INSTRUCTIONS for medical use of the medicinal product Valsacor® (Valsacor®)

Composition:

Active substance: 1 film-coated tablet contains 40 mg, or 80 mg, or 160 mg, or 320 mg of valsartan;

Excipients: lactose monohydrate, microcrystalline cellulose, povidone, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), macrogol 4000, iron oxide yellow (E 172) – present in film-coated tablets of 40 mg, 160 mg and 320 mg; iron oxide red (E 172) – present in film-coated tablets of 80 mg, 160 mg and 320 mg.

Medicinal form. Film-coated tablets.

Main physicochemical characteristics:

Tablets 40 mg: yellow-brown, round, slightly biconvex film-coated tablets with a notch on one side;

Tablets 80 mg: pink, round, biconvex film-coated tablets with a notch on one side;

Tablets 160 mg: yellow-brown, oval, biconvex film-coated tablets with a notch on one side;

Tablets 320 mg: light brown, capsule-shaped, biconvex film-coated tablets with a notch on one side.

Pharmacotherapeutic group. Simple preparations of angiotensin II antagonists.

ATC code C09C A03.

Pharmacological Properties.

Pharmacodynamics.

Valsartan is an active, specific antagonist of angiotensin II receptors. It selectively acts on the AT1 receptor subtype responsible for the known effects of angiotensin II. Increased plasma levels of angiotensin II following blockade of AT1 receptors by valsartan may stimulate unblocked AT2 receptors, which regulate the activity of AT1 receptors. Valsartan exhibits no agonistic activity at AT1 receptors and has significantly greater affinity (approximately 20,000 times) for AT1 receptors than for AT2 receptors. It is unknown whether valsartan binds to, or blocks, other hormonal receptors or ion channels important in cardiovascular regulation.

Valsartan does not inhibit the activity of angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and catalyzes the breakdown of bradykinin. Angiotensin II antagonists do not cause cough, as they do not affect angiotensin-converting enzyme activity and do not enhance bradykinin or substance P production.

Treatment with valsartan in patients with arterial hypertension results in a reduction in blood pressure without affecting heart rate.

In most patients, the antihypertensive effect develops within 2 hours after a single oral dose, with maximum blood pressure reduction achieved within 4–6 hours. The antihypertensive effect lasts more than 24 hours after dosing. With repeated administration, maximal reduction in blood pressure is reached after 4 weeks and is maintained throughout long-term treatment. Additional blood pressure reduction is achieved when co-administered with hydrochlorothiazide.

Abrupt discontinuation of valsartan does not lead to sudden increases in blood pressure or other adverse clinical events in patients.

With long-term use in patients with arterial hypertension, the drug has no significant effect on total cholesterol or uric acid levels, and fasting studies show no effect on serum triglyceride or glucose concentrations.

The use of the drug reduces hospitalizations due to heart failure, slows the progression of heart failure, improves functional class according to NYHA classification, increases ejection fraction, and reduces signs and symptoms of heart failure, improving quality of life compared to placebo.

Valsartan has also been effective in reducing mortality from cardiovascular disease, hospitalizations due to heart failure, and recurrent myocardial infarction. Valsartan positively influenced the time from the occurrence of acute myocardial infarction to the first manifestation of cardiovascular disease leading to fatal outcomes.

Two large randomized controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]) investigated the use of combinations of ACE inhibitors with angiotensin receptor blockers.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate significant beneficial effects on renal and/or cardiovascular outcomes or mortality, although an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Given their similar pharmacodynamic properties, these findings also apply to other ACE inhibitors and angiotensin receptor blockers.

Therefore, ACE inhibitors and angiotensin receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to evaluate the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin receptor blocker in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular events and stroke were more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalemia, arterial hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Children

The antihypertensive effect of valsartan was evaluated in four 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 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.

