Koripren

General characteristics. Structure:

Active agents: lerkanidipina hydrochloride of 10 mg; enalapril maleate of 10 mg

Excipients: lactoses monohydrate - 102 mg, cellulose microcrystallic - 40 mg, sodium carboxymethylstarch - 20 mg, K30 povidone - 8 mg, Natrii hydrocarbonas - 8 mg, magnesium stearate - 2 mg.

Structure of a cover: опадрай white (02F29056) - 6 mg (a gipromelloza 5cP - 3.825 mg, titanium dioxide (E171) - 1.275 mg, talc - 300 mkg, a macrogoal of 6000 - 600 mkg).

Pharmacological properties:

Pharmacodynamics. Enalapril a maleate — salt of maleic acid and enalapril, derivative two amino acids — L-alanine and L-пиролидин-α-карбоновой. APF is peptidildipeptidazy which catalyzes transformation of angiotensin I in the angiotonic agent angiotensin II. After absorption enalapril is hydrolyzed to enalaprilat which suppresses APF. The inhibition of APF leads to decrease in level of angiotensin II in a blood plasma that leads to increase in activity of a renin in plasma (owing to elimination of negative feedback of allocation of a renin) and to decrease in secretion of Aldosteronum. As APF is identical to a kinase of II, enalapril can also inhibit degradation of bradikinin, powerful vasodepressor peptide. However the role of this mechanism in therapeutic effects of enalapril is still not studied.
In spite of the fact that mainly carry suppression to the mechanism by means of which enalapril reduces the ABP system renin-angiotensin-aldosteronovoy, enalapril is hypotensive even for patients with low levels of a renin. Enalapril promotes decrease in the ABP without substantial increase of ChSS at patients with AG which are both in a dorsal decubitus, and in a standing position. Symptomatic postural arterial hypotension — the unusual occurrence. At some patients it can need several weeks of treatment for achievement of optimum control of the ABP. Sudden cancellation of enalapril does not lead to bystry increase in the ABP.
The effective inhibition of activity of APF occurs usually in 2–4 h after oral administration of one dose of enalapril. The beginning of hypotensive action is, as a rule, noted in 1 h with the maximum decrease in the ABP in 4–6 h after reception. Duration of action of a dozozavisim, but at the recommended doses hypotonic and hemodynamic effects lasted not less than 24 h.
After enalapril reception the renal blood stream raises while the speed of glomerular filtering remains not changed. Delay signs in an organism of sodium or water were not noted. However at patients with a low speed of glomerular filtering before treatment the speed of glomerular filtering, as a rule, increases.
After reception of enalapril during the short-term researches at patients with a diabetes mellitus and patients without it, but with a disease of kidneys decrease in an albuminuria and excretion with IgG urine and crude protein was noted.
Children
Use of drug for children aged <with AG showed 16 years that the enalapril pharmacokinetics at oral administration was similar that at adults. To patients with body weight <50 kg enalapril appointed 0,625 in a dose; 2,5 or 20 mg/days, and to patients with the body weight of ≥50 kg — 0,625; 5 or 40 mg/days. Reception of enalapril of 1 times a day reduced the ABP lower value depending on dosing. Dependence of hypotensive effect of enalapril on a dose was traced in all subgroups (age, a stage of development of Tanner, a floor, race).
Lerkanidipin is an antagonist of calcium of dihydropyridinic group and inhibits transmembrane intake of calcium to a cardiac muscle and unstriated muscles. The mechanism of hypotensive action is based on direct relaxation influence on vascular unstriated muscles which, thus, reduce the general peripheral resistance. Thanks to high coefficient of membrane division лерканидипин has the prolonged hypotonic effect and does not reveal negative myotropic effects owing to its high vascular selectivity. As the vazodilatation produced lerkanidipiny begins gradually, acute arterial hypotension with reflex tachycardia is seldom noted at patients with AG.
As well as in cases with other asymmetric 1,4 dihydropyridines, hypotonic activity of a lerkanidipin mainly is a consequence of its (S) - an enantiomer.

