Ренитек®

General characteristics. Structure:

Active ingredient: 5 mg, 10 mg or 20 mg of enalapril of a maleate.

Excipients: Natrii hydrocarbonas, lactoses monohydrate, starch corn, starch prezhelatinizirovanny, magnesium stearate, ferrous oxide red E172 (Renitek of 10 mg, 20 mg), ferrous oxide yellow E172 (Renitek of 20 mg).

Ренитек® (enalapril a maleate) treats the means influencing a renin-angiotenzinovuyu system – to APF inhibitors and is highly specific, it is long the APF inhibitor operating, not containing sulphhydryl group. It is applied to treatment of the arterial hypertension (AH) and the heart failure (HF).

Pharmacological properties:

Pharmacodynamics. RENITEK (enalapril a maleate) is derivative two amino acids: L-alanine and L-proline. Enalapril – APF inhibitor, the angiotensin I catalyzing transformation into pressor substance angiotensin II. After absorption the enalapril accepted inside turns by hydrolysis into enalaprilat which inhibits APF. The inhibition of APF leads to decrease in concentration of angiotensin II in a blood plasma that involves increase in activity of a renin of a blood plasma (owing to elimination of the back negative reaction on change of products of a renin) and reduction of secretion of Aldosteronum.

APF is identical to enzyme of a kininaz II therefore enalapril can also block destruction of bradikinin, the peptide possessing vazodilatiruyushchy action. Value of this effect in therapeutic effect of enalapril demands specification. Now it is considered that the mechanism by means of which enalapril reduces the arterial pressure (AP) is suppression renin-angiotensin-aldosteronovoy of the system playing an important role in regulation of the ABP. Enalapril shows anti-hypertensive action even at patients with reduced concentration of a renin.

Decrease in the ABP is followed by decrease in the general peripheric vascular resistance, increase in cordial emission and lack of changes or minor changes of heart rate. As a result of reception of enalapril the renal blood stream increases, but the level of glomerular filtering remains not changed. However at patients with initially reduced glomerular filtering, its level usually increases.

Anti-hypertensive therapy by enalapril leads to considerable regression of a hypertrophy of a left ventricle and preservation of its systolic function.

Therapy by enalapril is followed by favorable impact on a ratio of fractions of lipoproteins and lack of influence or favorable action on concentration of the general cholesterol.

Enalapril reception by patients with AG leads to decrease in the ABP irrespective of position of a body: both in a standing position, and in a prone position without significant increase in the heart rate (HR).

Symptomatic postural hypotension develops seldom. Achievement of optimum decrease in the ABP can demand several weeks of therapy from some patients.

Therapy interruption by enalapril does not cause sharp raising of the ABP.

The effective inhibition of activity of APF usually develops in 2-4 hours after a single dose of a dose of enalapril inside. The beginning of hypotensive action comes within 1 hour, the maximum decrease in the ABP is observed in 4-6 hours after administration of drug. Duration of action depends on a dose. However, when using of the recommended doses anti-hypertensive action and hemodynamic effects are supported within 24 hours.

Enalapril reduces the loss of potassium ions caused by use of a hydrochlorothiazide.

Pharmacokinetics. After intake enalapril is quickly soaked up, the maximum concentration of enalapril in blood serum is reached within 1 hour after intake.

Extent of absorption of enalapril of a maleate at intake makes about 60%. Meal does not exert impact on enalapril absorption.

After absorption enalapril is quickly hydrolyzed with formation of active agent of enalaprilat, APF powerful inhibitor. The maximum concentration of enalaprilat in blood serum is observed in 3-4 hours after reception of a dose of enalapril inside. Duration of absorption and hydrolysis of enalapril is similar for various recommended therapeutic doses.

Removal of enalapril is carried out preferential through kidneys. The main metabolites defined in urine are the enalaprilat making about 40% of a dose and not changed enalapril. There are no data on other metabolites of enalapril. The profile of concentration of enalaprilat in a blood plasma has the long final phase, apparently, caused by release of the enalaprilat connected with APF. At persons with normal function of kidneys stable concentration of enalaprilat is reached for the 4th day since the beginning of reception of enalapril. The elimination half-life (T1/2) of enalapril at course use of drug inside makes 11 hours.

