Valsartan krka

INSTRUCTIONS for medical use of the medicinal product Valsartan KRKA (Valsartan KRKA)

Composition:

Active substance: valsartan;

One film-coated tablet contains 80 mg, 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, yellow iron oxide (E 172) (present in 160 mg and 320 mg film-coated tablets), red iron oxide (E 172) (present in 80 mg, 160 mg, and 320 mg film-coated tablets).

Medicinal form. Film-coated tablets.

Main physicochemical properties:

80 mg tablets: – pink, round, biconvex, film-coated tablets with a score line on one side;

160 mg tablets: – yellowish-brown, oval, biconvex, film-coated tablets with a score line on one side;

320 mg tablets: – light brown, capsule-shaped, biconvex, film-coated tablets with a score line on one side.

Pharmacotherapeutic group.

Simple angiotensin II antagonists. ATC code: C09C A03.

Pharmacological Properties

Pharmacodynamics

Valsartan is an active, specific angiotensin II receptor antagonist (ARB). It acts selectively on the AT1 receptor subtype responsible for the known effects of angiotensin II. Elevated 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 higher) 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 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 ACE activity and do not increase bradykinin or substance P production.

Arterial Hypertension

Valsartan reduces arterial blood pressure in patients with arterial hypertension without affecting pulse rate.

In most patients, antihypertensive effects occur within 2 hours after a single oral dose, with peak blood pressure reduction achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after administration.

With repeated dosing, antihypertensive effects are essentially maintained over 2 weeks, maximal effect is reached within 4 weeks, and sustained throughout long-term therapy. When combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.

Abrupt discontinuation of valsartan has not been associated with sudden increases in blood pressure or other adverse clinical events in patients.

Administration of valsartan at doses of 160–320 mg leads to a clinically significant reduction in urinary albumin excretion in patients with type 2 diabetes and arterial hypertension.

Post-Myocardial Infarction State

Clinical trial data have demonstrated that valsartan, like captopril, reduces overall mortality following myocardial infarction. Valsartan was also effective in reducing cardiovascular mortality, hospitalizations due to heart failure, and recurrent myocardial infarction. Valsartan positively influenced the time from the acute myocardial infarction to the first occurrence of cardiovascular events leading to fatal outcomes.

Heart Failure

Treatment with valsartan 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, resulting in improved quality of life compared to placebo.

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)—evaluated the use of combined ACE inhibitors and angiotensin receptor blockers (ARBs).

ONTARGET was a study involving 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 involving patients with type 2 diabetes and diabetic nephropathy.

These trials did not demonstrate a significant beneficial effect 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 ARBs.

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 ARB 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 occurred more frequently in the aliskiren group than in the placebo group, and adverse and serious adverse events of interest (hyperkalemia, 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; and 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). Similar 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 enrolled, 41 also received concomitant antihypertensive therapy. Patients received 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 dose titration 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 BP 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 of valsartan tablets, peak plasma concentrations are reached within 2–4 hours; when administered as a solution, peak concentrations occur within 1–2 hours. The mean absolute bioavailability is 23% for tablets and 39% for solution. Food decreases exposure (as measured by AUC) of valsartan by approximately 40% and peak plasma concentration (Cmax) by approximately 50%, although plasma concentrations of valsartan from about 8 hours post-dose are similar between fasting and fed conditions. However, the reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered with or without food.

Distribution

The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 L, indicating that valsartan does not extensively distribute into tissues. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.

Biotransformation

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.

Excretion

The pharmacokinetic profile of valsartan is multiphasic (T½α <1 hour and T½ß approximately 9 hours). Valsartan is primarily eliminated via the biliary route in feces (approximately 83% of dose) and through the kidneys in urine (approximately 13% of dose), mainly unchanged. After intravenous administration, 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.

In patients with heart failure (80 mg and 160 mg tablets) and in healthy volunteers, the mean time to reach Cmax and elimination half-life of valsartan are similar. The area under the concentration-time curve (AUC) and Cmax of valsartan are nearly proportional to dose increases above the clinical dose range (from 40 to 160 mg twice daily). The accumulation ratio is on average 1.7. Predicted oral clearance of valsartan is approximately 4.5 L/h. Age does not influence predicted clearance in patients with heart failure.

