INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VALSAR (VALSAR)

Composition:

Active substance: valsartan;

One film-coated tablet contains 80 mg or 160 mg of valsartan;

Excipients: microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, crospovidone, hypromellose, sodium lauryl sulfate, talc, magnesium stearate, titanium dioxide (E 171), macrogol 8000, iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets of 80 mg: pale red, round, bevelled-edged, biconvex film-coated tablets, marked with "I" on one side and "74" on the other side, with a break line between "7" and "4";

Film-coated tablets of 160 mg: grey-orange, oval, bevelled-edged, biconvex film-coated tablets, marked with "I" on one side and "75" on the other side, with a break line between "7" and "5".

Pharmacotherapeutic group.

Simple angiotensin II antagonists. ATC code: C09CA03.

Pharmacological properties.

Pharmacodynamics.

Valsartan is an active, specific angiotensin II receptor antagonist intended for oral use. It selectively acts on AT1 receptors, which are responsible for 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 AT1 receptors and has a much greater affinity (approximately 20,000 times higher) for AT1 receptors than for AT2 receptors.

Valsartan does not inhibit ACE (angiotensin-converting enzyme), which converts angiotensin I to angiotensin II and degrades bradykinin. Administration of the drug to patients with arterial hypertension results in a reduction in 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 lasts more than 24 hours. The maximal therapeutic effect develops within 4 weeks of starting 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 use of the drug in patients with arterial hypertension has shown no significant effect on total cholesterol levels or uric acid. Fasting studies also show no significant effect on serum triglyceride and glucose concentrations.

Administration of the drug reduces hospitalization rates due to heart failure, slows progression of heart failure, improves functional class according to NYHA classification, increases ejection fraction, reduces symptoms of heart failure, and improves quality of life compared to placebo. The VALIANT study demonstrated that valsartan, like captopril, reduces 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 period from the acute myocardial infarction to the first occurrence of cardiovascular events leading to fatal outcomes.

Children

The antihypertensive effect of valsartan was evaluated in four randomized, double-blind clinical studies 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 causes of arterial hypertension in the children included in these studies.

Clinical experience with use in children aged 6 years and older

In a clinical study 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 with use 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, maximum plasma concentration (Cmax) is reached within 2–4 hours; when administered as a solution, Cmax occurs within 1–2 hours. The mean absolute bioavailability is 23% for tablets and 39% for the solution. Food reduces exposure (as measured by AUC) by approximately 40% and Cmax by approximately 50%. However, valsartan plasma concentrations from about 8 hours after dosing are similar between fasting and fed conditions. The reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be taken 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.

Metabolism

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 valsartan AUC). 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 the bile into feces (approximately 83% of the dose) and to a lesser extent via the kidneys into urine (approximately 13% of the dose), mostly unchanged. After intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Patients with heart failure (film-coated tablets, 80 mg and 160 mg)

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 approximately 4.5 L/h. Age does not affect predicted clearance in patients with heart failure.

Pharmacokinetics in specific patient groups.

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

Patients with renal impairment. No correlation was 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 unchanged. 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. However, in patients with biliary cirrhosis or biliary obstruction, AUC of valsartan is approximately doubled.

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), valsartan clearance (L/h/kg) was comparable across the entire age range of 1 to 16 years to that observed in adults receiving the same formulation.

Patients with renal impairment (in children).

The use of valsartan in children with creatinine clearance <30 mL/min or 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 closely monitored.

Clinical characteristics.

Indications.

• Treatment of arterial hypertension in adults and children aged 6 to 18 years.
• Post-myocardial infarction state.

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

• Heart failure.

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

Contraindications.

• Hypersensitivity to valsartan or to any excipient of the medicinal product.
• Pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding").
• Hereditary or ACE inhibitor- or angiotensin II receptor antagonist-induced angioedema.
• Concomitant use of angiotensin receptor antagonists, including Valsar, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type 1 or type 2) or renal impairment (glomerular filtration rate (GFR) < 60 mL/min).
• No data are available in patients with severe renal impairment (creatinine clearance < 10 mL/min).

Interaction with other medicinal products and other forms of interaction.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers (ARBs), ACE inhibitors, or aliskiren

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

Concomitant use of angiotensin receptor antagonists, including Valsar, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (< 60 mL/min) is contraindicated.

Concomitant use of ARBs, including Valsar, or ACE inhibitors with aliskiren is contraindicated in patients with type 1 and type 2 diabetes mellitus.

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

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentration and lithium toxicity have been reported during concomitant use of ACE inhibitors. Due to lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If combination therapy 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) may lead to increased serum potassium levels, and in patients with heart failure, to increased creatinine levels.

