Инспра®

General characteristics. Structure:

International unlicensed name: эплеренон; Dosage form: tablets, coated
Active agent: эплеренон 25 or 50 mg; excipients: lactoses monohydrate, microcrystallic cellulose, sodium of a kroskarmelloz, gipromelloz, sodium lauryl sulfate, talc, magnesium stearate;

film cover: опадрай yellow YS-1-12524-A *

* ferrous oxide yellow and ferrous oxide red contains a gipromelloza, titanium dioxide, a macrogoal, polysorbate 80, dyes.

Description:
tablets of 25 mg: yellow rhomboid tablets, coated, with a text of "NSR"
over figure "25" on one party and "Pfizer" on other party;
tablets of 50 mg: yellow rhomboid tablets, coated, with a text of "NSR"
over figure "50" on one party and "Pfizer" on other party.

Pharmacological properties:

Pharmacodynamics. Eplerenon has relative selectivity concerning mineralokortikoidny receptors at the person in comparison with glucocorticoid, progesteronovy and androgenic receptors and interferes with their linkng with Aldosteronum - key hormone the system renin-angiotensin-aldosteronovoy (SRAA) which participates in regulation of the arterial pressure (AP) and a pathogeny of cardiovascular diseases.

Eplerenon causes permanent increase in levels of a renin in a blood plasma and Aldosteronum in blood serum. In an effect, secretion of a renin is suppressed with Aldosteronum on a feedback mechanism. At the same time increase in activity of a renin or level of the circulating Aldosteronum does not influence effects of an eplerenon.

At patients with chronic heart failure of the II-IV functional class on NYHA classification addition of an eplerenon to standard therapy led to the predicted dozozavisimy increase in level of Aldosteronum. In the research EPHESUS on studying of function of heart and kidneys at patients significant increase in level of Aldosteronum as a result of therapy eplerenony was also established. These data confirm blockade of mineralokortikoidny receptors.

Effects of an eplerenon studied in the double blind platsebokontroliruyemy research EPHESUS at 6632 patients with the acute myocardial infarction (MI), dysfunction of a left ventricle (fraction of emission <40%) and with clinical signs of heart failure. Within 3-14 days (on average 7 days) after an acute myocardial infarction the patient appointed эплеренон or placebo in addition to standard therapy. Treatment began with a dose 25 mg once a day and by the end 4 weeks increased up to 50 mg once a day if potassium concentration in blood serum remained less than 5.0 mmol/l. During the research patients received standard therapy using acetylsalicylic acid (92%), inhibitors of the angiotensin-converting enzyme (ACE) (90%), beta adrenoblockers (83%), nitrates (72%), "loopback" diuretics (66%) or GMG KoA-reductases inhibitors (60%). The general mortality, and the combined final point - mortality or hospitalization concerning cardiovascular diseases was primary final point in the research EPHESUS. The general mortality in groups of an eplerenon and placebo made respectively 14,4 and 16,7%, and the combined final point of mortality or hospitalization concerning cardiovascular diseases was noted respectively at 26,7 and 30,0% of patients. Thus, according to the research EPHESUS, as a result of therapy eplerenony the risk of the general mortality was reduced by 15% (relative risk 0,85; 95% of DI, 0,75-0,96; р = 0,008) in comparison with placebo, mainly due to decline in mortality as a result of cardiovascular diseases. The risk of a lethal outcome or hospitalization concerning cardiovascular diseases at use of an eplerenon was reduced by 13% (relative risk 0,87; 95% of DI, 0,79-0,95; р = 0,002). Decrease in absolute risk for two final points – the general mortality and mortality/hospitalization concerning cardiovascular diseases – made 2,3 and 3,3% respectively. Clinical performance was shown, mainly, at use of an eplerenon to patients aged up to 75 years. Efficiency of therapy at patients is aged more senior than 75 years was not studied. Decrease or stabilization of a functional class on classification of NYHA in group of an eplerenon were noted considerably more often than in group of placebo. Hyperpotassemia frequency in groups of an eplerenon and placebo made 3,4% and 2,0% (р <0,001), hypopotassemias - 0,5% and 1,5% (p <0,001) respectively.

In researches on studying the ECG loudspeakers at 147 healthy volunteers of significant influence of an eplerenon on the heart rate (HR), duration of intervals of QRS, PR or QT it is not revealed.

Pharmacokinetics.

