INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIOCOR SOLO 80 (DIOCOR SOLO 80) DIOCOR SOLO 160 (DIOCOR SOLO 160)

Composition:

Active substance: valsartan;

One film-coated tablet contains valsartan 80 mg or 160 mg;

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, talc, magnesium stearate, coating for application of the film layer Opadry II White (polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

DioCor Solo 80 – round, biconvex film-coated tablets of white color with a score line;

DioCor Solo 160 – round, biconvex film-coated tablets of white color.

Pharmacotherapeutic group. Simple preparations of angiotensin II antagonists.

ATC code C09CA03.

Pharmacological Properties.

Pharmacodynamics.

Valsartan is an orally active, specific antagonist of the angiotensin II receptors. It selectively acts on AT1 receptors, which mediate the known effects of angiotensin II. Increased plasma angiotensin II levels following AT1 receptor blockade by valsartan may stimulate unblocked AT2 receptors, which counterbalance the effects of AT1 receptors. Valsartan exhibits no partial agonist activity at the AT1 receptor and has significantly greater (approximately 20,000 times) affinity for the AT1 receptor than for the AT2 receptor. Valsartan does not inhibit ACE (angiotensin-converting enzyme), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Administration of the drug to patients with arterial hypertension results in a reduction in blood pressure without affecting pulse rate. The onset of antihypertensive effect occurs within 2 hours, reaching maximum effect within 4–6 hours after oral administration; the duration of action exceeds 24 hours. The maximal therapeutic effect develops after 4 weeks of treatment and is maintained during long-term therapy. When used in combination with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved. Abrupt discontinuation of the drug does not lead to withdrawal syndrome. Long-term administration to patients with arterial hypertension has shown that the drug has no significant effect on total cholesterol or uric acid levels, and fasting studies show no significant effect on serum triglyceride or glucose concentrations. The use of the drug reduces hospitalization due to heart failure, slows the progression of heart failure, improves functional class according to NYHA classification, increases ejection fraction, and reduces symptoms of heart failure and improves quality of life compared to placebo.

It is known that the VALIANT trial demonstrated the efficacy of valsartan, as well as captopril, in reducing overall mortality after myocardial infarction. Valsartan was also effective in reducing cardiovascular mortality and hospitalizations due to heart failure, as well as recurrent myocardial infarction. Valsartan positively influenced the time interval from the acute myocardial infarction to the first occurrence of fatal cardiovascular events.

Children. The antihypertensive effect of valsartan has been evaluated in four randomized, double-blind clinical trials involving 561 children aged 6 to 18 years and 165 children aged 1 to 6 years. Renal and urinary tract disorders and obesity were the most common underlying medical conditions causing arterial hypertension in the children included in these studies.

Clinical experience in children aged 6 years and older. In a clinical study involving 261 hypertensive children aged 6 to 16 years, patients with body weight < 35 kg received 10, 40, or 80 mg of valsartan daily (low, medium, and high doses), while patients with body weight ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium, and high doses). At the end of 2 weeks, valsartan reduced systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium, and high) significantly reduced systolic blood pressure by 8, 10, and 12 mm Hg from baseline, respectively.

Clinical experience in children under 6 years of age.

Valsartan is not recommended for use in this age group.

Pharmacokinetics.

Absorption. After oral administration of valsartan, maximum plasma concentrations (Cmax) are reached within 2–4 hours; when administered as a solution, within 1–2 hours. The mean absolute bioavailability of the tablet and solution formulations is 23% and 39%, respectively. Food reduces exposure (as measured by AUC) of valsartan by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%. However, plasma concentrations of valsartan from about 8 hours post-dose are similar between fasting and fed conditions. The reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered with or without food.

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

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

Elimination. The pharmacokinetic profile of valsartan is multiphasic (T½α < 1 hour and T½ß approximately 9 hours). Valsartan is primarily eliminated via bile into feces (approximately 83% of the dose) and to a lesser extent via kidneys in urine (approximately 13% of the dose), mainly in unchanged form. After intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

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

Pharmacokinetics in specific patient populations

Elderly patients. In some elderly patients, systemic exposure to valsartan was slightly higher than in younger patients, but this difference has not shown any clinical significance.

Patients with renal impairment. No correlation has been observed between renal function and systemic exposure to valsartan. Therefore, dosage adjustment is not required in patients with impaired renal function (creatinine clearance > 10 mL/min). Currently, there are no data on the safety of valsartan in patients with creatinine clearance < 10 mL/min or in patients undergoing dialysis; therefore, valsartan should be used with caution in these patients. Valsartan is highly protein-bound, and its removal by hemodialysis is unlikely.

