Pharmacological properties

Pharmakodinamichesky parameters. the combined medicament koripren contains inhibitor apf enalapril (10 or 20 mg) and the antagonist of calcium lerkanidipin (10 mg), rendering complementary hypotensive effect.

Efficiency of the fixed combination of enalapril and a lerkanidipin in decrease in systolic and diastolic arterial blood pressure in comparison with monotherapy is proved to

by results of clinical trials.

Enalapril is dikarbotsilsoderzhashchy peptide with antihypertensive activity. Being pro-medicine, enalapril turns by a deesterifikation into an active form — enalaprilat which competitively communicates and inhibits APF, thereby blocking transformation of angiotensin I into angiotensin II. It prevents strong vasoconstrictive effect of angiotensin II and leads to a vazodilatation. The affinity of enalaprilat to APF is about 200,000 times higher, than at angiotensin I, and 300-1000 times above, than at enalapril. Enalapril also reduces the secretion by bark of adrenal glands of Aldosteronum induced by angiotensin II that leads to increase in excretion of sodium and, respectively, water outflow.

Hypotensive effect of a single oral dose of enalapril of a maleate is usually shown by

during 1 h and is maximum in 4–8 h. The hypotensive effect of usual doses of medicament usually remains during 12–24 h the ABP at use of enalapril decreases against the background of decrease in OPSS and increase in warm emission (perhaps slight increase of ChSS) and a renal blood-groove (SKF does not change or raises in case of its low values prior to therapy).

At patients with pathology of kidneys or diabetes during use of enalapril the severity of an albuminuria, proteinuria and excretion with IgG urine decreases.

Fast increase in the ABP level does not occur at the sharp termination of intake of enalapril.

Lerkanidipin inhibits inflow of extracellular calcium through cell membranes of a myocardium and unstriated muscles of vessels. Decrease in concentration of calcium in a cell leads to decrease in sokratitelny ability of unstriated muscles of a myocardium, causes expansion of coronary and system arteries that promotes increase in delivery of oxygen to myocardium tissue, decrease in OPSS, the system ABP and an afterload.

Vasodilating effect of a lerkanidipin develops gradually, with prolongation of antihypertensive action. Lerkanidipin as monotherapy or in combination with enalapril at repeated introduction does not cause the sympathetic activation secondary in relation to a peripheral vazodilatation. This aspect has important clinical value, considering that the sympathetic overload can be connected with development and progressing of injury of a target organ and cardiovascular events in patients with a hypertension.

Lerkanidipin increases bioavailability NO and an endoteliyzavisimy vazodilatation at patients with a hypertension. It also reduces the maintenance of markers of an oxidizing stress. Besides, medicament inhibits proliferation of cells of a neointima and unstriated muscles of vessels and also accumulation of cholesterol due to decrease in quantity of active forms of oxygen in cells. At patients with a hypertension lerkanidipin reduces quantity of leukocytes in blood plasma, SRB, E- and P-selectin, a lipoprotein (a) and the molecules of intracellular adhesion participating in trombotichesky process and damage of vessels/fabrics.

lerkanidipin expands with

at the level of kidneys both afferent, and efferent glomerular arteries, at the same time intra glomerular capillary pressure remains invariable.

Pharmacokinetic parameters. Changes of pharmacokinetic parameters of enalapril and a lerkanidipin at their combined use it is not established.

enalapril Pharmacokinetics. Enalapril the maleate is well soaked up after intake. About 55-75% of orally entered maleate enalapril dose quickly are soaked up in a GIT at healthy people and patients with a hypertension. Food significantly does not influence the speed or extent of absorption of enalapril of a maleate.

C _max in blood plasma is reached during about 1 h after oral administration of enalapril.

Stable concentration of enalaprilat in blood plasma are reached by

later 4 days at patients with normal function of kidneys.

About 50-60% of enalaprilat contact proteins of blood plasma.

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About 60% of an absorbed dose of enalapril it is intensively hydrolyzed by means of esterases to enalaprilat, mainly in a liver. About 20% are hydrolyzed at the first passing through a liver. Hydrolysis of enalapril to enalaprilat can be delayed and/or broken at patients with a heavy liver failure.

