Valtap

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

VALTAP, 80 mg, coated tablets
VALTAP, 160 mg, coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Valtap, 80 mg: Each coated tablet contains 80 mg of valsartan.
Valtap, 160 mg: Each coated tablet contains 160 mg of valsartan.

Excipients with known effect:
Valtap, 80 mg:
Each tablet contains:
sorbitol......................... 9.25 mg
lactose monohydrate.... 0.33 mg

Valtap, 160 mg:
Each tablet contains:
sorbitol......................... 18.50 mg
lactose monohydrate.... 0.95 mg

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet
Valtap 80 mg, film-coated tablets: pink, round, film-coated tablets with a score line on one side.
Valtap 160 mg, film-coated tablets: yellowish-brown, round, film-coated tablets with a score line on one side.
The tablet can be divided into equal doses.

4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension
Treatment of essential hypertension in adult patients and in children and adolescents aged 6 to below 18 years.

Status post recent myocardial infarction
Treatment of adult patients who are clinically stable and have symptomatic heart failure or asymptomatic systolic left ventricular dysfunction following a recent myocardial infarction (within 12 hours to 10 days; see sections 4.4 and 5.1).

Heart failure
Treatment of adult patients with symptomatic heart failure, either when angiotensin-converting enzyme (ACE) inhibitors are not tolerated, or in patients intolerant of beta-blockers as add-on therapy to ACE inhibitors when mineralocorticoid receptor antagonists cannot be used (see sections 4.2, 4.4, 4.5 and 5.1).

4.2 Dosage and Administration

Dosage
Hypertension
The recommended starting dose of the medicinal product Valtap is 80 mg once daily. The antihypertensive effect becomes clearly noticeable within 2 weeks and reaches its maximum within 4 weeks. In some patients in whom adequate blood pressure control is not achieved, the dose may be increased to 160 mg and up to a maximum of 320 mg once daily.
The medicinal product Valtap may be used concomitantly with other antihypertensive drugs (see sections 4.3, 4.4, 4.5 and 5.1). Additional use of a diuretic, such as hydrochlorothiazide, results in greater reduction of blood pressure in these patients.

Post-myocardial infarction state
In patients who are clinically stable, treatment may be initiated as early as 12 hours after diagnosis of myocardial infarction. After administration of the initial dose of 20 mg twice daily, the dose of valsartan should be gradually increased over the following weeks to 40 mg, 80 mg and 160 mg twice daily. The initial dose is provided by a divisible tablet of 40 mg strength.
The maximum target dose is 160 mg twice daily. It is generally recommended that after initiation of therapy, patients receive 80 mg twice daily for 2 weeks, and the maximum target dose of 160 mg twice daily should be introduced 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 receiving other drugs for the treatment of myocardial infarction, such as thrombolytics, acetylsalicylic acid, beta-adrenergic blockers, statins and diuretics. Concomitant use with ACE inhibitors is not recommended (see sections 4.4 and 5.1).
Assessment of patients after myocardial infarction should always include evaluation of renal function.

Heart failure
The recommended starting dose of the medicinal product Valtap is 40 mg twice daily. The dose should be increased stepwise to 80 mg and then to 160 mg twice daily at intervals of at least two weeks, until the highest dose tolerated by the patient is reached. If a diuretic is used concomitantly, consideration should be given to reducing its dose. The maximum daily dose used in clinical studies was 320 mg of valsartan administered in divided doses.
Valsartan may be administered concomitantly with other drugs used in heart failure. However, triple combination therapy with an ACE inhibitor, valsartan and a beta-blocker or potassium-sparing diuretic is not recommended (see sections 4.4 and 5.1). Assessment of patients with heart failure should always include evaluation of renal function.

Special patient groups
Elderly
No dosage adjustment is necessary in elderly patients.

Renal impairment
No dose adjustment is required in adult patients with creatinine clearance >10 ml/min (see sections 4.4 and 5.2).

Hepatic impairment
The use of the medicinal product Valtap is contraindicated in patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis (see sections 4.3, 4.4 and 5.2). In patients with mild to moderate hepatic impairment without cholestasis, doses exceeding 80 mg of valsartan per day should not be used.

Children and adolescents
Hypertension in children and adolescents
In children and adolescents who are unable to swallow tablets, use of other appropriate formulations available on the market is recommended. Systemic exposure and maximum plasma concentration of valsartan are approximately 1.7- and 2.2-fold higher with the oral solution compared to tablets.

Children and adolescents aged 6 to below 18 years
The initial dose is 40 mg once daily for children with body weight below 35 kg and 80 mg once daily for children with body weight of 35 kg or more. The dose of the medicinal product should be adjusted according to the antihypertensive response and tolerability. The maximum doses evaluated in clinical studies are shown in the table below.
Doses higher than those listed have not been evaluated in clinical studies and are therefore not recommended.

Body weight	Maximum dose evaluated in clinical trials
18 kg to <35 kg	80 mg
35 kg to <80 kg	160 mg
80 kg to ≤160 kg	320 mg

Children under 6 years of age
In children aged 1 to 5 years and in patients who have difficulty swallowing tablets, use of other suitable medicinal forms available on the market is recommended. Available data are presented in sections 4.8, 5.1, and 5.2. The efficacy and safety of valsartan have not been established in children under 1 year of age.

Switching from oral valsartan solution to the medicinal product Valtap in tablet form
If switching from oral solution to tablets is considered clinically necessary, the same dose in milligrams should initially be administered. Subsequently, blood pressure should be monitored, taking into account the possibility of an excessively low dose, and the dose should be adjusted according to the antihypertensive effect achieved and product tolerance.

Children and adolescents aged 6 to below 18 years with renal impairment
The use of the medicinal product has not been studied in children and adolescents with creatinine clearance <30 ml/min or in those undergoing dialysis; therefore, valsartan is not recommended in these patient groups. Dose adjustment is not necessary in children and adolescents with creatinine clearance greater than 30 ml/min. Renal function and serum potassium concentration should be closely monitored (see sections 4.4 and 5.2).

