Corsar® n duo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORSAR® H DUO (CORSAR H DUO)

Composition:

Active substances: valsartan, hydrochlorothiazide;

One film-coated tablet contains:

80 mg of valsartan and 12.5 mg of hydrochlorothiazide, or 160 mg of valsartan and 12.5 mg of hydrochlorothiazide, or 160 mg of valsartan and 25 mg of hydrochlorothiazide, or 320 mg of valsartan and 12.5 mg of hydrochlorothiazide, or 320 mg of valsartan and 25 mg of hydrochlorothiazide;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: hypromellose, titanium dioxide (E 171), polyethylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white to almost white, round, biconvex tablets, film-coated.

Pharmacotherapeutic group.

Agents acting on the renin-angiotensin system. Combined angiotensin II receptor antagonists. Angiotensin II blockers and diuretics. Valsartan and diuretics. ATC code C09DA03.

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 both direct and indirect involvement in the regulation of arterial 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 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 due to blockade of AT1 receptors by valsartan may stimulate unoccupied AT2 receptors, thereby counterbalancing the effects mediated by AT1 receptors. Valsartan has no partial agonist activity at AT1 receptors and has much greater (approximately 20,000 times) affinity for AT1 receptors than for AT2 receptors.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. No side effects related to bradykinin have been observed. In clinical studies comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who previously experienced dry cough during treatment with an ACE inhibitor, this complication occurred in 19.5% of cases during treatment with valsartan and in 19% of cases during treatment with a thiazide diuretic, whereas cough was observed in 68.5% of cases in the group receiving an ACE inhibitor (P < 0.05).

In controlled clinical studies, 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.

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

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

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

Discontinuation of valsartan does not lead to rebound hypertension or other adverse effects.

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

Pharmacokinetics

Valsartan

After oral administration of valsartan, maximum plasma concentration (Cmax) is reached within 2–4 hours. The mean value of absolute bioavailability of valsartan is 23% (range 23 ± 7). Within the studied dose range, the kinetics of valsartan are linear. No changes in kinetic parameters were observed upon repeated administration. With once-daily dosing, accumulation is minimal. Plasma concentrations of the drug are similar in women and men.

When valsartan is administered with food, the area under the concentration-time curve (AUC) decreases by 48% and Cmax by 59%, although approximately 8 hours after administration, plasma concentrations are similar whether the drug is taken fasting or with food. The reduction in AUC and Cmax is not associated with clinically significant reduction in therapeutic effect; therefore, valsartan can be administered independently of food intake.

Valsartan is highly bound to plasma proteins (94–97%), primarily to albumin. Steady-state conditions are achieved within 1 week. The volume of distribution at steady state is low (approximately 17 L), indicating that valsartan is not extensively distributed into tissues. Compared to hepatic blood flow (approximately 30 L/h), the plasma clearance of valsartan is relatively slow (approximately 2 L/h). Valsartan undergoes limited biotransformation, as only about 20% of the dose is excreted as metabolites. A hydroxymetabolite is detected in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Valsartan demonstrates multiphasic elimination kinetics (initial half-life < 1 hour, terminal (beta) half-life approximately 9 hours). Valsartan is primarily eliminated via feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mostly in unchanged form. After intravenous administration, the plasma clearance of valsartan is about 2 L/h, and renal clearance is 0.62 L/h (approximately 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption of hydrochlorothiazide after oral administration occurs rapidly (tmax approximately 2 hours). The increase in mean AUC is linear and proportional to dose within the therapeutic range. When hydrochlorothiazide is administered with food, both increases and decreases in systemic bioavailability have been observed compared to fasting administration. However, the range of these changes is minor and not clinically significant. Absolute bioavailability of hydrochlorothiazide is approximately 70% after oral administration. The pharmacokinetics of the drug during distribution and elimination phases are generally described as biphasic. The apparent volume of distribution is 4–8 L/kg. In circulation, hydrochlorothiazide binds to plasma proteins (40–70%), primarily to serum albumin. Accumulation of hydrochlorothiazide in erythrocytes is approximately three times higher than its plasma concentration.

Hydrochlorothiazide is primarily excreted unchanged. It is eliminated from plasma with a mean terminal half-life of 6–15 hours. No changes in hydrochlorothiazide kinetics occur upon repeated dosing; accumulation is minimal with once-daily administration. Over 95% of the absorbed amount is excreted in urine unchanged.

