Instructions for use VALSACOR® H160

Dosage form and composition

The medication is intended for oral administration and is available in the form of yellow film-coated tablets:

• Valsacor: contains the active substance valsartan - an antagonist of hormone receptors that provokes an increase in pressure in blood vessels, prevents the development of hypertensive attacks;
• Valsacor N80, ND160: a combination drug containing two active ingredients: valsartan and hydrochlorothiazide, has a more pronounced and long-lasting therapeutic effect, reduces blood pressure.

In addition to active compounds, pills contain auxiliary components: MCC, lactose, silicon dioxide, stabilizing and form-building additives.

Mechanism of action of drugs

Valsacor provides a long-term reduction in the resistance of vascular walls, prevents their spasms, improves myocardial contractility, and increases the volume of blood pumped by the heart. As a result, unfavorable symptoms of deficiency disappear:

• think in your ears and head;
• swelling;
• dyspnea;
• physical weakness;
• dizziness.

Valsacor N maintains normal blood pressure, reduces the likelihood of valsartan side effects, and helps hypertensive patients maintain good health. Hydrochlorothiazide in its composition has a diuretic effect, stimulates the excretion of excess sodium and chlorine.

The medicine quickly dissolves in the stomach after administration and is absorbed into the blood. The effect of one dose of tablets develops over 30–60 minutes, reaches a maximum after 4–5 hours and lasts up to a day. With regular use, Valsacor provides an increasing antihypertensive effect after 3-4 weeks - it prevents the development of high blood pressure.

About 60% of hydrochlorothiazide ingested interacts with blood proteins; in combination with valsartan, it is less bioavailable. The components of the drugs do not accumulate in the body. Metabolism occurs in the liver, then the remaining substances are excreted through the intestinal contents and through the kidneys. Disintegration and release occur approximately 9 hours after the dose of the drug.

Instructions for use VALSACOR® H160

Combined antihypertensive drug.

Valsartan/hydrochlorothiazide

In a double-blind, randomized, active-controlled study, patients who failed to achieve adequate BP control with hydrochlorothiazide 12.5 mg received a combination of valsartan/hydrochlorothiazide 160/12.5 mg had a decrease in mean BP (12.4/7.5 mmHg). ) compared with patients receiving only hydrochlorothiazide at a dose of 25 mg (5.2/2.1 mmHg). In addition, a greater number of patients (%) experienced a hypotensive effect on therapy with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (diastolic blood pressure <140/90 mm Hg or a decrease in SBP ≥20 mm Hg or DBP ≥10 mm Hg .st.) (50%) compared to taking hydrochlorothiazide at a dose of 25 mg (25%).

In a double-blind, randomized, active-controlled study, patients who failed to achieve adequate BP control with valsartan 160 mg received a combination of valsartan/hydrochlorothiazide 160/12.5 mg had a decrease in mean BP (14.6/11.9 mmHg). ) compared with patients receiving only valsartan at a dose of 160 mg (8.7/8.8 mmHg). The difference in blood pressure reduction when comparing doses of 160/25 mg and 160/12.5 mg reached statistical significance. In addition, a greater number of patients (%) experienced a hypotensive effect (diastolic blood pressure <90 mmHg or decrease ≥10 mmHg) to therapy with the combination of valsartan/hydrochlorothiazide 160/25 mg (68%) and 160/ 12.5 mg compared to valsartan 160 mg (49%).

A double-blind, randomized, placebo-controlled, factorial design study compared different doses of valsartan/hydrochlorothiazide combinations with their respective components. When comparing placebo (1.9/4.1 mmHg), hydrochlorothiazide at a dose of 12.5 mg (7.3/7.2 mmHg), hydrochlorothiazide at a dose of 25 mg (12.7/9.3 mmHg) and valsartan at a dose of 160 mg (12.1/9.4 mmHg) the greatest decrease in mean blood pressure was observed when taking the combination of valsartan/hydrochlorothiazide 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg (22.5/15.3 mmHg) . In addition, a greater number of patients (%) experienced a hypotensive effect (diastolic blood pressure <90 mmHg or a decrease ≥10 mmHg) to therapy with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (81%) and 160/ 12.5 mg (76%) compared with placebo (29%) and corresponding monotherapy with hydrochlorothiazide 12.5 mg (41%), 25 mg (54%), valsartan 160 mg (59%).

