Valsar-n

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VALSAR-H (VALSAR-H)

Composition:

Active substances: valsartan, hydrochlorothiazide;

One film-coated tablet contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide or 160 mg of valsartan and 25 mg of hydrochlorothiazide;

Excipients: microcrystalline cellulose; lactose monohydrate; crospovidone; colloidal anhydrous silicon dioxide; hypromellose; sodium lauryl sulfate; talc; magnesium stearate; titanium dioxide (E 171); iron oxide red (E 172); iron oxide yellow (E 172); polyethylene glycol 8000 – only for tablets 80 mg/12.5 mg; polyethylene glycol 4000 and iron oxide black (E 172) – only for tablets 160 mg/25 mg.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 80 mg/12.5 mg: light orange-colored, oval, beveled-edged, biconvex tablets, film-coated, marked with "I" on one side and "61" on the other side;

Tablets 160 mg/25 mg: brown-orange colored, oval, beveled-edged, biconvex tablets, film-coated, marked with "I" on one side and "63" on the other side.

Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. Valsartan and diuretics. ATC code C09D A03.

Pharmacological Properties

Pharmacodynamics

The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, formed from angiotensin I by the action of angiotensin-converting enzyme (ACE). Angiotensin II binds to specific receptors located on cell membranes in various tissues. It exerts a broad spectrum of physiological effects, including direct and indirect involvement in the regulation of arterial blood pressure. As a potent vasoconstrictor, angiotensin II produces a direct pressor effect. In addition, it promotes sodium retention and stimulates aldosterone secretion.

Valsartan is an active and specific antagonist of angiotensin II receptors intended for oral administration. It selectively acts on AT1 subtype receptors, which mediate the effects of angiotensin II. Increased levels of angiotensin II due to blockade of AT1 receptors by valsartan may stimulate unoccupied AT2 receptors, thereby counterbalancing the effects mediated by AT1 receptors. Valsartan has no partial agonist activity at AT1 receptors and exhibits much greater affinity (approximately 20,000 times higher) for AT1 receptors than for AT2 receptors.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin.

No bradykinin-related adverse effects have been observed. In clinical studies comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who previously experienced dry cough during ACE inhibitor therapy, this adverse effect occurred in 19.5% of cases during treatment with valsartan and in 19% of cases during treatment with a thiazide diuretic, whereas cough was observed in 68.5% of cases in the group receiving ACE inhibitor therapy (P < 0.05).

In controlled clinical trials, the incidence of cough in patients receiving the combination of valsartan and hydrochlorothiazide was 2.9%.

Valsartan does not interact with or block receptors of other hormones or ion channels known to play an important role in cardiovascular function regulation.

Administration of the drug to patients with hypertension results in a reduction in arterial blood pressure without affecting pulse rate.

In most patients, following oral administration of a single dose, onset of antihypertensive activity occurs within 2 hours, and maximum reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, maximal therapeutic effect is usually achieved within 2–4 weeks and is maintained at this level during long-term therapy. Combination with hydrochlorothiazide provides more effective blood pressure reduction.

Discontinuation of valsartan does not lead to sudden elevation in arterial blood pressure (rebound syndrome) or other adverse effects.

Valsartan does not affect total cholesterol, triglycerides, serum glucose, or uric acid levels in patients with arterial hypertension.

The site of action of thiazide diuretics is the cortical segment of the distal convoluted renal tubules, where receptors highly sensitive to diuretics are located and where inhibition of Na+ and Cl- ion transport occurs. The mechanism of action of thiazides involves inhibition of the Na+-Cl- cotransporter, likely due to competition for Cl- transport sites. As a result, excretion of sodium and chloride ions increases to a similar extent. Due to the diuretic effect, circulating plasma volume decreases, leading to increased renin activity, aldosterone secretion, potassium excretion in urine, and consequently, reduced serum potassium concentration. The renin-aldosterone relationship is mediated by angiotensin II; therefore, administration of an angiotensin II receptor antagonist reduces potassium loss associated with thiazide diuretic use.

Pharmacokinetics

Valsartan. After oral administration, absorption of valsartan and hydrochlorothiazide occurs rapidly, although the extent of absorption varies widely. The mean absolute bioavailability of Valsar-N is 23% (range: 23 ± 7). The pharmacokinetic profile of valsartan is characterized by a multiphasic decline (t1/2 α <1 hour, t1/2 β ≈ 9 hours).

Within the studied dose range, valsartan kinetics are linear. No changes in kinetic parameters were observed with repeated administration. With once-daily dosing, accumulation is minimal. Plasma concentrations of the drug are similar in women and men. Valsartan is highly bound to plasma proteins (94–97%), primarily to albumin. The volume of distribution at steady state is low (approximately 17 L). Plasma clearance of valsartan (approximately 2 L/hour) is relatively slow compared to hepatic blood flow (approximately 30 L/hour). Approximately 70% of the orally administered dose is excreted in feces, and nearly 30% of valsartan is excreted in urine, predominantly in unchanged form.