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 kinetics of valsartan. However, this interaction does not impact the efficacy of the combined use of valsartan and hydrochlorothiazide. In controlled clinical studies, a clear antihypertensive effect of this combination was demonstrated, exceeding the effect of either component alone.

Pharmacokinetics in Specific Patient Populations

Elderly Patients

In some elderly patients (>65 years), systemic exposure to valsartan was slightly higher than in younger patients, but this difference was not clinically significant. Steady-state concentrations of hydrochlorothiazide are higher, and systemic clearance is significantly slower in elderly patients compared to younger patients. Therefore, careful monitoring is required in elderly patients receiving hydrochlorothiazide.

Patients with Renal Impairment

As expected for a substance whose renal clearance accounts for only 30% of total plasma clearance, no correlation between renal function and systemic availability of valsartan has been observed. Therefore, dose adjustment is not required in patients with renal impairment (see section "Contraindications" for severe renal insufficiency). Studies in dialysis patients have not been conducted. However, since valsartan is highly bound to plasma proteins, dialysis removal is not expected.

Hydrochlorothiazide is eliminated by the kidneys through passive filtration and active secretion into the renal tubular lumen. Renal function plays a major role in the pharmacokinetics of hydrochlorothiazide, as this drug is eliminated solely by the kidneys. In patients with renal insufficiency, mean peak plasma levels and AUC values of hydrochlorothiazide are increased, and urinary excretion is reduced. In patients with mild to moderate renal impairment, the mean elimination half-life is nearly doubled due to a significant reduction in renal clearance. Hydrochlorothiazide is dialyzable.

Hepatic Impairment

In pharmacokinetic studies involving patients with mild to moderate hepatic impairment, valsartan concentrations were approximately twice as high as in healthy volunteers. Data in patients with severe hepatic impairment are lacking. Overall, hepatic disease with mild to moderate hepatic insufficiency does not significantly affect the pharmacokinetics of hydrochlorothiazide.

Non-melanoma Skin Cancer (NMSC)

Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (with 1,430,833 controls) and 8,629 cases of squamous cell carcinoma (with 172,462 controls). High-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal and squamous cell carcinomas. Another study suggested a possible link 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: 1.27–2.6), increasing to OR 3.9 (3.0–4.9) with high-dose use (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily administration of a 25 mg dose over a period exceeding 10 years.

Clinical characteristics.

Indications.

CORSTAR® H DUO is indicated for the treatment of mild to moderate essential arterial hypertension in patients whose blood pressure is not adequately controlled with monotherapy.

Contraindications.

• Hypersensitivity to any component of the medicinal product CORSTAR® H DUO or to other sulfonamide derivatives;
• severe impairment of liver function, liver cirrhosis, and cholestasis;
• anuria;
• refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia;
• concomitant use of angiotensin II receptor antagonists (ARBs), including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or type II) or renal impairment (eGFR < 60 mL/min/1.73 m²);
• pregnancy, planned pregnancy, and lactation (see section "Use during pregnancy or breastfeeding");
• hereditary angioedema or angioedema during previous treatment with ACE inhibitors or ARBs.

Interaction with other medicinal products and other forms of interaction.

Interactions associated with both valsartan and hydrochlorothiazide

Concomitant use not recommended

Lithium

Reversible increases in plasma lithium concentrations and symptoms of lithium toxicity have been reported with concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or thiazides, including hydrochlorothiazide. Due to the lack of experience with the combined use of valsartan and lithium, such combination is not recommended. Since thiazides reduce renal clearance of lithium, lithium toxicity may be potentiated after administration of CORSTAR® H DUO. If such combination is necessary, careful monitoring of plasma lithium levels is recommended.

Concomitant use requires caution

Other antihypertensive agents

The medicinal product CORSTAR® H DUO may enhance the effect of other antihypertensive agents (e.g., guanethidine, methyldopa, vasodilators, ACE inhibitors, angiotensin receptor antagonists, β-blockers, calcium channel blockers, direct renin inhibitors, and dopamine reuptake inhibitors).

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors

NSAIDs or COX-2 inhibitors may attenuate the antihypertensive effect of angiotensin II antagonists (ARBs).

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

Interactions associated with valsartan

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

Concomitant use of ARBs, including valsartan, with other medicinal products that block the RAAS, such as ACE inhibitors or aliskiren, requires caution.

This is due to an increased incidence of hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy. Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin receptor blockers, or aliskiren is not recommended. If dual RAAS blockade is considered absolutely necessary, treatment should be 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 or type II), diabetic nephropathy, or renal impairment (eGFR < 60 mL/min/1.73 m²) is contraindicated.