In a second clinical trial involving 300 pediatric patients aged 6 to 18 years with arterial hypertension, patients were randomized to receive either valsartan or enalapril tablets for 12 weeks. Children with body weight ≥18 kg to <35 kg received valsartan 80 mg or enalapril 10 mg; those with body weight ≥35 kg to <80 kg received valsartan 160 mg or enalapril 20 mg; those with body weight ≥80 kg received valsartan 320 mg or enalapril 40 mg. Reduction in systolic blood pressure was comparable between patients receiving valsartan (15 mm Hg) and enalapril (14 mm Hg) (p < 0.0001). Consistent results were observed for diastolic blood pressure, with reductions of 9.1 mm Hg and 8.5 mm Hg with valsartan and enalapril, respectively.

In a third open-label clinical trial involving 150 children aged 6 to 17 years with hypertension, eligible patients (systolic BP ≥95th percentile for age, sex, and height) received valsartan for 18 months to assess safety and tolerability. Of the 150 patients participating in this study, 41 also received concomitant antihypertensive therapy. Patients were prescribed initial and maintenance doses according to their weight categories. Patients with body weight >18 to <35 kg, ≥35 to <80 kg, and ≥80 to <160 kg received 40 mg, 80 mg, and 160 mg, respectively, with doses titrated to 80 mg, 160 mg, and 320 mg after one week. Half of the enrolled patients (50.0%, n=75) had CKD, with 29.3% (44 patients) having stage 2 CKD (eGFR 60–89 mL/min/1.73 m²) or stage 3 CKD (eGFR 30–59 mL/min/1.73 m²). Mean reduction in systolic blood pressure was 14.9 mm Hg in all patients (baseline 133.5 mm Hg), 18.4 mm Hg in patients with CKD (baseline 131.9 mm Hg), and 11.5 mm Hg in patients without CKD (baseline 135.1 mm Hg). The percentage of patients achieving overall blood pressure control (both systolic and diastolic BP <95th percentile) was slightly higher in the CKD group (79.5%) compared to the non-CKD group (72.2%).

Pharmacokinetics.

Absorption

After oral administration, peak plasma concentrations of valsartan are reached within 2–4 hours, or within 1–2 hours when administered as a solution. The mean absolute bioavailability of tablets and solution is 23% and 39%, respectively. Food intake reduces exposure to valsartan by approximately 40% and peak plasma concentrations by approximately 50%, although plasma concentrations of valsartan are similar approximately 8 hours after administration whether taken fasting or with food. However, this reduction in exposure 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 albumin.

Biological transformation

Valsartan undergoes minimal biotransformation, as only about 20% of the dose is recovered as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Elimination

Valsartan exhibits multi-exponential elimination kinetics (t1/2α <1 hour and t1/2β approximately 9 hours). Valsartan is primarily eliminated via the biliary route in feces (approximately 83% of the dose) and to a lesser extent via the kidneys in urine (approximately 13% of the dose), mostly unchanged. After intravenous administration, plasma clearance of valsartan is approximately 2 L/hour, and renal clearance is 0.62 L/hour (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Patients with heart failure (only 40 mg, 80 mg, and 160 mg)

The mean time to peak concentration and elimination half-life of valsartan are similar in patients with heart failure and healthy volunteers. Area under the concentration-time curve (AUC) and maximum concentration of valsartan increase linearly and nearly proportionally with increasing doses above the clinical range (40–160 mg twice daily). The accumulation ratio is on average 1.7. Oral clearance of valsartan is approximately 4.5 L/hour. Age does not affect drug clearance in patients with heart failure.

Specific patient populations

Elderly patients

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

Patients with renal impairment

No correlation has been found 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 is no experience regarding the safety of the drug in patients with creatinine clearance < 10 mL/min or in patients undergoing dialysis; therefore, valsartan should be used with caution in these patients. Valsartan is highly protein-bound, and its removal by hemodialysis is unlikely.

