Pharmacological properties

Pharmacodynamics. valsartan. valsartan is orally active and specific antagonist of receptors of ii angiotensin (at). it affects selectively a subtype of receptors at1 which is responsible for action at to ii. the increased levels at after blockade of a receptor at1 valsartany can stimulate with ii not blocked receptor of at2 which, quite possibly, neutralizes action of blockade of a receptor at1 in blood plasma. valsartan does not show activity of partial agonist concerning a receptor at1 and has the bigger affinity to receptors at1, than to at2 receptors is considerable. valsartan does not inhibit apf (also known as ii kinase) which turns at i in at ii and destroys bradykinin. during clinical trials in which valsartan compared to inhibitor apf the frequency of development of dry cough was much lower (r0.05) at the patients accepting valsartan than at treated inhibitor apf (2.6% in comparison with 7.9%). during clinical trial with participation of patients with dry cough in the anamnesis during treatment by inhibitors apf at 19.5% of the examinees accepting valsartan, and 19% of those who accepted thiazide diuretic, noted cough in comparison with 68.5% of the patients treated by inhibitors apf (r0.05).

Purpose of a valsartan the patient with AG leads

to decrease in the ABP, without influencing at the same time ChSS. At most of patients after reception of a single oral dose the antihypertensive action is shown 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 administration of medicament the maximum decrease in the ABP at any dose is generally reached during 2–4 weeks and remains throughout long-term treatment. In combination with a hydrochlorothiazide the significant additional decrease in the ABP is reached.

to

At patients with the raised ABP, diabetes of the 2nd type and a microalbuminuria it is shown that valsartan reduced albumine discharge with urine.

by

drew a conclusion that use of a valsartan in a dose of 160-320 mg leads to clinically significant reduction of excretion of albumine with urine at patients with the raised ABP and diabetes of the 2nd type.

Hydrochlorothiazide. The scene of action of thiazide diuretics, first of all — renal distal wavy tubules. It is shown that in bark of a kidney there are high-affine receptors which are the main binding site of effect of thiazide diuretics and oppressions of transportation of chloride sodium (NaCl) in distal wavy tubules. The mechanism of action of tiazid consists in oppression of Na ⁺ Cl ^– - the unidirectional carrier, perhaps, by the competition for the Cl-site, influences mechanisms of a reabsorption of electrolytes directly — increasing discharge of sodium and chlorine approximately to the same extent, and indirectly — by such diuretic action reduces volume in blood plasma with the subsequent increase in activity of renin in blood plasma, secretion of Aldosteronum, excretion of potassium with urine and decrease in potassium in blood plasma. Renin-aldosteronovaya communication is mediated by AT II therefore at a concomitant use of a valsartan the decrease in level of potassium in blood plasma is less significant, than at monotherapy by a hydrochlorothiazide.

Pharmacokinetics. The system bioavailability of a hydrochlorothiazide decreases approximately by 30% at simultaneous use with valsartany. Simultaneous use of a hydrochlorothiazide has no significant effect on kinetics of a valsartan. Noted interaction does not affect efficiency of the combined use of a valsartan and a hydrochlorothiazide as during controlled clinical trials the accurate antihypertensive effect of this combination which exceeded effect of active agent separately and also effect of placebo is revealed.

Valsartan

Absorption. After oral administration separately the valsartana of its C _max in blood plasma is reached during 2–4 h. The average bioavailability is 23%. Food reduces action approximately by 50%.

Distribution. The equilibrium volume of distribution of a valsartan in/in introductions is later about 17 l, indicating that it valsartan is not distributed widely in fabrics. Valsartan substantially contacts proteins of blood plasma (94–97%), mainly plasma albumine.

Biotransformation. Valsartan biotransformirutsya substantially as only about 20% of a dose reveal in the form of metabolites.

