INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VALSARIYA (VALSARIYA)

Composition:

Active substance: valsartan;

1 tablet contains 80 mg or 160 mg of valsartan;

Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol, iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172) – for 160 mg tablets only.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Valsariya 80 mg: pale red, round, film-coated tablets with beveled edges, with a score line on one side, marked (imprinted) «D» on one side of the score line and «V» on the other, and marked (imprinted) «NVR» on the reverse side of the tablet;

Valsariya 160 mg: grey-orange, oval, film-coated tablets, slightly convex in shape, with a score line on one side, marked (imprinted) «DX» on one side of the score line and «DX» on the other, and marked (imprinted) «NVR» on the reverse side of the tablet.

Pharmacotherapeutic group. Simple angiotensin II antagonists preparations.

ATC code C09CA03.

Pharmacological properties.

Pharmacodynamics.

Valsartan is an active, specific angiotensin II receptor antagonist intended for oral administration. It selectively acts on AT1 receptors, which mediate 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 counterbalance the effects of AT1 receptors. Valsartan exhibits no partial agonist activity at the AT1 receptor and has significantly 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 of arterial blood pressure without affecting pulse rate.

The onset of antihypertensive effect occurs within 2 hours, reaching maximum effect within 4–6 hours after oral administration; the duration of action exceeds 24 hours. The maximal 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 arterial blood pressure is achieved.

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

Long-term administration of the drug to patients with arterial hypertension has shown no clinically significant effect on total cholesterol or uric acid levels. When administered fasting, it does not affect serum triglyceride or glucose concentrations.

The drug reduces the number of hospitalizations due to heart failure, slows the progression of heart failure, improves functional class according to the New York Heart Association classification, increases ejection fraction, and alleviates symptoms of heart failure while improving quality of life compared to placebo.

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

Children

Renal and urinary tract disorders and obesity were the most common underlying medical conditions causing arterial hypertension in children during clinical studies.

Clinical experience in children aged 6 years and older

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 tablets, maximum plasma concentrations are reached within 2–4 hours; when administered as a solution, within 1–2 hours. The mean absolute bioavailability is 23% for tablets and 39% for the solution. Food reduces valsartan exposure (as measured by AUC) by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%. However, plasma valsartan concentrations from about 8 hours after dosing are similar between fasting and fed conditions. 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 steady-state volume of distribution of valsartan 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.

Metabolism

Valsartan is not significantly metabolized, as only about 20% of the dose is excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of valsartan AUC). This metabolite is pharmacologically inactive.

Elimination

The pharmacokinetic profile of valsartan is multiphasic (T½α < 1 hour and T½ß approximately 9 hours). Valsartan is primarily eliminated via bile into feces (approximately 83% of the dose) and 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

The mean time to reach Cmax and elimination half-life of valsartan in patients with heart failure are similar to those in healthy volunteers. AUC and Cmax values of valsartan are nearly proportional to dose increases within the clinical dosing range from 40 mg (in this case, valsartan should be administered in another dosage form allowing lower dosing) to 160 mg twice daily. The mean accumulation ratio is approximately 1.7. The predicted oral clearance of valsartan is about 4.5 L/h. Age does not influence predicted clearance in patients with heart failure.

Pharmacokinetics in specific patient groups

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 has been 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 is not expected to correlate with the degree of hepatic dysfunction. Therefore, dose adjustment is not required in patients with non-biliary liver insufficiency and in the absence of cholestasis. In patients with biliary cirrhosis or biliary obstruction, AUC of valsartan has been shown to increase approximately twofold.

Children

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

Patients with renal impairment

The use of valsartan in children with creatinine clearance < 30 mL/min or 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 carefully monitored.

Clinical characteristics.

Indications.

Arterial hypertension.

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

Post-infarction state.

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

Heart failure.

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

Contraindications.

• Hypersensitivity to valsartan or to any excipient.
• Severe hepatic impairment, biliary cirrhosis, and cholestasis.
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding").
• Concomitant use of angiotensin receptor antagonists, including Valsaria, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
• Lack of data in patients with severe renal impairment (creatinine clearance less than 10 mL/min).
• Hereditary or idiopathic angioedema, or angioedema that occurred during previous treatment with an ACE inhibitor or angiotensin II receptor antagonist.

Interaction with other medicinal products and other forms of interaction.

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

Concomitant use of ARB-class drugs, including Valsaria, 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 RAAS blockade through combined use of ACE inhibitors, ARBs, or aliskiren is not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be conducted only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

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

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

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

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been observed during concomitant use of ACE inhibitors. Due to the lack of experience with simultaneous use of valsartan and lithium, this combination is not recommended. If the combination is considered necessary, careful monitoring of serum lithium levels is recommended.

When diuretics are used concomitantly, the risk of lithium toxicity may increase with valsartan administration.

Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other agents that may increase potassium levels

Concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels, and in patients with heart failure, to an increase in serum creatinine.

If use of a medicinal product affecting potassium levels in combination with valsartan is considered necessary, monitoring of plasma potassium levels is recommended.

Caution required when used concomitantly

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective 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. Furthermore, 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 appropriate patient hydration are recommended at the start of treatment.

Transporters

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

Others

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

Since valsartan is minimally metabolized, no clinically significant drug interactions due to metabolic induction or inhibition of the cytochrome P450 system have been observed with concomitant use of valsartan. Despite the high plasma protein binding of valsartan, in vitro studies have shown no interaction at this level with several highly protein-bound molecules, including diclofenac, furosemide, and warfarin.

