INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Tiarа® (Tiara)

Composition:

Active substance: valsartan;

1 tablet contains 80 mg or 160 mg of valsartan;

Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II 85F pink.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

80 mg tablets — round, biconvex tablets, film-coated in pink color, with a score line;

160 mg tablets — oval, biconvex tablets, film-coated in pink color, with a score line.

Pharmacotherapeutic group. Simple angiotensin II antagonists. Valsartan.

ATC code C09CA03.

Pharmacological Properties

Pharmacodynamics

Valsartan is an active, specific angiotensin II receptor antagonist intended for oral administration. 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 the AT1 receptor and has a 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 in blood pressure without affecting pulse rate.

The onset of antihypertensive effect occurs within 2 hours, peaks within 4–6 hours after oral administration, and lasts for 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.

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

With prolonged use of valsartan in patients with arterial hypertension, the drug had no significant effect on total cholesterol levels, uric acid, and, when administered fasting, on serum triglyceride and glucose concentrations.

Administration of the drug reduces the number of hospitalizations due to heart failure, slows the progression of heart failure, improves functional class according to the NYHA [New York Heart Association] 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, 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 interval from acute myocardial infarction to the first occurrence of fatal cardiovascular events.

Children

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

Clinical experience in children aged 6 years and older. In a clinical trial involving 261 hypertensive children aged 6 to 16 years, patients with body weight < 35 kg received 10, 40, or 80 mg of valsartan daily (low, medium, and high doses), while patients with body weight ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium, and high doses). At the end of the second week, valsartan reduced systolic and diastolic blood pressure in a dose-dependent manner. 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 concentrations (Cmax) are reached within 2–4 hours; when administered as a solution, peak concentrations occur within 1–2 hours. The mean absolute bioavailability of tablets and oral solution is 23% and 39%, respectively.

Food reduces valsartan exposure (as measured by AUC) by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%. However, plasma concentrations of valsartan starting at about 8 hours after administration are similar in fasting and fed conditions. The reduction in AUC does not result in a 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 albumin.

Metabolism. Valsartan is largely not metabolized, as only about 20% of the dose is excreted as metabolites. A hydroxy metabolite was detected 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 kidneys into urine (approximately 13% of the dose), mostly unchanged. 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. The mean time to reach Cmax and elimination half-life of valsartan in tablet form (80 mg and 160 mg) are similar in patients with heart failure and 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. 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, 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, dosage adjustment is not required in patients with impaired renal function (creatinine clearance > 10 mL/min). Currently, there are no safety data available for patients with creatinine clearance < 10 mL/min or those undergoing dialysis; thus, valsartan should be used with caution in these patients. Due to the high degree of plasma protein binding, valsartan is unlikely to be removed by hemodialysis.

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

Patients with renal impairment. The use of the drug 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. Dosage 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 years and older.

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 inhibitors (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.
Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding").
Hereditary or idiopathic angioedema, or angioedema that developed during previous treatment with an ACE inhibitor or an angiotensin II receptor antagonist.
Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or II) or renal impairment (glomerular filtration rate (GFR) < 60 mL/min).
No data are available for patients with severe renal impairment (creatinine clearance less than 10 mL/min).
Severe hepatic impairment, biliary cirrhosis, and cholestasis.

Interaction with other medicinal products and other forms of interaction

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

Concomitant use of ARBs, including valsartan, with other medicinal products 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 necessary, it should be performed only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

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

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

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

Concomitant use not recommended

Lithium

Reversible increases in serum lithium 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 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 required when used concomitantly

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

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

Transporters

In vitro studies indicate that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these findings is unknown. Concomitant use with 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 end of concomitant use of these medicinal products.

Others

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

Children

Caution is recommended when administering valsartan concomitantly with other medicinal products that inhibit the RAAS and may increase serum potassium levels in children and adolescents with arterial hypertension. Renal function and serum potassium levels should be carefully monitored.

Special precautions for use

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

Renal impairment. There are no safety data available 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 creatinine clearance > 10 mL/min.

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

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

Patients with sodium and/or circulating blood volume deficiency. In patients with severe sodium and/or circulating blood volume (CBV) deficiency, such as those receiving high doses of diuretics, symptomatic arterial hypotension may occur after initiation of therapy with valsartan. Prior to starting valsartan therapy, correction of sodium and/or CBV deficiency should be considered, 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 to a solitary 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 sten游戏副本, as a precautionary measure, monitoring of renal function is recommended during treatment with valsartan.

