Valsaria n

for medical use of the medicinal product Valsariya H (Valsariya H)

Composition:

Active substance: valsartan/hydrochlorothiazide;

One tablet contains 80 mg of valsartan and 12.5 mg of micronized hydrochlorothiazide, or 160 mg of valsartan and 12.5 mg of micronized hydrochlorothiazide, or 160 mg of valsartan and 25 mg of micronized hydrochlorothiazide;

Excipients:

Valsariya H 80/12.5 mg: microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, hypromellose, talc, macrogol 8000, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172);

Valsariya H 160/12.5 mg: microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, hypromellose, talc, macrogol 8000, titanium dioxide (E 171), iron oxide red (E 172);

Valsariya H 160/25 mg: microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, hypromellose, talc, macrogol 4000, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties:

Valsariya H 80/12.5 mg: light orange, oval, slightly convex on both sides, with an imprint (engraving) «HGH» on one side and «CG» on the other side;

Valsariya H 160/12.5 mg: dark red, oval, slightly convex on both sides, with an imprint (engraving) «HNH» on one side and «CG» on the other side;

Valsariya H 160/25 mg: brown-orange, oval, slightly convex, with an imprint (engraving) «HXH» on one side and «NVR» on the other side.

Pharmacotherapeutic group. Angiotensin II antagonists 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 has a broad spectrum of physiological effects, including both direct and indirect involvement in the regulation of arterial blood pressure. As a potent vasoconstrictor, angiotensin II exerts a direct pressor effect. In addition, it promotes sodium retention and stimulates aldosterone secretion.

Valsartan is an active and specific oral antagonist of angiotensin II receptors. It acts selectively on AT1 subtype receptors, which are responsible for 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, the enzyme responsible for converting angiotensin I to angiotensin II and for degrading bradykinin. No bradykinin-mediated adverse effects are 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 inhibitors (P < 0.05). Valsartan does not interact with or block receptors of other hormones or ion channels known to play important roles in cardiovascular function regulation.

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

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

In most patients, after a single oral dose, onset of antihypertensive activity occurs within 2 hours, and maximal 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 rebound hypertension 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 diuretic action are located and where Na+ and Cl- ion transport is inhibited. The mechanism of thiazide action involves inhibition of the Na+/Cl- cotransporter, likely through competition for Cl- transport sites. As a result, excretion of sodium and chloride ions increases to a similar extent. Due to the diuretic effect, plasma volume decreases, leading to increased renin activity, aldosterone secretion, and 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.

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 and 8,629 cases of squamous cell carcinoma, matched with 1,430,833 and 172,462 individuals in the respective control groups. High cumulative doses of hydrochlorothiazide (≥50,000 mg) were 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 compared with 63,067 population-based controls using risk-set sampling. 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) for high dose (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily administration of the defined daily dose of 25 mg over a period exceeding 10 years.

Pharmacokinetics.

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

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

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

Hydrochlorothiazide. Absorption of hydrochlorothiazide after oral administration is rapid (tmax approximately 2 hours). The pharmacokinetics during distribution and elimination phases are generally described by a biphasic exponential decline; the terminal half-life 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 administration, and accumulation is minimal with once-daily dosing.

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

When hydrochlorothiazide is administered with food, both increases and decreases in systemic bioavailability have been observed compared to fasting administration. However, the range of these changes is small 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 each component alone and of placebo.

Pharmacokinetics in Specific Patient Populations

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

Some data suggest that systemic clearance of hydrochlorothiazide is lower in elderly patients, both healthy and those with hypertension, 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 the drug 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; in contrast, hydrochlorothiazide is eliminated during hemodialysis.

In patients with renal dysfunction, mean peak plasma levels and AUC values of hydrochlorothiazide increase, while urinary excretion decreases. In patients with mild to moderate renal insufficiency, the mean elimination half-life nearly doubles due to a marked reduction in renal clearance.

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

In patients with renal insufficiency, mean peak plasma levels and AUC values of hydrochlorothiazide are increased, and urinary excretion is reduced. In patients with mild to moderate renal insufficiency, a threefold increase in AUC of hydrochlorothiazide is observed. In patients with severe renal insufficiency, an eightfold increase in AUC is observed. Hydrochlorothiazide is contraindicated in patients with severe renal insufficiency.