Elderly patients. Systemic exposure to valsartan was slightly higher in some elderly patients compared to younger individuals, but this difference has not been shown to have clinical significance.

Patients with renal impairment. No correlation was 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 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. 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 unchanged. Valsartan undergoes minimal biotransformation, and systemic exposure is not expected to correlate with the degree of hepatic impairment. 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, AUC of valsartan is increased by approximately two-fold.

Children

In a study involving children with arterial hypertension (up to 16 years of age) receiving 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 age range of 1 to 16 years and similar to that observed in adults receiving the same formulation.

Patients with renal impairment

Use of the drug in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for such patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be carefully monitored.

Clinical characteristics.

Indications.

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

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

Post-infarction state (tablets 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 (within 12 hours to 10 days).

Heart failure (tablets 80 mg and 160 mg).

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients; severe hepatic impairment, biliary cirrhosis, and cholestasis; concomitant use of angiotensin receptor antagonists, including valsartan, or angiotensin-converting enzyme inhibitors (ACE inhibitors) with aliskiren in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Pregnant women or women planning to become pregnant, breastfeeding period (see "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Double blockade of the renin-angiotensin-aldosterone system (RAAS) with drugs from the ARB, ACE inhibitors, or aliskiren groups

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 frequency of adverse effects such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to using a single agent acting on the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special 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-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels

If concomitant use of a medicinal product affecting potassium levels with valsartan is required, monitoring of plasma potassium levels is recommended.

Precautions 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 result in reduced antihypertensive effect. Moreover, concomitant administration 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 of the patient are recommended.

Transporters

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

Absence of interactions

Others

No interaction was observed between valsartan and any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glipizide.

Children

Caution is recommended when administering valsartan concomitantly with other substances that suppress the RAAS in children with arterial hypertension, as this may increase serum potassium levels. Renal function and serum potassium levels should be monitored regularly.

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 necessary, monitoring of potassium levels should be performed.

Renal impairment

Concomitant use of aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m²) (see section "Contraindications").

Hepatic impairment

Valsartan should be administered with caution to patients with mild to moderate hepatic impairment without cholestasis (see sections "Posology and method of administration" and "Pharmacokinetics").

Patients with sodium and/or circulating blood volume imbalance

In patients with severe sodium and/or circulating blood volume depletion (e.g., those receiving high-dose diuretic therapy), symptomatic hypotension may occur in individual cases after initiation of valsartan therapy. Sodium and/or circulating blood volume imbalance should be corrected prior to starting valsartan treatment, 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 patients with secondary renovascular hypertension and unilateral renal artery stenosis did not cause any significant changes in renal hemodynamics, serum creatinine, or blood urea nitrogen. Other medicinal products affecting the RAS may increase blood urea and serum creatinine levels in patients with unilateral renal artery stenosis; therefore, monitoring of renal function is recommended during treatment with valsartan.

Kidney transplantation

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

Primary hyperaldosteronism

Valsartan is not recommended for patients with primary hyperaldosteronism, as the underlying disease affects the RAAS.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

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

Recent myocardial infarction (only 80 mg and 160 mg)

Combination therapy with captopril and valsartan did not demonstrate additional clinical benefit, while the risk of adverse reactions increased compared to treatment with individual agents (see section "Posology and method of administration"). 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 (see section "Posology and method of administration"). 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 (see section "Posology and method of administration").

Heart failure (only 80 mg and 160 mg)

The risk of adverse reactions, particularly arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), may increase when valsartan is used in combination with an ACE inhibitor. In patients with heart failure, triple combination therapy with an ACE inhibitor, β-blocker, and valsartan did not demonstrate any clinical benefit (see section "Pharmacokinetics"). This combination clearly increases the risk of adverse events and is therefore not recommended.

Triple combination therapy with an ACE inhibitor, mineralocorticoid receptor antagonist, and valsartan is also not recommended. The use of such combinations should only be performed 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 (see section "Posology and method of administration").

In patients in whom renal function may depend on renin-angiotensin-aldosterone system (RAAS) 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 fatal outcomes. Since valsartan is an angiotensin II receptor antagonist, renal function impairment cannot be excluded with valsartan use.