Removal. Valsartan shows kinetics of polyexponential disintegration (T _½ α 1 h and T _½ β about 9 h). Valsartan is generally brought with a stake (about 83% of a dose) and 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 is 0.62 l/h (about 30% of the general clearance). T _½ valsartana makes 6 h

Hydrochlorothiazide

Absorption. After oral administration the absorption of a hydrochlorothiazide happens quickly (t _max — about 2 h) to similar characteristics of absorption both in the form of suspension, and in the form of tablets. The absolute bioavailability of a hydrochlorothiazide is 60–80% after oral administration of drug.

Distribution. The kinetics of distribution and removal is usually described by function of biexponentsialny disintegration. The expected volume of distribution is 4–8 l/kg.

Distributed hydrochlorothiazide contacts proteins of blood plasma (40–70%), generally plasma albumine.

Removal. 95% of the absorbed hydrochlorothiazide are removed in not changed view with urine. The renal clearance consists of passive filtration and active secretion in renal tubules. T _½ makes 6–15 h

Special groups of patients

Patients of advanced age. Limited data indicate that the general clearance of a hydrochlorothiazide decreases both at healthy volunteers, and at patients of advanced age with the raised ABP, in comparison with young healthy volunteers.

Renal failure. At use of Vanatex Kombi in the recommended dose patients have no need for dose adjustment with clearance of creatinine of 30-70 ml/min.

there Is no

data on use of the medicament Vanatex Kombi for patients with a heavy renal failure (clearance of creatinine of 30 ml/min.) and the patients who are on dialysis. Valsartan substantially contacts proteins of blood plasma and is not brought by means of dialysis whereas the hydrochlorothiazide is removed by dialysis.

Renal clearance of a hydrochlorothiazide consists of passive filtration and active secretion in renal tubules. As expected for medicament which is emitted almost only with kidneys the function of kidneys considerably influences hydrochlorothiazide kinetics.

Liver failure. During the pharmacokinetic research of patients with easy (n=6) and the liver dysfunction moderated (n=5) the action of a valsartan was approximately twice more in comparison with healthy volunteers.

do not have

data on use of a valsartan for patients with heavy dysfunction of a liver. Liver diseases significantly do not influence hydrochlorothiazide pharmacokinetics.

Indication

Ag at patients at whom hell is not regulated properly by monotherapy valsartany or a hydrochlorothiazide.

Use

Recommended dose vanatex komb of 80/12.5 mg — 1 tablet of 1 times a day. at insufficient decrease hell in 3–4 weeks of treatment recommend to consider the possibility of continuation of treatment in a dosage 1 tablet of 160/12.5 mg of 1 times a day. tablets of 160/25 mg are appointed to patients at whom hell at use of tablets of 160/12.5 mg is not reached sufficient decrease. if further at use of tablets of 160/25 mg hell decreases insufficiently, it is recommended to consider the possibility of continuation of treatment in a dosage of 320/12.5 mg (it is necessary to apply to receiving such dosing valsartan and a hydrochlorothiazide in other dosage form). the dose of 320/25 mg is appointed to patients at whom hell at use of a dose of 320/12.5 mg is not reached sufficient decrease.

Maximum daily dose makes 320/25 mg (2 tablets of 160/12.5 mg).

Maximum antihypertensive effect is reached by

during 2–4 weeks

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

Additional information for special groups of patients

Renal failure. Selection of a dose is not required from patients with a slight and moderate renal failure (clearance of creatinine of ≥30 ml/min.). Because of existence of a hydrochlorothiazide of Vanatex Kombi it is contraindicated to patients with a heavy renal failure.

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

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

Contraindication

Hypersensitivity to a valsartan, a hydrochlorothiazide, other medicines on the basis of sulfonamide or to any of excipients. heavy liver failure, cirrhosis and cholestasia. heavy renal failure (clearance of creatinine of 30 ml/min.), anury. steady hypopotassemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia.

