Valsartan + Hydrochlorothiazide (Tablets) Instructions for Use

ATC Code

C09DA03 (Valsartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Valsartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Angiotensin II receptor antagonist in combination with a 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 diuretic.

Angiotensin II is an active hormone of the RAAS and is formed from angiotensin I with the participation of ACE. Angiotensin II binds to specific receptors located on cell membranes in various tissues. It has a wide spectrum of physiological effects, including primarily both direct and indirect participation in the regulation of blood pressure. Being a potent vasoconstrictor, angiotensin II causes a direct pressor response. In addition, it stimulates aldosterone secretion and promotes sodium ion retention.

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. An 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 towards AT₁ receptors. The affinity of valsartan for the AT₁ receptor subtype is approximately 20,000 times higher than for the AT₂ 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 bradykinin accumulation is unlikely.

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

Hydrochlorothiazide is a thiazide diuretic. The site of action of thiazide diuretics is the distal convoluted renal tubules. When thiazide diuretics act on the highly sensitive receptors of the distal tubules of the renal cortex, the reabsorption of sodium (Na⁺) and chloride (Cl^–) ions is suppressed. The suppression of the Na⁺ and Cl^– co-transport system appears to occur due to competition for Cl^– ion binding sites in this system. As a result, the excretion of sodium and chloride ions increases approximately equally. As a result of the diuretic action, a decrease in circulating blood volume is observed, which leads to increased renin activity, aldosterone secretion, renal potassium excretion, and consequently, a decrease in serum potassium levels.

Pharmacokinetics

When used concomitantly with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by approximately 30%. Concurrent administration of hydrochlorothiazide, in turn, does not significantly affect the pharmacokinetics of valsartan. This noted interaction does not affect the efficacy of the combined use of valsartan and hydrochlorothiazide. In controlled clinical studies, a pronounced antihypertensive effect of this combination was identified, which exceeded the effect of each component individually, as well as the effect of placebo.

Indications

Arterial hypertension (for patients who require combination therapy).

ICD codes

Dosage Regimen

Tablets

Before starting therapy, water and electrolyte imbalances must be corrected.

The dose of the combination should be selected based on the individual antihypertensive effect. To reduce the risk of a sharp decrease in blood pressure and the manifestation of other undesirable phenomena, 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 on valsartan or hydrochlorothiazide monotherapy, a switch to a fixed-dose combination of the active components may be possible, preceded by a dose titration phase of valsartan and hydrochlorothiazide.

The initial dose is 80 mg valsartan + 12.5 mg hydrochlorothiazide once daily. If the effect is insufficient, the combination of 160 mg valsartan + 12.5 mg hydrochlorothiazide can be used. In the absence of adequate blood pressure control, the dose of the combination can be gradually increased. The maximum daily dose is 320 mg valsartan + 12.5 mg hydrochlorothiazide or 320 mg valsartan + 25 mg hydrochlorothiazide.

Maximum blood pressure reduction is usually achieved within 2-4 weeks of therapy. However, some patients may require 4 to 8 weeks of treatment to achieve adequate blood pressure control. This should be taken into account during the dose titration period.

Adverse Reactions

Definition of frequency criteria for adverse effects: very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%), frequency unknown (frequency cannot be established from available data).

Metabolism and nutrition disorders: uncommon – decreased circulating blood volume.

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

Eye disorders: uncommon – decreased visual acuity.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac and vascular disorders: uncommon – pronounced decrease in blood pressure, peripheral edema.

Respiratory, thoracic and mediastinal disorders: uncommon – cough; frequency unknown – non-cardiogenic pulmonary edema.

Gastrointestinal disorders: uncommon – nausea; very rare – diarrhea.

Musculoskeletal and connective tissue disorders: uncommon – myalgia; very rare – arthralgia.

Renal and urinary disorders: frequency unknown – renal function impairment.

General disorders and administration site conditions: uncommon – increased fatigue.

Investigations: frequency unknown – increased serum uric acid concentration, increased serum bilirubin, increased serum creatinine, hypokalemia, hyponatremia, increased blood urea nitrogen concentration, neutropenia.

Adverse effects associated with the intake of each component of the combination

Valsartan

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

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

Metabolism and nutrition disorders: frequency unknown – increased serum potassium, hyponatremia.

