Valmisar 40
UkraineTable of Contents
- INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valmisar 40/Valmisar 40 Valmisar 80/Valmisar 80 Valmisar 160/Valmisar 160 Valmisar 320/Valmisar 320
- Composition:
- Pharmacological Properties.
- Clinical characteristics.
- Special precautions for use.
- Method of Administration and Dosage
- Adverse reactions
- reported by patients with heart failure
- reported more frequently by patients with heart failure (frequent: dizziness, renal function disorders, hypotension; infrequent: headache, nausea)
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valmisar 40/Valmisar 40 Valmisar 80/Valmisar 80 Valmisar 160/Valmisar 160 Valmisar 320/Valmisar 320
Composition:
Active substance: valsartan;
1 tablet contains: 40 mg, 80 mg, 160 mg or 320 mg of valsartan;
Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
coating composition: Opadry Yellow 03F82329 for 40 mg tablets only; Opadry Pink 03F84641 for 80 mg tablets only; Opadry Yellow 03F520004 for 160 mg tablets only; Opadry Purple 02F50251 for 320 mg tablets only.
Dosage form. Film-coated tablets.
Main physicochemical properties:
Dosage 40 mg: biconvex oval film-coated tablets of yellow color, with embossing: "L" and "12" separated by a break line on one side and smooth on the other;
Dosage 80 mg: biconvex oval film-coated tablets of pale red color, with embossing "L13" on one side and smooth on the other;
Dosage 160 mg: biconvex oval film-coated tablets of gray-orange color, with embossing "L14" on one side and smooth on the other;
Dosage 320 mg: biconvex oval film-coated tablets of dark gray-violet color, with embossing "L15" on one side and smooth on the other.
Pharmacotherapeutic group. Simple angiotensin II antagonists.
ATC code C09C A03.
Pharmacological Properties.
Pharmacodynamics.
Valsartan is an orally active, specific angiotensin II receptor antagonist. It selectively acts on AT1 receptors, which mediate the known effects of angiotensin II. Increased plasma levels of angiotensin II 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 approximately 20,000 times greater 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, with maximum effect achieved within 4–6 hours after oral administration; the duration of action lasts more than 24 hours. The maximal therapeutic effect develops after 4 weeks of treatment and is maintained during long-term therapy. When administered in combination with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt discontinuation of the drug does not result in withdrawal syndrome.
Long-term administration of the drug to patients with arterial hypertension has shown no clinically significant effects on total cholesterol, uric acid levels, or on fasting serum concentrations of triglycerides and glucose.
The use of the drug leads to a reduction in hospitalizations due to heart failure, slows 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.
Studies have demonstrated the efficacy of valsartan in reducing overall mortality after myocardial infarction and mortality due to cardiovascular disease. Valsartan was also effective in reducing cardiovascular mortality and hospitalizations due to heart failure, as well as recurrent myocardial infarction. Valsartan positively influenced the time interval from the acute myocardial infarction to the first occurrence of fatal cardiovascular events.
Children
Valsartan reduced systolic and diastolic blood pressure in a dose-dependent manner. Overall, 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 tablets, maximum plasma concentration is reached within 2–4 hours; when administered as a solution, it is achieved within 1–2 hours. The mean absolute bioavailability of the tablet and solution formulations is 23% and 39%, respectively. Food reduces exposure (as defined by AUC) to valsartan by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%, although plasma valsartan concentrations approximately 8 hours after administration are similar between fasting and fed conditions. However, the reduction in AUC does not result in a clinically significant reduction in therapeutic effect; therefore, valsartan may be administered independently of food intake.
Distribution
The volume of distribution at steady state after intravenous administration is approximately 17 L, indicating that valsartan does not extensively distribute into tissues. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.
Metabolism
Valsartan 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 the AUC of valsartan). 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 feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mainly in unchanged form. After intravenous administration, the plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Patients with heart failure (administration of 40 mg, 80 mg, and 160 mg tablets)
The mean time to reach Cmax and the elimination half-life of valsartan in patients with heart failure are similar to those in healthy volunteers. AUC and Cmax values of valsartan are nearly dose-proportional when doses exceed the clinical dosage range (from 40 mg 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 been shown to have 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; thus, valsartan should be used with caution in such 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 impairment. Therefore, dosage adjustment of valsartan is not required in patients with non-biliary hepatic insufficiency and in the absence of cholestasis. However, in patients with biliary cirrhosis or biliary obstruction, the AUC of valsartan has been shown to increase approximately twofold.