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

Other conditions involving RAAS stimulation (only 320 mg)

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

Angioedema

Cases of angioedema (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 effects").

Intestinal angioedema

Intestinal angioedema has been reported in patients receiving angiotensin II receptor antagonists (see section "Adverse reactions"). These patients experienced symptoms such as abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until complete symptom resolution.

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.

Concomitant use of the combination valsartan/hydrochlorothiazide with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see section "Contraindications").

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.

Special warnings regarding inactive ingredients

Valsartan KRKA contains lactose. This medicinal product is contraindicated in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Children

Renal impairment

The use of the medicinal product has not been studied in children with creatinine clearance < 30 mL/min or in children undergoing dialysis; therefore, valsartan is not recommended for such patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be carefully monitored, 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 with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m²) (see section "Contraindications").

Hepatic impairment

As in adults, valsartan is contraindicated in children with severe hepatic insufficiency, biliary cirrhosis, or cholestasis. Clinical experience with valsartan 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

Angiotensin II receptor antagonists are contraindicated throughout pregnancy.

Epidemiological data on teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. Since there are no controlled epidemiological data on the risk of angiotensin II receptor antagonists, similar risks may exist for this class of medicinal products. Women 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 alternative therapy should be initiated if possible.

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

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

Newborns whose mothers received angiotensin II receptor antagonists should be closely 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 contraindicated. If treatment is necessary, breastfeeding should be discontinued.

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 animals. This dose is 6 times higher than the maximum recommended human dose on a mg/m² basis (oral dose of 320 mg/day at a patient body weight of 60 kg).

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect 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

Valsartan KRKA should be taken independently of food intake, with water.

The 80 mg, 160 mg, and 320 mg tablets have a score line, which allows for the possibility of dividing the tablet into equal parts.

Dosage

Arterial Hypertension in Adults

The recommended initial dose of Valsartan KRKA 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.

Valsartan KRKA can also be used in combination with other antihypertensive agents. The addition of a diuretic such as hydrochlorothiazide provides additional blood pressure reduction.

Recent Myocardial Infarction (80 mg and 160 mg tablets)

Treatment of clinically stable patients may be initiated as early as 12 hours after a myocardial infarction. After an initial dose of 20 mg (administer valsartan in an appropriate dosage form) twice daily, the dose of valsartan should be increased by titration to 40 mg, 80 mg, and 160 mg twice daily over the following weeks. The maximum dose is 160 mg twice daily. Generally, it is recommended that the dosage level of 80 mg twice daily be reached within 2 weeks after initiation of treatment, and the maximum dose of 160 mg twice daily within 3 months, depending on patient tolerance. If symptomatic arterial hypotension or impaired renal function 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, β-blockers, statins, and diuretics. Combination with ACE inhibitors is not recommended (see section "Special Warnings and Precautions for Use").

Evaluation of patients after myocardial infarction should always include assessment of renal function.

Heart Failure (80 mg and 160 mg tablets)

The recommended initial dose of Valsartan KRKA is 40 mg twice daily. This dose should be gradually increased to 80 mg and then to 160 mg twice daily, with 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 used in clinical trials was 320 mg, divided into multiple doses.

Valsartan may be used in combination with other drugs for the treatment of heart failure. However, triple combination of an ACE inhibitor, β-blocker, and valsartan is not recommended (see section "Special Warnings and Precautions for Use").

Evaluation of patients with heart failure should always include assessment of renal function.

Additional Information on Special Patient Populations

Elderly Patients

Dose adjustment is not required for elderly patients.

Renal Impairment

Concomitant use with aliskiren is contraindicated in patients with impaired renal function (eGFR < 60 mL/min/1.73 m²) (see section "Contraindications").

Diabetes Mellitus

Concomitant use of valsartan and aliskiren is contraindicated in patients with diabetes mellitus (see section "Contraindications").

Hepatic Impairment

The drug is contraindicated in patients with severe hepatic insufficiency or biliary cirrhosis and cholestasis (see sections "Contraindications", "Special Warnings and Precautions for Use"). For patients with mild to moderate hepatic insufficiency without cholestasis, the dose of valsartan should not exceed 80 mg.