Children and adolescents aged 6 to below 18 years with hepatic impairment
As in adult patients, the medicinal product Valtap is contraindicated in patients with severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis (see sections 4.3, 4.4, and 5.2). Clinical experience with administration of valsartan to children and adolescents with mild to moderate hepatic impairment is limited. In these patients, the dose of valsartan must not exceed 80 mg.

Heart failure and post-myocardial infarction in children and adolescents
The medicinal product Valtap is not recommended for the treatment of heart failure or recent myocardial infarction in children and adolescents under 18 years of age due to lack of data on safety and efficacy.

Method of administration
The medicinal product Valtap can be taken independently of food and should be taken with water.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Severe hepatic impairment, biliary cirrhosis and cholestasis.
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
• Concomitant use of valsartan with products containing aliskiren is contraindicated in patients with diabetes or renal impairment (glomerular filtration rate, GFR <60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

4.4 Special Warnings and Precautions for Use

Hyperkalaemia
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. Serum potassium levels should be monitored.

Renal Impairment
As there is currently no experience regarding the safety of the medicinal product in patients with creatinine clearance <10 ml/min and in patients undergoing dialysis, caution should be exercised when using valsartan in these patient groups. Dose adjustment is not required in adult patients with creatine clearance >10 ml/min (see sections 4.2 and 5.2).

Hepatic Impairment
Valsartan should be used with caution in patients with mild to moderate hepatic impairment without cholestasis (see sections 4.2 and 5.2).

Sodium depletion and/or dehydration
In rare cases, symptomatic hypotension may occur at the initiation of treatment with valsartan in patients with significant sodium depletion and/or dehydration, e.g. due to treatment with high doses of diuretics. Sodium and/or circulating blood volume should be corrected before starting valsartan therapy, e.g. by reducing the diuretic dose.

Renal artery stenosis
The safety of valsartan has not been established in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney.
Short-term administration of valsartan to 12 patients with renovascular hypertension due to unilateral renal artery stenosis did not cause significant hemodynamic changes in the kidneys and did not affect serum creatinine or blood urea nitrogen (BUN) levels. However, since other drugs acting on the renin-angiotensin system may increase blood urea and serum creatinine levels, as a precautionary measure, regular monitoring of renal function is recommended in patients with unilateral renal artery stenosis treated with valsartan.

Post-renal transplant state
There is currently no experience regarding the safety of using valsartan in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism
Valsartan should not be used in patients with primary hyperaldosteronism due to suppression of the renin-angiotensin system activity in these patients.

Aortic and mitral valve stenosis, hypertrophic cardiomyopathy with left ventricular outflow tract obstruction
As with other vasodilating agents, special caution is indicated in patients with aortic or mitral valve stenosis or hypertrophic cardiomyopathy with left ventricular outflow tract obstruction.

Pregnancy
Initiation of treatment with angiotensin II receptor antagonists (AIIRAs) during pregnancy is not recommended. If further treatment with AIIRAs is not necessary, alternative antihypertensive therapy with a well-established safety profile during pregnancy should be used in women planning pregnancy. If pregnancy is diagnosed, AIIRA treatment should be discontinued immediately and, if appropriate, alternative therapy initiated (see sections 4.3 and 4.6).

Post-myocardial infarction
Concomitant use of captopril with valsartan showed no additional clinical benefit but increased the risk of adverse reactions compared to monotherapy with either drug (see sections 4.2 and 5.1). Therefore, concomitant use of valsartan and ACE inhibitors is not recommended.
Caution should be exercised when initiating treatment in patients after myocardial infarction. Assessment of patients after myocardial infarction should always include evaluation of renal function (see section 4.2).
Treatment with valsartan in patients after myocardial infarction usually causes some reduction in blood pressure, but discontinuation of therapy due to persistent symptomatic hypotension is usually not necessary, provided the patient follows dosing recommendations (see section 4.2).

Heart failure
The risk of adverse reactions, especially hypotension, hyperkalaemia, and worsening renal function (including acute renal failure), may be increased when valsartan is used concomitantly with an ACE inhibitor. In patients with heart failure, triple combination therapy with an ACE inhibitor, a beta-blocker, and valsartan showed no clinical benefit (see section 5.1). Such combination significantly increases the risk of adverse reactions and is therefore not recommended.
Triple combination therapy with an ACE inhibitor, a mineralocorticoid receptor antagonist, and valsartan is also not recommended. If such combination is used, it should be under specialist supervision, with close monitoring of renal function, electrolyte levels, and blood pressure.

Caution should be exercised when initiating treatment in patients with heart failure. Assessment of patients with heart failure should always include evaluation of renal function (see section 4.2).
Treatment with valsartan in patients with heart failure usually leads to a reduction in blood pressure, but discontinuation of therapy due to persistent symptomatic hypotension is usually not necessary, provided the patient follows dosing recommendations (see section 4.2).
In patients in whom renal function may depend on renin-angiotensin-aldosterone system activity (e.g. patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotaemia, and in rare cases with acute renal failure and/or death. Since valsartan blocks the angiotensin II receptor, renal impairment cannot be excluded with valsartan use.

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

History of angioedema
Cases of angioedema, including laryngeal and glottal oedema causing airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling, have been reported in patients treated with valsartan. In some of these patients, angioedema occurred previously during treatment with other medicinal products, including ACE inhibitors. If angioedema occurs, valsartan should be discontinued immediately and must never be restarted.