Children
It has been reported that in children aged 1 to 16 years with arterial hypertension who received a single dose of valsartan suspension (mean dose 0.9–2 mg/kg, maximum dose 80 mg), clearance (L/h/kg) of valsartan was comparable across the entire age range (1–16 years) to that observed in adults receiving the same formulation.
Patients with renal impairment
The use of the drug in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended in these patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be carefully monitored.
Clinical characteristics.
Indications.
Arterial hypertension (40 mg tablets)
Treatment of arterial hypertension in children aged 6 to 18 years.
Arterial hypertension (80 mg, 160 mg and 320 mg tablets)
Treatment of arterial hypertension in adults and children aged 6 to 18 years.
Post-infarction state (40 mg, 80 mg and 160 mg tablets)
Treatment of clinically stable adult patients with symptomatic heart failure or asymptomatic systolic left ventricular dysfunction following a recent (12 hours–10 days) myocardial infarction.
Heart failure (40 mg, 80 mg and 160 mg tablets)
Treatment of symptomatic heart failure in adult patients when angiotensin-converting enzyme (ACE) inhibitors cannot be used, or as adjunctive therapy with ACE inhibitors when beta-blockers cannot be used.
Contraindications.
- Hypersensitivity to valsartan or to any excipient.
- Severe hepatic impairment, biliary cirrhosis, and cholestasis.
- Pregnancy or planned pregnancy (see section "Use in pregnancy or breast-feeding").
- Concomitant use of angiotensin receptor antagonists, including Valmisar, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
- Hereditary or previous angioedema associated with prior treatment with an ACE inhibitor or angiotensin II receptor antagonist.
- No data are available in patients with severe renal impairment (creatinine clearance less than 10 mL/min).
Interaction with other medicinal products and other forms of interaction.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with drugs from the ARB, ACEI or aliskiren classes
Concomitant use of ARB-class drugs, including Valmisar, with other drugs acting on the RAAS is associated with an increased frequency of arterial hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) compared to monotherapy. Dual blockade of the RAAS by combined use of ACE inhibitors, ARBs or aliskiren is therefore not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be carried out only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.
Concomitant use of angiotensin receptor antagonists, including Valmisar, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.
Concomitant use of ARBs, including Valmisar, or ACE inhibitors with aliskiren is contraindicated in patients with type 1 or type 2 diabetes.
ACE inhibitors, including Valmisar, 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 the 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) may lead to increased serum potassium levels, and in patients with heart failure, to increased creatinine levels.
If concomitant use of a medicinal product affecting potassium levels with valsartan is considered necessary, monitoring of plasma potassium levels is recommended.
Caution required with concomitant use
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 reduce the antihypertensive effect. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function and elevate serum potassium levels. Therefore, monitoring of renal function and appropriate patient hydration are recommended at the start of treatment.
Transporters
In vitro studies have shown that valsartan is a substrate of 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 uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation or discontinuation of concomitant therapy with these medicinal products.
Others
During drug interaction studies, no clinically significant interactions were observed between valsartan and any of the following: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.
Children
Caution is recommended when co-administering valsartan with other substances that inhibit the renin-angiotensin-aldosterone system (RAAS) in children and adolescents with arterial hypertension, as this may increase serum potassium levels. Renal function and serum potassium levels should be closely monitored.
Special precautions for use.
Hyperkalemia
Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels (e.g., heparin, etc.) is not recommended. If necessary, potassium levels should be monitored.
Hypotension
Symptomatic hypotension may occur rarely after initiation of valsartan therapy.
Renal impairment
There are no safety data available on the use of the drug in patients with creatinine clearance < 10 mL/min or in patients undergoing dialysis; therefore, valsartan should be used with caution in such patients. Dose adjustment is not required in adult patients with creatinine clearance > 10 mL/min.
Concomitant use of angiotensin receptor antagonists, including Valmisar, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.
Hepatic impairment
Valmisar should be used with caution in patients with mild to moderate hepatic impairment without cholestasis.
Patients with sodium and/or circulating blood volume (CBV) 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 in isolated cases after initiation of Valmisar therapy. Prior to starting Valmisar therapy, correction of sodium and/or circulating blood volume should be performed, for example, by reducing the diuretic dose.