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

Primary hyperaldosteronism. Valsartan is not recommended in patients with primary hyperaldosteronism, as the renin-angiotensin system (RAS) is not activated in these patients.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.

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

Pregnancy. Angiotensin II receptor antagonists are contraindicated during pregnancy. If continued use of the medicinal product is considered necessary, patients who are planning pregnancy should switch from valsartan to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is confirmed, treatment should be discontinued immediately and, if necessary, alternative therapy initiated.

Recent myocardial infarction. The combination of captopril and valsartan did not 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 valsartan in patients after myocardial infarction often causes some reduction in blood pressure, which usually leads to the need to discontinue therapy due to prolonged symptomatic arterial hypotension despite adherence to the recommended dosage.

Heart failure. In patients with heart failure, triple combination therapy with an ACE inhibitor, β-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 strict monitoring of renal function, electrolyte levels, and blood pressure.

Safety and efficacy of valsartan in pediatric patients have not been studied.

History of angioedema. Angioedema, including laryngeal and glottis edema leading to airway obstruction and/or facial, lip, pharyngeal, and/or tongue swelling, has been reported during treatment with valsartan. Some of these patients had previously experienced angioedema during treatment with other medicinal products, including ACE inhibitors. Development of angioedema requires immediate discontinuation of valsartan, and re-administration of valsartan 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 (RAS). In patients in whom renal function may depend on RAS 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 function impairment cannot be excluded with valsartan use.

Dual blockade of the RAAS. Concomitant use of angiotensin receptor antagonists, including valsartan, with other medicinal products 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 valsartan and other medicinal products affecting the RAAS.

Pediatric population

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

Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with impaired renal function (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 or women planning to become pregnant.

Epidemiological data on the 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 teratogenic risk of ARBs, such a risk may exist. Unless continuation of therapy is considered necessary, alternative antihypertensive therapy with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, ARB treatment should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during 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 of mothers who received ARBs should be carefully monitored for the development of arterial hypotension.

Due to lack of information on the use of valsartan during breastfeeding, the medicinal product 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 or operate machinery have been conducted. It should be considered that dizziness or weakness may occur during treatment with this medicinal product.

Dosage and Administration

Route of administration

The medicinal product can be administered regardless of food intake; tablets should be taken with water.

Dosage

Arterial hypertension

The recommended initial dose of valsartan is 80 mg once daily. Antihypertensive effect is achieved within 2 weeks, and maximal 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 of 320 mg.

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

Recent myocardial infarction

Treatment may be initiated in clinically stable patients as early as 12 hours after myocardial infarction. After an initial dose of valsartan 20 mg (tablets cannot be divided into doses — appropriate dosage forms must be selected) twice daily, the dose should be increased to 40 mg (tablets cannot be divided into doses — appropriate dosage forms must be selected), 80 mg, and 160 mg twice daily over the following weeks.

The target maximum dose is 160 mg twice daily. Generally, it is recommended that the dosage level 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 administered to patients who are receiving 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 cannot be divided into doses — appropriate dosage forms must be selected) twice daily. Gradual dose escalation to 80 mg and 160 mg twice daily should be performed at intervals of at least 2 weeks to the highest dose, depending on patient tolerance. 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 medicinal products for the treatment of heart failure. 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

Arterial hypertension in children

Children and adolescents aged 6 to 18 years. The initial dose is 40 mg (tablets cannot be divided into doses — appropriate dosage forms must be selected) once daily for children with body weight below 35 kg and 80 mg once daily for children with body weight of 35 kg and above. Dose adjustment should be based on blood pressure response. The maximum valsartan doses studied in clinical trials are shown in Table 1.

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

Table 1

	Body weight of patient	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 valsartan in children aged 1 to 6 years have not been established.

Children aged 6 to 18 years with renal impairment. The use of valsartan in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for 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, valsartan is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis. Clinical experience with the use of valsartan in children with mild to moderate hepatic impairment is limited. The dose of valsartan should not exceed 80 mg in such patients.

Heart failure and recent myocardial infarction in children

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

Elderly patients

Dose adjustment is not required in elderly patients.

