Valsakor^®-inda (Tablets) Instructions for Use

ATC Code

C09DA03 (Valsartan and diuretics)

Active Substances

Valsartan (Rec.INN registered by WHO)

Indapamide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combined antihypertensive drug. Angiotensin II receptor antagonist + diuretic

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists (ARBs), combinations; angiotensin II receptor antagonists and diuretics

Pharmacological Action

A combined antihypertensive drug containing an angiotensin II receptor blocker and a thiazide-like diuretic.

Valsartan is an active, specific angiotensin II receptor blocker. It selectively blocks the AT₁ receptor subtype, which is responsible for the vasopressor effect of angiotensin II. The increase in serum angiotensin II concentration due to valsartan blockade of AT₁ receptors may lead to stimulation of unblocked AT₂ receptors, which counterbalances the vasopressor effects associated with AT₁ receptor stimulation.

Valsartan does not have any significant agonistic activity at the AT₁ receptors. The affinity of valsartan for the AT₁ receptor subtype is approximately 20,000 times higher than for the AT₂ receptor subtype.

Since Valsartan does not inhibit ACE, which converts angiotensin I to angiotensin II and causes the breakdown of bradykinin, the development of side effects associated with the accumulation of bradykinin is unlikely.

Valsartan does not interact with or block receptors of other hormones or ion channels that are important for the regulation of cardiovascular function.

Indapamide is a sulfonamide derivative. Its pharmacological properties are similar to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to an increase in the renal excretion of sodium and chloride ions, and to a lesser extent potassium and magnesium ions, thereby enhancing diuresis and reducing blood pressure.

Pharmacokinetics

Valsartan is rapidly absorbed after oral administration, with C_max in plasma reached within 2-4 hours. The average absolute bioavailability of valsartan is 23%. Concurrent food intake reduces AUC by 40%, although from about 8 hours after valsartan intake, its plasma concentration is the same whether taken on an empty stomach or with food. The reduction in AUC, however, is not accompanied by a clinically significant decrease in therapeutic effect, so Valsartan can be taken regardless of meal time. Valsartan is largely bound to plasma proteins (94-97%), mainly albumin. It does not undergo significant metabolism (about 20% of the administered dose is determined as metabolites). Low concentrations of a hydroxyl metabolite (less than 10% of the valsartan AUC) have been detected in plasma. This metabolite is pharmacologically inactive. Elimination is biphasic: an α-phase with T_1/2α of less than 1 hour and a β-phase with T_1/2β of about 9 hours. Valsartan is excreted mainly unchanged in the bile via the intestine (about 83%) and by the kidneys (about 13%).

Indapamide after oral administration is rapidly and completely absorbed from the gastrointestinal tract, C_max in plasma is reached within 1-2 hours. Plasma protein binding is 79%. It is widely distributed in the body. Does not accumulate.

T_1/2 is 18 hours. It is excreted by the kidneys mainly as metabolites, 5% unchanged.

Indications

Essential arterial hypertension (when simultaneous therapy with valsartan and indapamide in doses used as monotherapy with individual components is necessary to achieve adequate control).

ICD codes

Dosage Regimen

Tablets

Before starting therapy, it is necessary to correct water and electrolyte imbalances.

It is recommended to select the dose of the combination based on the individual antihypertensive effect. To reduce the risk of a sharp decrease in blood pressure and the manifestation of other adverse events, it is recommended to gradually increase the dose of the combination at each stage of dose selection.

In cases where it is acceptable, in patients with inadequate blood pressure control during monotherapy with valsartan or indapamide, a switch to a fixed-dose combination of the active components may be possible, preceded by a dose titration phase of valsartan and indapamide.

Take orally at a dose of 160 mg valsartan + 1.5 mg indapamide.

Treatment is carried out under regular medical supervision.

Adverse Reactions

Metabolism: uncommon – decreased blood volume.

Nervous system: common – headache; uncommon – paresthesia; very rare – dizziness; frequency unknown – syncope.

Vision: uncommon – decreased visual acuity.

Hearing and vestibular system: uncommon – tinnitus.

Cardiovascular system: uncommon – pronounced decrease in blood pressure, peripheral edema.

Respiratory system: uncommon – cough; frequency unknown – non-cardiogenic pulmonary edema.

