Ко-ренитек®

General characteristics. Structure:

Active ingredients: 20 mg of enalapril of a maleate, 12,5 mg of a hydrochlorothiazide.

Excipients: sodium bicarbonate, lactoses monohydrate (lactose water), starch corn, starch corn prezhelatinizirovanny, dye ferrous oxide yellow, magnesium stearate.

Pharmacological properties:

Pharmacodynamics. The combined anti-hypertensive drug which part are APF inhibitor (enalapril a maleate) and thiazide diuretic (hydrochlorothiazide). Has anti-hypertensive and diuretic effect.

Enalapril – APF inhibitor, the angiotensin I catalyzing transformation into pressor substance angiotensin II. After absorption enalapril 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 mechanism in therapeutic effect of enalapril demands specification. In spite of the fact that enalapril reduces the ABP by means of suppression renin-angiotensin-aldosteronovoy of system which plays an important role in regulation of the ABP, drug reduces the ABP even at patients with arterial hypertension with the low maintenance of a renin.

Decrease in the ABP is followed by decrease in OPSS, small increase in cordial emission and lack of changes or minor changes of ChSS. As a result of reception of enalapril the renal blood stream increases, the glomerular filtration rate remains not changed. However at patients with initially reduced glomerular filtering its speed usually increases.

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

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

Enalapril reception by patients with arterial hypertension leads to decrease in the ABP as a standing position, and in a prone position without significant increase in ChSS.

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 h after a single dose of a dose of enalapril inside. The beginning of anti-hypertensive action comes during 1 h, the maximum decrease in the ABP is observed in 4-6 h after administration of drug. Duration of action depends on a dose. However at use in the recommended doses anti-hypertensive action and hemodynamic effects remain during 24 h.

The hydrochlorothiazide has diuretic and anti-hypertensive effect, increases activity of a renin. Though enalapril in itself shows anti-hypertensive action even at patients with arterial hypertension against the background of low concentration of a renin, the accompanying use of a hydrochlorothiazide for such patients leads to more expressed decrease in the ABP.

Enalapril reduces the loss of potassium ions caused by use of a hydrochlorothiazide. Enalapril and a hydrochlorothiazide have the similar mode of dosing. Therefore Co-renitek represents a convenient dosage form for joint purpose of enalapril and a hydrochlorothiazide.

Use of a combination of enalapril and hydrochlorothiazide leads to more expressed decrease in the ABP in comparison with monotherapy by each drug separately and allows to keep anti-hypertensive effect of drug of Co-renitek at least during 24 h.

Pharmacokinetics. Enalapril. Absorption. After enalapril intake the maleate is quickly soaked up. Cmax of enalapril in blood serum is observed during 1 h after reception. After intake absorption makes about 60%.

Meal does not exert impact on enalapril absorption. Duration of absorption and hydrolysis of enalapril is similar for various recommended therapeutic doses.

After absorption enalapril is quickly hydrolyzed with formation of active agent of enalaprilat, APF powerful inhibitor. Cmax of enalaprilat in blood serum is observed in 3-4 h after reception of a dose of enalapril inside.

Removal. Enalapril is removed preferential by kidneys. The main metabolites defined in urine are the enalaprilat making about 40% of a dose, and not changed enalapril. Data on other significant ways of metabolism of enalapril, except for hydrolysis in enalaprilat, are not available. The curve of concentration of enalaprilat in a blood plasma has the long final phase caused, apparently, by its linkng 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. Enalaprilat T1/2 at course use of drug inside makes 11 h.

Hydrochlorothiazide. Metabolism and distribution. Is not exposed to metabolism. The hydrochlorothiazide gets through a placental barrier, but does not get through GEB.

Removal. T1/2 of a hydrochlorothiazide from 5.6 to 14.8 h. It is quickly removed by kidneys. Not less than 61% of the dose accepted inside are removed in not changed look during 24 h.

Combination of enalaprilat of a maleate and hydrochlorothiazide. Regular reception of a combination of enalapril and a hydrochlorothiazide does not influence or slightly influences bioavailability of each component of drug. Use of the combined tablet of drug of Co-renitek bioekvivalentno to a concomitant use of its ingredients in separate dosage forms.

Indications to use:

— treatment of arterial hypertension at patients to whom the combination therapy is shown.

Route of administration and doses:

Drug is appointed inside, irrespective of meal.

At arterial hypertension an initial dose - 1 таб. 1 times/days. In case of need the dose can be increased to 2 таб. 1 times/days.

At the beginning of Co-renitekom therapy development of symptomatic arterial hypotension, a thicket at patients with disturbances of water and electrolytic balance owing to the previous treatment by diuretics is possible. Therapy by diuretics should be stopped in 2-3 days prior to Co-reniteka use.