Ear and labyrinth disorders: uncommon – vertigo.

Cardiac and vascular disorders: frequency unknown – vasculitis.

Gastrointestinal disorders: uncommon – abdominal pain.

Hepatobiliary disorders: frequency unknown – increased liver enzyme activity.

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

Renal and urinary disorders: frequency unknown – renal failure.

Hydrochlorothiazide

Metabolism and nutrition disorders: very common – increased plasma lipid concentrations (especially with high doses of hydrochlorothiazide); common – hypomagnesemia and hyperuricemia; rare – hypercalcemia, hyperglycemia, glucosuria and worsening of diabetes mellitus; very rare – hypochloremic alkalosis.

Blood and lymphatic system disorders: rare – thrombocytopenia, sometimes in combination with purpura; very rare – agranulocytosis, bone marrow depression, hemolytic anemia, leukopenia; frequency unknown – aplastic anemia.

Immune system disorders: very rare – hypersensitivity reactions.

Psychiatric disorders: rare – sleep disorders, depression.

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

Cardiac and vascular disorders: common – orthostatic hypotension (may be enhanced by alcohol, sedatives, or analgesics).

Heart disorders: rare – arrhythmias.

Respiratory, thoracic and mediastinal disorders: very rare – respiratory distress syndrome, including pulmonary edema and pneumonitis.

Gastrointestinal disorders: common – decreased appetite, mild nausea, vomiting; rare – abdominal discomfort, constipation, diarrhea; very rare – pancreatitis.

Hepatobiliary disorders: rare – intrahepatic cholestasis or jaundice.

Skin and subcutaneous tissue disorders: common – urticaria and other types of skin rash; rare – photosensitivity; very rare – necrotizing vasculitis and toxic epidermal necrolysis, lupus-like reactions, exacerbation of skin manifestations of systemic lupus erythematosus; frequency unknown – erythema multiforme.

Reproductive system and breast disorders: common – impotence.

Eye disorders: rare – visual impairment (especially in the first few weeks of treatment); frequency unknown – acute attack of angle-closure glaucoma.

Renal and urinary disorders: frequency unknown – acute renal failure, renal function impairment.

Musculoskeletal and connective tissue disorders: frequency unknown – muscle spasms.

General disorders and administration site conditions: frequency unknown – hyperthermia, asthenia.

Contraindications

Hypersensitivity to valsartan, hydrochlorothiazide, and other sulfonamide derivatives; severe liver dysfunction (more than 9 points on the Child-Pugh scale); biliary cirrhosis; cholestasis; severe renal impairment (GFR <30 ml/min/1.73 m²); anuria; refractory hypokalemia, hyponatremia, hypercalcemia; symptomatic hyperuricemia; simultaneous 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); pregnancy and planning pregnancy; lactation period (breastfeeding); children under 18 years of age (efficacy and safety of the drug use in this category of patients have not been established to date).

With caution

Simultaneous 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 imbalances: salt-losing nephropathy, and prerenal (cardiogenic) renal dysfunction, patients with hypokalemia, hypomagnesemia, hyponatremia, hypercalcemia.

Patients with severe sodium deficiency and/or reduced circulating 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, hypercholesterolemia and hypertriglyceridemia, in patients with angle-closure glaucoma, as well as in patients after kidney transplantation.

Particular caution is required when using the drug concomitantly in patients with hereditary angioedema, or angioedema during previous therapy with angiotensin II receptor blockers or ACE inhibitors.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindication — biliary cirrhosis.

Use in Renal Impairment

Contraindication — chronic renal failure (creatinine clearance less than 30 ml/min).

With caution renal artery stenosis (single or bilateral).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Changes in serum electrolyte levels

Valsartan. 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.

Hydrochlorothiazide. Thiazide diuretics, due to their ability to reduce serum potassium and magnesium levels, should be used with caution in patients with conditions accompanied by electrolyte imbalances: salt-losing nephropathy and prerenal (cardiogenic) renal dysfunction. If clinical manifestations of hypokalemia occur (muscle weakness, paresis, changes in ECG parameters), treatment with this combination should be discontinued. Before starting the combination, hypokalemia and hypomagnesemia must be corrected. All patients taking drugs containing thiazide diuretics require regular monitoring of plasma electrolyte levels, especially potassium.

