INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VALSARTAN

Composition:

Active substance: valsartan;

1 tablet contains 40 mg of valsartan;

Excipients: mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, magnesium stearate, Opadry Yellow 02F52181;

1 tablet contains 80 mg of valsartan;

Excipients: mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, magnesium stearate, Opadry Pink 02F54189;

1 tablet contains 160 mg of valsartan;

Excipients: mannitol, microcrystine cellulose, povidone, sodium croscarmellose, magnesium stearate, Opadry Yellow 02F52182;

1 tablet contains 320 mg of valsartan;

Excipients: mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, magnesium stearate, Opadry Purple 02F50107.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Valsartan 40: yellow, capsule-shaped, biconvex, film-coated tablets with a break line on one side, engraved with "18" on one side of the line and "2" on the other side, and "N" on the reverse side of the tablet;

Valsartan 80: pink, round, biconvex, film-coated tablets, engraved with "183" on one side and "N" on the other side;

Valsartan 160: yellowish-brown, oval, biconvex, film-coated tablets, engraved with "184" on one side and "N" on the other side;

Valsartan 320: dark grey-purple, capsule-shaped, biconvex, film-coated tablets, engraved with "185" on one side and "N" on the other side.

Pharmacotherapeutic group. Simple angiotensin II antagonists.

ATC Code: C09CA03.

Pharmacological Properties

Pharmacodynamics

Valsartan is an orally active, specific antagonist of angiotensin II receptors. It acts selectively on AT1 subtype receptors, which mediate the known effects of angiotensin II. Elevated 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, but has much 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 leads to 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 lasts more than 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 is not associated with a withdrawal syndrome.

Long-term administration of the drug to patients with arterial hypertension has shown no clinically significant effect on total cholesterol, uric acid levels, or, in fasting studies, on serum triglyceride and glucose concentrations.

Administration of the drug reduces hospitalization due to heart failure, slows progression of heart failure, improves functional class according to NYHA classification, increases ejection fraction, and alleviates symptoms of heart failure and improves quality of life compared to placebo.

The VALIANT study demonstrated that valsartan, like captopril, is effective 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 from acute myocardial infarction to the first occurrence of cardiovascular events leading to fatal outcomes.

Children

The antihypertensive effect of valsartan was evaluated in 4 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 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, maximum plasma concentrations of valsartan are reached within 2–4 hours with tablets and within 1–2 hours with solution. The mean absolute bioavailability is 23% for tablets and 39% for solution. Food reduces exposure (as measured by AUC) by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%. However, plasma concentrations of valsartan from about 8 hours after dosing 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.

Biotransformation

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.

Excretion

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 into 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 (40 mg, 80 mg, and 160 mg tablets)

The mean time to reach Cmax and 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. 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. Systemic exposure to valsartan was somewhat higher in some elderly patients compared to younger individuals, 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, dose adjustment is not required in patients with impaired renal function (creatinine clearance > 10 mL/min). There are currently 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 impairment. Therefore, dose adjustment 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, AUC of valsartan has been shown to increase 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 drug.

Patients with renal impairment

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 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

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

Post-myocardial infarction

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

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

Contraindications.

• Hypersensitivity to valsartan or to any excipient.
• Pregnancy or planned pregnancy (see "Use in pregnancy or breastfeeding").
• Hereditary or ACE inhibitor- or angiotensin II receptor antagonist-induced angioedema.
• Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or II) or impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
• Lack of data 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 ARBs, ACE inhibitors, or aliskiren

Concomitant use of ARBs, including valsartan, with other drugs acting on the RAAS is associated with an increased incidence of arterial hypotension, syncope, hyperkalemia, and renal function changes (including acute renal failure) compared to monotherapy. Thus, 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 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 impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.

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

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

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of ACE inhibitors. Due to 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 advised.

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

Caution required during 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 result in reduced antihypertensive effect. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs increases 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 of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of these findings is unknown. Concomitant use of inhibitors of 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 or discontinuation of concomitant use of these medicinal products.

Other

During drug interaction studies with valsartan, no clinically significant interactions were observed between valsartan and any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.

Children

Caution is recommended when administering valsartan concomitantly with other substances that inhibit the renin-angiotensin-aldosterone system in children 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 co-administration is necessary, potassium levels should be monitored.

Patients with sodium and/or circulating blood volume deficiency. In patients with severe sodium and/or circulating blood volume (CBV) deficiency, such as those receiving high doses of diuretics, symptomatic arterial hypotension may occur in individual cases after initiation of Valsartan therapy. Prior to starting Valsartan therapy, correction of sodium and/or CBV deficiency should be performed, for example, by reducing the diuretic dose.

Renal artery stenosis. The safety of Valsartan use in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney has not been established. Short-term use of Valsartan in 12 patients with renovascular hypertension secondary to unilateral renal artery sten游戏副本

Method of Administration and Dosage

Method of Administration

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

Dosage

Arterial Hypertension in Adults

The recommended initial dose of Valsartan 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.

Valsartan 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 twice daily, the dose should be increased to 40 mg, 80 mg, and then 160 mg twice daily over the following weeks. The initial dose should be administered in the form of a 40 mg tablet, which can be divided into equal halves.

The maximum dose is 160 mg twice daily. It is generally recommended that the dose level of 80 mg twice daily be reached within 2 weeks after initiation of 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 medications following myocardial infarction, 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

The recommended initial dose of Valsartan is 40 mg twice daily. Gradual dose escalation to 80 mg and then to 160 mg twice daily should be performed at intervals of at least 2 weeks, up to the highest dose tolerated by the patient. 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, a beta-blocker, and valsartan 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

Adult patients with creatinine clearance > 10 ml/min do not require dose adjustment.

Concomitant use of valsartan 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 valsartan 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 valsartan should not exceed 80 mg.

Children

Valsartan is indicated for the treatment of arterial hypertension in children aged 6 to 18 years. Safety and efficacy of valsartan 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 Aged 6 Years and Older

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 ≥ 35 kg. Dose adjustments should be based on blood pressure response. Maximum doses studied in clinical trials are shown in Table 1.

Doses higher than those listed have not been studied and therefore should not be recommended.

Table 1

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 years and older 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 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 years and older with hepatic impairment

As in adults, Valsartan is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and cholestasis. Clinical experience with the use of Valsartan 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

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.

Overdose.

Following an overdose of Valsartan, marked hypotension may develop, which could lead to impaired 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. If 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

During controlled clinical studies in adult patients with arterial hypertension, the incidence of adverse reactions was similar between those receiving placebo and those receiving valsartan. The incidence of adverse reactions was found to be unrelated to dose or duration of treatment. No association with patient sex, age, or race has been demonstrated.

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 for which the frequency cannot be estimated from the available data are listed as "not known."

Table 2

* reported by patients in post-infarction condition

reported by patients with heart failure

** infrequently reported by patients in post-infarction condition

reported more frequently by patients with heart failure (common: dizziness, renal impairment, hypotension; uncommon: headache, nausea).

Laboratory test results

In isolated cases, valsartan caused a decrease in hemoglobin levels and hematocrit count.

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 increased 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.

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.

Elevated serum creatinine levels (doubled) were observed 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 group treated with valsartan compared to the group receiving captopril (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 (e.g., 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 years and older and the previously established safety profile in adult patients.

Neurocognitive assessment and evaluation of development 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.

Hyperkalemia was observed 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 disease. 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 in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. Film-coated tablets, 40 mg, 80 mg, 160 mg, 320 mg: 10 tablets per blister in a cardboard box; 30 tablets in a container in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of business activity.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.