Valsacor® n 320

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valsacor® H 320 Valsacor® HD 320 (Valsacor® H 320) (Valsacor® HD 320)

Composition:

Active substances: 1 film-coated tablet contains 320 mg of valsartan and 12.5 mg of hydrochlorothiazide or 320 mg of valsartan and 25 mg of hydrochlorothiazide;

Excipients: microcrystalline cellulose, lactose monohydrate, magnesium stearate, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide; hypromellose, titanium dioxide (E 171), macrogol 4000, red iron oxide (E 172) – only in Valsacor® H 320, yellow iron oxide (E 172) – only in Valsacor® HD 320.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Valsacor® H 320: oval, biconvex, film-coated tablets of pink color;

Valsacor® HD 320: oval, biconvex, film-coated tablets of light yellow color, with a notch on one side.

Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. ATC code C09DA03.

Pharmacological properties.

Pharmacodynamics.

Valsartan/hydrochlorothiazide

The positive effect of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity has not yet been established.

Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.

Valsartan

Valsartan is a potent, active, and specific oral angiotensin II receptor antagonist (ARA II). It acts selectively on the AT1 receptor subtype, which mediates the known actions of angiotensin II. When plasma angiotensin II concentrations increase following AT1 receptor blockade, unblocked AT2 receptors are stimulated, which regulate AT1 receptor activity. Valsartan exhibits no agonistic activity at AT1 receptors and has significantly greater affinity (approximately 20,000 times higher) for AT1 receptors than for AT2 receptors. It is unknown whether valsartan binds to or blocks other hormonal receptors or ion channels important in cardiovascular regulation.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and catalyzes bradykinin breakdown. Because there is no effect on ACE and no increase in bradykinin or substance P levels, angiotensin II antagonists are unlikely to be associated with cough.

Administration of valsartan to patients with arterial hypertension reduces blood pressure without changing pulse rate. In most patients, after a single oral dose, antihypertensive effects begin within 2 hours, and maximal blood pressure reduction is achieved within 4–6 hours. The antihypertensive effect lasts more than 24 hours after dosing. With repeated dosing, maximum effect is reached within 2–4 weeks and persists during long-term therapy. Additional blood pressure reduction is achieved when combined with hydrochlorothiazide.

Abrupt discontinuation of valsartan does not lead to rebound hypertension or other adverse clinical effects.

Hydrochlorothiazide

The site of action of thiazide diuretics is the cortical segment of the distal convoluted renal tubules, where receptors highly sensitive to thiazide diuretics are located, and where Na+ and Cl- ion transport into the distal convoluted tubules is inhibited. The mechanism of action of thiazides involves inhibition of the Na+Cl- cotransporter, likely due to competition at Cl- transport sites. As a result, electrolyte reabsorption mechanisms are altered: excretion of sodium and chloride increases to a similar extent. Due to diuretic action, plasma volume decreases, leading to increased renin activity, aldosterone secretion, and urinary excretion of potassium, thereby reducing serum potassium concentration. The renin-aldosterone relationship is mediated by angiotensin II; therefore, with concomitant treatment with valsartan, possibly due to blockade of the renin-angiotensin-aldosterone system (RAAS), hydrochlorothiazide-induced potassium excretion may be reduced compared to hydrochlorothiazide monotherapy.

Non-melanoma skin cancer

Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of non-melanoma skin cancer (NMSC). One study included a population of 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), corresponding to 1,430,833 and 172,462 control groups, respectively. High cumulative use of hydrochlorothiazide (≥ 50,000 mg) was associated with an adjusted OR of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear cumulative dose-response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and hydrochlorothiazide exposure: 633 cases of lip cancer corresponded to 63,067 population control groups using a sampling strategy. A cumulative dose 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 use (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see "Special warnings and precautions for use").

Pharmacokinetics.

Valsartan/hydrochlorothiazide

Systemic bioavailability of hydrochlorothiazide is reduced by approximately 30% when co-administered with valsartan. The pharmacokinetics of valsartan are less noticeably affected by concomitant hydrochlorothiazide administration. This apparent interaction does not affect the combined use of valsartan and hydrochlorothiazide, as controlled clinical trials have demonstrated a clear antihypertensive effect greater than that achieved with either active ingredient alone or placebo.