Indications to use:

• Essential hypertensia
• Renovascular hypertensia
• Heart failure of any stage

At patients with existence of clinical displays of heart failure of RENITEK it is also shown for:
• increases in survival of patients
• delays of progressing of heart failure
• decrease in frequency of hospitalization concerning heart failure.

• Prevention of development of clinically expressed heart failure

At patients without clinical symptoms of heart failure with dysfunction of a left ventricle of RENITEK it is shown for:
• delays of development of clinical displays of heart failure;
• decrease in frequency of hospitalization concerning heart failure.

• Prevention of coronary ischemia at patients with dysfunction of a left ventricle.

RENITEK is shown for:
• reduction of frequency of development of a myocardial infarction;
• decrease in frequency of hospitalization concerning unstable stenocardia.

Route of administration and doses:

Inside, irrespective of meal as absorption of tablets РЕНИТЕКа does not depend on meal.

Arterial hypertension. The initial dose makes 10-20 mg depending on severity of AG and 1 time a day is appointed. At soft degree of AG the recommended initial dose makes 10 mg a day. At other degrees of AG the initial dose makes 20 mg a day at a single dose. A maintenance dose – 1 tablet of 20 mg once a day. The dosage is selected individually for each patient, but the dose should not exceed 40 mg a day.

Renovascular hypertensia. As at patients of this ABP group and renal function can be especially sensitive to APF inhibition, begin therapy with a low initial dose – 5 mg and less. Then the dose is selected according to needs of the patient. The dose of 20 mg РЕНИТЕКа in days at daily reception is usually effective. It is necessary to be careful at treatment РЕНИТЕКом of patients who shortly before it received treatment by diuretics (see. "The accompanying treatment of AG diuretics").

The accompanying treatment of arterial hypertension diuretics. After the first reception РЕНИТЕКа arterial hypotension can develop. Such effect is most probable at patients who receive treatment by diuretics. It is recommended to appoint drug with care as at such patients deficit of liquid or sodium can be observed. Treatment by diuretics should be stopped in 2-3 days prior to treatment РЕНИТЕКом. If it is impossible, then it is necessary to lower initial dose РЕНИТЕКа (to 5 mg or less), for determination of primary effect of drug. Further the dosage should be selected taking into account a condition of the patient.

Dosage at a renal failure. The interval between receptions РЕНИТЕКа has to be increased and/or the dose is reduced.

* See the sections "With Care", "Special Instructions"
** Enalapril is exposed to a hemodialysis. Dose adjustment in days when the hemodialysis is not carried out, has to осуществлятьря depending on the ABP level.

Cordial insufficiency / asymptomatic dysfunction of a left ventricle. Initial dose РЕНИТЕКа at patients with heart failure or with asymptomatic dysfunction of a left ventricle makes 2,5 mg, at the same time purpose of drug has to be carried out under careful medical control for establishment of primary effect of drug on the ABP. RENITEK can be used for treatment of SN with the expressed clinical manifestations usually together with diuretics and when it is necessary, with cardiac glycosides. In case of absence of the symptomatic hypotension (which resulted from treatment РЕНИТЕКом) or after its corresponding correction, the dose should be raised gradually to a usual maintenance dose – 20 mg which is appointed or once, or is divided into 2 receptions depending on portability of drug the patient. Selection of a dose can be carried out within 2-4 weeks or to shorter terms if there are residual signs and symptoms of SN.

Such therapeutic mode effectively reduces rates of mortality of patients from clinically expressed SN. Both to, and after initiation of treatment РЕНИТЕКом it is necessary to carry out careful control of the ABP and function of kidneys (see the section "Special Instructions") at sick SN as there were messages on development as a result of administration of drug of arterial hypotension with the subsequent (that is observed much less often) developing of a renal failure. At the patients receiving diuretics, the dose of diuretics has to be whenever possible reduced prior to treatment РЕНИТЕКом. Development of arterial hypotension after reception of the first dose РЕНИТЕКа does not mean that arterial hypotension will remain at prolonged treatment, and does not indicate the termination of administration of drug the need. At treatment РЕНИТЕКом it is also necessary to control potassium level in blood serum (see the section "Medicinal Interactions").

