Valtap

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

VALTAP, 80 mg, film-coated tablets
VALTAP, 160 mg, film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Valtap, 80 mg: Each film-coated tablet contains 80 mg of valsartan.
Valtap, 160 mg: Each film-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
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: yellow-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 from 6 to less than 18 years of age.
Post-myocardial infarction
Treatment of clinically stable adult patients with symptomatic heart failure or asymptomatic left ventricular dysfunction after a recent myocardial infarction (12 hours to 10 days) (see sections 4.4 and 5.1).
Heart Failure
Treatment of adult patients with symptomatic heart failure when angiotensin-converting enzyme (ACE) inhibitors are not tolerated, or in patients who are intolerant to beta-adrenergic 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 Posology and Method of Administration

Dosage
Hypertension
The recommended initial dose of Valtap is 80 mg once daily. The antihypertensive effect is evident within 2 weeks, and maximum by 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 160 mg, and up to 320 mg.
Valtap can be administered with other antihypertensive agents (see sections 4.3, 4.4, 4.5, and 5.1). The addition of a diuretic, such as hydrochlorothiazide, results in a greater reduction in blood pressure in these patients.
Post-myocardial infarction
Treatment can be initiated as early as 12 hours after the onset of myocardial infarction. After an initial dose of 20 mg twice daily, the dose should be titrated to 40 mg, 80 mg, and 160 mg twice daily over the next several weeks. The initial dose of 40 mg is provided by dividing a 80 mg tablet.
The target maximum dose is 160 mg twice daily. It is usually recommended that patients receive 80 mg twice daily for 2 weeks after initiation and the target maximum dose of 160 mg twice daily is reached by 3 months, depending on patient tolerance. If symptomatic hypotension or renal dysfunction occurs, the dose should be reduced.
Valsartan can be used in patients treated with other post-myocardial infarction therapies, such as thrombolytics, acetylsalicylic acid, beta-blockers, statins, and diuretics. Concomitant use with ACE inhibitors is not recommended (see sections 4.4 and 5.1).
Assessment of post-myocardial infarction patients should always include evaluation of renal function.
Heart Failure
The recommended initial dose of Valtap is 40 mg twice daily. Uptitration to 80 mg and 160 mg twice daily should be done at intervals of at least two weeks to the highest dose tolerated by the patient. When used in combination with diuretics, consideration of a dose reduction is recommended. The maximum daily dose administered in clinical trials was 320 mg of valsartan in divided doses.
Valsartan can be administered with other heart failure therapies. However, triple combination therapy with an ACE inhibitor, valsartan, and a beta-adrenergic blocker, or a potassium-sparing diuretic is not recommended (see sections 4.4 and 5.1). Assessment of heart failure patients should always include evaluation of renal function (see section 4.2).
Valtap can be administered with food or without food.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Hyperkalemia
Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase potassium levels (heparin, etc.) is not recommended. Monitor serum potassium levels.
Renal Impairment
As there is limited experience in patients with severe renal impairment (creatinine clearance <10 ml min), caution is required when administering valsartan to such patients. no dose adjustment for adult patients with creatinine 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).
Patients with Sodium Depletion and (or) Dehydration
In rare cases, on initiation of valsartan therapy, patients with marked sodium depletion and (or) dehydration may experience symptomatic hypotension. Before initiating therapy with valsartan, sodium and (or) fluid depletion should be corrected, for example by reducing the diuretic dose.
Renal Artery Stenosis
The safety of valsartan in patients with bilateral renal artery stenosis or stenosis of a solitary kidney has not been established. Short-term administration of valsartan to 12 patients with renovascular hypertension secondary to unilateral renal artery stenosis did not induce any significant changes in renal hemodynamics or serum creatinine and BUN levels. However, since other drugs that affect the renin-angiotensin-aldosterone system have caused increases in serum creatinine and BUN in patients with unilateral renal artery stenosis, it is recommended, as a precaution, that renal function be monitored during the first few weeks of therapy in patients with unilateral renal artery stenosis treated with valsartan.
Post-Transplant Renal Patients
There is limited experience with the use of valsartan in patients who have undergone renal transplantation. Primary Hyperaldosteronism
Valsartan should not be used in patients with primary hyperaldosteronism.
Aortic and Mitral Valve Stenosis, Hypertrophic Obstructive Cardiomyopathy