When valsartan is administered with food, the area under the concentration-time curve (AUC) decreases by 48%, although from approximately 8 hours after administration, plasma concentrations are similar whether the drug is taken fasting or with food. This reduction in AUC is not associated with a clinically significant decrease in therapeutic effect.

Hydrochlorothiazide. Absorption of hydrochlorothiazide after oral administration occurs rapidly (time to maximum concentration [tmax] is approximately 2 hours). Pharmacokinetics during distribution and elimination phases are generally described by a biphasic decline; the terminal elimination half-life (t1/2) ranges from 6 to 15 hours. Within the therapeutic dose range, mean AUC increases proportionally with dose. Pharmacokinetics of hydrochlorothiazide do not change with repeated dosing; accumulation is minimal when administered once daily.

Absolute oral bioavailability of hydrochlorothiazide is approximately 70%. Elimination occurs via the kidneys: more than 95% of the dose is excreted unchanged, and approximately 4% as a hydrolysis product—2-amino-4-chloro-m-benzenedisulfonamide.

When hydrochlorothiazide is taken with food, both increases and decreases in systemic bioavailability have been observed compared to fasting conditions. However, the magnitude of these changes is minor and not clinically significant.

Valsartan/hydrochlorothiazide. When administered concomitantly with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by approximately 30%. Conversely, coadministration of hydrochlorothiazide does not significantly affect the pharmacokinetics of valsartan. However, this interaction does not impact the efficacy of the combined use of valsartan and hydrochlorothiazide. In controlled clinical trials, a clear antihypertensive effect of this combination was demonstrated, exceeding the effects of either component alone and placebo.

Pharmacokinetics in Specific Patient Populations

Elderly Patients

In some elderly patients, systemic exposure to valsartan is somewhat higher than in younger patients, but this difference is not clinically significant.

Some data suggest that systemic clearance of hydrochlorothiazide is lower in elderly individuals compared to healthy young volunteers.

Patients with Renal Impairment

Dose adjustment is not required in patients with creatinine clearance of 30–70 mL/min.

There are no data on the use of valsartan with hydrochlorothiazide in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients undergoing hemodialysis. Valsartan is highly protein-bound and is not removed by hemodialysis; hydrochlorothiazide, in contrast, is eliminated during hemodialysis.

In the presence of renal dysfunction, mean peak plasma levels and AUC of hydrochlorothiazide increase, while urinary excretion decreases. In patients with mild to moderate renal impairment, mean t1/2 is nearly doubled due to significantly reduced renal clearance.

Renal elimination of hydrochlorothiazide occurs via passive filtration and active secretion into the renal tubular lumen. Renal function plays a major role in the pharmacokinetics of hydrochlorothiazide, which is expected given that this drug is eliminated solely by the kidneys.

In patients with renal insufficiency, mean peak plasma levels and AUC of hydrochlorothiazide are elevated, and urinary excretion is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in AUC of hydrochlorothiazide is observed. In patients with severe renal impairment, an 8-fold increase in AUC is observed. Hydrochlorothiazide is contraindicated in patients with severe renal impairment.

Patients with Hepatic Impairment

Systemic exposure to valsartan is approximately 2-fold higher in patients with mild (n = 6) and moderate (n = 5) hepatic impairment compared to healthy volunteers.

There are no data on the use of valsartan in patients with severe hepatic impairment.

Liver disease does not significantly affect the pharmacokinetics of hydrochlorothiazide; therefore, dose reduction is not required.

Non-melanoma Skin Cancer (NMSC)

Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (with 1,430,833 controls) and 8,629 cases of squamous cell carcinoma (with 172,462 controls). High-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal cell and squamous cell carcinomas. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were matched with 63,067 population-based controls using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high-dose use (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily administration of a defined daily dose of 25 mg over a period exceeding 10 years.

Clinical characteristics.

Indications.

Essential arterial hypertension in patients whose blood pressure is not adequately controlled with monotherapy.

Contraindications.

• Hypersensitivity to any component of Valsar-N or to other sulfonamide derivatives.
• Severe impairment of liver function, liver cirrhosis, and cholestasis.
• Anuria.
• Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
• Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or type II) or renal impairment (eGFR <60 mL/min/1.73 m²).
• Pregnancy, planned pregnancy (see section "Use during pregnancy or breastfeeding").
• Hereditary angioedema or angioedema during previous treatment with ACE inhibitors or ARBs.

Interaction with other medicinal products and other forms of interaction.