Effective the T _½ for accumulation of enalaprilat averages about 11 h at patients with normal function of kidneys. Patients with clearance of creatinine have 30 ml/min. effective T _½ increases.

Enalapril badly gets through GEB; gets through a placenta, it is distributed in milk in trace quantities.

enalapril and enalaprilat are removed by

After intake with urine and a stake. At healthy people on average of 60-78% (43–56% in the form of enalaprilat and the rest in the form of not changed medicine) enalapril of a maleate also about 33% (about 27% in the form of enalaprilat and 6% in not changed look) — with a stake during 24–48 h after introduction of a dose of 10 mg are removed with urine.

Renal clearance of enalapril can be reduced by

at patients with a hypertension. At elderly people the renal clearance and/or volume of distribution can also decrease.

Pharmacokinetics of a lerkanidipin. After oral introduction lerkanidipin it is well soaked up in a GIT. Absorption of a lerkanidipin increases at meal with the high content of fats therefore it should be accepted before food. The C _max is reached during about 1.5-3 h Lerkanidipin has high linking with proteins of blood plasma (98%) and quickly collects in membranes of arteriolar cells.

At patients with a hypertension average final the T _½ after single oral administration in a dose of 10-20 mg makes 8-10.5 h. Despite short T _½ in blood plasma, pharmakodinamichesky action covers 24 h. The high coefficient of membrane division of a lerkanidipin provides long-term effect at the level of receptors and membranes, allowing to enter it 1 time a day.

Lerkanidipin is metabolized by

in a liver of CYP 3A4 and turns into inactive metabolites which are removed with urine (50%) and a stake.

Pharmacokinetic properties of a lerkanidipin do not change depending on age, presence of a slight or moderate liver or renal failure.

Indication

Pervichnaya ag.

Use

Per os 1 tablet a day, generally in the morning (before a breakfast in ≥15 min.).

Contraindication

Hypersensitivity to any active pharmaceutical ingredient, any inhibitor apf either to the antagonist of calcium of a dihydropyridinic row, or any other component of drug; a Quincke's edema (idiopathic, hereditary or postponed in connection with use of inhibitors apf); pregnancy or its planning; the combined reception with the medicaments containing aliskiren against the background of diabetes or a renal failure (skf 60 ml/min. / 1.73 sq.m); obstacle to outflow of blood from a left ventricle; heart failure on a big circle of blood circulation (at the patients who were not receiving treatment in this occasion); stenocardia (unstable form); the postponed myocardial infarction (within 1 month); the profound renal failure (clearance of creatinine of 30 ml/min.), as well at the patients receiving treatment by a hemodialysis; profound abnormal liver function; combined use of cyclosporine, strong inhibitors of suras 3a4, grapefruit juice.

Side effects

Decrease in level of hemoglobin, thrombocytes (150 109/l); hypersensitivity; increase in content of potassium in blood; uneasiness; cephalalgia and dizziness (including postural), tinnitus; increase chss (90 ud. / mines), palpitation; decrease hell (90/60 mm Hg.), insufficientia vascularis; cough, dryness, sore throat; abdominal pain, nausea, constipation, dispeptic manifestations, hypostasis of lips, speech disorders, xerostomia, diarrhea, inflammation of a mucous membrane of gums; increase in activity of aminotransferases; Quincke's edema, face edema, dermatitis, rashes, urticaria; arthralgia; a pollakiuria, prevalence of a night part of a diuresis over day, the increased urine discharge; impotence; weakness, fatigue, peripheral hypostases, feeling of heat.

Special instructions

Koripren of 20 mg / 10 mg ag do not apply

to starting therapy.

Therapy of patients of advanced age is defined by a functional condition of kidneys.

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Needs discretion on start of therapy of patients with insufficiency of function of a liver or kidneys of light or moderate severity.