Pharmacokinetics. Pharmacokinetic interactions at the accompanying purpose of enalapril and a lerkanidipin were not noted.
Enalapril pharmacokinetics
Absorption. Enalapril is quickly absorbed with Cmax of plasma concentration which are noted within 1 h. Existence of food in a GIT does not influence absorption of enalapril. After absorption enalapril is quickly and extensively hydrolyzed in enalaprilat — the APF strong inhibitor. Cmax of plasma concentration of enalaprilat is noted in 3–4 h after oral administration of a dose of enalapril of a maleate. Effective T½ for accumulation of enalapril is reached by further use of enalaprilat in 4 days after treatment.
Distribution. At border concentration which are therapeutic significant there is a linkng of enalapril with proteins of a blood plasma which does not exceed 60%.
Metabolism. Except conversion in enalaprilat, given about considerable metabolism of enalapril is not present.
Removal. Excretion of enalaprilat is generally carried out by kidneys. The main components of urine is enalaprilat that makes about 40% of a dose, and enalapril which did not undergo transformation or metabolism (about 20%).
The profile of concentration of enalaprilat in a blood plasma has the long final phase which is authentically caused by release of enalaprilat which is connected with APF. At persons with normal function of kidneys stable Cmax of enalapril is reached for the 4th day after the beginning of reception of enalapril. Enalapril T½ at course use of drug inside makes 11 h.
Pharmacokinetics of a lerkanidipin
Absorption. Lerkanidipin is completely absorbed after oral administration, and Cmax in a blood plasma are reached in 1,5–3 h. Two enantiomer of a lerkanidipin showed identical profiles of levels in a blood plasma: Cmax time in a blood plasma is identical; and both Cmax in plasma, and AUC is on average 1,2 times higher for (S) - an enantiomer. Elimination of half-decay of 2 enantiomer generally identical. In vivo is not noted interchangeability of 2 enantiomer.
Owing to the expressed metabolism of the first passing absolute bioavailability of a peroral lerkanidipin in conditions without starvation makes about 10%. However bioavailability at reception by healthy volunteers in the conditions of starvation decreases to 1/3 in comparison with the above-stated value. Peroral availability of a lerkanidipin increases by 4 times at its reception in 2 h after meal with the high content of fat. Drug should be used to food.
Distribution. Distribution from a blood plasma in fabrics and bodies is bystry and extensive. Degree of affinity of proteins of a blood plasma to a lerkanidipin> 98%. As the level of protein is reduced at patients with heavy renal or hepatic dysfunction, contents of free fractions of a lerkanidipin can be higher.
Metabolism. Lerkandipin is extensively metabolized by CYP 3A4; no products of metabolism are revealed in urine and Calais. Preferential лерканидипин it is transformed to inactive metabolites and ≅50% of a dose are excreted with urine.
in vitro experiments with human microsomes of a liver showed what лерканидипин shows insignificant inhibition of two CYP 3A4 and CYP 2A6 enzymes at concentration in 160 and 40 times above, than Cmax in a blood plasma which are reached after reception of a dose of 20 mg. Besides, studying of interaction at people showed what лерканидипин does not modify plazmovy levels of midazolam (typical CYP 3A4 substrate) or a metoprolol (typical CYP 2A6 substrate). Besides, in therapeutic doses at reception of a lerkanidipin biotransformation of drugs which are metabolized by CYP 3A4 or CYP 2A6 will probably not inhibit.
Removal. Elimination is mainly carried out by biotransformation. The average time of terminal elimination by calculations makes 8–10 h and owing to high affinity to lipidic membranes therapeutic activity lasts 24 h. After repeated reception of cumulation it is not noted.
Linearity/nonlinearity. Oral administration of a lerkanidipin leads to plazmovy levels which are not directly proportional to a dose (nonlinear kinetics). After 10; 20 or 40 mg of Cmax in a blood plasma were in the ratio 1:3:8, and AUC in plasma — in the ratio 1:4:18, provide a progressive saturation of effect of primary passing through a liver. Respectively availability increases with increase in a dose.
Additional information on special populations. It is shown that the pharmacokinetics of a lerkanidipin at elderly people and at patients from weak to moderate renal dysfunction or hepatic disturbance from weak to moderate is similar that which is noted in the general population of patients. Patients with heavy renal dysfunction or persons who depend on dialysis showed higher Cmax (about 70%). At patients with moderate and severe damage of a liver system bioavailability of a lerkanidipin is probably increased owing to normal extensive metabolism of drug in a liver.

Indications to use:

Essential AG.

Route of administration and doses:

Koripren apply to treatment of essential AG at patients whose ABP is insufficiently controlled only by one enalapril 10 and 20 of mg. / 10 mg of a lerkanidipin and 20 mg of enalapril / 10 mg of a lerkanidipin do not apply the fixed Koripren's combination of 10 mg of enalapril to initial treatment of AG.
Adults. Tablets apply orally, the recommended dose — 1 tablet of 1 times a day. Drug should be accepted not later than 15 min. to food, it is desirable in the morning. The dose is selected individually. Increase in a dose should be carried out not more often than 1 time to 2 weeks. The maximum daily dose of enalapril should not exceed 40 mg, a lerkanidipin — 20 mg. This drug should not be used along with grapefruit or grapefruit juice.
Patients of advanced age. The dose should be korrigirovat taking into account a functional condition of kidneys and the patient's liver. Extra care is required in an initiation of treatment.
Dosing at a renal failure: Koripren of 10 mg of enalapril / 10 to mg of a lerkanidipin and 20 mg of enalapril / 10 to mg of a lerkanidipin is contraindicated to patients with a renal failure. With care appoint Koripren to persons with a renal failure moderate or moderate severity (clearance of creatinine> of 30 ml/min.). Koripren of 10 mg of enalapril / 10 to mg of a lerkanidipin is contraindicated to patients with a heavy renal failure (clearance of creatinine <30 ml/min.) and to the persons which are on a hemodialysis. The maximum daily dose — 1 tablet of Koripren of 10 mg of enalapril / 10 mg of a lerkanidipin.
Dosing at a liver failure. Koripren is contraindicated to patients with a heavy abnormal liver function. It is necessary to appoint with care drug to patients with an abnormal liver function of moderate or average degree.

