Valz, 160 mg 28 pcs.

Pharmacotherapeutic group: angiotensin II receptor antagonist

ATX code: C09CA03

Pharmacological properties

Pharmacodynamics

p> Valsartan is an active specific angiotensin II receptor antagonist for oral administration. It selectively blocks the AT₁ subtype receptors, which are responsible for the effects of angiotensin II. The consequence of blockade of AT₁ receptors is an increase in plasma concentration of angiotensin II, which may stimulate unblocked AT₂ receptors. Valsartan has no significant agonist activity against AT₁ receptors. The affinity of valsartan for AT₁ receptors is approximately 20,000 times higher than for AT₂ receptors.

Valsartan does not interact with or block other hormone receptors or ion channels that are important in the regulation of cardiovascular function.

The likelihood of coughing with valsartan is very low due to the lack of effect on angiotensin-converting enzyme (ACE), which is responsible for bradykinin degradation.

When comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly (p < 0.05) lower in patients receiving valsartan than in patients taking an ACE inhibitor (2.6% versus 7.9%, respectively). In the group of patients who had previously developed dry cough when treated with an ACE inhibitor, this adverse event (AE) occurred in 19.5% of cases when treated with valsartan and in 19.0% of cases when treated with a thiazide diuretic, whereas cough occurred in 68.5% of cases when treated with an ACE inhibitor (p < 0.05).

Application in arterial hypertension in patients over 18 years

The treatment of patients with arterial hypertension with valsartan shows a decrease in blood pressure (BP) with no change in heart rate.

After oral administration of a single dose of the drug, the onset of antihypertensive action is seen within 2 hours in most patients, and maximum BP reduction is achieved within 4-6 hours, lasting more than 24 hours. During repeated use of the drug, the maximum BP reduction, regardless of the dose taken, is usually achieved within 2-4 weeks and is maintained at the achieved level during prolonged therapy. In case of concomitant use of the drug with hydrochlorothiazide, a significant additional BP decrease is achieved.

An abrupt discontinuation of valsartan is not accompanied by a significant increase in BP (recoil phenomenon) or other NTs. Patients with arterial hypertension, type 2 diabetes mellitus, and nephropathy taking valsartan at doses of 160-320 mg have a significant reduction in proteinuria (36-44%).

Application after acute myocardial infarction in patients over 18 years of age

. When valsartan is used for 2 years in patients who started taking it between 12 h and 10 days after an acute myocardial infarction (complicated by left ventricular failure and/or left ventricular systolic dysfunction) total mortality, cardiovascular mortality, and time to first hospitalization for exacerbation of chronic heart failure (CHF), recurrent myocardial infarction, sudden cardiac arrest, and stroke (non-fatal) are reduced. The safety profile of valsartan in patients with acute myocardial infarction is similar to that of other conditions.

CHF in patients older than 18 years

. The mechanism of action of valsartan in CHF is based on its ability to eliminate the negative effects of chronic hyperactivation of the renin-angiotensin-aldosterone system (RAAS) and its main effector, angiotensin II, namely, vasoconstriction; fluid retention in the body; cell proliferation, leading to the remodeling of target organs (heart, kidneys, vessels); stimulation of excessive synthesis of hormones that act synergistically with the RAAS (catecholamines, aldosterone, vasopressin, endothelin). Against the background of using valsartan in CHF, preload decreases, pulmonary capillary congestion pressure and diastolic pressure in the pulmonary artery decrease, and cardiac output increases. In addition to hemodynamic effects, valsartan, through indirect blockade of aldosterone synthesis, reduces sodium and water retention in the body.

In general, valsartan leads to fewer hospitalizations for CHF, delays CHF progression, improves NYHA functional class of CHF, increases left ventricular ejection fraction, and decreases signs and symptoms of heart failure and improves quality of life compared with placebo.

Application in patients over 18 years of age with arterial hypertension and impaired glucose tolerance

With valsartan and lifestyle changes, there was a statistically significant reduction in the risk of developing diabetes mellitus in this patient population. Valsartan had no effect on the incidence of fatal cardiovascular events, nonfatal myocardial infarction and ischemic attacks, hospitalizations for heart failure or unstable angina, arterial revascularization, in patients with impaired glucose tolerance and arterial hypertension of different age, gender and race.

