Valsartan n-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valsartan H-Teva (Valsartan H-Teva)

Composition:

Active substances: valsartan, hydrochlorothiazide;

One tablet contains valsartan 80 mg, hydrochlorothiazide 12.5 mg or valsartan 160 mg, hydrochlorothiazide 12.5 mg, or valsartan 160 mg, hydrochlorothiazide 25 mg, or valsartan 320 mg, hydrochlorothiazide 12.5 mg, or valsartan 320 mg, hydrochlorothiazide 25 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, povidone K29-K32, talc, magnesium stearate, colloidal anhydrous silicon dioxide;

Coating of the 80/12.5 mg tablet: Opadry II 85G34642 Pink (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172));

Coating of the 160/12.5 mg tablet: Opadry II 85G25455 Red (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, iron oxide red (E 172), Sunset Yellow dye (E 110));

Coating of the 160/25 mg tablet: Opadry II 85G23675 Orange (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172));

Coating of the 320/12.5 mg tablet: Opadry II Pink 85G34643 (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, iron oxide red (E 172), iron oxide yellow (E 172));

Coating of the 320/25 mg tablet: Opadry II Yellow 85G32408 (polyvinyl alcohol, talc, titanium dioxide (E 171), macrogol 3350, lecithin, iron oxide yellow (E 172), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:
80/12.5 mg tablets – pink, oval, biconvex film-coated tablets, marked with "V" on one side and "H" on the other;

160/12.5 mg tablets – red, oval, biconvex film-coated tablets, marked with "V" on one side and "H" on the other;

160/25 mg tablets – orange, oval, biconvex film-coated tablets, marked with "V" on one side and "H" on the other;

320/12.5 mg tablets – pink, oval, biconvex film-coated tablets, marked with "H" on one side and "V" on the other;

320/25 mg tablets – yellow, oval, biconvex film-coated tablets, marked with "H" on one side and "V" on the other, with a break line on one side and side lines.

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 with the participation 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 direct and indirect involvement in the regulation of arterial blood pressure. As a potent vasoconstrictor substance, angiotensin II exerts a direct pressor effect. In addition, it promotes sodium retention and stimulates aldosterone secretion.

Valsartan is an active and specific angiotensin II receptor antagonist (ARB-II) intended for oral administration. It selectively acts on AT1 subtype receptors, which are responsible for the effects of angiotensin II. Increased levels of angiotensin II resulting from AT1 receptor blockade by valsartan may stimulate unoccupied AT2 receptors, thereby counterbalancing the effects mediated via 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 that converts angiotensin I into angiotensin II and degrades bradykinin. No side effects related to bradykinin accumulation have been observed. In clinical studies comparing valsartan with angiotensin-converting enzyme inhibitors (ACEIs), the incidence of dry cough was significantly lower (P<0.05) in patients treated with valsartan than in those receiving ACEIs (2.6% vs. 7.9%, respectively). In patients who previously experienced dry cough during ACEI therapy, this adverse event 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 patients receiving ACEIs (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 that play an important role in cardiovascular function regulation. Administration of the drug to hypertensive patients leads to a reduction in arterial blood pressure without affecting pulse rate.

In most patients, after 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 abrupt increases in blood pressure (rebound phenomenon) or other adverse effects. Valsartan does not affect total cholesterol, triglycerides, serum glucose, or serum uric acid levels in patients with arterial hypertension.

Thiazide diuretics act primarily at 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 action of thiazides involves inhibition of the Na+/Cl− cotransporter, likely through competitive inhibition at chloride transport sites. As a result, urinary 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, and consequently, reduced serum potassium concentration. The relationship between renin and aldosterone is mediated by angiotensin II; therefore, administration of ARBs 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 Valsartan H-Teva is 23%. The pharmacokinetic curve of valsartan is characterized by a multiphasic decline (t1/2α <1 hour and t1/2β approximately 9 hours). Within the studied dose range, valsartan kinetics are linear. No changes in kinetic parameters were observed with repeated dosing. With once-daily administration, accumulation is minimal. Plasma concentrations of the drug are similar in men and women. 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 administered dose is excreted in feces, and nearly 30% is excreted in urine, predominantly unchanged.

