Tiara duo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Tiarа Duo

Composition:

Active substances: 1 tablet contains: valsartan 80 mg, hydrochlorothiazide 12.5 mg; or valsartan 160 mg, hydrochlorothiazide 12.5 mg; or valsartan 160 mg, hydrochlorothiazide 25 mg;

Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II 85F pink – for tablets of 80/12.5 mg and 160/25 mg; Opadry II 85F white – for tablets of 160/12.5 mg.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

Tiara Duo 80/12.5 mg: round, pink film-coated tablets with a biconvex surface;

Tiara Duo 160/12.5 mg: round, white or almost white film-coated tablets with a biconvex surface;

Tiara Duo 160/25 mg: round, pink film-coated tablets with a biconvex surface.

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

Pharmacological Properties.

Pharmacodynamics.

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

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

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

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

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

The medicinal product reduces arterial blood pressure in patients with arterial hypertension without affecting pulse rate.

In most patients, after a single oral 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 maintained at this level during long-term therapy. Combination with hydrochlorothiazide provides more effective blood pressure reduction.

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

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

Thiazide diuretics act on the cortical segment of the distal convoluted renal tubules, where receptors highly sensitive to diuretics are located, and where inhibition of Na+ and Cl- ion transport occurs. The mechanism of action of thiazides is associated with inhibition of the Na+Cl- cotransporter, likely through competition at Cl- transport sites.

As a result, excretion of sodium and chloride ions increases to a similar extent. Due to diuretic action, circulating blood volume (CBV) decreases, leading to increased renin activity, aldosterone secretion, and urinary potassium excretion, thereby reducing serum potassium concentration. The renin-aldosterone relationship is mediated by angiotensin II; therefore, administration of an angiotensin II receptor antagonist (ARA II) 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 the medicinal product Tiarra Duo is 23%. The pharmacokinetic profile 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 women and men. Valsartan is highly bound to plasma proteins (94–97%), primarily to albumin. The volume of distribution at steady state is low (~17 L). Compared to hepatic blood flow (~30 L/h), plasma clearance of valsartan is relatively slow (~2 L/h). Approximately 70% of the administered dose is excreted in feces, and nearly 30% is excreted in urine, primarily unchanged.

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

Hydrochlorothiazide. Absorption of hydrochlorothiazide after oral administration is rapid (tmax ~ 2 hours). Pharmacokinetics during distribution and elimination phases are generally described by a biexponential decline; the terminal elimination half-life ranges from 6 to 15 hours. Within the therapeutic dose range, the mean area under the concentration-time curve (AUC) increases proportionally with dose. Pharmacokinetics of hydrochlorothiazide do not change with repeated dosing; accumulation is minimal when administered once daily. Absolute oral bioavailability of hydrochlorothiazide is approximately 70%. Excretion occurs primarily via urine: more than 95% of the dose is excreted unchanged, and about 4% as a 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 conditions. However, the range of these changes is small and not clinically significant.

Valsartan/hydrochlorothiazide. When administered concomitantly with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by approximately 30%. Conversely, coadministration of hydrochlorothiazide does not significantly affect the pharmacokinetics of valsartan. However, this interaction does not impair 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.

Limited data suggest that systemic clearance of hydrochlorothiazide is lower in elderly patients (both healthy and those with arterial hypertension) compared to healthy young volunteers.

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

There are no data on the use of the medicinal product Tiarra Duo 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; hydrochlorothiazide, on the contrary, is eliminated during hemodialysis.

In the presence of renal dysfunction, mean peak plasma levels and AUC values of hydrochlorothiazide increase, while urinary excretion decreases. In patients with mild to moderate renal insufficiency, the mean elimination half-life 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 the pharmacokinetics of hydrochlorothiazide, which is expected, given that this drug is eliminated solely by the kidneys.

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

Hepatic Impairment. Systemic exposure to valsartan in patients with mild (n = 6) and moderate (n = 5) hepatic impairment was twice as high as in healthy volunteers. Data on the use of valsartan in patients with severe hepatic impairment are lacking. Liver disease does not significantly affect the pharmacokinetics of hydrochlorothiazide, and therefore dose reduction is not required.