Application in children and adolescents 6 to 18 years of age for arterial hypertension

In children and adolescents 6 to 18 years of age, valsartan provides a dose-dependent, smooth reduction in BP. With valsartan, maximum BP reduction, regardless of the dose taken, is usually achieved within 2 weeks, and is maintained during long-term therapy.

Pharmacokinetics

absorption

. After oral administration of valsartan, its maximum plasma concentration (C_max) is reached within 2-4 hours. The average absolute bioavailability is 23%. When valsartan is taken with food, the area under the concentration-time curve (AUC) is reduced by 48%, although starting about 8 hours after taking the drug, plasma concentrations of valsartan, both when taken on an empty stomach and when taken with food, are the same. The decrease in AUC, however, is not associated with a clinically significant decrease in therapeutic effect, so valsartan can be taken regardless of the time of ingestion.

Distribution

The volume of distribution (V_d) of valsartan at equilibrium after intravenous (IV) administration was approximately 17 liters, indicating that there was no marked distribution of valsartan in tissues. Valsartan is largely bound to serum proteins (94-97%), predominantly to albumin.

Metabolism

Valsartan is not significantly biotransformed (only about 20% of the ingested dose is excreted as metabolites). The hydroxyl metabolite is determined in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Elevation

The pharmacokinetic curve of valsartan has a descending multiexponential character (the elimination half-life of the initial phase (T_1/2α) less than 1 hour and the final phase (T_1/2β) about 9 hours). Valsartan is excreted mainly unchanged through the intestine (about 83%) and the kidneys (about 13%). After IV administration, plasma clearance of valsartan is about 2 l/h, and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life (T_1/2) of valsartan is 6 hours.

In the range of doses studied, the kinetics of valsartan is linear. No changes in pharmacokinetic parameters were observed with repeated administration of valsartan. When valsartan is administered once daily, cumulation is insignificant. Plasma concentrations of valsartan in women and men were similar.

Pharmacokinetics in selected patient groups

Patients with CHF

In this category of patients, the time to reach C_max and T_1/2 are similar to those in healthy volunteers. The increase in AUC and C_max is directly proportional to the increase in the drug dose (from 40 mg to 160 mg 2 times daily). The cumulation factor averages 1.7. When administered orally, the clearance of valsartan was approximately 4.5 l/h. Age of patients with CHF had no effect on valsartan clearance.

Elderly patients (>65 years)

In some elderly patients, the systemic bioavailability of valsartan is greater than that of younger patients, but this has not been found to have any clinical significance.

Patients with impaired renal function

There has been no correlation between renal function and systemic bioavailability of valsartan. No dose adjustment is required in patients with impaired renal function (creatinine clearance (CK) greater than 10 mL/min). However, valsartan is highly bound to plasma proteins, so its excretion by hemodialysis is unlikely.

Patients with impaired hepatic function

About 70% of the absorbed dose of valsartan is excreted through the intestine (with bile), mostly unchanged. Valsartan is not significantly biotransformed. In patients with mild to moderate hepatic impairment, the bioavailability (AUC) of valsartan is increased by a factor of 2 compared to healthy volunteers. However, there is no correlation between the AUC of valsartan and the degree of hepatic impairment. The use of the drug in patients with severe hepatic impairment has not been studied.

Patients 6 to 18 years

The pharmacokinetic properties of valsartan in children and adolescents 6 to 18 years of age do not differ from the pharmacokinetic properties of valsartan in patients older than 18 years.

Indications

Adults

Children and adolescents

Active ingredient

Composition

1 tablet 160 mg contains:

Active ingredient: valsartan 160 mg;

Auxiliary substances: lactose monohydrate 84.44 mg, microcrystalline cellulose 72.00 mg, croscarmellose sodium 21.60 mg, povidone K29-32 14.40 mg, talc 3.6 mg, magnesium stearate 2.52 mg, colloidal silicon dioxide 1.44 mg;

Shell film:

. Opadray II 85G32408 Yellow about 14.40 mg (polyvinyl alcohol 6.336 mg, talc 2.880 mg, titanium dioxide 1.976 mg, macrogol – 3350 1.778 mg, iron oxide yellow dye 0.910 mg, iron oxide red dye 0.016 mg, lecithin 0.504 mg).