Intestinal angioedema
Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including valsartan (see section 4.8). Symptoms in these patients included abdominal pain, nausea, vomiting, and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Other conditions associated with activation of the renin-angiotensin system (applies only to the 320 mg dose)
In patients in whom renal function may depend on renin-angiotensin system activity (e.g. patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors has been associated with oliguria and/or progressive azotaemia, and in rare cases with acute renal failure and/or death. Since valsartan is an angiotensin II antagonist, renal impairment cannot be excluded with valsartan use.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists (AIIRAs), or aliskiren increases the risk of hypotension, hyperkalaemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections 4.5 and 5.1).
If dual blockade is considered absolutely necessary, it should be performed under specialist supervision, with close monitoring of vital parameters such as renal function, electrolyte levels, and blood pressure.

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

Children and adolescents
Renal impairment
The use of the medicinal product has not been studied in children and adolescents with creatinine clearance <30 ml/min or those undergoing dialysis; therefore, valsartan is not recommended in these patient groups. Dose adjustment is not required in children and adolescents with creatinine clearance >30 ml/min (see sections 4.2 and 5.2). Renal function and serum potassium levels should be closely monitored during treatment with valsartan, especially in situations where other conditions (e.g. fever, dehydration) may affect renal function.

Hepatic impairment
As in adult patients, valsartan is contraindicated in children and adolescents with severe hepatic impairment, biliary cirrhosis, or cholestasis (see sections 4.3 and 5.2). Clinical experience with valsartan in children and adolescents with mild to moderate hepatic impairment is limited. In these patients, the dose of valsartan must not exceed 80 mg.

Warnings regarding excipients
Valtap, 80 mg: This product contains 9.25 mg of sorbitol in each tablet.
Valtap, 160 mg: This product contains 18.50 mg of sorbitol in each tablet.
Patients with hereditary fructose intolerance should not take this medicinal product.
The product contains lactose monohydrate. The product should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
The product contains less than 1 mmol (23 mg) of sodium per tablet, i.e. it is considered "sodium-free".

4.5 Interactions with other medicinal products and other forms of interaction

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARBs), or aliskiren
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia, and renal dysfunction (including acute kidney failure), compared to treatment with a single RAAS-acting agent (see sections 4.3, 4.4, and 5.1).

Concomitant use not recommended
Lithium
Cases of reversible increases in serum lithium concentrations and symptoms of lithium toxicity have been reported during concomitant use of lithium with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, including with valsartan. If concomitant treatment is necessary, close monitoring of serum lithium levels is recommended. When a diuretic is used concomitantly, the risk of lithium toxicity may be further increased.

Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels
If products affecting potassium levels must be used concomitantly with valsartan, monitoring of serum potassium levels is recommended.

Concomitant use requiring caution
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid at doses >3 g/day, and non-selective NSAIDs
When angiotensin II receptor antagonists are administered together with NSAIDs, the antihypertensive effect may be attenuated. Furthermore, concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels. Therefore, renal function should be monitored at the start of treatment, and adequate hydration of the patient should be ensured.

Transporter proteins
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 the uptake transporter (e.g. rifampicin, cyclosporine) or efflux transporter (e.g. ritonavir) may increase systemic exposure to valsartan. Caution is advised when initiating or discontinuing concomitant treatment with these medicinal products.

Other
Interaction studies have shown no clinically significant interactions between valsartan and any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glibenclamide.

Children and adolescents
In children and adolescents with arterial hypertension, in whom renal dysfunction often coexists, caution is recommended when administering valsartan concomitantly with other substances that inhibit the renin-angiotensin-aldosterone system and may increase serum potassium levels. Renal function and serum potassium levels should be closely monitored.

4.6 Fertility, pregnancy and lactation

Pregnancy
Angiotensin II receptor antagonists (AIIRAs) are not recommended during the first trimester of pregnancy (see section 4.4). AIIRAs are contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological data on the risk of teratogenicity following ACE inhibitors administration during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be ruled out. There are no data from controlled epidemiological studies regarding the risk associated with AIIRAs, although such a risk may exist for this class of drugs. In women planning pregnancy, antihypertensive therapy with a well-established safety profile in pregnancy should be considered instead of AIIRAs. If pregnancy is detected, AIIRA treatment should be discontinued immediately and, if appropriate, alternative therapy should be initiated.
Administration of AIIRAs during the second and third trimesters has been shown to cause fetal toxicity (renal dysfunction, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia) (see also section 5.3).
In cases of exposure to AIIRAs from the second trimester of pregnancy onwards, regular ultrasound examinations to monitor renal function and skull development of the fetus are recommended.
Newborns whose mothers were treated with AIIRAs should be closely observed for signs of hypotension (see also sections 4.3 and 4.4).

Breast-feeding
Valsartan is not recommended during breast-feeding, as there is a lack of information regarding its use during this period. Medicinal products with a better-established safety profile during breast-feeding should be considered, especially when nursing a newborn or preterm infant.

Fertility
Valsartan did not impair reproductive performance in male and female rats following oral administration at doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose, based on mg/m² (assuming an oral dose of 320 mg daily in a 60 kg patient).

4.7 Effects on ability to drive and use machines

Studies on the effect of valsartan on the ability to drive vehicles have not been conducted. When driving vehicles or operating machinery, one should take into account the possibility of experiencing dizziness or fatigue.

4.8 Undesirable effects

In controlled clinical trials involving adult patients with hypertension, the overall incidence of adverse effects in the group treated with valsartan was comparable to that in the placebo group and corresponded to its pharmacological properties. The incidence of adverse effects appeared not to be related to dose or duration of treatment; no relationship with patient sex, age, or race was demonstrated either. Adverse effects reported during clinical trials, after marketing authorization, and derived from laboratory investigations are listed in the table below, classified by system organ classes.

Adverse effects have been classified according to frequency of occurrence (most frequent effects listed first) as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), and not known (frequency cannot be estimated from the available data). Within each frequency category, adverse effects are listed in decreasing order of severity.

For some adverse effects reported after marketing authorization and derived from laboratory investigations, it is not possible to determine the frequency; therefore, they are listed as "not known".