Absorption and distribution

absolute bioavailability of an eplerenon is not known. The maximum concentration in a blood plasma (Cmax) is reached approximately in 2 hours. Cmax and the area under pharmacokinetic curve (AUC) linearly depend on a dose in the range from 10 to 100 mg and not linearly - in a dose more than 100 mg. The equilibrium state is reached within 2 days. Meal does not influence absorption.

Eplerenon approximately for 50% contacts proteins of a blood plasma, is preferential with alfa1-acid group of glycoproteins. The settlement volume of distribution in an equilibrium state makes 50 (±7) l. Eplerenon does not contact erythrocytes.

Metabolism and removal

metabolism of an eplerenon is carried out, generally under the influence of CYP3A4. Active metabolites of an eplerenon in a blood plasma of the person are not identified.

In not changed view with urine and a stake less than 5% of a dose of an eplerenon are removed. After a single dose in marked drug about 32% of a dose were removed with a stake and about 67% - with urine. The elimination half-life of an eplerenon makes about 3-5 hours, clearance of a blood plasma – about 10 l/h.

Special groups

Age, sex and race: the pharmacokinetics of an eplerenon in a dose of 100 mg was studied at elderly patients (65 years are more senior), men and women, and the Afro-Americans once a day. The drug pharmacokinetics significantly did not differ at men and women. In an equilibrium state at elderly patients of Cmax and AUC were respectively for 22% and 45% above, than at young patients (18-45 years). In an equilibrium state at the Afro-Americans of Cmax and AUC also 26% were respectively 19% lower.

Renal failure

The pharmacokinetics of an eplerenon was studied at patients with a renal failure of varying severity and at the patients who are on a hemodialysis. In comparison with patients of control group at patients with a heavy renal failure revealed increase in equilibrium AUC and Cmax by 38% and 24% respectively, and at the patients who are on a hemodialysis – their decrease by 26% and 3%. Correlation between clearance of an eplerenon from a blood plasma and clearance of creatinine is not revealed. Eplerenon does not leave at a hemodialysis.


Liver failure

the pharmacokinetics of an eplerenon in a dose of 400 mg was compared at patients to a moderate abnormal liver function (a class B on Chayld-Pyyu) and healthy volunteers. Equilibrium Cmax and AUC of an eplerenon were increased by 3,6% and 42% respectively. At patients with a heavy liver failure эплеренон it was not studied therefore its use in this group of patients is contraindicated.

Heart failure: the pharmacokinetics of an eplerenon in a dose of 50 mg was studied at patients with heart failure (a class II-IV on NYHA classification). Patients with heart failure had equilibrium AUC and Cmax respectively for 38 and 30% is higher, than at the healthy volunteers who are picked up for age, body weight and a floor. In the population pharmacokinetic analysis which is carried out in subgroup of the patients participating in the research EPHESUS it was established that the clearance of an eplerenon at patients with heart failure is similar to that at healthy elderly people.

Indications to use:

Inspr's drug is shown as an additional tool to standard therapy (including using beta adrenoblockers), for the purpose of decrease in risk of development of cardiovascular diseases and mortality at patients with stable dysfunction of a left ventricle (fraction of emission <40%) and clinical signs of heart failure after recently postponed myocardial infarction.  

Route of administration and doses:

Inside. Use of drug of Inspr is not connected with meal. For individual selection of a dose dosages of 25 and 50 mg can be used. Treatment it is necessary to begin with a dose 25 mg once a day and to increase it to 50 mg once a day within 4 weeks taking into account potassium concentration in blood serum (see tab. 1). It is reasonable to begin therapy with drug within 3-14 days after an acute myocardial infarction. The recommended maintenance dose of drug makes 50 mg once a day.

Potassium concentration in blood serum should be defined before purpose of drug, within the first week and in 1 month after the beginning of therapy or at change of a dose of drug. Further it is also necessary to control periodically potassium concentration in blood serum.

Table 1: Selection of a dose after an initiation of treatment

Concentration

potassium in blood serum (mmol/l)
Action
Change of a dose

<5.0
Increase in a dose
from 25 mg every other day to 25 mg once a day

from 25 mg once a day to 50 mg once a day

5,0 – 5,4
Maintenance dose
The dose remains former

5,5 – 5,9
Dose decline
from 50 mg once a day to 25 mg once a day

from 25 mg once a day to 25 mg every other day

from 25 mg every other day - temporary drug withdrawal

> 6,0
Drug withdrawal
It is not applicable

After the temporary termination of administration of drug in connection with increase in potassium concentration in blood serum to more than 6,0 mmol/l, therapy by drug it is possible to renew in a dose 25 mg every other day when potassium concentration in blood serum makes <5,0 mmol/l.


