Kasark of N

General characteristics. Structure:

Active ingredients: candesartancilexetil, hydrochlortiazide;

1 tablet contains a kandesartan of a tsileksetil, in terms of 100% substance, 16 mg and Hydrochlorthiazidum, in terms of 100% substance, 12,5 mg;

excipients: lactose, monohydrate; starch corn; povidone; calcium of a karmeloz (calcium carboxymethylcellulose); magnesium stearate; tartrazine (Е 102).

Pharmacological properties:

Pharmacodynamics. Angiotensin ІІ is primary vasoactive hormone system renin-angiotensin-aldosteronovoy, it plays a role in a pathophysiology of the arterial hypertension (AH), heart failure and other cardiovascular disturbances. The main physiologic effects of angiotensin ІІ, such as narrowing of blood vessels, stimulation of secretion of Aldosteronum, regulation of a salt and water homeostasis and stimulation of growth of cells, are mediated through a receptor of type 1 (AT1).

Kandesartan is an antagonist of a receptor of angiotensin ІІ, the selection dlyaat1-receptors, with strong linkng with a receptor and slow dissociation with it. Kandesartan does not inhibit an angiotensin-converting enzyme (APF) which turns angiotensin І into angiotensin ІІ and bradikinin destroys. There is no influence on APF and potentiation of bradikinin or substance P. When comparing a kandesartan with APF inhibitors development of cough occurred less often at patients who received кандесартан.

Kandesartan does not contact receptors of other hormones and does not block ion channels which, as we know, play a role in cardiovascular regulation. Antagonism of AT1-receptors leads to dozozavisimy increase in level of a renin of plasma, angiotensin levels І and angiotensin ІІ, and also to decrease in concentration of Aldosteronum in a blood plasma.

Hydrochlorthiazidum blocks a sodium reabsorption, mainly in distal renal tubules, and promotes removal of sodium, chlorides and waters. Renal removal of potassium and magnesium increases depending on a drug dose whereas calcium reabsorbirutsya more. Hydrochlorthiazidum reduces the volume of plasma and extracellular liquid and reduces minute cordial emissions and the ABP. At long therapy reduced peripheric resistance promotes decrease in the ABP.

Kandesartan and Hydrochlorthiazidum have the additive anti-hypertensive effect. At the patients having arterial hypertension, KacapkÒH leads to dozozavisimy and long-term decrease in the ABP. Anti-hypertensive activity is predetermined by reduction of system peripheric resistance without reflex increase in heart rate. There is no information of rather heavy or excessive arterial hypotension after reception of the first dose or a withdrawal.

After reception of a single dose of KacapkaÒH the beginning of anti-hypertensive effect usually comes within 2 hours. At continuous treatment the greatest decrease in the ABP with any dose is usually reached within 4 weeks and supported at long-term treatment.

KacapkÒH at reception of 1 times a day provides effective and uniform decrease in the ABP for 24 hours, with a small difference between the maximum and minimum effect during a dosing interval. KacapkÒH is equally effective at patients irrespective of age and a floor.

There are no data concerning use of a kandesartan цилексетила / Hydrochlorthiazidum to patients with diseases of a kidneys/nephropathy, depression of function of the left ventricle / congestive heart failure and a state after the postponed myocardial infarction today.

Pharmacokinetics. Absorption and distribution.

Kandesartana tsileksetit.

Kandesartana tsileksetit is the pro-medicine suitable for oral administration. It quickly turns into active agent, кандесартан, by ester hydrolysis during absorption from digestive tract, strongly contacts AT1-receptors and slowly dissociates. Absolute bioavailability of a tablet makes 40%. Average maximum concentration in blood serum (Cmax) is reached in 3-4 hours after reception of a tablet. Concentration of a kandesartan grow in serum linearly with increase in doses within a therapeutic dose.

The difference in pharmacokinetics of a kandesartan which would be connected with a floor is not observed. Meal concentration – time" has no significant effect on the area under a curve "(AUC).

Kandesartan substantially contacts proteins of a blood plasma (more than 99%). The visible volume of distribution of a kandesartan makes 0,1 l/kg.