Features of use:

Use in pediatrics. Age up to 18 years (efficiency and safety are not established).

Use at pregnancy. Use of drug during pregnancy is not recommended. At pregnancy approach reception РЕНИТЕКа has to be immediately stopped.

APF inhibitors can cause a disease or death of a fruit or the newborn at appointment to their pregnant women during the second and third trimesters of pregnancy.

Use of APF inhibitors during these periods was followed by negative impact on a fruit and the newborn, including development of arterial hypotension, renal failure, a hyperpotassemia and/or hypoplasia of a skull in the newborn. Development of an oligogidramnion, apparently, owing to depression of function of kidneys of a fruit is possible. This complication can lead to a contracture of extremities, deformation of a skull, including its front part, hypoplasias of lungs. At appointment РЕНИТЕКа it is necessary to inform the patient of rather potential risk for a fruit.

These undesirable phenomena on an embryo and a fruit, apparently, are not result of pre-natal influence of APF inhibitors during the first trimester of pregnancy.

Newborns, whose mothers accepted RENITEK, have to be observed carefully concerning identification of decrease in the ABP, an oliguria and a hyperpotassemia. Enalapril which gets through a placenta can be partially removed from blood circulation of the newborn by means of peritoneal dialysis; theoretically it can be removed by means of exchange hemotransfusion.

Use during feeding by a breast. Enalapril and enalaprilat are defined in maternal milk in trace concentration. If use of drug is necessary, the patient has to stop feeding by a breast.

Clinically expressed arterial hypotension. Clinically expressed arterial hypotension seldom is observed at patients with not complicated arterial hypertension. At patients from AG receiving RENITEK, arterial hypotension develops more often against the background of the hypovolemia arising, for example, as a result of therapy by diuretics, salt consumption restrictions at the patients who are on a hemodialysis, and also suffering from diarrhea or vomiting (see the sections "INTERACTION WITH OTHER MEDICINES" and "SIDE EFFECT"). Clinically expressed arterial hypotension was observed also at patients with the heart failure which is followed or not followed by a renal failure. Arterial hypotension is observed more often at patients with more severe forms of heart failure at which higher doses of "loopback" diuretics, with a hyponatremia or renal failures are used. At such patients treatment РЕНИТЕКом should be begun under medical control which has to be especially careful at change of dose РЕНИТЕКа and/or diuretic. Similarly it is necessary to watch patients with coronary heart disease, and also with diseases of vessels of a brain at which sharp decrease in the ABP can lead to a myocardial infarction or a stroke.

At development of arterial hypotension of the patient it is necessary to lay and, in case of need, to enter intravenously normal saline solution of sodium of chloride. Tranzitorny arterial hypotension at reception РЕНИТЕКа is not a contraindication to further treatment by drug which can be continued after completion of volume of liquid and normalization of the ABP.

With heart failure and with normal or reduced the ABP RENITEK can cause additional decrease in the ABP in some patients. Such reaction to administration of drug can be expected, and it should not be regarded as the basis for the treatment termination. When arterial hypotension accepts stable character, it is necessary to lower a dose and/or to stop treatment by diuretic and/or РЕНИТЕКом.

Aortal stenosis / hypertrophic cardiomyopathy. As well as all vazodilatator, to patients with obstruction of an aortal opening of a left ventricle APF inhibitors have to be appointed with care.

Renal failure. Some patients have an arterial hypotension developing after an initiation of treatment APF inhibitors, can lead to deterioration in function of kidneys. It was in certain cases reported about development of an acute renal failure, usually reversible character.

Patients with a renal failure can have a need of a dose decline and/or frequency of administration of drug (see the section "Route of Administration and Doses"), At some patients with a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney increase in content of urea in blood and serumal creatinine was observed. Changes usually had reversible character and indicators were returned to norm after the treatment termination. Such nature of changes is most probable at patients with a renal failure.