Interactions associated with both valsartan and hydrochlorothiazide

Concomitant use not recommended

Lithium. Reversible increases in plasma lithium concentrations and symptoms of toxicity have been reported with concomitant use of ACE inhibitors and thiazides, including hydrochlorothiazide. Due to lack of experience with the combined use of valsartan and lithium, this combination is not recommended. If such combination therapy is necessary, careful monitoring of plasma lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Valsar-N may enhance the effect of other antihypertensive agents (e.g., guanethidine, methyldopa, vasodilators, ACE inhibitors, ARBs, β-blockers, calcium channel blockers, direct renin inhibitors, and dopamine reuptake inhibitors).

Pressor amines (e.g., noradrenaline, adrenaline)

A reduced response to pressor amines such as noradrenaline may occur, but not to an extent sufficient to preclude their use.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid >3 g/day, and nonselective NSAIDs

NSAIDs may reduce the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. Additionally, concomitant administration of Valsar-N and NSAIDs may lead to impaired renal function and increased plasma potassium levels. Therefore, monitoring of renal function at the beginning of treatment and adequate patient hydration are recommended.

In elderly patients, patients with reduced circulating blood volume (including those receiving diuretic therapy), or patients with impaired renal function, concomitant use of NSAIDs (or cyclooxygenase-2 (COX-2) inhibitors) with ARBs II increases the risk of renal impairment, including acute renal failure. Combined use of these drugs requires caution and monitoring of renal function.

Interactions associated with valsartan

Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren

Caution is required when ARBs, including valsartan, are used concomitantly with other medicinal products that block the RAAS, such as ACE inhibitors or aliskiren.

This is due to an increased incidence of hypotension, loss of consciousness, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy. Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin receptor blockers, or aliskiren is not recommended. If dual RAAS blockade is considered absolutely necessary, treatment should be conducted only under specialist supervision and accompanied by monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or type II), diabetic nephropathy, or renal impairment (eGFR <60 mL/min/1.73 m²) is contraindicated.

Concomitant use not recommended

Potassium-sparing diuretics, potassium-containing dietary supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels

If it is necessary to use a medicinal product that affects potassium levels in combination with valsartan, monitoring of plasma potassium levels is recommended.

Concomitant use of angiotensin II receptor antagonists with other medicinal products capable of increasing serum potassium levels (e.g., potassium-sparing diuretics, potassium-containing medicinal products, heparin) increases the risk of hyperkalemia. In such cases, Valsar-N containing valsartan should be used with caution and potassium levels should be monitored.

Transporters

In vitro data indicate that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these data has not been fully established. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may lead to increased systemic exposure to valsartan. Caution is recommended when initiating or discontinuing concomitant treatment with such medicinal products.

Absence of interaction

In drug interaction studies with valsartan, no clinically significant interactions were observed between valsartan and any of the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of Valsar-N (see "Interactions associated with hydrochlorothiazide" below).

Interactions associated with hydrochlorothiazide

Concomitant use requiring caution

MEDICINAL PRODUCTS ASSOCIATED WITH POTASSIUM LOSS AND HYPOKALEMIA
The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, and antiarrhythmic agents.

If it is necessary to prescribe these medicinal products together with the combination of hydrochlorothiazide and valsartan, monitoring of plasma potassium levels is recommended.

MEDICINAL PRODUCTS THAT MAY INDUCE TORSADES DE POINTES VENTRICULAR TACHYCARDIA
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution concomitantly with medicinal products that may induce torsades de pointes ventricular tachycardia, particularly class Ia and III antiarrhythmics, as well as certain antipsychotics.

MEDICINAL PRODUCTS AFFECTING SERUM SODIUM LEVELS
The hyponatremic effect of diuretics may be enhanced when taken concomitantly with antidepressants, antipsychotics, and antiepileptic drugs. Caution is recommended during prolonged use of these medicinal products.

MEDICINAL PRODUCTS THAT MAY CAUSE TORSADES DE POINTES (TWISTED TACHYCARDIA):

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide).
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide).
• Some neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sulthiame, amisulpride, tiapride, pimozide, haloperidol, droperidol).
• Others, e.g., bepridil, cisapride, difemanil, erythromycin (intravenous administration), halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, vinca alkaloids (intravenous administration).

Due to the risk of developing hypokalemia, hydrochlorothiazide should be used with caution concomitantly with medicinal products that may cause torsades de pointes.

Cardiac glycosides

Thiazide-induced hypokalemia or hypomagnesemia may occur as an adverse effect, predisposing to cardiac arrhythmias induced by digitalis preparations.

Calcium salts and vitamin D

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may promote an increase in plasma calcium levels. Concomitant use of thiazide diuretics with calcium salts may cause hypercalcemia in susceptible patients (e.g., patients with hyperparathyroidism, malignancies, or vitamin D-mediated conditions) due to enhanced tubular reabsorption of calcium.