Hypertension

Blood and lymphatic system disorders
Unknown	Decreased haemoglobin concentration, decreased haematocrit, neutropenia, thrombocytopenia
Immune system disorders
Unknown	Hypersensitivity, including serum sickness
Metabolism and nutrition disorders
Unknown	Increased serum potassium concentration, hyponatraemia
Ear and labyrinth disorders
Not very common	Labyrinthine origin vertigo
Vascular disorders
Unknown	Vasculitis
Respiratory, thoracic and mediastinal disorders
Not very common	Cough
Gastrointestinal disorders
Not very common	Abdominal pain
Very rare	Intestinal angioedema
Hepatobiliary disorders
Unknown	Increased liver enzyme activity, increased serum bilirubin concentration
Skin and subcutaneous tissue disorders
Unknown	Angioedema, bullous dermatitis, rash, pruritus
Musculoskeletal and connective tissue disorders
Unknown	Myalgia
Renal and urinary disorders
Unknown	Renal failure and renal function disorders, increased serum creatinine concentration
General disorders and administration site conditions
Not very common	Feeling of fatigue

Children and adolescents
Hypertension
The antihypertensive effect of valsartan was evaluated in two randomized, double-blind clinical trials (each followed by an extension period or study) and one open-label trial. A total of 711 pediatric patients aged 6 to less than 18 years with or without chronic kidney disease (CKD) participated in these studies. Among these patients, 560 received valsartan. Except for isolated cases of gastrointestinal disorders (such as abdominal pain, nausea, vomiting) and dizziness, no significant differences were observed in the type, frequency, and severity of adverse reactions between the safety profile in pediatric patients aged 6 to less than 18 years and the previously reported safety profile in adult patients.
An assessment of neurocognitive function and development in pediatric patients aged 6 to 16 years showed that treatment with valsartan for up to one year had no overall clinically significant negative impact on these functions.
A pooled analysis was conducted in 560 pediatric patients with hypertension (aged 6–17 years) receiving valsartan as monotherapy [n=483] or combination antihypertensive therapy containing valsartan [n=77]. Among these 560 patients, 85 (15.2%) had chronic kidney disease (baseline eGFR < 90 mL/min/1.73m²). Overall, 45 (8.0%) patients discontinued the study due to adverse events. A total of 111 (19.8%) patients experienced adverse reactions. The most common were headache (5.4%), dizziness (2.3%), and hyperkalemia (2.3%).
In patients with chronic kidney disease, the most common adverse reactions were hyperkalemia (12.9%), headache (7.1%), increased blood creatinine (5.9%), and hypotension (4.7%).
In patients without chronic kidney disease, the most common adverse reactions were headache (5.1%) and dizziness (2.7%). Adverse reactions were observed more frequently in patients receiving valsartan in combination with another antihypertensive agent compared to those receiving valsartan as monotherapy.
The antihypertensive effect of valsartan in children aged 1 to less than 6 years was evaluated in three randomized, double-blind clinical trials (each followed by an extension study). In the first trial involving 90 children aged 1 to less than 6 years, two deaths and isolated cases of marked increase in liver transaminase activity were reported. These events occurred in a population of patients with significant comorbidities. A causal relationship with valsartan treatment has not been established.
In two subsequent trials including 202 children aged 1 to less than 6 years, no cases of marked increase in liver transaminase activity or treatment-related deaths were observed.
In a pooled analysis of the two subsequent trials involving 202 children with hypertension (aged 1 to less than 6 years), all patients received valsartan as monotherapy during the double-blind treatment periods (excluding the placebo withdrawal phase). Of these, 186 children subsequently participated in an extension study or an open-label treatment period. Chronic kidney disease (baseline eGFR <90 mL/min) was present in 33 (16.3%) of the 202 patients. During the double-blind treatment period, two (1%) patients discontinued treatment due to an adverse event. During the open-label treatment period or extension study, four patients (2.1%) discontinued treatment due to an adverse event. During the double-blind treatment period, at least one adverse drug reaction occurred in 13 (7.0%) patients. The most frequently reported adverse drug reactions were vomiting n=3 (1.6%) and diarrhea n=2 (1.1%).
One adverse drug reaction (diarrhea) was reported in the group of patients with chronic kidney disease. During the open-label treatment period, at least one adverse drug reaction occurred in 5.4% (10/186) of patients. The most frequently reported adverse drug reaction was decreased appetite, reported by two (1.1%) patients. Hyperkalemia was observed in one patient during each of the double-blind and open-label treatment periods. Hypotension and dizziness were not observed during either the double-blind or open-label treatment periods.
Hyperkalemia was observed more frequently in children and adolescents aged 1 to less than 18 years with concomitant chronic kidney disease. The risk of hyperkalemia may be higher in children aged 1 to 5 years compared to children aged 6 to less than 18 years.
The safety profile observed in controlled clinical trials in adult patients post-myocardial infarction and/or with heart failure differs from the general safety profile observed in patients with hypertension. This may be related to the underlying disease of the patient. Adverse reactions that occurred in adult patients post-myocardial infarction and/or with heart failure are listed below:
Post-myocardial infarction and/or heart failure (studied exclusively in adult patients)

Blood and lymphatic system disorders
Unknown	Thrombocytopenia
Immune system disorders
Unknown	Hypersensitivity, including serum sickness
Metabolism and nutrition disorders
Not very common	Hyperkalaemia
Unknown	Increased serum potassium concentration, hyponatraemia
Nervous system disorders
Common	Dizziness, positional dizziness
Not very common	Syncope, headache
Ear and labyrinth disorders
Not very common	Vertigo of labyrinthine origin
Cardiac disorders
Not very common	Heart failure
Vascular disorders
Common	Hypotension, orthostatic hypotension
Unknown	Vasculitis
Respiratory, thoracic and mediastinal disorders
Not very common	Cough
Gastrointestinal disorders
Not very common	Nausea, diarrhoea
Hepatobiliary disorders
Unknown	Increased liver enzyme activity
Skin and subcutaneous tissue disorders
Not very common	Angioedema
Unknown	Bullous dermatitis, rash, pruritus
Musculoskeletal and connective tissue disorders
Unknown	Muscle pain
Renal and urinary disorders
Common	Renal failure and renal function disorders
Not very common	Acute renal failure, increased serum creatinine concentration
Unknown	Increased blood urea nitrogen concentration
General disorders and administration site conditions
Not very common	Weakness, fatigue

Reporting suspected adverse reactions
After authorisation of the medicinal product, it is important to report suspected adverse reactions.
This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the Department of Monitoring Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw.
Tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl

4.9 Overdose

Symptoms
Overdose of valsartan may cause marked hypotension, which may lead to
disturbances in consciousness, circulatory collapse, and (or) shock.