Hydrochlorthiazidum.
Hydrochlorthiazidum is quickly absorbed from a digestive tract with absolute bioavailability of 70%. Meal improves absorption of Hydrochlorthiazidum approximately for 15%. Bioavailability can decrease at patients with heart failure and the expressed hypostases. Linkng of Hydrochlorthiazidum with proteins of plasma makes about 60%. The visible volume of distribution - about 0,8 l/kg.

Metabolism and removal from an organism.

Kandesartana tsileksetit.

Kandesartan is mainly brought from an organism with urine and bile in not changed look and only in an insignificant measure - by hepatic metabolism.

The elimination half-life of a kandesartan makes about 9 hours. After reception of repeated doses of cumulation of drug in an organism does not occur.

The general plasma clearance of a kandesartan makes about 0,37 ml/min., and renal clearance – about 0,19 ml/min. Renal excretion of a kandesartan is carried out by both glomerular filtering, and active tubular secretion. After reception of a peroral dose of the 14C-marked kandesartan of a tsileksetil about 26% of a dose it is removed with urine in the form of a kandesartan and 7% – in the form of an inactive metabolite though about 56% of a dose are defined in excrements in the form of a kandesartan and 10% – in the form of an inactive metabolite.

Hydrochlorthiazidum.
Hydrochlorthiazidum is not metabolized and removed generally in not changed look by glomerular filtering and active tubular secretion. The final elimination half-life makes 8 hours. About 70% of the dose accepted orally are removed with urine within 48 hours. The elimination half-life of Hydrochlorthiazidum remains invariable at a combination from a kandesartan tsileksetily. Additional cumulation of Hydrochlorthiazidum after reception of repeated doses of a combination in comparison with monotherapy does not happen.

Pharmacokinetics at special categories of patients.

Kandesartana tsileksetit.

At patients of advanced age (65 years are more senior) Cmax and AUC of a kandesartan are raised approximately for 50% and 80% respectively compared with young patients. However reaction of the ABP and frequency of emergence of side effects is identical after reception of the established dose of a kandesartan at young patients and patients of advanced age.

At patients with a renal failure from easy to moderate severity, compared with patients with normal renal function, Cmax and AUC of a kandesartan increase after multiple dose of doses approximately by 50% and 70% respectively whereas the elimination half-life of drug remains invariable. Corresponding changes at patients with a heavy renal failure make about 50% and 110% respectively, and the elimination half-life of drug increases twice.

The indicator of AUC of a kandesartan at the patients who are on a hemodialysis is similar to that which is observed at patients with a heavy renal failure.

At patients with a liver failure from easy to moderate severity increase in an indicator of AUC of a kandesartan for 23% was noted.

Hydrochlorthiazidum.
The final elimination half-life of Hydrochlorthiazidum increases at patients with a renal failure.

Main physical and chemical properties: tablets of yellow color, an oval form, with a biconvex surface, with risky for division of a naodny storonetabletka.

Indications to use:

Essential hypertensia in cases when monotherapy of a kandesartan tsileksetily or Hydrochlorthiazidum is insufficient.

Route of administration and doses:

Dosage.

The recommended initial and usual maintenance dose of a kandesartan of a tsileksetil makes 16 mg of 1 times a day.

The recommended initial and usual maintenance dose of Hydrochlorthiazidum makes 12,5 mg of 1 times a day.

Therapy needs to be adjusted according to reaction of the arterial pressure (AP).

The maximum anti-hypertensive effect is reached within 4 weeks from an initiation of treatment.

Before transfer of the patient into KacapkÒH the dose of a kandesartan of a tsileksetil should be titrated taking into account the ABP.

At clinical expediency it is possible to consider direct transition from monodrugs to the combined drug KacapkÒH.

Use.

KacapkÒH should accept 1 time a day together with food or without it.

Patients of advanced age.

Correction of an initial dose is not necessary to patients of advanced age.

Patients with reduction of the intravascular the volume of the circulating blood (VCB).