Hepatic impairment. Systemic exposure to valsartan in patients with mild (n = 6) and moderate (n = 5) hepatic impairment was twice as high as in 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.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to any component of the medicinal product or to other sulfonamide derivatives.
• Severe impairment of liver function, liver cirrhosis, and cholestasis.
• Anuria, severe renal impairment (creatinine clearance < 30 mL/min).
• 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 or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
• Hereditary angioedema or angioedema during previous treatment with ACE inhibitors or ARBs.
• Contraindicated in pregnancy and in women planning to become pregnant (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Interactions related to both valsartan and hydrochlorothiazide

Concomitant use not recommended

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

Concomitant use requires caution

Other antihypertensive agents

The medicinal product Valsaria N may enhance the effect of other medicinal products with antihypertensive properties (e.g., guanethidine, methyldopa, vasodilators, ACE inhibitors, angiotensin receptor antagonists, beta-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, although not sufficient to preclude their use.

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

NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. In addition, concomitant use of Valsaria 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, in patients with volume depletion (including those on diuretic therapy), or in patients with renal dysfunction, concomitant use of NSAIDs (or cyclooxygenase-2 (COX-2) inhibitors) with ARBs II increases the risk of renal impairment, including acute renal failure. Concomitant use of these agents requires caution and monitoring of renal function.

Interactions related to valsartan

Dual blockade of the RAAS: 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 carried out 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 or diabetic nephropathy, or with renal impairment (GFR < 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 medicinal products that may increase potassium levels

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

Concomitant use of ARBs II 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, Valsaria N containing valsartan should be used with caution and plasma 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 advised when initiating or discontinuing concomitant treatment with such medicinal products.

No clinically significant interactions of valsartan with the following medicinal products were observed: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glimepiride.

Absence of interaction

In drug interaction studies, no clinically significant interactions were observed between valsartan and any of the following: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glimepiride. Digoxin and indomethacin may interact with the hydrochlorothiazide component of Valsaria N (see "Interactions related to hydrochlorothiazide").

Interactions related to 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, 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 CAPABLE OF INDUCING 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 used concomitantly with antidepressants, antipsychotics, and antiepileptic drugs. Caution is advised with prolonged use of these medicinal products.

MEDICINAL PRODUCTS THAT MAY CAUSE TORSADES DE POINTES (DOUBLE-PHASE TACHYCARDIA)

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide).

• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide).

• Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

• Others (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vincaamine).

Due to the risk of 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 increased plasma calcium levels. Concomitant use of thiazide diuretics with calcium salts may cause hypercalcemia in patients predisposed to hypercalcemia (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.

Beta-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-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)

Dosage adjustment of uricosuric agents may be necessary, as hydrochlorothiazide may increase plasma uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased. 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 reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may reduce the bioavailability of thiazide-type diuretics.

Amantadine

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

Diazoxyde

Thiazide diuretics may enhance the hyperglycemic effect of diazoxide.

Ion-exchange resins

The 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 minimizes the risk of interaction.

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

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

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

Concomitant use of thiazide diuretics with agents that may also lower blood pressure (e.g., due to reduced activity of the central sympathetic nervous system or direct vasodilatory effect) may potentiate orthostatic hypotension.

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. These 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 doses of iodine-containing agents. Adequate fluid replacement should be ensured before administration of the medicinal product.

Special precautions for use.

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 Valsaria N contains an angiotensin II receptor antagonist, caution should be exercised when co-administering the drug 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. Frequent monitoring of serum potassium levels is recommended in patients with conditions involving increased potassium loss.

Regular monitoring of potassium and magnesium levels is necessary. In all patients receiving thiazide diuretics, electrolyte balance should be monitored.

Treatment with thiazide diuretics is often associated with the development of hyponatremia or worsening of pre-existing hyponatremia and hypochloremic alkalosis. This may be accompanied by neurological symptoms (nausea, 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 result in hypomagnesemia.

Patients with sodium deficiency and/or reduced circulating blood volume (CBV)

In patients with severe sodium deficiency and/or reduced CBV, such as those receiving high doses of diuretics, symptomatic hypotension may occur in isolated cases after initiation of Valsaria N therapy. Therefore, correction of sodium and/or CBV levels should be performed prior to starting 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 increased 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 and/or progressive azotemia, rarely with acute renal failure. Use of Valsaria N in patients with severe chronic heart failure is not justified. Since it cannot be excluded that suppression of RAAS activity by the medicinal product may also be associated with renal dysfunction, it should not be used in such patients.

Renal artery stenosis. Valsaria N should be used with particular caution in patients with unilateral or bilateral renal artery stenosis or stenosis affecting a solitary kidney, as such patients may experience increased blood urea and plasma creatinine levels.

Primary hyperaldosteronism

Valsaria 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

Administration of vasodilators to patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM) requires special caution.

Renal impairment. No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min).

The medicinal product should be used with caution in severe renal impairment (creatinine clearance <30 mL/min). Thiazide diuretics may provoke azotemia in patients with chronic renal dysfunction. 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, including Valsaria N, or ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (creatinine clearance <60 mL/min).

