Tiara Solo

APPROVED

by the Order of the Ministry of Health of Ukraine

17.09.2020 No. 2119

Marketing Authorization

No.UA/18327/01/01

     UA/18327/01/02

PACKAGE LEAFLET

for medical use of a medicinal product

Tiara Solo

Qualitative and quantitative composition:

active substance: valsartan;

1 ml of tablet contains 80 mg or 160 mg of valsartan;

list of excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate, opadry II 85F pink.

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties:

80 mg tablets - round tablets with a biconvex surface, coated with a pink color, with a dash;

160 mg tablets - oval tablets with a biconvex surface, coated with a pink color, with a dash.

Pharmacotherapeutic group. Angiotensin II receptor blockers (ARBs). Valsartan.

ATC code С09С А03.

Pharmacological properties.

Pharmacodynamic properties.

Valsartan is an active specific angiotensin II receptor antagonist for oral use. It acts selectively on AT₁ subtype receptors responsible for the known effects of angiotensin II. Elevated plasma angiotensin II levels after AT₁ receptor blockade by valsartan may stimulate an unblocked AT₂ receptor that balances the effect of the AT₁ receptor. Valsartan does not show any partial agonist activity against the AT₁ receptor, but has a much greater (approximately 20,000 times) affinity for the AT₁ receptor than for the AT₂ receptor.

Valsartan does not inhibit angiotensin converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. The use of the medicinal product in patients with hypertension leads to decreasing of blood pressure without affecting the heart rate.

The onset of hypotensive effect is observed within 2 hours, the maximum - within 4-6 hours after oral administration; duration of action - more than 24 hours. The maximum therapeutic effect develops in 4 weeks from the beginning of treatment and remains at long therapy. When used with hydrochlorothiazide, a significant additional reduction of blood pressure is achieved.

Sudden withdrawal of the medicinal product is not accompanied by the development of withdrawal syndrome.

With long-term use of the medicinal product in patients with hypertension, it was found that the medicinal product did not have a significant effect on the level of total cholesterol, uric acid, as well as in studies on an empty stomach - the concentration of triglycerides and glucose in serum.

The medicinal product reduces the number of hospitalizations for heart failure, slows the progression of heart failure, improves the functional class according to the NYHA classification, increases the ejection fraction, and reduces the symptoms of heart failure and improves quality of life compared to placebo.

The VALIANT study demonstrated the effectiveness of valsartan, like captopril, in reducing overall mortality after myocardial infarction. Valsartan was also effective in reducing mortality from cardiovascular disease and hospitalization for heart failure as well as recurrent myocardial infarction. Valsartan had a positive effect on such an indicator as the period of time after an acute myocardial infarction before the first manifestations of cardiovascular pathology, which lead to death.

Children.

The antihypertensive effect of valsartan was evaluated in 4 randomized double-blind clinical trials in 561 children aged 6 to 18 years and in 165 children aged 1 to 6 years. Renal and urinary disorders and obesity were the most common major medical causes of hypertension in the children enrolled in these studies.

Clinical experience in children 6 years of age and older.

In a clinical study of 261 children with hypertension aged 6 to 16 years, patients weighing <35 kg received 10, 40, or 80 mg of valsartan per day (low, medium, and high doses), patients weighing ≥ 35 kg received 20, 80 and 160 mg of valsartan per day (low, medium and high doses). At the end of week 2, valsartan reduced dose-dependent systolic and diastolic blood pressure. Three equal doses of valsartan (low, medium and high) significantly reduced systolic blood pressure by 8, 10, 12 mm Hg. from the initial level, respectively.

Clinical experience in children under 6 years of age.

Valsartan is not recommended for use in this age group.

Pharmacokinetic properties.

Adsorption.

After oral administration of valsartan, peak plasma concentrations (C_max) are reached within 2 to 4 hours and as a solution within 1 to 2 hours. The average absolute bioavailability of tablets and solution of medicinal product is 23% and 39%, respectively.

Food reduces the exposure (as determined by AUC) of valsartan by approximately 40% and the maximum plasma concentration (C_max) by approximately 50%, although plasma concentrations of valsartan starting from approximately 8 hours after administration of medicinal product are similar in the groups of medicinal product use on an empty stomach and after meals. However, the decrease in AUC is not accompanied by a clinically significant decrease in therapeutic effect, so valsartan can be used with or without food.