Non-melanoma Skin Cancer (NMSC).

Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (with 1,430,833 individuals in the control group) and 8,629 cases of squamous cell carcinoma (with 172,462 individuals in the control group). High-dose hydrochlorothiazide (≥ 50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal cell and squamous cell carcinomas.

Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were compared with 63,067 controls from the general population 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 exposure (~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 Tiarа Duo or to other sulfonamide derivatives.
• Severe impairment of liver function, liver cirrhosis, and cholestasis.
• Severe renal impairment (creatinine clearance < 30 mL/min), anuria.
• Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
• Concomitant use of ARAs, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I and II) or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
• Pregnancy or women planning to become pregnant (see section "Use during pregnancy or breastfeeding").
• Hereditary angioedema or angioedema during previous treatment with ACE inhibitors or ARAs.

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 signs of lithium toxicity have been reported with concomitant use of ACE inhibitors and thiazide diuretics, including hydrochlorothiazide. Due to the lack of experience with the concomitant use of valsartan and lithium, this combination is not recommended. If such a combination is necessary, careful monitoring of plasma lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive medicinal products

The medicinal product Tiarа Duo may enhance the effect of other antihypertensive agents (e.g., guanethidine, methyldopa, vasodilators, ACE inhibitors, ARAs, β-blockers, calcium channel blockers, and dopamine reuptake inhibitors).

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

A reduced response to pressor amines such as noradrenaline may occur, although not sufficient to contraindicate their use.

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

NSAIDs may reduce the antihypertensive effect of both ARAs II and hydrochlorothiazide when used concomitantly. Furthermore, concomitant use of the medicinal product Tiarа Duo and NSAIDs may lead to impaired renal function and increased plasma potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate patient hydration are recommended.

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

Interactions associated with valsartan

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

When ARAs, including valsartan, are used concomitantly with other medicinal products that block the RAAS, such as ACE inhibitors or aliskiren, there is an increased incidence of arterial hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy. Dual blockade of the RAAS with ACE inhibitors, ARAs, or aliskiren is not recommended. If dual RAAS blockade therapy is necessary, it should be conducted only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

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

Concomitant use not recommended

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

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

Concomitant use of ARAs II with other medicinal products capable of increasing serum potassium levels (e.g., potassium-sparing diuretics, potassium-containing medicinal products, heparin) increases the risk of hyperkalemia. In such cases, the medicinal product Tiarа Duo 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 treatment with such medicinal products.

Absence of interaction

In drug interaction studies, no clinically significant interactions between valsartan and any of the following medicinal products were observed: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glipizide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of the medicinal product Tiarа 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 hormones (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, and antiarrhythmic agents.

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

Medicinal products capable of inducing torsades de pointes ventricular tachycardia

Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution concomitantly with medicinal products that may induce torsades de pointes ventricular tachycardia, particularly antiarrhythmic agents of class Ia and III, as well as certain antipsychotics.

Medicinal products affecting serum sodium levels

The hyponatremic effect of diuretics may be enhanced when used concomitantly with antidepressants, antipsychotic medicinal products, antiepileptic medicinal products, etc. Caution should be exercised during prolonged use of these medicinal products.

Medicinal products that may cause bidirectional tachycardia (torsades de pointes)

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide).
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide).
• Some 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 developing hypokalemia, hydrochlorothiazide should be used with caution concomitantly with medicinal products that may cause torsades de pointes.

Cardiac glycosides (digitalis)

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

Calcium salts and vitamin D

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may lead to 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 medicinal products and insulin)

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

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

β-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers 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)

Dosage adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase plasma uric acid levels.

Dosage 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 and other medicinal products affecting gastrointestinal motility
The bioavailability of thiazide diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), likely due to reduced gastrointestinal motility and gastric emptying rate. Conversely, prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics.