Features of use:

Symptomatic hypotension
Special careful control at enalapril reception is necessary:

• at heavy arterial hypotension with the systolic ABP <90 mm of mercury.;
• at dekompensirovanny heart failure.
Patients from uncomplicated AG have a symptomatic hypotension — an unusual occurrence. At patients from AG applying enalapril, symptomatic hypotension is noted if they reduced OTsK, for example, as a result of therapy by diuretic medicines, an electrolyte-deficient diet, dialysis, diarrhea or vomiting. At persons with heart failure (connected or untied with a renal failure) symptomatic hypotension is also noted. Symptomatic hypotension is probably possible at patients with the heavy heart failure noted at use of high doses of loopback diuretics, a hyponatremia or a renal failure. At these patients therapy should be begun under control of the doctor, and they have to observe accurately the treatment mode every time when the dose of enalapril and/or diuretic means changes. Similar cautions are necessary for patients with an ischemic heart disease or cerebrovascular diseases at which excessive decrease in the ABP can lead to a myocardial infarction or a stroke. In case of developing of arterial hypotension of the patient it is required to put on a back and if necessary to enter into isotonic solution in the form of infusion. Passing hypotensive reaction is not a contraindication to further purpose of drug in the corresponding dosing when the ABP raises after physical increase in OTsK. At some patients with heart failure with the normal or low ABP at reception of enalapril additional decrease in the general ABP can be noted. This effect can be predicted and, as a rule, is not the reason of cancellation of treatment. If arterial hypotension becomes symptomatic, there can be a need for a dose decline and/or cancellation of diuretic means and/or enalapril.

Syndrome of weakness of a sinus node
With care it is necessary to appoint drug at patients with a syndrome of weakness of a sinus node (if the pacemaker is not implanted).
Dysfunction of a left ventricle and ischemic heart disease
In spite of the fact that controlled researches of a hemodynamics did not show dysfunction of ventricles, it is necessary to use with care drug at treatment of patients with dysfunction of a left ventricle. It is authentically known that use of some dihydropyridines of short-term action can be associated with the increased cardiovascular risk at patients with an ischemic heart disease. Though лерканидипин is drug of the prolonged action, it is necessary to show care at its use. In the rare occurences of use of some dihydropyridines there can be precardiac pain or stenocardia. Very seldom patients with the previous stenocardia can feel increase in frequency, duration or weight of such attacks. The isolated myocardial infarction cases are possible.

Use at a renal failure
Koripren is contraindicated to patients with a renal failure (clearance of creatinine <30 ml/min.) and to patients who were on a hemodialysis. Extra care is necessary at purpose of enalapril for patients with the insignificant or moderated renal failures. Continuous monitoring of potassium and calcium in a blood plasma is a part of medical care to these patients.
The message on the renal failure connected using enalapril concerned mainly patients with heavy heart failure or a basic disease of kidneys, including a renal artery stenosis. At timely diagnosis and the corresponding treatment the renal failure caused by enalapril use is reversible. With AG without the previous disease of kidneys association of enalapril with diuretic medicine can cause increase in level of urea and creatinine in a blood plasma in some patients. The dose decline of enalapril and/or cancellation of diuretic drug can be necessary. In such cases it is necessary to consider a possibility of a renal artery stenosis.

Renovascular hypertensia
Patients with a bilateral renal artery stenosis or a stenosis of an artery of the only functioning kidney are especially inclined to risk of development of arterial hypotension or renal failure at therapy by APF inhibitors. Such patients need to begin treatment under direct medical control with low doses and to carefully raise them. Function of kidneys should be estimated in an initiation of treatment and to control accurately during therapy.
Renal transplantation
The patients who recently transferred transplantation of kidneys have no experience of use of a lerkanidipin or enalapril. It is not recommended to apply Koripren at such patients.

Liver failure
The hypotensive effect of a lerkanidipin can amplify at patients with the broken function of a liver. Occasionally at treatment APF inhibitors note a syndrome which begins cholestatic jaundice and progresses to the sudden and quickly developing liver necrosis (sometimes lethal). The mechanism of development of this syndrome is unknown. Patients at whom jaundice developed or considerably the level of liver enzymes at reception of APF inhibitors increased, have to stop reception of APF inhibitors, they need to appoint the corresponding treatment.