Distribution.

The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 l, indicating that valsartan is not extensively distributed in tissues. Valsartan is highly bound to serum proteins (94-97%), mainly albumin.

Biotransformation.

In most cases, valsartan is not metabolized, as only approximately 20% of the dose is excreted as metabolites. Hydroxymetabolite was excreted in plasma at low concentrations (less than 10% AUC of valsartan). This metabolite is pharmacologically inactive.

Excretion.

The pharmacokinetic curve of valsartan is multiexponential (T_½α <1 h and T_½ß about 9 hours). Valsartan is excreted predominantly through the bile in the feces (approximately 83% of the dose) and the kidneys in the urine (approximately 13% of the dose), preferably unchanged. Following intravenous administration, the plasma clearance of valsartan is approximately 2 l/h and the renal clearance is 0.62 l/h (approximately 30% of the total clearance). The half-life of valsartan is 6 hours.

Patients with heart failure (80 mg and 160 mg tablets).

The mean time to C_max and half-life of valsartan in patients with heart failure and in healthy volunteers are similar. The AUC and C_max of valsartan are almost proportional to the dose increase above the clinical dosing range (40 to 160 mg twice daily). The average accumulation factor is approximately 1.7. The estimated clearance of valsartan after oral administration is approximately 4.5 l/h. Age does not affect the expected clearance in patients with heart failure.

Pharmacokinetic properties in certain groups of patients.

Elderly patients. In some elderly patients, the systemic effects of valsartan were slightly more pronounced than in young patients, but no clinical significance was shown.

Patients with impaired renal function. No correlation was found between renal function and systemic effects of valsartan. Therefore, no dose adjustment is required for patients with impaired renal function (creatinine clearance> 10 ml/min). There are currently no data on the safety of patients with creatinine clearance <10 ml/min and dialysis patients, so valsartan should be used with caution in these patients. Valsartan has a high degree of binding to plasma proteins, so its removal by hemodialysis is unlikely.

Patients with impaired liver function. Approximately 70% of the absorbed dose of the medicinal product is excreted in the bile, mostly unchanged. Valsartan does not undergo significant biotransformation, and systemic effects of valsartan are not expected to correlate with the degree of hepatic impairment. Therefore, no dose adjustment of valsartan is required for patients with hepatic insufficiency of nonbiliary origin and in the absence of cholestasis. The AUC of valsartan has been shown to be approximately doubled in patients with biliary cirrhosis or biliary obstruction.

Children.

In a study of 26 children with hypertension (1 to 16 years of age) receiving a single dose of valsartan suspension (mean dose 0.9–2 mg/kg, maximum dose 80 mg), clearance (l/h/kg) valsartan was comparable throughout the age range from 1 to 16 years with similar clearance in adults who used the same medicinal product.

Patients with impaired renal function.

The use of the medicinal product in children with creatinine clearance <30 ml/min and in children on dialysis has not been studied, therefore valsartan is not recommended in such patients. No dose adjustment is required for children with creatinine clearance > 30 ml/min. Renal function and serum potassium should be closely monitored.

Clinical particulars.

Therapeutic indications.

Hypertension.

Treatment of arterial hypertension in adults and children over 6 years of age.

Postinfarction condition.

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

Heart failure.

Treatment of symptomatic heart failure in adult patients when ACE inhibitors cannot be used, or as adjunctive therapy with ACE inhibitors when β-blockers cannot be used.

Contraindications.

• Hypersensitivity to valsartan or to any of the excipients.
• Pregnancy or pregnancy planning (see section “Fertility, pregnancy and lactation”).
• Congenital angioneurotic edema or that has developed during previous treatment with an ACE inhibitor or angiotensin II receptor antagonist.
• Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or II) 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).
• Severe liver dysfunction, biliary cirrhosis and cholestasis.

Interaction with other medicinal products and other forms of interaction.

Double blockade of the renin-angiotensin-aldosterone system (RAAS) by medication of angiotensin receptor blockers (ARBs), ACE inhibitors or aliskiren.