How to take, the dosage

Ingestion, without chewing, regardless of the time of the meal, with water.

Adults

Arterial hypertension./em>

The drug may be prescribed in doses of 80 mg, 160 mg, 320 mg.

The recommended starting dose of Valz is 80 mg once daily, regardless of the race, age, or sex of the patient. Antihypertensive effect is noted in the first 2 weeks of treatment; the maximum effect develops after 4 weeks. For those patients who do not achieve adequate therapeutic response the daily dose of Valz may be increased up to 160 mg and up to maximum daily dose of 320 mg, diuretics may be additionally prescribed.

Chronic heart failure

The drug may be prescribed in doses of 40 mg, 80 mg, 160 mg.

The recommended starting dose of Valz is 40 mg 2 times daily. The dose of the drug should be gradually increased over at least 2 weeks to 80 mg twice daily, and if tolerated well, to 160 mg twice daily. The maximum daily dose is 320 mg in 2 doses. In this case, it may be necessary to reduce the dose of concomitantly used diuretics.

The evaluation of patients with CHF should include evaluation of renal function.

To improve survival of patients after myocardial infarction

The drug may be prescribed in doses of 40 mg, 80 mg, 160 mg.

Treatment is started within 12 hours after a myocardial infarction with an initial dose of 20 mg (1/2 tablet 40 mg) 2 times daily, with subsequent dose increases (40 mg, 80 mg, 160 mg 2 times daily) over the next few weeks, until the target dose of 160 mg 2 times daily is reached.

The achievement of the dose to 80 mg 2 times daily is recommended by the end of the 2nd week of treatment. Reaching the maximum target dose of 160 mg 2 times daily is recommended by the end of the 3rd month of therapy with Valz. Increasing the dose depends on the tolerability of the drug during the period of dose selection.

In case of arterial hypotension accompanied by clinical manifestations or impaired renal function, dose reduction should be considered.

The evaluation of patients after myocardial infarction should include evaluation of renal function.

The maximum daily dose is 320 mg in 2 doses.

Use in elderly patients (over 65 years)

Dose adjustment in elderly patients is not required.

Application in renal impairment

Dose adjustment is not required in patients with renal impairment with a CKR greater than 10 ml/min. Concomitant administration of valsartan with aliskiren is contraindicated in patients with moderate to severe renal function impairment (FFR less than 60 mL/min/1.73 m2 body surface area). There are currently no data on the use of the drug in patients with a CKR of less than 10 ml/min.

Application in hepatic dysfunction

. In patients with mild to moderate hepatic dysfunction of non-biliary genesis without cholestasis, the drug should be used with caution; the daily dose should not exceed 80 mg. In patients with severe hepatic impairment (more than 9 points by Child-Pugh score), biliary cirrhosis and cholestasis the use of Valz is contraindicated.

Children and adolescents

. Arterial hypertension

. The recommended starting dose of Valz in children and adolescents from 6 to 18 years of age is 40 mg once a day if the body weight of the child is less than 35 kg and 80 mg once a day if the body weight of the child is more than 35 kg. The dose is recommended to be adjusted taking into account the decrease of BP.

The maximum recommended daily doses are shown in the table below. Higher doses are not recommended.

Body weight

Maximum recommended daily dose

> 8 kg < 35 kg

80 mg

> 35 kg <80 kg

160 mg

> 80 kg < 160 kg

320 mg

Interaction

Double blockade of the RAAS by angiotensin receptor antagonists, ACE inhibitors or aliskiren:

The concomitant use of angiotensin II receptor antagonists with drugs containing aliskiren is contraindicated in patients with diabetes and/or moderate to severe renal impairment (FFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

The concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Combined administration is not recommended

Lithium preparations

. Concomitant use of lithium with ACE inhibitors and angiotensin II receptor antagonists has resulted in a reversible increase in serum lithium and an increase in its toxic effects. Due to the lack of experience with lithium and valsartan, coadministration is not recommended. Serum lithium should be monitored if Valsartan and lithium preparations are to be coadministered.