Renal impairment

Dose adjustment is not required in adult patients with creatinine clearance > 10 mL/min. Concomitant use of valsartan with aliskiren in patients with renal impairment (eGFR < 60 mL/min/1.73 m²) is contraindicated.

Diabetes

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

Hepatic impairment

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

Children

The medicinal product can be 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 medicinal product 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 an overdose of valsartan, marked arterial hypotension may develop, which may lead to impaired consciousness, vascular collapse, and/or shock. Therapeutic measures depend on the time of ingestion and the type and severity of symptoms; stabilization of circulation is of primary importance. 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.

Side effects

Arterial hypertension / heart failure / myocardial infarction

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

Adverse reactions reported during clinical, post-marketing, and laboratory studies are listed by organ systems.

For adverse reactions categorized as "very rare," "rare," and "uncommon," which were not identified during 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 (> 1/10000, < 1/1000), very rare (< 1/100000), including isolated case reports. Within each frequency group, adverse reactions are listed in decreasing order of severity.

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

Ear and labyrinth disorders: uncommon — vertigo.

Respiratory, thoracic and mediastinal disorders: uncommon — cough.

Gastrointestinal disorders: uncommon — diarrhea, abdominal pain; very rare — nausea##, vomiting, intestinal angioedema.

Hepatobiliary disorders: unknown — increased liver function parameters, including elevated serum bilirubin levels.

Renal and urinary disorders: very rare — renal failure**##, acute renal failure**, renal impairment**.

Metabolism and nutritional disorders: uncommon — hyperkalaemia*#.

Nervous system disorders: common — postural dizziness#; uncommon — syncope*; rare — dizziness##; very rare — headache##.

Psychiatric disorders: uncommon — insomnia, decreased libido.

Cardiac disorders: uncommon — heart failure*; very rare — cardiac rhythm disturbances.

Vascular disorders: common — orthostatic hypotension#; uncommon — hypotension*##; very rare — vasculitis.

Blood and lymphatic system disorders: uncommon — neutropenia; very rare — thrombocytopenia.

Immune system disorders: very rare — hypersensitivity reactions, including serum sickness.

Skin and subcutaneous tissue disorders: very rare — angioedema**, rash, pruritus, exanthema; unknown — bullous dermatitis.

Musculoskeletal and connective tissue disorders: uncommon — back pain; very rare — arthralgia, myalgia.

Pregnancy and perinatal conditions: very rare — fetal developmental complications.

General disorders: uncommon — fatigue, asthenia, edema.

Infections: common — viral infections; uncommon — upper respiratory tract infections, pharyngitis, sinusitis; very rare — rhinitis.

Laboratory findings: common — increased serum creatinine, increased blood urea; very rare — elevated serum bilirubin, decreased hemoglobin/hematocrit levels, liver function parameters outside normal range.

* Reported in post-myocardial infarction patients.

Reported in patients with heart failure.

** Uncommonly reported in post-myocardial infarction patients.

More frequently reported in patients with heart failure (common: dizziness, renal function impairment, hypotension; uncommon: headache, nausea).

Laboratory findings

Valsartan occasionally caused reductions in hemoglobin levels and hematocrit values. 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, only 0.1% of placebo-treated patients experienced reductions in both hematocrit and hemoglobin levels.

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

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

Isolated cases of 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 monitoring.

In heart failure patients, serum creatinine levels increased by more than 50% in 3.9% of patients receiving valsartan, compared to 0.9% of placebo-treated patients. Serum potassium levels increased by more than 20% in 10% of patients receiving 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 receiving valsartan, compared to 6.3% of placebo-treated patients.

In post-myocardial infarction patients, serum creatinine levels doubled in 4.2% of patients receiving valsartan, 4.8% of patients receiving valsartan plus captopril, and 3.4% of patients receiving captopril.

The rate of drug discontinuation due to adverse reactions was lower in the valsartan 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 observed 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 revealed no clinically significant negative effects after up to one year of valsartan treatment.

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

Hyperkalaemia 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 above.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and/or lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

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

Packaging

Film-coated tablets, 80 mg: 14 tablets in a blister pack; 2 blister packs in a carton.

Film-coated tablets, 160 mg: 14 tablets in a blister pack; 2 or 6 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's location and address of business activity. 13 Borispilska St., Kyiv, 02093, Ukraine.