As with other vasodilators, special caution is indicated in patients with aortic and mitral valve stenosis, or with hypertrophic obstructive cardiomyopathy.
Pregnancy
AIIRAs should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Post-Myocardial Infarction
Concomitant use of captopril with valsartan did not show any additional clinical benefit, but did increase the risk of adverse events compared to either treatment alone (see sections 4.2 and 5.1). Therefore, concomitant use of valsartan and ACE inhibitors is not recommended.
Caution should be exercised when initiating valsartan therapy in patients after myocardial infarction. Assessment of post-myocardial infarction patients should always include evaluation of renal function (see section 4.2).
Use of valsartan in post-myocardial infarction patients usually results in some reduction in blood pressure, but discontinuation of therapy because of persistent symptomatic hypotension is not usually necessary, provided that the patient is monitored for changes in renal function and serum potassium (see section 4.2).
Heart Failure
The risk of adverse reactions, particularly hypotension, hyperkalemia, and decreased renal function (including acute renal failure), may be increased when valsartan is used in combination with an ACE inhibitor. In patients with heart failure, the use of a triple combination of an ACE inhibitor, a beta-adrenergic blocker, and valsartan has not been shown to be of additional clinical benefit (see section 5.1). Such combination is also associated with a higher frequency of adverse events, and therefore, is not recommended.
Also, the use of a quadruple combination of an ACE inhibitor, a mineralocorticoid receptor antagonist, a beta-adrenergic blocker, and valsartan is not recommended.
Patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia and, in rare cases, acute renal failure and/or death. Since valsartan blocks the action of angiotensin II, a similar effect may occur with valsartan.
Concomitant use of ACE inhibitors and AIIRAs should not be used in patients with diabetic nephropathy.
Angioedema
Angioedema has been reported in patients treated with valsartan (see section 4.8). Angioedema of the face, lips, tongue, glottis, and/or larynx has been reported rarely in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs, including ACE inhibitors. Valsartan should be immediately discontinued in patients who develop angioedema, and should not be re-administered.
Intestinal Angioedema
Intestinal angioedema has been reported in patients treated with AIIRAs, including valsartan (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting) and/or elevated serum creatinine levels; symptoms resolved after discontinuation of valsartan. Intestinal angioedema should be considered in the differential diagnosis of patients on valsartan presenting with abdominal pain.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS) by Combination of ACE Inhibitors, AIIRAs, or Aliskiren
Data from clinical trials have shown that the combination of an ACE inhibitor and an AIIRA, or the combination of an AIIRA and aliskiren, is associated with a higher frequency of adverse events, such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure), compared to the use of a single RAAS agent (see sections 4.3, 4.4, and 5.1).
Concomitant Use Not Recommended
Lithium
Reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with ACE inhibitors or AIIRAs, including valsartan. If such combination is deemed necessary, monitor serum lithium levels (see section 4.4).
Potassium-Sparing Diuretics, Potassium Supplements, Potassium-Containing Salt Substitutes, and Other Drugs That May Increase Potassium Levels
If a medicinal product that affects potassium levels is to be co-administered with valsartan, monitor serum potassium in such patients (see section 4.4).
Concomitant Use to Be Used with Caution
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Including Selective Cyclooxygenase-2 (COX-2) Inhibitors, Acetylsalicylic Acid (>3 g/day), and Non-Selective NSAIDs
When AIIRAs are administered concomitantly with NSAIDs, the antihypertensive effect of valsartan may be attenuated. In addition, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening renal function, including acute renal failure, and an increase in serum potassium levels. Monitor renal function at the beginning of the concomitant treatment and ensure adequate hydration of the patient (see section 4.4).
Transporter Proteins
In vitro data indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter (e.g., rifampicin, cyclosporin) or efflux transporter (e.g., ritonavir) may increase the systemic exposure to valsartan. Exercise caution when concomitant use of these agents is required.
Other
No clinically significant interactions were found between valsartan and the following: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, and glibenclamide.
Paediatric Population
In hypertension in children and adolescents, where underlying renal abnormalities are common, caution is recommended when co-administering valsartan with substances that affect the renin-angiotensin-aldosterone system. Monitor serum potassium and renal function (see section 4.4).