Drugs that may lead to increased plasma potassium

When concomitant use with dietary supplements, potassium-containing salt substitutes, or other drugs that may cause increased blood potassium, regular monitoring of plasma potassium should be performed.

Combinations requiring caution when using

Non-steroidal anti-inflammatory drugs (NSAIDs)

Special Instructions

Hyperkalemia

. When used concomitantly with potassium supplements, potassium-saving diuretics, potassium-containing salt substitutes, or other drugs that may cause an increase in blood potassium (e.g., heparin), caution should be exercised and blood potassium should be monitored regularly.

Renal dysfunction

There is no experience of safe use in patients with IQ less than 10 mL/min and in patients on hemodialysis, so valsartan should be used with caution in these patients. No dose adjustment is required in patients with a CKR greater than 10 mL/min.

Hepatic disorders

In patients with mild to moderate hepatic impairment without cholestasis, use valsartan with caution.

Sodium deficiency and/or decreased BOD

. In patients with severe sodium deficiency and/or decreased blood pressure, e.g., those receiving high doses of diuretics, arterial hypotension with clinical manifestations may occur in rare cases after initiation of valsartan therapy. Before starting therapy with Valz, the sodium content in the body should be corrected and/or the BOD should be replenished, including by reducing the dose of diuretic.

Renal artery stenosis

. Short-course drug administration in patients with renovascular hypertension secondary to unilateral arterial stenosis of the sole renal artery does not result in any significant change of renal hemodynamic parameters, serum creatinine concentration or blood urea nitrogen. However, taking into account that other drugs influencing RAAS may cause increase of serum urea and creatinine concentration in patients with bilateral renal artery stenosis or arterial stenosis of the uniciliary artery, monitoring of these parameters is recommended as a precautionary measure.

Kidney transplantation

There are no data on the safety of Valz in patients undergoing kidney transplantation.

Primary hyperaldosteronism

The drug is not effective in treating arterial hypertension in patients with primary hyperaldosteronism because there is no activation of the RAAS in this patient category.

Aortic and mitral stenosis, obstructive hypertrophic cardiomyopathy

. As with other vasodilating agents, caution should be exercised when taking Valz in patients with aortic or mitral stenosis and obstructive hypertrophic cardiomyopathy.

Pregnancy

The use of angiotensin II receptor antagonists is contraindicated during pregnancy. Patients planning to become pregnant should be treated with alternative medications that have a proven safety profile for use during pregnancy. If pregnancy is diagnosed during treatment with Valz, it should be discontinued as soon as possible and alternative treatment should be prescribed (see sections Contraindications and Pregnancy and Breast-feeding).

CRC/Period after myocardial infarction

Patients with CHF or after myocardial infarction who start valsartan treatment often have a slight decrease in BP, so BP monitoring at the beginning of therapy is recommended. There is usually no need to withdraw the drug due to hypotension if the recommendations for changing the dosing regimen are followed. Evaluation of patients with CHF should include evaluation of renal function.

RaAS inhibition may cause renal dysfunction in some patients. In patients with CHF of II-IV functional class according to NYHA classification, treatment with ACE inhibitors and angiotensin II receptor antagonists may be accompanied by oliguria and/or increase in azotemia and in rare cases by development of acute renal failure and/or lethal outcome. Therefore, in these categories of patients renal function assessment should be performed before the use of Valz, as well as periodically during treatment.

Combination therapy in arterial hypertension

In arterial hypertension, Valz may be used in monotherapy as well as in combination with other hypotensive agents, particularly diuretics.

Combination therapy in the period after myocardial infarction

The use of Valz in combination with other drugs used after myocardial infarction, viz: thrombolytics, acetylsalicylic acid as an antiplatelet agent, beta-adrenoblockers, HMG-CoA reductase inhibitors and diuretics. It is not recommended to use Valz concomitantly with ACE inhibitors in this patient population because this combination therapy has no advantage over valsartan or ACE inhibitor monotherapy with respect to the rates of total mortality from any cause.