Digestive system: uncommon – nausea; very rare – diarrhea.

Musculoskeletal system: uncommon – myalgia; very rare – arthralgia.

Urinary system: frequency unknown – renal function impairment.

General reactions: uncommon – increased fatigue.

Laboratory and instrumental data: frequency unknown – increased serum uric acid concentration, increased serum bilirubin, increased serum creatinine, hypokalemia, hyponatremia, increased serum urea nitrogen concentration, neutropenia.

Valsartan

Blood and lymphatic system: frequency unknown – decreased hemoglobin, decreased hematocrit, thrombocytopenia.

Immune system: frequency unknown – hypersensitivity/allergic reactions, including serum sickness.

Metabolism: frequency unknown – increased serum potassium, hyponatremia.

Hearing and labyrinth disorders: uncommon – vertigo.

Cardiovascular system: frequency unknown – vasculitis.

Digestive system: uncommon – abdominal pain.

Liver and biliary tract: frequency unknown – increased liver enzyme activity.

Skin and subcutaneous tissues: frequency unknown – angioedema, skin rash, pruritus, bullous dermatitis.

Urinary system: frequency unknown – renal failure.

Indapamide

Hematopoietic system: very rare – thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Nervous system: rare – dizziness, fatigue, headache, paresthesia.

Vision: frequency unknown – myopia, blurred vision, visual impairment.

Cardiovascular system: very rare – arrhythmia, arterial hypotension; frequency unknown – torsades de pointes type arrhythmia.

Digestive system: uncommon – vomiting; rare – nausea, constipation, dry mouth; very rare – pancreatitis.

Liver and biliary tract: very rare – liver function impairment; frequency unknown – development of hepatic encephalopathy in case of liver failure.

Skin and subcutaneous tissues: hypersensitivity reactions, mainly dermatological, in patients with a predisposition to allergic and asthmatic reactions. Common – maculopapular rash; uncommon – purpura; very rare – angioedema and/or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome; frequency unknown – in patients with acute systemic lupus erythematosus, exacerbation of the disease may occur, photosensitivity.

Urinary system: very rare – renal failure.

Laboratory parameters: very rare – hypercalcemia; frequency unknown – increased QT interval on ECG, hyperuricemia, increased blood uric acid and glucose concentrations, increased liver transaminase activity, decreased potassium levels with the development of hypokalemia (especially important for patients in high-risk groups), hyponatremia with hypovolemia (leading to dehydration and orthostatic hypotension), hypochloremia (may cause secondary metabolic alkalosis).

Contraindications

Hypersensitivity to valsartan, indapamide and other sulfonamide derivatives; severe liver diseases (including biliary cirrhosis, cholestasis, hepatic encephalopathy); severe renal impairment (GFR <30 ml/min/1.73 m²); anuria; refractory hypokalemia, concurrent use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m²); patients with renal impairment and diabetes mellitus taking an ACE inhibitor; pregnancy, breastfeeding period, children and adolescents under 18 years of age.

With caution

Concomitant use of the combination with potassium salts, potassium-sparing diuretics, potassium-sparing salt substitutes, as well as with drugs that can cause an increase in blood potassium levels (e.g., heparin).

Patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, in the presence of conditions accompanied by water and electrolyte disturbances: salt-losing nephropathy, and prerenal (cardiogenic) renal impairment, patients with hypokalemia, hypomagnesemia, hyponatremia, hypercalcemia.

Patients with marked sodium deficiency and/or reduced blood volume (e.g., during treatment with high doses of diuretics), with moderately severe liver dysfunction, CHF III-IV FC according to NYHA classification, mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy, systemic lupus erythematosus, primary hyperaldosteronism, diabetes mellitus, hyperuricemia, as well as in patients after kidney transplantation.

Caution is required when used in patients with angle-closure glaucoma.

Particular caution is necessary when used concomitantly in patients with hereditary angioedema, or angioedema during previous therapy with angiotensin II receptor blockers or ACE inhibitors.

Use with caution in debilitated patients, in chronic heart failure, in patients with prolonged QT interval or in patients receiving concomitant therapy with drugs that can prolong the QT interval.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated for use in severe liver diseases.

Use in Renal Impairment

Contraindicated for use in severe kidney diseases.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

When used concomitantly with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that can cause an increase in blood potassium levels (e.g., heparin), caution should be exercised and regular monitoring of blood potassium levels should be performed.

In patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, taking the combination may be accompanied by an increase in serum urea and creatinine concentrations, so this combination should be used with caution in such patients.

As with the use of other vasodilators, caution should be exercised when taking the combination in patients with aortic or mitral stenosis and obstructive hypertrophic cardiomyopathy.

In patients with renal impairment taking the combination, periodic monitoring of serum potassium, creatinine and uric acid concentrations is required.

In patients with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) liver dysfunction without concomitant cholestasis, the combination should be used with caution.

In patients whose renal function depends on the state of the RAAS (e.g., patients with chronic heart failure), therapy with ACE inhibitors and angiotensin II receptor blockers may be accompanied by oliguria and/or progressive azotemia, and in rare cases, acute renal failure. Examination of patients with circulatory insufficiency and patients who have had myocardial infarction should include an assessment of renal function.

Before conducting a parathyroid gland examination, it is necessary to discontinue the use of this combination.

During treatment with valsartan, there have been reports of the development of angioedema, accompanied by edema of the larynx and vocal cords, leading to airway obstruction, and/or edema of the face, lips, pharynx and/or tongue. Some of these patients had previously experienced angioedema while taking other drugs, including ACE inhibitors. If angioedema develops, the combination should be discontinued immediately; further use of the combination is contraindicated.

In case of liver dysfunction, thiazide and thiazide-like diuretics may lead to the development of hepatic encephalopathy. In this case, the use of diuretics must be stopped immediately.

Cases of photosensitivity reactions have been reported with the use of thiazide and thiazide-like diuretics. If photosensitivity reactions occur during therapy, it is necessary to immediately discontinue indapamide. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

The plasma sodium ion concentration must be determined before starting treatment and then this indicator must be regularly monitored. Hyponatremia and hypovolemia can lead to dehydration and orthostatic hypotension. A concomitant decrease in chloride ion concentration can lead to secondary metabolic alkalosis. For patients with liver cirrhosis and elderly patients, more frequent monitoring of plasma sodium ion concentration is indicated.

Long-term use of thiazide and thiazide-like diuretics poses a risk of decreased plasma potassium concentration and the development of hypokalemia. It is necessary to prevent the risk of developing hypokalemia (< 3.4 mmol/l), especially in elderly patients, debilitated patients or those receiving combined drug therapy, in patients with cirrhosis of the liver accompanied by edema and ascites, in patients with coronary artery disease and heart failure, since hypokalemia increases the likelihood of arrhythmia (hypokalemia in these patient groups enhances the toxic effect of cardiac glycosides). The risk of hypokalemia is also possible in patients with a prolonged QT interval. Hypokalemia predisposes to the occurrence of severe arrhythmias, especially the deadly polymorphic ventricular tachycardia of the ‘torsades de pointes’ type. It is necessary to regularly monitor plasma potassium levels in all the above cases.

Thiazide and thiazide-like diuretics can reduce the renal excretion of calcium ions, which can lead to a moderate and temporary increase in plasma calcium concentration.

It is necessary to regularly monitor plasma glucose concentration in patients with diabetes mellitus, especially in the presence of hypokalemia.

With increased uric acid concentration, gout attacks are possible; in such cases, the dose of indapamide should be adjusted accordingly.

Hypovolemia caused by the loss of fluid and sodium ions during treatment with diuretics can cause a decrease in glomerular filtration, which may result in an increase in plasma urea and creatinine concentrations.

Effect on the ability to drive vehicles and mechanisms

Since dizziness or fainting may occur during therapy with this combination, it should be used with caution in patients who drive vehicles and engage in other potentially hazardous activities.

Drug Interactions

Lithium preparations – when lithium preparations are used concomitantly with ACE inhibitors and angiotensin II receptor blockers or thiazide diuretics, a reversible increase in plasma lithium concentration and associated increased toxic manifestations have been observed. The risk of toxic manifestations associated with the use of lithium preparations may be further increased when used concomitantly with this combination, since the renal clearance of lithium preparations is reduced under the influence of thiazide diuretics. Concomitant use of the Valsartan + hydrochlorothiazide combination is contraindicated.