4.6 Fertility, Pregnancy and Lactation

Pregnancy
AIIRAs should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has shown that an increased risk may exist for this group of drugs compared to other antihypertensives. However, it cannot be excluded that this observation might be due to confounding. There are no controlled data on the use of AIIRAs in pregnant women. AIIRAs may cause fetal harm when administered to pregnant women. If AIIRAs are used during the second or third trimester of pregnancy, or during labour and delivery, adverse effects on fetal and neonatal blood pressure control and renal function can occur, potentially resulting in fetal or neonatal renal failure, oligohydramnios, and skull hypoplasia. In addition, use of AIIRAs during the second and third trimesters of pregnancy has been associated with an increased incidence of the following fetal and neonatal adverse events: hypotension, neonatal skull hypoplasia, anuria, and/or oligohydramnios. If exposure to AIIRAs has occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also sections 4.3 and 4.4).
Breast-feeding
It is not recommended to use valsartan during breast-feeding, as there is no information on the use of valsartan during breast-feeding. Alternative treatments with established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Fertility
Valsartan had no adverse effects on the reproductive performance of male and female rats at oral doses up to 200 mg/kg/day, a dose that is approximately 6 times the maximum recommended human dose of 320 mg/day, based on body surface area.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles or operating machines, it should be taken into account that dizziness or fatigue may occur.

4.8 Undesirable Effects

In controlled clinical trials in adult patients with hypertension, the overall incidence of adverse events with valsartan was comparable to that of placebo and similar to that of other antihypertensive agents. The frequency of adverse events did not appear to be dose- or treatment-duration-dependent. Adverse events were usually mild and transient and did not differ in nature from those seen with other antihypertensive agents. The most common adverse events reported in clinical trials and post-marketing experience are listed below.
Paediatric Population
Hypertension
The antihypertensive effect of valsartan was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 711 paediatric patients aged 6 to 16 years with hypertension. No relevant differences in the incidence of adverse events were observed between the valsartan and placebo treatment groups. In a pooled analysis of these two trials, the incidence of cough was 2.5% in the valsartan group and 1.4% in the placebo group. In the paediatric population, where underlying renal abnormalities are common, the most frequently reported adverse reactions (greater than or equal to 1% and on treatment) were headache (7.3%), upper respiratory tract infection (5.4%), and dizziness (1.7%).
Post-Myocardial Infarction and/or Heart Failure (studied in adult patients only)

Reporting of Suspected Adverse Reactions
It is important to report suspected adverse reactions after authorisation of the medicinal product. This allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in the contact details below:
Department for Medicinal Product Monitoring, Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych, Al. Jerozolimskie 181C, 02-222 Warszawa.
Tel.: + 48 22 49 21 301, fax: + 48 22 49 21 309, website: https://smz.ezdrowie.gov.pl