RENITEK in combination with diuretics caused usually slight and passing increase of content of urea in blood in some patients in whom diseases of kidneys prior to treatment were not found and creatinine in blood serum. In such cases the dose decline and/or cancellation of diuretic and/or РЕНИТЕКа can be required.

The increased sensitivity / the Quincke's disease. At purpose of APF inhibitors, including RENITEK, the exceptional cases of a Quincke's disease of the person, extremities, lips, language, a glottis and/or throat arising during the different periods of treatment were described. In such cases it is necessary to stop immediately treatment РЕНИТЕКом and to establish constant observation of the patient to be convinced of total disappearance of symptoms. Even when there is only a difficulty of swallowing without breath disturbance, patients have to be a long time under medical observation as therapy by antihistamines and corticosteroids can be insufficient.

The Quincke's disease of a throat or language can lead to a lethal outcome. When hypostasis is localized in the field of language, a glottis or a throat and can cause obstruction of respiratory tracts, it is necessary to begin quickly the corresponding therapy which can include hypodermic administration of solution of Epinephrinum (adrenaline) of 0,1% (0,3-0,5 ml) and/or urgent measures for ensuring passability of respiratory tracts.

The patients having the Quincke's disease which is not connected with use of APF inhibitors in the anamnesis can have the increased risk of its emergence and at treatment by APF inhibitor (see also section "CONTRAINDICATIONS").

At patients of negroid race the frequency of development of a Quincke's disease at reception of APF inhibitors is higher, than at representatives of other races.

Anaphylactic reactions during desensitization allergen from poison of Hymenoptera. In rare instances at the patients receiving APF inhibitors during desensitization allergen from poison of Hymenoptera the anaphylactic reactions posing a threat for life of patients developed. Similar reactions can be avoided if prior to the beginning of desensitization it is temporary to stop APF inhibitor reception.

The patients who are on a hemodialysis. At the patients who were on dialysis with use of membranes of high capacity (for example, AN 69®) and receiving at the same time APF inhibitor, anaphylactic reactions in certain cases developed. Therefore for such patients use of dialysis membranes of other type or antihypertensive of other group is recommended.

Cough. There are messages on developing of cough at treatment by APF inhibitors. Usually cough has unproductive, constant character and stops after drug withdrawal. Cough owing to treatment by APF inhibitor has to be considered at differential diagnosis of cough.

Surgery / General anesthesia. During big surgeries or during the general anesthesia with use of the means causing hypotensive effect, enalapril blocks formation of angiotensin II for the second time in relation to compensatory release of a renin. If at the same time the expressed decrease in the ABP explained with the similar mechanism it develops it is possible to adjust increase in volume of the entered liquid.

Hyperpotassemia (see also "INTERACTION WITH OTHER MEDICINES"). Risk factors for development of a hyperpotassemia are the renal failure, a diabetes mellitus, co-administration of kaliysberegayushchy diuretics (Spironolactonum, Triamterenum or amiloride), and also use of kaliysoderzhashchy additives and salts.

Use of potassium additives, kaliysberegayushchy diuretics or kaliysoderzhashchy salts, especially at patients with a renal failure, can lead to considerable increase of content of potassium in blood serum.

The hyperpotassemia can cause serious, in some cases fatal, disturbances of a heart rhythm. In need of the accompanying purpose of the kaliysoderzhashchy or increasing the content of potassium drugs listed above, it is necessary to be careful and to regularly control the content of potassium in blood serum.

Hypoglycemia. The patients with a diabetes mellitus receiving hypoglycemic means for intake or insulin before use of APF inhibitors have to be informed on need of careful control of level of glucose of blood (hypoglycemia), especially within the first month of combined use of these drugs.

Use at elderly patients. Elderly and younger patients had similar clinical trials of efficiency and portability of enalapril.

Impact on ability to drive the car and/or to work with mechanisms. During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions (dizziness, especially after reception of an initial dose of APF inhibitor at the patients accepting diuretic medicines is possible).