Concomitant use not recommended

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

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

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

Transporters

In vitro studies 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 is not fully established. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate safety precautions should be observed when initiating or discontinuing concomitant use of these medicinal products.

Absence of interaction

In drug interaction studies, no clinically significant interactions were observed between valsartan and the following agents: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glipizide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of CORSTAR® H DUO (see "Interactions associated with hydrochlorothiazide").

Interactions associated with hydrochlorothiazide

Concomitant use requiring caution

Medicinal products associated with potassium loss and hypokalemia

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

If administration of the above-mentioned medicinal products together with the hydrochlorothiazide and valsartan combination is necessary, monitoring of plasma potassium levels is recommended.

Medicinal products that may induce torsades de pointes

Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution when administered concomitantly with medicinal products that may induce torsades de pointes, including class Ia and class III antiarrhythmics, and certain antipsychotics.

Medicinal products affecting plasma sodium levels

The hyponatremic effect of diuretics may be enhanced when used concomitantly with antidepressants, antipsychotics, antiepileptics, and others. CORSTAR® H DUO should be prescribed with caution during prolonged use of such medicinal products.

Medicinal products that may induce 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, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).
• Others (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinpocetine).

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

Cardiac glycosides

Thiazide-induced hypokalemia or hypomagnesemia may predispose to cardiac arrhythmias induced by cardiac glycosides.

Calcium salts and vitamin D

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may increase 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.

β-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-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 because hydrochlorothiazide may increase plasma uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.

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

The bioavailability of thiazide diuretics may be increased by anticholinergic agents, likely due to decreased gastrointestinal motility and delayed gastric emptying. Conversely, prokinetics such as cisapride may 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, which may result in subtherapeutic effects. However, minimizing the interaction risk is possible by separating the administration times so that hydrochlorothiazide is taken at least 4 hours before or 4–6 hours after the resin.

Cytoxic 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 effect of curare derivatives.

Cyclosporine

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

Alcohol, anesthetics, and sedatives

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

Methyldopa

Isolated reports of hemolytic anemia have been observed 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.

Iodine-containing contrast agents

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

Pressor amines

Hydrochlorothiazide may reduce the response to pressor amines such as norepinephrine. However, the clinical significance of this effect is not sufficiently established to preclude their use.

Special precautions for use.

Electrolyte changes

Potassium

Thiazide diuretics may cause hypokalemia or exacerbate existing hypokalemia.

Hypokalemia should be corrected prior to initiating thiazide therapy. Concomitant hypomagnesemia may render hypokalemia more difficult to correct.

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

Sodium and/or circulating blood volume (CBV) depletion

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

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

In patients with severe sodium and/or CBV depletion, such as those receiving high doses of diuretics, symptomatic hypotension may occasionally occur after initiation of KORSAR® H DUO. Therefore, sodium and/or CBV levels should be corrected before starting therapy with this medicinal product.

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

Calcium

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

Renal artery stenosis

KORSAR® H DUO should be used with particular caution in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, as such patients may experience increased blood urea and plasma creatinine levels.

Renal impairment

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

KORSAR® H DUO 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 impairment (creatinine clearance < 30 mL/min), but may be used with appropriate caution in combination with loop diuretics, even in patients with creatinine clearance < 30 mL/min.

Concomitant use of angiotensin receptor blockers, including KORSAR® H DUO, or ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (creatinine clearance < 60 mL/min).

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

Renal transplantation

Currently, there are no data on the safety of using the medicinal product in patients who have recently undergone kidney transplantation.

Hepatic impairment

Caution is required when treating patients with hepatic impairment. Dose adjustment is not required in patients with mild to moderate hepatic impairment without cholestasis. However, KORSAR® H DUO should be used with caution. Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide.

Thiazides may cause electrolyte imbalances, hepatic encephalopathy, and hepatorenal syndrome. Therefore, KORSAR® H DUO should be prescribed to such patients only after careful assessment of the risk-benefit ratio and monitoring of clinical and laboratory parameters. KORSAR® H DUO is contraindicated in patients with biliary cirrhosis or cholestasis.

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 other angiotensin II receptor antagonists, including ACE inhibitors. If angioedema occurs, treatment with angiotensin II receptor antagonists should be discontinued immediately. Re-administration of KORSAR® H DUO is contraindicated.