Side effects

Side reactions at use valsartana / a hydrochlorothiazide

from a metabolism and food: infrequently — dehydration.

from nervous system: very seldom — dizziness; infrequently — paresthesias, a hypesthesia; it is unknown — a faint, insomnia.

from an organ of sight: infrequently — illegibility of sight, a disorder of vision.

from an organ of hearing: infrequently — a ring in ears, average otitis.

from a cardiovascular system: infrequently — arterial hypotension, tachycardia.

from a respiratory system: infrequently — cough; it is unknown — not cardiogenic fluid lungs.

from a GIT: very seldom — diarrhea.

from a musculoskeletal system: infrequently — myalgia (muscle pain); very seldom — an arthralgia.

from an urinary system: it is unknown — a renal failure.

General disturbances: infrequently — fatigue.

Laboratory indicators: it is unknown — increase in level of uric acid in blood plasma, increase in level of bilirubin and creatinine in blood plasma, a hypopotassemia, a hyponatremia, increase in level of urea nitrogen in blood, a neutropenia.

Additional information on separate components of drug. Undesirable reactions about which it was reported earlier, caused by one of separate components of medicament can be also potential undesirable influence of Vanatex Kombi.

Side reactions at use of a valsartan

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

from the immune system: it is unknown — other allergic reactions / reactions of hypersensitivity, including a serum disease.

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

from an organ of hearing: infrequently — dizziness (vertigo).

from a cardiovascular system: it is unknown — a vasculitis.

from a GIT: infrequently — an abdominal pain.

from digestive system: 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 an urinary system: it is unknown — a renal failure and a renal failure, increase in level of creatinine in blood plasma.

from a respiratory system: very seldom — bronchitis, upper respiratory tract infections.

Side reactions at use of a hydrochlorothiazide. The hydrochlorothiazide was widely applied for many years, it is frequent in higher doses, than contained in Vanatex Kombi. It is reported about the side below-mentioned reactions at the patients receiving monotherapy by thiazide diuretics including a hydrochlorothiazide.

from the system of blood and lymphatic system: seldom — thrombocytopenia, sometimes with a purpura; very seldom — an agranulocytosis, a leukopenia, hemolytic anemia, oppression of function of marrow.

from the immune system: very seldom — allergic reactions (reactions of hypersensitivity).

from mentality: seldom — a depression, a sleep disorder.

from nervous system: seldom — a headache.

from a cardiovascular system: seldom — arrhythmia; often — orthostatic hypotension.

from a respiratory system: very seldom — the complicated breath (asthma), including pneumonia and a fluid lungs.

from a GIT: often — lack of appetite, slight nausea and vomiting; seldom — a constipation, discomfort in a GIT; very seldom — pancreatitis.

from digestive system: seldom — a cholestasia, jaundice.

from skin and hypodermic fabrics: often — a small tortoiseshell and other types of rash; seldom — a photosensitization; very seldom — a necrotizing vasculitis and a toxic epidermal necrolysis, a system lupus erythematosus, eritematozopodobny reactions, reactivation of skin manifestations of a lupus erythematosus.

from a reproductive system and mammary glands: often — impotence.

Special instructions

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

Hydrochlorothiazide. It is reported about a hypopotassemia at treatment by thiazide diuretics, including a hydrochlorothiazide. Recommend frequent control of content of potassium in blood plasma.

Treatment by thiazide diuretics, including a hydrochlorothiazide, was connected with a hyponatremia and a gipokhloremichesky alkalosis. Tiazida, including a hydrochlorothiazide, increase magnesium discharge with urine that can lead to a hypomagnesiemia. Discharge of calcium decreases owing to intake of thiazide diuretics. It can lead to a hypercalcemia.

As well as at any patient receiving treatment by diuretics needs to carry out by

periodic determination of level of electrolytes in blood plasma through the corresponding periods.

Patients with a hypovolemia. Behind a condition of the patients accepting thiazide diuretics, including a hydrochlorothiazide, it is necessary to establish observation of rather clinical manifestations of a water and electrolytic imbalance. At a heavy hypovolemia the patients accepting diuretics in high doses can seldom have a symptomatic hypotension after the begun therapy by the medicament Vanatex Kombi. The hypovolemia needs to be adjusted before an initiation of treatment the medicament Vanatex Kombi.