Side effects:

In general, RENITEK is well transferred. Total frequency of side effects when using РЕНИТЕКа does not exceed that at purpose of placebo. In most cases side effects are insignificant, are temporary and do not demand therapy cancellation.

At appointment РЕНИТЕКа the following side effects are observed: dizziness and a headache meet most often. Increased fatigue and an adynamy are observed at 2-3% of patients. Other side effects (arterial hypotension, orthostatic hypotension, a syncope, nausea, diarrhea, muscular spasms, skin rash and cough) occur less than at 2% of patients. There are rare messages on disturbances of functions of kidneys, a renal failure, an oliguria and proteinuria.

The increased sensitivity / the Quincke's disease. In rare instances when using РЕНИТЕКа the Quincke's disease of the person, extremities, lips, language, a glottis and/or throat was observed (see the section "Special Instructions"), it is very rare – an intestinal Quincke's disease.

Seldom or never the following side effects meet:

Cardiovascular system. A myocardial infarction or a stroke, perhaps, secondary in relation to the expressed arterial hypotension at the patients belonging to risk group (see the section "Special Instructions"), stethalgias, strong heartbeat, disturbance of a rhythm, stenocardia, Reynaud's syndrome.

Alimentary system. Intestinal impassability, pancreatitis, a liver failure, hepatitis (hepatocellular or cholestatic), jaundice, pains in a stomach, vomiting, dyspepsia, a lock, anorexia, stomatitis, dryness in a mouth.

Metabolic frustration. A hypoglycemia at the patients suffering from a diabetes mellitus, receiving hypoglycemic means for intake or insulin (see. "Interaction WITH OTHER MEDICINES").

Central nervous system. A depression, confusion of consciousness, drowsiness, sleeplessness, the increased nervousness, paresthesias, dizziness, sleep disorders, uneasiness.

Respiratory system. Pulmonary infiltrates, bronchospasm / bronchial asthma, asthma, rhinorrhea, pharyngalgia, hoarseness of a voice.

Integuments. The increased sweating, a polymorphic erythema, exfoliative dermatitis, Stephens-Johnson's syndrome, a toxic epidermal necrolysis, a pempigus, a skin itch, a small tortoiseshell, baldness.

Others. Impotence, erubescence of the person, taste disturbance, sonitus, glossitis, sight illegibility.

It was reported about development of a difficult symptom complex which can include all or some of the following symptoms: fever, serositis, vasculitis, миалгия / miositis, атралгия / arthritis, positive test for antinuclear antibodies, increase in the blood sedimentation rate (BSR), eosinophilia and leukocytosis. As side effects there can also be rash, a photosensitization and other skin reactions.

Laboratory indicators. Clinically significant changes of standard laboratory indicators are seldom connected using РЕНИТЕКа. Increase in level of urea in blood, serumal creatinine, increase in activity of enzymes of a liver and/or bilirubin in blood serum is possible. These changes usually have reversible character and are normalized after the termination of reception РЕНИТЕКа. Sometimes the hyperpotassemia and a hyponatremia meet.

There are messages on decrease in concentration of hemoglobin and a hematocrit. There are messages on separate cases of a neutropenia, thrombocytopenia, suppression of function of marrow and an agranulocytosis in which it is impossible to exclude bonds using РЕНИТЕКа.

The listed below side effects are revealed during post-marketing observation, however relationship of cause and effect is not established with administration of drug of RENITEK: pneumonia, an urological infection, an upper respiratory tract infection, the bronchitis, a cardiac standstill, fibrillation of auricles surrounding herpes, a melena, an ataxy, a thromboembolism of branches of a pulmonary artery, hemolitic anemia including hemolysis cases at patients with deficit glyukozo-6-fosfatdegidrogenazy.

Interaction with other medicines:

Other antihypertensives. At purpose of the drug RENITEK® in combination with other antihypertensives summation of hypotensive effect can be observed.

Blood serum potassium. Content of potassium in blood serum: usually remains within norm. At patients from AG receiving the drug RENITEK® more than 48 weeks increase in content of potassium of blood serum to 0,2 ¼Ý¬ó/l is observed.