Intestinal angioedema

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

Systemic lupus erythematosus

It has been reported that thiazide diuretics may exacerbate or activate manifestations of systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels, potentially exacerbating hyperuricemia and leading to gout. Therefore, KORSAR® H DUO is not recommended for patients with hyperuricemia and/or gout. Patients with diabetes mellitus may require adjustment of insulin or oral hypoglycemic agent dosages. Thiazide drugs may reduce urinary calcium excretion and cause transient and slight elevation of serum calcium in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate underlying hyperparathyroidism. Thiazide therapy should be discontinued prior to tests assessing parathyroid function.

General recommendations

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

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

Sulfonamides and their derivatives may cause idiosyncratic reactions leading to choroidal effusion with retinal detachment, transient myopia, and acute angle-closure glaucoma. Symptoms include acute vision loss or eye pain and usually occur within hours or weeks after starting treatment. Untreated angle-closure glaucoma may lead to permanent vision loss. Initial treatment involves immediate discontinuation of the drug. If intraocular pressure remains elevated, immediate medical treatment or surgical intervention should be considered. Risk factors for developing angle-closure glaucoma include a history of allergy to sulfonamides or penicillin.

Patients with heart failure, previous myocardial infarction

In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (RAAS) (e.g., patients with severe heart failure), treatment with ACE inhibitors or angiotensin receptor antagonists may be associated with oliguria and/or progressive azotemia, and in some cases, acute renal failure and death. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.

Fertility

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

Dose adjustment is not required for elderly patients.

Hydrochlorothiazide may decrease the level of protein-bound iodine in plasma.

Hydrochlorothiazide may increase the concentration of free bilirubin in serum.

Non-melanoma skin cancer (NMSC)

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

Patients taking hydrochlorothiazide should be informed about the risk of NMSC. Regular skin examinations for new lesions are recommended, and any suspicious skin changes should be reported to the physician immediately.

Preventive measures to minimize the risk of skin cancer, such as limiting exposure to sunlight and ultraviolet radiation, are recommended. Adequate protection should be used when exposed to sunlight. Suspicious lesions should be promptly evaluated, including histological examination and biopsies. The use of hydrochlorothiazide should also be reconsidered in patients who have experienced NMSC.

Hydrochlorothiazide

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 taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening of lung condition, and hypotension. If ARDS is suspected, the drug should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.

Patients with severe chronic heart failure or other conditions with increased RAAS activity

In patients whose renal function may depend on RAAS activity (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure. The use of KORSAR® H DUO in patients with severe chronic heart failure is not justified.

Since it cannot be excluded that RAAS inhibition with KORSAR® H DUO may also be associated with renal dysfunction, the drug should not be used in such patients.

Primary hyperaldosteronism

KORSAR® H DUO should not be used in patients with primary hyperaldosteronism, as their renin-angiotensin system is not activated.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy (HOCM)

As with other vasodilators, administration of KORSAR® H DUO to patients with aortic or mitral valve stenosis or HOCM requires particular caution.

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

Angiotensin II receptor antagonists should not be initiated during pregnancy unless continuation of angiotensin II receptor antagonist therapy is considered necessary. Women planning pregnancy should be switched to alternative antihypertensive treatments with an established safety profile during pregnancy. If pregnancy is detected, treatment with angiotensin II receptor antagonists should be immediately discontinued and alternative therapy initiated if necessary.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Valsartan

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

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

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

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

Hydrochlorothiazide

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

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

Due to the mechanism of action of angiotensin II receptor antagonists, the risk of embryopathy and fetal disease cannot be excluded. According to retrospective data, the use of ACE inhibitors in the first trimester is associated with a potential risk of congenital defects. Moreover, fetal injury and fetal death have been reported with drugs directly affecting the RAAS during the second and third trimesters. Fetal renal perfusion, which depends 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 of pregnancy. Reports of spontaneous abortions, oligohydramnios, and renal dysfunction in newborns have been documented when pregnant women inadvertently took valsartan.

Newborns exposed to the drug in utero require careful monitoring of diuresis, hyperkalemia, and blood pressure. If necessary, appropriate medical measures (e.g., rehydration) should be taken to remove the drug 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.

Lactation

In animal studies (rats), valsartan passed into breast milk. Hydrochlorothiazide crosses the placenta and is excreted in breast milk. There are no studies in breastfeeding women; therefore, treatment with KORSAR® H DUO should not be used during breastfeeding.

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

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 work that could lead to an accident are prohibited due to the possibility of dizziness or fatigue. The extent of the restriction later is determined by the physician.

Method of Administration and Dosage.

The recommended dose of the medicinal product KORSAR® H DUO is 1 tablet 80 mg/12.5 mg once daily.