At patients with renal failures of a tiazida can be insufficiently effective, and at KK ≤ 30 ml/min. (i.e. at a renal failure of average and heavy degree) are inefficient.

At KK of 80-30 ml/min. of Co-renitek it is necessary to apply only after preliminary selection of doses of each of components.

At a renal failure of easy degree the recommended dose of enalapril of the maleate accepted separately makes from 5 mg to 10 mg.

Features of use:

Use at pregnancy and feeding by a breast. Use of drug of Co-renitek at pregnancy is not recommended. At the established pregnancy administration of drug should be stopped immediately.

Purpose of APF inhibitors in II and III trimesters of pregnancy can cause a disease or death of a fruit or the newborn. Negative influence of APF inhibitors on a fruit and the newborn is shown by arterial hypotension, a renal failure, a hyperpotassemia and/or a hypoplasia of a skull. Development of an oligogidramnion, apparently, owing to a fruit renal failure is possible. This complication can lead to a contracture of extremities, deformation of a skull, including its front part, to a hypoplasia of lungs.

Use of diuretics for women at pregnancy is not recommended as at the same time there is a risk of development of jaundice in a fruit and the newborn, thrombocytopenia and, perhaps, other side effects observed at adult patients.

If Co-renitek is appointed at pregnancy, then the patient should be warned about the existing potential risk for a fruit. In those exceptional cases when purpose of drug at pregnancy is considered necessary, it is necessary to conduct periodic ultrasonic examinations for assessment of a condition of a fruit, and also intraamniotichesky space.

Newborns, whose mothers accepted Co-renitek, should be observed carefully concerning development of arterial hypotension, an oliguria and a hyperpotassemia. Enalapril which gets through a placental barrier was removed from blood circulation of the newborn by means of peritoneal dialysis with some favorable clinical effect, theoretically it can be removed by means of exchange hemotransfusion.

Enalapril and tiazida, including hydrochlorothiazide, are emitted with breast milk. In need of use of drug in the period of a lactation breastfeeding should be stopped.

Use at abnormal liver functions. With care it is necessary to appoint drug at a liver failure.

Use at renal failures. At patients with renal failures of a tiazida can be insufficiently effective, and at KK less or equal 30 ml/min. (i.e. at the expressed renal failure) are inefficient.

At KK of 80-30 ml/min. of Co-renitek it is necessary to apply only after preliminary selection of doses of each of components.

At a moderate renal failure the recommended dose of enalapril of the maleate accepted separately makes from 5 mg to 10 mg.

Special instructions. During Co-renitekom treatment, as well as at Ljubo of anti-hypertensive therapy, development of symptomatic hypertensia is possible. Patients need to be inspected for the purpose of identification of clinical signs of disturbance of water and electrolytic balance, i.e. dehydration of an organism, a hyponatremia, a gipokhloremichesky alkalosis, a hypomagnesiemia or a hypopotassemia which can arise owing to episodes of diarrhea or vomiting. At such patients during therapy it is necessary to carry out periodic definition of electrolytic composition of blood through certain periods.

With extra care patients should appoint drug with an ischemic heart disease or cerebrovascular diseases since excessive decrease in the ABP can lead to development of a myocardial infarction or stroke.

At development of arterial hypotension the bed rest and in case of need - in/in introduction of normal saline solution is shown. Passing arterial hypotension at Co-reniteka appointment is not a contraindication to its further use. After normalization of the ABP and OTsK therapy can be resumed or in slightly reduced doses, or each of components of drug can be applied separately.

Patients should not appoint Co-renitek with a renal failure (KK <80 ml/min.) until selection of separate components of drug does not show that necessary doses for this patient are present at this dosage form.

Some patients without any symptoms of a disease of kidneys prior to treatment at therapy by enalapril in combination with diuretic had usually insignificant and passing increase in content of urea in blood and creatinine in serum. In such cases Co-renitekom treatment should be stopped. Further resuming of therapy in the reduced doses or purpose of each of drug components separately is possible.

As well as patients at whom outflow of blood from a left ventricle of heart is complicated should appoint all drugs possessing vazodilatiruyushchy action, APF inhibitors with care.

At some patients with a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney at treatment APF inhibitors observed increase in content of urea in blood and creatinine in serum. These changes had reversible character, as a rule, indicators were returned to norm after the treatment termination.

It is necessary to apply with care thiazide diuretics at patients with abnormal liver functions or with the progressing liver diseases as even little changes of water and electrolytic balance can lead to a hepatic coma.

