INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valsartan-Teva

Composition:

Active substance: valsartan;

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

Excipients: magnesium stearate, sodium croscarmellose, talc, colloidal anhydrous silicon dioxide, microcrystalline cellulose, povidone, lactose monohydrate;

Coating mixture:

for 40 mg – Opadry II 85G32407 Yellow (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, yellow iron oxide (E 172));

for 80 mg – Opadry II 85G34643 Pink (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, red iron oxide (E 172), yellow iron oxide (E 172));

for 160 mg – Opadry II 85G32408 Yellow (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, yellow iron oxide (E 172), red iron oxide (E 172));

for 320 mg – Opadry II 85G20236 Brown (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, sunset yellow (E 110), black iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

40 mg tablets: yellow, oval, biconvex film-coated tablets, marked with the logo "V" on one side and a break line on the other side, with break lines on the sides;

80 mg tablets: pink, round, biconvex film-coated tablets, with a break line on both sides, the logo "V" on one side, and break lines on the sides;

160 mg tablets: yellow, oval, biconvex film-coated tablets, marked with the logo "V" on one side and a break line on the other side, with break lines on the sides;

320 mg tablets: brown, oval, biconvex film-coated tablets, with a break line on one side, the logo "V" on the other side, and break lines on the sides.

Pharmacotherapeutic group. Angiotensin II antagonists, plain preparations.

ATC code: C09CA03.

Pharmacological Properties

Pharmacodynamics

Valsartan is an orally active, specific antagonist of angiotensin II receptors. 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 AT1 receptors and has much greater (approximately 20,000 times) affinity for AT1 receptors than for AT2 receptors. There is no evidence that valsartan binds to or blocks other hormone receptors or ion channels important in cardiovascular regulation.

Valsartan does not inhibit ACE (angiotensin-converting enzyme), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Administration of the drug to patients with arterial hypertension results in a reduction in blood pressure without affecting pulse rate.

The onset of antihypertensive effect occurs within 2 hours, reaching maximum effect within 4–6 hours after oral administration; the duration of action lasts more than 24 hours. The maximal therapeutic effect develops after 4 weeks of treatment and is maintained during long-term therapy. When used in combination with hydrochlorothiazide, a significant additional reduction in arterial pressure is achieved.

Abrupt discontinuation of the drug is not associated with a withdrawal syndrome.

Long-term administration of the drug to patients with arterial hypertension has shown no clinically significant effect on total cholesterol, uric acid levels, or on serum concentrations of triglycerides and glucose when measured in the fasting state.

Heart Failure

Administration of the drug reduces hospitalization rates due to heart failure, slows progression of heart failure, improves functional class according to the NYHA (New York Heart Association) classification, increases ejection fraction, and reduces signs and symptoms of heart failure (including dyspnea, increased fatigue, edema, and rales), as well as improves quality of life compared to placebo.

Post-Myocardial Infarction State

With regard to overall mortality rate after myocardial infarction, the efficacy of valsartan is comparable to that of captopril. The overall mortality rate was similar in patient groups receiving valsartan (19.9%), captopril (19.5%), and valsartan + captopril (19.3%). Concomitant administration of captopril and valsartan did not result in additional benefits compared to captopril alone. No differences were observed between valsartan and captopril regarding overall mortality, regardless of sex, age, race, treatment received at the time of myocardial infarction, or underlying disease. Valsartan was also effective in reducing cardiovascular mortality and hospitalizations due to heart failure, as well as recurrent myocardial infarction. Valsartan positively influenced the time interval from the acute myocardial infarction to the first occurrence of cardiovascular events leading to fatal outcomes.

Children

Arterial Hypertension. 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 the children included in these studies.

