INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT

Valsartan 40 Macleods / Valsartan 40 Macleods
Valsartan 80 Macleods / Valsartan 80 Macleods
Valsartan 160 Macleods / Valsartan 160 Macleods
Valsartan 320 Macleods / Valsartan 320 Macleods

Composition:

Active substance: valsartan;

1 tablet contains: 40 mg, 80 mg, 160 mg, or 320 mg of valsartan;

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

Coating composition: Opadry Yellow 03F82329 for 40 mg tablets only; Opadry Pink 03F84641
for 80 mg tablets only; Opadry Yellow 03F520004 for 160 mg tablets only; Opadry Purple 02F50251
for 320 mg tablets only.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

40 mg dosage: biconvex, oval-shaped, film-coated yellow tablets, embossed with "L12" divided by a break line on one side and smooth on the other;

80 mg dosage: biconvex, oval-shaped, film-coated light-red tablets, embossed with "L13" on one side and smooth on the other;

160 mg dosage: biconvex, oval-shaped, film-coated grey-orange tablets, embossed with "L14" on one side and smooth on the other;

320 mg dosage: biconvex, oval-shaped, film-coated dark grey-purple tablets, embossed with "L15" on one side and smooth on the other.

Pharmacotherapeutic group. Simple angiotensin II antagonist preparations.
ATC code: C09CA03.

Pharmacological Properties.

Pharmacodynamics.

Valsartan is an orally active, specific angiotensin II receptor antagonist. It selectively acts on AT1 receptors, which are responsible for the known effects of angiotensin II. Elevated 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 ACE (angiotensin-converting enzyme), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Administration of the drug to patients with arterial hypertension results in a reduction 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 more than 24 hours. The maximum therapeutic effect develops within 4 weeks of starting treatment and is maintained during long-term therapy. When used in combination with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.

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

With long-term use of valsartan in patients with arterial hypertension, it was established that the drug had no significant effect on total cholesterol levels, uric acid, and, in fasting studies, on serum triglyceride and glucose concentrations.

Administration of valsartan reduces the number of hospitalizations due to heart failure, slows the progression of heart failure, improves 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, is effective in reducing overall mortality after myocardial infarction. Valsartan was also effective in reducing cardiovascular mortality and in decreasing the number of hospitalizations due to heart failure, as well as recurrent myocardial infarction. Valsartan positively influenced the time to first occurrence of cardiovascular events after acute myocardial infarction leading to fatal outcomes.

Children

The antihypertensive effect of valsartan was evaluated in four randomized, double-blind clinical studies involving 561 children aged 6 to 18 years and 165 children aged 1 to 6 years. Renal and urinary tract disorders and obesity were the most common 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 study involving 261 children with arterial hypertension aged 6 to 16 years, patients with body weight < 35 kg received 10, 40, or 80 mg of valsartan daily (low, medium, and high doses), while patients with body weight ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium, and high doses). At the end of 2 weeks, valsartan reduced systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium, and high) significantly reduced systolic blood pressure by 8, 10, and 12 mm Hg from baseline, respectively.

Clinical experience in children under 6 years of age.

Valsartan is not recommended for use in this age group.

Pharmacokinetics.

Absorption.

After oral administration of valsartan in tablet form, maximum plasma concentrations (Cmax) are reached within 2–4 hours; as a solution, within 1–2 hours. The mean absolute bioavailability of the tablet and solution formulations is 23% and 39%, respectively.

Food reduces valsartan exposure (as measured by AUC) by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%, although plasma concentrations of valsartan beginning at approximately 8 hours post-dose are similar between fasting and fed conditions. However, the reduction in AUC is not associated with 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 serum 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 ~ 9 hours). Valsartan is primarily eliminated via bile into feces (approximately 83% of the dose) and to a lesser extent via kidneys in urine (approximately 13% of the dose), mainly in unchanged form. After intravenous administration, the plasma clearance of valsartan is about 2 L/h, and renal clearance is 0.62 L/h (approximately 30% of total clearance). The elimination half-life of valsartan is 6 hours.

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

The mean time to reach Cmax and the 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. The predicted clearance of valsartan after oral administration is about 4.5 L/h. Age does not affect predicted clearance in patients with heart failure.

Pharmacokinetics in specific patient groups.

Elderly patients.

In some elderly patients, systemic exposure to valsartan was slightly higher than in younger patients, although this difference has not been shown to be clinically significant.

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). Currently, there are no data on the safety of valsartan 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 liver 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 approximately doubled.

Children.