Amantadine

Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions 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 so that hydrochlorothiazide is taken at least 4 hours before or 4–6 hours after the resin may minimize the risk of interaction.

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

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

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

Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives.

Cyclosporine

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

Alcohol, anesthetics, and sedative medicinal products

Concomitant use of thiazide diuretics with medicinal products that may also lower blood pressure (e.g., due to reduced central sympathetic nervous system activity or direct vasodilatory effects) may lead to potentiation of orthostatic hypotension.

Metildopa

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, particularly with high doses of iodine-containing agents. Adequate fluid replacement should be ensured before administration.

Special precautions for use.

Electrolyte changes.

Potassium

Thiazide diuretics may cause hypokalemia or exacerbate pre-existing hypokalemia.

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

Since the medicinal product Tiara Duo contains an angiotensin II receptor antagonist (ARA II), caution should be exercised when co-administering this medicinal product Tiara 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. In all patients receiving thiazide diuretics, electrolyte balance should be monitored.

Patients with sodium deficiency and/or intravascular volume 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 be monitored regularly.

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

In patients with severe sodium deficiency and/or intravascular volume depletion (e.g., those receiving high doses of diuretics), symptomatic hypotension may occur in isolated cases after initiation of Tiara Duo. Therefore, correction of sodium and/or intravascular volume status should be performed before starting therapy with this medicinal product.

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

Calcium

Thiazide diuretics reduce calcium excretion in urine and may cause elevated serum calcium levels. Thiazide diuretics should be used 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 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 and fatal outcomes. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.

Use of the medicinal product Tiara Duo in patients with severe chronic heart failure is not justified. Since inhibition of RAAS by Tiara Duo may also be associated with renal dysfunction, Tiara Duo should not be used in such patients.

Renal artery stenosis.

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

Primary hyperaldosteronism.

The medicinal product Tiara Duo should not be used in patients with primary hyperaldosteronism, as their RAAS is not activated.

Stenosis of aortic and mitral valves, hypertrophic obstructive cardiomyopathy.

As with other vasodilators, patients with aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy require special caution.

Renal impairment.

For patients with renal insufficiency and creatinine clearance ≥30 mL/min, dose adjustment is not required.

When using Tiara Duo in patients with renal impairment, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended.

Thiazide diuretics may precipitate azotemia in patients with chronic renal impairment. Concomitant use of angiotensin receptor blockers, including Tiara 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.

There is currently no experience regarding 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. In patients with mild to moderate hepatic impairment without cholestasis, dose adjustment is not required, but Tiara 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, Tiara Duo should be prescribed to such patients only after careful risk-benefit assessment and with monitoring of clinical and laboratory parameters.

Tiara Duo is contraindicated in patients with biliary cirrhosis or cholestasis.

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 worsening hyperuricemia and leading to gout. Therefore, Tiara Duo 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 inconsistent and slight elevation of serum calcium in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate underlying hyperparathyroidism.

Thiazide use should be discontinued before performing tests to assess parathyroid function.

Photosensitivity.

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

Pregnancy.

ARA II should not be initiated during pregnancy. Unless continuation of ARA II therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive treatments with established safety profiles during pregnancy. If pregnancy is detected, ARA II treatment should be discontinued immediately, and alternative therapy initiated if necessary.

General warnings.

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

Angioedema.

Cases of angioedema (including Quincke's edema, such as laryngeal and glottal edema leading to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling) have been reported in patients taking valsartan. Some of these patients had a history of angioedema with other medicinal products, including other ARA II and ACE inhibitors. If angioedema develops, ARA II therapy should be discontinued immediately. Re-administration of the medicinal product is contraindicated.

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

Use of hydrochlorothiazide, sulfonamides, or sulfonamide derivatives has been associated with idiosyncratic reactions that may lead to choroidal effusion with visual field defects, transient myopia, acute transient myopia, and acute angle-closure glaucoma.

Use of hydrochlorothiazide, sulfonamides, or sulfonamide derivatives may cause an idiosyncratic reaction resulting in 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 glaucoma may lead to irreversible vision loss.

The primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, medical or surgical treatment should be initiated. Risk factors for developing acute angle-closure glaucoma include allergic reaction to sulfonamides or penicillin.

Dual blockade of the RAAS.

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual blockade therapy with two RAAS inhibitors is considered absolutely necessary, it should be administered only under specialist supervision with frequent and careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Non-melanoma skin cancer (NMSC).

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

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

Dose adjustment is not required for elderly patients.

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

Acute respiratory toxicity

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

Use during pregnancy or breastfeeding.

Pregnancy

Val­sar­tan

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

It is known that use of ARA II during the second and third trimesters causes fetotoxicity in humans (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If ARA II use occurred from the second trimester of pregnancy, ultrasound monitoring of renal function and skull development is recommended. Infants whose mothers took ARA II require careful monitoring for arterial 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 in the fetus and newborn: 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 ARA II, there is a risk of embryopathy and fetal disease. According to retrospective data, use of ACE inhibitors in the first trimester is associated with a potential risk of congenital defects. Moreover, fetal injury and fatal outcomes have been reported due to use of RAAS-acting drugs during the second and third trimesters. In humans, fetal renal perfusion dependent on RAAS development begins during the second trimester. Thus, the risk associated with valsartan treatment is higher during the second and third trimesters. Reports of spontaneous abortions, oligohydramnios, and renal dysfunction in newborns have occurred when pregnant women inadvertently took valsartan.

Newborns exposed to the medicinal 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 eliminate the drug from circulation.

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

Breastfeeding period

If use of the medicinal product is absolutely necessary, breastfeeding should be discontinued.

There is no information on the use of valsartan during breastfeeding. Hydrochlorothiazide passes into breast milk in small amounts. Thiazides in high doses cause diuresis, which may suppress breast milk production. During breastfeeding, alternative treatment methods with better-established safety profiles are preferred, especially when breastfeeding newborns or premature infants.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

At the beginning of treatment with the medicinal product (duration individually determined by the physician), driving vehicles and performing tasks that could lead to accidents is 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 the medicinal product Taira Duo is 1 tablet of 80 mg/12.5 mg once daily. If blood pressure is not sufficiently reduced after 3–4 weeks of treatment, consider increasing the dose to 1 tablet of 160 mg/12.5 mg once daily. Tablets of 160 mg/25 mg 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 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 Taira Duo after 8 weeks, consider adding another antihypertensive agent or switching to an alternative therapy.

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

The medicinal product Taira Duo can be administered regardless of food intake. Tablets should be taken with a small amount of water.

Use in Patients with Renal Impairment

Dose reduction may be necessary in patients with renal impairment.

For patients with mild to moderate renal impairment (eGFR ≥ 30 mL/min), dose adjustment is not required.

Since the medicinal product contains hydrochlorothiazide, it is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min) and in those with anuria.

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.

Use in Patients with Hepatic Impairment

Since Taira Duo contains valsartan, its use is contraindicated in patients with biliary cirrhosis or cholestasis.

The dose of valsartan in patients with mild to moderate non-biliary hepatic impairment and cholestasis should not exceed 80 mg.

Dose adjustment of hydrochlorothiazide is not required in patients with mild to moderate hepatic impairment.

Use in Elderly Patients (aged 65 years and older)

Dose adjustment in elderly patients is not required.

Children

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

Overdose

Valsartan overdose may lead to pronounced arterial hypotension, which in turn may result in decreased level of consciousness, circulatory failure, and/or shock.

Overdose with hydrochlorothiazide may cause the following signs and symptoms: nausea, drowsiness, hypovolemia, electrolyte imbalance, and consequently arrhythmias and muscle spasms. The most characteristic signs and symptoms of overdose also include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, altered consciousness, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen (mainly due to renal failure).

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

Therapeutic interventions depend on the time elapsed since ingestion and the severity of symptoms. The primary measure is restoration of hemodynamic stability.

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

In cases of arterial 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 in removing hydrochlorothiazide from the body.

