Pharmacological properties

Pharmacodynamics. valsartan is an active, powerful and specific antagonist of receptors of ii angiotensin (ang ii). it affects selectively a subtype of receptors at1 which is responsible for action of ANG ii. the increased ANG ii levels after blockade of a receptor at1 valsartany can stimulate not blocked receptor in blood plasma at2 which, most likely, neutralizes action of a receptor at1. valsartan does not show activity of partial agonist concerning a receptor at1 and has considerably bigger (about 20 000-fold) affinity to a receptor at1, than to a receptor at2. it is unknown whether contacts valsartan other receptors of hormones or ion channels which, as we know, play an important role in cardiovascular regulation, or blocks them. valsartan does not inhibit apf (also known as ii kinase) which turns ang i into ang ii and destroys bradykinin. as there is no influence on apf and potentiations of bradykinin or albumen, antagonists of ANG ii can be hardly connected with cough.

AG. Purpose of a valsartan the patient with AG as a result leads to decrease in the ABP, without influencing at the same time ChSS.

antihypertensive activity is noted by

At most of patients after reception of a single oral dose during 2 h, and the maximum decrease in the ABP is reached during 4–6 h. The hypotensive effect remains during 24 h after administration of drug. At repeated use of medicine the hypotensive effect generally remains during 2 weeks, and the maximum effect is reached during 4 weeks and remains during the long period. In combination with a hydrochlorothiazide the significant additional decrease in the ABP is reached.

Fast cancellation of a valsartan is not connected by

with "ricochet" AG or other undesirable clinical phenomena.

Recently postponed myocardial infarction. Results of a research showed efficiency of a valsartan, as well as captopril, in decrease in the general mortality after a myocardial infarction. Valsartan was also effective concerning decline in mortality from cardiovascular pathology, reduction of quantity of cases of hospitalization concerning heart failure and a repeated myocardial infarction. The profile of safety of a valsartan answered a course of the disease of the patients treated after the established myocardial infarction.

Heart failure. Patients who accepted valsartan showed considerable improvement on signs and symptoms of heart failure, including short wind, fatigue, hypostasis and rattles, in comparison with those who accepted placebo. The patients with chronic heart failure accepting valsartan had the best quality of life from initial to a final indicator in comparison with patients who accepted placebo. The patients accepting valsartan had a fraction of emission much more, and the final diastolic diameter of a left ventricle significantly decreased from initial to a final indicator in comparison with patients who accepted placebo.

Pharmacokinetics

Absorption. After oral administration of the C _max valsartana in blood plasma is reached in 2–4 h. The average absolute bioavailability is 23%. Food reduces influence of a valsartan (that is determined by average concentration in urine/AUC) approximately by 40%, and the C _max in blood plasma — approximately by 50% though approximately in 8 h after reception the concentration of a valsartan in blood plasma is similar that in group of the patients eating food and in group of the patients taking the medicament on an empty stomach. However such decrease in average concentration in urine is not followed by clinically significant decrease in therapeutic effect and therefore valsartan it is possible to accept either with food, or without it.

Distribution. The equilibrium volume of distribution of a valsartan in/in introductions is later 17 l, indicating that it valsartan is not distributed intensively in fabrics. It strongly contacts proteins of blood plasma (94–97%), generally albumine.

Biotransformation. Valsartan biotransformirutsya in full as only about 20% of a dose are restored in the form of metabolites. Hydroksimetabolit it is revealed in blood plasma in low concentration (less than 10% of average concentration of a valsartan in urine). This metabolite pharmacological is inactive.

Removal. Valsartan shows multiexponential kinetics of disintegration (T _½ α 1 h and T _½ β about 9 h). He is generally brought with a stake (about 83% of a dose) and kidneys with urine (about 13% of a dose), mainly in not changed look. Later in/in introductions the plasma clearance of a valsartan is about 2 l/h, and its renal clearance — 0.62 l/h (about 30% of the general clearance). T _½ valsartana makes 6 h

Patients with heart failure

Average time to the C _max and T _½ a valsartana at patients with heart failure is similar to that which was noted at healthy volunteers. Indicators of AUC and C _max a valsartana are almost proportional (are identical) at reception of the dose exceeding the range of therapeutic doses (from 40 to 160 mg 2 times a day). The average coefficient of cumulation makes about 1.7.

Clearance of a valsartan after oral administration is about 4.5 l/h. The age does not affect clearance at patients with heart failure.

Special groups of patients

Patients of advanced age. A little increased system influence of a valsartan was noted at some patients of advanced age in comparison with persons of young age, however it had no clinical value.