Renal artery stenosis
The safety of the drug in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney has not been established. Short-term use of Valmisar in 12 patients with renovascular hypertension due 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 Valmisar treatment.
Renal transplantation
Currently, there are no data on the safety of Valmisar use in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism
Valmisar should not be used in patients with primary hyperaldosteronism, as the renin-angiotensin system is not activated in these patients.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, the drug should be prescribed with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Pregnancy
Angiotensin II receptor antagonists are contraindicated during pregnancy. If continuation of treatment with the drug is considered necessary, women 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 (tablets 40 mg, 80 mg, and 160 mg)
The combination of captopril and valsartan did not show additional clinical benefit, while the risk of adverse reactions increased compared to treatment with each agent alone. 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.
Use of Valmisar in patients after myocardial infarction often leads to some reduction in blood pressure, but usually there is no need to discontinue therapy due to persistent symptomatic arterial hypotension, provided dosing instructions are followed.
Heart failure (tablets 40 mg, 80 mg, and 160 mg)
The use of triple combination therapy with an ACE inhibitor, beta-blocker, and Valmisar did not show any clinical benefits in patients with heart failure. This combination is likely to increase the risk of adverse effects and is therefore not recommended. Caution should be exercised in patients with heart failure, and renal function should always be evaluated.
Use of Valmisar in patients with heart failure often leads to some reduction in blood pressure, but usually there is no need to discontinue therapy due to persistent symptomatic arterial hypotension, provided dosing instructions are followed.
In patients in whom renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia, and in isolated cases, acute renal failure and/or fatal outcomes. Since valsartan is an angiotensin II antagonist, it cannot be excluded that Valmisar use may be associated with impaired renal function.
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 Valmisar. In some of these patients, angioedema had previously occurred during treatment with other medicinal products, including ACE inhibitors. Development of angioedema requires immediate discontinuation of the drug. Re-administration of Valmisar in such cases is not recommended.
Other conditions with stimulation of the renin-angiotensin system (tablets 320 mg)
In patients in whom renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia and, in isolated cases, acute renal failure and/or fatal outcomes. Since Valmisar is an angiotensin II antagonist, its use may also be associated with impaired renal function.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ARBs, including Valmisar, 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 electrolytes is recommended in patients receiving Valmisar and other agents affecting the RAAS.
Children
Renal impairment
Use in children with creatinine clearance < 30 mL/min or in children undergoing dialysis has not been studied; therefore, Valmisar 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 Valmisar treatment, particularly in cases where other conditions (e.g., high fever, dehydration) that may impair renal function are present.
Concomitant use of angiotensin receptor antagonists, including Valmisar, or ACE inhibitors with aliskiren in patients with renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.
Hepatic impairment
As in adults, Valmisar is contraindicated in children with severe hepatic impairment, biliary cirrhosis, or cholestasis. Clinical experience with Valmisar in children with mild to moderate hepatic impairment is limited. The dose of the drug should not exceed 80 mg in such patients.
Use during pregnancy or breastfeeding
Use of angiotensin II receptor antagonists (AII-RAs) 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 increase in risk cannot be excluded. Since there are no controlled epidemiological data on the absence of risk 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 drug permitted for use during pregnancy.
It is known that use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy induces human fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).
If AII-RAs were used from the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull condition.
Newborns of mothers who used AII-RAs should be carefully monitored for the development of arterial hypotension.
Due to lack of information on Valmisar use during breastfeeding, the drug 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. This dose is 6 times higher than the maximum recommended human dose on a mg/m² basis (based on oral administration of 320 mg/day to a 60 kg patient).
Ability to influence reaction speed when driving vehicles 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 driving or operating machinery.
Method of Administration and Dosage
Valmisar can be taken independently of food intake; tablets should be swallowed with water.
Dosage
Arterial Hypertension (only 80 mg, 160 mg, and 320 mg tablets)
The recommended initial dose is 80 mg once daily. Antihypertensive effect is achieved within 2 weeks, and maximum effect within 4 weeks. In some patients with inadequately controlled blood pressure, the dose may be increased to 160 mg and up to the maximum of 320 mg.
Valmisar can also be used in combination with other antihypertensive agents. Concomitant use of diuretics, such as hydrochlorothiazide, will further reduce blood pressure.