Concomitant use of ARBs, including valsartan, with other medicinal products acting on RAAS has been associated with an increased incidence of hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) compared with monotherapy. Double blockade of RAAS due to the combined use of ACE inhibitors, ARBs or aliskiren is therefore not recommended. If therapy with dual RAAS blockade is considered necessary, it should be performed only under the supervision of a specialist and subject to careful monitoring of renal function, electrolyte levels and blood pressure.

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

Concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with type I and type II diabetes.

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

Concomitant use is not recommended.

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of ACE inhibitors. Due to the lack of experience with the 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 (heparin, etc.) may increase serum potassium in patients with cardiac insufficiency - to increase creatinine levels.

If the use of a medication that affects potassium levels is considered necessary in combination with valsartan, monitoring of plasma potassium levels is recommended.

Caution is required when used concomitantly.

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

Concomitant use of angiotensin II antagonists with NSAIDs may weaken the antihypertensive effect. In addition, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of impaired renal function and increased serum potassium. Therefore, at the beginning of treatment, monitoring of renal function is recommended, as well as appropriate hydration of the patient.

Transporters.

According to in vitro studies, valsartan is a substrate for the hepatic OATP1B1/OATP1B3 capture transporter and the hepatic MRP2 excretion transporter. The clinical significance of these data is unknown. Concomitant use of OATP1B1 transporter inhibitors (e.g., rifampicin, cyclosporine) or MRP2 (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate measures should be taken at the beginning and end of concomitant use of these medications.

Others.

No clinically relevant interactions were observed with valsartan or with any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Children.

Caution is advised when co-administered to children and adolescents with hypertension valsartan and other medicinal products that inhibit RAAS, which may increase serum potassium. Renal function and serum potassium should be closely monitored.

Special warnings and precautions for use.

Hyperkalemia.

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

Renal dysfunction. There are currently no data on the safety of the medicinal products in patients with creatinine clearance < 10 ml/min and in patients on dialysis, so valsartan should be used with caution in such patients. Adult patients with creatinine clearance > 10 ml/min dose adjustment do not require.

Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with renal impairment GFR <60 ml/min/1.73 m2) is contraindicated.

Liver dysfunction. Valsartan should be used with caution in patients with mild to moderate hepatic impairment without cholestasis.

Patients with a deficiency of sodium and/or circulating blood volume (BCV). Symptomatic hypotension may occur in patients with severe sodium and/or circulating blood volume deficiency, such as those receiving high doses of diuretics, in some cases after initiation of valsartan therapy. Sodium and/or BCC levels should be adjusted before starting valsartan therapy, for example by reducing the diuretic dose.

Renal artery stenosis. The safety of valsartan has not been established in patients with bilateral renal artery stenosis or single renal stenosis. Short-term use of valsartan in 12 patients with vasorenal hypertension, which is secondary to unilateral renal artery stenosis, does not cause any significant changes in renal hemodynamic parameters, serum creatinine or urea nitrogen. As other medications that affect RAAS may increase serum urea and creatinine in patients with unilateral renal artery stenosis, monitoring of renal function with valsartan is recommended as a precautionary measure.

Kidney transplantation.

There are currently no data on the safety of valsartan in patients with a recent kidney transplantation.

Primary hyperaldosteronism.

Valsartan should not be used in patients with primary hyperaldosteronism because they do not have an activated renin-angiotensin system (RAS).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.

As other vasodilators, the medicinal product should be used with extreme 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, patients planning pregnancy should be changed to alternative antihypertensive agents with an established safety profile for use during pregnancy. If pregnancy is confirmed, treatment should be stopped immediately and, if necessary, alternative therapy should be started.

Recently suffered myocardial infarction.

The combination of captopril and valsartan did not show an additional clinical effect, but the risk of adverse reactions increased compared with monotherapy with appropriate medications. Thus, the 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 assessment of renal function.

The use of valsartan in patients after myocardial infarction often results in some reduction in blood pressure, which usually results in the need to discontinue therapy due to prolonged symptomatic hypotension, provided that the dosing instructions are followed.

Heart failure.

In patients with heart failure, the triple combination of ACE inhibitor, β-blocker and valsartan did not show any clinical effects. This combination is likely to increase the risk of side effects, so it is not recommended. The triple combination of ACE inhibitors, mineralocorticoid receptor antagonists and valsartan is also not recommended.

Such combinations can be used only under the supervision of a specialist and subject to careful monitoring of renal function, electrolyte levels and blood pressure.