Renal failure. As well as it was supposed, with substance which renal clearance is only 30% of the general clearance of blood plasma, the correlation between a condition of function of kidneys and system exposure of a valsartan is noted. Therefore selection of a dose is not required to patients with a renal failure (clearance of creatinine of 10 ml/min.). For today there is no experience of safe use for patients with clearance of creatinine of 10 ml/min. and patients who are on dialysis therefore at such patients valsartan it is necessary to apply with care. Valsartan contacts proteins of blood plasma and can be hardly brought by means of dialysis.

Liver failure. About 70% of the absorbed dose are removed with bile, generally in not changed look. Valsartan does not give in to biotransformation which would deserve attention. At patients with a slight and moderate liver failure exposure (determined by AUC values) the valsartana on average twice exceeds that in comparison with healthy volunteers. However no interrelation between concentration of a valsartan in blood plasma and degree of hepatic dysfunction was noted. Did not study efficiency of a valsartan at patients with heavy hepatic dysfunction.

Indication

Ag. treatment ag at adults.

Postinfarction state. Treatment of clinically stable patients with symptomatic heart failure or asymptomatic systolic dysfunction of a left ventricle after recent (the 12th Part-10 of days) a myocardial infarction.

Heart failure. Treatment of symptomatic heart failure when it is impossible to apply APF inhibitors, or as auxiliary therapy at use of APF inhibitors when it is impossible to apply blockers of β-adrenoceptors.

Use

Valsartan can be accepted irrespective of meal, washing down with water.

AG. The recommended initial dose of a valsartan makes 80 mg (1 tablet Vanatex 80 mg or ½ tablets of Vanatex of 160 mg) 1 time a day. The antihypertensive effect is reached in the first 2 weeks, and the maximum effect is noted during 4 weeks

At some patients whose ABP is insufficiently controlled, the dose can be raised to 160 mg, a maximum — to 320 mg.

Valsartan can be accepted with other antihypertensive drugs.

Addition of diuretic means, such as hydrochlorothiazide, lowers the arterial blood pressure at such patients even more.

Postinfarction state. Treatment of clinically stable patients can be begun, applying valsartan already in 12 h after a myocardial infarction. After an initial dose of 20 mg 2 times a day a dose of a valsartan should be raised to 40; 80 and 160 mg 2 times a day within the next several weeks. Vanatex do not appoint for initial treatment. For achievement of smaller doses (20 mg) it is necessary to take the medicament in other dosage form. The maximum dose makes 160 mg 2 times a day. It is recommended that the dose of 80 mg 2 times a day was reached in 2 weeks after an initiation of treatment, and the maximum dose — 160 mg 2 times a day — in 3 months taking into account shipping of treatment by the patient. When developing symptomatic arterial hypotension or renal dysfunction it is necessary to consider a dose decline question.

Valsartan can be applied at patients who accepted other medicines after the postponed myocardial infarction, for example a trombolitika, acetylsalicylic acid, blockers of β-adrenoceptors, statines and diuretics. The combination with APF inhibitors is not recommended. Assessment of a condition of patients after the postponed myocardial infarction always has to include a research of function of kidneys.

Heart failure. The recommended initial dose of a valsartan makes 40 mg 2 times a day. It is necessary to raise a dose to 80 and 160 mg 2 times a day with intervals not less than 2 weeks, considering tolerance of medicament the patient. It is necessary to consider the possibility of a dose decline of the accompanying diuretics. The maximum daily dose which was appointed made 320 mg and was divided into several receptions.

Valsartan can be accepted with other medicines for treatment of heart failure. However the triple combination of APF inhibitor, a blocker of β-adrenoceptors and a valsartana is not recommended. Assessment of a condition of patients with heart failure always has to include a research of function of kidneys.

Additional information of rather special groups of patients

Patients of advanced age. Selection of a dose is not required for patients of advanced age.

Patients with a renal failure. Selection of a dose is not required for patients with clearance of creatinine of 10 ml/min.

Patients with a liver failure. For patients with a slight and moderate liver failure without cholestasia the dose of a valsartan should not exceed 80 mg. Valsartan is contraindicated to patients with a heavy liver failure and to patients with a cholestasia.

Contraindication

Hypersensitivity to active ingredient or any of excipients. heavy liver failure, cirrhosis and cholestasia.

Side effects

Are classified by

by frequency: very often (≥1/10); often (1/100, ≤1/10); sometimes (1/1000, ≤1/100); seldom (1/10,000, ≤1/1000); very seldom (1/10,000), including single messages. within each group the side reactions are provided as reduction of their weight.

cannot apply one of above-mentioned frequencies To all adverse side reactions about which it was reported during the post-market and laboratory researches and therefore their frequency is designated as it "is unknown".