When using the combination, the ability of thiazide diuretics to cause hyponatremia and hypochloremic alkalosis, as well as to exacerbate existing hyponatremia, should be taken into account. Hyponatremia in these cases is rarely accompanied by neurological symptoms. Regular monitoring of plasma sodium levels is necessary.

Sodium deficiency and/or reduced circulating blood volume. In patients receiving thiazide diuretics, including Hydrochlorothiazide, it is necessary to monitor for the appearance of clinical symptoms of sodium deficiency and/or reduced circulating blood volume. In patients with severe sodium deficiency and/or reduced circulating blood volume, for example, those receiving high doses of diuretics, in rare cases, a pronounced decrease in blood pressure accompanied by clinical manifestations may develop after starting therapy with the combination. Before starting treatment with the combination, sodium levels must be corrected and/or circulating blood volume replenished; otherwise, treatment must be started under strict medical supervision.

Renal artery stenosis

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.

Aortic and mitral stenosis, obstructive hypertrophic cardiomyopathy

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

Renal impairment

For patients with mild or moderate renal impairment (GFR>30 ml/min/1.73 m²), no dose adjustment of the drug is required. In patients with renal impairment taking the combination, periodic monitoring of serum potassium, creatinine, and uric acid levels is required.

Hepatic impairment

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

Chronic heart failure III-IV FC (according to NYHA classification), including after myocardial infarction

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 failure and patients who have had a myocardial infarction should include an assessment of renal function.

Systemic lupus erythematosus

There are reports of exacerbation and worsening of connective tissue diseases (e.g., systemic lupus erythematosus) with the use of thiazide diuretics, including Hydrochlorothiazide.

Other metabolic disorders

Thiazide diuretics, including Hydrochlorothiazide, can cause changes in glucose tolerance, as well as an increase in serum cholesterol, triglyceride, and uric acid concentrations. In patients with diabetes mellitus, dose adjustment of hypoglycemic agents may be required.

Decreased uric acid clearance can lead to hyperuricemia and the development of gout in predisposed patients.

Thiazide diuretics reduce the renal excretion of calcium and can cause a slight increase in plasma calcium levels in the absence of concomitant calcium metabolism disorders. Marked hypercalcemia during therapy with a thiazide diuretic (>12 mg/dl) or hypercalcemia that does not respond to drug withdrawal may indicate the presence of a concomitant calcium metabolism disorder. In several patients with hypercalcemia and hypophosphatemia during long-term use of thiazide diuretics, pathological changes in the parathyroid glands were determined.

Before examining the parathyroid glands, it is necessary to discontinue thiazide diuretics.

Hypersensitivity reactions

The occurrence of hypersensitivity reactions during the use of hydrochlorothiazide was most often noted in patients with a history of allergic reactions and bronchial asthma.

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 patients in this group 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.

Photosensitivity Reactions

Photosensitivity reactions have been reported with the use of thiazide diuretics. If photosensitivity reactions occur, it is recommended to discontinue the combination. If it is necessary to resume the diuretic, exposure to UV radiation should be avoided.

Acute Angle-Closure Glaucoma Attack

Cases of transient myopia and acute angle-closure glaucoma have been reported with the use of hydrochlorothiazide. A history of allergic reactions to sulfonamide and penicillin may be a risk factor for the acute development of angle-closure glaucoma. Symptoms: sudden onset, acute vision decrease or eye pain, usually occurring within hours to a week after starting therapy. Untreated angle-closure glaucoma can lead to permanent vision loss. The first step is to discontinue hydrochlorothiazide. Additional medical or surgical treatment may be required if intraocular pressure does not decrease after drug withdrawal.

Doping Control Results

Hydrochlorothiazide may yield a positive result in doping control.

Effect on Ability to Drive and Operate Machinery

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

Drug Interactions

Lithium preparations – reversible increases in serum lithium concentrations and related increased toxicity have been reported with concomitant use of lithium with ACE inhibitors and angiotensin II receptor blockers or thiazide diuretics. The risk of lithium toxicity may be further increased with concomitant use of this combination, as the renal clearance of lithium is decreased by thiazide diuretics. Concomitant use of the Valsartan + Hydrochlorothiazide combination is contraindicated.