Valsartan

Absorption

After oral administration of valsartan alone, maximum plasma concentration (Cmax) is reached within 2–4 hours. Mean absolute bioavailability is approximately 23%. Food intake reduces exposure to valsartan, measured as the mean area under the concentration-time curve (AUC), by about 40% and Cmax by about 50%, although plasma valsartan concentrations approximately 8 hours after administration are similar under fasting and fed conditions. However, this reduction in mean AUC is not associated with a clinically significant reduction in therapeutic effect; therefore, valsartan can be administered with or without food.

Distribution

The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 L, indicating that valsartan does not extensively distribute into tissues. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.

Metabolism

Valsartan is not extensively metabolized, as only about 20% of the dose is recovered as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the mean AUC of valsartan). This metabolite is pharmacologically inactive.

Elimination

Valsartan exhibits multiphasic exponential elimination kinetics (t1/2α <1 hour and t1/2β approximately 9 hours). Valsartan is primarily eliminated via the bile into feces (approximately 83% of the dose) and to a lesser extent via the kidneys in urine (approximately 13% of the dose), mainly in unchanged form. After intravenous administration, plasma clearance of valsartan is approximately 2 L/hour, and renal clearance is 0.62 L/hour (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption

Absorption of hydrochlorothiazide after oral administration is rapid (tmax approximately 2 hours), with similar absorption characteristics for suspension and tablet formulations. Absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration. Concomitant food intake has been reported to both increase and decrease systemic bioavailability of hydrochlorothiazide compared to fasting conditions. The frequency of such fluctuations is low and of minimal clinical significance. Increase in mean AUC is linear and dose-proportional within the therapeutic dose range. There are no changes in hydrochlorothiazide kinetics with repeated dosing, and accumulation is minimal with once-daily administration.

Distribution

Distribution and elimination kinetics are generally described by a biexponential decline curve. The apparent volume of distribution is 4–8 L/kg. Hydrochlorothiazide is bound to plasma proteins (40–70%) in systemic circulation, primarily to serum albumin.

Hydrochlorothiazide also accumulates in erythrocytes, reaching levels approximately 1.8 times higher than in plasma.

Elimination

More than 95% of absorbed hydrochlorothiazide dose is excreted unchanged in urine. Renal excretion involves passive filtration and active secretion in the renal tubules. The terminal elimination half-life ranges from 6 to 15 hours.

Special patient populations

Elderly

Slightly higher systemic exposure to valsartan has been observed in some elderly individuals compared to younger individuals; however, this has not been shown to have any clinical significance.

Limited data indicate that systemic clearance of hydrochlorothiazide is reduced in both healthy elderly individuals and elderly individuals with arterial hypertension compared to healthy young volunteers.

Renal impairment

No dose adjustment is required for valsartan/hydrochlorothiazide in patients with creatinine clearance of 30–70 mL/min at the recommended dose.

There are no data available for valsartan/hydrochlorothiazide in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients undergoing dialysis. Valsartan is highly protein-bound and is not removed by dialysis, whereas hydrochlorothiazide clearance can be achieved via dialysis.

Renal clearance of hydrochlorothiazide involves passive filtration and active tubular secretion. As expected for a substance almost entirely eliminated by the kidneys, renal function has a marked effect on hydrochlorothiazide kinetics.

Hepatic impairment

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.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the active substances or to any of the components of the medicinal product; hypersensitivity to any sulfonamide-derived drug; severe impairment of liver function, cirrhosis and cholestasis; anuria, severe renal impairment (creatinine clearance < 30 mL/min); hypokalemia, hyponatremia, hypercalcemia or symptomatic hyperuricemia resistant to treatment; concomitant use of angiotensin receptor antagonists – including valsartan – or angiotensin-converting enzyme inhibitors (ACE inhibitors) with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²); pregnancy or women planning to become pregnant (see "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Concomitant use not recommended

Lithium

Elevated and potentially toxic serum lithium concentrations have been reported during concomitant use of lithium with ACE inhibitors and thiazides, including hydrochlorothiazide. Due to insufficient experience with concomitant use of valsartan and lithium, this combination is not recommended. If concomitant use is necessary, monitoring of serum lithium concentrations is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Valsacor® H 320 and Valsacor® HD 320 may enhance the effects of other antihypertensive agents (e.g., ACE inhibitors, beta-blockers, calcium channel blockers).