AG

from blood and lymphatic system: it is unknown — decrease in level of hemoglobin, decrease in a hematocrit, a neutropenia, thrombocytopenia.

from the immune system: it is unknown — hypersensitivity, including a serum disease.

from a metabolism: it is unknown — increase in level of potassium in blood plasma, a hyponatremia.

from an organ of hearing and balance: infrequently — dizziness.

from vessels: it is unknown — a vasculitis.

from a respiratory system: infrequently — cough.

from a digestive tract: infrequently — an abdominal pain.

from a liver and a gall bladder: it is unknown — increase in indicators of function of a liver, including increase in level of bilirubin in blood plasma.

from skin and hypodermic fabrics: it is unknown — a Quincke's edema (Quincke's disease), rash, an itching.

from a musculoskeletal system and connective tissue: it is unknown — myalgia.

from kidneys and urinary tract: it is unknown — OPN and a renal failure, increase in level of creatinine in blood plasma.

General disturbances: infrequently — increased fatigue.

Adverse side reactions which arose at patients after the postponed myocardial infarction and/or heart failure, provided below.

After the postponed myocardial infarction and/or heart failure

from blood and lymphatic system: it is unknown — thrombocytopenia.

from the immune system: it is unknown — hypersensitivity, including a serum disease.

from a metabolism: infrequently — a hyperpotassemia; it is unknown — increase in level of potassium in blood plasma, a hyponatremia.

from nervous system: often — dizziness, postural dizziness; infrequently — a faint, a headache.

from an organ of hearing and balance: infrequently — dizziness.

from heart: infrequently — heart failure.

from vessels: often — arterial hypotension, orthostatic hypotension; it is unknown — a vasculitis.

from a respiratory system: infrequently — cough.

from digestive system: infrequently — nausea, diarrhea.

from a liver and a gall bladder: it is unknown — increase in activity of enzymes of a liver, increase in concentration of bilirubin in blood plasma.

from skin and hypodermic fabrics: infrequently — a Quincke's edema (Quincke's disease); it is unknown — rash, an itching.

from a musculoskeletal system and connective tissue: it is unknown — myalgia.

from kidneys and urinary tract: often — a renal failure and a renal failure; infrequently — OPN, increase in level of creatinine in blood plasma; it is unknown — increase in urea nitrogen in blood.

General disturbances: infrequently — an asthenia, increased fatigue.

Special instructions

Hyperpotassemia. simultaneous use with potassium additives, kaliysberegayushchy diuretics, the salt substitutes containing potassium or other means which can increase potassium levels (heparin, etc.) is not recommended. if necessary it is necessary to carry out control of content of potassium to blood.

Patients with deficiency of sodium. Patients with the significant deficiency of sodium, for example at those who accept diuretics in high doses seldom in an initiation of treatment can have a symptomatic arterial hypotension. Before an initiation of treatment it is necessary to carry out correction of content of sodium in an organism, for example, by a diuretic dose decline.

Patients with a hypovolemia. The patients with a heavy hypovolemia accepting high doses of diuretics can seldom have a symptomatic arterial hypotension after the begun therapy valsartany. The hypovolemia needs to be corrected before an initiation of treatment valsartany, for example, by a diuretic dose decline.

Renal artery stenosis. At patients with a bilateral renal artery stenosis or a stenosis of one kidney the safe use of a valsartan is not established.

Short-term reception of a valsartan with the renovascular hypertensia which arose owing to a unilateral renal artery stenosis did not cause in patients any significant changes in a renal hemodynamics, creatinine level in blood plasma or urea nitrogen. However other means influencing renin-angiotenzinovuyu a system can increase levels of urea of blood and creatinine in blood plasma at patients with a unilateral renal artery stenosis therefore monitoring of function of kidneys is recommended if the patient accepts valsartan.

Transplantation of kidneys. There is no experience of safe use of a valsartan for the patients who recently transferred transplantation of kidneys for today.

Primary hyper aldosteronism. At patients with primary hyper aldosteronism it is not necessary to apply valsartan as their renin-angiotenzinovaya a system is not activated.

Stenosis of aortal and mitral valves, subaortic hypertrophic stenosis. As well as in a case with other vazodilatator, it is necessary to be especially careful at treatment of patients with a stenosis of aortal or mitral valves or a hypertrophic subaortic stenosis.

Renal failure. Dose adjustment for patients with clearance of creatinine of 10 ml/min. is not required. For today there is no experience of safe use of a valsartan for patients with clearance of creatinine of 10 ml/min. and patients who are on dialysis therefore such patients valsartan should appoint with care.

Liver failure. Patients with a slight and moderate liver failure without cholestasia valsartan should appoint with care.