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

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 these patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be closely monitored.

Clinical characteristics.

Indications.

Arterial hypertension.

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

Post-myocardial infarction state.

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

Heart failure.

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

Contraindications.

• Hypersensitivity to valsartan or to any excipient.
• Pregnancy or planned pregnancy (see "Use in pregnancy or breastfeeding").
• Hereditary or ACE inhibitor- or angiotensin II receptor antagonist-induced angioedema.
• Concomitant use of angiotensin receptor antagonists, including Valsartan Macleods, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type 1 or type 2) or impaired renal function (glomerular filtration rate (GFR) < 60 mL/min).

Data in patients with severe renal impairment (creatinine clearance less than 10 mL/min) are lacking.

Interaction with other medicinal products and other forms of interaction.

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

Concomitant use of angiotensin II receptor blockers (ARBs), including valsartan, with other drugs acting on the RAAS is associated with an increased incidence of arterial hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Therefore, 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 administered only under specialist supervision with careful monitoring of renal function, electrolyte levels, and blood pressure.

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

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

ACE inhibitors, including Valsartan Macleods, 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 capable of increasing potassium levels (e.g., heparin, etc.) may lead to increased serum potassium levels, and in patients with heart failure, may also increase 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.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 (cyclooxygenase-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. In addition, concomitant use of angiotensin II antagonists and NSAIDs increases the risk of worsening renal function and elevated serum potassium levels. Therefore, monitoring of renal function and adequate patient hydration are recommended at the start of treatment.

Transporters.

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

Others.

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

Children.

Caution is recommended when administering valsartan concomitantly with other drugs that inhibit the renin-angiotensin-aldosterone system to children and adolescents with arterial hypertension, as serum potassium levels may increase. 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 agents that may increase potassium levels (e.g., heparin, etc.) is not recommended. If concomitant use is necessary, potassium levels should be monitored.

Angioedema of the intestine.

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including valsartan (see section "Adverse reactions"). These patients presented with 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 symptoms completely resolve.

Renal impairment.

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

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

Hepatic impairment.

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

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

In patients with severe sodium and/or circulating blood volume deficiency (e.g., those receiving high-dose diuretic therapy), symptomatic arterial hypotension may occur after initiation of therapy with Valsartan Mylan. Prior to starting Valsartan Mylan, correction of sodium and/or circulating blood volume deficiency should be considered, for example, by reducing the diuretic dose.

Renal artery stenosis.

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

Kidney transplantation.

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

Primary hyperaldosteronism.

Valsartan Mylan 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.

Like other vasodilators, Valsartan Mylan 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 treatment is considered necessary, patients 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 alternative therapy initiated if necessary.

Recent myocardial infarction.

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

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

Administration of Valsartan Mylan to patients after myocardial infarction often leads to some reduction in blood pressure, but discontinuation of therapy due to prolonged symptomatic hypotension is generally not required if dosing instructions are followed.

Heart failure.

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

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

Safety and efficacy of Valsartan Mylan in pediatric patients have not been established.

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 previously occurred during treatment with other drugs, including ACE inhibitors. Development of angioedema requires immediate discontinuation of Valsartan Mylan, and the drug should not be re-administered to such patients.

Other conditions with stimulation of the renin-angiotensin system.

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

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

Concomitant use of angiotensin II receptor antagonists, including Valsartan Mylan, with other agents acting on the RAAS is associated with increased incidence of arterial hypotension, hyperkalemia, and changes in renal function compared to monotherapy. Monitoring of blood pressure, renal function, and serum electrolytes is recommended in patients receiving Valsartan Mylan 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 treatment with valsartan, 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 Valsartan Mylan, or ACE inhibitors with aliskiren in patients with renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.

Hepatic impairment.

As in adults, Valsartan Mylan is contraindicated in children with severe hepatic impairment, biliary cirrhosis, or cholestasis. Clinical experience with Valsartan Mylan 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 teratogenic risk associated with ACE inhibitors during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. Since there are no controlled epidemiological data on teratogenic risk of angiotensin II receptor antagonists, such risk cannot be excluded with use of 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 confirmed, treatment with angiotensin II receptor antagonists should be discontinued immediately and, if necessary, replaced with a drug 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 in humans (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 use of valsartan during breastfeeding, Valsartan Mylan is not recommended for use in breastfeeding women.

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

Ability to drive and use machines.

Studies on the effect on the ability to drive and operate machinery have not been conducted. It should be noted that dizziness or weakness may occur during treatment with the drug.

Method of administration and dosage.