Antihypertensive drugs – the antihypertensive effect may be enhanced when used concomitantly with other blood pressure-lowering agents (ACE inhibitors, beta-blockers, slow calcium channel blockers, guanethidine, methyldopa, vasodilators, direct renin inhibitors, angiotensin II receptor blockers).

Pressor amines – the effect of pressor amines (norepinephrine, epinephrine) may be attenuated, which does not require discontinuation of concomitant use.

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

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

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

Dual blockade of the RAAS – treatment with drugs affecting the RAAS, especially in combination, has been reported to cause significant decreases in blood pressure, syncope, stroke, hyperkalemia, and impaired renal function (including acute renal failure) in susceptible 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 is contraindicated in patients with type 2 diabetes or impaired renal function (GFR < 60 ml/min/1.73 m²).

Transporter proteins – based on in vitro studies on hepatocyte cultures, Valsartan is a substrate for the transporter proteins OATP1B1 and MRP2. Concomitant administration of valsartan with inhibitors of the OATP1B1 transporter protein (rifampicin, cyclosporine) and with an inhibitor of the MRP2 transporter protein (ritonavir) may increase the systemic exposure to valsartan (C_max and AUC). Concomitant use is contraindicated.

Curare-like muscle relaxants – thiazide diuretics, including Hydrochlorothiazide, potentiate the effect of non-depolarizing muscle relaxants. Concomitant use is contraindicated.

Medicinal products affecting blood sodium levels – the hyponatremic effect caused by diuretics may be enhanced with concomitant use of antidepressants, antipsychotic anticonvulsants (carbamazepine). Caution should be exercised with long-term co-administration of hydrochlorothiazide with the aforementioned drugs.

Medicinal products that can provoke polymorphic ventricular tachycardia of the ‘torsades de pointes’ type – Class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide); Class III antiarrhythmics (amiodarone, dofetilide, ibutilide), sotalol; some antipsychotics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol); other drugs (bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vincamine). Due to the risk of hypokalemia, Hydrochlorothiazide should be used with caution concomitantly with drugs that can cause polymorphic ventricular tachycardia of the ‘torsades de pointes’ type.

Hypoglycemic agents – thiazide diuretics may alter glucose tolerance, which may require adjustment of insulin and oral hypoglycemic agent doses. Metformin should be used with caution due to the risk of lactic acidosis caused by possible renal function impairments associated with hydrochlorothiazide intake.

Beta-blockers and diazoxide – concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including Hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide.

Antigout drugs (probenecid, sulfinpyrazone and allopurinol) – dose adjustment of uricosuric agents (probenecid or sulfinpyrazone) may be required, as Hydrochlorothiazide may increase serum uric acid levels. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.

Cardiac glycosides – hypokalemia and hypomagnesemia (adverse effects of thiazide diuretics) may contribute to the development of cardiac arrhythmias in patients receiving cardiac glycosides.

N- and m-cholinoblockers (including atropine, biperiden) may increase the bioavailability of hydrochlorothiazide, which is associated with decreased gastrointestinal motility and gastric emptying rate. Accordingly, gastrointestinal motility stimulants (cisapride) may reduce the bioavailability of hydrochlorothiazide.

Cholestyramine and colestipol may impair the absorption of concomitantly administered drugs. The interval between administrations should be 4-6 hours.

Vitamin D and calcium salts – concomitant use of hydrochlorothiazide with vitamin D or calcium preparations may lead to hypercalcemia due to enhanced calcium reabsorption.

Cyclosporine – concomitant use of hydrochlorothiazide and cyclosporine increases the risk of hyperuricemia and exacerbation of gout.

Methyldopa – cases of hemolytic anemia have been reported with concomitant administration of hydrochlorothiazide and methyldopa.

Concomitant administration of thiazide diuretics, including Hydrochlorothiazide, may lead to an increased risk of adverse effects of amantadine; reduced renal excretion of drugs with cytotoxic action (e.g., cyclophosphamide, methotrexate), and potentiation of their myelosuppressive effect.

Ethanol, barbiturates and narcotic drugs – concomitant use with hydrochlorothiazide may potentiate the development of orthostatic hypotension.

When using iodinated contrast agents in high doses against the background of reduced circulating blood volume due to diuretic use, there is an increased risk of acute renal failure.

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.