C discretion is appointed the ischemic heart disease patient or with pathology of vessels of a brain (excess decrease in the ABP can become the reason of development of a stroke or myocardial infarction) and also Short's syndrome without the implanted pacemaker and at patients with dysfunction of a left ventricle.

Secondary hypotension at treatment by enalapril is possible

at patients with heart failure. Medical observation by the patient with the profound heart failure against the background of decrease in content of sodium in blood, disorder of renal functions or therapy with loopback diuretics in high doses (risk of secondary hypotension) is required.

At reduction of OCK at the sick AG accepting enalapril the likelihood of developing secondary hypotension raises.

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in case of development of secondary hypotension perhaps will need a dose decline or cancellation of diuretic medicaments and/or enalapril.

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From patients with disorder of renal function of easy or moderate degree needs constant control of content in blood plasma of creatinine and potassium. Increase in content in blood plasma of creatinine and potassium can arise at a number of the sick AG which do not have pathology of kidneys in the anamnesis against the background of use of diuretic in a combination with enalapril.

Against the background of intake of enalapril the development of a renal failure (as a rule, at patients with pathology of kidneys or with the significant disturbance of warm function), reversible is possible

at medicament withdrawal.

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Needs scrupulous medical supervision of patients with a stenosis of a. renalis (bilateral or the only functioning kidney) receiving treatment by APF inhibitors in view of the probability of a renal failure or decrease in the ABP (90/60 mm Hg.). Treatment is begun with low doses with their gradual increase against the background of control of renal function.

should not be accepted Koripren the patient after transplantation of kidneys.

Patient with a diabetic nephropathy should not accept APF inhibitors in combination with aliskireny.

In case of need uses of APF inhibitors in a combination aliskireny or antagonists of angiotensin II are required for

observation of the doctor and scrupulous control of the ABP, content of electrolytes in blood plasma and also renal functions.

strengthening of antihypertensive action of a lerkanidipin at patients with disorder of hepatic functions Is possible

. Use of APF inhibitors stops at patients at increase in activity of aminotransferases or development of jaundice.

With discretion appoint enalapril sick with the collagenoses (with damage of the vascular system) receiving therapy by immunosuppressants, procaineamide or Allopyrinolum (regular monitoring of a leykogramma and caution concerning development of infectious diseases is required).

Probability of developing of a Quincke's edema against the background of use of APF inhibitor increases at patients with the Quincke's edema (which is not connected with use of medicaments of this group) in the anamnesis.

development of anaphylactoid reactions against the background of use of APF inhibitors in combination with the desensibilizing therapy (poison of insects) or LPNP-aferezom is In rare instances possible

(a dextran sulfate).

At the patients receiving APF inhibitors the developing of cough is possible

.

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At the beginning (1st month) of therapy by APF inhibitors from the patients with diabetes receiving insulin or per os glucose-lowering medicaments needs scrupulous monitoring of a glycemia.

in case of decrease in the ABP of 90/60 mm Hg. during the performing large surgery or use the lowering arterial blood pressures of anesthetics are carried out by actions for increase in OCK.

At use of APF inhibitors the development of a hyperpotassemia is possible

. Regular control of content of potassium in blood plasma in case of need of the combined use of enalapril with kaliysberegayushchy diuretics, additives to a food allowance or substitutes of salt containing potassium is required.

Hypotensive effect of enalapril is reduced by

at representatives of negroid race in comparison with the Caucasian.

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In view of lactose content medicament is contraindicated to patients with a galactosemia, a lactose intolerance or a sprue of glucose galactose.

Use of antagonists of calcium can cause reversible changes of spermatozoa and, respectively, fertilization process disturbance.

At development of pregnancy in the patients receiving Koripren, means is immediately cancelled.

during feeding by a breast Koripren is not applied.

to the Persons running vehicles or during the work with other mechanisms at Koripren's reception should consider the probability of emergence of fatigue, weakness, dizziness, drowsiness.

Interaction

was Investigated only at adults.

strengthening of antihypertensive effect of medicament at the combined use with other antihypertensives Is possible

.