Antidiabetic agents (oral antidiabetics and insulin)

Thiazide therapy may affect glucose tolerance. Dose adjustment of antidiabetic medicinal products may be necessary.

Metformin should be used with caution due to the risk of lactic acidosis induced by possible functional renal impairment associated with hydrochlorothiazide.

β-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers increases the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.

MEDICINAL PRODUCTS USED IN THE TREATMENT OF GOUT (probenecid, sulfinpyrazone, and allopurinol)

Dose adjustment of uricosuric agents may be necessary because hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be required. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.

Anticholinergic agents (e.g., atropine, biperiden)

The bioavailability of thiazide diuretics may be increased by anticholinergic agents, likely due to decreased gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may be expected to reduce the bioavailability of thiazide diuretics.

Amantadine

Thiazides, including hydrochlorothiazide, increase the risk of adverse effects caused by amantadine.

Ion-exchange resins

Absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol. This may result in subtherapeutic effects of thiazide diuretics. However, staggering the administration of hydrochlorothiazide and the resin so that hydrochlorothiazide is taken at least 4 hours before or 4–6 hours after the resin may minimize the risk of interaction.

Cytoxic agents (e.g., cyclophosphamide, methotrexate)

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effect.

Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)

Thiazides, including hydrochlorothiazide, enhance the effect of skeletal muscle relaxants such as curare derivatives.

Cyclosporine

Concomitant use with cyclosporine increases the risk of hyperuricemia and gout-like complications.

Alcohol, anesthetics, and sedatives

When thiazide diuretics are used concomitantly with agents that may also lower blood pressure (e.g., by reducing central sympathetic nervous system activity or direct vasodilatory action), potentiation of orthostatic hypotension may occur.

Methyldopa

Isolated reports of hemolytic anemia have been reported in patients receiving methyldopa and hydrochlorothiazide concomitantly.

Carbamazepine

Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Such patients should be informed about the possibility of hyponatremic reactions and appropriately monitored.

Contrast agents containing iodine

In cases of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high-dose iodine-containing agents. Adequate fluid replacement should be performed before administration.

Special precautions for use.

Electrolyte disturbances

Potassium

Thiazide diuretics may cause hypokalemia or exacerbate existing hypokalemia.

Correction of hypokalemia is recommended prior to initiating thiazide therapy. Concomitant hypomagnesemia may cause hypokalemia that is more difficult to correct.

Since Valsar-N contains an angiotensin II receptor antagonist, caution should be exercised when co-administering it with potassium salts, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin). Cases of hypokalemia have been reported during treatment with thiazide diuretics. Regular monitoring of serum potassium and magnesium levels is recommended in patients with conditions involving increased potassium loss. Electrolyte balance should be monitored in all patients receiving thiazide diuretics.

Patients with sodium deficiency and/or reduced blood volume

Treatment with thiazide diuretics is often associated with the development of hyponatremia or worsening of existing hyponatremia and hypochloremic alkalosis. This may be accompanied by neurological symptoms (e.g., vomiting, confusion, apathy). Thiazide diuretics should only be administered after correction of hyponatremia. Serum sodium concentration should be monitored regularly.

Thiazides enhance urinary excretion of magnesium, which may eventually lead to hypomagnesemia.

In patients with severe sodium deficiency and/or reduced blood volume (e.g., those receiving high-dose diuretics), symptomatic hypotension may occur in isolated cases after initiation of Valsar-N therapy. Therefore, correction of sodium and/or blood volume should be performed before starting treatment with this medicinal product.

In case of hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous saline infusion. Treatment may be continued immediately after stabilization of blood pressure.

Calcium

Thiazide diuretics reduce calcium excretion in urine and may cause elevated serum calcium levels. Thiazide diuretics should only be administered after correction of hypercalcemia or treatment of conditions causing it. Serum calcium concentration should be monitored regularly.

Patients with severe chronic heart failure or other conditions with increased RAAS activity. In patients whose renal function may depend on RAAS activity (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria, progressive azotemia, and rarely, acute renal failure. The use of Valsar-N in patients with severe chronic heart failure has not been established.

Since it cannot be excluded that suppression of RAAS by Valsar-N may also be associated with renal function disturbances, Valsar-N should not be used in such patients.

Renal artery stenosis. Valsar-N should be used with particular caution in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, as increased blood urea and plasma creatinine levels may occur in such patients.

Primary hyperaldosteronism. Valsar-N should not be used in patients with primary hyperaldosteronism, as their renin-angiotensin system is not activated.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy. As with other vasodilators, patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM) require special caution.