4.9 Overdose

Symptoms
Overdose with valsartan may result in marked hypotension, which could lead to decreased renal function, and (or) shock.
Treatment
Treatment of overdose should be symptomatic and supportive. The patient should be kept in a supine position and vital signs should be closely monitored. If hypotension occurs, the patient should be placed in a supine position and salt and volume replacement should be given as needed.
Valsartan is unlikely to be removed by haemodialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs acting on the renin-angiotensin system, angiotensin II receptor blockers, plain, ATC code: C09CA03
Valsartan is active after oral administration, a strong and specific antagonist of the angiotensin II (Ang II) receptor. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased concentration of angiotensin II in the blood after blocking the AT1 receptor by valsartan may stimulate the unblocked AT2 receptor, which appears to act antagonistically to the action of the AT1 receptor. Valsartan does not exhibit even partial agonistic activity with respect to the AT1 receptor and has much greater (about 20,000 times) affinity for the AT1 receptor than for the AT2 receptor. It has not been found that valsartan binds to or blocks other hormone receptors or ion channels known to be important in cardiovascular regulation.
Valsartan does not inhibit the activity of angiotensin-converting enzyme (ACE, also known as kininase II), which converts Ang I to Ang II and causes the breakdown of bradykinin. Due to the lack of effect on ACE and the lack of enhancement of bradykinin's action or substance P, the likelihood of coughing when using angiotensin II receptor antagonists is low. In clinical trials in which valsartan was compared to an ACE inhibitor, the frequency of dry cough was significantly lower (p <0.05) in patients treated with valsartan than in patients receiving an ACE inhibitor (respectively 2.6% and 7.9%). In a clinical trial of patients with a dry cough during treatment with ACE inhibitors in their history, 19.5% of patients receiving valsartan and 19.0% of patients taking thiazide diuretics complained of coughing compared to 68.5% of patients treated with ACE inhibitors (p <0.05).
Hypertension
Administration of valsartan to patients with hypertension results in a decrease in blood pressure without affecting heart rate.
In most patients, after a single oral dose, the onset of antihypertensive action occurs within 2 hours, and maximum blood pressure reduction is achieved within 4-6 hours. The antihypertensive effect lasts for 24 hours after administration. During repeated administration, the antihypertensive effect is clearly noticeable within 2 weeks, and the maximum effect is achieved within 4 weeks and persists during long-term treatment. Combination therapy with hydrochlorothiazide significantly increases the antihypertensive effect of the medicinal product.
Sudden discontinuation of valsartan treatment was not associated with the occurrence of so-called rebound hypertension or clinically significant adverse events.
In patients with hypertension and type 2 diabetes with microalbuminuria, it has been shown that valsartan reduces urinary albumin excretion. The MARVAL study (Micro Albuminuria Reduction with Valsartan) evaluated the reduction of urinary albumin excretion (UAE) during treatment with valsartan (80-160 mg/day) compared to amlodipine (5-10 mg/day) in 332 patients with type 2 diabetes (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 μg/min; amlodipine: 55.4 μg/min), normal or high blood pressure, and preserved renal function (serum creatinine <120 μmol l). after 24 weeks, uae decreased (p <0.001) by 42% (-24.2 μg min; 95% confidence interval: -40.4 to -19.1) in patients treated with valsartan and about 3% (-1.7 -5.6 14.9) amlodipine, despite similar blood pressure reduction indices both groups.
In the DROP study (Diovan Reduction of Proteinuria), the efficacy of valsartan in reducing UAE was further evaluated in 391 patients with hypertension (blood pressure ≥150/88 mmHg) with type 2 diabetes, albuminuria (mean = 102 μg/min; 20-700 μg/min), and preserved renal function (mean serum creatinine = 80 μmol/l). Patients were randomized to one of three treatment groups: valsartan at 160, 320, or 640 mg/day. Treatment was conducted for 30 weeks. The goal of the study was to determine the optimal dose of valsartan in reducing UAE in patients with hypertension and type 2 diabetes. After 30 weeks, there was a significant percentage decrease in UAE by 36% compared to baseline values in the group treated with valsartan at a dose of 160 mg (95% confidence interval: 22% to 47%) and by 44% in the group treated with valsartan at a dose of 320 mg (95% confidence interval: 31% to 54%). It was found that a dose of 160-320 mg of valsartan caused a clinically significant reduction in UAE in patients with hypertension and type 2 diabetes.
Post-myocardial infarction condition
The VALIANT study (VALsartan In Acute myocardial iNfarcTion) was a randomized, controlled, international, double-blind trial conducted in 14,703 patients with acute myocardial infarction and signs of heart failure or left ventricular dysfunction (left ventricular ejection fraction ≤40% in radionuclide ventriculography or ≤35% in echocardiography or contrast angiography). Patients within 12 hours to 10 days after the onset of symptoms of myocardial infarction were randomly assigned to one of three treatment groups: valsartan, captopril, or valsartan in combination with captopril. The mean treatment duration was two years.