Patients with hepatic impairment

Approximately 70% of the absorbed dose is excreted in bile, primarily unchanged. Valsartan undergoes minimal biotransformation, and systemic exposure to valsartan is not expected to correlate with the degree of hepatic dysfunction. Therefore, dose adjustment is not required in patients with non-biliary hepatic insufficiency and in the absence of cholestasis. In patients with biliary cirrhosis or biliary obstruction, the AUC of valsartan has been shown to increase approximately twofold.

Children with renal impairment

The use of the drug has not been studied in children with creatinine clearance < 30 mL/min or in children undergoing dialysis; 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 carefully monitored.

Clinical characteristics.

Indications.

Arterial hypertension (tablets 80 mg, 160 mg, and 320 mg).

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

Arterial hypertension (tablets 40 mg).

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

Post-infarction state (tablets 40 mg, 80 mg, and 160 mg).

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

Heart failure (tablets 40 mg, 80 mg, and 160 mg).

Treatment of adult patients with symptomatic heart failure when angiotensin-converting enzyme (ACE) inhibitors are not tolerated, or in patients intolerant to beta-blockers as an add-on to ACE inhibitor therapy when mineralocorticoid receptor antagonists cannot be used (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", "Method of administration and dosage").

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product; severe hepatic impairment, biliary cirrhosis, and cholestasis; pregnancy or women planning to become pregnant (see "Use during pregnancy or breastfeeding"); concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR <60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

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

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalaemia, and impaired renal function (including acute renal failure), compared to treatment with a single agent acting on the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special warnings and precautions for use").

Concomitant use not recommended

Lithium

During concomitant use of ACE inhibitors or angiotensin II receptor antagonists, including valsartan, with lithium, reversible increases in serum lithium concentrations and lithium toxicity have been reported. If combination therapy is necessary, careful monitoring of serum lithium levels is recommended. The risk of lithium toxicity may be further increased if a diuretic is also used.

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 a medicinal product affecting potassium levels must be used in combination with valsartan, monitoring of plasma potassium levels is recommended.

Caution with concomitant use

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 reduce the antihypertensive effect. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may lead to worsening of renal function and increased serum potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate hydration are recommended.

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 with inhibitors of OATP1B1 transporters (e.g., rifampicin, cyclosporine) or MRP2 (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate monitoring is recommended at the initiation or discontinuation of concomitant therapy with these medicinal products.

Others

No interactions were observed between valsartan and any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.

Children

Caution is recommended when administering valsartan concomitantly with other agents that inhibit the renin-angiotensin-aldosterone system in children with arterial hypertension, as this may increase serum potassium levels.

Special precautions for use.

Hyperkalemia

Concomitant use with 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 concomitant use is necessary, monitoring of serum potassium levels is advised.

Renal impairment

Dose adjustment is not required in patients with impaired renal function (creatinine clearance > 10 mL/min). There is currently no experience regarding the safe use of valsartan in patients with creatinine clearance < 10 mL/min or in patients undergoing dialysis; therefore, valsartan should be used with caution in these patients.

Hepatic impairment

Valsartan should be administered with caution to patients with mild to moderate hepatic impairment without cholestasis.

Patients with sodium and/or circulating blood volume imbalance

In patients with severe sodium and/or circulating blood volume imbalance (e.g., those receiving high-dose diuretic therapy), symptomatic hypotension may occur after initiation of valsartan therapy. Sodium and/or circulating blood volume imbalance should be corrected prior to starting valsartan therapy, 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 single kidney. Short-term use of valsartan in patients with renovascular hypertension secondary to unilateral renal artery stenosis does not cause significant changes in renal hemodynamic parameters, serum creatinine, or blood urea nitrogen. Since other medicinal products affecting the renin-angiotensin-aldosterone system (RAAS) may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, monitoring of renal function is recommended as a safety precaution during treatment with valsartan.

Renal transplantation

There is currently no experience with the safe use of valsartan in patients who have recently undergone renal transplantation.