Pressor amines (e.g., adrenaline)

A reduced response to pressor amines may occur, but this is insufficient to preclude their use.

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

Concomitant use of angiotensin II receptor blockers (ARBs) with NSAIDs may result in diminished antihypertensive effect. Additionally, concomitant use of Valsacor® H 320 and Valsacor® HD 320 with NSAIDs may increase the risk of worsening renal function and lead to elevated serum potassium levels.

Therefore, monitoring of renal function at the start of treatment and adequate hydration are recommended.

Interactions related to valsartan

Double blockade of the renin-angiotensin-aldosterone system (RAAS) with ARBs, ACE inhibitors, or aliskiren

Concomitant use of ARBs, including valsartan, with other agents that block the RAAS, such as ACE inhibitors or aliskiren, increases the incidence of hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy. Dual blockade of the RAAS with ACE inhibitors, ARBs, or aliskiren is not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with severe renal impairment (GFR < 60 mL/min/1.73 m²), patients with type 1 or type 2 diabetes, and patients with diabetic nephropathy.

Concomitant use not recommended

Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other agents that may increase potassium levels

If co-administration of a drug affecting potassium levels with valsartan is necessary, monitoring of plasma potassium levels is recommended.

Transporters

In vitro studies have shown that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these findings is unknown. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation or discontinuation of concomitant therapy with these medicinal products.

Absence of interaction

Studies have not revealed any clinically significant interaction between valsartan and any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of Valsacor® H 320 and Valsacor® HD 320 (see "Interactions related to hydrochlorothiazide").

Interactions related to hydrochlorothiazide

Concomitant use requiring caution

Medicinal products associated with increased potassium loss and hypokalemia (e.g., potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormones, amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives).

If these agents are to be co-administered with the combination of valsartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended. These medicinal products may potentiate the effect of hydrochlorothiazide on serum potassium levels.

Medicinal products capable of inducing ventricular tachycardia "torsades de pointes"

Due to the risk of hypokalemia, hydrochlorothiazide should be used cautiously with medicinal products that may induce ventricular tachycardia of the "torsades de pointes" type, including 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 medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Caution is recommended during prolonged use of these medicinal products.

Medicinal products that may cause ventricular tachycardia "torsades de pointes":

• 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, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• others (e.g., bepridil, cisapride, diphenylamine, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinca alkaloids).

Due to the risk of hypokalemia, hydrochlorothiazide should be administered cautiously with medicinal products that may induce ventricular tachycardia "torsades de pointes".

Cardiac glycosides

In cases of digoxin-induced cardiac arrhythmias, hypokalemia or hypomagnesemia may occur during thiazide therapy.

Calcium salts and vitamin D

The use of thiazide diuretics, including hydrochlorothiazide, together with vitamin D or calcium salts may increase serum calcium levels. Concomitant use of thiazide diuretics with calcium salts may lead to 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 agents and insulin)

Thiazide therapy may affect glucose tolerance. Dose adjustment of antidiabetic agents may be required. Metformin should be used with caution due to the risk of lactic acidosis caused by possible functional renal impairment associated with hydrochlorothiazide use.

Beta-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may 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, as hydrochlorothiazide may increase serum uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

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

These agents may increase the bioavailability of thiazide-type diuretics, possibly due to reduced gastrointestinal and intestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may be expected to reduce the bioavailability of thiazide-type diuretics.

Amantadine

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

Ion-exchange resins

The absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol, which may result in subtherapeutic effects. 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.

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, potentiate the action of curare derivatives.

Cyclosporine

Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and complications such as gout.

Alcohol, barbiturates, narcotics, or antidepressants

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

Methyldopa

Cases of hemolytic anemia have been reported during concomitant use of hydrochlorothiazide and methyldopa.

Carbamazepine

Symptomatic hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Such patients should therefore be informed about the possibility of hyponatremic reactions and appropriate monitoring should be performed.