Combination therapy in CHF

In CHF, Valz may be used either in monotherapy or simultaneously with other agents such as diuretics, cardiac glycosides, and ACE inhibitors or beta-adrenoblockers.

The use of triple combination therapy with ACE inhibitor, beta-adrenoblocker and Valz is not recommended in this category of patients.

Angeoneurotic edema (Quincke’s edema)

In treatment with Valsartan, there have been reports of angioedema with laryngeal and vocal cord edema leading to airway obstruction, and/or edema of the face, lips, pharynx and/or tongue. Some patients in this group have had previous angioedema with other drugs, including ACE inhibitors. If angioedema develops, Valz should be discontinued immediately, after which drugs containing valsartan should not be taken in the future.

Double blockade of the RAAS

When treated with drugs affecting the RAAS, especially in combination, marked BP decreases, syncope, stroke, hyperkalemia, and changes in renal function (including acute renal failure) have been reported in sensitive patients.

Caution is required when combining angiotensin II receptor antagonists, including valsartan, with other drugs that block the RAAS, such as ACE inhibitors or aliskiren.

The concomitant use of angiotensin II receptor antagonists, including valsartan, with drugs containing aliskiren is contraindicated in patients with diabetes and/or moderate to severe renal impairment (FFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

The concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Other RAAS stimulation conditions (320 mg dose only)

. In patients in whom renal function may depend on RAAS activity (e.g., patients with severe congenital heart failure), treatment with ACE inhibitors is associated with the occurrence of oliguria and/or progressive azotemia and, in rare cases, acute renal failure and/or mortality. Because valsartan is an angiotensin II receptor antagonist, it cannot be excluded that its use may be associated with impaired renal function.

Children and adolescents under 18 years

Kidney function impairment

In patients 6 to 18 years of age with impaired renal function at CK < 30 ml/min, as well as in patients on hemodialysis, the use of the drug has not been studied, so its use in this group of patients is not recommended. In patients from 6 to 18 years old with CKR over 30 ml/min, no dose adjustment is required. Renal function and serum potassium content should be carefully monitored while taking Valz. Especially these precautions should be taken when taking Valz against the background of fever or with decreased blood circulation, because in this case renal dysfunction may occur.

Hepatic impairment

As in adult patients, Valz is contraindicated in patients 6 to 18 years of age with severe hepatic impairment, biliary cirrhosis, and cholestasis. There is limited experience with Valsartan in patients with mild to moderate hepatic impairment. The dose of 80 mg should not be exceeded in this group of patients.

Influence on driving and operating ability

Patients taking Valz should be careful when driving or performing other potentially dangerous activities as dizziness or syncope may occur with this medication.

Synopsis

Contraindications

Cautions

Bilateral renal artery stenosis; artery stenosis of the sole kidney; primary hyperaldosteronism, maintenance of a diet with limited intake of table salt; in conditions accompanied by decreased circulating blood volume (CBC) (including diarrhea and vomiting); severe renal insufficiency (CK less than 10 ml/min), as there is no clinical evidence; in patients aged 6-18 years old with CKR less than 30 ml/min, including those on hemodialysis; mild and moderate liver function abnormalities of non-biliary genesis without cholestasis, CHF class II-IV (by NYHA), mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy, patients after renal transplantation; concurrent use of drugs that block RAAs (ACE inhibitors, aliskiren).

Side effects

In controlled clinical trials of valsartan in adult patients with arterial hypertension, the incidence of NS was comparable to placebo.

There are no data on dose- or duration-of-treatment, gender, age, or race correlating the incidence of any of the NIHs. The safety profile of Valz in patients with arterial hypertension aged 6 to 18 years does not differ from the safety profile of valsartan in adult patients.

The following are the NFRs that have been observed in clinical studies as well as in clinical practice.

Frequency of side effects: Very common (>10%); common (>1% and <10%); infrequent (>0.1% and <1%); rare (>0.01% and <0.1%); very rare (<0.01%), including individual reports; frequency unknown (incidence cannot be determined from available data).

Within each frequency group, NIHs are categorized in decreasing order of importance.