Recent Myocardial Infarction (only 40 mg, 80 mg, and 160 mg tablets)
Treatment may be initiated in clinically stable patients as early as 12 hours after myocardial infarction. After an initial dose of Valmisar 20 mg (1/2 of a 40 mg tablet) twice daily, the dose should be increased to 40 mg, 80 mg, and then 160 mg twice daily over the following weeks.
The target maximum dose is 160 mg twice daily. Generally, it is recommended that the dosage level 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.
Valmisar can 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 must always have kidney function monitored.
Heart Failure (only 40 mg, 80 mg, and 160 mg tablets)
The recommended initial dose of Valmisar is 40 mg twice daily. Gradual dose escalation to 80 mg and then 160 mg twice daily should be performed at intervals of at least 2 weeks, up to the highest tolerated dose. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose used in clinical trials was 320 mg, divided into multiple doses.
Valsartan may be used in combination with other heart failure medications. However, triple combination of an ACE inhibitor, beta-blocker, and Valmisar is not recommended.
Patients with heart failure require monitoring of kidney function.
Use in Specific Patient Populations
Elderly Patients
Dose adjustment is not required in elderly patients.
Renal Impairment
No dose adjustment is required in adult patients with creatinine clearance > 10 mL/min. Concomitant use of Valmisar 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 Valmisar with aliskiren in patients with diabetes mellitus is contraindicated.
Hepatic Impairment
Valsartan 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 Valmisar should not exceed 80 mg.
Children
Valmisar is used for the treatment of arterial hypertension in children aged 6 to 18 years. Safety and efficacy of Valmisar in children aged 1 to 6 years have not been established. The drug is not recommended for the treatment of heart failure or post-infarction state in children due to lack of data on safety and efficacy.
Arterial Hypertension in Children
Children and Adolescents Aged 6 to 18 Years
The initial dose is 40 mg once daily for children with body weight below 35 kg and 80 mg once daily for children with body weight of 35 kg or more. Dose should be adjusted according to blood pressure response. Maximum doses studied in clinical trials are listed in Table 1.
Doses higher than those specified have not been studied and therefore are not recommended.
Table 1
| Body weight |
Maximum dose of Valmisar |
||
| From ≥ 18 kg to < 35 kg |
80 mg |
||
| From ≥ 35 kg to < 80 kg |
160 mg |
||
| From ≥ 80 kg to ≤ 160 kg |
320 mg |
Children under 6 years of age
The safety and efficacy of Valsartan in children aged 1 to 6 years have not been established.
Use in children aged 6 to 18 years with renal impairment
Use in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, Valsartan is not recommended 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 closely monitored.
Use in children aged 6 to 18 years with hepatic impairment
As in adults, Valsartan is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis. Clinical experience with the use of Valsartan in children with mild to moderate hepatic impairment is limited. The dose of the drug should not exceed 80 mg in such patients.
Heart failure and recent myocardial infarction in children
Valsartan is not recommended for the treatment of heart failure or recent myocardial infarction in children due to lack of data on safety and efficacy.
Children.
The medicinal product can be used in children as specified in the sections "Indications" and "Dosage and administration".
Overdose.
Marked arterial hypotension may develop following overdose, which may lead to depressed consciousness, vascular collapse, and/or shock. Therapeutic measures depend on the time of ingestion and the type and severity of symptoms; primary importance is given to stabilization of circulation. In case of arterial hypotension, the patient should be placed in a supine position, and blood volume should be corrected.
It is unlikely that Valsartan can be removed from the body by hemodialysis.
Adverse reactions
Arterial hypertension/heart failure/myocardial infarction
During controlled clinical trials in adult patients with arterial hypertension, the incidence of adverse reactions was similar between the placebo and valsartan groups. The occurrence 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 identified during clinical, post-marketing, and laboratory studies are listed below by system organ class.
With regard to adverse reactions categorized as "very rare", "rare", and "uncommon" that were not detected during clinical trials, a cumulative search was conducted in the safety database.