Contrast media containing iodine

In cases of dehydration caused by diuretics, there is an increased risk of acute renal failure, particularly with high doses of iodinated contrast agents. Fluid balance should be restored in patients prior to administration.

Special precautions for use.

Electrolyte imbalance in blood serum

Valsartan

Concomitant use with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin) is not recommended. If necessary, monitoring of potassium levels is advised.

Hydrochlorothiazide

Hypokalemia has been reported during treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium levels is recommended.

Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatremia and hypochloremic alkalosis. Thiazides, including hydrochlorothiazide, enhance magnesium excretion in urine, which may lead to hypomagnesemia. Thiazide diuretics reduce calcium excretion. This may result in hypercalcemia.

For each patient undergoing diuretic therapy, periodic analysis of serum electrolyte levels should be performed at appropriate intervals.

Patients with sodium and/or circulating blood volume imbalance

Patients receiving thiazide diuretics should be monitored for clinical signs of fluid or electrolyte imbalance.

Symptomatic hypotension may rarely occur after initiation of therapy with Valsacor® H 320 and Valsacor® HD 320 in patients with marked sodium and/or circulating blood volume imbalance (e.g., those receiving high doses of diuretics). Sodium and/or circulating blood volume imbalance should be corrected prior to initiating treatment with Valsacor® H 320 and Valsacor® HD 320.

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

Patients with severe congestive heart failure or other conditions with activation of the renin-angiotensin-aldosterone system (RAAS)

In patients whose renal function primarily depends on RAAS activity (e.g., patients with severe congestive heart failure), treatment with agents acting on the RAAS may cause oliguria and/or progressive azotemia, and rarely, acute renal failure. The safety of Valsacor® H 320 and Valsacor® HD 320 has not been established in patients with severe congestive heart failure.

Therefore, renal failure due to RAAS inhibition during treatment with Valsacor® H 320 and Valsacor® HD 320 cannot be excluded.

Valsacor® H 320 and Valsacor® HD 320 should not be used in such patients.

Renal artery stenosis

Valsacor® H 320 and Valsacor® HD 320 should not be used for the treatment of arterial hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, as serum urea and creatinine levels may increase in these patients.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Valsacor® H 320 and Valsacor® HD 320, as their RAAS is not activated.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilating agents, caution should be exercised in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Renal function impairment

Dose adjustment is not required in patients with mild to moderate renal impairment and creatinine clearance ≥ 30 mL/min. Valsacor® H 320 and Valsacor® HD 320 should be used with caution in patients with severe renal impairment (creatinine clearance <30 mL/min). Thiazide diuretics may precipitate azotemia in patients with chronic renal impairment. They are ineffective as monotherapy in severe renal failure (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.

Kidney transplantation

There is no experience with the safe use of Valsacor® H 320 and Valsacor® HD 320 in patients who have recently undergone kidney transplantation.

Hepatic function impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment without cholestasis. However, Valsacor® H 320 and Valsacor® HD 320 should be used with caution. Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide.

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 Quincke's edema with other drugs, including other angiotensin II receptor antagonists (ARA II). If angioedema occurs, treatment with ARA II should be discontinued immediately. Re-administration of the drug is contraindicated.

Intestinal angioedema

Intestinal angioedema has been reported in patients receiving angiotensin II receptor antagonists (see section "Adverse reactions"). Symptoms observed in these patients included abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, the drug should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Systemic lupus erythematosus

Exacerbation or activation of systemic lupus erythematosus has been reported during treatment with thiazide diuretics, including hydrochlorothiazide.

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may impair glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels. Dose adjustment of antidiabetic agents, including insulin, may be required in diabetic patients.

Thiazides may reduce calcium excretion in urine and cause a concomitant slight increase in serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued prior to parathyroid function testing.

Photosensitivity

Photosensitivity reactions have been reported during treatment with thiazide diuretics. If a photosensitivity reaction occurs during treatment, discontinuation of therapy is recommended. If re-administration of the diuretic is necessary, protection of sun-exposed areas or areas exposed to artificial ultraviolet light is advised.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. If continuation of treatment is considered necessary, patients planning pregnancy should switch to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is confirmed, treatment should be discontinued immediately and, if necessary, alternative therapy initiated.