If insufficient reduction of arterial pressure is observed after 3–4 weeks of treatment, consider continuing therapy with a dose of 1 tablet 160 mg/12.5 mg once daily. Tablets 160 mg/25 mg should be prescribed to patients in whom adequate reduction of arterial pressure is not achieved with tablets 160 mg/12.5 mg. If arterial pressure remains insufficiently controlled with tablets 160 mg/25 mg, consider continuing treatment with a dose of 320 mg/12.5 mg. Tablets 320 mg/25 mg should be prescribed to patients in whom adequate reduction of arterial pressure is not achieved with tablets 320 mg/12.5 mg.

The maximum daily dose is 320 mg/25 mg.

If there is no response after 8 weeks of treatment with KORSAR® H DUO, consider using an additional or alternative medicinal product.

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

The medicinal product KORSAR® H DUO can be taken independently of food intake. Tablets should be taken with a small amount of water.

Special Patient Groups

Patients with Renal Impairment

Dose reduction may be required in patients with renal impairment. Since KORSAR® H DUO contains hydrochlorothiazide, it is contraindicated in patients with anuria, and special caution is required when administered 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.

Patients with Hepatic Impairment

Dose reduction may be required in patients with hepatic impairment. Since KORSAR® H DUO contains hydrochlorothiazide, it should be used with caution in patients with hepatic impairment. Since KORSAR® H DUO 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.

Elderly Patients

The medicinal product KORSAR® H DUO can be used in patients of any age.

Children

KORSAR® H DUO is not recommended for use in children under 18 years of age due to lack of data on safety and efficacy.

Overdose.

Symptoms

Overdose with valsartan may lead to pronounced arterial hypotension, which in turn may result in impaired consciousness, circulatory failure, and/or shock. Additionally, overdose with hydrochlorothiazide may cause the following signs and symptoms: nausea, drowsiness, hypovolemia, and electrolyte disturbances associated with cardiac 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 (mainly due to renal failure).

Treatment

In all cases of overdose, general supportive measures should be implemented, including monitoring of the patient's condition and measures to stabilize cardiovascular function. Therapeutic interventions depend on the time elapsed since ingestion of the excessive dose and the severity of symptoms, with the primary goal being normalization of hemodynamics.

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

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

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

Adverse Reactions

The following adverse reactions were observed in 5 controlled clinical trials involving 7616 patients, of whom 4372 received valsartan in combination with hydrochlorothiazide.

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

Adverse reactions of valsartan/hydrochlorothiazide

Infections and infestations: uncommon – viral infections, fever.

Metabolism and nutrition disorders: uncommon – dehydration; frequency not known – hypokalemia, hyponatremia.

Nervous system disorders: common – headache, fatigue, somnolence; uncommon – asthenia, dizziness, insomnia, anxiety, paresthesia; rare – depression; frequency not known – syncope.

Eye disorders: uncommon – visual disturbances; rare – conjunctivitis.

Ear and labyrinth disorders: uncommon – otitis media, tinnitus.

Cardiac disorders: uncommon – palpitations, tachycardia.

Vascular disorders: uncommon – edema, hypotension, hyperhidrosis.

Respiratory, thoracic and mediastinal disorders: common – cough, rhinitis, pharyngitis, upper respiratory tract infections; uncommon – bronchitis, dyspnea, sinusitis, pharyngolaryngeal pain, dry mouth; very rare – epistaxis, acute respiratory distress syndrome (ARDS); frequency not known – non-cardiogenic pulmonary edema.

Gastrointestinal disorders: common – diarrhea; uncommon – abdominal pain, dyspepsia, nausea, gastroenteritis.

Musculoskeletal and connective tissue disorders: common – back pain, arthralgia; uncommon – limb pain, chest pain, neck pain, arthritis, sprains and deformities, muscle cramps, myalgia.

Renal and urinary disorders: uncommon – frequent urination, urinary tract infections; very rare – renal function impairment.

Reproductive system and breast disorders: common – erectile dysfunction.

General disorders: uncommon – increased fatigue.

Investigations: frequency not known – increased plasma uric acid, increased plasma bilirubin and creatinine, hypokalemia, hyponatremia, increased blood urea nitrogen, neutropenia.

A decrease in serum potassium levels by more than 20% was observed in 3.7% of patients receiving the valsartan/hydrochlorothiazide combination 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 valsartan/hydrochlorothiazide combination, respectively, and in 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: hypoesthesia, influenza, insomnia, ligament sprain, muscle strain, nasal congestion, nasopharyngitis, neck pain, peripheral edema, sinus congestion.