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

Hydrochlorothiazide. Absorption of hydrochlorothiazide after oral administration is rapid (tmax approximately 2 hours). Pharmacokinetics during distribution and elimination phases are generally described by a biphasic decline curve; the terminal half-life ranges from 6 to 15 hours. Within the therapeutic dose range, mean AUC increases proportionally with dose. Pharmacokinetics do not change with repeated administration; accumulation is minimal with once-daily dosing. Absolute oral bioavailability of hydrochlorothiazide is 70%. Excretion occurs primarily in urine: over 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 magnitude of these variations is small and not clinically significant.

Valsartan/hydrochlorothiazide. When administered concomitantly with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by approximately 30%. Concurrent administration of hydrochlorothiazide does not significantly affect the pharmacokinetics of valsartan. However, this interaction does not compromise the efficacy of the combined use of valsartan and hydrochlorothiazide. Controlled clinical trials have demonstrated a clear antihypertensive effect of this combination, which exceeds the effect of either component alone and that 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 may be 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 H-Teva in patients with severe renal impairment (creatinine clearance <30 mL/min) or in patients undergoing hemodialysis. Valsartan is highly bound to plasma proteins 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 are increased, while urinary excretion is reduced. In patients with mild to moderate renal impairment, the mean elimination half-life is nearly doubled due to significantly reduced renal clearance.

Renal excretion of hydrochlorothiazide occurs via passive filtration and active secretion into the renal tubular lumen. Renal function plays a major role in hydrochlorothiazide pharmacokinetics, as this drug is eliminated exclusively by the kidneys. In patients with renal impairment, mean peak plasma concentrations and AUC values of hydrochlorothiazide are elevated, and urinary excretion is reduced. In patients with mild to moderate renal impairment, a threefold increase in AUC of hydrochlorothiazide is observed. In patients with severe renal impairment, an eightfold increase in AUC is observed. Hydrochlorothiazide is contraindicated in patients with severe renal impairment.

Hepatic impairment. Systemic exposure to valsartan was approximately twice as high 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 (BCC) (with 1,430,843 individuals in the control group) and 8,629 cases of squamous cell carcinoma (SCC) (with 172,462 individuals in the control group). High-dose hydrochlorothiazide exposure (≥50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A cumulative dose-response relationship was observed for both BCC and SCC. Another study suggested 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 the 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 the medicinal product or to other sulfonamide derivatives, as well as to peanuts or soy.
• Severe impairment of liver function, biliary cirrhosis, and cholestasis.
• Anuria.
• Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
• Concomitant use of angiotensin II receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme inhibitors (ACE inhibitors) with aliskiren in patients with diabetes mellitus (type I and type II) or renal impairment (eGFR <60 mL/min/1.73 m²).
• Pregnancy, planned pregnancy (see section "Use in 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 lithium toxicity have been reported with concomitant use of ACE inhibitors and thiazide diuretics, including hydrochlorothiazide. Due to the lack of experience with concomitant use of valsartan and lithium, such combination is not recommended. If combination therapy is necessary, careful monitoring of plasma lithium levels is recommended.

Concomitant use requires caution

Other antihypertensive agents. Valsartan H-Teva may enhance the effect of other antihypertensive agents (such as guanethidine, methyldopa, vasodilators, ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, and direct renin inhibitors).