Renal impairment. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance >30 mL/min).

Valsar-N is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min). Thiazide diuretics may provoke azotemia in patients with chronic renal impairment. They are ineffective as monotherapy in severe renal impairment (creatinine clearance <30 mL/min), but may be used with appropriate caution in combination with loop diuretics, even in patients with creatinine clearance <30 mL/min.

Concomitant use of angiotensin receptor blockers (ARBs), including the combination of valsartan/hydrochlorothiazide, or ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (creatinine clearance <60 mL/min).

There is no experience with the use of valsartan in patients with end-stage renal disease (creatinine clearance <10 mL/min) or in patients undergoing dialysis.

Kidney transplantation. There is currently no experience regarding the safety of using this medicinal product in patients who have recently undergone kidney transplantation.

Hepatic impairment. Caution is required when treating patients with hepatic impairment. Dose adjustment is not required in patients with mild to moderate hepatic impairment without cholestasis. However, Valsar-N should be used with caution. Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide. Thiazides may cause electrolyte imbalances, hepatic encephalopathy, and hepatorenal syndrome. Therefore, Valsar-N should be prescribed to such patients only after careful risk-benefit assessment and monitoring of clinical and laboratory parameters. Valsar-N is contraindicated in patients with biliary cirrhosis or cholestasis.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Systemic lupus erythematosus. Thiazide diuretics have been reported to exacerbate or activate symptoms of systemic lupus erythematosus.

Other metabolic disturbances. Thiazide diuretics may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels, potentially exacerbating hyperuricemia and leading to gout. Therefore, Valsar-N is not recommended for patients with hyperuricemia and/or gout. Insulin or oral hypoglycemic agents may require dose adjustment in diabetic patients. Thiazides may reduce urinary calcium excretion and cause transient and slight elevation of serum calcium levels in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate underlying hyperparathyroidism. Thiazide use should be discontinued before performing tests to assess parathyroid function.

Photosensitivity. Cases of photosensitivity reactions have been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, discontinuation of therapy is recommended. If re-administration of the diuretic is considered necessary, protection of exposed skin from sunlight or artificial ultraviolet radiation is recommended.

Pregnancy

Angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. If continuation of ARB therapy is not considered necessary, women planning pregnancy should be switched to alternative antihypertensive treatments with established safety profiles during pregnancy. If pregnancy is detected, ARB therapy should be discontinued immediately and, if necessary, alternative therapy initiated.

General. Caution should be exercised when using the medicinal product in patients with a history of hypersensitivity to other ARBs. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.

Angioedema. Cases of Quincke's edema (including laryngeal and glottal edema leading to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling) have been reported in patients receiving valsartan; some of these patients had a history of angioedema with other drugs, including other ARBs and ACE inhibitors. If angioedema occurs, ARB therapy should be discontinued immediately. Re-administration of the drug is contraindicated.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset, decreased visual acuity, or eye pain, usually occurring within hours to weeks after starting the drug.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical intervention may be necessary. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Patients with heart failure, previous myocardial infarction

In patients whose renal function depends on RAAS activity (e.g., patients with severe heart failure), treatment with ACE inhibitors or ARBs may be associated with oliguria and/or progressive azotemia, and in rare cases, acute renal failure and fatal outcomes. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.

Non-melanoma skin cancer (NMSC)

An increased risk of NMSC (basal cell carcinoma and squamous cell carcinoma) with increasing cumulative dose of hydrochlorothiazide was observed in two epidemiological studies based on the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC. Regular skin examinations for new lesions are recommended, and any suspicious skin changes should be reported immediately. Preventive measures to minimize the risk of skin cancer, such as limiting exposure to sunlight and ultraviolet radiation and using adequate sun protection when exposed to sunlight, are recommended. Suspicious skin lesions should be promptly evaluated, including histological examination and biopsies. The use of hydrochlorothiazide should also be reconsidered in patients with a history of NMSC.

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.

Fertility

There is no information on the effect of valsartan on human fertility. Animal studies in rats did not show any effect of valsartan on fertility.

Dose adjustment is not required in elderly patients.

Hydrochlorothiazide may reduce plasma protein-bound iodine levels. Hydrochlorothiazide may increase the concentration of free bilirubin in serum.

This medicinal product contains less than 1 mmol of sodium per dose, i.e., essentially sodium-free.

If intolerance to certain sugars is established, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Valsartan

This medicinal product should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

It is known that the use of ARBs during the second and third trimesters of pregnancy causes fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia) in humans.

If ARBs were used from the second trimester of pregnancy, ultrasound monitoring of fetal kidneys and skull is recommended.

Infants whose mothers took ARBs require careful monitoring for hypotension.

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy is limited, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters of pregnancy may impair fetoplacental circulation and cause effects in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.