When carrying out big surgeries or during the general anesthesia with use of the means causing arterial hypotension, enalaprilat blocks the formation of angiotensin II caused by compensatory release of a renin. If at the same time the expressed arterial hypotension explained with the similar mechanism it develops it is possible to adjust increase in OTsK.

Thiazide diuretics can be insufficiently effective at patients with a renal failure and are inefficient at KK ≤ 30 ml/min. (i.e. at a renal failure of average and heavy degree).

Thiazide diuretics are capable to cause disturbance of tolerance to glucose. Correction of doses of hypoglycemic drugs, including insulin can be required.

Thiazide diuretics can reduce calcium excretion with urine, and also cause slight and passing increase of content of calcium in serum. The expressed hypercalcemia can be a sign of the hidden hyperparathyreosis. Reception of tiazid should be stopped before carrying out a research of function of epithelial bodies.

Increase in levels of cholesterol and TG can be also connected with therapy by thiazide diuretics, however at the dose of a hydrochlorothiazide of 12.5 mg which is contained in 1 tablet of Co-reniteka similar effects either were not observed, or were insignificant.

Therapy of a tiazidama can lead to a hyperuricemia and/or gout at some patients. However enalapril can increase the content in urine of uric acid and by that to weaken giperurikemichesky effect of a hydrochlorothiazide.

At treatment by APF inhibitors, including enalapril a maleate, exceptional cases of a Quincke's disease of the person, extremities, lips, language, a glottis and/or throat were described. These reactions can arise at any stage of therapy. In such cases it is necessary to stop immediately reception of enalapril of a maleate and to establish careful observation of a condition of the patient for the purpose of control and correction of clinical symptoms. Even when only the paraglossa without hypostasis of respiratory bodies is observed, long observation as therapies can be antihistamines and corticosteroids insufficiently can be required by patients.

There are rare messages on the lethal outcome in connection with a Quincke's disease which is followed by hypostasis of a throat or a paraglossa. A paraglossa, a glottis or a throat can lead to obstruction of respiratory tracts, especially at the patients who transferred surgical interventions on a respiratory organs.

When hypostasis is localized in the field of language, a glottis or a throat that can lead to obstruction of respiratory tracts, it is necessary to enter immediately п / to 0.3-0.5 ml of 0.1% of solution of Epinephrinum (adrenaline) and to quickly provide passability of respiratory tracts.

At the patients of negroid race accepting APF inhibitors, the Quincke's disease was observed more often than at other patients.

At instructions in the anamnesis on the Quincke's disease which is not connected with reception of APF inhibitors the risk degree of development of a Quincke's disease against the background of therapy by APF inhibitors significantly increases.

At the patients receiving tiazida, allergic reactions can arise irrespective of existence in the anamnesis of allergic states or bronchial asthma. It was reported about a recurrence or aggravation of weight of a current of hard currency at the patients receiving tiazida.

In rare instances at the patients receiving APF inhibitors life-threatening anaphylactoid reactions developed during desensitization allergen from poison of Hymenoptera. Similar reactions can be avoided if prior to carrying out desensitization it is temporary to stop APF inhibitor reception.

Co-reniteka appointment is contraindicated to the patients with a renal failure who are on a hemodialysis. Anaphylactoid reactions were observed at the patients who are on dialysis with use of membranes with a high capacity (such as AN69) and receiving at the same time treatment by APF inhibitors. At these patients it is necessary to use dialysis membranes of other type or anti-hypertensive drugs of other classes.

Against the background of therapy of APF cough cases are noted. As a rule, cough dry, has constant character and disappears after the end of therapy. The cough connected using APF inhibitors should be considered at differential diagnosis of cough.

At co-administration elderly and younger patients had similar results of clinical trials of efficiency and portability of enalapril of a maleate and hydrochlorothiazide.

Use in pediatrics. Safety and efficiency of use of Co-reniteka for children are not established therefore use in pediatrics is not recommended.

Side effects:

At clinical trials side effects were usually moderate, passing and in most cases did not demand treatment interruption.

From cardiovascular system: 1-2% - orthostatic effects, including arterial hypotension; seldom - a faint, arterial hypotension irrespective of position of a body, heartbeat, tachycardia, stethalgias.

From TsNS and peripheral nervous system: often - dizziness, increased fatigue (usually passed at a dose decline and seldom demanded drug withdrawal); 1-2% - an adynamy, headaches; seldom - sleeplessness, drowsiness, a rotatory vertigo, paresthesias, a hyperexcitability.

From respiratory system: 1-2% - cough; seldom - an asthma.

From the alimentary system: 1-2% - nausea; seldom - pancreatitis, diarrhea, vomiting, dyspepsia, abdominal pains, a meteorism, a lock, dryness in a mouth.