Pressor amines (e.g., noradrenaline, adrenaline). A reduced response to pressor amines such as noradrenaline may occur. The clinical significance of this effect is uncertain and not sufficient to preclude their use.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid >3 g/day, and non-selective NSAIDs. NSAIDs may attenuate the antihypertensive effect of both ARBs and hydrochlorothiazide when used concomitantly. Additionally, concomitant use of Valsartan H-Teva and NSAIDs may lead to worsening of renal function and increased plasma potassium levels. Therefore, monitoring of renal function at the beginning of treatment and adequate hydration of the patient are recommended.

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

Interactions associated with valsartan

Dual blockade of the RAAS. Caution is required when ARBs, including valsartan, are used concomitantly with other agents 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, ARBs, or aliskiren is not recommended. If dual RAAS blockade is considered absolutely necessary, treatment should be administered 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 and type II), diabetic nephropathy, or renal impairment (eGFR <60 mL/min/1.73 m²) is contraindicated (see section "Contraindications").

Concomitant use not recommended

Potassium-sparing diuretics, potassium-containing dietary supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels. When using a medicinal product that affects potassium levels in combination with valsartan, monitoring of plasma potassium levels is recommended. Concomitant use of ARBs with other agents capable of increasing serum potassium (e.g., potassium-sparing diuretics, potassium supplements, heparin) increases the risk of hyperkalemia. In such cases, Valsartan H-Teva 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. Appropriate caution is recommended when initiating or discontinuing concomitant therapy with such agents.

Absence of interaction

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

Interactions associated with hydrochlorothiazide

Concomitant use requires 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, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, antiarrhythmic agents. If co-administration of these agents with the combination of hydrochlorothiazide and valsartan is necessary, monitoring of plasma potassium levels is recommended.

Medicinal products affecting serum sodium levels. The hyponatremic effect of diuretics may be enhanced when used concomitantly with antidepressants, antipsychotics, antiepileptic drugs, etc. Caution is recommended during prolonged use of these agents.

Medicinal products that may induce ventricular tachycardia of the torsades de pointes type

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide).
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide).
• Certain antipsychotics (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 vinca alkaloids).

Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution when administered concomitantly with medicinal products that may induce ventricular tachycardia of the torsades de pointes type.

Cardiac glycosides (digitalis). Thiazide-induced hypokalemia or hypomagnesemia may predispose to digitalis-induced cardiac arrhythmias as an adverse effect.

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 treatment may affect glucose tolerance. Dose adjustment of antidiabetic agents 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). Dose adjustment of uricosuric agents may be required because hydrochlorothiazide may increase plasma uric acid levels. Increased doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.

Anticholinergic agents and other agents affecting gastrointestinal motility. The bioavailability of thiazide diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), likely due to decreased gastrointestinal motility and gastric emptying rate. 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. 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 such 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, enhance the effect of skeletal muscle relaxants such as curare derivatives.

Cyclosporine. Concomitant administration with cyclosporine may increase the risk of hyperuricemia and gout-like complications.

Alcohol, barbiturates, and anesthetic agents. When thiazide diuretics are used concomitantly with agents that may also lower blood pressure (e.g., due to reduced activity of the central sympathetic nervous system or direct vasodilatory effect), potentiation of orthostatic hypotension may occur.

Methyldopa. Isolated reports of hemolytic anemia have been reported in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide.

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 doses of iodine-containing agents. Adequate fluid replacement should be ensured prior to administration.

Special precautions for use.

Electrolyte changes in blood serum

Potassium. Thiazide diuretics may cause hypokalemia or exacerbate pre-existing hypokalemia. Correction of hypokalemia is recommended before initiating thiazide therapy. Concomitant hypomagnesemia may lead to hypokalemia that is more difficult to correct.

Concomitant use of valsartan with potassium-containing dietary supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin) is not recommended. Cases of hypokalemia have been reported during treatment with thiazide diuretics (including hydrochlorothiazide). 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 circulating blood volume (CBV). Thiazide diuretics may cause hyponatremia and hypochloremic alkalosis. These may be accompanied by neurological symptoms (e.g., vomiting, confusion, apathy). Thiazide diuretics should be administered only after correction of hyponatremia. Patients receiving thiazide diuretics (including hydrochlorothiazide) should be observed for clinical signs of fluid or electrolyte imbalance. Serum sodium concentration should be monitored regularly.