General

Caution is advised in patients with hypersensitivity to other ARA II. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies or asthma.

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

Sulfonamides and sulfonamide derivatives may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include sudden onset of decreased visual acuity or eye pain, typically occurring within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss.

Treatment with the drug should be discontinued as soon as possible. Emergency medical or surgical intervention may be required if intraocular pressure remains uncontrolled. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer (NMSC)

An increased risk of non-melanoma skin cancer (NMSC) (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) with increasing cumulative exposure to hydrochlorothiazide (HCTZ) was observed in two epidemiological studies based on the Danish Cancer Registry. The photosensitizing effects of hydrochlorothiazide may act as a potential mechanism for 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 skin changes. Patients should be advised to take preventive measures, such as limiting exposure to sunlight and ultraviolet radiation, and, when exposure occurs, using adequate protection to minimize skin cancer risk. Suspicious skin lesions should be promptly evaluated, potentially including histological examination of biopsies. Re-evaluation of hydrochlorothiazide use may also be necessary in patients with a history of prior NMSC (see "Adverse reactions").

Acute respiratory toxicity

Very rare 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 of lung function, and hypotension. If ARDS is suspected, valsartan/hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS after taking hydrochlorothiazide.

Dual blockade of the RAAS

Arterial hypotension, syncope, stroke, hyperkalemia, and changes in renal function, including acute renal failure, have been observed in susceptible individuals, particularly when combining medicinal products affecting this system. Due to dual blockade of the RAAS, concomitant use of aliskiren with ARA II or ACE inhibitors is not recommended.

Special information on certain excipients

Valsacor® H 320 and Valsacor® HD 320 contain lactose. This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Dose adjustment is not required for elderly patients.

Hydrochlorothiazide may decrease plasma protein-bound iodine levels. Hydrochlorothiazide is capable of increasing the concentration of free bilirubin in serum.

Use during pregnancy or breastfeeding.

Pregnancy

Like other medicinal products acting directly on the RAAS, Valsacor® H 320 and Valsacor® HD 320 are contraindicated during pregnancy or in women planning to become pregnant. If pregnancy is confirmed during treatment, Valsacor® H 320 or Valsacor® HD 320 should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during pregnancy.

ARA II may cause fetal harm similar to that caused by ACE inhibitors.

It is known that use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetal injury and death.

Hydrochlorothiazide crosses the placenta. The intrauterine effect of thiazide diuretics may lead to fetal or neonatal thrombocytopenia and may be associated with other adverse reactions observed in adults.

Period of breastfeeding

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

Ability to influence reaction speed when driving or operating machinery.

During the initial phase of treatment (duration individually determined by the physician), driving and performing tasks that may lead to accidents are prohibited. The extent of restriction thereafter is determined by the physician.

Dosage and Administration

Dosing

The recommended dose of Valsacor® H 320 and Valsacor® HD 320 is 1 tablet per day. Dose titration of individual components is recommended. In each case, dose escalation via titration of individual components should be carefully monitored to minimize the risk of arterial hypotension and other adverse effects.

For patients whose blood pressure is not adequately controlled with monotherapy with valsartan or hydrochlorothiazide, direct transition to a fixed-dose combination may be considered, provided that the recommended dose titration sequence for individual components is followed.

Appropriate clinical response to Valsacor® H 320 should be evaluated after initiation of therapy. If adequate blood pressure reduction is not achieved, patients should be prescribed Valsacor® HD 320.

The maximum daily dose is 320 mg/25 mg.

The antihypertensive effect is primarily observed within the first 2 weeks of treatment.

In most patients, the maximum effect is achieved within 4 weeks. However, some patients may require 4–8 weeks of treatment. This should be taken into account during dose titration.

If no additional beneficial effect is observed after 8 weeks of treatment with Valsacor® HD 320, a decision should be made regarding treatment with an additional or alternative antihypertensive agent.

Administration method

Valsacor® H 320 and Valsacor® HD 320 may be administered independently of food intake; tablets should be taken with water.

Renal impairment

Dose adjustment is not required in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min). Due to the presence of hydrochlorothiazide, the drug is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min) and anuria (see sections "Contraindications", "Interaction with other medicinal products and other forms of interactions", and "Pharmacokinetics"). Concomitant use with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²) (see section "Contraindications").