Clinical experience in children aged 6 years and older

In children with arterial hypertension aged 6 to 16 years with body weight <35 kg receiving 10, 40, or 80 mg of valsartan daily (low, medium, and high doses), and in children with body weight ≥35 kg receiving 20, 80, and 160 mg of valsartan daily (low, medium, and high doses), valsartan reduced systolic and diastolic blood pressure in a dose-dependent manner by the end of 2 weeks. Overall, the three dose levels of valsartan (low, medium, and high) significantly reduced systolic blood pressure by 8, 10, and 12 mm Hg from baseline, respectively.

Clinical experience in children under 6 years of age

Valsartan is not recommended for use in this age group.

Pharmacokinetics

Absorption

After oral administration of valsartan in tablet form, maximum plasma concentrations 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 the solution. Food decreases exposure (as measured by AUC) by approximately 40% and peak plasma concentration (Cmax) by approximately 50%. However, plasma concentrations of valsartan starting at about 8 hours after dosing are similar between fasting and fed conditions. The reduction in AUC does not result in a clinically significant reduction in therapeutic effect; therefore, valsartan can be administered with or without food.

Distribution

The volume of distribution 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.

Metabolism

Valsartan undergoes minimal metabolism, as only about 20% of the dose is excreted as metabolites. A hydroxymetabolite has been detected in plasma at low concentrations (less than 10% of the AUC of valsartan). 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 bile into feces (approximately 83% of the dose) and to a lesser extent via the kidneys in urine (approximately 13% of the dose), mainly in unchanged form. After intravenous administration, the plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

In patients with heart failure (40 mg, 80 mg, and 160 mg tablets)

The mean time to reach Cmax and the elimination half-life of valsartan in patients with heart failure are similar to those in healthy volunteers. AUC and Cmax values of valsartan are nearly proportional to dose increases above the clinical dose range (from 40 to 160 mg twice daily). The mean accumulation ratio is approximately 1.7. The predicted oral clearance of valsartan is approximately 4.5 L/h. Age does not affect predicted clearance in patients with heart failure.

Pharmacokinetics in specific patient groups

Elderly patients. Systemic exposure to valsartan was somewhat higher in some elderly patients compared to younger individuals, but this difference has not been shown to be clinically significant.

Patients with renal impairment. As expected for a compound with only 30% of total plasma clearance accounted for by renal clearance, no correlation was observed between renal function and systemic exposure to valsartan. Therefore, dose adjustment is not required in patients with impaired renal function (creatinine clearance >10 mL/min). Currently, there are no safety data available for patients with creatinine clearance <10 mL/min or for patients undergoing dialysis; thus, valsartan should be used with caution in these patients. Valsartan is highly bound to plasma proteins, and removal by hemodialysis is unlikely.

Patients with hepatic impairment. Approximately 70% of the absorbed dose is excreted via bile, primarily in unchanged form. Valsartan undergoes minimal biotransformation. In patients with mild to moderate hepatic dysfunction, exposure (AUC) to valsartan was approximately doubled compared to healthy volunteers, although plasma concentrations of valsartan do not correlate with the degree of hepatic impairment. Data in patients with severe hepatic impairment are not available.

Children

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

Patients with renal impairment. The use of the drug in children with creatinine clearance <30 mL/min or in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for 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: 40 mg tablets

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

Arterial hypertension: 80 mg, 160 mg and 320 mg tablets

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

Post-myocardial infarction: 40 mg, 80 mg and 160 mg tablets

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

Heart failure: 40 mg, 80 mg and 160 mg tablets

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, soybean oil, peanut oil, or any excipient.
• Hereditary or ACE inhibitor- or angiotensin II receptor antagonist-induced angioedema.
• Severe hepatic impairment, biliary cirrhosis, or cholestasis.
• Pregnancy or planned pregnancy (see "Use in pregnancy and lactation").
• 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).
• No data are available in patients with severe renal impairment (creatinine clearance less than 10 mL/min).

Interaction with other medicinal products and other forms of interaction.

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

Concomitant use of ARBs, including valsartan, with other drugs acting on the RAAS is associated with an increased incidence of hypotension, syncope, hyperkalemia, and renal function changes (including acute renal failure) compared to monotherapy. Therefore, dual RAAS blockade by combining ACE inhibitors, ARBs, or aliskiren is not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision with careful monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²) is contraindicated (see "Contraindications" section).