The primary endpoint was the time to death from any cause.
Valsartan was as effective as captopril in reducing mortality from any cause after myocardial infarction. The percentage of deaths from any cause was similar in all groups (valsartan: 19.9%, captopril: 19.5%, and valsartan + captopril: 19.3%). Adding valsartan to captopril did not provide any additional benefits compared to administering captopril alone. No differences were found between valsartan and captopril in terms of mortality from any cause, depending on age, sex, race, underlying treatment, or underlying disease. Valsartan also increased survival time and reduced cardiovascular mortality and shortened hospitalization time for heart failure, re-infarction, resuscitation, and non-fatal stroke (secondary composite endpoint).
In patients treated after myocardial infarction, the safety profile of valsartan was consistent with the clinical course. In terms of renal function, a twofold increase in serum creatinine was observed in 4.2% of patients treated with valsartan, in 4.8% of patients receiving combination therapy with valsartan and captopril, and in 3.4% of patients treated with captopril. Treatment was discontinued due to various types of renal dysfunction in 1.1% of patients treated with valsartan, in 1.3% of patients treated with valsartan and captopril, and in 0.8% of patients treated with captopril. In the evaluation of patients after myocardial infarction, renal function should be assessed.
No differences were found in total mortality, cardiovascular mortality, and morbidity during concomitant administration of beta-adrenergic receptor blockers with valsartan and captopril, administration of only valsartan, or only captopril. Regardless of the medication used, mortality was lower in the group of patients treated with beta-adrenergic receptor blockers, which confirms the known benefits of using beta-adrenergic receptor blockers in this patient population.
Heart failure
The Val-HeFT study was a randomized, controlled, international clinical trial comparing valsartan to placebo in terms of morbidity and mortality in 5,010 patients with heart failure (62% class II, 36% class III, and 2% class IV according to NYHA) receiving standard treatment, with left ventricular ejection fraction (LVEF) <40% and left ventricular internal diameter in diastole (LVIDD) >2.9 cm/m. The underlying therapy consisted of ACE inhibitors (93%), diuretics (86%), digoxin (67%), and beta-adrenergic receptor blockers (36%). The mean observation period of patients was almost two years. The mean daily dose of valsartan in the Val-HeFT study was 254 mg. The study evaluated two primary endpoints: mortality from any cause (survival time) and the composite endpoint of mortality and heart failure morbidity (time to the first morbidity event) defined as death, sudden death with resuscitation, hospitalization for heart failure, or intravenous administration of inotropic or vasodilating drugs for at least 4 hours without hospitalization.
Mortality from any cause was similar (p = NS) in the group treated with valsartan (19.7%) and the group receiving placebo (19.4%). The primary benefit was a 27.5% reduction (95% confidence interval: 17% to 37%) in the risk of time to first hospitalization for heart failure (respectively 13.9% and 18.5%). Results indicating superiority over placebo (composite endpoint of mortality and morbidity was 21.9% in the placebo group and 25.4% in the valsartan group) were observed in those patients who received combination therapy with three drugs: ACE inhibitor, beta-adrenergic receptor blocker, and valsartan.
The benefits in terms of morbidity were greatest in the subgroup of patients not receiving ACE inhibitors (n = 366). In this subgroup of patients, mortality from any cause was significantly lower, by 33%, during treatment with valsartan compared to placebo (95% confidence interval: -6% to 58%) (respectively 17.3% for valsartan and 27.1% for placebo), and the composite risk of mortality and morbidity was lower by 44% (respectively 24.9% for valsartan and 42.5% for placebo).
Among patients receiving ACE inhibitors without beta-adrenergic receptor blockers, mortality from any cause was similar (p = NS) in the group treated with valsartan (21.8%) and the group receiving placebo (22.5%). The composite risk of mortality and morbidity was significantly lower by 18.3% (95% confidence interval: 8% to 28%) for valsartan compared to placebo (respectively 31.0% and 36.3%).
In the entire population that participated in the Val-HeFT study, patients treated with valsartan showed significant improvement according to NYHA criteria, as well as objective and subjective symptoms of heart failure, including shortness of breath, fatigue, edema, and wheezing, compared to patients receiving placebo. The quality of life of patients treated with valsartan was better, as shown by the change in the Minnesota Living with Heart Failure Quality of Life score from baseline, compared to placebo. The left ventricular ejection fraction at the endpoint increased significantly in patients treated with valsartan, and the left ventricular internal diameter in diastole (LVIDD) decreased significantly compared to baseline and compared to placebo.
Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)
