INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VALSARTAN

Composition:

Active substance: valsartan;

1 tablet contains 40 mg of valsartan;

Excipients: mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, magnesium stearate, Opadry Yellow 02F52181;

1 tablet contains 80 mg of valsartan;

Excipients: mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, magnesium stearate, Opadry Pink 02F54189;

1 tablet contains 160 mg of valsartan;

Excipients: mannitol, microcrystine cellulose, povidone, sodium croscarmellose, magnesium stearate, Opadry Yellow 02F52182;

1 tablet contains 320 mg of valsartan;

Excipients: mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, magnesium stearate, Opadry Purple 02F50107.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Valsartan 40: yellow, capsule-shaped, biconvex, film-coated tablets with a break line on one side, engraved with "18" on one side of the line and "2" on the other side, and "N" on the reverse side of the tablet;

Valsartan 80: pink, round, biconvex, film-coated tablets, engraved with "183" on one side and "N" on the other side;

Valsartan 160: yellowish-brown, oval, biconvex, film-coated tablets, engraved with "184" on one side and "N" on the other side;

Valsartan 320: dark grey-purple, capsule-shaped, biconvex, film-coated tablets, engraved with "185" on one side and "N" on the other side.

Pharmacotherapeutic group. Simple angiotensin II antagonists.

ATC Code: C09CA03.

Pharmacological Properties.

Pharmacodynamics.

Valsartan is an orally active, specific angiotensin II antagonist. It acts selectively on AT1 receptors, which mediate the known effects of angiotensin II. Increased plasma levels of angiotensin II following AT1 receptor blockade by valsartan may stimulate unblocked AT2 receptors, which counterbalance the effects of AT1 receptors. Valsartan exhibits no partial agonist activity at the AT1 receptor but has much greater (approximately 20,000 times) affinity for the AT1 receptor than for the AT2 receptor.

Valsartan does not inhibit ACE (angiotensin-converting enzyme), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Administration of the drug to patients with arterial hypertension results in a reduction of blood pressure without affecting pulse rate.

The onset of antihypertensive effect occurs within 2 hours, reaching maximum effect within 4–6 hours after oral administration; the duration of action exceeds 24 hours. The maximal therapeutic effect develops after 4 weeks of treatment and is maintained during long-term therapy. When used in combination with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.

Abrupt discontinuation of the drug does not lead to withdrawal syndrome.

Long-term administration of the drug to patients with arterial hypertension has shown no significant effect on total cholesterol, uric acid levels, or on serum triglyceride and glucose concentrations measured in the fasting state.

Administration of the drug reduces hospitalization due to heart failure, slows the progression of heart failure, improves functional class according to NYHA classification, increases ejection fraction, and alleviates symptoms of heart failure and improves quality of life compared to placebo.

The VALIANT study demonstrated that valsartan, like captopril, is effective in reducing overall mortality after myocardial infarction. Valsartan was also effective in reducing cardiovascular mortality, hospitalizations due to heart failure, and recurrent myocardial infarction. Valsartan positively influenced the time from acute myocardial infarction to the first occurrence of fatal cardiovascular events.

Children

The antihypertensive effect of valsartan was evaluated in 4 randomized, double-blind clinical trials involving 561 children aged 6 to 18 years and 165 children aged 1 to 6 years. Renal and urinary tract disorders and obesity were the most common underlying medical conditions causing arterial hypertension in children included in these studies.

Clinical experience in children aged 6 years and older

In a clinical trial involving 261 hypertensive children aged 6 to 16 years, patients with body weight < 35 kg received 10, 40, or 80 mg of valsartan daily (low, medium, and high doses), while patients with body weight ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium, and high doses). At the end of 2 weeks, valsartan reduced systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium, and high) significantly reduced systolic blood pressure by 8, 10, and 12 mm Hg from baseline, respectively.

Clinical experience in children under 6 years of age

Valsartan is not recommended for use in this age group.

Pharmacokinetics

Absorption

After oral administration of valsartan tablets, peak plasma concentrations are reached within 2–4 hours; when administered as a solution, peak concentrations occur within 1–2 hours. The mean absolute bioavailability is 23% for tablets and 39% for the solution. Food reduces valsartan exposure (as measured by AUC) by approximately 40% and peak plasma concentration (Cmax) by approximately 50%. However, plasma concentrations of valsartan from about 8 hours after dosing are similar in both fasting and fed conditions. The reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered with or without food.

Distribution

The volume of distribution at steady state after intravenous administration is approximately 17 L, indicating that valsartan does not extensively distribute into tissues. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.