Treatment
Management of overdose depends on the time of ingestion, as well as the type and severity of symptoms; the most important step is stabilizing circulation.
If arterial hypotension occurs, the patient should be placed in a supine position and circulating blood volume should be corrected.
Hemodialysis is poorly effective in removing valsartan from the circulation.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs acting on the renin-angiotensin system, angiotensin II receptor blockers, plain preparations,
ATC code: C09CA03

Valsartan is an orally active, potent and specific antagonist of the angiotensin II (Ang II) receptor. It selectively acts on the AT₁ receptor subtype, which mediates the known actions of angiotensin II. The increased plasma concentration of angiotensin II resulting from AT₁ receptor blockade by valsartan may stimulate the unblocked AT₂ receptor, which appears to counteract the effects of the AT₁ receptor. Valsartan exhibits no partial agonist activity at the AT₁ receptor and has much greater affinity (approximately 20,000 times) for the AT₁ receptor than for the AT₂ receptor. Valsartan has not been shown to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Due to the lack of effect on ACE and absence of potentiation of bradykinin or substance P activity, the likelihood of cough during treatment with angiotensin II receptor antagonists is low. In clinical trials comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower (p<0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% and 7.9%, respectively). In a clinical trial of patients with dry cough during ACE inhibitor therapy, 19.5% of patients receiving valsartan and 19.0% of those receiving thiazide diuretics reported cough, compared with 68.5% of patients treated with ACE inhibitors (p<0.05).

Arterial hypertension
Administration of valsartan to patients with arterial hypertension reduces blood pressure without affecting heart rate.

In most patients, after a single oral dose, antihypertensive effects begin within 2 hours, and maximal reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after dosing. With repeated administration, the antihypertensive effect is clearly noticeable within 2 weeks, and maximal effect is achieved within 4 weeks and maintained during long-term treatment. Concomitant therapy with hydrochlorothiazide significantly enhances the antihypertensive effect of the medicinal product.

Abrupt discontinuation of valsartan treatment was not associated with rebound hypertension or clinically significant adverse events.

In patients with arterial hypertension, type 2 diabetes, and microalbuminuria, valsartan has been shown to reduce urinary albumin excretion. In the MARVAL study (Microalbuminuria Reduction with Valsartan), reduction in urinary albumin excretion (UAE) was evaluated during treatment with valsartan (80–160 mg/day) versus amlodipine (5–10 mg/day) in 332 patients with type 2 diabetes (mean age: 58 years; 265 men), microalbuminuria (valsartan: 58 μg/min; amlodipine: 55.4 μg/min), normal or high blood pressure, and preserved renal function (serum creatinine concentration <120 μmol/l). After 24 weeks, UAE decreased significantly (p<0.001) by 42% (–24.2 μg/min; 95% confidence interval: –40.4 to –19.1) in patients treated with valsartan and by approximately 3% (–1.7 μg/min; 95% confidence interval: –5.6 to 14.9) in those treated with amlodipine, despite similar blood pressure reductions in both groups.

In the DROP study (Diovan Reduction of Proteinuria), the efficacy of valsartan in reducing UAE was further evaluated in 391 patients with arterial hypertension (blood pressure =150/88 mmHg), type 2 diabetes, albuminuria (mean = 102 μg/min; range 20–700 μg/min), and preserved renal function (mean serum creatinine concentration = 80 μmol/l). Patients were randomized to one of three valsartan dose groups (160, 320, and 640 mg/day). Treatment lasted 30 weeks. The objective was to determine the optimal dose of valsartan for reducing UAE in patients with arterial hypertension and type 2 diabetes. After 30 weeks, there was a significant percentage reduction in UAE of 36% from baseline in the group treated with 160 mg valsartan (95% confidence interval: 22% to 47%) and 44% in the group treated with 320 mg valsartan (95% confidence interval: 31% to 54%). It was concluded that doses of 160–320 mg of valsartan produced clinically relevant reductions in UAE in patients with arterial hypertension and type 2 diabetes.

Post-myocardial infarction state
The VALIANT study (VALsartan In Acute myocardial iNfarcTion) was a randomized, controlled, international, double-blind trial involving 14,703 patients with acute myocardial infarction and clinical signs, symptoms, or radiological confirmation of congestive heart failure and/or confirmed left ventricular systolic dysfunction (defined as ejection fraction ≤40% by radionuclide ventriculography or ≤35% by echocardiography or contrast angiography). Patients were randomized between 12 hours and 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan, captopril, or valsartan in combination with captopril. The mean duration of treatment was two years. The primary endpoint was time to death from any cause.

Valsartan was as effective as captopril in reducing all-cause mortality after myocardial infarction. The percentage of deaths from any cause was similar across all groups (valsartan: 19.9%, captopril: 19.5%, valsartan + captopril: 19.3%). Adding valsartan to captopril provided no additional benefit compared to captopril alone. No differences were observed between valsartan and captopril in all-cause mortality across age, sex, race, background therapy, or underlying disease. Valsartan also increased survival time, reduced cardiovascular mortality, and shortened hospitalization duration due to heart failure, recurrent myocardial infarction, cardiopulmonary resuscitation, and non-fatal stroke (a secondary composite endpoint).