Patients with heavy chronic heart failure. Use of Vanatex Kombi for patients with heavy chronic heart failure was not investigated.

Renal artery stenosis. Vanatex Kombi should not apply to treatment of AG at patients about one - or a bilateral renal artery stenosis or a renal artery stenosis of the only kidney as at such patients the level of urea and creatinine in blood plasma can increase.

Primary hyper aldosteronism. Patients with primary hyper aldosteronism should not be treated the medicament Vanatex Kombi as their renin-angiotenzinovaya a system is not activated.

Stenosis of the aortal and mitral valve, subaortic hypertrophic stenosis. As well as in a case with other vazodilatator, it is necessary to observe extra care at treatment of patients with a stenosis of the aortal or mitral valve or a hypertrophic subaortic stenosis.

Renal failure. In view of oppression (inhibition) system renin-angiotensin-aldosteronovoy, use of Vanatex Kombi can be also connected with a renal failure. Vanatex Kombi should not be applied at such patients. it is not required by

Dose adjustment to p from patients with a renal failure and clearance of creatinine of ≥30 ml/min. Recommend periodic control of level of potassium in blood plasma, creatinine and urea if Vanatex Kombi apply at patients with a renal failure. At clearance of creatinine of 30 ml/min. of Vanatex Kombi it is not necessary to apply.

Transplantation of kidneys. There is no experience of safe use of Vanatex Kombi for the patients who recently transferred transplantation of kidneys now.

Liver failure. Patients with a slight and moderate liver failure without cholestasia of Vanatex Kombi should take with caution.

System lupus erythematosus. It was reported that thiazide diuretics, including a hydrochlorothiazide, aggravate or activate a system lupus erythematosus.

Other metabolic disturbances (disbolism). Thiazide diuretics, including a hydrochlorothiazide, can change tolerance to glucose and increase levels XC, TGi of uric acid in blood plasma. At patients with diabetes the selection (correction) of a dose of insulin or oral medicaments for decrease in level of glucose in blood can be required.

Tiazida's

can reduce removal of calcium with urine and lead to temporary and slight increase of level of calcium in blood plasma in the absence of the known disturbances of calcic exchange. The expressed hypercalcemia can testify to an expected hyperparathyreosis (hyperfunction of epithelial bodies). It is necessary to stop reception of tiazid before conducting a research of function of epithelial bodies.

Photosensitivity. It was reported about cases of reactions of photosensitivity at treatment by thiazide diuretics. If reaction of photosensitivity arises during treatment, recommend to stop administration of drug. If repeated prescribing of diuretic medicaments is considered necessary, recommend to protect vulnerable areas from the sun or artificial ultraviolet radiation And.

Doping control. It must be kept in mind that medicament can lead to positive reaction at anti-doping control.

General information. It is necessary to be careful to patients who in the anamnesis have a hypersensitivity to other antagonists of receptors of AT II. Allergic reactions to a hydrochlorothiazide are more probable at patients with an allergy and OH.

Excipients. Patients with rare hereditary conditions of intolerance of a galactose, a lactose intolerance or a sprue of glucose should not take this drug.

Use during pregnancy and feeding by a breast

Pregnancy. Valsartan. Use of antagonists of receptors of AT II (AIIRAs) is not recommended in the I trimester of pregnancy. It is known that action of antagonists of receptors of AT II (AIIRAs) on a uterus in case of their appointment to pregnant women in II and III trimester leads to disturbance and death of the developing fruit. Use of antagonists of receptors of AT II is contraindicated in II and III trimester of pregnancy.

Hydrochlorothiazide. Experience of use of a hydrochlorothiazide during pregnancy, especially in the I trimester, is organic. Administration of thiazide diuretic in a cavity of the uterus led to development of thrombocytopenia in a fruit or the newborn and also to development of other undesirable phenomena. The hydrochlorothiazide gets through a placenta. Considering the pharmacological mechanism of action of a hydrochlorothiazide, its use in II and III trimester can lead to threat of disturbance of fetoplacental perfusion and can cause such disturbances in a fruit and the newborn as jaundice, disturbance of electrolytic balance and thrombocytopenia.