Biotransformation

Valsartan is not significantly metabolized, as only about 20% of the dose is excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Elimination

The pharmacokinetic profile of valsartan is multiphasic (T½α <1 hour and T½ß approximately 9 hours). Valsartan is primarily eliminated via bile into feces (approximately 83% of the dose) and via kidneys into urine (approximately 13% of the dose), mostly in unchanged form. After intravenous administration, plasma clearance of valsartan is about 2 L/h, and renal clearance is 0.62 L/h (approximately 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Patients with heart failure (40 mg, 80 mg, and 160 mg tablets)

The mean time to reach Cmax and elimination half-life of valsartan in patients with heart failure are similar to those in healthy volunteers. AUC and Cmax values of valsartan are nearly proportional to dose increases above the clinical dose range (from 40 to 160 mg twice daily). The mean accumulation ratio is approximately 1.7. Predicted oral clearance of valsartan is about 4.5 L/h. Age does not affect predicted clearance in patients with heart failure.

Pharmacokinetics in specific patient populations

Elderly patients. Systemic exposure to valsartan was somewhat higher in some elderly patients compared to younger individuals, but this difference has not been shown to have clinical significance.

Patients with renal impairment. No correlation has been observed between renal function and systemic exposure to valsartan. Therefore, dose adjustment is not required in patients with impaired renal function (creatinine clearance > 10 mL/min). There are currently no data on the safety of valsartan in patients with creatinine clearance < 10 mL/min or in patients undergoing dialysis; therefore, valsartan should be used with caution in these patients. Valsartan is highly protein-bound, and removal by hemodialysis is unlikely.

Patients with hepatic impairment. Approximately 70% of the absorbed dose is excreted in bile, primarily in unchanged form. Valsartan undergoes minimal biotransformation, and systemic exposure to valsartan is not expected to correlate with the degree of hepatic dysfunction. Therefore, dose adjustment is not required in patients with non-biliary liver insufficiency and in the absence of cholestasis. In patients with biliary cirrhosis or biliary obstruction, AUC of valsartan has been shown to increase approximately twofold.

Children

In a study involving 26 children with arterial hypertension (aged 1 to 16 years) who received a single dose of valsartan suspension (mean dose 0.9–2 mg/kg, maximum dose 80 mg), clearance (L/h/kg) of valsartan was comparable across the entire age range of 1 to 16 years to that observed in adults receiving the same drug.

Patients with renal impairment

The use of valsartan in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for these patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be carefully monitored.

Clinical characteristics.

Indications.

Arterial hypertension

Treatment of arterial hypertension in adults and children aged 6 to 18 years.

Post-infarction state

Treatment of clinically stable adult patients with symptomatic heart failure or asymptomatic systolic dysfunction of the left ventricle following a recent (12 hours – 10 days) myocardial infarction.

Heart failure

Treatment of symptomatic heart failure in adult patients when angiotensin-converting enzyme inhibitors (ACE inhibitors) cannot be used, or as add-on therapy with ACE inhibitors when beta-blockers cannot be used.

Contraindications.

• Hypersensitivity to valsartan or to any excipient.
• Pregnancy or planned pregnancy (see "Use during pregnancy or breastfeeding").
• Hereditary or idiopathic angioedema, or angioedema that developed during previous treatment with an ACE inhibitor or an angiotensin II receptor antagonist.
• Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or type II) or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
• Lack of data in patients with severe renal impairment (creatinine clearance less than 10 mL/min).

Interaction with other medicinal products and other forms of interaction.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with drugs of the ARB class, ACE inhibitors, or aliskiren

Concomitant use of ARB-class drugs, including valsartan, with other drugs acting on the RAAS is associated with an increased incidence of arterial hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Dual blockade of the RAAS by combined use of ACE inhibitors, ARBs, or aliskiren is therefore not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be performed only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.

Concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with type I and type II diabetes mellitus.

ACE inhibitors, including valsartan, and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of ACE inhibitors. Due to lack of experience with the concomitant use of valsartan and lithium, this combination is not recommended. If the combination is considered necessary, careful monitoring of serum lithium levels is recommended.

Potassium

Potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, potassium-containing salt substitutes, and other medicinal products that may increase potassium levels (e.g., heparin, etc.) may lead to increased serum potassium levels and, in patients with heart failure, to increased creatinine levels.

If a medicinal product affecting potassium levels is considered necessary in combination with valsartan, monitoring of plasma potassium levels is recommended.

Caution required during concomitant use

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs

Concomitant use of angiotensin II antagonists with NSAIDs may result in reduced antihypertensive effect. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs increases the risk of worsening renal function and elevated serum potassium levels. Therefore, monitoring of renal function and adequate patient hydration are recommended at the start of treatment.