Primary hyperaldosteronism

Valsartan 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, 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 treatment with the medicinal product is considered necessary, patients planning pregnancy should switch to alternative antihypertensive therapies with an established safety profile during pregnancy. If pregnancy is confirmed, treatment should be discontinued immediately and, if necessary, alternative therapy should be initiated.

Recent myocardial infarction (only 40 mg, 80 mg, and 160 mg)

Combination therapy with captopril and valsartan did not demonstrate additional clinical benefit but was associated with an increased risk of adverse reactions compared to monotherapy with either agent. Therefore, concomitant use of valsartan and an ACE inhibitor is not recommended.

Therapy should be initiated with caution in patients who have recently experienced myocardial infarction. Renal function assessment should be included in the evaluation of patients after myocardial infarction. Valsartan use in 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 (only 40 mg, 80 mg, and 160 mg)

The risk of adverse reactions, particularly arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), may be increased when valsartan is used concomitantly with an ACE inhibitor. In patients with heart failure, triple therapy with an ACE inhibitor, β-blocker, and valsartan has not shown clinical benefit. This combination clearly increases the risk of adverse events and is therefore not recommended. Triple therapy with an ACE inhibitor, mineralocorticoid receptor antagonist, and valsartan is also not recommended. The use of such combinations should occur only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure.

Therapy should be initiated with caution in patients with heart failure. Evaluation of patients with heart failure should always include assessment of renal function.

Valsartan use in patients with heart failure 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.

In patients in whom renal function may depend on renin-angiotensin system activity (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death. Since valsartan is an angiotensin II antagonist, renal impairment cannot be excluded during valsartan therapy.

History of angioedema

Cases of Quincke's edema (including laryngeal and glottal edema leading to airway obstruction and/or facial, lip, pharyngeal, and/or tongue swelling) have been reported in patients receiving valsartan. Some of these patients had a history of angioedema with other medicinal products, including ACE inhibitors. If angioedema occurs, treatment with the drug should be discontinued immediately. Re-administration is contraindicated. (See section "Adverse reactions").

Other conditions with renin-angiotensin system stimulation (320 mg tablets)

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

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If dual blockade therapy is considered absolutely necessary, it should be conducted only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure.

ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Fertility

Oral administration of valsartan at doses up to 200 mg/kg/day did not show adverse effects on reproductive function in male and female rats. This dose is 6 times higher than the maximum recommended human dose on a mg/m² basis (calculations based on 320 mg/day orally and a patient body weight of 60 kg).

Special warnings regarding inactive ingredients

Valsakor® contains lactose. This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Children

Renal impairment

The use of the medicinal product in children with creatinine clearance < 30 mL/min or in children undergoing dialysis has not been studied; therefore, valsartan is not recommended in these patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be carefully monitored during valsartan therapy, particularly in cases where other conditions (e.g., high fever, dehydration) that may impair renal function are present.

Hepatic impairment

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

Use during pregnancy or breastfeeding

Pregnancy

The use of angiotensin II receptor antagonists is contraindicated in pregnant women or women planning to become pregnant.

Epidemiological data on the teratogenic risk of 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 the risk of angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Except when continuation of therapy is considered necessary, patients planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, angiotensin II receptor antagonists should be discontinued immediately, and, if necessary, alternative therapy should be initiated.

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

If angiotensin II receptor antagonists are used from the second trimester of pregnancy, ultrasound evaluation of renal function and skull ossification is recommended.

Newborns whose mothers received angiotensin II receptor antagonists should be carefully monitored for the development of arterial hypotension.

Breastfeeding period

Due to the lack of any information on the use of valsartan during breastfeeding, valsartan is not recommended. Alternative medicinal products with better-established safety profiles during breastfeeding should be preferred, especially when breastfeeding newborns or preterm infants.

Ability to influence reaction speed when driving or operating machinery

Studies on the effect of valsartan on the ability to drive or operate machinery have not 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

Valzakor® should be taken independently of food intake, swallowed with water.