At combined use of the drug RENITEK® with the diuretics causing loss of potassium ions, the hypopotassemia caused by effect of diuretics as a rule is weakened thanks to effect of enalapril.

Risk factors for development of a hyperpotassemia are the renal failure, a diabetes mellitus, co-administration of kaliysberegayushchy diuretics (Spironolactonum, Triamterenum or amiloride), and also use of kaliysoderzhashchy additives and salts. Use of potassium additives, kaliysberegayushchy diuretics or kaliysoderzhashchy salts, especially at patients with a renal failure, can lead to considerable increase of content of potassium in blood serum. In need of the accompanying purpose of the kaliysoderzhashchy or increasing the content of potassium drugs listed above, it is necessary to be careful and to regularly control the content of potassium in blood serum.

The drugs used for treatment of a diabetes mellitus. Combined use of APF inhibitors and hypoglycemic means (insulin, hypoglycemic means for intake) can strengthen hypoglycemic effect of the last with risk of development of a hypoglycemia. This phenomenon as a rule was most often noted within the first weeks of their combined use, and also at patients with a renal failure. At patients with the diabetes mellitus receiving hypoglycemic means for intake or insulin it is regularly necessary to control concentration of glucose of blood, especially within the first month of combined use with APF inhibitors.

Lithium drugs. APF inhibitors reduce lithium removal by kidneys, and strengthen risk of development of lithium intoxication. In need of purpose of drugs of salts of lithium it is necessary to control the content of lithium in blood serum.

Non-steroidal anti-inflammatory drugs (NPVP). NPVP, including the selection inhibitors of cyclooxygenase 2 (TsOG-2), can reduce effect of diuretics and other antihypertensives. Thus, the anti-hypertensive effect of antagonists of receptors of angiotensin II or APF inhibitors can be weakened by NPVP, including TsOG-2 inhibitors.

At some patients with an impaired renal function and accepting NPVP including TsOG-2 inhibitors, the accompanying use of APF inhibitors can lead to further deterioration in function of kidneys up to development of an acute renal failure. These changes are usually reversible. Thus, joint treatment should be applied with care at patients with a renal failure.

Gold drugs. The symptom complex including face reddening, nausea, vomiting and arterial hypotension is described in rare instances at combined use of drugs of gold for parenteral use (sodium ауротиомалат) and APF inhibitors (enalapril).

Contraindications:

• Hypersensitivity to any of drug components
• The Quincke's disease in the anamnesis connected with appointment before APF inhibitors and also a hereditary or idiopathic Quincke's disease.

RENITEK should be applied with care at treatment of patients with a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney, at primary hyper aldosteronism, a hyperpotassemia, a state after transplantation of a kidney; an aortal stenosis, a mitral stenosis (with disturbances of indicators of a hemodynamics), an idiopathic hypertrophic subaortal stenosis; general diseases of connecting fabric; coronary heart disease; cerebrovascular diseases; diabetes mellitus; a renal failure (a proteinuria – more than 1 g/days); liver failure; at the patients keeping to a diet with restriction of salt or being on a hemodialysis; at a concomitant use with immunodepressants and diuretics, elderly patients (65 years are more senior), oppression of a marrowy hemopoiesis; the states which are followed by decrease in volume of the circulating blood (including diarrhea, vomiting).

Overdose:

Data on overdose are limited. The most known symptoms of overdose: the expressed decrease in the ABP beginning approximately in 6 hours after administration of drug and a stupor. The concentration of enalaprilat in a blood plasma exceeding by 100-200 times of concentration which are observed at purpose of therapeutic doses there were after reception respectively 300 and 440 mg of enalapril.

The recommended overdose treatment: in/in infusion of isotonic solution of sodium of chloride, at an opportunity – angiotensin II infusion; provoking of vomiting. Removal of enalaprilat by means of a hemodialysis is possible.

Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years 6 months. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets on 5 mg, 10 mg or 20 mg: on 7 tablets in the aluminum blister. One, two or four blisters place together with the application instruction in a cardboard pack. Tablets on 10 mg and 20 mg: on 100 tablets in a bottle of dark glass. One bottle is placed together with the application instruction in a cardboard pack.