Elderly patients of Correction of a starting dose it is not required from elderly patients. Due to age depression of function of kidneys at elderly patients the risk of development of a hyperpotassemia, especially in the presence of the associated diseases promoting increase in concentration of an eplerenon in blood serum, in particular at an abnormal liver function from easy to moderate severity increases. It is recommended to define periodically potassium concentration in blood serum (see the section "Special Instructions").

The renal failure of Correction of a starting dose with an easy renal failure is not required from patients. It is recommended to define periodically potassium concentration in blood serum (see the section "Special Instructions"). Eplerenon does not leave at dialysis.

The abnormal liver function of Correction of a starting dose with an abnormal liver function from easy to moderate severity is not required from patients. Considering increase in concentration of an eplerenon at such patients, it is regularly recommended to control potassium concentration in blood serum, especially at elderly patients (see the section "Special Instructions").

The accompanying therapy At simultaneous use of drugs, for example, Amiodaronum having the weak or moderately expressed inhibiting effect on CYP3A4, diltiazem and verapamil, treatment it is possible to begin with Inspr's drug with a dose 25 mg once a day, at the same time the dose of the last should not exceed 25 mg once a day (see the section "Interaction with Other Medicines").

Features of use:

Hyperpotassemia:

at treatment eplerenony the hyperpotassemia which is caused by its mechanism of action can develop. In an initiation of treatment and at change of a dose of drug at all patients it is necessary to control potassium concentration in blood serum. Further periodic control of potassium concentration is recommended to be carried out to patients with the increased risk of development of a hyperpotassemia, for example, (elderly) patient with a renal failure (see the section "Route of Administration and Doses") and a diabetes mellitus. Considering the increased risk of development of a hyperpotassemia, purpose of drugs of potassium after an initiation of treatment eplerenony it is not recommended. The dose decline of an eplerenon leads to decrease in potassium concentration in blood serum. In one research addition of Hydrochlorthiazidum to an eplerenon interfered with increase in potassium concentration in blood serum.

Renal failure:

at patients with a renal failure, including a diabetic microalbuminuria, it is regularly recommended to control potassium concentration in blood serum. The risk of development of a hyperpotassemia increases at depression of function of kidneys. Though the number of patients with a diabetes mellitus 2 types and a microalbuminuria in the research EPHESUS was limited, nevertheless, in this small selection increase in frequency of a hyperpotassemia was noted. In this regard at such patients treatment should be carried out with care. Eplerenon does not leave at a hemodialysis.

Abnormal liver function:

at patients with an easy or moderate abnormal liver function (a class A and B on Chayld-Pyyu) increases in potassium concentration in blood serum more than 5,5 mmol/l were not revealed. At such patients it is necessary to control the level of electrolytes. At patients with a heavy abnormal liver function эплеренон it was not studied therefore its use is contraindicated (see the section "Contraindications").

Inductors CYP3A4:

simultaneous use of an eplerenon with the powerful inductors CYP3A4 is not recommended (see the section "Interaction with Other Medicines").

Cyclosporine, такролимус, the drugs containing lithium:

during treatment eplerenony it is necessary to avoid purpose of these means (see the section "Interaction with Other Medicines").

Lactose:

tablets contain lactose therefore it is not necessary to appoint them the patient with rare hereditary diseases, such as intolerance of a galactose, a lactose intolerance of Lapp and a sprue of glucose galactose.

Effects on ability to drive the car and to use the equipment

Effects of an eplerenon on ability to drive the car or to use the equipment were not studied. Eplerenon does not cause drowsiness or disturbance of cognitive function, however, it is necessary to consider a possibility of emergence of dizziness at treatment by this drug.

Side effects:

In the research EPHESUS the general frequency of the undesirable phenomena at drug use Inspra (78,9%) was similar to that when using placebo (79,5%). Because of the undesirable phenomena treatment by drug and placebo was stopped at 4,4% and 4,3% of patients respectively. The undesirable phenomena registered in the research EPHESUS which could be connected with treatment, and also the serious undesirable phenomena which frequency considerably exceeded that in group of placebo are listed below. The undesirable phenomena are distributed on systems of an organism and frequency: frequent> 1/100, <1/10; infrequent> 1/1000, <1/100.

From system of a hemopoiesis and lymphatic system

Infrequent: eosinophilia.