Patients with hepatic impairment. Approximately 70% of the absorbed dose is excreted in bile, primarily in unchanged form. Valsartan undergoes minimal biotransformation, and systemic exposure to valsartan is not expected to correlate with the degree of hepatic dysfunction. Therefore, dosage adjustment of valsartan is not required in patients with non-biliary hepatic insufficiency and in the absence of cholestasis. It has been shown that in patients with biliary cirrhosis or biliary obstruction, the AUC of valsartan increases by approximately twofold.

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

Patients with renal impairment (children). The use of valsartan in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for these patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be closely monitored.

Clinical characteristics.

Indications.

Arterial hypertension.

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

Post-infarction state.

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

Heart failure.

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

Contraindications.

• Hypersensitivity to valsartan or to any excipient.
• Pregnancy or planned pregnancy (see "Use during pregnancy or breastfeeding").
• Severe hepatic impairment, biliary cirrhosis, and cholestasis.
• Hereditary or ACE inhibitor- or angiotensin II receptor antagonist-induced angioedema.
• Concomitant use of angiotensin receptor blockers, including DioCor Solo, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type 1 or type 2) or renal impairment (glomerular filtration rate (GFR) < 60 mL/min).
• No data are available in patients with severe renal impairment (creatinine clearance less than 10 mL/min).

Interaction with other medicinal products and other forms of interaction.

Combined blockade of the renin-angiotensin-aldosterone system (RAAS) with drugs of the ARB, ACE inhibitor, or aliskiren classes

Concomitant use of ARB-class drugs, including DioCor Solo, with other drugs acting on the RAAS is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and renal function changes (including acute renal failure) compared to monotherapy. Therefore, dual RAAS blockade through combined use of ACE inhibitors, ARBs, or aliskiren is not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be performed only under specialist supervision and with strict monitoring of renal function, electrolyte levels, and blood pressure.

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

Concomitant use of ARBs, including DioCor Solo, or ACE inhibitors with aliskiren is contraindicated in patients with type 1 or type 2 diabetes mellitus. ACE inhibitors, including DioCor Solo and ARBs, should not be used concomitantly in patients with diabetic nephropathy.

Concomitant use not recommended

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

Potassium. Potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, potassium-containing salt substitutes, and other medicinal products that may increase potassium levels (e.g., heparin, etc.) may lead to increased serum potassium levels; in patients with heart failure, this may also increase creatinine levels.

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

Caution required when used concomitantly

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and non-selective NSAIDs

Concomitant use of angiotensin II antagonists with NSAIDs may result in reduced antihypertensive effect. In addition, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels. Therefore, monitoring of renal function and adequate patient hydration are recommended at the start of treatment.

Transporters

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

Others. No clinically significant interactions with valsartan or any of the following substances were observed in drug interaction studies: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glipizide.

Children

Caution is recommended when administering valsartan concomitantly with other drugs that inhibit the renin-angiotensin-aldosterone system in children and adolescents with arterial hypertension, as this may increase serum potassium levels. Renal function and serum potassium levels should be carefully monitored.

Special precautions for use.

Hyperkalemia. Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels (e.g., heparin, etc.) is not recommended. If necessary, potassium levels should be monitored.

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

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

Hepatic impairment. DioCor Solo should be used with caution in patients with mild to moderate hepatic insufficiency without cholestasis.

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

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

Renal transplantation. Currently, there are no data on the safety of using DioCor Solo in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism. DioCor Solo should not be used in patients with primary hyperaldosteronism, as the renin-angiotensin system (RAS) is not activated in these patients.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.

As with other vasodilators, the medicinal product should be prescribed with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Pregnancy. Angiotensin II receptor antagonists are contraindicated during pregnancy. If continued treatment with the medicinal product is considered necessary, women who are planning pregnancy should switch to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is confirmed, treatment should be discontinued immediately, and, if necessary, alternative therapy should be initiated.

Recent myocardial infarction. The combination of captopril and valsartan did not demonstrate additional clinical benefit, while the risk of adverse reactions increased compared to monotherapy with the respective agents. Therefore, combination of valsartan with an ACE inhibitor is not recommended.

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

Administration of DioCor Solo to patients after myocardial infarction often leads to some reduction in blood pressure, which usually results in the need to discontinue therapy due to prolonged symptomatic arterial hypotension, even when dosing instructions are followed.

Heart failure. In patients with heart failure, triple combination therapy with an ACE inhibitor, beta-blocker, and DioCor Solo did not show any clinical benefit. This combination is likely to increase the risk of adverse effects and is therefore not recommended. Triple combination of ACE inhibitors, mineralocorticoid receptor antagonists, and valsartan is also not recommended. Such combinations may be used only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure. Safety and efficacy of DioCor Solo in children have not been studied.

