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

Composition:

Active substance: valsartan;

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

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: hypromellose, titanium dioxide (E 171), polyethylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: biconvex tablets from white to almost white in color, with a smooth surface, film-coated.

Pharmacotherapeutic group.

Agents acting on the renin-angiotensin system. Simple angiotensin II antagonists. Valsartan. ATC code C09CA03.

Pharmacological Properties

Pharmacodynamics

Valsartan is an active, specific angiotensin II receptor antagonist intended for oral use. It acts selectively on AT1 receptors, which are responsible for the known effects of angiotensin II. The increased plasma levels of angiotensin II following blockade of AT1 receptors 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 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 leads to a reduction in blood pressure without affecting pulse rate.

The onset of antihypertensive effect occurs within 2 hours, with peak effect achieved within 4–6 hours after oral administration; the duration of action lasts over 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.

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 levels or uric acid levels, and fasting measurements show no significant effect on serum triglyceride or glucose concentrations.

Administration of the drug reduces hospitalization rates due to heart failure, slows the progression of heart failure, improves functional class according to NYHA classification, increases ejection fraction, and reduces 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 and hospitalizations due to heart failure, as well as recurrent myocardial infarction. Valsartan positively influenced the time period from 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 trials involving 561 children aged 6–18 years and 165 children aged 1–6 years. Renal and urinary tract disorders and obesity were the most common underlying medical conditions causing arterial hypertension in the children included in these studies.

Clinical experience in children aged 6 years and older

In a clinical trial involving 261 hypertensive children aged 6–16 years, patients with body weight < 35 kg received 10 mg, 40 mg, or 80 mg of valsartan daily (low, medium, and high doses), while patients with body weight ≥ 35 kg received 20 mg, 80 mg, or 160 mg of valsartan daily (low, medium, and high doses). By the end of the second week, 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, maximum plasma concentration (Cmax) is reached within 2–4 hours, or within 1–2 hours when administered as a solution. The mean absolute bioavailability of the tablet and solution formulations is 23% and 39%, respectively. Food reduces exposure (as defined by AUC) to valsartan by approximately 40% and Cmax by approximately 50%, although plasma concentrations of valsartan beginning at approximately 8 hours after dosing are similar between fasting and postprandial conditions. However, 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 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.

Biological transformation

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 into feces (approximately 83% of the dose) and via the kidneys into urine (approximately 13% of the dose), mainly in unchanged form. After intravenous administration, the 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 (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 mg to 160 mg twice daily). The mean accumulation coefficient is approximately 1.7. The 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 populations

Elderly patients

In some elderly patients, systemic exposure to valsartan was slightly higher than in younger patients, although no clinical significance of this has been demonstrated.

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 renal impairment (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 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 of valsartan is not required in patients with non-biliary hepatic insufficiency and in the absence of cholestasis. It has been shown that in patients with biliary cirrhosis or biliary obstruction, the AUC of valsartan is increased by approximately two-fold.

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 (1–16 years) to that observed in adults receiving the same formulation.

Patients 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 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 left ventricular systolic dysfunction following a 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 β-blockers cannot be used.

Contraindications.

• Hypersensitivity to valsartan or to any excipient of the medicinal product;
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breast-feeding");
• Hereditary or ACE inhibitor- or angiotensin II receptor antagonist-induced angioedema;
• Concomitant use of angiotensin receptor blockers, including the medicinal product Corsar® Mono, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or II) or renal impairment (glomerular filtration rate (GFR) < 60 mL/min);
• No data available in patients with severe renal impairment (creatinine clearance less than 10 mL/min).

Interaction with other medicinal products and other types of interactions.

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

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

Concomitant use of angiotensin receptor antagonists, including the medicinal product Corsar® Mono, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min) is contraindicated.

Concomitant use of ARBs, including the medicinal product Corsar® Mono, or ACE inhibitors with aliskiren is contraindicated in patients with type I or II diabetes mellitus.

ACE inhibitors, including the medicinal product Corsar® Mono, and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of ACE inhibitors. Due to the lack of experience with 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 use of a medicinal product affecting potassium levels is considered necessary in combination with valsartan, monitoring of plasma potassium levels is recommended.

Caution is required when used concomitantly

Non-steroidal 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 attenuation of the antihypertensive effect. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased 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 of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of these findings is unknown. Concomitant use with 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 and upon discontinuation of concomitant use of these medicinal products.

Others

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

Children

Caution is recommended when administering valsartan concomitantly with other RAAS-inhibiting agents to children and adolescents with arterial hypertension, as this may increase serum potassium levels. Renal function and serum potassium levels should be closely 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, etc.) is not recommended. If necessary, potassium levels should be monitored.