For patients who have a risk of arterial hypotension for example for patients with possible reduction of volume of the circulating blood, it is necessary to consider an initial dose of a kandesartan of a tsileksetil of 4 mg. Purpose of the combined drug in a dose of 16/12,5 mg or 32/25 mg is not recommended to such patients. To such patients appoint monodrug of a kandesartan tsileksetit (KacapkÒ) in a dose of 4 or 8 mg depending on severity and portability with addition of the corresponding dose of Hydrochlorthiazidum if necessary.

Patients with a renal failure.

It is desirable for these categories of patients to apply loopback, but not thiazide diuretics. KacapkÒH should not apply to treatment of patients with a heavy renal failure (clearance of creatinine <30 ml/min. / 1,73 PPT sq.m). Titration of a dose of a kandesartan of a tsileksetil for patients with a renal failure, the clearance of creatinine at whom makes ≥ 30 ml/min. / 1,73 PPT sq.m prior to treatment by the drug KacapkÒH (for patients with a renal failure from easy to moderate severity the recommended initial dose of a kandesartan of a tsileksetil makes 4 mg) is recommended.

Patients with a liver failure.

Titration of a dose of a kandesartan of a tsileksetil for patients with a liver failure from easy to moderate severity prior to treatment                    of КасаркомÒH is recommended (the recommended initial dose of a kandesartan of a tsileksetil for such patients makes 2 mg). The dose can be adjusted taking into account the ABP. KacapkÒH should not apply to treatment of patients with a heavy liver failure and/or a cholestasia.

Features of use:

Renal failure.

It is desirable for this category of patients to apply loopback diuretics, but not tiazida.

At drug KacapkÒH use periodic monitoring an urovnyakaliya, creatinine and uric acid in blood serum is recommended to patients with a renal failure.

Transplantation of a kidney.

There is no experience of use of KacapkaÒH to the patients who recently transferred transplantation of a kidney.

Renal artery stenosis.

Other medicines influencing renin-angiotensin-aldosteronovuyu system, for example inhibitors of an angiotensin-converting enzyme (APF) can increase the level of urea of blood and creatinine of blood serum at patients with a bilateral or monolateral renal artery stenosis. The similar effect can be expected at use of antagonists of receptors of angiotensin II.

Reduction of OTsK.

Patients with reduction by OTsK and/or a hyponatremia can have a symptomatic hypotension, as well as at use of other means influencing renin-angiotensin-aldosteronovuyu system. Therefore it is not recommended to apply KacapkÒH until OTsK is modified.

Anesthesia and surgical interventions.

At the patients receiving treatment by antagonists of receptors of angiotensin II, arterial hypotension can develop in time of anesthesia and surgical intervention owing to blockade system renin-angiotensin-aldosteronovoy. In isolated cases arterial hypotension can be so heavy that use of intravenous liquids and/or vazopressor can be required.

Liver failure.

Tiazida it is necessary to apply with care at patients with a liver failure or with the progressing liver diseases as minor changes of water and electrolytic balance can provoke a hepatic coma. Patients do not have clinical experience of use of the drug KacapkÒ H with a liver failure.

Stenosis of an aorta or mitral valve, subaortic hypertrophic stenosis.

As well as at use of other vasodilators, it is necessary to be especially careful at treatment of patients with hemodynamically significant stenosis of an aorta or the mitral valve or a subaortic hypertrophic stenosis.

Primary hyper aldosteronism.

Patients with primary hyper aldosteronism usually do not react to the anti-hypertensive medicines operating by inhibition system renin-angiotensin-aldosteronovoy. Therefore such patients are not recommended to use drug.

Disturbances of electrolytic balance.

As well as at any patients receiving therapy by diuretics through the corresponding intervals of time it is necessary to carry out periodic definition of electrolytes of blood serum.

Tiazida, including Hydrochlorthiazidum, can entail disturbance of water or electrolytic balance (a hypercalcemia, a hypopotassemia, a hyponatremia, a hypomagnesiemia and a gipokhloremichesky alkalosis).

Thiazide diuretics can reduce removal of calcium with urine and cause passing and slight increase of concentration of calcium in serum.

The noticeable hypercalcemia can be a sign of the hidden hyperparathyreosis. Before conducting check of function of epithelial body use of tiazid should be stopped.