The physician prescribing a drug acting on the RAAS should inform the woman about the potential risks during pregnancy.

Due to the mechanism of action of angiotensin II receptor antagonists, the risk of embryopathy and fetal disease cannot be excluded. According to retrospective data, the use of ACE inhibitors in the first trimester is associated with a potential risk of congenital defects. Moreover, fetal injury and fatal outcomes have been reported with drugs directly affecting the RAAS during the second and third trimesters of pregnancy. In humans, fetal renal perfusion, dependent on RAAS development, begins during the second trimester. Thus, the risk associated with valsartan treatment is higher during the second and third trimesters of pregnancy. Reports of spontaneous abortions, oligohydramnios, and renal dysfunction in newborns have occurred when pregnant women inadvertently took valsartan.

Newborns exposed to the drug in utero should be carefully monitored for adequate urine output, hyperkalemia, and blood pressure. If necessary, appropriate medical measures (e.g., rehydration) should be taken to remove the drug from circulation.

Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, may cause jaundice or thrombocytopenia in the fetus and newborn, or other adverse reactions observed in adults.

Lactation

If use of the drug is absolutely necessary, breastfeeding should be discontinued. There is no information on the use of valsartan during lactation. Hydrochlorothiazide crosses the placenta and passes into human breast milk in small amounts. Thiazides in high doses cause diuresis, which may suppress milk production. During lactation, alternative treatment methods with better-established safety profiles are preferred, especially during breastfeeding of newborns, including premature infants.

Ability to affect reaction speed when driving or operating machinery.

At the beginning of treatment with the medicinal product (duration individually determined by the physician), driving and performing tasks that may lead to accidents are prohibited due to the potential occurrence of dizziness or fatigue. The extent of restriction thereafter is determined by the physician.

Method of Administration and Dosage

The recommended dose of Valsar-N is 1 tablet of 80 mg/12.5 mg once daily. If blood pressure is not sufficiently reduced after 3–4 weeks of treatment, consider increasing the dose to 1 tablet of 160 mg/12.5 mg once daily. Tablets of 160 mg/25 mg are prescribed to patients in whom adequate blood pressure reduction is not achieved with 160 mg/12.5 mg tablets. If blood pressure remains insufficiently controlled with 160 mg/25 mg tablets, consider increasing the dose to 320 mg/12.5 mg. Tablets of 320 mg/25 mg are prescribed to patients in whom adequate blood pressure reduction is not achieved with 320 mg/12.5 mg tablets.

The maximum daily dose is 320 mg/25 mg.

If there is no response to treatment with Valsar-N after 8 weeks, consider using an additional or alternative antihypertensive agent.

Maximum antihypertensive effect is achieved within 2–4 weeks. For some patients, 4–8 weeks of treatment may be required.

Valsar-N can be taken independently of food intake. Tablets should be swallowed with a small amount of water.

Use in elderly patients (aged 65 years and older)

Valsar-N can be used in patients of any age.

Use in patients with renal impairment

Dose reduction may be necessary in patients with renal impairment. Since Valsar-N contains hydrochlorothiazide, it is contraindicated in patients with anuria, and special caution is required when administering the drug to patients with severe renal impairment (creatinine clearance <30 mL/min).

There are no data on the use of valsartan in patients with end-stage renal disease (creatinine clearance <10 mL/min) or in patients undergoing dialysis.

Hepatic impairment

Dose reduction may be necessary in patients with hepatic impairment. Since Valsar-N contains hydrochlorothiazide, the drug should be used with caution in patients with hepatic impairment. As the drug contains valsartan, it is contraindicated in patients with biliary cirrhosis or cholestasis.

The dose of valsartan in patients with mild to moderate non-biliary hepatic impairment and without cholestasis should not exceed 80 mg.

Children

Valsar-N is contraindicated in children (under 18 years of age) due to lack of data on safety and efficacy in this age group.

Overdose

Overdose with valsartan may cause pronounced hypotension, which in turn may lead to decreased consciousness, circulatory failure, and/or shock.

Overdose with hydrochlorothiazide may cause symptoms such as nausea, drowsiness, hypovolemia, electrolyte imbalance, and as a consequence – arrhythmia and muscle spasms. The most characteristic signs of overdose also include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, disturbances of consciousness, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen levels (primarily due to renal failure).

In all cases of overdose, general supportive measures should be taken, including continuous monitoring of the patient and interventions to stabilize cardiovascular function.

Therapeutic measures depend on the time elapsed since ingestion of the excessive dose and the severity of symptoms; the primary goal is to restore hemodynamic stability.

If the drug was recently ingested, induce vomiting. If a significant time has passed since ingestion, administer activated charcoal.