In controlled clinical studies of the combination of valsartan/hydrochlorothiazide, a dose-dependent decrease in serum potassium was observed. A decrease in serum potassium was observed more often in patients receiving hydrochlorothiazide at a dose of 25 mg than in patients receiving hydrochlorothiazide at a dose of 12.5 mg.

In controlled clinical trials of the valsartan/hydrochlorothiazide combination, the hypokalemic effect of hydrochlorothiazide was reduced as a result of the potassium-sparing effect of valsartan.

The beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.

Valsartan

Valsartan is a selective angiotensin II receptor antagonist for oral administration. It has a selective antagonistic effect on receptors of the AT1 subtype. A consequence of AT1 receptor blockade is an increase in plasma concentrations of angiotensin II, which can stimulate unblocked AT2 receptors, which is believed to regulate the effects of AT1 receptors. Valsartan does not have agonist activity against AT1 receptors. Its affinity for receptors of the AT1 subtype is approximately 20,000 times greater than for receptors of the AT2 subtype. Valsartan does not interact with or block other hormone receptors or ion channels involved in regulating the function of the cardiovascular system.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Due to the lack of influence on ACE, the effects of bradykinin and substance P are not potentiated, therefore, when taking angiotensin II receptor antagonists, the development of a dry cough is unlikely.

Clinical studies in which valsartan was compared with an ACE inhibitor showed that the incidence of dry cough was significantly lower in patients receiving valsartan compared to patients receiving an ACE inhibitor (2.6% versus 7.9%, respectively, p>0.05). In clinical trials in patients with a history of cough during ACE inhibitor therapy, dry cough was observed in 19.5% of patients switched to valsartan and 19% of patients treated with thiazide diuretics, compared with 68.5% of patients treated with an ACE inhibitor (p>0.05).

In the treatment of arterial hypertension, valsartan reduces blood pressure without affecting heart rate.

In most patients, after oral administration of a single dose of valsartan, the antihypertensive effect develops within 2 hours, and the maximum reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours. With repeated prescriptions of valsartan, the maximum decrease in blood pressure is achieved, regardless of the dose , is achieved after 2-4 weeks and remains at the achieved level during long-term therapy. In combination with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.

Abrupt withdrawal of valsartan is not accompanied by rebound hypertension or other adverse clinical events.

During observations, it was revealed that as a result of the use of valsartan in patients with type 2 diabetes mellitus and microalbuminuria, protein excretion in the urine decreases. The MARVAL (Microalbuminuria Reduction with Valsartan) study assessed the reduction in urinary protein excretion with valsartan (80-160 mg once daily) compared with amlodipine (5-10 mg once daily) in 332 patients with type 2 diabetes mellitus (average age 58 years; 265 male patients) with microalbuminuria (valsartan - 58 mcg/min; amlodipine - 55.4 mcg/min), normal or elevated blood pressure and preserved renal function (blood creatinine <120 μmol/l) . At 24 weeks, urinary protein excretion decreased (p<0.001) by 42% (-24.2 μg/min; 95% CI:

• -40.4 to -19.1) when using valsartan and approximately 3% (-1.7 mcg/min;
• 95% CI: -5.5 to 14.9) with amlodipine, despite the same level of blood pressure reduction in both groups.

The DROP (The Diovan Reduction of Proteinuria) study continued to study the effectiveness of valsartan in reducing urinary protein excretion in 391 patients with arterial hypertension (BP 150/88 mm Hg) and type 2 diabetes mellitus, albuminuria (mean value - 102 µg/min; 20-700 µg/min) and preserved renal function (mean serum creatinine = 80 µmol/L). Patients were randomized to receive one of 3 doses of valsartan (160, 320, and 640 mg once daily) and were treated for 30 weeks. The purpose of the study was to establish the optimal dose of valsartan to reduce urinary protein excretion in hypertensive patients with type 2 diabetes mellitus. At 30 weeks, the percentage change in urinary protein excretion was significantly reduced by 36% from baseline with valsartan 160 mg (95% CI: 22 to 47%), with a 44% reduction with valsartan 320 mg. (95% CI:

• 31 to 54%). It was concluded that the use of valsartan 160-320 mg caused a clinically significant reduction in urinary protein excretion in patients with hypertension and type 2 diabetes mellitus.