Dosage

Arterial Hypertension in Adults (80 mg, 160 mg, and 320 mg tablets)

The recommended initial dose of Valzakor® is 80 mg once daily. The antihypertensive effect is achieved within 2 weeks, and the maximum antihypertensive effect is reached within 4 weeks of treatment. For patients in whom adequate blood pressure reduction is not achieved, the daily dose may be increased to 160 mg and up to the maximum of 320 mg.

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

Recent Myocardial Infarction (40 mg, 80 mg, and 160 mg tablets)

Therapy may be initiated in clinically stable patients as early as 12 hours after a myocardial infarction. Following an initial dose of 20 mg twice daily, the dose of valsartan should be titrated upward to 40 mg, 80 mg, and then 160 mg twice daily over the subsequent weeks. The initial dose is administered using a 40 mg tablet, which can be divided into equal halves.

The maximum dose is 160 mg twice daily. It is generally recommended that the dose of 80 mg twice daily be reached within 2 weeks of starting treatment, and the maximum dose of 160 mg twice daily within 3 months, depending on patient tolerance. If symptomatic arterial hypotension or renal dysfunction occurs, dose reduction should be considered.

Valsartan may be prescribed to patients who are taking 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 should always undergo renal function assessment.

Heart Failure (40 mg, 80 mg, and 160 mg tablets)

The recommended initial dose of Valzakor® is 40 mg twice daily. This dose should be gradually increased to 80 mg and then to 160 mg twice daily at intervals of at least 2 weeks, up to the highest dose tolerated by the patient. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical studies was 320 mg given in divided doses.

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

Patients with heart failure should always undergo renal function assessment.

Additional Information on Special Patient Populations

Elderly Patients

No dose adjustment is required for elderly patients.

Renal Impairment

No dose adjustment is required for patients with creatinine clearance > 10 mL/min.

Hepatic Impairment

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

Children

Arterial Hypertension in Children Aged 6 to 18 Years

The initial dose is 40 mg 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. The dose should be adjusted based on blood pressure response and tolerability. 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.

Table 1

Body weight	Maximum dose of Valsakor® 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

Use in 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 must be carefully monitored.

Use in children aged 6 to 18 years with hepatic impairment

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

Children.

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

Overdose.

Symptoms

Valsartan overdose may lead to marked hypotension, which can result in depressed consciousness, vascular collapse, and/or shock.

Treatment

Therapeutic measures depend on the time of ingestion and the type and severity of symptoms. The most important measure is stabilization of the circulatory condition. In case of arterial hypotension, the patient should be placed in a supine position and blood volume should be corrected.

It is unlikely that valsartan can be effectively removed by hemodialysis.

Adverse Reactions

In adult patients with arterial hypertension, the overall frequency of adverse reactions is consistent with the pharmacology of valsartan. The incidence of adverse reactions was found to be unrelated to dose or duration of treatment and does not depend on sex, age, or race.

Adverse reactions are grouped by system organ classes according to the frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), unknown (frequency cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

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

Arterial Hypertension

Blood and lymphatic system disorders

Unknown: decreased hemoglobin, decreased hematocrit, neutropenia, thrombocytopenia.

Immune system disorders

Unknown: hypersensitivity, including serum sickness.

Metabolism and nutrition disorders

Unknown: increased serum potassium, hyponatremia.

Ear and labyrinth disorders

Uncommon: vertigo.

Vascular disorders

Unknown: vasculitis.

Respiratory, thoracic and mediastinal disorders

Uncommon: cough.

Gastrointestinal disorders

Uncommon: abdominal pain.

Hepatobiliary disorders

Unknown: increased liver function test values, including elevated serum bilirubin.

Skin and subcutaneous tissue disorders

Uncommon: angioedema, rash, pruritus.

Unknown: bullous dermatitis.

Musculoskeletal and connective tissue disorders

Unknown: myalgia.