Renal impairment

There are no safety data on the use of the medicinal product 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 creatine clearance > 10 mL/min.

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

Hepatic impairment

Corsar® Mono should be used with caution in patients with mild to moderate hepatic impairment without cholestasis.

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

In patients with severe sodium and/or CBV depletion, such as those receiving high-dose diuretic therapy, symptomatic arterial hypotension may occur after initiation of therapy with Corsar® Mono. Prior to starting treatment with Corsar® Mono, correction of sodium and/or CBV status should be performed, for example, by reducing the diuretic dose.

Renal artery stenosis

The safety of Corsar® Mono 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 RAAS may increase blood urea and serum creatinine 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 Corsar® Mono in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Corsar® Mono 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 medicinal product 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 the respective 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.

Use of Corsar® Mono in patients after myocardial infarction often leads to some reduction in blood pressure, which usually necessitates discontinuation of therapy due to persistent symptomatic arterial hypotension, even when dosing instructions are followed.

Heart failure

In patients with heart failure, triple combination therapy with an ACE inhibitor, β-blocker, and Corsar® Mono showed no clinical benefit. This combination is likely to increase the risk of adverse reactions 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 Corsar® Mono 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. In some of these patients, angioedema had occurred previously with other medicinal products, including ACE inhibitors. Angioedema requires immediate discontinuation of Corsar® Mono, and the drug should not be re-administered to such patients.

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 symptom resolution.

Other conditions with stimulation of the renin-angiotensin-aldosterone system (RAAS)

In patients in whom renal function may depend on RAAS 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 fatal outcomes. Since valsartan is an angiotensin II antagonist, renal dysfunction associated with the use of Corsar® Mono cannot be excluded.

Dual blockade of the RAAS

Concomitant use of ARBs, including Corsar® Mono, with other medicinal products 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 electrolyte levels is recommended in patients receiving Corsar® Mono and other RAAS-acting agents.

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 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 therapy, particularly in cases where other conditions (e.g., high fever, dehydration) that may impair renal function are present.

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

Hepatic impairment

As in adults, Corsar® Mono is contraindicated in children with severe hepatic impairment, biliary cirrhosis, or cholestasis. Clinical experience with Corsar® Mono 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 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 ARBs, 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, ARB therapy must be discontinued immediately and replaced with a pregnancy-approved medicinal product if necessary.

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).

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 carefully monitored for signs of arterial hypotension.

Due to lack of information on valsartan use during breastfeeding, Corsar® Mono 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 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

No studies on the effect on the ability to drive vehicles or operate machinery have been conducted. It should be noted that dizziness or weakness may occur during treatment with the medicinal product.

Method of Administration and Dosage

Method of Administration

The medicinal product Corzar® Mono can be administered independently of food intake; tablets should be taken with water.

Dosage

Arterial Hypertension

The recommended initial dose of Corzar® Mono 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.

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

Recent Myocardial Infarction

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

The target maximum dose is 160 mg twice daily. Generally, it is recommended that the dose of 80 mg twice daily be achieved 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 medications following myocardial infarction, such as thrombolytics, acetylsalicylic acid, β-blockers, statins, and diuretics. Combination with ACE inhibitors is not recommended.

Patients after myocardial infarction must always have renal function monitored.

Heart Failure

The recommended initial dose of valsartan is 40 mg (tablets must not be split; appropriate dosage forms must be taken) twice daily. Gradual dose escalation to 80 mg and then 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, β-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

No dose adjustment is required in adult patients with creatinine clearance > 10 mL/min. Concomitant use of Corzar® Mono with aliskiren in patients with renal impairment (eGFR < 60 mL/min/1.73 m²) is contraindicated.

Diabetes Mellitus

Concomitant use of Corzar® Mono with aliskiren in patients with diabetes mellitus is contraindicated.

Hepatic Impairment

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

Children

Corzar® Mono may be used for the treatment of arterial hypertension in children aged 6 to 18 years. Safety and efficacy in children aged 1 to 6 years have not been established. The medicinal product 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 and Adolescents Aged 6 to 18 Years

The initial dose is 40 mg (tablets must not be split; appropriate dosage forms must be taken) once daily for children with body weight below 35 kg, and 80 mg once daily for children with body weight ≥ 35 kg. Dose should be adjusted according to blood pressure response. The maximum doses studied in clinical trials are shown in the table below.

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

Patient body weight	Maximum dose of valsartan studied in clinical trials
From ≥ 18 kg to < 35 kg	80 mg
From ≥ 35 kg to < 80 kg	160 mg
From ≥ 80 kg to ≤ 160 kg	320 mg

Children under 6 years of age

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

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.