In case of hypotension, the patient should be placed in a supine position and immediate restoration of fluid and electrolyte balance should be achieved by intravenous infusion of isotonic saline solution.

Valsartan cannot be effectively removed by hemodialysis due to its high plasma protein binding; however, hemodialysis is effective for elimination of hydrochlorothiazide from the body.

Adverse reactions

The adverse reactions most commonly reported during clinical trials with valsartan/hydrochlorothiazide, compared to placebo, and in the post-marketing period, are listed below by system organ classes.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated based on available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Adverse reactions of valsartan/hydrochlorothiazide

Infections
Uncommon:	viral infections, fever.
Metabolism and nutrition disorders
Uncommon:	dehydration.
Frequency unknown:	hypokalemia, hyponatremia.
Nervous system disorders
Common:	headache, fatigue, dizziness.
Uncommon:	asthenia, dizziness, insomnia, anxiety, paresthesia.
Rare:	depression.
Frequency unknown:	syncope.
Eye disorders
Uncommon:	blurred vision.
Rare:	conjunctivitis.
Ear and labyrinth disorders
Uncommon:	otitis media, tinnitus.
Cardiac disorders
Uncommon:	palpitations, tachycardia.
Vascular disorders
Uncommon:	edema, hypotension, hyperhidrosis.
Respiratory, thoracic and mediastinal disorders
Common:	cough, rhinitis, pharyngitis, upper respiratory tract infections.
Uncommon:	bronchitis, dyspnea, sinusitis, pharyngolaryngeal pain, dry mouth.
Very rare:	epistaxis.
Frequency unknown:	non-cardiogenic pulmonary edema.
Gastrointestinal disorders
Common:	diarrhea.
Uncommon:	abdominal pain, dyspepsia, nausea, gastroenteritis.
Musculoskeletal and connective tissue disorders
Common:	back pain, arthralgia.
Uncommon:	limb pain, chest pain, neck pain, arthritis, sprains and deformities, muscle cramps, myalgia.
Renal and urinary disorders
Uncommon:	frequency of urination, urinary tract infections.
Very rare:	renal dysfunction.
Reproductive system disorders
Common:	erectile dysfunction.
General disorders
Uncommon:	increased fatigue.
Investigations
Frequency unknown:	elevated plasma uric acid, elevated plasma bilirubin and creatinine, hypokalemia, hyponatremia, increased blood urea nitrogen, neutropenia.

A more than 20% reduction in serum potassium levels was observed in 3.7% of patients receiving the valsartan/hydrochlorothiazide combination and in 3.1% of patients receiving placebo.

Increased blood creatinine and blood urea nitrogen levels were observed in 1.9% and 14.7% of patients, respectively, receiving the valsartan/hydrochlorothiazide combination, and in 0.4% and 6.3%, respectively, of patients receiving placebo in controlled clinical trials.

During clinical trials in hypertensive patients, the following events were observed regardless of causal relationship to the investigational drug: hypoaesthesia, influenza, insomnia, ligament sprain, muscle strain, nasal congestion, nasopharyngitis, neck pain, peripheral oedema, and sinus congestion.

The reactions described below were associated with monotherapy with valsartan but were not observed with the combination of valsartan/hydrochlorothiazide.

In rare cases, therapy with valsartan may be associated with decreased haemoglobin and haematocrit levels. In controlled clinical trials, significant (>20%) reductions in haematocrit and haemoglobin levels were observed in 0.8% and 0.4% of patients, respectively. Decreased haematocrit or haemoglobin levels were observed in 0.1% of patients receiving placebo.

Neutropenia was observed in 1.9% of patients receiving valsartan and in 1.6% of patients receiving ACE inhibitors.

In controlled clinical trials, significant increases in serum creatinine, potassium, and total bilirubin levels were observed in 0.8%, 4.4%, and 6% of patients receiving valsartan, respectively, and in 1.6%, 6.4%, and 12.9% of patients receiving ACE inhibitors, respectively.

Elevated liver function parameters were infrequently observed in patients receiving valsartan.

There is no need for special laboratory monitoring in patients with essential hypertension receiving valsartan therapy.

The following reactions were observed during clinical trials in patients with hypertensive disease: upper abdominal pain, anxiety, arthritis, back pain, bronchitis, acute bronchitis, chest pain, dizziness, dyspepsia, dyspnoea, dry mouth, epistaxis, impotence, gastroenteritis, headache, increased sweating, hypoaesthesia, influenza, insomnia, ligament sprain, muscle cramps, muscle strain, nausea, nasal congestion, nasal congestion in paranasal sinuses, neck pain, oedema, peripheral oedema, otitis media, limb pain, palpitations, pharyngolaryngeal pain, polyuria, increased temperature, nasopharyngitis, sinusitis, somnolence, tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, and visual disturbances. It is unknown whether these effects were causally related to therapy.