Antihypertensive drugs – an enhancement of the antihypertensive effect is possible when used concomitantly with other agents that lower blood pressure (ACE inhibitors, beta-blockers, slow calcium channel blockers, guanethidine, methyldopa, vasodilators, direct renin inhibitors, angiotensin II receptor blockers).

Pressor amines – a weakening of the effect of pressor amines (norepinephrine, epinephrine) is possible, which does not require discontinuation of concomitant use.

NSAIDs, including selective COX-2 inhibitors – may weaken the antihypertensive effect of both angiotensin II receptor antagonists and hydrochlorothiazide when taken concomitantly. Concomitant intake of the Valsartan + hydrochlorothiazide combination and NSAIDs may lead to impaired renal function and increased serum potassium levels. If concomitant use of this combination and NSAIDs is necessary, renal function should be assessed and water and electrolyte imbalances should be corrected before starting treatment.

Potassium-containing salt substitutes; other medicinal products that increase serum potassium levels (e.g., heparin) require precautionary measures (including frequent determination of blood potassium levels).

Medicinal products that can cause hypokalemia – the risk of hypokalemia caused by diuretics may be enhanced with the concomitant use of corticosteroids, laxatives, ACTH, amphotericin B, carbenoxolone, penicillin, acetylsalicylic acid or its derivatives, and antiarrhythmic drugs.

Dual blockade of the RAAS – during treatment with drugs affecting the RAAS, especially in combination, cases of marked decrease in blood pressure, syncope, stroke, hyperkalemia, and impaired renal function (including acute renal failure) have been reported in sensitive patients. Concomitant use of the Valsartan + hydrochlorothiazide combination is contraindicated.

Caution is required when combining angiotensin II receptor blockers, including Valsartan, with other drugs blocking the RAAS, such as ACE inhibitors or aliskiren. Concomitant use of angiotensin II receptor blockers, including Valsartan, or ACE inhibitors with aliskiren in patients with type 2 diabetes or impaired renal function (GFR < 60 ml/min/1.73 m²) is contraindicated.

When indapamide is used concomitantly with systemically applied corticosteroids, tetracosactide, the antihypertensive effect is reduced due to water and sodium ion retention under the influence of corticosteroids.

Concomitant use of indapamide with ACE inhibitors increases the risk of hyponatremia.

There is a risk of sudden arterial hypotension and/or acute renal failure when indapamide is combined with ACE inhibitors against a background of pre-existing reduced plasma sodium ion concentration (especially in patients with renal artery stenosis).

Concomitant use of indapamide with NSAIDs (for systemic use) may reduce the antihypertensive effect of indapamide. In case of significant fluid loss, acute renal failure may develop (due to a sharp decrease in glomerular filtration).

Concomitant use of indapamide with calcium preparations may lead to hypercalcemia due to reduced urinary excretion of calcium ions.

Concomitant use of indapamide with cardiac glycosides, corticosteroids increases the risk of hypokalemia.

Concomitant use of indapamide and agents that can cause hypokalemia (amphotericin B, gluco- and mineralocorticoids, tetracosactide, stimulant laxatives) increases the risk of hypokalemia.

Concomitant use of indapamide with tricyclic antidepressants (including imipramine) enhances the antihypertensive effect and increases the risk of orthostatic hypotension (additive effect).

Concomitant use of indapamide with astemizole, bepridil, erythromycin (IV), pentamidine , sultopride, terfenadine, vincamine, quinidine, disopyramide, amiodarone, bretylium tosilate, sotalol creates a risk of developing torsades de pointes arrhythmia.

Concomitant use with baclofen enhances the hypotensive effect.

Concomitant use of indapamide with halofantrine increases the likelihood of cardiac rhythm disturbances (including ventricular torsades de pointes arrhythmia).

Concomitant use of indapamide with lithium carbonate increases the risk of lithium toxicity due to decreased renal clearance.

Concomitant use of indapamide with metformin may lead to lactic acidosis, which is apparently associated with the development of functional renal failure caused by the action of diuretics (mainly “loop” diuretics).

Concomitant use of indapamide with cyclosporine may increase plasma creatinine levels, which is observed even with normal water and sodium ion levels.

Dehydration while taking diuretics increases the risk of acute renal failure, especially when using high doses of iodine-containing X-ray contrast agents. Fluid loss must be compensated before administration.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.