Thiazides (including hydrochlorothiazide) enhance urinary magnesium excretion, which may result in hypomagnesemia. In patients with severe sodium deficiency and/or reduced circulating blood volume (e.g., those receiving high-dose diuretics), symptomatic hypotension may occur after initiation of treatment with this medicinal product. Therefore, correction of sodium levels and/or circulating blood volume should be performed before starting therapy with this product.

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

Calcium. Thiazide diuretics reduce calcium excretion, which may lead to hypercalcemia. Thiazide diuretics should be administered only 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 depends on the activity of the renin-angiotensin-aldosterone system (RAAS) (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 and/or fatal outcomes. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function. Use of the medicinal product in patients with severe chronic heart failure is not justified. Since it cannot be excluded that inhibition of RAAS by this product may also impair renal function, Valsartan H-Teva should not be used in such patients.

Renal artery stenosis. The product should not be administered to patients with unilateral or bilateral renal artery stenosis or stenosis of the renal artery of a single kidney, as plasma urea and creatinine levels may increase in these patients.

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

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

Renal impairment. No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance >30 mL/min) (see section "Posology and method of administration"). The product 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 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. Periodic monitoring of serum potassium, creatinine, and uric acid is recommended when administering the product to patients with renal impairment.

Concomitant use of ARBs II, including valsartan, or ACE inhibitors with aliskiren in patients with renal impairment (eGFR <60 mL/min/1.73 m²) is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). 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.

Renal transplantation. There is currently no experience regarding the safety of the product in patients who have recently undergone renal transplantation.

Hepatic impairment. Caution is required when treating patients with hepatic impairment. Valsartan H-Teva should be used with caution in patients with mild to moderate hepatic impairment without cholestasis (see section "Posology and method of administration"). Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide. Thiazides may cause electrolyte imbalances, hepatic encephalopathy, and hepatorenal syndrome. Thiazides should be used with caution in patients with hepatic impairment or progressive liver disease, as even minor changes in fluid and electrolyte balance may precipitate hepatic coma. Therefore, the product should be prescribed to such patients only after careful risk-benefit assessment and monitoring of clinical and laboratory parameters. Valsartan H-Teva is contraindicated in patients with biliary cirrhosis or cholestasis.

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

Other metabolic disturbances. Thiazide diuretics (including hydrochlorothiazide) may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels, potentially exacerbating hyperuricemia and leading to gout. Therefore, Valsartan H-Teva is not recommended for patients with hyperuricemia and/or gout. Diabetic patients may require adjustment of insulin or oral hypoglycemic agent dosage. Thiazides may reduce urinary calcium excretion and cause a transient slight increase in serum calcium levels in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate underlying hyperparathyroidism. Thiazide use should be discontinued prior to testing 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 areas from sunlight or artificial ultraviolet radiation is recommended.

Pregnancy. ARBs II should not be initiated during pregnancy. If continuation of ARB II therapy is not considered necessary, women planning pregnancy should be switched to alternative antihypertensive treatments with established safety profiles during pregnancy. ARB II therapy should be discontinued immediately upon confirmation of pregnancy, and alternative therapy should be initiated if necessary.

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

Angioedema. Angioedema (including laryngeal and glottal edema leading to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling) has been observed in patients receiving valsartan; some of these patients had a history of angioedema with other drugs, including ACE inhibitors. If angioedema develops, treatment with this product should be discontinued immediately. Re-administration of the product is contraindicated.

Intestinal angioedema. Intestinal angioedema has been reported in patients receiving ARBs II, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of ARB II. If intestinal angioedema occurs, this medicinal product should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Sulfonamide drugs 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 of decreased visual acuity or eye pain and usually occur within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment includes prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, a decision on rapid medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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 to hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening pulmonary status, and hypotension. If ARDS is suspected, this product should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide.