Method of administration.

Valsartan Macleods can be administered regardless of food intake; tablets should be taken with water.

Dosage.

Arterial hypertension.

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

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

Recent myocardial infarction.

Treatment may be initiated in clinically stable patients as early as 12 hours after myocardial infarction. After the initial dose of valsartan 20 mg twice daily, the dose should be increased to 40 mg, 80 mg, and then 160 mg twice daily over the following weeks.

The target maximum dose is 160 mg twice daily. Generally, it is 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 can be administered to patients who are being treated with other medications following myocardial infarction, such as thrombolytics, acetylsalicylic acid, beta-blockers, statins, and diuretics. Combination with ACE inhibitors is not recommended.

Patients after myocardial infarction must always have renal function monitored.

Heart failure

The recommended initial dose of valsartan is 40 mg (tablets should not be divided — dosage forms with appropriate strength should 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, administered in divided doses.

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

Patients with heart failure require monitoring of renal function.

Use in specific patient populations.

Elderly patients.

Dose adjustment is not required in elderly patients.

Renal impairment.

Dose adjustment is not required in adult patients with creatinine clearance > 10 ml/min. Concomitant use of Valsartan Macleods with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 ml/min/1.73 m²) is contraindicated.

Diabetes mellitus.

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

Hepatic impairment.

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

Children.

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

Arterial hypertension in children.

Children and adolescents aged 6 to 18 years.

The initial dose is 40 mg (tablets should not be divided — dosage forms with appropriate strength should be taken) once daily for children with body weight less than 35 kg, and 80 mg once daily for children with body weight of 35 kg or more. Dose should be adjusted according to blood pressure response. Maximum doses studied in clinical trials are shown in Table 1.

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

Table 1

	Body weight of the patient	Maximum dose of Valsartan Macleods, investigated 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 Mylan 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 use in these patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be closely monitored.

Children aged 6 to 18 years with hepatic impairment

As in adults, Valsartan Mylan is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis. Clinical experience with Valsartan Mylan 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 Mylan 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 overdose with Valsartan Mylan, marked hypotension may develop, 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 stabilization of circulation. If hypotension occurs, the patient should be placed in a supine position and blood volume should be corrected.

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

Adverse reactions.

Arterial hypertension / heart failure / myocardial infarction.

During controlled clinical studies in adult patients with arterial hypertension, the incidence of adverse reactions with valsartan was comparable to that with placebo. 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 systems.

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

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

For adverse reactions with frequencies of "very rare," "rare," and "uncommon," which were not detected in clinical trials, a cumulative search was conducted in the safety data system.

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*#
Psychiatric disorders
Uncommon	Insomnia, decreased libido
Nervous system disorders
Common	Dizziness##, postural dizziness#
Uncommon	Syncope*
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 system disorders
Uncommon	Cough
Gastrointestinal disorders
Uncommon	Diarrhea, abdominal pain
Very rare	Nausea##, vomiting, angioneurotic intestinal edema
Hepatobiliary disorders
Unknown	Elevated liver function parameters, including increased serum bilirubin levels
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
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
Very rare	Elevated serum bilirubin, decreased hemoglobin/hematocrit levels, liver function parameters outside normal range.

* Observed in post-myocardial infarction patients.

Observed in patients with heart failure.

** Infrequently observed in post-myocardial infarction patients.

Observed more frequently in patients with heart failure (frequent: dizziness, renal function impairment, hypotension; infrequent: headache, nausea).

Laboratory test results

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

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

In controlled clinical trials involving patients with arterial hypertension, significant increases in serum creatinine, 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 special laboratory parameter monitoring.

In cases of heart failure, serum creatinine levels increased by more than 50% in 3.9% of patients taking valsartan, compared to 0.9% of 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 patients taking placebo.

Serum creatinine levels doubled in 4.2% of patients receiving valsartan, in 4.8% of patients treated with a combination of valsartan and captopril, and in 3.4% of patients treated with captopril during the post-infarction period.

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

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

In a double-blind, randomized trial involving 90 children aged 1 to 6 years, followed by an open-label study lasting one year, two fatal cases and isolated cases of marked elevation in liver transaminases were recorded. These cases occurred in a population with significant comorbidities. A causal relationship with Valsartan Macleods has not been established. In a second study involving 75 randomized children aged 1 to 6 years, no significant elevations in liver 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 condition. Adverse reactions observed in adult patients after myocardial infarction and/or with heart failure are listed in Table 2.

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets per blister; 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and location of operations.

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.