Disturbances of metabolism and food

Frequent: hyperpotassemia.

Infrequent: dehydration, hypercholesterolemia, gipertriglitseridemiya, hyponatremia.

Mental disorders

Infrequent: sleeplessness.

Neurologic disturbances

Frequent: dizziness.

Infrequent: headache.

From heart

Infrequent: fibrillation of auricles, myocardial infarction, left ventricular failure.

Vascular disorders

Frequent: lowering of arterial pressure.

Infrequent: orthostatic hypotonia, thrombosis of arteries of the lower extremities.

From system of breath, a thorax and a mediastinum

Infrequent: pharyngitis.

From digestive tract

Frequent: diarrhea, nausea.

Infrequent: meteorism, vomiting.

From integuments and a hypodermic fatty tissue

Infrequent: the increased perspiration, an itch.

From a musculoskeletal system and connecting fabric

Infrequent: a dorsodynia, spasms in gastrocnemius muscles of legs.

From kidneys and urinary tract

Frequent: renal failure.

The general and local

Infrequent: adynamy, indisposition.

Laboratory indicators

Infrequent: increase in level of residual nitrogen of urea, creatinine.

Infections

Infrequent: pyelonephritis.


In the research EPHESUS increase in number of cases of a stroke at patients of advanced age is noted (75 years are more senior). However, stroke frequency authentically did not differ between groups of an eplerenon (30) and placebo (22).

Interaction with other medicines:

Kaliysberegayushchy diuretics and drugs of potassium:

considering the increased risk of development of a hyperpotassemia, эплеренон it is not necessary to appoint the patient receiving kaliysberegayushchy diuretics and drugs of potassium (see the section "Contraindications"). Kaliysberegayushchy diuretics can strengthen effects of anti-hypertensive means and other diuretics.

The drugs containing lithium:

interaction of an eplerenon with lithium was not studied. However, at the patients receiving lithium in combination with diuretics and APF inhibitors intoxication cases are described by lithium. It is necessary to avoid simultaneous use of an eplerenon and lithium. If the similar combination is necessary, it is reasonable to control concentration of lithium in a blood plasma (see the section "Special Instructions").

Cyclosporine, takrolumus:

cyclosporine and такролимус can cause a renal failure and increase risk of development of a hyperpotassemia. It is necessary to avoid simultaneous use of an eplerenon and cyclosporine or a takrolimus. If during treatment eplerenony purpose of cyclosporine or a takrolimus is required, it is recommended to control carefully potassium concentration in blood serum and function of kidneys (see the section "Special Instructions").

Non-steroidal anti-inflammatory drugs (NPVP):

treatment of NPVP can lead to an acute renal failure due to direct suppression of glomerular filtering, especially patients have risk groups (elderly patients and/or patients with dehydration). At combined use of these means prior to the beginning of and during treatment it is necessary to provide an adequate water relationships and to control function of kidneys.

Trimethoprimum:

simultaneous use of Trimethoprimum with eplerenony increases risk of development of a hyperpotassemia. It is recommended to control potassium concentration in blood serum and function of kidneys, especially at patients with a renal failure and at elderly people.

APF inhibitors and antagonists of receptors of angiotensin II:

it is necessary to apply эплеренон with APF inhibitors or antagonists of receptors of angiotensin II with care. The similar combination can lead to increase in risk of development of a hyperpotassemia, especially at patients with a renal failure, including at elderly people. It is recommended to control carefully function of kidneys and potassium concentration in blood serum.

Alfa1-adrenoblokatory (Prazozinum, альфузозин):

at simultaneous use of alfa1-adrenoblockers with eplerenony hypotensive action can amplify and/or increase risk of development of orthostatic hypotension in this connection it is recommended to control the ABP at a body postural change.

Tricyclic antidepressants, neuroleptics, амифостин, Baclofenum:

at simultaneous use of these means with eplerenony the anti-hypertensive effect can amplify or increase risk of development of orthostatic hypotension.

Glucocorticoids, тетракозактид:

simultaneous use of these means with eplerenony can lead to easing of anti-hypertensive effect (a delay of sodium and liquid).

Pharmacokinetic interactions

The researches in vitro demonstrate to what эплеренон does not inhibit isoenzymes of CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenon is not substrate or inhibitor of a glycoprotein of River.

Digoxin: the area under pharmacokinetic curve (AUC) of digoxin at simultaneous

use with eplerenony increases by 16% (90% of DI: 4% - 30%). It is necessary to be careful if digoxin is applied in the doses close to maximum therapeutic.