Adverse Reactions

Adverse reactions most commonly reported during clinical trials with 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 (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); 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

Eye disorders: uncommon – blurred vision; rare – conjunctivitis.

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

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

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

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

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

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

Cardiac disorders: uncommon – palpitations, tachycardia.

Vascular disorders: uncommon – edema, hypotension, hyperhidrosis.

Infections and infestations: uncommon – viral infections, pyrexia.

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

Reproductive system and breast disorders: common – erectile dysfunction.

General disorders and administration site conditions: uncommon – increased fatigue.

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

Additional information on selected adverse reactions

In clinical trials, serum potassium reduction of more than 20% was observed in 3.7% of patients receiving valsartan/hydrochlorothiazide and in 3.1% of patients receiving placebo.

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

During clinical trials in patients with arterial hypertension, the following events were observed regardless of causal relationship to valsartan/hydrochlorothiazide: 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 during treatment with valsartan/hydrochlorothiazide.

In rare cases, valsartan therapy may be associated with decreased hemoglobin and hematocrit levels. In controlled clinical trials, marked (>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 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, marked increases in serum creatinine, potassium, and total bilirubin 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.

Elevated liver function tests were uncommonly observed in patients receiving valsartan.

No special laboratory monitoring is required in patients with essential hypertension receiving valsartan therapy.

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

During the post-marketing period, reports with valsartan/hydrochlorothiazide use included syncope, 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; frequency is unknown.

Additional information on individual components

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

Adverse reactions with valsartan:

Ear and labyrinth disorders: uncommon – vestibular vertigo.

Gastrointestinal disorders: uncommon – abdominal pain, gastroenteritis.

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

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

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

Nervous system disorders: uncommon – asthenia, insomnia, dizziness; rare – neuralgia.

Cardiac disorders: very rare – cardiac arrhythmia.

Vascular disorders: frequency not known – vasculitis.

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

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

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

Musculoskeletal and connective tissue disorders: common – arthralgia.

Reproductive system and breast disorders: uncommon – decreased libido.

Reactions observed during clinical trials in hypertensive patients, regardless of causal relationship to valsartan: arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections, viral infections.

Adverse reactions with hydrochlorothiazide:

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

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

Respiratory, thoracic and mediastinal disorders: very rare – respiratory failure, including pneumonia and pulmonary edema.

Gastrointestinal disorders: common – loss of appetite, mild nausea and vomiting; rare – constipation, gastrointestinal discomfort, diarrhea; very rare – pancreatitis.

Hepatobiliary disorders: rare – intrahepatic cholestasis or jaundice.

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

Metabolism and nutrition disorders: very common – hypokalemia; with high-dose use – increased blood lipid levels; common – hyponatremia, hypomagnesemia, hyperuricemia; rare – hypercalcemia, hyperglycemia, glucosuria, and worsening of metabolism in patients with diabetes mellitus; very rare – hypochloremic alkalosis.

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

Psychiatric disorders: rare – depression, sleep disturbances.

Cardiac disorders: rare – arrhythmia.

Vascular disorders: common – postural hypotension, which may be exacerbated by alcohol, anesthetics, or sedatives.

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 – hypersensitivity reactions.

Skin and subcutaneous tissue disorders: common – urticaria and other types of rash; rare – photosensitivity; very rare – necrotic vasculitis, toxic epidermal necrolysis, lupus-like skin reactions, exacerbation of cutaneous lupus erythematosus; frequency not known – erythema multiforme.

Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency not known – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

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

Reproductive system and breast disorders: common – impotence.

General disorders and administration site conditions: frequency not known – increased body temperature, fatigue.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

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

Packaging.

Tablets 80/12.5 mg and 160/12.5 mg

7 tablets in a blister pack; 2 or 4 blisters per carton; 14 tablets in a blister pack; 1, 2, or 6 blisters per carton.

Tablets 160/25 mg

7 tablets in a blister pack; 2 or 4 blisters per carton; 14 tablets in a blister pack; 1 or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13 Borispilska Street, Kyiv, 02093, Ukraine.