Neutropenia/agranulocytosis
At the patients accepting APF inhibitors the neutropenia/agranulocytosis, thrombocytopenia and anemia is noted. The neutropenia arises in rare instances at patients with normal renal function and without special risk factors. Enalapril should be applied with extra care at the persons with vascular collagenoses accepting immunodepressive medicines, Allopyrinolum, procaineamide or with several of these risk factors, especially at the previous renal failure. At some of these patients serious infections which sometimes do not react to intensive use of antibiotics are noted. At use of enalapril for such patients it is regularly recommended to control a leukocytic formula, and patients should be instructed concerning need to report to the doctor about any symptoms of an infection.
Hypersensitivity / Quincke's disease
It was reported about cases of a Quincke's disease (Quincke's edema) with distribution on a face, extremities, lips, language, a glottis and/or a throat at the patients applying treatment by APF inhibitors including enalapril. It can happen during any period of treatment. In such cases it is necessary to stop enalapril reception immediately. Patients have to be under careful control to an extract from a hospital to be convinced that symptoms completely disappeared. Namely in case of a swelling of the person and lips, symptoms, as a rule, pass in cases of restriction of places of manifestation of symptoms without therapy. However use of antihistaminic drugs is important for reduction of expressiveness of these symptoms. The Quincke's disease which extended to a throat can become lethal. When language, glottises or a throat are struck, and there is probable a possibility of obstruction of respiratory tracts, it is necessary to appoint urgently the corresponding treatment (for example hypodermic introduction of Epinephrinum [cultivation 1:1000]) and/or to take measures which will provide intake of air in respiratory tracts. According to messages, at reception of APF inhibitors the frequency of emergence of a Quincke's edema at patients of negroid race is much higher in comparison with patients of other races. At patients in whose anamnesis there is a Quincke's disease which is not connected with APF inhibitor reception the risk of development of a Quincke's disease can be much higher if they receive APF inhibitor.
Anaphylactic reactions during desensitization by poison of Hymenoptera
Anaphylactic reactions, life-threatening, happen seldom during the desensibiliziatsionny therapy directed against poisons of Hymenoptera and accompanying APF inhibitor use. These reactions can be avoided in case of temporary cancellation of APF inhibitor before each desensitization.

Anaphylactic reactions during LPNP-aferez
Anaphylactic reactions, life-threatening, seldom arise at LPNP-aferez using sulfate of a dextran and the accompanying APF inhibitor use. These reactions can be avoided in case of temporary cancellation of APF inhibitor before each aferez.
At patients who are on dialysis with use of membranes of high capacity (for example AN 69) and applied at the same time APF inhibitor, anaphylactoid reactions in certain cases developed. Therefore at them recommend to apply dialysis membranes of other type or antihypertensives of other group.
Cough. Due to the use of APF inhibitors there is cough. As a rule, it is the dry and persistent cough disappearing after therapy cancellation. The cough caused by APF inhibitor needs to be considered also at the differentiated diagnosis of cough.
Surgical intervention / anesthesia
At patients to whom carried out surgical intervention or anesthesia at reception of medicines, the reducing ABP, enalapril inhibits formation of angiotensin II that can lead to compensatory secretion of a renin. If arterial hypotension develops as a result of this mechanism, it can be eliminated with physical increase in OTsK.
Hyperpotassemia. At some patients accepting APF inhibitors including enalapril, increase in potassium in a blood plasma is noted. Risk factors of development of a hyperpotassemia are: a renal failure, a diabetes mellitus, the accompanying treatment by kaliysberegayushchy diuretic medicines, additives of potassium or kaliysoderzhashchy salts, the accompanying treatment by other drugs causing increase in indicators of plasma potassium (for example heparin). If the accompanying use of one of the above-stated substances takes place, it is necessary to carry out regular monitoring of plasma potassium.

Ethnic differences
As well as in a case with other APF inhibitors, enalapril is less effective for decrease in the ABP at patients of negroid race in comparison with persons of Caucasian race in connection with renin level in a blood plasma which it is frequent in population of patients with AG of negroid race much lower.

Lactose. Patients with hereditary intolerance of a galactose, deficit of lactase of Lapp or a syndrome of insufficiency of absorption of glucose galactose should not appoint Koripren.
Use during pregnancy and feeding by a breast
During pregnancy and feeding by a breast Koripren's use is contraindicated.
Women of reproductive age have to apply appropriate means of contraception during treatment by drug Koripren.
Fertility. Reversible biochemical changes in heads of spermatozoa which can break fertilization at some patients undergoing treatment by blockers of calcium channels are noted. In cases when repeated fertilisations of in vitro were unsuccessful and when it does not have other explanations, the possible reason consider blockers of calcium channels.

Children
Efficiency and safety of use of Koripren for children are not established. Drug is not used in pediatric practice.

Ability to influence speed of response at control of vehicles or work with mechanisms
Considering a possibility of development of such side reactions as dizziness, a loss of consciousness, arterial hypotension, muscular spasms, confusion of consciousness, drowsiness, a sight illegibility, it is necessary to refrain from control of vehicles and work with mechanisms.

Side effects:

Side effects of the combined drug are similar to those which are noted at reception of its active ingredients separately.
The undesirable reactions registered during clinical trials are given in the table below. The class of system of bodies for MedDRA and frequency of emergence are such: very often (> 1/10), it is frequent (≥1/100 — <1/10), sometimes (≥1/1000 — <1/100), is rare (≥1/10 000 — <1/1000), is very rare (<1/10 000) and unknown (it is impossible to define according to the available data).