Feeding by a breast. There are no data on use of a valsartan during feeding by a breast. The hydrochlorothiazide gets into breast milk. Thus, Vanatex Kombi do not recommend to apply during feeding by a breast. If pregnancy is revealed during treatment, medicament should be cancelled as soon as possible.

Children. Safety and efficiency of use of Vanatex Kombi for children are not established.

Ability to influence speed of response at control of vehicles or work with other mechanisms. As well as at use of other antihypertensive drugs, it is desirable to be careful at control of vehicles and work with other mechanisms.

Interaction

Interaction, connected as with valsartany, and the Combined use is not recommended to

by a hydrochlorothiazide

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

Combined use demanding care

Other antihypertensive drugs. Vanatex Kombi can strengthen effect of other medicaments with antihypertensive properties (for example APF inhibitors, blockers of β-adrenoceptors, blockers of calcium channels).

Pressor amines (for example Norepinephrinum, epinephrine). The reduction of expressiveness of reaction to pressor amines insufficient is possible to exclude use.

NPVP, including selection TsOG-2 inhibitors, acetylsalicylic acid (3 g/days) and non-selective NPVP. NPVP can weaken antihypertensive effect of antagonists of receptors of AT II and hydrochlorothiazide at simultaneous use. Besides, simultaneous use of the medicament Vanatex Kombi and NPVP can lead to deterioration in function of kidneys and increase in level of potassium in blood plasma. Thus, control of function of kidneys in an initiation of treatment and also the corresponding hydration is recommended.

Interaction, connected with valsartany

Simultaneous use is not recommended to

Kaliysberegayushchy diuretics, potassium additives, the salt substitutes containing potassium, and other substances which can increase potassium levels in blood plasma. If it is considered that medicine which influences potassium level needs to be combined with valsartany, control of level of potassium in blood plasma is recommended.

Interaction is absent. Researches of interaction of medicines with valsartany did not reveal clinically significant interactions with valsartany or any of the following medicines: Cimetidinum, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipin, glibenclamide. Digoxin and indometacin can interact with a component of the medicament Vanatex Kombi a hydrochlorothiazide (see the Interactions connected with a hydrochlorothiazide).

Interaction, connected with a hydrochlorothiazide

Simultaneous use demanding care

Medicines which use is connected with potassium loss, and at a hypopotassemia (for example at co-administration of potassiumuretic diuretics, GKS, depletive, AKTG, Amphotericinum, a karbenoksolon, penicillin G, salicylic acid and its derivatives). If it is necessary to appoint these medicines in a combination with a hydrochlorothiazide and valsartany, control of level of potassium in blood plasma is recommended. These medicines can strengthen influence of a hydrochlorothiazide on potassium level in blood plasma.

Medicines which can cause piruetny ventricular tachycardia:

• antiarrhytmic medicaments of the class Ia (for example quinidine, hydroquinidine, Disopyramidum);
• antiarrhytmic medicaments of class III (for example Amiodaronum, sotalol, dofetilid, ibutilid);
• some neuroleptics (for example thioridazine, Chlorpromazinum, levomepromazinum, trifluoperazin, tsiamemazin, Sulpiridum, sultoprid, amisulprid, tiaprid, Pimozidum, haloperidol, Droperidolum);
• others (for example bepridit, tsizaprid, difemanit, erythromycin (in / c), galofantrin, ketanserin, mizolastin, pentamidine, sparfloksatsin, terfenadin, Vincaminum (in / c).

Because of risk of a hypopotassemia a hydrochlorothiazide should be applied with care in combination with medicines which can cause piruetny ventricular tachycardia.