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 some 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 exposure to hydrochlorothiazide was observed in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for NMSC development. 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. Preventive measures such as limiting exposure to sunlight and ultraviolet radiation or using appropriate protective measures during exposure to sunlight or ultraviolet radiation should be recommended to reduce the risk of skin cancer. Suspicious skin lesions should be promptly evaluated with histological examination of biopsy material. Re-evaluation of hydrochlorothiazide use may be necessary in patients with a history of NMSC (see also section "Adverse reactions").

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

No dose adjustment is required for elderly patients.

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

Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption. This product should not be administered to patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Lecithin. This product should not be administered to patients with peanut or soy allergy.

Hypersensitivity. Valsartan H-Teva 160/12.5 mg tablets contain Sunset yellow FCF (E 110), which may cause hypersensitivity reactions.

Use during pregnancy or breastfeeding.

Pregnancy.

Valsartan. The medicinal product should not be used in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this product, it should be discontinued immediately and replaced with another product approved for use during pregnancy. It is known that use of ARBs II during the second and third trimesters causes fetotoxicity (renal dysfunction, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia) in humans. If ARB II use occurred from the second trimester of pregnancy, ultrasound monitoring of renal function and skull development is recommended. Infants whose mothers took ARBs II 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 medicinal product acting on the RAAS should inform the woman about the potential risks during pregnancy. Due to the mechanism of action of ARBs II, the risk of embryopathy and fetal disease cannot be excluded. According to retrospective data, use of ACE inhibitors during the first trimester is associated with a potential risk of congenital defects. Moreover, fetal injury and death have been reported with use of drugs directly affecting the RAAS during the second and third trimesters. Fetal renal perfusion, dependent on RAAS development, begins during the second trimester in humans. Thus, the risk associated with valsartan treatment is higher during the second and third trimesters. Reports of spontaneous abortions, oligohydramnios, and renal dysfunction in newborns have occurred when pregnant women inadvertently took valsartan.

Newborns exposed to the product 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 product from the 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.

Period of breastfeeding. If use of the product is absolutely necessary, breastfeeding should be discontinued. There is no information on the use of valsartan during breastfeeding, while hydrochlorothiazide passes into human milk. Thiazides in high doses cause diuresis, which may suppress milk production. During the breastfeeding period, alternative treatment methods with better-established safety profiles should preferably be used, especially when breastfeeding a newborn or premature infant.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

The recommended dose of Valsartan H-Teva is 1 tablet of 80 mg/12.5 mg once daily. If blood pressure is not adequately 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 should be 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 further increasing the dose to 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 320 mg/12.5 mg tablets.

The maximum daily dose is 320 mg/25 mg.

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

The maximum antihypertensive effect is achieved within 2–4 weeks. For some patients, 4–8 weeks of treatment may be required. Valsartan H-Teva can be taken regardless of food intake. Tablets should be swallowed with a small amount of water.

Use in elderly patients (over 65 years of age). Valsartan H-Teva can be used in patients of any age.

Use in patients with renal impairment. Dose reduction may be required in patients with renal impairment. Since Valsartan H-Teva contains hydrochlorothiazide, it is contraindicated in patients with anuria. Special caution is required when administering 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 required in patients with hepatic impairment. Since Valsartan H-Teva contains hydrochlorothiazide, it should be used with caution in patients with hepatic impairment. Since Valsartan H-Teva 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 without cholestasis should not exceed 80 mg.

Children.

Valsartan H-Teva is not recommended for use in children due to lack of data on safety and efficacy.

Overdose.

Symptoms. Overdose with valsartan may cause marked hypotension, which in turn may lead to decreased 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 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 increased blood urea nitrogen levels (primarily due to renal failure).