From a musculoskeletal system: 1-2% - muscular spasms; seldom - an arthralgia.

Allergic reactions: seldom - a Quincke's disease of the person, extremities, lips, language, a glottis and/or throat. There are rare messages on development of a Quincke's disease of intestines in connection with reception of APF inhibitors, including enalapril.

Dermatological reactions: seldom - Stephens-Johnson's syndrome, a hyperhidrosis, skin rash, an itch.

From an urinary system: seldom - a renal failure, a renal failure.

From a reproductive system: 1-2% - impotence; seldom - decrease in a libido.

From laboratory indicators: the hyperglycemia, a hyperuricemia, hypo - or a hyperpotassemia, increase in concentration in blood of urea, serumal creatinine, increase in activity of liver enzymes and/or increase in serumal bilirubin are possible (these indicators were usually normalized after the termination of therapy of Co-renitekom); in some cases - decrease in hemoglobin and a hematocrit.

Others: seldom - a sonitus, gout. The symptom complex which possible manifestations are fever, a serositis, a vasculitis, a mialgiya, a miositis, arthralgia/arthritis, positive test for antinuclear antibodies, acceleration SOE, an eosinophilia and a leukocytosis is described; development of a photosensitization is possible.

Interaction with other medicines:

At purpose of enalapril in combination with other hypotensive drugs effect summation is possible.

Potassium loss which is caused by diuretics of a tiazidovy row, as a rule, decreases under the influence of enalaprilat. Potassium concentration in serum usually remains within norm.

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 serum.

Diuretics and APF inhibitors reduce lithium removal by kidneys and strengthen risk of development of intoxication by lithium. Lithium drugs are not appointed, as a rule, along with diuretics or APF inhibitors.

NPVS, including the selection TsOG-2 inhibitors, can reduce efficiency of diuretics and other anti-hypertensive drugs. Therefore reduction of hypotensive effect of APF inhibitors at co-administration with NPVS, including the selection TsOG-2 inhibitors is possible.

At the patients with renal failures receiving NPVS including the selection TsOG-2 inhibitors, at the accompanying reception of APF inhibitors perhaps further deterioration in function of kidneys. These changes are, as a rule, reversible.

Thiazide diuretics can strengthen effect of tubocurarine.

The hypotensive effect of drug is reduced by NPVS, estrogen, ethanol.

Immunodepressants, Allopyrinolum, cytostatics increase risk of development of a gematotoksichnost.

Contraindications:

— anury;

— the Quincke's disease in the anamnesis connected with appointment before APF inhibitors and also a hereditary or idiopathic Quincke's disease;

— hypersensitivity to drug components;

— hypersensitivity to other derivatives of sulfonamide.

With care it is necessary to appoint drug at an aortal stenosis, cerebrovascular diseases (including insufficiency of cerebral circulation), an ischemic heart disease, chronic heart failure, serious autoimmune general diseases of connecting fabric (including a system lupus erythematosus, a scleroderma), oppression of a marrowy hemopoiesis, a diabetes mellitus, a hyperpotassemia, a bilateral stenosis of renal arteries, a stenosis of an artery of the only kidney, a state after transplantation of a kidney, a renal and/or liver failure, against the background of a diet with sodium restriction, at the states which are followed by decrease in OTsK (including diarrhea, vomiting), to patients of advanced age.

Overdose:

Symptoms: the expressed arterial hypotension beginning approximately in 6 h after administration of drug and a stupor. After maleate enalapril reception in doses of 330 mg and 440 mg of concentration of enalaprilat in a blood plasma exceeded respectively in 100 and 200 times of its concentration at therapeutic doses.

At overdose of a hydrochlorothiazide the symptoms caused by a hypopotassemia, a hypochloraemia, a hyponatremia and dehydration owing to an excessive diuresis are most often observed. If earlier therapy was carried out by digitalis drugs, aggravation of a course of arrhythmia owing to a hypopotassemia is possible.

Treatment: Co-renitek should cancel; careful observation of the doctor is required. The gastric lavage is recommended if drug was accepted recently; carrying out a symptomatic and maintenance therapy for the purpose of correction of disturbances of water and electrolytic balance and arterial hypotension. Data on specific therapy of overdose are not available.

At overdose of enalapril of a maleate it is recommended in/in injection of normal saline solution, administration of angiotensin II is effective. Enalaprilat can be removed from system blood circulation by means of a hemodialysis.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity for tablets in blisters – 3 years, for tablets in bottles of high density – 2 years.

Issue conditions:

According to the recipe

Packaging:

7 pieces - blisters (2) - packs cardboard.
7 pieces - blisters (4) - packs cardboard.
56 pieces - bottles polyethylene (1) - packs cardboard.