Children aged 6 to 18 years with hepatic impairment

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

The medicinal product Corsar® Mono 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 an overdose of the medicinal product Corsar® Mono, marked arterial hypotension may develop, which can 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 unrelated to dose or duration of treatment, and did not depend on patient's sex, age, or race.

Adverse reactions reported 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 (> 1/10,000, < 1/1000), very rare (< 1/100,000), including isolated case reports. Within each frequency group, adverse reactions are listed in order of decreasing occurrence.

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

MedDRA System Organ Classes	Adverse Reactions	Frequency
Infections and infestations	Viral infections	Common
	Upper respiratory tract infections, pharyngitis, sinusitis	Uncommon
	Rhinitis	Very rare
Blood and lymphatic system disorders	Neutropenia	Uncommon
	Thrombocytopenia	Very rare
Immune system disorders	Hypersensitivity reactions, including serum sickness	Very rare
Metabolism and nutrition disorders	Hypokalemia*#	Uncommon
Psychiatric disorders	Insomnia, decreased libido	Uncommon
Nervous system disorders	Dizziness##, postural dizziness#	Common
	Syncope*	Uncommon
	Headache##	Very rare
Ear and labyrinth disorders	Vertigo	Uncommon
Cardiac disorders	Heart failure*	Uncommon
	Cardiac rhythm disorders	Very rare
Vascular disorders	Orthostatic hypotension#	Common
	Arterial hypotension*##	Uncommon
	Vasculitis	Very rare
Respiratory, thoracic and mediastinal disorders	Cough	Uncommon
Gastrointestinal disorders	Diarrhea, abdominal pain	Uncommon
	Nausea##, vomiting, angioneurotic edema of the intestine	Very rare
Hepatobiliary disorders	Increased liver function parameters, including increased serum bilirubin levels	Frequency unknown
Skin and subcutaneous tissue disorders	Angioedema**, rash, pruritus, exanthema	Very rare
	Bullous dermatitis	Frequency unknown
Musculoskeletal and connective tissue disorders	Back pain	Uncommon
	Arthralgia, myalgia	Very rare
Renal and urinary disorders	Renal failure**##, acute renal failure**, renal dysfunction**	Very rare
Pregnancy and perinatal conditions	Fetal developmental complications	Very rare
General disorders	Fatigue, asthenia, edema	Uncommon
Investigations	Increased serum creatinine levels, increased blood urea levels	Common
	Increased serum bilirubin levels, decreased hemoglobin/hematocrit levels, liver function parameters outside normal range	Very rare

* Reported in post-myocardial infarction patients;

Reported in patients with heart failure;

** Infrequently reported in post-myocardial infarction patients;

More frequently reported in patients with heart failure (frequent: dizziness, renal impairment, arterial hypotension; infrequent: headache, nausea).

Description of selected adverse reactions:

Cases of angioneurotic edema of the intestine have been reported following administration of angiotensin II receptor blockers (see section "Special warnings and precautions for use").

Laboratory test findings

Valsartan has occasionally caused a reduction in hemoglobin and hematocrit levels. In controlled clinical trials, significant reductions (> 20%) in hematocrit and hemoglobin levels were observed in 0.8% and 0.4% of patients receiving valsartan, respectively. In comparison, reductions in both parameters (hematocrit and hemoglobin) were observed in 0.1% of placebo-treated patients.

Neutropenia was observed in 1.9% of patients treated with valsartan versus 1.6% of patients treated with an ACE inhibitor in controlled clinical trials.

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.

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

In heart failure, serum creatinine levels increased by more than 50% in 3.9% of patients taking valsartan compared to 0.9% of placebo-treated patients, and serum potassium levels increased by more than 20% in 10% of patients taking valsartan compared to 5.1% of placebo-treated patients.

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

An increase in serum creatinine levels by two-fold was observed in 4.2% of patients receiving valsartan, 4.8% of patients treated with a combination of valsartan and captopril, and 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 population

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 isolated gastrointestinal disorders (such as abdominal pain, nausea, vomiting) and dizziness, 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 adult patients.

Neurocognitive and developmental assessments in children aged 6 to 16 years did not reveal any clinically significant overall negative effects after treatment with valsartan for up to one 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 events 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 has not been established. In a second study involving 75 randomized children aged 1 to 6 years, no significant elevations in hepatic transaminases or fatal events 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. Adverse reactions observed in adult patients after myocardial infarction and/or with heart failure are listed in the table above.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging. 10 tablets per blister. 3 or 9 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.

Marketing Authorization Holder. JSC "Farmak".

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