INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORSAR® (CORSAR)

Composition:

Active substance: valsartan;

One tablet contains 80 mg of valsartan;

Excipients: microcrystalline cellulose, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate;

coating: Opadry II pink (lactose monohydrate, hypromellose, titanium dioxide (E 171), polyethylene glycol, red iron oxide (E 172)).

One tablet contains 160 mg of valsartan;

Excipients: microcrystalline cellulose, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate;

coating: Opadry II yellow (lactose monohydrate, hypromellose, titanium dioxide (E 171), polyethylene glycol, yellow iron oxide (E 172), triacetin (E 1518), ponzo 4R (E 124), FD&C Blue № 2 (E 132)).

One tablet contains 320 mg of valsartan;

Excipients: microcrystalline cellulose, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate;

coating: Opadry II violet (lactose monohydrate, hypromellose, titanium dioxide (E 171), polyethylene glycol, red iron oxide (E 172), FD&C Blue № 2 (E 132), FD&C Yellow № 6 (E 110)).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

Round film-coated tablets, pink (80 mg), yellow (160 mg), or violet (320 mg) in color, without a break line.

Pharmacotherapeutic group. Simple preparations of angiotensin II antagonists.

ATC code C09CA03.

Pharmacological properties.

Pharmacodynamics.

Valsartan is an orally active, specific angiotensin II receptor antagonist. It selectively acts 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 and has much greater (approximately 20,000 times) affinity for the AT1 receptor than for the AT2 receptor.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), 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 lasts more than 24 hours. Maximum 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.

Sudden withdrawal of the drug is not associated with a withdrawal syndrome.

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

The drug reduces the number of hospitalizations due to heart failure, slows progression of heart failure, improves functional class according to NYHA classification, increases ejection fraction, and also alleviates 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 and the number of hospitalizations due to heart failure, as well as recurrent myocardial infarction. Valsartan positively influenced the time from acute myocardial infarction to the first occurrence of fatal cardiovascular events.

Pharmacokinetics.

Absorption

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

Distribution

The volume of distribution of valsartan 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 bile (approximately 83% of dose) and urine (approximately 13% of dose), mainly in unchanged form. After intravenous administration, plasma clearance of valsartan is approximately 2 L/hour, and renal clearance is 0.62 L/hour (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

In patients with heart failure

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/hour. Age does not affect predicted clearance in patients with heart failure.

Pharmacokinetics in specific patient populations

Elderly patients. Systemic exposure to valsartan was slightly 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 the drug in patients with creatinine clearance <10 mL/min or in patients undergoing dialysis; thus, valsartan should be used with caution in these patients. Valsartan is highly protein-bound, and its removal during 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 of valsartan is not required in patients with non-biliary hepatic insufficiency and in the absence of cholestasis. However, in patients with biliary cirrhosis or biliary obstruction, AUC of valsartan is increased by approximately two-fold.

Clinical characteristics.

Indications.

Arterial hypertension

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

Post-myocardial infarction state

Treatment of clinically stable adult patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction following recent (within 12 hours to 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 of the excipients of the medicinal product.
Severe hepatic impairment, biliary cirrhosis, and cholestasis.
Concomitant use of angiotensin receptor antagonists, including Corsar, 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/1.73 m²).
Pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding").
Lack of data in patients with severe renal impairment (creatinine clearance less than 10 mL/min).
Hereditary or idiopathic angioedema, or angioedema that occurred during previous treatment with an ACE inhibitor or angiotensin II receptor antagonist.

Interaction with other medicinal products and other forms of interaction.

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

Concomitant use of ARBs 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. Therefore, dual blockade of the RAAS by combined use of 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 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 (GFR <60 mL/min/1.73 m²) is contraindicated (see section "Contraindications").

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

ACE inhibitors 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 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, potassium supplements, potassium-containing salt substitutes, and other agents that may increase potassium levels (e.g., heparin) may lead to increased serum potassium levels. In patients with heart failure, this may also lead 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 is required with 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 increases the risk of impaired 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 indicate that valsartan is a substrate for the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of these findings is unknown. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (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.

Others

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

Children

Caution is recommended when administering valsartan concomitantly with other agents that suppress the RAAS to 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 medicinal products that may increase potassium levels (e.g., heparin) is not recommended. If necessary, potassium levels should be monitored.