Safety and efficacy of valsartan in children have not been studied.

History of angioneurotic edema.

Valsartan has been reported to cause angioneurotic edema in patients, including laryngeal and glottis edema, leading to airway obstruction and/or swelling of the face, lips, pharynx and/or tongue; in some of these patients, the development of angioneurotic edema has been observed previously with other medications, including ACE inhibitors. The development of angioneurotic edema requires immediate discontinuation of valsartan and valsartan should not be re-administered to such patients.

Other conditions for stimulation of the renin-angiotensin system (RAS).

In patients in whom renal function may be dependent on PAC activity (e.g., patients with severe congestive heart failure), ACE inhibitor therapy has been associated with oliguria and/or progressive azotemia and, in some cases, with acute renal failure and/or death. As valsartan is an angiotensin II antagonist, it cannot be ruled out that valsartan may be associated with renal impairment.

Double blockade of RAAS.

Concomitant use of angiotensin receptor antagonists, including valsartan, with other RAAS-related medicinal products is associated with an increased incidence of hypotension, hyperkalaemia and changes in renal function compared with monotherapy. Monitoring of blood pressure, renal function and electrolyte levels is recommended in patients receiving valsartan and other medicinal products that affect RAAS.

Children.

Renal dysfunction.

Use in children with creatinine clearance <30 ml/min and in dialysis children has not been studied, therefore valsartan is not recommended in such patients. No dose adjustment is required for children with creatinine clearance> 30 ml/min. Renal function and serum potassium should be closely monitored during valsartan treatment. This applies in particular to cases where valsartan is used in the presence of other conditions (fever, dehydration) that are likely to impair renal function.

Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with renal impairment GFR <60 ml/min/1.73 m2) is contraindicated.

Liver dysfunction.

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

Fertility, pregnancy and lactation.

The use of angiotensin II receptor antagonists (ARAII) is contraindicated in pregnant women or women planning to become pregnant.

Epidemiological evidence regarding the risk of teratogenicity due to the use of ACE inhibitors during the first trimester of pregnancy is inconclusive, but a slight increase in risk cannot be excluded. As there are no controlled epidemiological data on the risk of ARAII, the risk of teratogenicity may be for this class of medications. Unless continued therapy is considered necessary, patients planning pregnancy should be prescribed alternative antihypertensive therapy with an established safety profile for use during pregnancy. If pregnancy is diagnosed, treatment with ARAII should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use by pregnant women.

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

If ARAII has been used since the second trimester of pregnancy, it is recommended that an ultrasound be performed to check kidney function and the condition of the skull bones.

The condition of infants whose mothers have received ARAII should be carefully monitored for the development of hypotension.

Due to the lack of information on the use of valsartan during breast-feeding, the medication is not recommended for use in breast-feeding 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 dose for a person in terms of mg/m2 (calculations were performed for oral administration of a dose of 320 mg/day to patients weighing 60 kg).

Effects on ability to drive and use machines.

No studies on the effects on the ability to drive and use machines have been performed. It should be borne in mind that dizziness or weakness may occur during treatment with this medicinal product.

Posology and method of administration.

Method of administration.

The medicinal product can be used regardless of food intake; tablets should be washed down with water.

Posology.

Hypertension.

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

The medicinal product can also be used with other antihypertensive medications. Concomitant use of diuretics, such as hydrochlorothiazide, will further lower blood pressure in patients.

Recently suffered myocardial infarction.

Therapy for clinically stable patients can be started as early as 12 hours after myocardial infarction. After the initial dose of valsartan 20 mg (tablets cannot be divided into doses, it is necessary to take dosage forms in the appropriate dosage) 2 times a day should increase the dose to 40 mg (tablets cannot be divided into doses, it is necessary to take dosage forms in the appropriate dosage), 80 mg and 160 mg twice daily for the next few weeks.

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

Valsartan can be used in patients who have used other medicines after a myocardial infarction, such as thrombolytics, acetylsalicylic acid, a β-blocker, statins and diuretics. Combination with ACE inhibitors is not recommended.

Patients after myocardial infarction should always be monitored for renal function.

Heart failure.