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

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

Concomitant use not recommended

Lithium

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

Caution required during concomitant use

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

Transporters

In vitro studies indicate that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical 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.

Others

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

Children

Caution is recommended when administering valsartan concomitantly with other substances that inhibit the renin-angiotensin-aldosterone system in children and adolescents 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) is not recommended. If necessary, potassium levels should be monitored.

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

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

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

Patients with sodium and/or circulating blood volume depletion. In patients with severe sodium and/or circulating blood volume depletion, e.g., those receiving high-dose diuretics, symptomatic arterial hypotension may occur in isolated cases after initiation of valsartan therapy. Prior to starting valsartan therapy, correction of sodium and/or circulating blood volume depletion should be performed, for example, by reducing the diuretic dose.

Renal artery stenosis. The safety of valsartan use in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney has not been established. Short-term use of valsartan in 12 patients with renovascular hypertension secondary to unilateral renal artery stenosis did not cause any significant changes in renal hemodynamic parameters, serum creatinine, or blood urea nitrogen. Since other medicinal products affecting the renin-angiotensin-aldosterone system may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, monitoring of renal function is recommended as a safety measure during treatment with valsartan.

Kidney transplantation

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

Primary hyperaldosteronism

Valsartan-Teva 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, the drug should be prescribed with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Pregnancy

Angiotensin II receptor antagonists are contraindicated during pregnancy. Unless continuation of therapy is considered necessary, alternative antihypertensive therapy with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists must be discontinued immediately, and, if necessary, alternative therapy approved for use during pregnancy should be initiated.

Recent myocardial infarction

Combination of captopril and valsartan did not show additional clinical benefit, whereas the risk of adverse reactions increased compared to monotherapy with the respective agents. Therefore, combination of valsartan with an ACE inhibitor is not recommended.

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

Valsartan use in patients after myocardial infarction often leads to some reduction in blood pressure, which usually results in the need to discontinue therapy due to persistent symptomatic arterial hypotension, despite adherence to dosing instructions.

Heart failure

The risk of adverse reactions, particularly 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 of an ACE inhibitor, beta-blocker, and valsartan did not show any clinical benefit. This combination is likely to increase the risk of adverse effects and is therefore not recommended. Triple combination of ACE inhibitors, mineralocorticoid receptor antagonists, and valsartan is also not recommended.

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

Safety and efficacy of Valsartan-Teva in children have not been studied.

History of angioedema

Angioedema, including laryngeal and glottal edema leading to airway obstruction and/or facial, lip, pharyngeal, and/or tongue swelling, has been reported in patients receiving valsartan. In some of these patients, angioedema occurred previously during treatment with other medicinal products, including ACE inhibitors. Development of angioedema requires immediate discontinuation of valsartan, and the drug should not be re-administered.

Intestinal angioedema

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

Other conditions with stimulation of the renin-angiotensin system

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

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

Concomitant use of ARBs, including valsartan, with other agents acting on the RAAS is associated with increased incidence of arterial hypotension, hyperkalemia, and changes in renal function compared to monotherapy. Monitoring of blood pressure, renal function, and electrolyte levels is recommended in patients receiving valsartan and other agents affecting the RAAS.

Children

Renal impairment. Use in children with creatinine clearance <30 mL/min or in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for use in 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 during valsartan treatment, particularly in cases where valsartan is used in the presence of other conditions (e.g., high fever, dehydration) that may impair renal function. Concomitant use of angiotensin receptor antagonists, including Valsartan-Teva, or ACE inhibitors with aliskiren in pediatric patients with impaired renal function (glomerular filtration rate (GFR) <60 mL/min/1.73 m²) is contraindicated.

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

Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption

This medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Lecithin

This medicinal product should not be used in patients with hypersensitivity to peanuts or soy.