In two large, randomized, controlled clinical trials, ONTARGET (ONgoing Telmistartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nefropathy in Diabetes), the concomitant use of an ACE inhibitor with an angiotensin II receptor antagonist was evaluated.
The ONTARGET study was conducted in patients with cardiovascular disease, cerebrovascular disease in history, or type 2 diabetes with proven target organ damage. The VA NEPHRON-D study was conducted in 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 the pharmacodynamic properties of these drugs, the results also apply to other ACE inhibitors and angiotensin II receptor antagonists.
Therefore, in patients with diabetic nephropathy, ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly.
The ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to evaluate the benefits of adding aliskiren to standard treatment with an ACE inhibitor or an angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease and/or cardiovascular disease. The study was prematurely terminated due to increased risk of adverse events. Cardiovascular deaths and strokes occurred more frequently in the group receiving aliskiren compared to the placebo group. The group receiving aliskiren also reported more adverse events, including serious adverse events (hyperkalemia, hypotension, and kidney failure), compared to the placebo group.
Children and adolescents
Hypertension
The antihypertensive effect of valsartan was evaluated in four randomized, double-blind clinical trials involving 561 pediatric patients aged 6 to less than 18 years and 165 children aged 1 to 6 years. The most common concomitant diseases with potential impact on the occurrence of hypertension in study participants included kidney and urinary tract disorders and obesity.
Clinical experience in children aged 6 years or older
In a clinical trial involving 261 pediatric patients aged 6 to 16 years with hypertension, patients with a body weight of <35 kg received valsartan tablets at a dose of 10, 40, or 80 mg per day (low, medium, and high doses), patients with body weight ≥35 20, 80, 160 doses). the end 2-week treatment period, caused dose-dependent decrease in both systolic diastolic blood pressure. summary, three doses high) significant pressure compared to baseline values, respectively by 8, 12 mmhg. were re-randomized continue same receive placebo. continuing medium valsartan, lowest values -4 -7 mmhg lower than placebo group. treated low was similar that observed consistently showed antihypertensive effect all demographically differentiated subgroups.
In a second clinical trial involving 300 pediatric patients aged 6 to less than 18 years with hypertension, patients meeting the inclusion criteria were randomized to receive valsartan tablets or enalapril for 12 weeks. Children with a body weight of ≥18 kg to <35 kg received 80 mg of valsartan or 10 enalapril; children with a body weight ≥35 to <80 160 20 enalapril, and ≥80 320 40 enalapril. in patients treated valsartan, the decrease systolic blood pressure was comparable effect achieved enalapril (respectively 15 mmhg 14 mmhg) (p-value <0.0001 equivalence study). similar results were obtained for diastolic pressure, 9.1 group 8.5 group.
In a third, open-label clinical trial involving 150 pediatric patients aged 6 to 17 years with hypertension, patients meeting the inclusion criteria received valsartan for 18 months to evaluate the safety and tolerability of the drug. Of the 150 patients participating in this study, 41 received another antihypertensive drug concomitantly. Patients received doses based on body weight categories for initial and maintenance doses. Patients weighing >18 to <35 kg, ≥35 to <80 and ≥80 <160 kg received 40 mg, 80 160 respectively. after one week, the doses were increased 320 in half of patients enrolled study (50.0%, n=75), chronic kidney disease was present, including 29.3% (44) with stage 2 (gfr 60 – 89 ml min 1.73m) or 3 30-<59 1.73m). mean decrease systolic blood pressure 14.9 mmhg all (compared baseline value 133.5 mmhg), 18.4 131.9 11.5 without 135.1 mmhg). percentage who achieved stabilized (both diastolic <95th percentile) slightly higher group concomitant (79.5%) compared (72.2%).
Clinical experience in children under 6 years of age
Three clinical trials were conducted involving 291 patients aged 1 to 5 years. The studies did not include children under 1 year of age. In the first study involving 90 patients, no dose-response relationship was found, 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 with hypertension aged 1 to 5 years, with or without chronic kidney disease, who were randomly assigned to receive 0.25 mg/kg or 4 mg/kg. At the endpoint, the decrease in mean systolic/diastolic blood pressure during treatment with valsartan at a dose of 4.0 mg/kg was respectively 8.5/6.8 mmHg and 4.1/0.3 mmHg; (p = 0.0157/p <0.0001). Also, in the subgroup with chronic kidney disease, a decrease in mean systolic/diastolic blood pressure was observed during treatment with valsartan at a dose of 4.0 mg/kg compared to 0.25 mg/kg (respectively 9.2/6.5 mmHg and 1.2/+1.3 mmHg).
The European Medicines Agency has waived the obligation to present the results of studies with valsartan in all subsets of pediatric patients with heart failure and heart failure after myocardial infarction. See section 4.2, information on the use of the medicinal product in pediatric patients.