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. Dose adjustment should be based on blood pressure response and tolerability. Maximum doses are shown in the table below. Doses higher than those specified have not been studied and are therefore not recommended.

Body weight	Maximum dose of valsartan
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 should be closely monitored (see section "Special precautions for use").

Use in 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 valsartan in children with mild to moderate hepatic impairment is limited. The dose of valsartan should not exceed 80 mg in such patients.

Children with recent myocardial infarction and heart failure

Due to lack of data on efficacy and safety, valsartan is not recommended for use in children with these conditions.

Children

The drug is indicated for the treatment of arterial hypertension in children aged 6 years and older. Safety and efficacy of the drug in children under 6 years of age have not been established. The drug is not recommended for use in children with heart failure or recent myocardial infarction due to lack of data on safety and efficacy.

Overdose

Symptoms

Valsartan overdose may lead to marked hypotension, accompanied by drowsiness, collapse, and/or shock.

Treatment

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

It is unlikely that the drug will be effectively removed by hemodialysis, as valsartan is highly protein-bound.

Adverse Reactions

Adverse reactions are grouped by organ systems according to the frequency of their occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); not known (frequency cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity of their manifestations.

For all adverse reactions reported for the drug during post-marketing experience and laboratory analyses, frequency cannot be determined and therefore they are listed as not known.

Arterial Hypertension

Blood and lymphatic system disorders

Not known: decreased hemoglobin, decreased hematocrit, neutropenia, thrombocytopenia.

Immune system disorders

Not known: hypersensitivity, including serum sickness.

Metabolism and nutrition disorders

Not known: increased serum potassium, hyponatremia.

Aural disorders

Uncommon: vertigo.

Vascular disorders

Not known: vasculitis.

Respiratory, thoracic and mediastinal disorders

Uncommon: cough.

Gastrointestinal disorders

Uncommon: abdominal pain.

Very rare: intestinal angioedema.

Hepatobiliary disorders

Not known: increased liver function test values, including increased serum bilirubin.

Skin and subcutaneous tissue disorders

Uncommon: angioedema, rash, pruritus.

Not known: bullous dermatitis.

Musculoskeletal and connective tissue disorders

Not known: myalgia.

Renal and urinary disorders

Not known: renal failure and impaired renal function, increased serum creatinine, increased blood urea nitrogen.

General disorders

Uncommon: increased fatigue.

Children

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 adults.

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

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), with the most commonly reported being headache (5.4%), dizziness (2.3%), and hyperkalemia (2.3%). In patients with CKD, the most common 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 were more frequently observed in patients receiving valsartan in combination with other antihypertensive agents compared to valsartan alone.

Hyperkalemia was more frequently observed in children aged 6 to 18 years with chronic kidney disease. The safety profile in controlled clinical trials in adult patients after myocardial infarction and/or with heart failure differs from the general safety profile in patients with arterial hypertension. This may relate to the underlying disease 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 (Adult Patients Only)

Blood and lymphatic system disorders

Not known: thrombocytopenia.

Immune system disorders

Not known: hypersensitivity, including serum sickness.

Metabolism and nutrition disorders

Uncommon: hyperkalemia.

Not known: increased serum potassium, hyponatremia.

Nervous system disorders

Common: dizziness, postural dizziness.

Uncommon: syncope, headache.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

Uncommon: heart failure.

Vascular disorders

Common: arterial hypotension, orthostatic hypotension.

Not known: vasculitis.

Respiratory, thoracic and mediastinal disorders

Uncommon: cough.

Gastrointestinal disorders

Uncommon: nausea, diarrhea.

Hepatobiliary disorders

Not known: increased liver function test values.

Skin and subcutaneous tissue disorders

Uncommon: angioedema.

Not known: bullous dermatitis, rash, pruritus.

Musculoskeletal and connective tissue disorders

Not known: myalgia.

Renal and urinary disorders

Common: renal failure and impaired renal function.

Uncommon: acute renal failure, increased serum creatinine.

Not known: increased blood urea nitrogen.

General disorders

Uncommon: asthenia, increased fatigue.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows ongoing 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 through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture.

Keep out of reach and sight of children.

Packaging.

14 tablets in a blister, 2 or 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

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

Manufacturer's address and location of business operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia /
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.