Patients with arterial hypertension

Hematopoietic and lymphatic system: frequency unknown – decrease in hemoglobin, hematocrit, neutropenia, thrombocytopenia.

From the immune system:frequency unknown – hypersensitivity reactions, including serum sickness.

From the side of metabolism and nutrition: frequency unknown – increased serum potassium, hyponatremia.

Hearing organ and labyrinth disorders: infrequently – vertigo.

Vascular aspects:frequency unknown – vasculitis.

In the respiratory system, thoracic and mediastinal organs:infrequent – cough.

From the gastrointestinal tract: infrequently – abdominal pain.

Hepatic and biliary tract disorders: incidence unknown – impaired liver function, including increased plasma bilirubin concentrations.

Skin and subcutaneous tissue: very rare – angioedema, skin rash, itching; frequency unknown – bullous dermatitis.

Musculoskeletal and connective tissue disorders: frequency unknown – myalgia.

Recreational and urinary tract disorders: frequency unknown – impaired renal function, increased serum creatinine concentration.

General disorders and disorders at the site of administration:infrequent – increased fatigue.

Also in clinical studies of valsartan in patients with arterial hypertension, the following ONs have been observed without a causal relationship to its ingestion: arthralgia, asthenia, back pain, diarrhea, dizziness, insomnia, decreased libido, nausea, peripheral edema, pharyngitis, rhinitis, sinusitis, upper respiratory infections, viral infections.

Patients receiving valsartan after acute myocardial infarction and/or CHF

Hematopoietic and lymphatic system: frequency unknown – thrombocytopenia.

From the immune system:frequency unknown – hypersensitivity reactions, including serum sickness.

From the side of metabolism and nutrition: infrequent – hyperkalemia; frequency unknown – increased serum potassium, hyponatremia.

Nervous system disorders:often – dizziness, postural dizziness; infrequently – fainting, headache.

Hearing organ and labyrinth disorders: infrequently – vertigo.

Cardiac side: infrequent – worsening of CHF symptoms.

vascular disorders: frequent – marked decrease in BP, orthostatic hypotension; frequency unknown – vasculitis.

In the respiratory system, thoracic and mediastinal organs: infrequently – cough.

Gastrointestinal tract: infrequently – nausea, vomiting.

Hepatic and biliary tract disorders: incidence unknown – impaired liver function.

Skin and subcutaneous tissue: infrequent – angioedema; frequency unknown – skin rash, itching, bullous dermatitis.

Musculoskeletal and connective tissue disorders: frequently – rhabdomyolysis; frequency unknown – myalgia.

Renal and urinary tract disorders: frequent – renal dysfunction; infrequent – acute renal failure, increased serum creatinine concentration; frequency unknown – increased plasma urea nitrogen.

General disorders and disorders at the site of administration: infrequent – asthenia, increased fatigue.

Also in clinical studies of valsartan in patients after acute myocardial infarction and/or in CHF, the following NIs have been observed, the causal relationship of which to its intake has not been established: Arthralgia, abdominal pain, back pain, asthenia, insomnia, decreased libido, neutropenia, peripheral edema, pharyngitis, rhinitis, sinusitis, upper respiratory infections, and viral infections.

Overdose

Pregnancy use

As any other drug affecting the RAAS, Valz should not be used in women planning pregnancy. When prescribing any drug affecting the RAAS, the doctor should inform women of childbearing age about the potential danger of using these drugs during pregnancy.

The use of the drug Valz in pregnancy is contraindicated because, given the mechanism of action of angiotensin II receptor antagonists, the risk to the fetus cannot be excluded. The effect of ACE inhibitors (drugs which also influence the RAAS) on the fetus, if used in the second and third trimesters of pregnancy, can lead to fetal damage and death.

Based on retrospective data, the use of ACE inhibitors in the first trimester of pregnancy increases the risk of birth defects. There have been reports of spontaneous abortions, oligohydramnios (oligohydramnios), and renal dysfunction in newborns whose mothers inadvertently received valsartan during pregnancy.

If pregnancy is diagnosed during treatment with Vals, it should be discontinued as soon as possible.

It is not known whether valsartan is excreted into human breast milk, so it is contraindicated to use Valsz during breastfeeding.

Similarities