Renal and urinary disorders

Unknown: renal failure and impaired renal function, increased serum creatinine.

General disorders

Uncommon: increased fatigue.

Reactions observed in patients with arterial hypertension, regardless of causal relationship to the investigational drug: arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections, viral infections.

Children

Arterial Hypertension

The antihypertensive effect of valsartan was evaluated in two randomized, double-blind clinical trials involving 561 children aged 6 to 18 years. Except for individual gastrointestinal disorders (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 that previously established in adults.

Neurocognitive and developmental assessments in children aged 6 to 16 years revealed no clinically significant overall negative impact after up to 1 year of treatment with valsartan.

A pooled analysis was conducted in 560 hypertensive children (aged 6–17 years) receiving either valsartan monotherapy [n=483] or combination antihypertensive therapy including valsartan [n=77]. Of the 560 patients, 85 (15.2%) had CKD (baseline eGFR <90 mL/min/1.73 m²). Overall, 45 (8.0%) patients discontinued the study due to adverse effects. A total of 111 (19.8%) patients experienced an adverse drug reaction (ADR), most commonly headache (5.4%), dizziness (2.3%), and hyperkalemia (2.3%). In patients with CKD, the most frequent adverse reactions were hyperkalemia (12.9%), headache (7.1%), increased blood creatinine (5.9%), and arterial hypotension (4.7%). In patients without CKD, the most common adverse reactions were headache (5.1%) and dizziness (2.7%). Adverse reactions occurred more frequently in patients receiving valsartan in combination with other antihypertensive agents than with valsartan alone.

Hyperkalemia was more frequently observed in children aged 6 to 18 years with underlying chronic kidney disease. The risk of hyperkalemia may be higher in children aged 1 to 5 years compared to those aged 6 to 18 years.

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

Post-Myocardial Infarction and/or Heart Failure

Blood and lymphatic system disorders

Unknown: thrombocytopenia.

Immune system disorders

Unknown: hypersensitivity, including serum sickness.

Metabolism and nutrition disorders

Uncommon: hyperkalemia.

Unknown: increased serum potassium, hyponatremia.

Nervous system disorders

Common: dizziness, postural dizziness.

Uncommon: syncope, headache.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac and vascular disorders

Common: arterial hypotension, orthostatic hypotension.

Uncommon: heart failure.

Unknown: vasculitis.

Respiratory, thoracic and mediastinal disorders

Uncommon: cough.

Gastrointestinal disorders

Uncommon: nausea, diarrhea.

Hepatobiliary disorders

Unknown: increased liver function test values.

Skin and subcutaneous tissue disorders

Uncommon: angioedema.

Unknown: bullous dermatitis, rash, pruritus.

Musculoskeletal and connective tissue disorders

Unknown: myalgia, arthralgia.

Renal and urinary disorders

Common: renal failure and impaired renal function.

Uncommon: acute renal failure, increased serum creatinine.

Unknown: increased blood urea nitrogen.

General disorders

Uncommon: asthenia, increased fatigue.

Shelf life.

5 years.

Storage conditions.

Tablets 40 mg, 80 mg, 160 mg: Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Tablets 320 mg: Store at a temperature not exceeding 30 °C in the original packaging to protect from moisture. Keep out of the reach of children.

Packaging.

Tablets 40 mg: 7 tablets in a blister; 4 blisters in a cardboard box;
10 tablets in a blister; 3 blisters in a cardboard box;
14 tablets in a blister; 2 blisters in a cardboard box.

Tablets 80 mg, 160 mg: 7 tablets in a blister; 4 or 12 blisters in a cardboard box;
10 tablets in a blister; 3 blisters in a cardboard box;
14 tablets in a blister; 2 or 6 blisters in a cardboard box.

Tablets 320 mg: 10 tablets in a blister; 3 or 6 blisters in a cardboard box;
14 tablets in 2 or 4 blisters in a cardboard box;
15 tablets in a blister; 2 or 4 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's location and address of place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.