5.2 Pharmacokinetic properties

Absorption
After oral administration of valsartan alone, the maximum concentration of valsartan in plasma occurs after 2-4 hours in the case of tablets and after 1-2 hours in the case of the solution. The mean absolute bioavailability of the drug is 23% and 39% respectively after administration of tablets and solution.
Systemic exposure and maximum valsartan concentration in plasma are about 1.7- and 2.2-fold higher in the case of the solution compared to tablets.
When valsartan is administered with food, the area under the curve (AUC) for valsartan is reduced by about 40%, and the maximum plasma concentration (Cmax) is reduced by about 50%, although from about 8 hours after administration, the valsartan plasma concentrations are similar in the group receiving the drug with a meal and in the group receiving the drug on an empty stomach. Along with the reduction in AUC, there is no clinically significant weakening of the therapeutic effect, so valsartan can be administered with or without food.
Distribution
The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 liters, indicating that valsartan does not have extensive tissue distribution. Valsartan is highly bound to plasma proteins (94–97%), mainly to albumins.
Metabolism
Valsartan is not biotransformed to a significant extent, as only about 20% of the dose is detected in the form of metabolites. A hydroxymetabolite was detected in plasma at low concentrations (below 10% of the area under the curve - AUC for valsartan). This metabolite is pharmacologically inactive.
Elimination
Valsartan exhibits multi-exponential kinetics of the elimination process (t½ <1 hour and t½ approximately 9 hours).
Valsartan is eliminated primarily with bile in feces (about 83% of the dose) and through the kidneys in urine (about 13% of the dose), mainly in unchanged form. After intravenous administration, the clearance of valsartan from plasma is approximately 2 l/h, and renal clearance is approximately 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
Patients with heart failure
The mean time to reach maximum concentration and the half-life of valsartan in the elimination phase in patients with heart failure and healthy volunteers are similar. The AUC and C values of valsartan are nearly proportional to the increased dose in the clinical dose range (40 mg to 160 mg of valsartan twice daily). The mean accumulation factor is approximately 1.7.
The clearance of valsartan after oral administration is approximately 4.5 l/h. Age does not affect the observed clearance in patients with heart failure.
Special populations
Elderly patients
In some elderly patients, slightly increased systemic exposure to valsartan was observed compared to younger individuals, but it was not found to have any clinical significance.
Renal impairment
As expected for a substance whose renal clearance is only 30% of the total plasma clearance, no correlation was found between renal function and systemic exposure to valsartan. Therefore, there is no need to modify the dosage of the medicinal product in patients with renal impairment (creatinine clearance >10 ml/min). Currently, there is a lack of experience regarding the safe use of the medicinal product in patients with creatinine clearance <10 ml min and patients undergoing dialysis, so valsartan should be used with caution in these patient groups (see sections 4.2 4.4). is highly bound to plasma proteins, the use of dialysis remove from circulation not very effective.
Hepatic impairment
About 70% of the absorbed dose is excreted in the bile, mainly in unchanged form. Valsartan does not undergo significant biotransformation. In patients with mild to moderate liver dysfunction, a twofold increase in exposure (AUC) was observed compared to healthy individuals. However, no correlation was found between valsartan plasma concentration and the degree of liver dysfunction. Valsartan has not been studied in patients with severe liver dysfunction (see sections 4.2, 4.3, and 4.4).
Children and adolescents
In a study involving 26 pediatric patients (aged 1 to 16 years) with hypertension, who received a single dose of valsartan suspension (mean 0.9 to 2 mg/kg, maximum dose 80 mg), the clearance (l/h/kg) of valsartan was comparable across the age range from 1 to 16 years and was similar to the clearance observed in adult patients receiving the medicinal product in the same form (see information on absorption, which is presented in section 5.2).