Hydrochlorthiazidum дозозависимо strengthens removal of potassium with urine that can lead to a hypopotassemia. This effect of Hydrochlorthiazidum is less expressed at use of its combination from a kandesartan tsileksetily. The risk of a hypopotassemia can be raised at patients with cirrhosis, with a profound diuresis, with insufficient oral administration of electrolytes and at patients who receive the accompanying therapy by corticosteroids or adrenocorticotropic hormone.

Relying on experience of use of other medicines which influence renin-angiotensin-aldosteronovuyu system, the accompanying use of KacapkaÒH and kaliysberegayushchy diuretics, potassium additives or salt substitutes or other means which can increase potassium level in serum (for example heparin) can lead to increase in level of potassium in blood serum.

Treatment by APF inhibitors or antagonists of receptors of angiotensin ІІ can cause a hyperpotassemia, especially in the presence of heart failure and/or a renal failure.

Tiazida increase removal of magnesium with urine that can lead to a hypomagnesiemia.

Influence on metabolism and endocrine system.

Treatment by thiazide diuretics can break portability of glucose. Correction of dosing of antidiabetic means, including insulin can be necessary. During therapy of a tiazidama the latent diabetes mellitus can be shown. Increase in levels of cholesterol and triglycerides was associated with therapy by thiazide diuretics. However at the dose of Hydrochlorthiazidum of 12,5 mg which is contained in drug, side effects are minimum or they are absent.

Thiazide diuretics increase concentration of uric acid in serum and can provoke gout at patients, inclined to it.

General information.

At patients whose vascular tone and which function of kidneys depend preferential on activity system renin-angiotensin-aldosteronovoy (naprimerpatsiyenta with heavy congestive heart failure or with diseases of kidneys, including a renal artery stenosis) treatment by other medicines influencing this system was associated with acute arterial hypotension, an azotemia, an oliguria or, in rare instances, with an acute renal failure. The possibility of similar effects cannot be excluded at use of antagonists of receptors of angiotensin ІІ.

As well as in a case with any other anti-hypertensive drugs, excessive decrease in the ABP at patients with an ischemic cardiomyopathy or an ischemic cerebrovascular disease can lead to a myocardial infarction or a stroke.

Reactions of hypersensitivity to Hydrochlorthiazidum can arise at patients with or without allergy, or bronchial asthma in the anamnesis, however are more probable at patients with such diseases.

The aggravation or activation of a system lupus erythematosus at use of thiazide diuretics is possible.

Drug contains lactose as excipient therefore it should not be accepted to patients with exceptional hereditary cases of intolerance of a galactose, a lactose intolerance of Lapp or malabsorption of glucose galactose.

Ability to influence speed of response at control of motor transport or work with other mechanisms. Influence of drug on ability to manage motor transport or to work with other mechanisms was not studied, however, considering pharmakodinamichesky properties of a kandesartan, it is improbable that it had such ability. At control of motor transport or work with other mechanisms it is necessary to take into account possibility of arterial hypotension during treatment of КасаркомÒH who can be followed by dizziness and increased fatigue.

Side effects:

Side reactions at reception of a kandesartan цилексетила / Hydrochlorthiazidum easy and temporary.

Kandesartana цилексетил / Hydrochlorthiazidum.

Are possible stated below extended (> 1/100) side reactions:

from a nervous system: dizziness / вертиго.

Kandesartana tsileksetit.

Very seldom (<1/10000) side reactions are possible:

 from blood and lymphatic system: leukopenia, neutropenia and agranulocytosis;

metabolic disturbances: hyperpotassemia, hyponatremia;

from a nervous system: dizziness, headache;

from a digestive tract: nausea;

gepatobiliarny disturbances: increase in levels of enzymes of a liver, abnormal liver function or hepatitis;

from skin and hypodermic cellulose: Quincke's disease, rash, small tortoiseshell, itch;

from a musculoskeletal system: dorsodynia, arthralgia, mialgiya;

from kidneys and urinary tract: renal failures, including a renal failure at patients, inclined to it.

