Tiara trio

INSTRUCTION for medical use of medicinal product Tiara Trio® (Tiara Trio) Composition: amlodipine, hydrochlorothiazide, valsartan; 1 tablet of 5 mg/12.5 mg/160 mg contains: active substances: amlodipine besylate equivalent to amlodipine 5 mg, hydrochlorothiazide 12.5 mg, valsartan 160 mg; excipients: microcrystalline cellulose, sodium croscarmellose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II 85 F pink. 1 tablet of 10 mg/12.5 mg/160 mg contains: active substances: amlodipine besylate equivalent to amlodipine 10 mg, hydrochlorothiazide 12.5 mg, valsartan 160 mg; excipients: microcrystalline cellulose, sodium croscarmellose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II 85 F white. Medicinal form. Film-coated tablets. Basic physico-chemical properties: tablets of 5 mg/12.5 mg/160 mg – round-shaped, film-coated, pink tablets with a biconvex surface; tablets of 10 mg/12.5 mg/160 mg – round-shaped, film-coated, white tablets with a biconvex surface. Pharmacotherapeutic group. Angiotensin II receptor blockers, other combinations. Valsartan, amlodipine and hydrochlorothiazide. ATC code C09D X01. Pharmacological properties. Pharmacodynamics. The medicinal product Tiara Trio® contains three antihypertensive agents with different mechanisms of controlling blood pressure in patients with essential hypertension, which complement each other: amlodipine belongs to the class of calcium channel antagonists, valsartan – to the class of angiotensin II receptor antagonists (ARBs), and hydrochlorothiazide – to the class of thiazide diuretics. The combination of these three components is characterized by complementary antihypertensive action. Amlodipine Amlodipine, included in the composition of the medicinal product Tiara Trio®, inhibits transmembrane influx of calcium ions into cardiac muscles and vascular smooth muscles. The antihypertensive effect of amlodipine occurs due to direct relaxant effect on vascular smooth muscles, causing a decrease in peripheral vascular resistance and blood pressure. Experimental data confirm that amlodipine binds at dihydropyridine and non-dihydropyridine binding sites. Contractility of cardiac muscle and vascular smooth muscles depends on the passage of extracellular calcium into cells through specific ion channels. Amlodipine at therapeutic doses causes vasodilation in patients with arterial hypertension, leading to a decrease in blood pressure in both supine and standing positions. This decrease in blood pressure is not accompanied by pronounced changes in heart rate or plasma catecholamine levels during long-term use. Plasma concentrations of amlodipine correlate with the effect in both young and elderly patients. In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses causes a decrease in renal vascular resistance and an increase in glomerular filtration rate (GFR) and effective renal plasma flow without changing the filtration fraction or proteinuria. Valsartan Valsartan is a potent and specific orally active ARB. Valsartan acts selectively on the AT1 subtype of receptors responsible for the known effects of angiotensin II. In patients with arterial hypertension, valsartan promotes a decrease in blood pressure without affecting pulse rate. In most patients, after single oral administration, the onset of hypotensive effect occurs within 2 hours, and maximum blood pressure reduction is achieved within 4–6 hours. The antihypertensive effect lasts for 24 hours after administration of the medicinal product. With repeated administration, maximum blood pressure reduction (at all dosage regimens) is usually achieved within 2–4 weeks. Hydrochlorothiazide The site of action of thiazide diuretics is mainly the distal convoluted tubules of the kidneys. It has been confirmed that high-affinity receptors are present in the renal cortex, which are the primary binding site for thiazide diuretics and inhibition of NaCl transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of Na+Cl– transporters, possibly by competing for Cl– sites, which in turn affects electrolyte reabsorption mechanisms: directly increases excretion of sodium and chloride in approximately equal amounts and indirectly, due to diuretic effect, reduces plasma volume with subsequent increase in plasma renin activity, aldosterone secretion, and potassium excretion in urine, as well as a decrease in serum potassium levels. Non-melanoma skin cancer: Based on data from epidemiological studies, a cumulative dose-dependent association between hydrochlorothiazide use and the development of non-melanoma skin cancer has been identified. One study included a population consisting of 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma, in the control group of 1,430,833 and 172,462 cases, respectively. High-dose hydrochlorothiazide use (cumulative dose ≥ 50,000 mg) was characterized by the following adjusted odds ratio: 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. For both basal cell and squamous cell carcinoma, a pronounced cumulative dose-effect dependence was observed. Another study showed a possible association between lip cancer (squamous cell carcinoma) and hydrochlorothiazide exposure: 633 cases of lip cancer corresponded to 63,067 cases in the control group (a risk-set sampling strategy was used). Cumulative dose-effect dependence was demonstrated using