In patients treated after myocardial infarction, the safety profile of valsartan was consistent with the clinical course. Regarding renal function, a doubling of serum creatinine concentration occurred in 4.2% of patients treated with valsartan, 4.8% of patients receiving combination therapy with valsartan and captopril, and 3.4% of patients treated with captopril. Treatment was discontinued due to various renal function disorders in 1.1% of patients on valsartan, 1.3% on valsartan and captopril, and 0.8% on captopril. Renal function should be assessed in patients after myocardial infarction.

No differences in total mortality, cardiovascular mortality, or morbidity were observed when β-blockers were co-administered with valsartan and captopril, or with valsartan or captopril alone. Regardless of the treatment used, mortality was lower in patients receiving β-blockers, confirming the known benefits of β-blockers in this patient population.

Heart failure
The Val-HeFT study was a randomized, controlled, international clinical trial comparing valsartan with placebo regarding morbidity and mortality in 5,010 patients with heart failure (62% NYHA class II, 36% class III, 2% class IV), receiving standard therapy, with left ventricular ejection fraction (LVEF) <40% and left ventricular internal diameter in diastole (LVIDD) >2.9 cm/m². Background therapy included ACE inhibitors (93%), diuretics (86%), digoxin (67%), and β-blockers (36%). The mean observation period was nearly two years. The mean daily dose of valsartan in the Val-HeFT study was 254 mg. Two primary endpoints were evaluated: all-cause mortality (survival time) and a composite endpoint of mortality and morbidity related to heart failure (time to first morbidity event), defined as death, sudden death with resuscitation, hospitalization due to heart failure, or intravenous administration of inotropic or vasodilating agents for at least 4 hours without hospitalization.

All-cause mortality was similar (p=NS) in the valsartan group (19.7%) and the placebo group (19.4%). The main benefit was a 27.5% reduction (95% confidence interval: 17% to 37%) in the risk of time to first hospitalization due to heart failure (13.9% vs. 18.5%, respectively). A disadvantage for valsartan (composite endpoint of mortality and morbidity: 21.9% in placebo group vs. 25.4% in valsartan group) was observed in patients receiving combination therapy with an ACE inhibitor, a β-blocker, and valsartan.

Benefits in morbidity were greatest in the subgroup not receiving an ACE inhibitor (n=366). In this subgroup, all-cause mortality was significantly lower by 33% with valsartan compared to placebo (95% confidence interval: –6% to 58%) (17.3% for valsartan vs. 27.1% for placebo), and the composite risk of mortality and morbidity was lower by 44% (24.9% vs. 42.5%, respectively).

Among patients receiving an ACE inhibitor but not a β-blocker, all-cause mortality was similar (p=NS) in the valsartan group (21.8%) and placebo group (22.5%). The composite risk of mortality and morbidity was significantly lower by 18.3% (95% confidence interval: 8% to 28%) with valsartan compared to placebo (31.0% vs. 36.3%, respectively).

In the overall population of the Val-HeFT study, patients treated with valsartan showed significant improvement according to NYHA criteria and in objective and subjective symptoms of heart failure, including dyspnea, fatigue, edema, and rales, compared to placebo. Quality of life was better in patients treated with valsartan, as shown by changes in the Minnesota Living with Heart Failure Quality of Life score from baseline compared to placebo. Ejection fraction at endpoint significantly increased, and left ventricular internal diameter in diastole (LVIDD) significantly decreased compared to placebo.

Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Two large, randomized, controlled clinical 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 combined use of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET trial included patients with cardiovascular disease, cerebrovascular disease, or type 2 diabetes with proven target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These studies showed no significant beneficial effect on renal parameters and/or cardiovascular morbidity and mortality outcomes, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Due to the similarities in pharmacodynamic properties of these drugs, the cited results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists.

Therefore, in patients with diabetic nephropathy, concomitant use of ACE inhibitors and angiotensin II receptor antagonists should not be initiated.

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to investigate the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease and/or cardiovascular disease. The trial was prematurely terminated due to increased risk of adverse events. Cardiovascular deaths and strokes occurred more frequently in the aliskiren group compared to placebo. The aliskiren group also experienced more frequent adverse events, including serious adverse events (hyperkalemia, hypotension, and renal failure), compared to placebo.

Children and adolescents

Arterial hypertension
The antihypertensive effect of valsartan was evaluated in four randomized, double-blind clinical trials involving 561 pediatric patients aged 6 to below 18 years and 165 children aged 1 to 6 years. Common comorbidities potentially influencing hypertension in study participants included renal and urinary tract disorders and obesity.

Clinical experience in children aged 6 years and older
In a clinical trial involving 261 pediatric patients aged 6 to 16 years with hypertension, patients with body weight <35 kg received valsartan tablets at doses of 10, 40, or 80 mg daily (low, medium, and high doses), and patients with body weight ≥35 kg received 20, 80, or 160 mg daily (low, medium, and high doses). At the end of the 2-week treatment period, valsartan produced dose-dependent reductions in both systolic and diastolic blood pressure. Overall, the three dose levels of valsartan (low, medium, and high) significantly reduced systolic blood pressure from baseline by 8, 10, and 12 mmHg, respectively. Patients were re-randomized to continue the same dose of valsartan or switch to placebo. In patients continuing medium or high doses of valsartan, the lowest systolic blood pressure values were 4 and 7 mmHg lower than those in the placebo group. In patients treated with low-dose valsartan, the lowest systolic blood pressure was similar to that in the placebo group. In summary, valsartan consistently produced dose-dependent antihypertensive effects across all demographically defined subgroups.