Treatment. In all cases of overdose, general supportive measures should be initiated, including continuous monitoring of the patient and measures to stabilize cardiovascular function. Therapeutic interventions depend on the time elapsed since ingestion and the severity of symptoms; the primary goal is to restore hemodynamic stability. If the drug was recently ingested, induce vomiting. If a significant amount of time has passed since ingestion, administer activated charcoal. In case of hypotension, place the patient in a supine position and immediately restore fluid and electrolyte balance by intravenous administration of isotonic saline solution. Valsartan cannot be effectively removed by hemodialysis due to its high plasma protein binding; however, hemodialysis is effective for removing hydrochlorothiazide from the body.

Adverse Reactions

Adverse reactions most commonly reported during clinical trials of valsartan/hydrochlorothiazide compared to placebo, as well as during the post-marketing period, are listed below by system organ class. 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); unknown (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Adverse reactions associated with valsartan/hydrochlorothiazide

Infections. Uncommon: viral infections, fever.

Metabolism and nutrition disorders. Uncommon: dehydration.

Nervous system disorders. Common: headache, fatigue, dizziness. Uncommon: asthenia, insomnia, anxiety, paraesthesia. Rare: depression. 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: oedema, hypotension, hyperhidrosis.

Respiratory, thoracic and mediastinal disorders. Common: cough, rhinitis, pharyngitis, upper respiratory tract infections. Uncommon: bronchitis, dyspnoea, sinusitis, pharyngolaryngeal pain, dry mouth. Very rare: epistaxis. Unknown: non-cardiogenic pulmonary oedema.

Gastrointestinal disorders. Common: diarrhoea. 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: frequent urination, urinary tract infections. Very rare: renal function impairment.

Reproductive system and breast disorders. Common: erectile dysfunction.

General disorders and administration site conditions. Uncommon: increased fatigue.

Investigations. Unknown: increased plasma uric acid, increased plasma bilirubin and creatinine, hypokalaemia, hyponatraemia, increased blood urea nitrogen, neutropenia.

A decrease in serum potassium levels by more than 20% was observed in 3.7% of patients receiving the combination of valsartan/hydrochlorothiazide and in 3.1% of patients receiving placebo. Increases in creatinine and blood urea nitrogen were observed in 1.9% and 14.7% of patients receiving the combination of valsartan/hydrochlorothiazide, respectively, compared to 0.4% and 6.3% 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: hypaesthesia, influenza, insomnia, ligament sprain, muscle strain, nasal congestion, nasopharyngitis, neck pain, peripheral oedema, sinus congestion.

The following reactions 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%) decreases in haematocrit and haemoglobin levels were reported 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, compared to 1.6%, 6.4%, and 12.9% of patients receiving ACE inhibitors. Increased liver function test results were uncommon 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 hypertension: upper abdominal pain, restlessness, arthritis, back pain, bronchitis, acute bronchitis, chest pain, dizziness, dyspepsia, dyspnoea, dry mouth, nosebleeds, impotence, gastroenteritis, headache, increased sweating, hypaesthesia, influenza, insomnia, ligament sprain, muscle cramps, muscle strain, nausea, nasal congestion, sinus congestion, neck pain, oedema, peripheral oedema, otitis media, limb pain, rapid heartbeat, pharyngolaryngeal pain, polyuria, increased 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.

During the post-marketing period, reports included syncope and very rare cases of angioedema, 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 previously observed with valsartan and hydrochlorothiazide when used separately may also potentially occur with Valsartan H-Teva, even if they were not observed during clinical trials or the post-marketing period of this combination.

Adverse reactions associated with valsartan

Blood and lymphatic system disorders. Unknown: decreased haemoglobin, decreased haematocrit, thrombocytopenia.

Immune system disorders. Unknown: other hypersensitivity/allergic reactions, including serum sickness.

Metabolism and nutrition disorders. Unknown: increased plasma potassium, hyponatraemia.