During the post-marketing period, there have been reports of syncope and very rare cases of angioneurotic oedema, rash, loss of consciousness, and other hypersensitivity reactions such as serum sickness and vasculitis, as well as cases of renal dysfunction.

Bullous dermatitis has been reported, with frequency unknown.

Additional information regarding individual components

Adverse reactions observed with the use of valsartan and hydrochlorothiazide separately may also be potential adverse effects with the use of the valsartan/hydrochlorothiazide combination, even if they were not observed in clinical trials or during the post-marketing period.

Adverse reactions with the use of valsartan

From the blood and lymphatic system
Frequency unknown:	decreased hemoglobin levels, decreased hematocrit, thrombocytopenia.
From the immune system
Frequency unknown:	other hypersensitivity/allergic reactions, including serum sickness.
Metabolism and nutritional disorders
Frequency unknown:	elevated plasma potassium levels, hyponatremia.
From the ear and labyrinthine disorders
Uncommon:	vestibular vertigo.
Vascular disorders
Frequency unknown:	vasculitis.
From the gastrointestinal system
Uncommon:	abdominal pain, gastroenteritis.
Very rare:	intestinal angioedema.
From the hepatobiliary system
Frequency unknown:	elevated liver function tests.
From the skin and subcutaneous tissue
Frequency unknown:	edema, angioedema, rash, pruritus, bullous dermatitis.
From the urinary system
Frequency unknown:	renal failure, acute renal failure.
From the musculoskeletal and connective tissue
Common:	arthralgia.
From the nervous system
Uncommon:	asthenia, insomnia, dizziness.
Rare:	neuralgia.
From the reproductive system
Uncommon:	decreased libido.
From the heart
Very rare:	cardiac arrhythmia.

There has been one reported case of angioneurotic edema.

Adverse reactions observed during clinical trials in patients with hypertension, regardless of their causal relationship to the investigational drug: arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.

Adverse reactions associated with the use of hydrochlorothiazide

Hydrochlorothiazide has been widely used for many years, often at doses higher than those contained in the drug Valsar-N. The adverse reactions listed below have been reported in patients receiving thiazide diuretics, including hydrochlorothiazide, as monotherapy:

From the metabolism and endocrine system
Very common:	with high-dose use – increased blood lipid levels, hypokalemia.
Common:	hyponatremia, hypomagnesemia, hyperuricemia.
Uncommon:	hypercalcemia, hyperglycemia, glucosuria, and metabolic disturbances in patients with diabetes mellitus.
Rare:	hypochloremic alkalosis.
Blood and lymphatic system disorders
Uncommon:	thrombocytopenia, sometimes with purpura.
Rare:	agranulocytosis, leukopenia, hemolytic anemia, bone marrow suppression.
Frequency not known:	aplastic anemia.
Immune system disorders
Rare:	hypersensitivity reactions.
Psychiatric disorders
Uncommon:	depression, sleep disturbances.
Nervous system disorders
Uncommon:	headache, dizziness, paresthesia.
Eye disorders
Uncommon:	blurred vision during the first few weeks of treatment.
Frequency not known:	acute myopia, acute angle-closure glaucoma, choroidal effusion.
Cardiac disorders
Uncommon:	arrhythmia.
Vascular disorders
Common:	postural hypotension, which may be exacerbated by alcohol consumption, anesthetics, or sedative drugs.
Respiratory, thoracic and mediastinal disorders
Rare:	respiratory failure, including pneumonia and pulmonary edema, acute respiratory distress syndrome.
Gastrointestinal disorders
Common:	loss of appetite, mild nausea and vomiting.
Uncommon:	constipation, gastrointestinal discomfort, diarrhea.
Rare:	pancreatitis.
Hepatobiliary disorders
Uncommon:	intrahepatic cholestasis or jaundice.
Skin and subcutaneous tissue disorders
Common:	urticaria and other types of rashes.
Uncommon:	photosensitization.
Rare:	necrotic vasculitis and toxic epidermal necrolysis, skin reactions resembling lupus erythematosus, reactivation of cutaneous lupus erythematosus.
Frequency not known:	erythema multiforme.
Reproductive system disorders
Common:	impotence.
Renal and urinary disorders
Frequency not known:	acute renal failure, renal dysfunction.
General disorders
Frequency not known:	fever, fatigue.
Musculoskeletal and connective tissue disorders
Frequency not known:	muscle spasms.
Benign, malignant and unspecified neoplasms (including cysts and polyps)
Frequency not known:	non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Shelf life. 2 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Packaging. 7 film-coated tablets in a blister pack, 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited – Unit VII, India.

Manufacturer's address and location of business operations.

Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.