Cardiac glycosides. The hypopotassemia or a hypomagnesiemia caused tiazidy can arise as side effect which contributes to the development of digitalis arrhythmia.

Salt of calcium and vitamin D. Use of thiazide diuretics, including a hydrochlorothiazide, with vitamin D or salts of calcium can increase calcium level in blood plasma.

Anti-diabetic means (oral medicaments and insulin). Treatment by thiazide diuretics can affect tolerance to glucose. Dose adjustment of antidiabetic medicines can be required. Metformin should be applied with care because of risk of the lactacidemia caused by the possible functional renal failure connected with a hydrochlorothiazide.

Blockers of β-adrenoceptors and diazoxide. Simultaneous use of thiazide diuretics, including a hydrochlorothiazide, with blockers of β-adrenoceptors can increase risk of a hyperglycemia. Thiazide diuretics, including a hydrochlorothiazide, can strengthen hyper glycemic influence of diazoxide.

Medicines used at treatment of gout (probenetsid, Sulfinpyrazonum and Allopyrinolum). Dose adjustment of uricosuric medicaments as the hydrochlorothiazide can increase the level of uric acid in blood plasma can be required. Increase in a dose of a probenetsid or Sulfinpyrazonum can be required. Co-administration of thiazide diuretics, including a hydrochlorothiazide, can increase the frequency of allergic reactions to Allopyrinolum.

Anticholinergics (for example atropine, Biperidinum). The bioavailability of thiazide diuretics can increase anticholinergics probably because of reduction of motility of a GIT and speed of gastric emptying.

Amantadin. Tiazida, including a hydrochlorothiazide, can increase risk of emergence of adverse effects of an amantadin.

Kolestiraminovaya and kolestipolovy pitches. Absorption of thiazide diuretics, including a hydrochlorothiazide, is broken in the presence of anionno-exchange pitches.

Cytotoxic means (for example cyclophosphamide, methotrexate). Tiazida, including a hydrochlorothiazide, can reduce discharge of cytotoxic substances kidneys and enhance their myelosuppressive effect.

not depolarizing muscle relaxants (for example tubocurarine). Tiazida, including a hydrochlorothiazide, strengthen action of derivative curares.

Cyclosporine. The accompanying reception with cyclosporine can increase risk of emergence of a hyperuricemia and emergence of the symptoms reminding exacerbation of gout.

Alcohol, anesthetics and sedatives. Can strengthen orthostatic hypotension.

Methyldopum. The patients receiving the accompanying treatment metildopy and a hydrochlorothiazide have separate messages about cases of hemolytic anemia.

Karbamazepin. At patients who receive a hydrochlorothiazide along with carbamazepine the hyponatremia can develop. Therefore, such patients have to be informed on a possibility of giponatriyemichesky reactions and be under control.

Yodosoderzhashchy contrast agents. In case of the dehydration caused by diuretic there is an increased risk of development of OPN, especially at high doses of iodine. Sufficient hydration before reception is necessary.

Overdose

Symptoms. the overdose of a valsartan 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). besides, such signs and symptoms can arise at overdose of a hydrochlorothiazide: the nausea, drowsiness, a hypovolemia and electrolytic disturbances connected with cardiac arrhythmias and muscular spasms.

Treatment. Therapeutic measures depend on time of meal and type and weight of symptoms, blood circulation stabilization is very important.

Therapeutic measures depend on time which passed from the overdose moment and also a look and weight of symptoms, at the same time a primary measure is haemo circulation normalization.

If the medicament was taken by

recently, it is necessary to cause vomiting. If after use of medicament there passed the long time, use of activated carbon in enough is necessary.

In arterial hypotension should give to the patient horizontal position and to urgently provide recovery of water-salt balance by administration of isotonic salt solution.

Valsartan cannot be brought out of an organism by means of a hemodialysis owing to its linking with proteins of blood plasma, but for removal from a hydrochlorothiazide organism the hemodialysis is effective.

Storage conditions

B the dry, protected from light place at a temperature not above 30 °C. to store out of children's reach.