If use of 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 non-selective NSAIDs

Concomitant use of angiotensin II antagonists with NSAIDs may result in reduced antihypertensive effect. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of renal function impairment 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 indicate that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of these findings is unknown. Concomitant use of inhibitors of OATP1B1 transporters (e.g., rifampicin, cyclosporine) or MRP2 (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation and termination of concomitant therapy with these medicinal products.

Others

No clinically relevant interactions with valsartan or any of the following substances were observed in drug interaction studies: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glipizide.

Children

Caution is recommended when administering valsartan concomitantly with other drugs that suppress the RAAS in children and adolescents 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) is not recommended. If necessary, potassium levels should be monitored.

Renal impairment

There are no safety data available on the use of the drug 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 antagonists, including Valsar, or ACE inhibitors with aliskiren in patients with renal impairment (eGFR <60 mL/min/1.73 m²) is contraindicated.

Hepatic impairment

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

Patients with sodium and/or circulating blood volume deficiency (CBV)

In patients with severe sodium and/or CBV deficiency, e.g., those receiving high-dose diuretic therapy, symptomatic arterial hypotension may occur in individual cases after initiation of Valsar therapy. Prior to starting the medication, correction of sodium and/or CBV deficiency should be performed, e.g., by reducing the diuretic dose.

Renal artery stenosis

The safety of Valsar has not been established in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney. Short-term administration of valsartan in 12 patients with renovascular hypertension secondary to unilateral renal artery stenosis did not cause any significant changes in renal hemodynamic parameters, serum creatinine, or blood urea nitrogen.

Since other drugs affecting the RAAS may increase serum urea and creatinine levels in patients with unilateral renal artery stenosis, monitoring of renal function is recommended during valsartan therapy for safety reasons.

Kidney transplantation

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

Primary hyperaldosteronism

Valsar 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, the drug should be prescribed with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Pregnancy

Angiotensin II receptor antagonists are contraindicated during pregnancy. If continued treatment with the drug 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 alternative therapy initiated if necessary.

Recent myocardial infarction

The combination of captopril and valsartan did not show additional clinical benefit, while the risk of adverse reactions increased compared to monotherapy with either agent. 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.

Valsartan use in patients after myocardial infarction often leads to some reduction in arterial pressure, resulting in the need to discontinue therapy due to persistent symptomatic arterial hypotension despite adherence to dosing instructions.

Heart failure

In patients with heart failure, triple combination therapy with an ACE inhibitor, beta-blocker, and valsartan did not demonstrate any clinical benefits. 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 arterial pressure.

Safety and efficacy of Valsar 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 taking valsartan. Some of these patients had previously experienced angioedema during treatment with other drugs, including ACE inhibitors. Development of angioedema requires immediate discontinuation of Valsar; re-administration of Valsar to such patients is not recommended.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Other conditions with stimulation of the renin-angiotensin system

In patients in whom renal function may depend on renin-angiotensin system activity (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 function disturbances cannot be excluded with Valsar use.

Dual blockade of the RAAS

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

Children

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 carefully monitored during valsartan therapy, particularly in cases where valsartan is used under other conditions (e.g., high fever, dehydration) that may impair renal function.

Concomitant use of angiotensin receptor antagonists, including Valsar, or ACE inhibitors with aliskiren in patients with renal impairment (eGFR <60 mL/min/1.73 m²) is contraindicated.

Hepatic impairment

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

Excipients

Since the medicinal product contains lactose as an excipient, consultation with a physician is necessary before taking this medicinal product in cases of intolerance to certain sugars.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding

Use of angiotensin II receptor antagonists (ARBs) is contraindicated in pregnant women or women planning pregnancy.

Epidemiological data on teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. Since there are no controlled epidemiological data on the risk of angiotensin II receptor antagonists, a teratogenic risk may also exist for this class of drugs. Except when continuation of 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, treatment with angiotensin II receptor antagonists should be discontinued immediately and replaced, if necessary, 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 fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) in humans.

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

Newborns whose mothers used ARBs should be carefully monitored for the development of arterial hypotension.

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

Fertility

Valsartan at doses up to 200 mg/kg/day did not cause adverse effects on reproductive function in rats. The dose of 200 mg/kg/day is 6 times higher than the maximum recommended human dose, adjusted by mg/m² (based on oral administration of 320 mg/day in a 60 kg patient).

Ability to influence reaction rate when driving vehicles or operating machinery

Studies on the effect on the ability to drive vehicles or operate machinery have not been conducted. It should be noted that dizziness or weakness may occur during driving or operating machinery.

Method of Administration and Dosage

Method of Administration

Valsar tablets can be taken independently of food intake, swallowed with water.

Dosage

Arterial Hypertension

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

Valsar may also be used in combination with other antihypertensive agents. Concomitant use with diuretics such as hydrochlorothiazide will provide additional blood pressure reduction in these patients.