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

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

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Concomitant use of ARBs, including DioCor Solo, with other agents acting on the RAAS is associated with increased incidence of arterial hypotension, hyperkalemia, and renal function changes compared to monotherapy. Monitoring of blood pressure, renal function, and electrolyte levels is recommended in patients receiving DioCor Solo and other RAAS-acting agents.

Children

Renal impairment. Use in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for use in such patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be carefully monitored during treatment with valsartan. This is particularly important in cases where valsartan is used in the presence of other conditions (e.g., high fever, dehydration) that may impair renal function. Concomitant use of angiotensin receptor antagonists, including DioCor Solo, or ACE inhibitors with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.

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

Use during pregnancy or breastfeeding.

Use of angiotensin II receptor antagonists (ARBs) is contraindicated in pregnant women or women planning to become pregnant.

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

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

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

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

Due to lack of information on the use of valsartan during breastfeeding, DioCor Solo is not recommended for use in breastfeeding women.

Fertility

Valsartan at doses up to 200 mg/kg/day did not cause adverse effects on reproductive function in rats. The dose of 200 mg/kg/day is 6 times higher than the maximum recommended human dose on a mg/m² basis (based on oral dose of 320 mg/day in a 60 kg patient).

Ability to influence reaction rate while driving or operating machinery.

Studies on the effect on the ability to drive vehicles or operate machinery have not been conducted. It should be noted that dizziness or weakness may occur during treatment with the medicinal product.

Method of Administration and Dosage

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

Dosage

Arterial Hypertension

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

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

Recent Myocardial Infarction

Treatment may be initiated in clinically stable patients as early as 12 hours after myocardial infarction. After an initial dose of valsartan 20 mg (tablets must not be divided; appropriate dosage forms must be used) twice daily, the dose should be increased to 40 mg (tablets must not be divided; appropriate dosage forms must be used), then to 80 mg and 160 mg twice daily over the following weeks.

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

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

Patients after myocardial infarction require regular monitoring of renal function.

Heart Failure

The recommended initial dose of valsartan is 40 mg (tablets must not be divided; appropriate dosage forms must be used) twice daily. The dose should be gradually increased to 80 mg and then to 160 mg twice daily, with intervals of at least 2 weeks between dose increases, up to the highest tolerated dose. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose used in clinical trials was 320 mg, administered in divided doses.

Valsartan may be used in combination with other heart failure medications. However, triple combination therapy with an ACE inhibitor, beta-blocker, and valsartan is not recommended.

Patients with heart failure require monitoring of renal function.

Use in Specific Patient Groups

Elderly Patients

Dose adjustment is not required in elderly patients.

Renal Impairment

Dose adjustment is not required in adult patients with creatinine clearance > 10 mL/min. Concomitant use of DioCor Solo with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.

Diabetes Mellitus

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

Hepatic Impairment

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

Children

DioCor Solo is used for the treatment of arterial hypertension in children aged 6 to 18 years. The safety and efficacy of DioCor Solo in children aged 1 to 6 years have not been established. The drug is not recommended for the treatment of heart failure or post-infarction state in children due to lack of safety and efficacy data.

Arterial Hypertension in Children

Children and adolescents aged 6 to 18 years

The initial dose is 40 mg (tablets must not be divided; appropriate dosage forms must be used) once daily for children with body weight less than 35 kg, and 80 mg once daily for children with body weight of 35 kg or more. Dose should be adjusted based on blood pressure response. The maximum doses studied in clinical trials are shown in Table 1.

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

Table 1

	Body weight of the patient	Maximum dose of Diokor Solo
	From ≥ 18 kg to < 35 kg	80 mg
	From ≥ 35 kg to < 80 kg	160 mg
	From ≥ 80 kg to ≤ 160 kg	320 mg

Children under 6 years of age

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

Children aged 6 to 18 years with renal impairment

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

Children aged 6 to 18 years with hepatic impairment

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

Heart failure and recent myocardial infarction in children

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

Overdose.

Following an overdose of DioCor Solo, marked arterial hypotension may develop, which can lead to impaired consciousness, vascular collapse, and/or shock. Therapeutic measures depend on the time of ingestion and the type and severity of symptoms; stabilization of circulation is of primary importance. If arterial hypotension occurs, the patient should be placed in a supine position, and blood volume should be corrected.

It is unlikely that valsartan can be removed from the body by hemodialysis.

Adverse reactions.

Arterial hypertension/heart failure/myocardial infarction

It has been reported that in controlled clinical trials in adult patients with arterial hypertension, the incidence of adverse reactions with placebo was comparable to that with valsartan. The incidence of adverse reactions was found to be unrelated to dose or duration of treatment and did not depend on patient's sex, age, or race.

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

With regard to adverse reactions categorized as "very rare," "rare," and "uncommon," which were not identified during clinical trials, a cumulative search in the safety data system was performed.