Warfarin:

clinically significant pharmacokinetic interaction with warfarin is not revealed. It is necessary to be careful if warfarin is applied in the doses close to maximum therapeutic.

CYP3A4 substrates:

in special researches of signs of pharmacokinetic interaction of an eplerenon with CYP3A4 substrates, for example, midazolam and tsizapridy, it was not revealed.

CYP3A4 inhibitors:

powerful CYP3A4 inhibitors: at use of an eplerenon with the means inhibiting CYP3A4, perhaps significant pharmacokinetic interaction. Powerful CYP3A4 inhibitor (кетоконазол 200 mg two times a day) caused increase in AUC of an eplerenon by 441%. Simultaneous use of an eplerenon with powerful CYP3A4 inhibitors, such as кетоконазол, итраконазол, ритонавир, нелфинавир, кларитромицин, телитромицин and нефазадон, it is contraindicated (see the section "Contraindications").

weak and moderate CYP3A4 inhibitors: simultaneous use with erythromycin, sakvinaviry, Amiodaronum, diltiazem, verapamil and flukonazoly was followed by significant pharmacokinetic interaction (extent of increase in AUC varied from 98% to 187%). At simultaneous use of these means with eplerenony the dose of the last should not exceed 25 mg (see the section "Route of Administration and Doses").

Inductors CYP3A4:

the concomitant use of tincture of a St. John's Wort (St John's Wort, the powerful inductor CYP3A4) with eplerenony caused decrease in AUC of the last by 30%. At use of more powerful inductors CYP3A4, such as rifampicin, perhaps more expressed decrease in AUC of an eplerenon. Considering possible decrease in efficiency of an eplerenon, simultaneous use of the powerful inductors CYP3A4 (rifampicin, carbamazepine, Phenytoinum, phenobarbital, St. John's Wort tincture) it is not recommended (see the section "Special Instructions").

Antacids:

on the basis of pharmacokinetic clinical trial of considerable interaction of antacids with eplerenony at their simultaneous use it is not supposed.

Contraindications:

Hypersensitivity to an eplerenon or other components of drug;

potassium concentration in blood serum in an initiation of treatment more than 5,0 mmol/l;

the moderated or expressed renal failure (clearance of creatinine less than 50 ml/min.);

heavy liver failure (a class C on Chayld-Pyyu);

concomitant use of kaliysberegayushchy diuretics, drugs of potassium or powerful CYP3A4 inhibitors, for example, an itrakonazola, a ketokonazola, a ritonavira, a nelfinavira, a klaritromitsina, a telitromitsina and a nefazodona (see the section "Interaction with Other Medicines");

rare hereditary diseases, such as intolerance of a galactose, lactose intolerance of Lapp and sprue of glucose galactose (see the section "Special Instructions");

there is no experience of use of drug for children aged up to 18 years therefore its appointment is not recommended to patients of this age group.

With care: a diabetes mellitus 2 types and a microalbuminuria (see the section "Special Instructions");

simultaneous use of an eplerenon and

- APF inhibitors or antagonists of receptors of angiotensin II;

- the drugs containing lithium;

- cyclosporine or takrolimus;

- digoxin and warfarin in the doses close to the maximum therapeutic

(see the sections "Special Instructions" and "Interaction with Other Medicines").



Pregnancy and feeding by a breast. There are no data on use of drug for pregnant women. It is necessary to appoint drug with care and only when the expected advantage for mother considerably exceeds possible risk for the fruit/child.

There are no data on removal of an eplerenon after intake with breast milk. Possible undesirable effects of an eplerenon on the newborns who are on breastfeeding are not known therefore reasonablly or to stop feeding by a breast, or to cancel drug, depending on its importance for mother.

Overdose:

Cases of overdose of an eplerenon at the person are not described. The lowering of arterial pressure and a hyperpotassemia can be the most probable manifestations of overdose. Eplerenon does not leave at a hemodialysis. It is established what эплеренон actively contacts absorbent carbon. At emergence of symptomatic hypotension it is necessary to appoint the supporting treatment. In case of development of a hyperpotassemia standard therapy is shown.

Storage conditions:

To store at a temperature not above Z0 ºС in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated 25 mg or 50 mg. On 14 tablets in the blister; on 2 blisters together with the application instruction in a cardboard pack. On 10 tablets in the blister; on 2, 3, 5, 10 or 20 blisters together with the application instruction in a cardboard pack.