Hydrochlorthiazidum.

At monotherapy nizheukazannyepobochny reactions can be noted by Hydrochlorthiazidum which doses, as a rule, make 25 mg or more. Frequency of side reactions following: extended (> 1/100), not widespread (> 1/1000 and <1/100) and seldom widespread (<1/1000):

from blood and lymphatic system: seldom widespread - a leukopenia, a neutropenia/agranulocytosis, thrombocytopenia, aplastichny anemia, oppression of marrow, hemolitic anemia;

from immune system: seldom widespread - anaphylactic reactions;

metabolic disturbances: extended - a hyperglycemia, a hyperuricemia, disturbances of electrolytic balance (including a hyponatremia and a hypopotassemia);

mental disturbances: seldom widespread - sleep disorders, a depression, concern;

from a nervous system: extended - dizziness, вертиго; seldom widespread - paresthesia;

from organs of sight: seldom widespread - a temporary vagueness of the image;

from cardiovascular system: not widespread - postural hypotension; seldom widespread - cardiac arrhythmia; necrotizing angiitis (vasculitis, skin vasculitis);

from respiratory system: seldom widespread - disturbances of external respiration (including a pneumonitis and a fluid lungs);

from a digestive tract: not widespread - anorexia, appetite loss, irritation of a mucous membrane of a stomach, diarrhea, a lock; seldom widespread - pancreatitis;

gepatobiliarny disturbances: seldom widespread - jaundice (intra hepatic cholestatic jaundice);

from skin and hypodermic cellulose: not widespread - rash, urticaria, reactions of a photosensitization; seldom widespread - a toxic epidermal necrolysis, skin reactions, similar to a system lupus erythematosus, reactivation of a skin form of a system lupus erythematosus;

from a musculoskeletal system: seldom widespread - a muscular spasm;

from kidneys and urinary tract: extended - a glucosuria; seldom widespread - renal dysfunction and intersticial nephrite;

general disturbances: extended - weakness; seldom widespread - fever;

changes of laboratory indicators: extended - increase in levels of cholesterol and triglycerides; not widespread - increase in levels of an urea nitrogen of blood and creatinine of serum; there are increases in levels of uric acid, glucose and ALT given about cases in serum, insignificant decrease in level of hemoglobin and increase in nuclear heating plant, increase in level of creatinine, urea or potassium and decrease in level of sodium.

Interaction with other medicines:

Clinically significant medicinal interaction of a kandesartan with connections which contain Hydrochlorthiazidum, warfarin, digoxin, oral contraceptives, such as ethinylestradiol/levonorgestrel, glibenclamide and nifedipine is not revealed.

Other anti-hypertensive means can strengthen anti-hypertensive effect of KacapkaÒH.

It is possible to expect that the reduction of level of potassium characteristic of Hydrochlorthiazidum amplifies other medicines which are associated with loss of potassium and a hypopotassemia (naprimerdrugy kaliysberegayushchy diuretics, purgatives, Amphotericinum, karbenoksolony, sodium penicillin G, derivatives of salicylic acid).

Experience of use of other medicines influencing renin-angiotensin-aldosteronovuyu system assumes that the accompanying use of KacapkaÒH with kaliysberegayushchy diuretics, potassium additives, salt substitutes containing potassium or other medicines which can increase potassium level (напримерс heparin) can lead to increase in level of potassium in blood serum.

The hypopotassemia caused by diuretics, and hypomagnesiemia promote potential cardiotoxic effects of glycosides of a digitalis and antiarrhythmic means. At simultaneous use of KacapkaÒH with these medicines it is recommended to carry out periodic monitoring of level of potassium of blood serum.

Perhaps reversible increase in concentration of lithium in blood serum and its toxicity during simultaneous use of lithium with APF inhibitors or Hydrochlorthiazidum. The similar effect can arise with antagonists of receptors of angiotensin ІІ, and therefore at simultaneous use careful monitoring of level of lithium in blood serum is recommended.