Two large randomized controlled trials, ONTARGET (ONgoing Telmisartan Alone and incombination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes), examined the use of ACE inhibitors in combination with angiotensin II receptor antagonists.

The ONTARGET study was conducted in patients with cardiovascular disease, cerebrovascular disease, or type 2 diabetes with evidence of end-organ damage.

The VA NEPHRON-D study was conducted in patients suffering from type 2 diabetes mellitus and diabetic nephropathy.

Compared with monotherapy, these studies did not show significant beneficial effects on renal function and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalemia, acute renal failure and/or hypotension was observed. Due to similar pharmacodynamic properties, these results are relevant to other ACE inhibitors and angiotensin II receptor antagonists. Therefore, ACE inhibitors and angiotensin II receptor antagonists should not be used simultaneously in patients with diabetic nephropathy.

The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease End points) study was designed to determine the benefits of adding aliskiren to standard ACE inhibitor or angiotensin II receptor antagonist therapy in patients with type 2 diabetes mellitus, chronic renal failure, cardiovascular diseases. The study was stopped early due to an increased risk of adverse outcomes. Stroke and cardiovascular mortality were observed more often in the aliskiren group than in the placebo group. Also, in the group taking aliskiren, undesirable side effects (hyperkalemia, hypotension, renal dysfunction) were more often observed.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic whose site of action is primarily in the distal renal tubules. In the renal cortex there are receptors that have high affinity and are the main binding site for thiazide diuretics, where the transport of NaCl into the distal tubules is suppressed. The mechanism of action of thiazides is due to inhibition of the cotransport of Na+ and Cl- ions, possibly due to competition for Cl- transport sites, which affects the mechanisms of electrolyte reabsorption:

• the excretion of sodium and chloride ions increases approximately equally in direct proportion. Indirectly, as a result of this diuretic effect, there is a decrease in plasma volume, resulting in increased renin activity, aldosterone secretion, and urinary excretion of potassium, resulting in a decrease in serum potassium concentration.

The relationship between renin and aldosterone is mediated by angiotensin II, therefore, with simultaneous use of valsartan, the decrease in serum potassium concentration is less pronounced than with the use of hydrochlorothiazide as monotherapy.

Non-melanoma skin cancer (NMSC)

Based on available data from epidemiological studies, there is a cumulative dose-dependent association between hydrochlorothiazide and NMSC. One study included a population of 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma matched to 1,430,833 and 172,462 control populations, respectively. High-dose hydrochlorothiazide (cumulative ≥50,000 mg) was associated with an adjusted OR of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A clear dose-response relationship was observed for both basal cell carcinoma and squamous cell carcinoma. Another study showed a possible association between lip cancer (SCC) and HCTZ exposure: 633 cases of lip cancer were matched to 63,067 population controls using a risk-adjusted sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI:

• 1.7-2.6), increasing to OR 3.9 (3.0-4.9) for the highest cumulative dose (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg).

Valsacor: use according to instructions

The drug is taken as prescribed by a cardiologist for the following pathologies:

• heart failure of non-acute severity: with functional disorders while maintaining a stable physical condition and during periods of remission;
• after a heart attack, with persisting dysfunction of the left ventricle of the myocardium;
• chronic heart failure without correction of the condition with ACE inhibitors;

Valsacor N and ND are prescribed in cases of hypertension as part of complex treatment.

The treatment regimen depends on the existing health problems:

• average daily dosage at the initial stage: 20–40 mg of the drug twice a day;
• if necessary, the dose of the drug is increased to 160 mg per day;
• The maximum dose of medication per day is 320 mg.

The tablets are taken with a sufficient amount of water, regardless of meal time. There is no need to chew or crush the medicine beforehand. Valsacor is used for long-term correction of physical condition. The general course of its use is at least several months. If side effects are detected, the dose of the drug is reduced or it is recommended to buy a similar antihypertensive drug.

Valsacor N160 tablets 160 mg + 12.5 mg 30 pcs.