Transporters

In vitro studies have shown that valsartan is a substrate for the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these data is unknown. Concomitant use of inhibitors of the OATP1B1 transporter (e.g., rifampicin, cyclosporine) or MRP2 (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation or discontinuation of concomitant use of these medicinal products.

Other

During drug interaction studies, no clinically significant interactions were observed between valsartan and any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.

Children

Caution is recommended when concomitantly administering valsartan and other substances that suppress the renin-angiotensin-aldosterone system to children with arterial hypertension, as this may increase serum potassium levels. Renal function and serum potassium levels should be carefully monitored.

Special precautions for use.

Hyperkalemia

Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels (e.g., heparin, etc.) is not recommended. If concomitant use is necessary, potassium levels should be monitored.

Patients with sodium deficiency and/or reduced circulating blood volume (CBV). In patients with severe sodium and/or circulating blood volume depletion, such as those receiving high-dose diuretic therapy, symptomatic arterial hypotension may occur in individual cases after initiation of valsartan therapy. Prior to starting valsartan therapy, correction of sodium and/or circulating blood volume status should be performed, for example, by reducing the diuretic dose.

Renal artery stenosis. The safety of valsartan use in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney has not been established. Short-term use of valsartan in 12 patients with renovascular hypertension secondary to unilateral renal artery sten0sis did not cause any significant changes in renal hemodynamic parameters, serum creatinine, or blood urea nitrogen. Since other medicinal products affecting the renin-angiotensin-aldosterone system (RAAS) may increase blood urea and serum creatinine in patients with unilateral or bilateral renal artery stenosis, monitoring of renal function is recommended as a safety precaution during treatment with valsartan.

Renal impairment. There are no data on the safety of valsartan use in patients with creatinine clearance < 10 mL/min or in patients undergoing dialysis; therefore, valsartan should be used with caution in such patients. Dose adjustment is not required in adult patients with creatinine clearance > 10 mL/min.

Concomitant use of angiotensin receptor blockers, including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.

Hepatic impairment. Valsartan should be used with caution in patients with mild to moderate hepatic impairment without cholestasis.

Kidney transplantation

Currently, there are no data on the safety of valsartan use in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Valsartan should not be used in patients with primary hyperaldosteronism, as the renin-angiotensin system is not activated in these patients.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, valsartan should be administered with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Pregnancy

Angiotensin II receptor antagonists should not be administered during pregnancy. If continued treatment is considered necessary, women planning pregnancy should switch to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is confirmed, treatment should be discontinued immediately and, if necessary, alternative therapy initiated.

Recent myocardial infarction

The combination of captopril and valsartan did not demonstrate additional clinical benefit, while the risk of adverse reactions increased compared to treatment with individual agents. Therefore, combination of valsartan with an ACE inhibitor is not recommended.

Caution should be exercised in patients after myocardial infarction. Assessment of patients after myocardial infarction should always include evaluation of renal function.

Administration of valsartan to patients after myocardial infarction often leads to some reduction in blood pressure, but therapy usually does not need to be discontinued due to persistent symptomatic arterial hypotension, provided dosing instructions are followed.

Heart failure

In patients with heart failure, triple combination therapy with an ACE inhibitor, beta-blocker, and valsartan has not demonstrated any clinical benefit. This combination is likely to increase the risk of adverse effects and is therefore not recommended. Triple combination of ACE inhibitors, mineralocorticoid receptor antagonists, and valsartan is also not recommended.

Such combinations may be used only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

Safety and efficacy of valsartan in children have not been studied.

History of angioedema

Angioedema, including laryngeal and glottal edema leading to airway obstruction and/or facial, lip, pharyngeal, and/or tongue swelling, has been reported in patients receiving valsartan. In some of these patients, angioedema had previously occurred with other medicinal products, including ACE inhibitors. Angioedema requires immediate discontinuation of valsartan, and re-administration of valsartan is not recommended.

Other conditions involving stimulation of the renin-angiotensin system

In patients in whom renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia, and in some cases, acute renal failure and/or death. Since valsartan is an angiotensin II antagonist, renal impairment cannot be excluded with valsartan use.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Concomitant use of ARBs, including valsartan, with other agents acting on the RAAS is associated with increased incidence of arterial hypotension, hyperkalemia, and changes in renal function compared to monotherapy. Monitoring of blood pressure, renal function, and electrolytes is recommended in patients receiving valsartan and other RAAS-acting agents.

Pediatric use

Renal impairment

Use in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended in such patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be closely monitored during valsartan treatment. This is particularly important in cases where valsartan is used in the presence of other conditions (e.g., high fever, dehydration) that may impair renal function.

Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.

Hepatic impairment

As in adults, valsartan is contraindicated in children with severe hepatic impairment, biliary cirrhosis, or cholestasis. Clinical experience with valsartan in children with mild to moderate hepatic impairment is limited. The dose of valsartan should not exceed 80 mg in such patients.

Use during pregnancy or breastfeeding

Use of angiotensin II receptor antagonists (ARBs) is contraindicated throughout pregnancy.

Epidemiological data on teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. As there are no controlled epidemiological data on teratogenic risk with angiotensin II receptor antagonists, a teratogenic risk may also exist for this class of drugs. Except when continued therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is diagnosed during treatment with angiotensin II receptor antagonists, treatment should be discontinued immediately and, if necessary, replaced with a medication approved for use in pregnancy.

It is known that use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy induces human fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If ARBs have been used from the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull ossification.

Newborns of mothers who received ARBs should be closely monitored for signs of arterial hypotension.

Due to lack of information on valsartan use during breastfeeding, valsartan is not recommended for use in breastfeeding women.

Fertility

Valsartan at doses up to 200 mg/kg/day did not adversely affect reproductive function in rats. This dose is 6 times higher than the maximum recommended human dose on a mg/m² basis (based on oral dose of 320 mg/day in a 60 kg patient).

Ability to influence reaction speed when driving or operating machinery

As with other antihypertensive agents, caution should be exercised when driving or operating machinery due to the possibility of dizziness or weakness.

Method of Administration and Dosage

Method of Administration

Valsartan may be administered independently of food intake; tablets should be taken with water.

Dosage

Arterial Hypertension in Adults

The recommended initial dose of Valsartan is 80 mg once daily. Antihypertensive effect is achieved within 2 weeks, and maximum effect within 4 weeks. In some patients with inadequately controlled blood pressure, the dose may be increased to 160 mg and up to the maximum dose of 320 mg.

Valsartan may also be used in combination with other antihypertensive agents. Concomitant use of diuretics such as hydrochlorothiazide will further reduce blood pressure in these patients.

Recent Myocardial Infarction

Treatment may be initiated in clinically stable patients as early as 12 hours after a myocardial infarction. After an initial dose of valsartan 20 mg twice daily, the dose should be increased to 40 mg, 80 mg, and then 160 mg twice daily over the following weeks. The initial dose should be administered using a 40 mg tablet, which can be divided into equal halves.

The maximum dose is 160 mg twice daily. It is generally recommended that the dose level of 80 mg twice daily be reached within 2 weeks of starting treatment, and the maximum dose of 160 mg twice daily be reached within 3 months, depending on patient tolerance. If symptomatic arterial hypotension or renal dysfunction occurs, dose reduction should be considered.

Valsartan may be administered to patients who are being treated with other post-myocardial infarction medications, such as thrombolytics, acetylsalicylic acid, beta-blockers, statins, and diuretics. Combination with ACE inhibitors is not recommended.

Patients after myocardial infarction must always have kidney function monitored.

Heart Failure

The recommended initial dose of Valsartan is 40 mg twice daily. Gradual dose escalation to 80 mg and then 160 mg twice daily should be performed at intervals of at least 2 weeks, depending on patient tolerance, up to the highest tolerated dose. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose used in clinical trials was 320 mg, divided into multiple doses.

Valsartan may be used in combination with other heart failure medications. However, triple combination of an ACE inhibitor, beta-blocker, and valsartan is not recommended.

Patients with heart failure require monitoring of kidney function.

Use in Specific Patient Populations

Elderly Patients

Dose adjustment is not required in elderly patients.

Renal Impairment

Dose adjustment is not required in adult patients with creatinine clearance > 10 mL/min.

Concomitant use of valsartan with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.

Diabetes Mellitus

Concomitant use of valsartan with aliskiren in patients with diabetes mellitus is contraindicated.

Hepatic Impairment

Valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis. For patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg.

Children

Valsartan is indicated for the treatment of arterial hypertension in children aged 6 to 18 years. Safety and efficacy of valsartan in children aged 1 to 6 years have not been established. The drug is not recommended for the treatment of heart failure or post-infarction state in children due to lack of safety and efficacy data.

Arterial Hypertension in Children

Children Aged 6 Years and Older

The initial dose is 40 mg once daily for children with body weight below 35 kg and 80 mg once daily for children with body weight ≥ 35 kg. Dose adjustments should be made based on blood pressure response. Maximum doses studied in clinical trials are shown in Table 1.

Doses higher than those specified have not been studied and therefore should not be recommended.