Ear and labyrinth disorders. Uncommon: vestibular dizziness (vertigo).

Vascular disorders. Unknown: vasculitis.

Gastrointestinal disorders. Uncommon: abdominal pain, gastroenteritis. Very rare: intestinal angioedema.

Hepatobiliary disorders. Unknown: increased liver function tests.

Skin and subcutaneous tissue disorders. Unknown: oedema, angioedema, rash, pruritus, bullous dermatitis.

Renal and urinary disorders. Unknown: renal failure, acute renal failure.

Musculoskeletal and connective tissue disorders. Common: arthralgia.

Nervous system disorders. Uncommon: asthenia, insomnia, dizziness. Rare: neuralgia.

Reproductive system and breast disorders. Uncommon: decreased libido.

Cardiac disorders. Very rare: cardiac arrhythmia.

There has been one reported case of angioedema.

Reactions observed during clinical trials in patients with hypertension, regardless of causal relationship to the investigational drug: arthralgia, asthenia, back pain, diarrhoea, dizziness, headache, insomnia, decreased libido, nausea, oedema, pharyngitis, rhinitis, sinusitis, upper respiratory tract inflammation, viral infections.

Adverse reactions associated with hydrochlorothiazide

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

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

Metabolism and nutrition disorders. Very common: with high-dose use – increased blood lipid levels, hypokalaemia. Common: hyponatraemia, hypomagnesaemia, hyperuricaemia. Rare: hypercalcaemia, hyperglycaemia, glucosuria, and worsening of metabolism in patients with diabetes mellitus. Very rare: hypochloraemic alkalosis.

Blood and lymphatic system disorders. Rare: thrombocytopenia, sometimes with purpura. Very rare: agranulocytosis, leucopenia, haemolytic anaemia, bone marrow suppression. Unknown: aplastic anaemia.

Immune system disorders. Very rare: hypersensitivity reactions.

Psychiatric disorders. Rare: depression, sleep disturbances.

Nervous system disorders. Rare: headache, dizziness, paraesthesia.

Eye disorders. Rare: blurred vision during the first few weeks of treatment. Unknown: choroidal effusion, acute myopia, and acute angle-closure glaucoma.

Cardiac disorders. Rare: arrhythmia.

Vascular disorders. Common: postural hypotension, which may be exacerbated by alcohol, anaesthetics, or sedatives.

Respiratory, thoracic and mediastinal disorders. Very rare: respiratory failure, including pneumonitis and pulmonary oedema; acute respiratory distress syndrome.

Gastrointestinal disorders. Common: loss of appetite, mild nausea, and vomiting. Rare: constipation, gastrointestinal discomfort, diarrhoea. Very rare: pancreatitis.

Hepatobiliary disorders. Rare: intrahepatic cholestasis or jaundice.

Skin and subcutaneous tissue disorders. Common: urticaria and other types of rash. Rare: photosensitization. Very rare: necrotizing vasculitis, toxic epidermal necrolysis, lupus-like skin reactions, skin lupus reactivation. Unknown: erythema multiforme.

Reproductive system and breast disorders. Common: impotence.

Renal and urinary disorders. Unknown: acute renal failure, renal disorders.

General disorders and administration site conditions. Unknown: increased temperature, fatigue.

Musculoskeletal and connective tissue disorders. Unknown: muscle spasms.

Shelf life.

For dosage strengths 80/12.5 mg, 160/12.5 mg, 160/25 mg – 4 years.

For dosage strengths 320/12.5 mg, 320/25 mg – 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets in a blister; 3 or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturers.

Actavis Ltd.

Balkanpharma-Dupnitsa AD.

Manufacturers' locations and addresses of their business operations.

VBL015, VBL016 Bulebel Industrial Building, Zietun ZTN 3000, Malta.

3 Samokovsko Shose Str., Dupnitsa, 2600, Bulgaria.