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

Renal transplantation

There is currently no experience regarding the safety of using the drug 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, Valsaria 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, Valsaria N should be prescribed to such patients only after careful assessment of risk versus benefit and with monitoring of clinical and laboratory parameters. The drug is contraindicated in patients with biliary cirrhosis or cholestasis.

Systemic lupus erythematosus. There have been reports that thiazide diuretics may exacerbate or activate manifestations of systemic lupus erythematosus.

Other metabolic disturbances. Thiazide diuretics may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels. They may also exacerbate hyperuricemia and lead to gout. Therefore, Valsaria N is not recommended for patients with hyperuricemia and/or gout. Patients with diabetes may require adjustment of insulin or oral hypoglycemic agent dosages. Thiazides may reduce urinary calcium excretion and cause transient and slight increases in serum calcium levels in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate underlying hyperparathyroidism. Thiazide use should be discontinued prior to tests evaluating parathyroid function.

Photosensitivity

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

General recommendations

Caution should be exercised when administering the drug to patients with a history of hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.

Angioedema

Angioedema (including angioedema of the larynx and glottis leading to airway obstruction and/or angioedema of the face, lips, pharynx, and tongue) has been observed in patients receiving valsartan. Some of these patients had a history of angioedema with other drugs, including other angiotensin II receptor antagonists, such as ACE inhibitors. If angioedema develops, treatment with angiotensin II receptor antagonists should be discontinued immediately. Re-administration of the drug is contraindicated.

Acute angle-closure glaucoma

Use of hydrochlorothiazide, a sulfonamide, has been associated with idiosyncratic reactions that may lead to acute transient myopia and acute angle-closure glaucoma. Symptoms include acute decrease in visual acuity or eye pain and usually occur within hours to weeks after starting the drug. Untreated glaucoma may lead to permanent vision loss.

The drug should be discontinued as quickly as possible. Medical or surgical treatment may be required. Risk factors for acute angle-closure glaucoma include a history of allergic reaction to sulfonamides or penicillin.

Medicinal products containing sulfonamide or sulfonamide derivatives may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and typically occur within hours to weeks of 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 acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

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 ARAs 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 in the development of NMSC.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for new lesions and promptly report any suspicious changes. Preventive measures to minimize the risk of skin cancer, such as limiting exposure to sunlight and ultraviolet radiation and using adequate protection when exposed to sunlight, are recommended. Suspicious skin lesions should be promptly evaluated, potentially including histological examination of biopsies. Use of hydrochlorothiazide should also be reconsidered in patients who have experienced NMSC.

No dose adjustment is required for elderly patients.

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

Use during pregnancy or breastfeeding.

Pregnancy

Valsartan

The medicinal product is contraindicated in pregnant women and women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

It is known that use of angiotensin II receptor antagonists during the second and third trimesters causes fetal toxicity in humans (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If angiotensin II receptor antagonists were used starting from the second trimester of pregnancy, ultrasound monitoring of renal and skull function is recommended.

Infants whose mothers took angiotensin II receptor antagonists require careful monitoring for hypotension.

Hydrochlorothiazide

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

The physician prescribing a drug acting on the RAAS should inform the patient about 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, use of ACE inhibitors during pregnancy is associated with a potential risk of congenital defects. Additionally, fetal injury and fatal outcomes have been reported with use of drugs directly affecting the RAAS during the second and third trimesters. 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. Reports include spontaneous abortions, oligohydramnios, and renal dysfunction in newborns when pregnant women inadvertently took valsartan.

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

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

Breastfeeding period

If use of the drug is absolutely necessary, breastfeeding should be discontinued. There is no information on use of valsartan during breastfeeding. Hydrochlorothiazide crosses the placenta and is excreted in human milk in small amounts. Thiazides in high doses cause diuresis, which may suppress milk production. During breastfeeding, alternative treatment methods with better-established safety profiles are preferred, especially when breastfeeding a newborn or preterm infant.

Fertility

There is no information on the effect of valsartan on human fertility. Animal studies in rats showed no effects of valsartan on fertility.

Ability to affect reaction speed when driving or operating machinery.

During initial treatment (duration determined individually by the physician), driving and performing tasks that could lead to accidents are prohibited due to the potential for dizziness or fatigue. The extent of restriction later should be determined by the physician.

Method of administration and dosing.

The recommended dose of the medicinal product Valsaria 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, consideration should be given to continuing therapy with a dose of 1 tablet of 160 mg/12.5 mg once daily. Tablets of 160 mg/25 mg should be prescribed to patients in whom adequate blood pressure reduction is not achieved with tablets of 160 mg/12.5 mg. If blood pressure remains insufficiently controlled with tablets of 160 mg/25 mg, consideration should be given to continuing treatment with a dose of 320 mg/12.5 mg. Tablets of 320 mg/25 mg should be prescribed to patients in whom adequate blood pressure reduction is not achieved with tablets of 320 mg/12.5 mg.