In a second clinical trial involving 300 pediatric patients aged 6 to below 18 years with hypertension, eligible patients were randomized to receive either valsartan or enalapril for 12 weeks. Children with body weight ≥18 kg to <35 kg received 80 mg valsartan or 10 mg enalapril; those with body weight ≥35 kg to <80 kg received 160 mg valsartan or 20 mg enalapril; and those with body weight ≥80 kg received 320 mg valsartan or 40 mg enalapril. In patients treated with valsartan, the reduction in systolic blood pressure was comparable to that achieved with enalapril (15 mmHg and 14 mmHg, respectively) (p<0.0001 for equivalence).

Similar results were obtained for diastolic blood pressure, with reductions of 9.1 mmHg in the valsartan group and 8.5 mmHg in the enalapril group.

In a third, open-label clinical trial involving 150 pediatric patients aged 6 to 17 years with hypertension, eligible patients (systolic blood pressure ≥95th percentile for age, sex, and height) received valsartan for 18 months to assess safety and tolerability. Of the 150 patients, 41 also received another antihypertensive agent. Doses were adjusted according to weight categories for initial and maintenance dosing. Patients weighing >18 to <35 kg, ≥35 to <80 kg, and ≥80 to <160 kg received 40 mg, 80 mg, and 160 mg, respectively. After one week, doses were increased to 80 mg, 160 mg, and 320 mg, respectively. Half of the patients (50.0%, n=75) had chronic kidney disease, including 29.3% (44 patients) with stage 2 (GFR 60–89 ml/min/1.73m²) or stage 3 (GFR 30–59 ml/min/1.73m²) chronic kidney disease. Mean reduction in systolic blood pressure was 14.9 mmHg in all patients (from baseline of 133.5 mmHg), 18.4 mmHg in patients with chronic kidney disease (from baseline of 131.9 mmHg), and 11.5 mmHg in those without chronic kidney disease (from baseline of 135.1 mmHg). The percentage of patients achieving controlled blood pressure (both systolic and diastolic blood pressure <95th percentile) was slightly higher in patients with comorbid chronic kidney disease (79.5%) compared to those without (72.2%).

Clinical experience in children under 6 years of age
Three clinical trials were conducted in 291 patients aged 1 to 5 years. Children under 1 year of age were not included. In the first study involving 90 patients, a dose-response relationship could not be established, but in the second study involving 75 patients, higher doses of valsartan were associated with greater blood pressure reduction.

The third study was a 6-week, randomized, double-blind trial to evaluate the dose response of valsartan in 126 children aged 1 to 5 years with hypertension, with or without chronic kidney disease, randomly assigned to receive 0.25 mg/kg body weight or 4.0 mg/kg body weight. At endpoint, the reduction in mean systolic blood pressure/mean diastolic blood pressure with 4.0 mg/kg body weight of valsartan compared to 0.25 mg/kg body weight was 8.5/6.8 mmHg and 4.1/0.3 mmHg, respectively (p=0.0157/p<0.0001). In the subgroup with chronic kidney disease, a reduction in mean systolic blood pressure/mean diastolic blood pressure was also observed with 4.0 mg/kg body weight compared to 0.25 mg/kg body weight (9.2/6.5 mmHg and 1.2/+1.3 mmHg, respectively).

The European Medicines Agency has waived the obligation to present results of studies with valsartan in all pediatric subgroups with heart failure and post-myocardial infarction heart failure. See section 4.2 for information on use in pediatric patients.

5.2. Pharmacokinetic properties

Absorption
After oral administration of walsartan alone, peak plasma concentration of walsartan occurs at 2–4 hours with tablets and at 1–2 hours with solution. The mean absolute bioavailability of the drug is 23% and 39% following administration of tablets and solution, respectively. Systemic exposure and peak plasma concentration of walsartan are approximately 1.7- and 2.2-fold higher with solution compared to tablets.
When walsartan is administered with food, the area under the curve (AUC) for walsartan is reduced by approximately 40% and the peak plasma concentration (C_max) by approximately 50%. However, from about 8 hours after dose administration, plasma concentrations of walsartan are similar in subjects taking the drug with food and those taking it fasting. Despite the reduction in AUC, there is no clinically significant weakening of the therapeutic effect; therefore, walsartan can be administered with or without food.

Distribution
The volume of distribution of walsartan at steady state after intravenous administration is approximately 17 litres, indicating limited tissue distribution of walsartan. Walsartan is highly bound to plasma proteins (94–97%), primarily to albumin.

Metabolism
Walsartan undergoes limited biotransformation, as only about 20% of the dose is recovered as metabolites. A hydroxymetabolite has been detected in plasma at low concentrations (less than 10% of the AUC for walsartan). This metabolite is pharmacologically inactive.

Elimination
Walsartan exhibits multi-exponential elimination kinetics (t_½α <1 hour and t_½β about 9 hours). Walsartan is primarily eliminated via bile into faeces (about 83% of dose) and via kidneys in urine (about 13% of dose), mainly as unchanged drug. After intravenous administration, plasma clearance of walsartan is about 2 L/h, and renal clearance is about 0.62 L/h (about 30% of total plasma clearance). The elimination half-life of walsartan is 6 hours.

Patients with heart failure
The mean time to reach peak concentration and elimination half-life of walsartan in patients with heart failure and healthy volunteers are similar. AUC and C_max values for walsartan are nearly proportional to increasing dose within the clinical dose range (40 mg to 160 mg of walsartan twice daily). The mean accumulation factor is about 1.7. Oral plasma clearance of walsartan is about 4.5 L/h. Age does not influence observed clearance in patients with heart failure.

Special patient groups

Elderly patients
In some elderly patients, slightly increased systemic exposure to walsartan has been observed compared to younger individuals; however, this has not been shown to have any clinical significance.

