment: with the development of a marked decrease in blood pressure, it is necessary to appoint supporting treatment. In the case of hyperkalemia, standard therapy is indicated. Eplerenone not removed during hemodialysis. Determined that eplerenone actively binds to activated carbon.

Interaction:

Pharmacodynamic interactions

Potassium-sparing diuretics and potassium preparations: taking into account the increased risk of hyperkalemia, eplerenone should not be prescribed to patients receiving potassium-sparing diuretics and potassium preparations (cf.section "Contraindications"), Potassium-sparing diuretics can enhance the effects of antihypertensive drugs and other diuretics.

Preparations containing lithium: The interaction of eplerenone with lithium preparations has not been studied. However, patients who received lithium preparations in combination with diuretics and ACE inhibitors, described cases of increased concentration and intoxication with lithium. If such a combination is necessary, it is advisable to monitor the concentration of lithium in the blood plasma (see section "Special instructions").

Cyclosporin, tacrolimus: ciclosporin and tacrolimus may cause impaired renal function and increase the risk of hyperkalemia. You should avoid the simultaneous use of eplerenone and cyclosporine or tacrolimus. If the administration of cyclosporine or tacrolimus is required during treatment with eplerenone, it is recommended that the serum potassium content and renal function be carefully monitored (see section "Special instructions").

Non-steroidal anti-inflammatory drugs (NSAIDs): treatment of NSAIDs can lead to acute renal failure by directly suppressing glomerular filtration, especially in patients at risk (elderly patients and / or patients with dehydration).With the joint application of these funds before and during treatment, it is necessary to provide an adequate water regime and monitor kidney function.

Trimethoprim: simultaneous use of trimethoprim with eplerenone increases the risk of hyperkalemia. It is recommended to control the serum potassium content and kidney 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, the serum potassium content should be carefully monitored. This combination can lead to an increased risk of hyperkalemia, especially in patients with impaired renal function, including in elderly patients. Do not use a triple combination of an ACE inhibitor and angiotensin II receptor antagonists with eplerenone.

Alpha 1-adrenoblockers (prazozin, alfuzosin): with the simultaneous use of alpha 1-blockers with eplerenone, the antihypertensive effect may increase and / or the risk of development of orthostatic hypotension may increase, and therefore it is recommended to control blood pressure,especially when changing the position of the body.

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

Glucocorticoids, tetracosactide: the simultaneous use of these drugs with eplerenone can lead to a delay in sodium and liquid.

Pharmacokinetic interactions

Research in vitro evidence that eplerenone does not inhibit isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenone is not a substrate or inhibitor of the glycoprotein R.

Digoxin: area under the curve "concentration-time" digoxin with simultaneous use 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: clinically significant pharmacokinetic interaction with warfarin was not revealed. Care must be taken if warfarin is used in doses close to the maximum therapeutic dose.

Substrates of the isoenzyme CYP3A4: in special studies of signs pharmacokinetic interaction of eplerenone with isoenzyme substrates CYP3A4, for example, midazolam and cisapride, was not identified.

Inhibitor inhibitors CYP3A4:

strong inhibitors of isoenzyme CYP3A4: when using eplerenone with isozyme inhibitory agents CYP3A4, possibly significant pharmacokinetic interaction. Strong inhibitor of isoenzyme CYP3A4 (ketoconazole 200 mg twice a day) caused an increase area under the curve "concentration-time"eplerenone by 441%. Simultaneous use of eplerenone with strong inhibitors of isoenzyme CYP3A4, such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone, is contraindicated (see section "Contraindications");

weak and moderate inhibitors of isoenzyme CYP3A4: simultaneous use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by significant pharmacokinetic interaction (the degree of increase area under the curve "concentration-time" ranged from 98% to 187%). With the simultaneous use of these funds with eplerenone, the dose of the latter should not exceed 25 mg (see section "Method of administration and dose").

Inductors of isoenzyme CYP3A4

Simultaneous administration of preparations containing St. John's Wort (St John's Wort, strong isoenzyme inducer CYP3A4) with eplerenone caused a decrease area under the curve "concentration-time" the latter by 30%. When using more powerful isoenzyme inducers CYP3A4, such as rifampicin, perhaps a more pronounced decrease area under the curve "concentration-time" eplerenone. Considering the possible decrease in the effectiveness of eplerenone, the simultaneous use of strong isoenzyme inducers CYP3A4 (rifampicin, carbamazepine, phenytoin, phenobarbital, preparations containing St. John's wort) is not recommended (see section "Special instructions").

Antacids: based on a pharmacokinetic clinical study significant interaction of antacids with eplerenone in their simultaneous application is not expected.

Special instructions:

Hyperkalemia

When treated with Insprp®, 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 should monitor the potassium content in the blood serum. Further periodic monitoring of potassium content is recommended for patients with an increased risk of hyperkalemia, for example, the elderly, patients with renal insufficiency (see the "Method of administration and dose" section) and diabetes mellitus. Given the increased risk of hyperkalemia, the appointment of potassium drugs after the initiation of eplerenone treatment is not recommended. Reducing the dose of the preparation Inspr® leads to a decrease in the potassium content in the blood serum. In one study, the addition of hydrochlorothiazide to eplerenone prevented an increase in potassium in the serum.

Impaired renal function

In patients with impaired renal function, including diabetic microalbuminuria, it is recommended to regularly monitor the potassium content in the blood serum. The risk of hyperkalemia increases with a decrease in kidney function. Although the number of patients with type 2 diabetes mellitus and microalbuminuria was limited in the studies, nevertheless, in this small sample there was an increase in the frequency of hyperkalemia (see the section "With caution"). In this regard, in such patients, treatment should be conducted with caution. The drug Inspra® is not removed during hemodialysis.The use of the drug Inspra® is contraindicated in cases of severe renal failure (see "Contraindications").

Impaired liver function

In patients with mild or moderate impairment of liver function (5-6 and 7-9 points according to the Child-Pugh classification), no increase in serum potassium levels greater than 5.5 mmol / l was detected. In such patients, the concentration of electrolytes should be monitored. In patients with severe hepatic impairment eplerenone not studied, therefore its use is contraindicated (see the section "Contraindications").

Inductors of isoenzyme CYP3A4

The simultaneous use of Insprp® with strong isoenzyme inducers CYP3A4 not recommended (see section "Interaction with other drugs").

Cyclosporine, tacrolimus, preparations containing lithium

During treatment with Inspra®, these agents should be avoided (see section "Interaction with other drugs").

Lactose

Tablets of the preparation Inspra® contain lactose, therefore they should not be prescribed to patients with rare hereditary diseases, such as lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

Effect on the ability to drive transp. cf. and fur:

Effects of the preparation Inspra® on the ability to drive vehicles or use machinery have not been studied. However, given the possibility of the drug to cause dizziness and fainting, care should be taken when driving vehicles or using equipment against the background of taking Inspra®.

Form release / dosage:

Tablets coated with a film coating, 25 mg or 50 mg.

Packaging:

For 14 tablets in a PVC / Al-foil blister; 2 blisters together with instructions for use are placed in a cardboard box with the control of the first opening.

For 10 tablets in a PVC / Al-foil blister; 2, 3, 5, 10 or 20 blisters together with the instruction for use are placed in a cardboard box with the control of the first opening.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-004052/10

Date of registration:07.05.2010

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

Fareva Amboise France

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp26.05.2015

Illustrated instructions

Instructions

Inspra® (Inspra®)