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

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

Table 2

Infections
Common	Viral infections
Uncommon	Upper respiratory tract infections, pharyngitis, sinusitis
Very rare	Rhinitis
Blood and lymphatic system disorders
Uncommon	Neutropenia
Very rare	Thrombocytopenia
Immune system disorders
Very rare	Hypersensitivity reactions, including serum sickness
Metabolism and nutrition disorders
Uncommon	Hyperkalemia*#
Psychiatric disorders
Uncommon	Insomnia, decreased libido
Nervous system disorders
Common	Dizziness##, postural dizziness#
Uncommon	Syncope*
Very rare	Headache##
Ear and labyrinth disorders
Uncommon	Vertigo
Cardiac disorders
Uncommon	Heart failure*
Very rare	Cardiac arrhythmia
Vascular disorders
Common	Orthostatic hypotension#
Uncommon	Hypotension*##
Very rare	Vasculitis
Respiratory system disorders
Uncommon	Cough
Gastrointestinal disorders
Uncommon	Diarrhea, abdominal pain
Very rare	Nausea##, vomiting, angioneurotic intestinal edema
Hepatobiliary disorders
Unknown	Elevated liver function parameters, including increased serum bilirubin levels
Skin and subcutaneous tissue disorders
Very rare	Angioedema**, rash, pruritus, exanthema
Unknown	Bullous dermatitis
Musculoskeletal and connective tissue disorders
Uncommon	Back pain
Very rare	Arthralgia, myalgia
Renal and urinary disorders
Very rare	Renal failure**##, acute renal failure**, renal dysfunction**
Pregnancy and perinatal conditions
Very rare	Fetal developmental complications
General disorders
Uncommon	Malaise, asthenia, edema
Investigations
Common	Increased serum creatinine, increased blood urea nitrogen
Very rare	Elevated serum bilirubin, decreased hemoglobin/hematocrit levels, liver function parameters outside normal range.

* reported by patients in the post-infarction period

reported by patients with heart failure

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

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

Laboratory test results

It is known that in isolated cases valsartan has caused a reduction in hemoglobin levels and hematocrit count. In controlled clinical trials, significant reductions (> 20%) in hematocrit and hemoglobin levels were observed in 0.8% and 0.4% of patients receiving DioCor Solo, respectively. In comparison, reductions in both parameters – hematocrit and hemoglobin levels – were noted in 0.1% of patients receiving placebo.

Neutropenia was reported to occur in 1.9% of patients treated with valsartan in controlled clinical trials, compared to 1.6% of patients treated with an ACE inhibitor. In controlled clinical trials involving patients with arterial hypertension, significant increases in serum creatinine, potassium, and total bilirubin levels were observed in 0.8%, 4.4%, and 6% of patients treated with valsartan, respectively, compared to 1.6%, 6.4%, and ̄12.9% of patients treated with an ACE inhibitor.

Isolated cases of elevated liver function parameters have been reported in patients treated with valsartan. No special laboratory monitoring is required for patients with arterial hypertension receiving valsartan therapy. In cases of heart failure, serum creatinine levels increased by more than 50% in 3.9% of patients taking valsartan, compared to 0.9% of patients taking placebo, and serum potassium levels increased by more than 20% in 10% of patients taking valsartan, compared to 5.1% of patients taking placebo.

It is known that in heart failure studies, increased blood urea nitrogen levels were observed in 16.6% of patients taking valsartan, compared to 6.3% of patients taking placebo. In 4.2% of patients receiving valsartan, 4.8% of patients treated with a combination of valsartan and captopril, and in 3.4% of patients treated with captopril, a doubling of serum creatinine levels was observed in the post-infarction period.

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

Children

Arterial hypertension

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

Neurocognitive assessment and developmental evaluation of children aged 6 to 16 years did not reveal any clinically significant overall negative consequences after treatment with DioCor Solo for up to 1 year.

It is known that in a double-blind randomized trial involving 90 children aged 1 to 6 years, which continued as an open-label study lasting one year, two fatal cases and isolated cases of marked elevation of liver transaminases were recorded. These cases occurred in a population with significant comorbidities. A causal relationship was not established. In a second study, which randomized 75 children aged 1 to 6 years, no significant elevations in liver transaminases or fatal cases were observed during treatment with valsartan.

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

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

Shelf life. 3 years.

Storage conditions.

Store out of reach of children, in the original packaging at a temperature not exceeding 25 °C.

Packaging.

10 tablets in a blister; 1, 3, 4, or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "Pharma Start", Ukraine.

Manufacturer's address and location of business activity.

8 Vatslava Gaydela Boulevard, Kyiv, 03124, Ukraine.

If adverse effects occur or if you have any questions regarding the safety of using the medicinal product, please contact LLC "ASINO UKRAINE" at 8 Vatslava Gaydela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333