Class of system of bodies	Often (≥1/100 — <1/10)	Sometimes (≥1/1000 — <1/100)
Disturbances from immune system		Quincke's disease *, hypersensitivity
Disturbances from circulatory and lymphatic system		Thrombocytopenia
Disturbances from metabolism and the alimentary system		Gipertriglitseridermiya *
Mental disturbances		Fear *
Disturbances from TsNS	Headache, dizziness (including caused by position of a body)
Disturbances from cardiovascular system		The accelerated heartbeat, tachycardia *
Vascular disorders	Rush of blood to the person	Hypotension *, tsirkulyatorny collapse *
Disturbances from breath, thoracic and mediastinal disturbances	Cough	Pharyngolaryngeal pain *, dryness in a throat *
Disturbances from a GIT		Abdominal cavity pain, lock *, dyspepsia *, nausea *, defeat of language *
Disturbances from skin and hypodermic fabrics		Erythema *, dermatitis *, hypostasis of lips *, rash *, small tortoiseshell *
Skeletal and muscular disturbances and disturbances from connecting fabrics		Arthralgia *
Disturbances from an ear and a labyrinth	Dizziness, including position dizziness	Ear and labyrinth disturbances
Disturbances from kidneys and urinary tract		Nocturia *, polyuria *, pollakiuria *
Disturbances from a reproductive system and mammary glands		Erectile dysfunction *
Nonspecific disturbances and condition of an injection site	Peripheral hypostasis	Fatigue *, adynamy *, feeling of heat *
Laboratory indicators		Decrease in level of hemoglobin *, increase in ALAT, ASAT

* Only at 1 patient.
The side reactions concerning active ingredients of drug separately.
Enalapril
From system of blood and lymphatic system: sometimes — anemia (including aplastic and hemolitic forms); seldom — a neutropenia, thrombocytopenia, an agranulocytosis, damage of marrow, a panhemocytopenia, a lymphadenopathy.
From immune system: often — hypersensitivity; seldom — a Quincke's edema (a Quincke's disease of the person), hypostasis of extremities, lips, language, a glottis and/or throat, autoimmune disorders.
From metabolism and digestion: sometimes — a hypoglycemia (especially at patients with a diabetes mellitus), anorexia, nausea, diarrhea.
Mental disturbances: often — a depression; sometimes — confusion of consciousness, drowsiness, increased fatigue, subconscious state, sleeplessness, a hyperexcitability; seldom — abnormal dreams, a sleep disorder.
From TsNS: very often — dizziness; often — a headache; sometimes — paresthesia, a loss of consciousness, nervousness.
From an organ of sight: very often — a sight zatumanennost.
From an ear and disturbance of a labyrinth: sometimes — dizziness, a sonitus.
From heart: often — a myocardial infarction, perhaps, secondary in relation to excessive arterial hypotension at patients with high risk, arrhythmia, stenocardia, tachycardia; sometimes — the accelerated heartbeat.
From vascular system: often — arterial hypotension, unconsciousness, cerebrovascular disturbances, perhaps, secondary to excessive arterial hypotension at patients with high risk; sometimes — sudden face reddening, orthostatic hypotension, arterial hypotension; seldom — Reynaud's phenomenon.
From endocrine system: syndrome of disturbance of secretion of antidiuretic hormone.
From a respiratory organs, thoracic and mediastinal disturbances: very often — cough; often — диспноэ; sometimes — a rhinorrhea, faringorinoreyny pain and an asthma, a hoarseness, a bronchospasm / OH; seldom — pulmonary infiltrate, rhinitis, an allergic alveolitis / eosinophilic pneumonia.
From a GIT: very often — nausea; often — diarrhea, an abdominal pain, taste change; sometimes — impassability of intestines, pancreatitis, vomiting, dyspepsia, a lock, discomfort in a stomach, dryness in a mouth, a peptic ulcer; seldom — stomatitis, aphthous stomatitis, a glossitis; very seldom — a Quincke's disease of intestines.
From a liver and biliary tract: very seldom — a liver failure, hepatitis (hepatocellular or cholestatic) or a liver necrosis, a cholestasia (including jaundice).
From skin and hypodermic fabrics: often — rash; sometimes — a hyperhidrosis, an itch, urticaria, an alopecia; very seldom — a polymorphic erythema, Stephens's syndrome — Johnson, exfoliative dermatitis, a toxic epidermal necrolysis, a pemphigus, a pempigus, erubescence of the person. A symptomatic complex which can include all or some of below-mentioned symptoms: fever, a serositis, a vasculitis, миалгия / a miositis, arthralgia/arthritis, positive anti-nuclear antibodies, the raised blood sedimentation rate, an eosinophilia and a leukocytosis, rash, a photosensitivity or other dermatological manifestations, the increased sweating can be noted.
From connecting fabric and skeletal and muscular disturbances: sometimes — muscular spasms.
From kidneys and urinary tract: sometimes — a renal failure, renal damages, a proteinuria; seldom — an oliguria.
From a reproductive system and mammary glands: sometimes — erectile dysfunction; very seldom — a gynecomastia, impotence.
Nonspecific disturbances and condition of an injection site: very often — an adynamy; often — fatigue, thorax pain; sometimes — discomfort, disturbance of flavoring feelings, a language inflammation.
Laboratory indicators: often — increase in level of potassium and/or creatinine in blood; sometimes — increase in urea in blood, decrease in sodium in blood; seldom — decrease in hemoglobin, decrease in a hematocrit, increase in liver enzymes, increase in bilirubin in blood.
Lerkanidipin (monotherapy)
Side reactions are noted approximately at 1,8% of the patients who received treatment. The side reactions which are most often arising during controlled clinical trials — a headache, dizziness, peripheral hypostasis, tachycardia, the accelerated heartbeat and inflow of blood to the person. Each of the above-stated reactions was noted at <1% of patients.
From immune system: very seldom — hypersensitivity.
Mental disturbances: very seldom — drowsiness.
From TsNS: sometimes — a headache, dizziness.
From heart: sometimes — tachycardia, the accelerated heartbeat; very seldom — stenocardia.
From vascular system: sometimes — sudden face reddening; very seldom — a loss of consciousness.
From a GIT: seldom — nausea, dyspepsia, diarrhea, an abdominal pain, vomiting.
From skin and hypodermic fabrics: seldom — rash.
From connecting fabric and skeletal and muscular disturbances: very seldom — a mialgiya.
From kidneys and urinary tract: seldom — a polyuria.
Nonspecific disturbances and condition of an injection site: sometimes — peripheral hypostasis; seldom — an adynamy, fatigue.
In spontaneous messages such very rare side reactions are specified (<1/10 000): hypertrophy of gums, reversible increase in plasma level of hepatic transaminases, arterial hypotension, frequent urination and thorax pain.