Valsartan. Valsartan is a selective ARA II for oral administration, of a non-protein nature. Selectively blocks AT1 receptors responsible for the vasopressor effect of angiotensin II. The consequence of AT1 receptor blockade is an increase in the concentration of angiotensin II in the blood plasma, which can stimulate unblocked AT2 receptors, which balances the vasopressor effects associated with the stimulation of AT1 receptors. Valsartan does not have agonist activity against AT1 receptors. Its affinity for AT1 receptors is approximately 20,000 times higher than for AT2 receptors. Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Due to the lack of influence on ACE, the effects of bradykinin and substance P are not potentiated. The incidence of dry cough is lower in patients receiving ARA II compared to patients receiving ACE inhibitors. Valsartan does not interact with or block receptors of other hormones or ion channels involved in the regulation of the functions of the cardiovascular system. In the treatment of arterial hypertension (AH), valsartan reduces blood pressure (BP) without affecting heart rate (HR). After oral administration of a single dose of valsartan, the antihypertensive effect develops within 2 hours, and the maximum reduction in blood pressure is achieved after 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours after its use. With continuous use of valsartan, the maximum reduction in blood pressure, regardless of the dose, is achieved after 2-4 weeks and is maintained at this level during long-term therapy. Simultaneous use with hydrochlorothiazide allows achieving a significant additional reduction in blood pressure. Sudden withdrawal of valsartan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences. Hydrochlorothiazide (HCTZ). The point of action of thiazide diuretics is the distal convoluted renal tubules. When thiazide diuretics act on highly sensitive receptors of the distal tubules of the renal cortex, the reabsorption of sodium (Na+) and chlorine (Cl-) ions is suppressed. Suppression of the Na+ and Cl- co-transport system apparently occurs due to competition for Cl- binding sites in this system, which leads to an increase in the excretion of Na+ and Cl- to approximately the same extent. As a result of the diuretic effect, a decrease in circulating blood volume (CBV) is observed, as a result of which renin activity, aldosterone secretion, potassium excretion by the kidneys and, consequently, a decrease in the potassium content in the blood serum increase. The connection between renin and aldosterone is mediated by angiotensin II, therefore the decrease in serum potassium with simultaneous use of HCTZ with valsartan is less pronounced than with HCTZ monotherapy.

Side effects

During treatment with Valsacor, the following are likely:

• severe hypotension;
• muscle weakness, drowsiness, fatigue;
• loss of appetite, nausea, impaired intestinal motility;
• back pain;
• cough;
• insomnia.

In case of overdose, vomiting, disturbances in heart rhythm, coordination of movements, water-salt balance develop, a sharp headache occurs, a feeling of stunnedness, fainting, and toxic shock are possible.

Precautions and contraindications

Valsacor requires careful use and constant monitoring of well-being in cases of impaired renal and liver function during treatment after a heart attack. The drug enhances the toxic effect of medications containing acetylsalicylic acid. It is not advisable to take Valsacor simultaneously with cardiac glycosides, anti-gout medications, or potassium-sparing agents.

When combined with barbiturates, adrenergic blockers, vasodilators, the diuretic and hypotensive effect of Valsacor is enhanced. It is important to remember this when choosing dosages.

The medicine affects psychomotor reactions, so during the treatment period caution is required when creating vehicles and operating special equipment.

The drug is incompatible with alcohol and can provoke a sharp drop in blood pressure, hypoxia and vascular collapse.

It is necessary to refuse therapy with Valsacor:

• with renal artery stenosis, not on hemodialysis, with severe renal failure;
• with cirrhosis, severe hepatosis;
• acute dehydration;
• during pregnancy and lactation;
• in case of individual intolerance to the components.

Caution is required in various forms of cardiomyopathy, stenosis of the mitral valve or aorta.

Valsacor®

When using Valsacor® in patients with hypertension, regular monitoring of laboratory parameters is not required.

Double blockade of the RAAS

In some patients, double blockade of the RAAS was accompanied by the development of severe arterial hypotension, syncope, stroke, hyperkalemia and renal dysfunction (including acute renal failure).

The simultaneous use of ARB II, including valsartan, with drugs that affect the RAAS, such as ACE inhibitors or aliskiren, is not recommended; if such therapy is necessary, blood pressure, renal function, and blood plasma electrolyte levels should be carefully monitored.

Concomitant use of ARB II, including valsartan, with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

Concomitant use of ARB II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Hyponatremia and/or dehydration

In patients with severe hyponatremia and/or dehydration, for example, due to taking large doses of diuretics, in rare cases, arterial hypotension with clinical manifestations may develop at the beginning of therapy with Valsacor®. Before starting treatment, it is recommended to restore sodium levels and/or replenish blood volume, in particular by reducing the doses of diuretics.