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg (see section "Special precautions for use"). Dose adjustment of hydrochlorothiazide is not required in patients with mild or moderate hepatic impairment. Due to the presence of valsartan, the drug is contraindicated in patients with severe hepatic impairment or biliary cirrhosis and cholestasis (see sections "Contraindications", "Special precautions for use", and "Pharmacokinetics").

Diabetes mellitus

Concomitant use of valsartan and aliskiren is contraindicated in patients with diabetes mellitus (see section "Contraindications").

Elderly patients

No dose adjustment is required for elderly patients.

Children

Valsacor® H 320 and Valsacor® HD 320 are not recommended for use in children due to lack of data on safety and efficacy.

Overdose

Symptoms

Overdose with valsartan may lead to marked arterial hypotension, which may result in depressed consciousness, circulatory collapse, and/or shock. Additional manifestations and symptoms due to hydrochlorothiazide overdose may include nausea, drowsiness, hypovolemia, and electrolyte imbalance, accompanied by cardiac arrhythmias and muscle spasms. Other characteristic signs and symptoms of overdose 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).

Treatment

Therapeutic measures depend on the time of ingestion, type, and severity of symptoms; the primary goal is to stabilize circulatory status.

In case of arterial hypotension, the patient should be placed in a supine position and blood volume and electrolyte balance should be corrected.

Valsartan cannot be removed by hemodialysis due to its strong plasma protein binding, whereas hydrochlorothiazide can be eliminated by dialysis.

Adverse Reactions

The adverse reactions listed below are those observed more frequently with the combination of valsartan and hydrochlorothiazide than with placebo, reported during clinical trials and laboratory observations, as well as individual post-marketing reports. Adverse reactions associated with each individual component, but not observed during clinical trials, may also occur during treatment with the combination of valsartan and hydrochlorothiazide.

Adverse reactions are categorized by frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Frequency of adverse reactions during treatment with valsartan/hydrochlorothiazide

Infections

Uncommon: viral infections, fever.

Metabolism and nutrition disorders

Uncommon: dehydration.

Not known: hypokalemia, hyponatremia.

Nervous system disorders

Very common: headache, fatigue.

Uncommon: asthenia, dizziness, insomnia, anxiety, paresthesia.

Rare: depression.

Not known: loss of consciousness (syncope).

Eye disorders

Uncommon: blurred vision.

Rare: conjunctivitis.

Ear and labyrinth disorders

Uncommon: otitis media, tinnitus.

Vascular disorders

Uncommon: arterial hypotension, edema, hyperhidrosis.

Respiratory, thoracic and mediastinal disorders

Common: cough, nasal congestion, pharyngitis, upper respiratory tract infections.

Uncommon: bronchitis, dyspnea, sinusitis, throat pain, dry mouth.

Very rare: epistaxis.

Not known: non-cardiogenic pulmonary edema.

Gastrointestinal disorders

Very rare: diarrhea.

Uncommon: abdominal pain, dyspepsia, nausea, gastroenteritis.

Musculoskeletal and connective tissue disorders

Common: back pain, arthralgia.

Uncommon: pain in limbs, chest pain, neck pain, arthritis, sprains and deformities, muscle cramps, myalgia.

Renal and urinary disorders

Uncommon: frequent urination, urinary tract infections.

Not known: renal function impairment.

General disorders and administration site conditions

Uncommon: increased fatigue.

Investigations

Not known: increased serum uric acid, increased serum bilirubin and creatinine, hypokalemia, hyponatremia, increased blood urea nitrogen, neutropenia.

The following reactions were observed during clinical trials in patients with hypertension, regardless of their causal relationship to the investigational drug: abdominal pain, upper abdominal pain, restlessness, arthritis, back pain, bronchitis, acute bronchitis, chest pain, dizziness, dyspepsia, dyspnea, dry mouth, epistaxis, impotence, gastroenteritis, headache, increased sweating, hypesthesia, influenza, insomnia, ligament sprain, muscle cramps, muscle strain, nausea, nasal congestion, nasal sinus congestion, neck pain, swelling, peripheral edema, otitis media, limb pain, palpitations, pharyngolaryngeal pain, polyuria, increased body temperature, 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.