Interaction with other medicines:

The hypotensive effect of Koripren can be potentiated by other medicines, the reducing ABP, such as diuretic medicines, blockers α-, β-adrenoceptors, etc.
Besides, below-mentioned interactions with active ingredients which are a part of the combined product are noted.

Not recommended combinations
Enalapril maleate
The hyperpotassemia can be promoted by some active agents or therapeutic classes: potassium salts, kaliysokhranyayushchy diuretic lekarstenny means, APF inhibitors, inhibitors of angiotensin II, NPVP, heparins (with a low molecular weight or unfractionated), cyclosporine and такролимус, Trimethoprimum.
Kaliysberegayushchy diuretic medicines or potassium additives
APF inhibitors reduce the potassium loss caused by diuretic means. Kaliysberegayushchy diuretic means (for example Spironolactonum, Triamterenum or amiloride), can lead the potassium additives or substances containing potassium salts to substantial increase of level of potassium in a blood plasma. At the accompanying their use at the expressed hypopotassemia it needs to be carried out with care and at frequent monitoring of plasma potassium.

Lithium
During the accompanying administration of lithium with APF inhibitors reversible increase in concentration of plasma lithium and increase in toxic effects was noted. The accompanying use of thiazide diuretic medicines can increase concentration of plasma lithium and risk of lithium intoxication at use with APF inhibitors. Therefore use of enalapril with lithium is not recommended, but if the combined use is necessary, the level of plasma lithium has to be under strict control.

Estramustinum
There is a risk of increase in side reactions, such as a Quincke's disease.

Lerkanidipina hydrochloride
CYP 3A4 inhibitors
As лерканидипин it is metabolized by CYP 3A4 enzyme, at simultaneous administration of inhibitors and stimulators of CYP 3A4, at metabolism and excretion of a lerkanidipin there can be an interaction. The combined use of a lerkanidipin and strong CYP 3A4 inhibitor (for example a ketokonazola, an itrakonazola, a ritonavira, erythromycin, a troleandomitsin) is contraindicated. The interaction research with ketokonazoly, strong CYP 3A4 inhibitor, showed noticeable increase in level of a lerkanidipin in a blood plasma (15-fold increase in AUC and 8-fold increase in Cmax of S-lerkanidipina isomer).

Cyclosporine
Cyclosporine and лерканидипин it is not necessary to be applied combined. After simultaneous use of these medicines increase in concentration in a blood plasma of both drugs is noted. Researches did not show changes in levels of a plasma lerkanidipin at healthy volunteers when cyclosporine was applied in 3 h after reception of a lerkanidipin, but AUC cyclosporine raised to 27%. The general introduction of a lerkanidipin with cyclosporine led to increase by 3 times of level of a lerkanidipin in a blood plasma and to increase in AUC cyclosporine for 21%.

Grapefruit juice
Lerkanidipin it is not necessary to accept with grapefruit juice (see CONTRAINDICATIONS).
As well as in a case with other dihydropyridines, metabolism of a lerkanidipin can be inhibited by the use of grapefruit juice which leads to increase in system availability of a lerkanidipin and hypotensive effect.