The recommended starting dose of valsartan is 40 mg (tablets should not be divided into doses; it is necessary to take dosage forms in the appropriate dosage) 2 times a day. Gradual dose escalation to 80 mg and 160 mg twice daily should be performed at intervals of at least 2 weeks to the highest dose, depending on the patient's tolerability. Dose reduction of concomitant diuretics should be considered. The maximum daily dose used in clinical trials was 320 mg and was divided into several doses.

Valsartan can be used in combination with other medicines to treat heart failure. However, a triple combination of an ACE inhibitor, a β-blocker and valsartan is not recommended.

Patients with heart failure need monitoring of renal function.

Using in certain groups of patients.

Hypertension in children.

Children and adolescents aged 6 to 18 years.

The initial dose is 40 mg (tablets cannot be divided into doses, it is necessary to take dosage forms in the appropriate dosage) 1 time per day for children weighing up to 35 kg and 80 mg 1 time per day for children weighing 35 kg. The dose should be adjusted depending on the blood pressure response. The maximum doses of valsartan studied in clinical trials are shown in Table 1.

Doses higher than these have not been studied, so their use is not recommended.

 

Table 1

	Patient body weight	The maximum dose of valsartan studied in clinical trials
	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.

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

Children aged 6 to 18 years with renal failure.

Use in children with creatinine clearance <30 ml/min and in dialysis children has not been studied, therefore valsartan is not recommended in such patients. No dose adjustment is required for children with creatinine clearance> 30 ml/min. Renal function and serum potassium should be closely monitored.

Children aged 6 to 18 years with liver failure.

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

Heart failure and recent myocardial infarction in children.

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

Elderly patients.

No dose adjustment is required for elderly patients.

Renal failure.

Adult patients with creatinine clearance> 10 ml/min dose adjustment do not require. Concomitant use of valsartan with aliskiren in patients with renal impairment (GFR <60 ml/min/1.73 m2) is contraindicated.

Diabetes.

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

Hepatic failure.

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

Children.

The medicinal product is used to treat hypertension in children aged 6 to 18 years. The safety and efficacy of valsartan in children aged 1 to 6 years have not been established. The medicinal product is not recommended for the treatment of heart failure or post-infarction conditions in children due to lack of data on safety and efficacy.

Overdose.

Overdose of valsartan may lead to severe hypotension, which may lead to depression of consciousness, vascular collapse and/or shock. Therapeutic measures depend on the time of admission and the type and severity of symptoms; stabilization of blood circulation is of paramount importance. If hypotension occurs, the patient should be in a supine position and blood volume should be adjusted.

It is unlikely that valsartan can be removed by hemodialysis.

Undesirable effects.

Hypertension/heart failure/myocardial infarction

In controlled clinical trials in adult patients with hypertension, the frequency of adverse reactions with placebo was the same as with valsartan. The incidence of adverse reactions was not related to the dose or duration of treatment and did not depend on the patient's sex, age or race.

Adverse reactions reported in clinical, post-marketing and laboratory studies are listed by organ system class.

For adverse reactions from the categories "very rare", "rare" and "uncommon", which were not detectable in clinical trials, a cumulative search was performed in the safety data system.

Adverse events have been ranked under headings of frequency using the following convention: 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 reports. In each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions reported during post-marketing and laboratory studies for which it is not possible to determine the frequency of occurrence are listed with a frequency of "unknown".

Ear and labyrinth disorders: uncommon - vertigo.

Respiratory, thoracic and mediastinal disorders: uncommon - cough.

Gastrointestinal disorders: uncommon- diarrhea, abdominal pain; very rare - nausea, vomiting.

Hepatobiliary disorders: unknown - increased liver function, including increased serum bilirubin.

Renal and urinary disorders: very rare - renal failure ^{** ##,} acute renal failure ^**, renal dysfunction ^**.

Metabolism and nutrition disorders: uncommon- hyperkalemia ^{* #.}

Nervous system disorders: common- postural dizziness^#; uncommon - syncope^*; rare - dizziness^##; very rare - headache^##.

Psychiatric disorders: uncommon- insomnia, decreased libido.

Cardiac disorders: uncommon- heart failure ^*; very rare - heart rhythm disorders.

Vascular disorders: common - orthostatic hypotension^#; infrequently - hypotension^{* ##}; very rare - vasculitis.

Blood and lymphatic system disorders: uncommon- neutropenia; very rare - thrombocytopenia.

Immune system disorders: very rare - hypersensitivity reactions, including serum sickness.