If arterial hypotension with clinical manifestations develops, the patient must be placed in a horizontal position and, if necessary, a 0.9% sodium chloride solution should be administered intravenously. Therapy with Valsacor® can be continued only after stabilization of hemodynamic parameters.

Hyperkalemia

Concomitant use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium supplements, potassium-containing nutritional supplements or other drugs that can increase serum potassium levels (for example, heparin) is not recommended. It is necessary to monitor the potassium content in the blood plasma.

Renal artery stenosis

Short-term use of valsartan in patients with renovascular hypertension, which developed secondary to unilateral stenosis of the artery of a single kidney, was not accompanied by significant changes in renal hemodynamics, creatinine concentrations or serum urea nitrogen. Because other drugs that affect the RAAS can increase serum urea and creatinine concentrations in patients with bilateral renal artery stenosis or solitary renal artery stenosis, continuous monitoring of these values ​​is recommended as a precaution.

Condition after kidney transplantation

The safety of Valsacor® in patients who have recently undergone kidney transplantation has not been established.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are resistant to antihypertensive drugs that affect the RAAS, therefore the use of Valsacor® is not recommended for such patients.

Stenosis of the aortic and/or mitral valves, HOCM

The drug Valsacor® should be used with caution in patients with hemodynamically significant stenosis of the aortic and/or mitral valves or with HOCM.

Renal dysfunction

In patients with impaired renal function, no change in drug dosage is required, because There is no data on the use of the drug Valsacor® in severe renal failure (creatinine clearance less than 10 ml/min or 0.167 ml/s) and in patients on hemodialysis; in such cases, the drug is recommended to be used with caution.

Concomitant use of ARB II, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with impaired renal function (GFR less than 60 ml/min/1.73 m2 body surface area).

Liver dysfunction

For patients with impaired liver function, biliary cirrhosis and cholestasis, Valsacor® at a dosage of 320 mg is contraindicated, because the maximum daily dose should not exceed 80 mg.

History of angioedema

Among patients with angioedema (swelling of the larynx and vocal cords, causing obstruction of the airways and/or swelling of the face, lips, pharynx and/or tongue) during treatment with Valsacor®, cases of development of angioedema in the anamnesis were observed, including when taking ACE inhibitors. If angioedema develops, the drug should be immediately discontinued and the possibility of its re-use should be excluded.

Arterial hypertension

For hypertension, the drug Valsacor® can be used in monotherapy or simultaneously with other antihypertensive drugs, in particular with diuretics.

CHF/increasing survival of patients with acute myocardial infarction

It is possible to use the drug Valsacor® in combination with other drugs used for acute myocardial infarction (thrombolytics, acetylsalicylic acid as an antiplatelet agent, beta-blockers and HMG-CoA reductase inhibitors (statins)). The simultaneous use of Valsacor® and ACE inhibitors in this category of patients is not recommended, because this combination therapy does not lead to additional clinical effect and is accompanied by an increased risk of developing AEs compared to therapy with two drugs separately.

In patients with CHF, triple combination therapy (with Valsacor®, an ACE inhibitor and a beta blocker) is not recommended, because does not lead to additional clinical effect and is accompanied by an increased risk of developing AEs.

The use of Valsacor® in patients with CHF or acute myocardial infarction often leads to a slight decrease in blood pressure. As a rule, discontinuation of the drug is not required if dosing instructions are followed.

In patients whose renal function may depend on the activity of the RAAS (for example, in patients with CHF II–IV FC according to the NYHA classification), therapy with ACE inhibitors and ARB II is accompanied by oliguria and/or an increase in azotemia, and in rare cases, acute renal failure and/or fatal. Since valsartan is a II ARA, the possibility of deterioration of renal function with its use cannot be excluded.

Initiation of therapy in patients with CHF or acute myocardial infarction should be done with caution.

Renal function should always be assessed when assessing patients.

Special information on excipients

The drug Valsacor® contains lactose, therefore the drug is contraindicated in patients with lactase deficiency, lactose intolerance, and glucose-galactose malabsorption syndrome.

Impact on the ability to drive vehicles and machinery

Care must be taken when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, because Dizziness or weakness may develop due to arterial hypotension.