The combinations demanding careful appointment
Enalapril maleate
Anti-diabetic medicines
During the epidemiological researches there was an assumption that administration of APF inhibitors and anti-diabetic drugs (insulin, peroral anti-diabetic drugs) can lead to decrease in level of glucose in blood and to risk of development of a hypoglycemia. These cases are noted in the first weeks of the combined use of the above-stated drugs for patients with renal disturbances.
Diuretic medicines (tiazida or loopback diuretic medicines)
The previous treatment by high doses of diuretic medicines can lead to decrease in OTsK and risk of development of arterial hypotension in case of an initiation of treatment enalapril. The hypotensive effect can be reduced if to cancel diuretic drugs, to korrigirovat decrease in OTsK, to appoint salts or to begin therapy with a low dose of enalapril.

NPVP
Long treatment of NPVP can reduce anti-hypertensive effect of APF inhibitor. NPVP and APF inhibitors which have additional effect on increase in plasma potassium can lead to deterioration in function of kidneys. It is usually reversible. In rare instances OPN can be noted, especially patients with disturbance of renal function have patients of advanced age or dehydrated.

Baclofenum
At the combined use increase in hypotensive effect is noted. Monitoring of the ABP and correction of an anti-hypertensive dose are carried out as necessary.

Cyclosporine
Cyclosporine increases risk of a hyperpotassemia at the combined use with APF inhibitors.

Alcohol
Alcohol strengthens hypotensive effect at the combined use with APF inhibitors.

Lerkanidipina hydrochloride
Alcohol
It is necessary to avoid alcohol intake as it can exponentiate effect of vasodilating hypotensive medicines.

CYP 3A4 substrates
It is necessary to be careful at the combined purpose of a lerkanidipin with other CYP 3A4 substrates, such as терфенадин, астемизол, antiarrhytmic medicines III of a class (for example Amiodaronum, quinidine).

CYP 3A4 stimulators
To the combined use of a lerkanidipin with CYP 3A4 stimulators, such as anticonvulsant medicines (for example Phenytoinum, carbamazepine) and rifampicin, it is necessary to approach with care as the hypotensive effect of a lerkanidipin can be reduced. In such cases monitoring of the ABP is required to be carried out much more more often than usually.

Digoxin
The combined use of 20 mg of a lerkanidipin for patients who take a long course of treatment β-methyldigoxin did not show cases of pharmacokinetic interaction. Healthy volunteers who received therapy by digoxin after introduction of 20 mg of a lerkanidipin showed average increase in Cmax of digoxin for 33% whereas neither AUC, nor renal clearance had no considerable changes. Patients at the combined use of digoxin have to be under strict control of rather clinical signs of digoksinovy intoxication.

Combinations which should be considered
Enalapril maleate
Amifostin
At the combined use increase in hypotensive effect is noted.
Tricyclic antidepressants / antipsychotic medicinal means / the anesthetizing medicinal means / narcotic medicines
The combined use of some anesthetics of medicines, tricyclic antidepressants and antipsychotic medicines with APF inhibitors can lead to further decrease in the ABP.
Corticosteroids, тетракозактид (system), except for a hydrocortisone which is applied at replacement therapy of a disease of Addison.
At the combined use decrease in hypotensive effect is noted (a corticosteroid - the induced water salt/delay in an organism).
Other hypotensive medicines
The combined use with other hypotensive medicines can lead to increase in hypotensive effect of enalapril. Simultaneous use of nitroglycerine and other nitrates or other vasodilating medicines can lead to further decrease in the ABP.
Allopyrinolum, cytostatic or immunosuppressive medicines, system corticosteroids or procaineamide
The accompanying administration of the above-stated drugs with APF inhibitors can lead to increase in risk of a leukopenia.

Antacids
Antiacid medicines lead to decrease in biological availability of APF inhibitors.
Sympathomimetic medicines
Sympathomimetic medicines can reduce anti-hypertensive effect of APF inhibitors. Decrease in effect of amines, повышающихт the ABP is possible (for example Epinephrinum).

Acetylsalicylic acid and thrombolytic medicines
Enalapril can be applied at the same time with acetylsalicylic acid (in the corresponding dose to cardiovascular prevention) and thrombolytic medicines.
Gold drugs
Nitrite reactions (the symptoms including rush of blood to the person, vomiting, nausea and arterial hypotension) are seldom noted at patients who receive treatment by injections of drugs of gold (sodium ауротиомалат) and the accompanying therapy by APF inhibitors, including enalapril.

Lerkanidipina hydrochloride
Midazolam
At volunteers of advanced age the combined use of midazolam orally in a dose of 20 mg increases absorption of a lerkanidipin (almost to 40%) and reduces the speed of its absorption (Tmax from 1,75 to 3 h were reduced). Changes in concentration of midazolam were not noted.

Metoprolol
At the combined use of a lerkanidipin and metoprolol (blockers of β-adrenoceptors, which eliminirutsya preferential by a liver) bioavailability of a metoprolol did not change whereas bioavailability of a lerkanidipin decreased to 50%. This effect can be a consequence of decrease in the blood-groove in a liver caused by blockers of β-adrenoceptors, and it can happen to other drugs of this class. However лерканидипин it is possible to apply safely combined with blockers of β-adrenoceptors..........