adjusted odds ratios, which was 2.1 (95% CI: 1.7–2.6). The indicator increased to 3.9 (3.0–4.9) with high-dose hydrochlorothiazide use (~25,000 mg) and to 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see section "Special precautions for use"). Pharmacokinetics. Linearity Amlodipine, valsartan and hydrochlorothiazide demonstrate linear pharmacokinetics. Amlodipine/valsartan/hydrochlorothiazide After oral administration of the medicinal product containing amlodipine/valsartan/hydrochlorothiazide to adult volunteers, maximum plasma concentrations (Cmax) of amlodipine, valsartan and hydrochlorothiazide were reached within 6–8 hours, 3 hours and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide when administered as the medicinal product were similar to those observed when its components were administered as individual medicinal products. Amlodipine Absorption. After oral administration at therapeutic doses, maximum plasma concentration of amlodipine alone was reached within 6–12 hours. Absolute bioavailability ranged from 64% to 80%. Food intake does not affect amlodipine bioavailability. Distribution. Volume of distribution is approximately 21 L/kg. In vitro studies of amlodipine showed that approximately 97.5% of the drug in circulating blood is bound to plasma proteins. Metabolism. Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites. Elimination. Amlodipine is eliminated from plasma in two phases, with a terminal elimination half-life of approximately 30–50 hours. Steady-state plasma levels are achieved after continuous administration for 7–8 days. 10% of amlodipine and 60% of amlodipine metabolites are excreted in urine. Valsartan Absorption. After oral administration of valsartan alone, maximum concentrations are reached within 2–4 hours. Mean absolute bioavailability is 23%. Food intake reduces valsartan exposure by approximately 40% (as measured by area under the pharmacokinetic concentration-time curve (AUC)), and Cmax by approximately 50%, although approximately 8 hours after administration, valsartan concentration is similar in groups receiving the drug fasting and after food. However, this decrease in AUC is not clinically significant, so valsartan can be administered regardless of food intake. Distribution. The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 liters, indicating that valsartan is not extensively distributed into tissues. Valsartan is actively bound to serum proteins (94–97%), primarily to serum albumins. Metabolism. Valsartan is not significantly transformed, as only approximately 20% of the dose is excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of valsartan AUC). This metabolite is pharmacologically inactive. Elimination. Valsartan is primarily excreted in feces (approximately 83% of dose) and urine (approximately 13% of dose), mainly as unchanged substance. After intravenous administration, plasma clearance of valsartan is approximately 2 L/hour, and renal clearance is 0.62 L/hour (approximately 30% of total clearance). The elimination half-life of valsartan is 6 hours. Hydrochlorothiazide Absorption. Absorption of hydrochlorothiazide after oral administration occurs rapidly (Tmax – approximately 2 hours). Increase in mean AUC is linear and proportional to dose when administered in the therapeutic dose range. No changes in hydrochlorothiazide kinetics were observed with repeated administration, and accumulation was minimal with once-daily dosing. When taken simultaneously with food, both increased and decreased systemic availability of hydrochlorothiazide were observed compared to fasting. The extent of these effects is insignificant and has minimal clinical significance. Absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration. Distribution. Apparent volume of distribution is 4–8 L/kg. Hydrochlorothiazide in circulating blood is bound to plasma proteins (40–70%), primarily to serum albumins. Hydrochlorothiazide also accumulates in erythrocytes at levels 1.8 times higher than plasma levels. Metabolism. Hydrochlorothiazide is excreted unchanged. Elimination. More than 95% of the absorbed dose is excreted unchanged in urine. Renal clearance consists of passive filtration and active secretion in renal tubules. Elimination half-life is 6–15 hours. Special patient groups Children (under 18 years of age) There are no data on pharmacokinetics in children. Elderly patients (aged 65 years and older) Time to reach Cmax of amlodipine is similar in young and elderly patients. In elderly patients, clearance of amlodipine tends to decrease, causing an increase in AUC and elimination half-life. Mean systemic AUC of valsartan is 70% higher in elderly patients than in younger patients, therefore, dose should be increased with caution in these patients. Systemic exposure to valsartan is slightly higher in elderly patients compared to younger patients, but this is not clinically significant. Some data indicate that systemic clearance of hydrochlorothiazide is reduced in both healthy elderly subjects and elderly patients with arterial hypertension compared to younger healthy volunteers. Since all three components of the medicinal product are equally well tolerated by young and elderly patients, the recommended dosage regimen is standard. Renal impairment Renal impairment does not significantly affect the pharmacokinetics of amlodipine. For