Combined use of enalapril of a maleate with other APF inhibitors, aliskireny, antagonists of receptors of angiotensin II raises a likelihood of development of side effects (decrease in the ABP of 90/60 mm Hg., increase in level of potassium in blood, disorder of renal functions).

Removal of potassium from an organism caused by use of diuretics decreases at use of APF inhibitors. Use of kaliysberegayushchy diuretics, dietary additives with potassium or the substances containing salts of this macrocell in combination with enalapril a maleate can lead to a hyperpotassemia.

Combined use of diuretics (loopback or a thiazide row) at the beginning of therapy by enalapril can cause decrease in OCK and increase the probability of decrease in the ABP (90/60 mm Hg.).

Combined use of enalapril of a maleate with vazodilatator (including nitroglycerine drugs, other nitrates) can enhance hypotensive effect.

should not apply combined enalapril a maleate with lithium medicaments in view of increase in content in blood and, respectively, toxicity of the last. In case of need uses of the specified combination scrupulous control of content in lithium blood plasma is required.

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In rare instances at patients who received injections of sodium of the aurotiomalat and at the same time treatment by APF inhibitors (including enalapril) observed vasomotor reactions.

Combined use with inhibitors of enzyme of a mTOR-kinase can raise a likelihood of developing a Quincke's edema.

Antihypertensive effect of APF inhibitors are exponentiated by alcohol, anti-psychotics and also the means applied to anesthesia and tricyclic antidepressants.

Antihypertensive effect of APF inhibitors decreases at the combined use from adrenomimetika of indirect action, NPVP.

Combination to NPVP also promotes increase in content of potassium in blood and to possible disturbance of renal functions (it is rare — OPN).

probability of emergence of a hyperglycemia at a combination of APF inhibitors to glucose-lowering medicaments Increases, especially on start of such therapy and at patients with a renal failure.

is not applied lerkanidipin in combination with strong CYP inhibitors 3A4, cyclosporine or juice of grapefruit.

With discretion is applied lerkanidipin in combination with other CYP substrates 3A4.

In view of possible decrease in hypotensive action at a combination of a lerkanidipin to inductors CYP 3A4 (rifampicin, antikonvulsant) their simultaneous use demands more frequent control of the ABP of the patient.

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Because of strengthening of hypotensive effect did not recommend the combined reception of a lerkanidipin with alcohol; for the same reason the discretion at a combination to Cimetidinum in a dose of 800 mg/days is required (the bioavailability of a lerkanidipin increases).

absorption of a lerkanidipin Increases (with simultaneous delay of its speed) at the combined use with midazolam in a dose of 20 mg at elderly people.

scrupulous control of clinical manifestations of toxic effect of digoxin is necessary for

in case of simultaneous use of a lerkanidipin with digoxin.

Overdose

Excess use of enalapril is shown by decrease hell (90/60 mm Hg.) approximately later 6 h after reception and development of a stupor. at reception of an excess dose of inhibitors apf can note vascular shock, disturbance of balance of electrolytes, functions of kidneys, a hyperventilation, increase chss (90 ud. / mines) or decrease chss (60 ud. / mines), heartbeat, dizziness, concern and cough.

Carry out by

in to infusion 0.9% of NaCl solution. In case of decrease in the ABP (90/60 mm Hg.) give to the patient antishock position of a body; enter in into catecholamines or angiotensin II. At recent reception cause artificially vomiting, carry out gastric lavage, appoint adsorbents and Na ₂ SO ₄ . In case of decrease in ChSS, resistant to treatment (60 ud. / mines) apply a pacemaker. Carrying out a hemodialysis is effective. Continuous monitoring of content in blood plasma of creatinine and electrolytes, indicators of functions of vitals and systems is necessary.

Excess use of a lerkanidipin can be shown by overshot vasodilating effect in peripheral vascular network with significant decrease in the ABP (90/60 mm Hg.) and reflex increase in ChSS (90 ud. / mines).

use in/in atropine Is reasonable

. Carrying out dialysis not productively. Monitoring of a condition of the patient during 1 days

is recommended to

Storage conditions

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In the place inaccessible for children, at a temperature of ≤25 °C in original packing.