Skin and subcutaneous tissue disorders: very rare - angioneurotic edema^**, rash, itching, exanthema; unknown - bullous dermatitis.

Musculoskeletal and connective tissue disorders: uncommon- back pain; rare -

arthralgia, myalgia.

Pregnancy and perinatal conditions: very rare - complications of fetal development.

General disorders and administration site condition: uncommon- fatigue, asthenia, edema.

Infections and invasions: common- viral infections; uncommon- infections of the upper respiratory tract, pharyngitis, sinusitis; very rare - rhinitis.

Investigations: common- increase in serum creatinine, increase in blood urea; very rare - increase in serum bilirubin, decrease in hemoglobin/hematocrit in the blood, liver function parameters that are outside the normal range.

^* reported patients in a postinfarction condition.

^#reported by patients with heart failure.

^** infrequently reported in postinfarction patients.

^## has been reported more frequently in patients with heart failure (common: dizziness, renal impairment, hypotension; uncommon: headache, nausea).

Investigations.

In isolated cases, valsartan caused a decrease in hemoglobin and hematocrit. In controlled clinical trials, a significant decrease (> 20%) in hematocrit and hemoglobin, respectively, was observed in 0.8% and 0.4% of patients receiving valsartan. In comparison, 0.1% of patients receiving placebo had a decrease in both hematocrit and hemoglobin.

In controlled clinical trials, neutropenia was observed in 1.9% of patients treated with valsartan compared with 1.6% of patients treated with an ACE inhibitor.

In controlled clinical trials in patients with hypertension, there was a significant increase in serum creatinine, potassium and total bilirubin in 0.8%, 4.4% and 6% of patients treated with valsartan, respectively, compared with 1.6%, 6.4% and 12.9% of patients treated with an ACE inhibitor.

Isolated cases of hepatic impairment have been reported in patients treated with valsartan.

Patients with hypertension receiving valsartan therapy do not require any special monitoring of laboratory parameters.

In the case of heart failure, serum creatinine increased by more than 50% in 3.9% of patients receiving valsartan compared with 0.9% of patients receiving placebo, and an increase in serum potassium increased by more than 20%. was observed in 10% of patients taking valsartan compared with 5.1% of patients taking placebo.

In heart failure studies, an increase in blood urea nitrogen was observed in 16.6% of patients taking valsartan compared with 6.3% of patients taking placebo.

4.2% of patients receiving valsartan, 4.8% of patients treated with the combination of valsartan and captopril, and 3.4% of patients treated with captopril had a 2-fold increase in serum creatinine in the postinfarction period.

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

Children.

Hypertension.

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

Neurocognitive and developmental assessment of children 6 to 16 years of age did not reveal a clinically significant overall adverse effect after treatment with valsartan for up to 1 year.

In a double-blind, randomized, study of 90 children aged 1 to 6 years, which was continued as an open-label study lasting 1 year, two fatalities and isolated cases of marked elevations in hepatic transaminases were reported. These cases were observed in the population with significant comorbidities. No causal relationship has been established with valsartan. In the second study, which randomized 75 children aged 1 to 6 years, no significant increase in hepatic transaminases or deaths was observed during valsartan treatment.

Hyperkalemia was more common in children aged 6 to 18 years with major chronic kidney disease.

The safety profile observed in controlled clinical trials in adult patients after myocardial infarction and/or heart failure differs from the general safety profile observed in patients with hypertension. This may apply to patients with the underlying disease. Adverse reactions observed in adult patients after myocardial infarction and/or heart failure are listed above.

Reported suspected adverse reactions.

Reporting suspected adverse reactions after registration of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk ratio for the respective drug. Healthcare providers should be informed of any suspected adverse reactions through the national alert system.

Shelf life. 2 years.

Special precautions for storage.

Store in the original package at a temperature below 25° C. Keep out of the reach of children.

Nature and contents of container.

Film-coated tablets, 80 mg; 14 tablets in a blister container; 2 blister containers in a pack.

Film-coated tablets, 160 mg; 14 tablets in a blister container; 2 or 6 blister containers in a pack.

Category of release.Prescription only medicine.

Manufacturer.PrJSC “Pharmaceutical firm “Darnitsa”.

The manufacturer's location and address of the place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.

Date of last revision. 17.09.2020.