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

In patients with severe sodium and/or CBV deficiency, such as those receiving high doses of diuretics, symptomatic arterial hypotension may occur in individual cases after initiation of valsartan therapy. Prior to starting valsartan, correction of sodium and/or CBV deficiency should be performed, for example, by reducing the diuretic dose.

Renal artery stenosis

The safety of valsartan has not been established in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney. Short-term use 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 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 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.

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 in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Valsartan should not be administered to 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 to 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, patients 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 should be 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 the individual agents. Therefore, combination of valsartan with an ACE inhibitor is not recommended.

Caution should be exercised in patients after myocardial infarction. Renal function should always be assessed in patients after myocardial infarction.

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

Heart failure

In patients with heart failure, triple combination of an ACE inhibitor, beta-blocker, and valsartan did not demonstrate 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 the drug Corsar have not been studied in children.

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 during treatment with other medicinal products, including ACE inhibitors. Development of angioedema requires immediate discontinuation of Corsar; re-administration is not recommended.

Other conditions involving stimulation of the renin-angiotensin system

In patients whose 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 fatal outcomes. Since valsartan is an angiotensin II antagonist, its use may be associated with renal function disturbances.

Dual blockade of the RAAS

Concomitant use of ARBs, including Corsar, with other agents 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 Corsar and other RAAS-affecting agents.

If intolerance to certain sugars is present, consult a physician before taking this medicinal product. The drug may cause allergic reactions due to the presence of azo dyes.

Children

Renal impairment

Use in children with creatinine clearance <30 mL/min or 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 treatment with valsartan. This is particularly important in cases when valsartan is used under conditions (e.g., high fever, dehydration) that may impair renal function. Concomitant use of angiotensin receptor antagonists, including Corsar, or ACE inhibitors with aliskiren in patients with renal impairment (eGFR <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 in pregnant women and in 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 ARBs, a teratogenic risk may also exist for this class of drugs. Except when continuation of therapy is considered necessary, patients 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 alternative therapy should be initiated if necessary.

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

If ARBs were 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 the development of arterial hypotension.

Due to lack of information on the use of valsartan during breastfeeding, valsartan should not be used during this period. If treatment is necessary, breastfeeding should be discontinued.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

Valsartan can be administered with or without food. Tablets should be taken with water.

Arterial Hypertension

Arterial Hypertension in Adults

The recommended starting dose of valsartan is 80 mg once daily. Antihypertensive effect is achieved within 2 weeks, and the maximum effect is reached 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, provides additional blood pressure reduction in these patients.

Arterial Hypertension in Children

Children aged 6 years and older

The starting dose is 40* mg once daily for children with body weight below 35 kg and 80 mg once daily for children with body weight of 35 kg or more. Dose adjustment should be based on blood pressure response. Maximum doses are shown in Table 1.

Doses higher than those specified are not recommended.

Table 1

Body weight	Maximum dose of valsartan
≥18 kg to <35 kg	80 mg
≥35 kg to <80 kg	160 mg
≥80 kg to ≤160 kg	320 mg

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

The use of the drug 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 in patients with 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.

Heart failure and post-myocardial infarction state in children

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

Post-myocardial infarction state

Therapy 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 160 mg twice daily over the following weeks. The initial dose of 20* mg is achieved by taking a 40* mg tablet, which can be divided into two equal parts.

The maximum 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 have been 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 require regular monitoring of renal function.

Heart failure

The recommended initial dose of valsartan is 40 mg twice daily. Gradual dose escalation to 80 mg and 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 heart failure medications. However, triple combination of an ACE inhibitor, a beta-blocker, and valsartan is not recommended.

Patients with heart failure require monitoring of renal function.

Use in specific patient groups

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 the drug Corsar with aliskiren in patients with impaired renal function (eGFR <60 mL/min/1.73 m²) is contraindicated.

Diabetes mellitus

Concomitant use of the drug Corsar 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. In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg.

∗administer valsartan preparations at the appropriate dosage.

Children

Valsartan is used for the treatment of arterial hypertension in children aged 6 to 18 years. The 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-myocardial infarction state in children due to lack of data on safety and efficacy.

Overdose

Overdose with valsartan may result in marked arterial hypotension, which may lead to loss of 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 hemodynamic stabilization. In case of arterial hypotension, 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 with placebo was comparable to that with 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 identified during clinical, post-marketing, and laboratory studies are listed below by organ system classes.