Colourant Sunset yellow FCF (E110)

Valsartan-Teva 320 mg tablets contain the colourant Sunset yellow FCF (E110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy

Use of angiotensin II receptor antagonists (ARBs) is contraindicated throughout pregnancy and in women planning pregnancy.

Epidemiological data on the teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. Since there are no controlled epidemiological data on the risk of angiotensin II receptor antagonists, a teratogenic risk may also exist for this class of drugs. Unless continuation of therapy is considered necessary, alternative antihypertensive therapy with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists must be discontinued immediately, and, if necessary, alternative therapy approved for use during pregnancy should be initiated.

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

If ARBs have been used from the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull ossification.

Newborns of mothers who received ARBs should be carefully monitored for the development of arterial hypotension.

Breastfeeding period

Due to lack of information on the use of valsartan during breastfeeding, Valsartan-Teva is not recommended for use in breastfeeding women. During breastfeeding, alternative treatments with better-established safety profiles should be preferred, especially when breastfeeding a newborn or preterm infant.

Fertility

Valsartan at doses up to 200 mg/kg/day did not cause adverse effects on reproductive function in rats. This dose is 6 times higher than the maximum recommended human dose, adjusted by mg/m² (based on oral dose of 320 mg/day in patients with body weight of 60 kg).

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect on the ability to drive and operate machinery have not been conducted. It should be considered that dizziness or weakness may occur while driving or operating machinery.

Method of Administration and Dosage

Method of Administration

Valsartan-Teva may be administered independently of food intake; tablets should be taken with water.

Dosage

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

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

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

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

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, 80 mg, and then 160 mg twice daily over the following weeks. The initial dose should be administered using a 40 mg tablet, which can be divided into equal parts. The target maximum dose is 160 mg twice daily. Generally, it is recommended that the dose of 80 mg twice daily be reached within 2 weeks of starting treatment, and the maximum dose of 160 mg twice daily be reached within 3 months, depending on patient tolerance. If symptomatic arterial hypotension or renal dysfunction occurs, dose reduction should be considered.

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

Patients after myocardial infarction must always have kidney function monitored.

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

The recommended initial dose of valsartan is 40 mg twice daily. Gradual dose escalation to 80 mg and then 160 mg twice daily should be performed at intervals of at least 2 weeks, up to the highest tolerated dose. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose used in clinical trials was 320 mg, divided into multiple doses.

Valsartan may be used in combination with other heart failure medications. However, triple combination of an ACE inhibitor, valsartan, and a beta-blocker or potassium-sparing diuretic is not recommended. Patients with heart failure require monitoring of kidney function.

Use in Specific Patient Populations

Elderly Patients

Dose adjustment is not required in elderly patients.

Renal Impairment

No dose adjustment is required in adult patients with creatinine clearance >10 mL/min. Concomitant use of valsartan with aliskiren in patients with impaired renal function (eGFR <60 mL/min/1.73 m²) is contraindicated.

Diabetes Mellitus

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

Hepatic Impairment

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

Arterial Hypertension in Children

Children and adolescents 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 should be adjusted based on blood pressure response. Maximum doses studied in clinical trials are shown in Table 1.

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

Table 1

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

Children under 6 years of age

The safety and efficacy of valsartan in children aged 1 to 6 years have not been established.

Use in children aged 6 to 18 years with renal impairment

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

Use in children aged 6 to 18 years with hepatic impairment

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

Heart failure and recent myocardial infarction in children

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

Children.

Valsartan-Teva can be used for the treatment of arterial hypertension in children aged 6 years and older. Safety and efficacy of valsartan use 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. Overdose with valsartan may lead to pronounced arterial hypotension, which may result in impaired consciousness, vascular collapse, and/or shock.

Treatment. Therapeutic measures depend on the time of ingestion and the type and severity of symptoms; primary importance is given to stabilization of circulation. 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 removed from the body by hemodialysis.

Adverse reactions.