Additional information on individual components

Adverse reactions previously reported with either individual component may also occur during treatment with Valsacor® H 320 and Valsacor® HD 320, even if they were not observed during clinical trials or in the post-marketing period.

Frequency of adverse reactions during treatment with valsartan

Blood and lymphatic system disorders

Not known: decreased hemoglobin, decreased hematocrit, thrombocytopenia.

Immune system disorders

Very rare: necrotizing vasculitis, hypersensitivity/allergic reactions.

Metabolism and nutrition disorders

Common: hyponatremia, hypomagnesemia, hyperuricemia, loss of appetite.

Ear and labyrinth disorders

Uncommon: vertigo.

Vascular disorders

Not known: vasculitis.

Gastrointestinal disorders

Uncommon: abdominal pain.

Very rare: intestinal angioedema.

Hepatobiliary disorders

Not known: increased liver function test values.

Skin and subcutaneous tissue disorders

Not known: angioedema, rash, pruritus, bullous dermatitis.

Renal and urinary disorders

Not known: renal failure.

The following reactions were 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.

Frequency of adverse reactions during treatment with hydrochlorothiazide

Hydrochlorothiazide has been widely used for many years, often at higher doses than those contained in Valsacor® H 320 and Valsacor® HD 320. The following adverse reactions have been reported in patients receiving thiazide diuretics, including hydrochlorothiazide, as monotherapy:

Metabolism and nutrition disorders

Very common: increased blood lipid levels at high doses.

Common: hypomagnesemia, hyperuricemia.

Rare: hypercalcemia, hyperglycemia, glucosuria, and worsening of glucose metabolism in diabetic patients.

Very rare: hypochloremic alkalosis.

Blood and lymphatic system disorders

Rare: thrombocytopenia, sometimes with purpura.

Very rare: agranulocytosis, leukopenia, hemolytic anemia, bone marrow suppression.

Not known: aplastic anemia.

Immune system disorders

Very rare: hypersensitivity reactions.

Psychiatric disorders

Rare: depression, sleep disorders.

Nervous system disorders

Rare: headache, dizziness, paresthesia.

Eye disorders

Uncommon: blurred vision during the first few weeks of treatment.

Not known: acute angle-closure glaucoma, choroidal effusion.

Cardiac disorders

Rare: cardiac arrhythmia.

Vascular disorders

Common: postural hypotension, which may be exacerbated by alcohol, anesthetics, or sedatives.

Respiratory, thoracic and mediastinal disorders

Very rare: respiratory failure, including pneumonia and pulmonary edema, acute respiratory distress syndrome (ARDS) (see section "Special precautions").

Gastrointestinal disorders

Common: loss of appetite, mild nausea, vomiting.

Rare: constipation, gastrointestinal discomfort, diarrhea.

Very rare: pancreatitis.

Hepatobiliary disorders

Rare: intrahepatic cholestasis or jaundice.

Skin and subcutaneous tissue disorders

Common: urticaria and other types of rash.

Rare: photosensitivity.

Very rare: necrotizing vasculitis, toxic epidermal necrolysis, lupus-like skin reactions, reactivation of cutaneous manifestations of lupus.

Not known: erythema multiforme.

Reproductive system and breast disorders

Common: impotence.

Renal and urinary disorders

Not known: acute renal failure, renal disorders.

General disorders and administration site conditions

Not known: fever, fatigue.

Musculoskeletal and connective tissue disorders

Not known: muscle spasms.

Benign, malignant and unspecified neoplasms (including cysts and polyps): non-melanoma skin cancer (NMSC) (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC))¹.

¹ Non-melanoma skin cancer: Based on available epidemiological data, a cumulative dose-dependent association has been observed between hydrochlorothiazide and NMSC (see "Special precautions" and "Pharmacological properties").

Treatment with Valsacor® H 320 and Valsacor® HD 320 should be discontinued if severe adverse effects occur.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging to protect from light and moisture. Keep out of reach of children.

Packaging.

10 tablets in a blister, 3 or 6 blisters in a cardboard box;

14 tablets in a blister, 1, 2, or 4 blisters in a cardboard box;

15 tablets in a blister, 2 or 4 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.