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

The frequency of adverse reactions is defined as follows: very common (>1/10),
common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000),
very rare (<1/10,000), including isolated reports. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions identified during post-marketing and laboratory studies, for which the frequency could not be determined, are listed as "unknown."

Table 2

Infections
Common	Viral infections
Uncommon	Upper respiratory tract infections, pharyngitis, sinusitis
Very rare	Rhinitis
Blood and lymphatic system disorders
Uncommon	Neutropenia
Very rare	Thrombocytopenia
Immune system disorders
Very rare	Hypersensitivity reactions, including serum sickness
Metabolism and nutrition disorders
Uncommon	Hyperkalemia*#
Not known	Increased serum potassium, hyponatremia
Psychiatric disorders
Uncommon	Insomnia, decreased libido
Nervous system disorders
Common	Postural dizziness#
Uncommon	Syncope*
Rare	Dizziness##
Very rare	Headache##
Ear and labyrinth disorders
Uncommon	Vertigo
Cardiac disorders
Uncommon	Heart failure*
Very rare	Cardiac rhythm disorders
Vascular disorders
Common	Orthostatic hypotension#
Uncommon	Hypotension*##
Very rare	Vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon	Cough
Gastrointestinal disorders
Uncommon	Abdominal pain, diarrhea
Very rare	Nausea##, vomiting
Hepatobiliary disorders
Not known	Increased liver function parameters, including increased serum bilirubin levels
Skin and subcutaneous tissue disorders
Very rare	Angioedema**, rash, pruritus, exanthema
Musculoskeletal and connective tissue disorders
Uncommon	Back pain
Very rare	Myalgia, arthralgia
Renal and urinary disorders
Very rare	Renal failure##, acute renal failure, renal dysfunction
Pregnancy and perinatal conditions
Very rare	Fetal developmental complications
General disorders
Uncommon	Malaise, asthenia, edema
Investigations
Common	Increased serum creatinine, increased blood urea nitrogen
Very rare	Increased serum bilirubin, decreased hemoglobin/hematocrit levels, liver function parameters outside normal range.

* 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. Significant reductions (>20%) in hematocrit and hemoglobin levels have been observed.

Neutropenia was observed in 1.9% of patients treated with valsartan, compared to 1.6% of patients treated with an ACE inhibitor.

In patients with arterial hypertension, significant increases in serum creatinine, potassium, and total bilirubin levels may occur compared to patients taking ACE inhibitors.

Isolated cases of elevated 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 some patients taking valsartan compared to those taking placebo, and an increase in serum potassium levels by more than 20% was observed in 10% of patients taking valsartan compared to those on placebo.

Elevated blood urea nitrogen (BUN) levels were noted in some patients taking valsartan compared to those taking placebo. In some patients receiving valsartan, or treated with a combination of valsartan and captopril, or treated with captopril alone during the post-infarction period, serum creatinine levels doubled.

The number of cases of discontinuation of the drug due to adverse reactions was lower in the valsartan-treated group compared to the captopril group.

Pediatric population

Arterial hypertension

No significant differences in type, frequency, or severity of adverse reactions were identified between the safety profile in children aged 6 to 18 years and the previously established safety profile in adults (except for isolated gastrointestinal disorders such as abdominal pain, nausea, vomiting, and dizziness).

Neurocognitive and developmental assessments in children aged 6 to 16 years did not reveal any clinically significant overall negative effects after up to 1 year of valsartan treatment.

Isolated fatal cases and isolated cases of marked elevation of liver transaminases have been reported. These cases occurred in populations with significant comorbidities. A causal relationship with valsartan has not been established.

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

The safety profile observed 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. Adverse reactions observed in adult patients after myocardial infarction and/or with heart failure are listed in Table 2.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging, out of the reach of children, at a temperature not exceeding 25 °C.

Packaging.

Film-coated tablets: 80 mg (packs of 28, 98); 160 mg (packs of 28, 98); 320 mg (pack of 28). Blister packs of 14 tablets in cardboard boxes.

Prescription status. Prescription only.

Manufacturer.

Sanovel Ilac Sanayi ve Ticaret A.S., Turkey.

Manufacturer's address and location.

Balaban Mahallesi, Cihaner Sokagi, No 10, Istanbul, 34580 Silivri, Turkey.

Marketing Authorization Holder. JSC "Farmak".

Address of the Marketing Authorization Holder. 63 Kyrylivska St., Kyiv, 04080, Ukraine.