Table 1

Children under 6 years of age

The safety and efficacy of Valsartan in children aged 1 to 6 years have not been established.

Use in children aged 6 years and older with renal impairment

Use in children with creatinine clearance <30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for such patients. Dose adjustment is not required in children with creatinine clearance >30 mL/min. Renal function and serum potassium levels should be closely monitored.

Use in children aged 6 years and older with hepatic impairment

As in adults, Valsartan is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and cholestasis. Clinical experience with the use of Valsartan in children with mild to moderate hepatic impairment is limited. The dose of valsartan should not exceed 80 mg in such patients.

Heart failure and recent myocardial infarction in children

Valsartan is not recommended for the treatment of heart failure or recent myocardial infarction in children due to lack of data on safety and efficacy.

Overdose.

Following valsartan overdose, marked hypotension may develop, which could lead to drowsiness, circulatory collapse, and/or shock. Therapeutic measures depend on the time of ingestion and the type and severity of symptoms; the primary goal is stabilization of circulation. If hypotension occurs, the patient should be placed in a supine position, and blood volume should be corrected.

It is unlikely that valsartan can be removed from the body by hemodialysis.

Adverse reactions.

Arterial hypertension/heart failure/myocardial infarction

During controlled clinical trials in adult patients with arterial hypertension, the incidence of adverse reactions with placebo was comparable to that with valsartan. The occurrence of adverse reactions was found to be unrelated to dose or duration of treatment. No association with patient's sex, age, or race has been demonstrated.

The frequency of adverse reactions is defined as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/100000), including isolated reports. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions for which the frequency could not be determined are listed as "unknown".

Table 2

* reported by patients in the post-infarction period

reported by patients with heart failure

** infrequently reported by patients in the post-infarction period

reported more frequently by patients with heart failure (common: dizziness, renal function abnormalities, hypotension; infrequent: headache, nausea).

Laboratory test results

In isolated cases, valsartan caused a decrease in hemoglobin levels and hematocrit count.

In controlled clinical trials, neutropenia was observed in 1.9% of patients treated with valsartan, compared to 1.6% of patients treated with an ACE inhibitor.

In controlled clinical trials involving patients with arterial hypertension, significant increases in serum creatinine, potassium, and total bilirubin levels were observed in 0.8%, 4.4%, and 6% of patients treated with valsartan, respectively, compared to 1.6%, 6.4%, and 12.9% of patients treated with an ACE inhibitor.

Isolated cases of increased liver function parameters have been reported in patients treated with valsartan.

No special laboratory monitoring is required for patients with arterial hypertension receiving valsartan therapy.

In cases of heart failure, serum creatinine levels increased by more than 50% in 3.9% of patients taking valsartan, compared to 0.9% of patients taking placebo; and an increase in serum potassium levels by more than 20% was observed in 10% of patients taking valsartan, compared to 5.1% of patients taking placebo.

In heart failure studies, increased blood urea nitrogen levels were observed in 16.6% of patients taking valsartan, compared to 6.3% of patients taking placebo.

An increase in serum creatinine levels by 2 times was observed in 4.2% of patients receiving valsartan, in 4.8% of patients treated with a combination of valsartan and captopril, and in 3.4% of patients treated with captopril during the post-infarction period.

The number of cases of discontinuation of the medicinal product due to adverse reactions was lower in the group treated with valsartan compared to the group receiving captopril (5.8% vs. 7.7%, respectively).

Children

Arterial hypertension

The antihypertensive effect of valsartan was evaluated in two randomized, double-blind clinical trials involving 561 children aged 6 to 18 years. Except for individual gastrointestinal disorders (e.g., abdominal pain, nausea, vomiting) and dizziness, no significant differences were identified in the type, frequency, and severity of adverse reactions between the safety profile in children aged 6 years and older and the previously established safety profile in adult patients.

Neurocognitive assessment and evaluation of development in children aged 6 to 16 years did not reveal any clinically significant overall negative consequences after treatment with Valsartan for up to 1 year.

Hyperkalemia was observed more frequently in children aged 6 to 18 years with underlying chronic kidney diseases.

The safety profile observed in controlled clinical trials in adult patients after myocardial infarction and/or with heart failure differs from the general safety profile observed in patients with arterial hypertension. This may be related to patients with underlying conditions. Adverse reactions observed in adult patients after myocardial infarction and/or with heart failure are listed in Table 2.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. Film-coated tablets, 40 mg, 80 mg, 160 mg, 320 mg; 10 tablets per blister in a cardboard box; 30 tablets in a container in a cardboard box.

Prescription status.

By prescription.

Date of last review.