Cimetidinum
The combined use of Cimetidinum in a dose of 800 mg/days does not cause considerable modifications of level of a lerkanidipin in a blood plasma, but extra care at purpose of high doses as bioavailability of a lerkanidipin and its hypotensive effect can increase is necessary.

Fluoxetine
The interaction research with fluoxetine (as CYP 2D6 and CYP 3A4 inhibitor) which conducted with the assistance of healthy volunteers at the age of 65±7 years (average возраст±стандартное a deviation), did not show clinically significant modification of pharmacokinetics of a lerkanidipin.

Simvastatin
When лерканидипин in a dose of 20 mg repeatedly at the same time applied from 40 mg of a simvastatin, AUC of a lerkanidipin changed slightly whereas AUC of a simvastatin raised to 56% and AUC of its main active metabolite, β-hydroxyacid — — to 28%. It is improbable that such changes are clinically significant. Interaction if лерканидипин accept in the morning, and симвастатин — in the evening, as shown for medicines of this group is not expected.

Warfarin
The combined use of a lerkanidipin in a dose of 20 mg on an empty stomach to healthy volunteers did not lead to change of pharmacokinetics of warfarin.

Contraindications:

• hypersensitivity to any active ingredient (enalapril or a lerkanidipin), any APF inhibitor or a dihydropyridinic blocker of a calcium channel, or to any other component of medicine;
• obstruction of outflow from a left ventricle, including at an aorta stenosis;
• uncured congestive heart failure;
• unstable stenocardia;
• use for 1 month after a myocardial infarction;
• a heavy renal failure (clearance of creatinine <30 ml/min.), including at patients who are on a hemodialysis;
• heavy liver failure;
• at the accompanying reception: strong CYP 3A4 inhibitors; cyclosporine; grapefruit juice;
• existence in the anamnesis of the Quincke's disease connected with the previous treatment by APF inhibitors;
• hereditary or idiopathic Quincke's disease.

Overdose:

To today about cases of overdose by Koripren it was not reported. The most probable symptoms of overdose are arterial hypotension, bradycardia, reflex tachycardia, shock, a stupor, disturbance of electrolytic balance and a renal failure, myocardium ischemia, cardiogenic shock, drowsiness.
Therapy at overdose
Treatment is generally directed to elimination of the acting agents and recovery of a stable cardiovascular state. After oral administration the plentiful gastric lavage is shown.
Enalapril overdose cases
About overdose of enalapril at the person only limited data are available.
Overdose symptoms known for today — the expressed arterial hypotension (begins approximately in 6 h after administration of drug), which blockade accompanies a renin-angiotenzinovoy of system and a stupor. Symptoms which are associated with overdose of APF inhibitors can include disturbance of a hemodynamics, electrolytic balance, a renal failure, a hyperventilation, tachycardia, the accelerated heartbeat, bradycardia, dizziness, feeling of fear and cough. Enalapril level in a blood plasma in 100 and 200 times is higher, than usually after reception of a therapeutic dose, according to messages, after reception of 300 and 440 mg of enalapril respectively.
Treatment: in/in infusion of physiological solution. If necessary do angiotensin II infusion. If arterial hypotension is noted, the patient it is necessary to put as at shock and to carry out a symptomatic treatment. If administration of drug was carried out recently, it is necessary to take measures for maleate enalapril elimination (vomiting, a gastric lavage, reception of the absorbing agents or sodium sulfate). Enalapril can be removed from the patient's blood by a hemodialysis. Indicators of the vital functions, electrolytes and creatinine of a blood plasma should be controlled constantly.
Cases of overdose of a lerkanidipin
Symptoms. As well as in cases with other dihydropyridines, the overdose of a lerkanidipin can cause an excessive peripheral vazodilatation with noticeable arterial hypotension and reflex tachycardia. It was reported about 3 cases of overdose (150; 280 and 800 mg of a lerkanidipin were accepted in attempt of implementation of a suicide). At patients drowsiness, cardiogenic shock with heavy ischemia of a myocardium and an insignificant renal failure, vomiting and arterial hypotension is recorded.
Treatment: to wash out a stomach; high doses of catecholamines, furosemide, foxglove and parenteral plasma substitutes; absorbent carbon, purgatives and in/in a dopamine. In case of heavy arterial hypotension, bradycardia and a loss of consciousness therapy by the atropine entered in/in for counteraction of bradycardia will be useful. Considering long pharmacological action of a lerkanidipin, a condition of the patient who accepted an overdose, it is necessary to control not less than 24 h. There is no information concerning efficiency of dialysis. As drug has high lipophilicity, it is very improbable that the level of a lerkanidipin in a blood plasma was the proof of continuation of a phase of risk. Dialysis is inefficient.

Storage conditions:

In original packaging for protection against light and moisture at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

Tab. п / captivity. cover of 10 mg + 10 mg blister, No. 28
 
Tab. п / captivity. cover of 20 mg + 10 mg blister, No. 28.