The frequency of adverse reactions is defined as follows: very common (> 1/10),
common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000),
very rare (< 1/100000), including isolated case reports. Within each frequency group, adverse reactions are listed in order of decreasing 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, thoracic and mediastinal disorders |
||||||
| Uncommon |
Cough |
|||||
| Gastrointestinal disorders |
||||||
| Uncommon |
Diarrhea, abdominal pain |
|||||
| Very rare |
Nausea##, vomiting |
|||||
| Hepatobiliary disorders |
||||||
| Not known |
Elevated liver function parameters, including increased serum bilirubin levels |
|||||
| Skin and subcutaneous tissue disorders |
||||||
| Very rare |
Angioedema**, rash, pruritus, exanthema |
|||||
| Not known |
Bullous dermatitis |
|||||
| Musculoskeletal and connective tissue disorders |
||||||
| Uncommon |
Back pain |
|||||
| Very rare |
Arthralgia, myalgia |
|||||
| Renal and urinary disorders |
||||||
| Very rare |
Renal failure**##, acute renal failure**, renal dysfunction** |
|||||
| Pregnancy and perinatal conditions |
||||||
| Very rare |
Fetal developmental complications |
|||||
| General disorders |
||||||
| Uncommon |
Malaise, asthenia, edema |
|||||
| Investigations |
||||||
| Common |
Elevated serum creatinine, elevated blood urea |
|||||
| Very rare |
Elevated serum bilirubin, decreased hemoglobin/hematocrit levels, liver function parameters outside normal range. |
|||||
* reported by patients in the post-infarction period
reported by patients with heart failure
** infrequently reported by patients in the post-infarction period
reported more frequently by patients with heart failure (frequent: dizziness, renal function disorders, hypotension; infrequent: headache, nausea)
Laboratory findings
In isolated cases, valsartan caused a reduction in hemoglobin levels and hematocrit count. In controlled clinical trials, significant decreases (> 20%) in hematocrit count and hemoglobin levels were observed in 0.8% and 0.4% of patients receiving valsartan, respectively. In comparison, decreases in both parameters – hematocrit count and hemoglobin levels – were noted in 0.1% of patients receiving placebo.
In controlled clinical trials, neutropenia was observed in 1.9% of patients treated with valsartan, compared to 1.6% of patients treated with an ACE inhibitor.
In controlled clinical trials involving patients with arterial hypertension, significant increases in serum creatinine, serum 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.
Patients with arterial hypertension receiving valsartan therapy do not require any specific laboratory monitoring.
In cases of heart failure, serum creatinine levels increased by more than 50% in 3.9% of patients taking valsartan, compared to 0.9% of patients taking placebo, and serum potassium levels increased by more than 20% in 10% of patients taking valsartan, compared to 5.1% of patients taking placebo.
In heart failure studies, increased blood urea nitrogen levels were observed in 16.6% of patients taking valsartan, compared to 6.3% of patients taking placebo.
Serum creatinine levels doubled in 4.2% of patients receiving valsartan, 4.8% of patients treated with a combination of valsartan and captopril, and 3.4% of patients treated with captopril during the post-infarction period.
The number of cases of drug discontinuation due to adverse reactions was lower in the valsartan-treated group compared to the captopril group (5.8% vs. 7.7%, respectively).
Children
Arterial hypertension
The antihypertensive effect of valsartan was evaluated in two randomized, double-blind clinical trials involving 561 children aged 6 to 18 years. Except for isolated gastrointestinal disorders (such as abdominal pain, nausea, vomiting) and dizziness, no significant differences in type, frequency, or severity of adverse reactions were identified between the safety profile in children aged 6 to 18 years and the previously established safety profile in adult patients.
Neurocognitive assessment and developmental evaluation in children aged 6 to 16 years did not reveal any clinically significant overall negative consequences after treatment with valsartan for up to 1 year.
In a double-blind, randomized study involving 90 children aged 1 to 6 years, followed by an open-label study lasting 1 year, two fatal cases and isolated cases of marked elevation of hepatic transaminases were recorded. These cases occurred in a population with significant comorbidities. A causal relationship with valsartan was not established. In a second study involving 75 children aged 1 to 6 years, no significant elevations in hepatic transaminases or fatal cases were observed during treatment with valsartan.
Hyperkalemia was more frequently observed in children aged 6 to 18 years with underlying chronic kidney disease.
The safety profile observed in controlled clinical trials in adult patients after myocardial infarction and/or with heart failure differs from the general safety profile observed in patients with arterial hypertension. This may be related to underlying disease conditions. 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 at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging.
10 tablets per blister, 1 or 3 blisters per cardboard box.
Prescription category. By prescription only.
Manufacturer.
MACLEODS PHARMACEUTICALS LIMITED.
Manufacturer's address and location of operations.
Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.