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. 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 necessary, potassium levels should be monitored.

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

In patients with severe sodium and/or circulating blood volume depletion, such as those receiving high doses of diuretics, symptomatic arterial hypotension may occur in individual cases after initiation of Valsaria therapy. Prior to starting Valsaria, correction of sodium and/or circulating blood volume should be performed, for example by reducing the diuretic dose.

If arterial hypotension occurs, the patient should be placed in a supine position with elevated legs. If necessary, plasma volume should be corrected by administration of physiological saline. Treatment may be continued once blood pressure has stabilized.

Renal artery stenosis

The safety of Valsaria has not been established in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney. Short-term use of Valsaria in 12 patients with renovascular hypertension secondary to unilateral renal artery sten游戏副本

Dosage and Administration

Route of Administration

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

Dosage

Arterial hypertension in adults

The recommended initial dose of Valsaril is 80 mg once daily. The antihypertensive effect is achieved within 2 weeks, and the maximum effect is reached 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.

Valsaril can also be used in combination with other antihypertensive agents. Concomitant use of diuretics, such as hydrochlorothiazide, provides additional blood pressure reduction in patients.

Arterial hypertension in children

Children aged 6 years and older

The initial dose is 40 mg once daily for children weighing less than 35 kg (in such cases, valsartan in another pharmaceutical form allowing lower dosing should be used) and 80 mg once daily for children with body weight of 35 kg and above. Dose adjustment should be based on blood pressure response. Maximum doses are listed in Table 1.

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

Table 1

Children under 6 years of age

The safety and efficacy of Valsaria in children under 6 years of age have not been established.

Use in children aged 6 years and older with renal impairment

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

Use in children aged 6 years and older with hepatic impairment

As in adults, Valsaria is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and cholestasis. Clinical experience with the use of Valsaria 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

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

Post-infarction state in adults

Treatment may be initiated in clinically stable patients as early as 12 hours after myocardial infarction. After an initial dose of valsartan 20 mg twice daily, the dose should be increased to 40 mg twice daily (in this case, valsartan in another dosage form allowing lower dosing should be used), then to 80 mg and 160 mg twice daily over the following weeks.

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

Valsartan may be used in patients previously treated with other post-myocardial infarction medications, such as thrombolytics, acetylsalicylic acid, beta-blockers, statins, and diuretics. Combination with ACE inhibitors is not recommended.

Patients following myocardial infarction require regular monitoring of renal function.

Heart failure in adults

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

Valsartan may be used in combination with other drugs for the treatment of heart failure. However, triple combination of an ACE inhibitor, a 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 Valsaria 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 Valsaria with aliskiren in patients with diabetes mellitus is contraindicated.

Hepatic impairment

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

Children

Valsaria is indicated for the treatment of arterial hypertension in children aged 6 years and older with body weight ≥ 35 kg. 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

Following overdose with Valsaria, 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; stabilization of circulation is of primary importance. 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.

Hypertension/heart failure/myocardial infarction

During controlled clinical trials in adult patients with hypertension, the incidence of adverse reactions was similar between those receiving placebo and those receiving valsartan. The incidence of adverse reactions was found to be unrelated to dose or duration of treatment, and was independent of patient sex, age, or race.

Adverse reactions identified during clinical, postmarketing, and laboratory studies are listed below by system organ class.

For adverse reactions categorized as "very rare," "rare," and "uncommon," which were not identified during clinical trials, a cumulative search in the safety database was conducted.

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

Adverse reactions identified during postmarketing and laboratory studies for which the frequency cannot be estimated are listed as "not known."

Table 2

* reported by patients in the post-infarction period

reported by patients with heart failure

** infrequently reported by patients in the post-infarction period

reported more frequently by patients with heart failure (frequent: dizziness, renal function abnormalities, hypotension; infrequent: headache, nausea)

Laboratory findings

In isolated cases, valsartan caused a reduction 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 Valsarian, respectively. In comparison, reductions in both parameters (hematocrit count and hemoglobin level) were noted 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.

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

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 (BUN) levels were observed in 16.6% of patients taking valsartan, compared to 6.3% of patients taking placebo.

In post-infarction studies, 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.

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

Pediatric population

Arterial hypertension

The antihypertensive effect of valsartan was evaluated in two randomized, double-blind clinical trials involving 561 children aged 6 to 18 years. Except for isolated gastrointestinal disorders (such as abdominal pain, nausea, vomiting) and dizziness, no significant differences in type, frequency, or severity of adverse reactions were identified between the safety profile in children aged 6 to 18 years and the previously established safety profile in adult patients.

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

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

Hyperkalemia was more frequently observed in children aged 6 to 18 years with underlying chronic kidney disease.

The safety profile observed in controlled clinical trials in adult patients after myocardial infarction and/or with heart failure differs from the general safety profile observed in patients with arterial hypertension. This may be related to the underlying condition. Adverse reactions observed in adult patients after myocardial infarction and/or with heart failure are listed in Table 2.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging. Film-coated tablets, 80 mg or 160 mg.

14 tablets in a blister. 2 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Batch release:

Lek Pharmaceuticals d.d.

and

Novartis Pharma S.p.A.

Manufacturer's address and location of operations.

Verovškova 57, 1526 Ljubljana, Slovenia.

and

Via Provinciale Citto, 131, I-80058 Torre Annunziata, Italy.