Renal impairment
The medicinal product has not been studied in children and adolescents with creatinine clearance <30 ml min or those undergoing dialysis, so its use is not recommended in this patient group. there no need to adjust the dose children and adolescents with creatinine clearance>30 ml/min. Renal function and serum potassium should be closely monitored during treatment with valsartan (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 carcinogenic effect, do not indicate any special hazard for humans.
In rats, toxic doses to the mother (600 mg/kg/day) during the last days of pregnancy and lactation led to lower survival rates, lower body weight gain, and developmental delays (separate ear and auditory canal opening) in offspring (see section 4.6).
Such doses in rats (600 mg/kg/day) are about 18 times higher than the maximum recommended dose in humans, calculated based on mg/m² (assuming an oral dose of 320 mg/day and a patient weight of 60 kg).
In preclinical safety studies, high doses of valsartan (from 200 to 600 mg/kg) caused a decrease in red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and changes in renal hemodynamics (slight increase in blood urea nitrogen, renal tubular dilation, and basophilia in males). Doses used in rats (200 to 600 mg/kg/day) are about 6 and 18 times higher than the maximum recommended dose in humans, calculated based on mg/m² (assuming an oral dose of 320 mg/day and a patient weight of 60 kg).
In marmosets, changes were similar, although more severe, especially in terms of kidney damage, where nephropathy developed, including increased blood urea nitrogen and creatinine levels.
Both species also showed hyperplasia of the juxtaglomerular apparatus.
All changes were found to be caused by the pharmacological action of valsartan, which causes prolonged hypotension, especially in marmosets. In humans, when valsartan is used at therapeutic doses, it seems that hyperplasia of the juxtaglomerular apparatus is unlikely to occur.
Children and adolescents
Daily oral administration of valsartan at a dose of 1 mg/kg/day (representing about 10-35% of the maximum recommended dose in pediatric patients, calculated based on systemic exposure) to newborn or young rats (from 7 to 70 days after birth) caused permanent, irreversible kidney damage. The above-mentioned effects represent the predicted intensity of the pharmacological actions of ACE inhibitors and type 1 angiotensin II receptor antagonists; these effects are observed as a result of treatment of rats in the first 13 days of life. This period corresponds to the 36th week of gestation in humans and sometimes may extend up to 44 weeks after conception. In the valsartan study on young animals, rats received doses up to 70 days after birth, and it cannot be excluded that treatment with valsartan may affect kidney maturation (4-6 weeks after birth). Functional maturation of the kidneys is a process that occurs in the first year of human life. Therefore, it cannot be excluded that these data have clinical significance for children under 1 year of age, while preclinical data do not raise concerns about the safety of using the medicinal product in children over 1 year of age.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:
Microcrystalline cellulose
Anhydrous colloidal silica
Sorbitol (E 420)
Magnesium carbonate
Maize starch, pregelatinized
Povidone K-25
Sodium stearyl fumarate
Sodium lauryl sulfate
Crospovidone (type A)
Tablet coating:
Lactose monohydrate
Hypromellose
Talc
Macrogol 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 Incompatibilities

None.

6.3 Shelf life

2 years

6.4 Special precautions for storage

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

6.5 Nature and contents of container

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

6.6 Special precautions for disposal and preparation of the medicinal product

for use
No special requirements.

7. MARKETING AUTHORIZATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

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

8. MARKETING AUTHORIZATION NUMBERS

Valtap, 80 mg: Marketing Authorization No.: 17186
Valtap, 160 mg: Marketing Authorization No.: 17187

9. DATE OF FIRST MARKETING AUTHORIZATION

AND DATE OF LAST RENEWAL

Date of first marketing authorization: August 10, 2010
Date of last renewal: October 26, 2015

10. DATE OF REVISION OF THE TEXT

OF THE SUMMARY OF PRODUCT CHARACTERISTICS

06/2025