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

In rare cases, therapy with valsartan may be associated with decreased hemoglobin and hematocrit levels. In controlled clinical trials, significant (>20%) decreases in hematocrit and hemoglobin levels were observed in 0.8% and 0.4% of patients, respectively. Decreased hematocrit or hemoglobin levels were observed in 0.1% of placebo-treated patients.

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 were observed in 0.8%, 4.4%, and 6% of patients receiving valsartan, respectively, and in 1.6%, 6.4%, and 12.9% of patients receiving ACE inhibitors.

Elevated liver enzymes were uncommonly observed in patients receiving valsartan.

No special laboratory monitoring is required 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, dyspnea, dry mouth, nosebleeds, impotence, gastroenteritis, headache, increased sweating, hypoesthesia, influenza, insomnia, ligament sprain, muscle cramps, muscle strain, nausea, nasal congestion, sinus congestion, neck pain, swelling, peripheral edema, 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.

In 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 unknown frequency.

Additional information on individual components

Adverse reactions observed with valsartan and hydrochlorothiazide used separately may also potentially occur with the combination of valsartan/hydrochlorothiazide, even if they were not observed in clinical trials or during the post-marketing period.

Adverse reactions with valsartan

Blood and lymphatic system disorders: frequency not known – decreased hemoglobin, decreased hematocrit; very rare – thrombocytopenia.

Immune system disorders: frequency not known – other hypersensitivity/allergic reactions, including serum sickness.

Metabolism and nutrition disorders: frequency not known – increased plasma potassium, hyponatremia.

Ear and labyrinth disorders: uncommon – vestibular vertigo (vertigo).

Vascular disorders: frequency not known – vasculitis.

Gastrointestinal disorders: uncommon – abdominal pain; rare – gastroenteritis; very rare – intestinal angioedema.

Hepatobiliary disorders: frequency not known – increased liver function tests.

Skin and subcutaneous tissue disorders: frequency not known – pruritus, bullous dermatitis; uncommon – edema, rash.

Renal and urinary disorders: frequency not known – renal failure; very rare – 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, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.

Adverse reactions with hydrochlorothiazide

Hydrochlorothiazide has been widely used for many years, often at higher doses than those contained in the medicinal product KORSAR® N DUO. 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, hypokalemia; common – hyponatremia, hypomagnesemia, hyperuricemia, decreased appetite; rare – hypercalcemia, hyperglycemia, glucosuria, and worsening of metabolism in patients with diabetes mellitus; very rare – hypochloremic alkalosis.

Blood and lymphatic system disorders: rare – thrombocytopenia, sometimes with purpura; very rare – agranulocytosis, leukopenia, hemolytic anemia, bone marrow suppression; frequency not known – aplastic anemia.

Immune system disorders: very rare – necrotizing vasculitis, hypersensitivity reactions.

Psychiatric disorders: rare – depression, sleep disturbances.

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

Eye disorders: rare – blurred vision during the first few weeks of treatment; frequency not known – choroidal effusion, acute myopia, and acute angle-closure glaucoma.

Cardiac disorders: rare – 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.

Gastrointestinal disorders: common – mild nausea and 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 – toxic epidermal necrolysis, lupus-like skin reactions, reactivation of cutaneous lupus; frequency not known – erythema multiforme.

Reproductive system and breast disorders: common – impotence.

Renal and urinary disorders: frequency not known – acute renal failure, renal disorders.

General disorders: frequency not known – increased temperature, fatigue.

Musculoskeletal and connective tissue disorders: frequency not known – muscle spasms.

Neoplasms: frequency not known – non-melanoma skin cancer (NMSC) (basal cell and squamous cell carcinoma).

Description of selected adverse effects and additional information

Non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma). Based on available epidemiological data, a cumulative dose-dependent association has been observed between exposure to hydrochlorothiazide and the development of NMSC.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store at temperatures not exceeding 30°C in the original packaging.

Keep out of reach of children.

Packaging

For strengths 80 mg/12.5 mg, 160 mg/12.5 mg, and 160 mg/25 mg: 10 tablets per blister, 3 or 9 blisters per cardboard box.

For strengths 320 mg/12.5 mg and 320 mg/25 mg: 10 tablets per blister, 3 blisters per cardboard box.

Prescription category

By prescription only.

Manufacturer

JSC "Farmak".

Manufacturer's address and location of its operations

74, Kyrylivska Street, Kyiv, 04080, Ukraine.