Renal impairment
As expected for a substance with a renal clearance of only 30% of total plasma clearance, no correlation between renal function and systemic exposure to walsartan has been observed. Therefore, no dose adjustment is necessary in patients with renal impairment (creatinine clearance >10 mL/min). There is currently no experience regarding the safe use of the drug in patients with creatinine clearance <10 mL/min or in patients undergoing dialysis; therefore, walsartan should be used with caution in these patient groups (see sections 4.2 and 4.4). Walsartan is highly bound to plasma proteins, so dialysis is unlikely to be effective in removing walsartan from circulation.

Hepatic impairment
Approximately 70% of the absorbed dose is excreted in bile, essentially in unchanged form. Walsartan undergoes no significant biotransformation. In patients with mild to moderate hepatic impairment, systemic exposure (AUC) was doubled compared to healthy subjects. However, no correlation was observed between plasma walsartan concentration and the degree of hepatic dysfunction. Walsartan has not been studied in patients with severe hepatic impairment (see sections 4.2, 4.3 and 4.4).

Children and adolescents
In a study involving 26 paediatric patients (aged 1 to 16 years) with arterial hypertension receiving a single dose of walsartan suspension (mean 0.9 to 2 mg/kg body weight, maximum dose 80 mg), walsartan clearance (L/h/kg) was comparable across the entire age range of 1 to 16 years and similar to that observed in adult patients receiving the medicinal product in the same formulation (see absorption information presented in section 5.2).

Renal impairment
The use of the medicinal product has not been studied in children and adolescents with creatinine clearance <30 mL/min or in those undergoing dialysis; therefore, walsartan is not recommended in these patient groups. Dose adjustment is not necessary in children and adolescents with creatinine clearance >30 mL/min. Renal function and serum potassium levels should be closely monitored during treatment with walsartan (see sections 4.2 and 4.4).

5.3. Preclinical safety data

Non-clinical data obtained from conventional studies on pharmacological safety, repeated-dose toxicity, genotoxicity, and potential carcinogenicity reveal no particular hazard for humans.
In rats, toxic maternal doses (600 mg/kg body weight/day) administered during the last days of pregnancy and lactation resulted in reduced offspring survival rate, lower body weight gain, and developmental delay (delayed separation of the pinna and opening of the auditory canal) in the offspring (see section 4.6).
Such doses in rats (600 mg/kg body weight/day) are approximately 18 times higher than the maximum recommended human dose, when adjusted by mg/m^2 body surface area (based on an oral dose of 320 mg daily and a 60 kg patient).

In preclinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused reduced erythrocyte parameters (red blood cells, hemoglobin, hematocrit) and renal hemodynamic changes in rats (slight increase in plasma urea concentration, tubular hyperplasia, and basophilia in males). The doses used in rats (200 to 600 mg/kg body weight/day) are approximately 6 and 18 times higher, respectively, than the maximum recommended human dose, when adjusted by mg/m^2 body surface area (based on an oral dose of 320 mg daily and a 60 kg patient).

In cynomolgus monkeys, similar doses produced comparable but more severe changes, particularly in the kidneys, where nephropathy developed, including increased urea and creatinine concentrations.

In both species, glomerular juxtaglomerular apparatus cell hyperplasia was also observed. These changes were attributed to the pharmacological action of valsartan, which causes prolonged hypotension, especially in cynomolgus monkeys. With therapeutic doses of valsartan in humans, hyperplasia of the juxtaglomerular apparatus cells appears unlikely to occur.

Children and adolescents
Daily oral administration of valsartan at a dose of 1 mg/kg body weight/day (representing approximately 10–35% of the maximum recommended pediatric dose of 4 mg/kg body weight/day, based on systemic exposure) to newborn or young rats (from postnatal day 7 to day 70) caused permanent, irreversible kidney damage.
The aforementioned effects represent an expected exaggeration of the pharmacological effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. These effects are observed when rats are treated during the first 13 days of life. This period corresponds to week 36 of human gestation and may occasionally extend up to week 44 post-conception. In the study with valsartan in young animals, rats received treatment up to postnatal day 70, and an influence of valsartan treatment on renal maturation (occurring between 4–6 weeks post-birth) cannot be excluded. Functional renal maturation is a process occurring during the first year of human life. Therefore, these data may have clinical relevance for children under 1 year of age, whereas preclinical data do not raise safety concerns regarding the use of the medicinal product in children over 1 year of age.

6. PHARMACEUTICAL DATA
6.1 List of excipients
Tablet core:
Microcrystalline cellulose
Anhydrous colloidal silica
Sorbitol (E 420)
Magnesium carbonate
Pregelatinized starch, maize
Povidone K-25
Sodium stearyl fumarate
Sodium lauryl sulfate
Crospovidone (type A)

Tablet coating:
Lactose monohydrate
Hypromellose
Talc
Polyethylene glycol 6000
Valtap, 80 mg, additionally: iron oxide red (E 172).
Valtap, 160 mg, additionally: iron oxide yellow and brown (E 172) and indigo carmine (E 132).

6.2 Pharmaceutical incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 25°C. Store in the original packaging to protect from moisture.

6.5 Type and contents of the container

PVC-PE-PVDC/Aluminum blister or PVC-PVDC/Aluminum blister
Pack sizes: 28, 30, 56, 84, 90 film-coated tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for removal and preparation of the medicinal product

for use
No special requirements.

7. MARKETING AUTHORISATION HOLDER

FOR SALE
Zentiva k.s., U kabelovny 130, Dolni Měcholupy, 102 37 Prague 10, Czech Republic.

8. MARKETING AUTHORISATION NUMBERS

Valtap, 80 mg: Authorisation number: 17186
Valtap, 160 mg: Authorisation number: 17187

9. DATE OF FIRST AUTHORISATION

AND DATE OF REVISION

Date of first authorisation: 10 August 2010
Date of latest renewal: 26 October 2015

10. DATE OF ADOPTION OR PARTIAL CHANGE OF THE TEXT

SUMMARY OF PRODUCT CHARACTERISTICS
06/2025