Hypertension/heart failure/myocardial infarction

During controlled clinical studies in adult patients with hypertension, the incidence of adverse reactions with placebo was comparable to that with valsartan. The incidence of adverse reactions was not related to dose or duration of treatment, and no association with patient sex, age, or race was demonstrated.

Adverse reactions identified during clinical, post-marketing, and laboratory studies are listed below by organ system classes.

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

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

Adverse reactions identified during post-marketing and laboratory studies, for which frequency cannot be estimated, are listed as "not known."

Table 2

Infections
Common	Viral infections
Uncommon	Upper respiratory tract infections, pharyngitis, sinusitis
Very rare	Rhinitis
Blood and lymphatic system disorders
Uncommon			Neutropenia
Very rare			Thrombocytopenia
Immune system disorders
Very rare			Hypersensitivity reactions, including serum sickness
Metabolism and nutrition disorders
Uncommon			Hyperkalemia*#
Psychiatric disorders
Uncommon				Insomnia, decreased libido
Nervous system disorders
Common		Dizziness##, Postural dizziness#
Uncommon		Syncope*
Very rare		Headache##
Ear and labyrinth disorders
Uncommon			Vertigo
Cardiac disorders
Uncommon			Heart failure*
Very rare			Cardiac arrhythmia
Vascular disorders
Common			Orthostatic hypotension#
Uncommon			Hypotension*##
Very rare			Vasculitis
Respiratory system disorders
Uncommon			Cough
Gastrointestinal disorders
Uncommon			Diarrhea, abdominal pain
Very rare			Nausea##, vomiting, intestinal angioedema
Hepatobiliary disorders
Not known			Elevated liver function parameters, including increased serum bilirubin levels
Skin and subcutaneous tissue disorders
Very rare			Angioedema**, rash, pruritus, exanthema
Not known			Bullous dermatitis
Musculoskeletal and connective tissue disorders
Uncommon			Back pain
Very rare			Arthralgia, myalgia
Renal and urinary disorders
Very rare			Renal failure**##, acute renal failure**, renal function impairment**
Pregnancy and perinatal conditions
Very rare			Fetal developmental complications
General disorders
Uncommon			Fatigue, asthenia, swelling
Investigations
Common			Elevated serum creatinine, elevated blood urea
Very rare			Elevated serum bilirubin, decreased hemoglobin/hematocrit levels, liver function parameters outside normal range.

* 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 impairment, hypotension; infrequent: headache, nausea)

Laboratory findings

In isolated cases, valsartan caused a decrease in hemoglobin levels and hematocrit count. In controlled clinical trials, significant reductions (>20%) in hematocrit and hemoglobin levels were observed in 0.8% and 0.4% of patients receiving valsartan, respectively. In comparison, reductions in both parameters (hematocrit and hemoglobin) 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 increased 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 patients taking placebo, and serum potassium levels increased by more than 20% in 10% of patients taking valsartan, compared to 5.1% of patients taking placebo.

In heart failure studies, increased blood urea nitrogen levels were observed in 16.6% of patients taking valsartan, compared to 6.3% of patients taking placebo.

An increase in serum creatinine by a factor of 2 was observed in 4.2% of patients receiving valsartan, in 4.8% of patients treated with a combination of valsartan and captopril, and in 3.4% of patients treated with captopril during the post-infarction period.

The number of cases of discontinuation of the drug 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 did not reveal any clinically significant overall negative consequences after treatment with valsartan for up to 1 year.

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

Shelf life. For 40 mg, 80 mg, 160 mg dosage strengths – 4 years.

For 320 mg dosage strength – 3 years.

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

Packaging. 10 tablets per blister, 3 or 9 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturers.

Actavis LTD.

Balkanpharma-Dupnitsa AD.

Manufacturers' addresses and locations of business operations.

VBL015, VBL016 Bulabel Industrial Building, Zeitun ZTN 3000, Malta.

3 Samokovsko Shose Str., Dupnitsa, 2600, Bulgaria.