As well as at use of APF inhibitors, simultaneous use of antagonists of receptors of angiotensin ІІ with non-steroidal anti-inflammatory drugs can increase risk of development of a renal failure, including an acute renal failure, and also increase in level of potassium of serum, especially to patients with renal failures in the anamnesis. This combination should be applied with care, especially at patients of advanced age.

Patients have to receive enough liquid, and also it is necessary to consider need of monitoring of function of kidneys after the beginning of the accompanying therapy and periodic monitoring afterwards.

Non-steroidal anti-inflammatory drugs reduce diuretic, natriuretic and anti-hypertensive effect of Hydrochlorthiazidum.

Holestipol or холестирамин reduce absorption of Hydrochlorthiazidum.

Hydrochlorthiazidum can exponentiate effect of not polarizing relaxants of skeletal muscles (naprimertubokurarin).

Thiazide diuretics can increase serum calcium level because of its reduced removal. At purpose of calcic additives or Dneobkhodimo vitamin to watch calcium levels in serum and to respectively adjust a dose.

Tiazida can strengthen hyper glycemic effect of b-blockers and diazoxide.

Anticholinergic drugs (such as atropine, Biperidinum) can increase bioavailability of diuretics of thiazide type, reducing motility of digestive tract and speed of gastric emptying.

Tiazida can increase risk of the side effects caused amantadiny.

Tiazida can reduce renal removal of cytotoxic drugs (such as cyclophosphamide, a methotrexate) and to exponentiate their myelosuppressive effects.

The risk of a hypocalcemia can increase at simultaneous use of steroids or adrenocorticotropic hormone.

The concomitant use of alcohol, barbiturates or anesthetics can cause postural hypotension.

Treatment by thiazide diuretics can worsen portability of glucose. There can be a need for correction of a dose of antidiabetic means, including insulin.

Hydrochlorthiazidum can cause decrease in reaction of arteries to pressor amines (such as adrenaline), but it is not enough for an exception of pressor effect.

Hydrochlorthiazidum at simultaneous use with the iodated radiopaque substance in high doses can increase risk of an acute renal failure.

Meal does not influence bioavailability of a kandesartan.

There is no clinically significant interaction between Hydrochlorthiazidum and food.

Contraindications:

Hypersensitivity to active ingredients or to any of drug excipients. Heavy renal failure (clearance of creatinine <30 ml/min. / 1,73 sq.m of the body surface area (BSA)), heavy liver failure and/or stagnation of bile (cholestasia), resistant hypopotassemia or hypercalcemia, gout.

Use during pregnancy or feeding by a breast. KacapkÒH is contraindicated during pregnancy. If pregnancy is found during treatment by drug, therapy should be stopped. Today it is unknown whether gets кандесартан into breast milk. Due to the possible undesirable influence on babies of КасаркÒHне it is necessary to apply during feeding by a breast.

Children. Safety and efficiency of use of the drug КасаркÒHдетям are not established therefore it do not appoint this age category of patients.

Overdose:

Symptoms. It is possible to carry symptomatic hypotension and dizziness to the main manifestations of overdose of a kandesartan of a tsileksetil.

The main manifestation of overdose of Hydrochlorthiazidum is acute loss of liquid and electrolytes. Such symptoms as dizziness, arterial hypotension, thirst, tachycardia, ventricular arrhythmia, a sedation/loss of consciousness and muscular spasms can be also observed.

Treatment. There is no specific information concerning treatment of overdose of drug. However in case of overdose such actions are offered. It is necessary to cause vomiting or to carry out gastric lavage. When developing symptomatic arterial hypotension it is necessary to begin a symptomatic treatment and tracking of the vital functions. The patient it is necessary to put on a back, to raise to him the lower extremities. If it is not enough, it is necessary to increase blood plasma volume by infusion, naprimerizotonichesky saline solution. If necessary it is necessary to check and modify electrolytic and acid balance of serum. If above-mentioned actions are not enough, it is possible to apply symptomatic medicines.

Kandesartan is not brought by a hemodialysis. It is unknown in what measure Hydrochlorthiazidum by means of a hemodialysis is removed.

Storage conditions:

Period of validity 2 years of date of production of in bulk. To store in original packaging at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister, on 3 blisters in a pack.