Recently postponed myocardial infarction. The combination of captopril and a valsartan does not show additional clinical benefits whereas the risk of side effects increases in comparison with that at treatment by appropriate means. Thus, the combined use of a valsartan with APF inhibitor is not recommended. It is necessary to be careful in an initiation of treatment of patients after the postponed myocardial infarction. Assessment of a condition of patients after the postponed myocardial infarction always has to include a research of function of kidneys.

Use of a valsartan for patients after the postponed myocardial infarction generally leads

to some decrease in the ABP, but to stop treatment because of long symptomatic hypotension usually there is no need if to observe recommendations concerning a dosage.

Heart failure. Use for patients with heart failure of a triple combination of APF inhibitor, a blocker of β-adrenoceptors and the valsartana does not show any clinical advantages. This combination obviously increases risk of emergence of side effects and therefore it is not recommended.

In an initiation of treatment of patients should be careful with heart failure. Assessment of patients with heart failure always has to include a research of function of kidneys.

Use of a valsartan for patients with heart failure generally leads

to some decrease in the ABP, but to stop treatment because of long symptomatic hypotension usually there is no need if to follow the instruction concerning a dosage. At patients whose function of kidneys depends on activity system renin-angiotenzinovoy (for example at patients from heavy congestive / an acute heart failure) the treatment by APF inhibitors is connected with an oliguria and/or the progressing azotemia and, in some cases, with OPN and/or death. As valsartan is an antagonist of ANG II, it is impossible to exclude that use of a valsartan can be connected with a renal failure.

Excipients. Drug contains lactose (1 tablet of 80 mg contains 56.5 mg of lactose of monohydrate, 1 tablet of 160 mg contains 113 mg of lactose of monohydrate). Patients with rare hereditary intolerance have galactoses, a lactose intolerance or a sprue of glucose and a galactose it is not necessary to use this drug.

Use during pregnancy and feeding by a breast

Pregnancy. Use of antagonists of receptors of ANG II is not recommended during the entire period of pregnancy.

before administration of medicament of women of reproductive age should be surveyed for an exception of possible pregnancy. If the woman wishes to become pregnant, it is necessary to stop use of medicament and to replace it with any other antihypertensive medicine which has the established safety profile for use during pregnancy. If during treatment the pregnancy is confirmed, it is necessary to pass as soon as possible (under observation of the doctor) to alternative therapeutic means which represent smaller risk for a fruit.

Feeding by a breast. Due to the lack of information the use of a valsartan is not recommended during feeding by a breast.

Children. Valsartan do not recommend to apply at children (aged up to 18 years) due to the lack of data on its safety and efficiency.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Did not conduct a research about influence on ability to run vehicles. At control of vehicles or work with other mechanisms it is necessary to consider that there can sometimes be dizziness or the increased fatigue.

Simultaneous use is not recommended to

Interaction

by

Lities. It was reported about reversible increase in concentration of lithium in blood plasma and toxicity at the accompanying use of APF inhibitors. Due to the lack of experience of simultaneous use of a valsartan and lithium this combination is not recommended. If such combination is necessary, careful control of level of lithium in blood plasma is recommended.

Kaliysberegayushchy diuretics, potassium additives, the salt substitutes containing potassium, and other substances which can increase potassium level. If medicament which influences potassium level it is necessary to combine with valsartany, control of level of potassium in blood plasma is recommended.

Should be careful at simultaneous use of NPVP, including selection TsOG-2 inhibitors, acetylsalicylic acid (3 g/days) and non-selective NPVP. At co-administration of antagonists of ANG II and NPVP easing of antihypertensive effect is possible. Besides, simultaneous use of antagonists of ANG II and NPVP can result in the increased risk of deterioration in function of kidneys and increase in level of potassium in blood plasma. Thus, it is recommended to control function of kidneys in an initiation of treatment and also to carry out the corresponding hydration of the patient.

Other types of interactions. During the research it is not established any clinically significant interactions of a valsartan with any of the following substances: Cimetidinum, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipin, glibenclamide.

Overdose

Symptoms. the overdose valsartany can lead to the profound arterial hypotension that, in turn, can become the reason of oppression of consciousness, circulator collapse (vascular insufficiency) and/or shock (coma).

Treatment. Therapeutic measures depend on time of the consumption of food and also a look and weight of symptoms, blood circulation stabilization is extremely important.

In arterial hypotension the patient has to be in a prone position, at the same time it is necessary to carry out correction of OCK. It is improbable that valsartan is removed by a hemodialysis.

Storage conditions

In the dry place at a temperature not above 25 °C. to store out of children's reach.

Translation of the instruction Mose