Recent Myocardial Infarction

Treatment may be initiated in clinically stable patients as early as 12 hours after myocardial infarction. Following an initial dose of valsartan 20 mg (tablets must not be split into equal doses; appropriate dosage forms must be taken) twice daily, the dose should be increased to 40 mg, then to 80 mg and 160 mg twice daily over the following weeks.

The target maintenance dose is 160 mg twice daily. It is generally recommended that the dose 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 used in patients who are being treated with other medications following myocardial infarction, such as thrombolytics, acetylsalicylic acid, beta-blockers, statins, and diuretics. Combination with ACE inhibitors is not recommended.

Patients after myocardial infarction require regular monitoring of renal function.

Heart Failure

The recommended initial dose of Valsar is 40 mg (tablets must not be split into equal doses; appropriate dosage forms must be taken) twice daily. Gradual dose escalation to 80 mg and then to 160 mg twice daily should be performed at intervals of at least 2 weeks, 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 drugs for the treatment of heart failure. However, triple combination of an ACE inhibitor, beta-blocker, and valsartan is not recommended.

Patients with heart failure require monitoring of renal 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 Valsar with aliskiren in patients with impaired renal function (eGFR <60 mL/min/1.73 m²) is contraindicated.

Diabetes Mellitus

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

Hepatic Impairment

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

Arterial Hypertension in Children

Children aged 6 to 18 years

The initial dose is 40 mg (tablets must not be split into equal doses; appropriate dosage forms must be taken) once daily for children with body weight less than 35 kg, and 80 mg once daily for children with body weight of 35 kg or more. Dose adjustments should be based on blood pressure response. The maximum doses studied in clinical trials are shown in Table 1.

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

Table 1

Children under 6 years of age.

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

Use in children aged 6 to 18 years 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 to 18 years with hepatic impairment.

As in adults, Valsar is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis. Clinical experience with the use of the medicinal product 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.

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

Children.

Valsar is used for the treatment of arterial hypertension in children aged 6 to 18 years. The safety and efficacy of Valsar 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 data on safety and efficacy.

Overdose.

Following overdose with Valsar, marked arterial hypotension may develop, which could lead to impaired consciousness, vascular collapse, and/or shock. Therapeutic measures depend on the time of ingestion and the type and severity of symptoms; primary importance is given to stabilization of circulation. If arterial 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.

Hypertension/heart failure/myocardial infarction

During controlled clinical studies in adult patients with hypertension, the incidence of adverse reactions was similar with placebo and valsartan. The incidence of adverse reactions was found to be independent of dose and duration of treatment, as well as of patient's sex, age, or race.

Adverse reactions observed during clinical, post-marketing, and laboratory studies are listed below by system organ classes.

For adverse reactions in the categories "very rare," "rare," and "uncommon," which were not identified during clinical trials, a cumulative search in the safety database was performed.

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 case reports. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions identified from post-marketing and laboratory studies, for which the frequency cannot be estimated, are listed as "frequency not known."

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 (frequent: dizziness, renal dysfunction, hypotension; infrequent: headache, nausea).

Laboratory test results

In isolated cases, valsartan caused a decrease in hemoglobin levels and hematocrit count. In controlled clinical trials, significant reductions (>20%) in hematocrit count and hemoglobin levels were observed in 0.8% and 0.4% of patients receiving valsartan, respectively. In comparison, reductions in both parameters (hematocrit count and hemoglobin level) were noted in 0.1% of placebo-treated patients.

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, serum 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 elevated liver function parameters have been reported in patients treated with valsartan.

Patients with arterial hypertension receiving valsartan therapy do not require any specific laboratory parameter monitoring.

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.

Serum creatinine levels doubled 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 drug discontinuation due to adverse reactions was lower in the valsartan-treated group compared to the captopril group (5.8% vs. 7.7%, respectively).

Pediatric

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 (such as 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 to 18 years and the previously established safety profile in adult patients.

Neurocognitive and developmental assessments 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.

In a double-blind, randomized study involving 90 children aged 1 to 6 years, followed by an open-label, one-year extension study, two fatal cases and isolated cases of marked elevation in hepatic transaminases were recorded. These cases occurred in a population with significant comorbidities. A causal relationship with valsartan was not established. In a second study involving 75 randomized children aged 1 to 6 years, no significant elevations in hepatic transaminases or fatal cases were observed during valsartan treatment.

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

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 the underlying disease condition. Adverse reactions observed in adult patients after myocardial infarction and/or with heart failure are listed in Table 2.

Shelf life. 2 years.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Packaging. 7 tablets per blister pack, 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited – Unit VII, India / Aurobindo Pharma Limited – Unit VII, India.

Manufacturer's address and location of operations.

Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India / Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.