The maximum daily dose is 320 mg/25 mg.

If there is no response to treatment after 8 weeks, additional or alternative antihypertensive therapy should be considered.

Maximum antihypertensive effect is achieved within 2–4 weeks. Some patients may require 4–8 weeks of treatment.

Valsaria N may be administered regardless of food intake. Tablets should be taken with a small amount of water.

Elderly patients (aged 65 years and older)

The medicinal product can be used in patients of any age.

Patients with renal impairment

Dose reduction may be required in patients with renal impairment. Since the medicinal product contains hydrochlorothiazide, it is contraindicated in patients with anuria, and special caution is required when used in 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.

Patients with hepatic impairment

Dose reduction may be required in patients with hepatic impairment. Since Valsaria N contains hydrochlorothiazide, it should be used with caution in patients with hepatic impairment. Since the medicinal product contains valsartan, it is contraindicated in patients with biliary cirrhosis or cholestasis.

In patients with mild to moderate non-biliary hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg.

Children

Valsaria N is not recommended for use in children due to lack of data on safety and efficacy.

Overdose

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

Overdose with hydrochlorothiazide may result in symptoms such as nausea, drowsiness, hypovolemia, electrolyte imbalance, and consequently arrhythmias and muscle spasms. The most characteristic symptoms of overdose also include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle spasms, paresthesia, exhaustion, impaired 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 implemented, including continuous monitoring of the patient and measures to stabilize cardiovascular function.

Therapeutic interventions depend on the time elapsed since ingestion of the excessive dose and the severity of symptoms; the primary measure is normalization of hemodynamics.

If the drug was recently ingested, vomiting should be induced. If a significant time has passed since ingestion, the patient should be given an adequate amount of activated charcoal.

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

Valsartan cannot be effectively removed from the body 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, as well as those reported during the post-marketing period, are listed below by organ system.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Adverse reactions of valsartan/hydrochlorothiazide

A decrease in serum potassium levels by more than 20% was observed in 3.7% of patients receiving Valsaria N and in 3.1% of patients receiving placebo.

An increase in creatinine and blood urea nitrogen was observed in 1.9% and 14.7% of patients, respectively, taking Valsaria N, and in 0.4% and 6.3% of patients, respectively, receiving placebo in controlled clinical studies.

During clinical studies in patients with hypertension, the following events were observed regardless of causal relationship to the investigational medicinal product: hypesthesia, flu, insomnia, ligament sprain, muscle strain, nasal congestion, nasopharyngitis, neck pain, peripheral edema, sinus congestion.

The following reactions were associated with monotherapy with valsartan but were not observed with the use of Valsaria N.

In rare cases, therapy with valsartan may be associated with a decrease in hemoglobin and hematocrit levels. In controlled clinical studies, significant (>20%) reductions in hematocrit and hemoglobin levels were observed in 0.8% and 0.4% of patients, respectively. In 0.1% of patients receiving placebo, a decrease in hematocrit or hemoglobin levels was observed.

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

In controlled clinical studies, 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 tests were infrequently observed in patients receiving valsartan.

There is no need to perform 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, dyspnea, dry mouth, epistaxis, impotence, gastroenteritis, headache, increased sweating, hypesthesia, flu, insomnia, ligament sprain, muscle cramps, muscle strain, nausea, nasal congestion, nasal sinus congestion, neck pain, edema, peripheral edema, otitis media, limb pain, palpitations, pharyngolaryngeal pain, polyuria, fever, nasopharyngitis, sinusitis, somnolence, tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, visual disturbances. It is unknown whether these effects were causally related to therapy.

In the post-marketing period, there have been reports of syncope and very rare cases of angioneurotic edema, 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 occurring with the use of valsartan and hydrochlorothiazide separately may also be potential adverse effects with the use of Valsaria N, even if they were not observed in clinical trials or during the post-marketing period.

Adverse reactions associated with the use of valsartan

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 infections, viral infections.

Adverse reactions associated with the use of hydrochlorothiazide

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

Eye disorders

Unknown frequency: choroidal effusion.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30°C.

Keep in the original packaging to protect from light.

Packaging. Film-coated tablets containing 80 mg/12.5 mg, or 160 mg/12.5 mg, or 160 mg/25 mg. 14 tablets per blister. 1 or 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Lek Pharmaceuticals d.d.

or

Sandoz S.r.l.

or

Novartis Pharma S.p.A.

Manufacturer's address and address of operations.

Verovškova 57, 1526 Ljubljana, Slovenia

or

Str. Livezeni no. 7A, 540472 Târgu Mureș, Mureș County, Romania

or

Via Provinciale Citto, 131, 80058 Torre Annunziata, Italy.