the medicinal product, renal clearance of which is only 30% of total plasma clearance, no correlation between renal function and systemic exposure to valsartan was observed. Therefore, patients with mild to moderate renal impairment can use the medicinal product at the standard initial dose. Hepatic impairment In patients with hepatic impairment, clearance of amlodipine is reduced, leading to an increase in AUC by approximately 40–60%. In patients with chronic liver disease of mild to moderate severity (as measured by AUC), exposure to valsartan is on average 2 times higher than in healthy adults. The medicinal product should be prescribed with caution to patients with liver disease. The combination of amlodipine/valsartan/hydrochlorothiazide has not been tested for genotoxicity and carcinogenicity, as no signs of interaction between these medicinal products were found. However, amlodipine, valsartan and hydrochlorothiazide were tested separately for genotoxicity and carcinogenicity – results were negative. Clinical characteristics. Indications. Treatment of essential hypertension in adult patients with blood pressure adequately controlled by combination therapy with amlodipine, valsartan and hydrochlorothiazide, administered as three separate medicinal products or as two medicinal products, one of which is a combination. Contraindications.

• Hypersensitivity to active substances, other sulfonamides, dihydropyridine derivatives, or to any excipient of the medicinal product.
• Second and third trimesters of pregnancy (see section "Use during pregnancy or breastfeeding").
• Hepatic impairment, biliary cirrhosis or cholestasis.
• Severe renal impairment (GFR < 30 mL/min/1.73 m²), anuria, or patients on dialysis.
• Concomitant use of Tiara Trio® with aliskiren-containing products in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²).
• Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
• Severe hypotension.
• Shock (including cardiogenic shock).
• Obstruction of the left ventricular outflow tract (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction. Studies on interaction of the medicinal product Tiara Trio® with other medicinal products have not been conducted. The following information is only about the interaction of each individual active substance with other medicinal products. However, it is important to consider that the medicinal product Tiara Trio® may potentiate the hypotensive effect of other antihypertensive medicinal products. Concomitant use not recommended Interactions related to both valsartan and hydrochlorothiazide Lithium. Reversible increase in serum lithium concentration and toxicity have been reported during concomitant use of lithium with ACE inhibitors, ARBs including valsartan, or thiazides such as hydrochlorothiazide. Since thiazides reduce renal clearance of lithium, the risk of lithium toxicity is likely to increase with use of the medicinal product. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use of medicinal products. Interactions related to valsartan Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other agents that may increase potassium levels. If it is necessary to use a medicinal product affecting potassium levels in combination with valsartan, frequent monitoring of plasma potassium levels is recommended. Interactions related to amlodipine Grapefruit or grapefruit juice. Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients this combination may enhance the blood pressure-lowering effect. Concomitant use requires caution Interactions related to amlodipine CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir). Studies in elderly patients have demonstrated that diltiazem inhibits amlodipine metabolism, possibly via CYP3A4 (plasma concentration increases by approximately 50%, and amlodipine effect is enhanced). It cannot be excluded that more potent CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) may increase amlodipine plasma concentration more significantly than diltiazem. Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in amlodipine exposure. Clinical manifestations of these pharmacokinetic changes may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required. CYP3A4 inducers (anticonvulsant medicinal products (such as carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John's wort). There are no data on the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g., rifampicin, St. John's wort) may lead to a decrease in amlodipine plasma concentration. Clinical monitoring and adjustment of amlodipine doses during treatment with an inducer and after its discontinuation are recommended. Amlodipine should be used with caution together with CYP3A4 inducers. Simvastatin. Repeated doses of 10 mg amlodipine with 80 mg simvastatin result in a 77% increase in simvastatin exposure compared to simvastatin alone. It is recommended to reduce the daily dose of simvastatin to 20 mg in patients taking amlodipine. Dantrolene (infusions). In animals, fatal cases of ventricular fibrillation and cardiovascular collapse were observed following intravenous administration of verapamil and dantrolene due to hyperkalemia. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and in the treatment of malignant hyperthermia. Interactions related to both valsartan and hydrochlorothiazide 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 ARBs and hydrochlorothiazide when used concomitantly. Additionally, concomitant use of the medicinal product Tiara Trio® and NSAIDs may lead to renal impairment and increased serum potassium levels. Therefore, monitoring of renal function at the beginning of treatment and adequate patient hydration are recommended. Interactions related to valsartan Inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir). In vitro studies with human liver tissue showed that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir) may increase systemic exposure to valsartan. Interactions related to hydrochlorothiazide Alcohol, anesthetics and sedative medicinal products. Concomitant administration of thiazide diuretics with substances that also have a blood pressure-lowering effect (e.g., those reducing central nervous system sympathetic activity or causing direct vasodilation) may potentiate orthostatic hypotension. Amantadine. Thiazides, including hydrochlorothiazide, increase the risk of adverse reactions caused by amantadine. Anticholinergic medicinal products and other medicinal products affecting gastrointestinal motility. Bioavailability of thiazide diuretics may be increased by anticholinergic medicinal products (e.g., atropine, biperiden), apparently due to decreased gastrointestinal motility and gastric emptying rate. Conversely, prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics. Antidiabetic medicinal products (e.g., insulin and oral antidiabetic agents). Thiazides may alter glucose tolerance. It may be necessary to re-adjust the dose of insulin and oral hypoglycemic agents. Metformin. Metformin should be used with caution due to the risk of lactic acidosis induced by functional renal impairment associated with hydrochlorothiazide use. β-blockers and diazoxide. Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers increases the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide. Carbamazepine. In patients receiving hydrochlorothiazide concomitantly with carbamazepine, hyponatremia may develop. Therefore, such patients should be warned about the possibility of hyponatremic reactions and monitored. Cyclosporine. Concomitant treatment with cyclosporine increases the risk of hyperuricemia and gout-like complications. Cytotoxic medicinal products (e.g., cyclophosphamide, methotrexate). Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic medicinal products (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effect. Cardiac glycosides. Thiazide-induced hypokalemia or hypomagnesemia may occur as adverse effects, predisposing to digoxin-induced cardiac arrhythmias. Iodine-containing contrast agents. In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine-containing agents. Rehydration should be performed before administration. Ion-exchange resins. Absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol. This may lead to subtherapeutic effects of thiazide diuretics. However, the administration of hydrochlorothiazide and resins should be staggered so that hydrochlorothiazide is taken at least 4 hours before, or 4–6 hours after, the administration of resins, which potentially minimizes their interaction. Medicinal products affecting potassium levels (potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylate derivatives) and antiarrhythmic agents. The hypokalemic effect of hydrochlorothiazide may be enhanced by potassium-wasting diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylate derivatives and antiarrhythmic agents. If such medicinal products are prescribed with the combination amlodipine/valsartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended. Medicinal products affecting sodium levels. The hyponatremic effect of diuretics when used concomitantly may be enhanced by antidepressants, antipsychotics and antiepileptic medicinal products, etc. Caution is required with long-term use of these medicinal products. Medicinal products that may cause torsades de pointes. Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution with medicinal products that may cause torsades de pointes, particularly with class Ia and class III antiarrhythmic agents, as well as with some antipsychotic medicinal products. Medicinal products used for the treatment of gout (probenecid, sulfinpyrazone and allopurinol). Dose adjustment of uricosuric medicinal products may be necessary, as hydrochlorothiazide may increase serum uric acid levels. It may be necessary to increase the dose of probenecid or sulfinpyrazone. With concomitant use of thiazide diuretics, including hydrochlorothiazide, the frequency of hypersensitivity reactions to allopurinol increases. Methyldopa. There are data on the development of hemolytic anemia with concomitant use of hydrochlorothiazide and methyldopa. Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine). Thiazides, including hydrochlorothiazide, potentiate the effect of curare derivatives. Other antihypertensive medicinal products. Thiazides potentiate the antihypertensive effect of other antihypertensive medicinal products (such as guanethidine, methyldopa, β-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers, and direct renin inhibitors). Pressor amines (e.g., noradrenaline, adrenaline). Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and insufficient to discontinue their use. Vitamin D and calcium salts. Use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may increase serum calcium levels. Concomitant use of thiazide diuretics may lead to hypercalcemia in susceptible patients (e.g., hyperparathyroidism, malignancies or vitamin D-mediated conditions) due to increased tubular reabsorption of calcium. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARBs, ACE inhibitors or aliskiren. Clinical data have demonstrated that dual blockade of RAAS by concomitant use of ACE inhibitors, ARBs or aliskiren is associated with an increased risk of adverse reactions such as hypotension, hyperkalemia and renal impairment (including acute renal failure) compared to monotherapy with a RAAS-affecting substance. Special precautions for use. Safety and efficacy of amlodipine use in hypertensive crisis have not been studied. Patients with sodium deficiency and dehydration Excessive hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of Tiara Trio® (10 mg/320 mg/25 mg), compared to 1.8% of patients receiving valsartan/hydrochlorothiazide (320 mg/25 mg), 0.4% of patients receiving amlodipine/valsartan (10 mg/320 mg), and 0.2% of patients receiving hydrochlorothiazide/amlodipine (25 mg/10 mg), in a controlled study involving patients with moderate or severe uncomplicated hypertension. In patients with activated renin-angiotensin system (patients with salt deficiency and/or dehydration receiving high-dose diuretics), symptomatic arterial hypotension may occur after initiation of the medicinal product. It is recommended to correct this condition before administration of Tiara Trio® or to closely monitor the patient at the beginning of treatment. If pronounced arterial hypotension occurs during use of Tiara Trio®, the patient should be placed in a supine position with legs elevated, and if necessary, intravenous infusion of physiological saline should be administered. Treatment can be continued after stabilization of blood pressure. Changes in serum electrolyte levels Amlodipine/valsartan/hydrochlorothiazide. Based on data from clinical studies, the counteracting effect of 320 mg valsartan and 25 mg hydrochlorothiazide on serum potassium levels approximately balances each other in many patients. In other patients, one or the other effect may be dominant. Periodic monitoring of serum electrolyte and potassium levels is necessary to detect possible electrolyte imbalance. Periodic determination of serum electrolyte and potassium levels should be performed at appropriate intervals to prevent possible electrolyte imbalance, especially in patients with risk factors such as renal impairment, use of other medicinal products and history of electrolyte imbalance. Valsartan. Concomitant use with potassium-containing supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or with other medicinal products that may increase potassium levels (e.g., with heparin) is not recommended. If necessary, potassium levels should be monitored. Hydrochlorothiazide. Hypokalemia has been reported during treatment with thiazide diuretics, including hydrochlorothiazide. Use of the medicinal product should be initiated only after correction of hypokalemia and any coexisting hypomagnesemia. Thiazide diuretics may lead to hypokalemia or exacerbation of existing hypokalemia. Thiazide diuretics should be used with caution in patients with conditions involving potassium loss, such as salt-wasting nephropathy and prerenal (cardiogenic) renal impairment. If hypokalemia develops during hydrochlorothiazide therapy, use of the medicinal product should be discontinued until stable correction of potassium balance is achieved. Treatment with thiazide diuretics, including hydrochlorothiazide, is associated with the development of hyponatremia and hypochloremic alkalosis or exacerbation of existing hyponatremia. Hyponatremia is observed, accompanied by neurological symptoms (nausea, progressive disorientation, apathy). Treatment with hydrochlorothiazide should be initiated only after correction of existing hyponatremia. In case of development of severe or rapid hyponatremia during treatment with the medicinal product, its use should be discontinued until normalization of natremia. Thiazides, including hydrochlorothiazide, enhance magnesium excretion in urine, which may lead to hypomagnesemia. With use of thiazide diuretics, calcium excretion is reduced, which may lead to hypercalcemia. In all patients receiving thiazide diuretics, periodic monitoring of electrolyte levels, especially potassium, sodium and magnesium, is necessary. Renal impairment Thiazide diuretics may accelerate azotemia in patients with chronic kidney disease. There is no need to adjust the dose of Tiara Trio® in patients with mild to moderate renal impairment (GFR > 30 mL/min/1.73 m²). When using Tiara Trio®, periodic monitoring of potassium, creatinine and uric acid levels in serum of patients with renal impairment is recommended. Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m²). The medicinal product is contraindicated in patients with severe renal failure, anuria or patients on dialysis. Renal artery stenosis Tiara Trio® should be used with caution for the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, as serum urea and creatinine levels may increase. Kidney transplantation There is no experience with the safety of using Tiara Trio® in patients who have recently undergone kidney transplantation. Hepatic impairment Valsartan is primarily excreted unchanged in bile. The elimination half-life of amlodipine is prolonged, and AUC is higher in patients with hepatic impairment; dosage recommendations are not established. For patients with mild to moderate hepatic impairment not associated with cholestasis, the maximum recommended dose of valsartan is 80 mg. For this reason, Tiara Trio® is not indicated for such patients. Angioedema Angioedema, including laryngeal edema and edema of the glottis, which may lead to airway obstruction, and/or facial, lip, pharyngeal and/or tongue edema, has been observed in patients taking valsartan. Some of these patients had a history of angioedema with other medicinal products, including ACE inhibitors. Use of the medicinal product should be immediately discontinued if angioedema occurs, and re-administration is not recommended. Heart failure and coronary artery disease/post-myocardial infarction state Due to inhibition of RAAS, changes in renal function may be expected in patients with increased sensitivity. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists leads to oliguria and/or progressive azotemia (rarely) with acute renal failure and/or fatal outcome. Similar outcomes have been reported for valsartan. Assessment of patients with heart failure or post-myocardial infarction should always include evaluation of renal function. In a long-term placebo-controlled study of amlodipine (PRAISE-2) in patients with non-ischemic heart failure class III and IV according to NYHA (New York Heart Association) classification, the incidence of pulmonary edema was higher with amlodipine use, despite a negligible difference in the occurrence or worsening of heart failure compared to placebo. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and fatal outcome. It is recommended to use the medicinal product with caution in patients with heart failure and coronary artery disease, especially at the maximum dose – 10 mg/25 mg/320 mg, as data on use of the medicinal product in this patient group are limited. Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy As with other vasodilators, the medicinal product should be prescribed with particular caution in patients with aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy. Pregnancy Treatment with ARBs should not be initiated during pregnancy. If continuation of ARB therapy is necessary, patients planning pregnancy should switch to alternative antihypertensive therapy with established safety profile for use during pregnancy. If pregnancy occurs, ARB therapy should be immediately discontinued and, if necessary, alternative therapy initiated. Primary hyperaldosteronism Patients with primary hyperaldosteronism should not be treated with ARB valsartan, as the renin-angiotensin system is not activated in them. Therefore, Tiara Trio® is not recommended for this patient group. Systemic lupus erythematosus It has been reported that thiazide diuretics, including hydrochlorothiazide, may exacerbate systemic lupus erythematosus. Other metabolic disorders Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and increase serum cholesterol, triglycerides and uric acid levels. Dose adjustment of insulin or oral hypoglycemic agents may be necessary in patients with diabetes. Since Tiara Trio® contains hydrochlorothiazide, it is contraindicated in systemic hyperuricemia. Hydrochlorothiazide may increase serum uric acid levels due to decreased uric acid clearance and may cause exacerbation of hyperuricemia and sudden gout attacks in susceptible patients. Thiazides may reduce calcium excretion in urine and cause periodic slight increase in serum calcium levels in the absence of known calcium metabolism disorders. Use of the medicinal product should be discontinued if hypercalcemia develops during treatment. Serum calcium levels should be monitored periodically during thiazide therapy. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued before testing parathyroid function. Photosensitivity Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during use of Tiara Trio®, treatment should be discontinued. If resumption of diuretic use is considered necessary, protection of exposed skin areas from sunlight or artificial ultraviolet radiation is recommended. Choroidal effusion, acute myopia and secondary angle-closure glaucoma. Hydrochlorothiazide, sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defect, acute transient myopia and angle-closure glaucoma. Symptoms include sudden decrease in visual acuity or eye pain, usually appearing within hours or the first week after initiation of treatment. Untreated angle-closure glaucoma may lead to irreversible vision loss. Hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, immediate medical or surgical treatment should be considered. Risk factors for development of angle-closure glaucoma may include history of allergic reactions to sulfonamides or penicillin. General precautions The medicinal product should be prescribed with caution to patients who have experienced hypersensitivity to other ARBs. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma. Elderly patients (aged 65 years and older) The medicinal product should be prescribed with caution to elderly patients, especially maximum doses of Tiara Trio® 10 mg/25 mg/320 mg, as data on use of the medicinal product in this patient group are limited. Blood pressure should be monitored in these patients. Dual blockade of RAAS There is evidence that concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, may lead to increased incidence of hypotension, hyperkalemia and renal impairment (including acute renal failure). Therefore, dual blockade of RAAS by concomitant use of ACE inhibitors, ARBs or aliskiren is not recommended. If dual blockade is necessary, it should be performed under strict specialist supervision and with continuous monitoring of renal function, electrolyte levels and blood pressure. Concomitant use of ACE inhibitors and ARBs is not recommended in patients with diabetic nephropathy. Non-melanoma skin cancer In two epidemiological studies based on the Danish National Cancer Registry, a possible increased risk of non-melanoma skin cancer (basal cell and squamous cell carcinoma) associated with increasing cumulative dose of hydrochlorothiazide was noted. The photosensitizing effect of hydrochlorothiazide may be the cause of non-melanoma skin cancer development. Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer and the need for regular skin examination for new lesions and immediate reporting of any suspicious skin lesions. Possible preventive measures, such as limiting exposure to sunlight and ultraviolet radiation, should be advised to patients, and appropriate protection should be recommended to minimize the risk of skin cancer development. Suspicious skin lesions should be immediately examined, potentially including histological examination of biopsies. Use of hydrochlorothiazide should also be reconsidered in patients who have had non-melanoma skin cancer (see also section "Adverse reactions"). Acute respiratory toxicity Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome. 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 administration. 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 prescribed to patients who previously experienced ARDS after hydrochlorothiazide administration. Important information about excipients. This medicinal product contains sodium compounds, therefore patients on a sodium-controlled diet should be cautious when using this medicinal product. Use during pregnancy or breastfeeding. Pregnancy Amlodipine Safety studies of amlodipine use during pregnancy have not been conducted. In animal studies, reproductive toxicity was observed with high-dose administration. Use during pregnancy is recommended only if a safer alternative medicinal product is not available and if the disease poses a greater risk to the mother and embryo. Valsartan Use of ARBs is not recommended during the first trimester of pregnancy. Use of ARBs is contraindicated during the second and third trimesters of pregnancy. Epidemiological data on teratogenic risk after exposure to ACE inhibitors during the first trimester of pregnancy were not convincing; however, a small increased risk cannot be excluded. While there are no controlled epidemiological data on the risk of ARB use, similar risks may exist for this class of medicinal products. If ongoing ARB therapy is not considered necessary in patients planning pregnancy, it should be switched to alternative antihypertensive therapies with established safety profile for use during pregnancy. If pregnancy is confirmed during ARB therapy, ARB therapy should be immediately discontinued and, if necessary, replaced with another medicinal product permitted for use during pregnancy. It is known that ARB exposure during the second and third trimesters of pregnancy causes human fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If ARBs were used from the second trimester of pregnancy, ultrasound examination of fetal renal function and skull is recommended. Infants whose mothers took ARBs should be carefully monitored for hypotension. Hydrochlorothiazide Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Data from animal studies are insufficient. Hydrochlorothiazide crosses the placenta. The pharmacological mechanism of action of hydrochlorothiazide provides grounds to suggest that use of this medicinal product during the second and third trimesters of pregnancy may impair fetoplacental perfusion and cause fetal and neonatal reactions such as jaundice, electrolyte imbalance and thrombocytopenia, and may also be associated with other adverse reactions observed in adults. Amlodipine/valsartan/hydrochlorothiazide There is no experience with use of Tiara Trio® in pregnant women. Available data on the components of the medicinal product suggest that use of Tiara Trio® is not recommended during the first trimester and contraindicated during the second and third trimesters of pregnancy. Breastfeeding period Amlodipine is excreted in breast milk. The fraction of maternal dose received by the infant was estimated with an interquartile range of 3–7%, maximum 15%. The effect of amlodipine on the infant is unknown. Information on valsartan use during breastfeeding is lacking. Hydrochlorothiazide is detected in breast milk in small amounts. Thiazides in high doses causing strong diuresis may interfere with breast milk production. Use of Tiara Trio® during breastfeeding is not recommended. If use of Tiara Trio® is necessary during breastfeeding, the lowest possible dose should be used. Alternative antihypertensive therapies with more established safety profiles are recommended during breastfeeding, especially when breastfeeding a newborn or premature infant. Fertility There are no clinical studies related to fertility with use of Tiara Trio®. Valsartan Valsartan had no adverse effect on reproductive function in male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times higher than the maximum recommended human dose, calculated in mg/m² (calculations assume an oral dose of 320 mg/day for a 60 kg patient). Amlodipine In some patients receiving calcium channel blockers, reversible biochemical changes in sperm heads have been reported. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one study in rats, an adverse effect on male fertility was observed. Ability to affect reaction speed when driving or operating machinery. Dizziness or weakness may occur in patients taking Tiara Trio® after administration of the medicinal product, therefore they should consider this when driving or operating potentially dangerous machinery. Amlodipine may have a slight or moderate effect on the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue or nausea during amlodipine use, their reaction may be impaired. Method of administration and dosage. Method of administration Tiara Trio® can be taken regardless of food intake. Tablets should be swallowed whole with water, at the same time each day, preferably in the morning. Dosage The recommended dose of Tiara Trio® is 1 tablet per day, preferably in the morning. Before switching to Tiara Trio®, the patient's condition should be controlled with unchanged doses of concurrently administered monotherapy. The dose of Tiara Trio® should correspond to the doses of individual components of the combination at the time of switching medicinal products. The maximum recommended dose of Tiara Trio® is 10 mg/25 mg/320 mg. Special patient groups Renal impairment Since it contains hydrochlorothiazide, Tiara Trio® is contraindicated in patients with anuria and severe renal impairment (creatinine clearance < 30 mL/min). Concomitant use of Tiara Trio® with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m²). There is no need to adjust the dose in patients with mild to moderate renal impairment. Diabetes mellitus Concomitant use of Tiara Trio® with aliskiren is contraindicated in patients with diabetes mellitus. Hepatic impairment Since Tiara Trio® contains hydrochlorothiazide and valsartan, it is contraindicated in patients with severe hepatic impairment. For patients with mild to moderate hepatic impairment not associated with cholestasis, the maximum recommended dose of valsartan is 80 mg, therefore Tiara Trio® is not indicated for this patient group. Dosage recommendations for amlodipine in patients with mild to moderate hepatic impairment are not established. When switching hypertensive patients with hepatic impairment to Tiara Trio®, the lowest acceptable dose of amlodipine should be used. Heart failure and coronary artery disease Experience with use of Tiara Trio®, especially at maximum doses, in patients with heart failure and coronary artery disease is limited. It is recommended to use the medicinal product with caution in patients with heart failure and coronary artery disease, especially the maximum dose of Tiara Trio® 10 mg/25 mg/320 mg. Elderly patients (aged 65 years and older) It is recommended to prescribe the medicinal product with caution to elderly patients, especially maximum doses of Tiara Trio® – 10 mg/25 mg/320 mg, as data on use of the medicinal product in this patient group are limited. Blood pressure should be monitored in these patients. When switching elderly patients to Tiara Trio®, the lowest acceptable dose of amlodipine should be used. Pediatric populations There are no adequate data on use of Tiara Trio® in pediatric populations (patients under 18 years of age) for the indication of arterial hypertension. Children. Safety and efficacy in children have not been established, therefore the medicinal product is not used in this age group. Overdose. Symptoms There are no data on overdose of Tiara Trio®. The main possible symptom of overdose is pronounced arterial hypotension with dizziness. Amlodipine overdose may lead to pronounced vasodilation of peripheral vessels and reflex tachycardia. Pronounced and potentially prolonged systemic hypotension, including shock with fatal outcome, has been reported. Rarely, non-cardiogenic pulmonary edema has been reported as a consequence of amlodipine overdose, which may manifest with delayed onset (24–48 hours after ingestion) and require mechanical ventilation. Factors contributing to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) to support perfusion and cardiac output. Treatment Amlodipine/valsartan/hydrochlorothiazide Clinically significant arterial hypotension in overdose of Tiara Trio® requires active cardiovascular support, including monitoring of cardiac and respiratory function, control of circulating blood volume and diuresis. The patient should be placed in a supine position with legs elevated. Vasoconstrictor medicinal products may be appropriate to restore vascular tone and blood pressure, provided there are no contraindications to their use. Intravenous administration of calcium gluconate may be effective in reversing the effects of calcium channel blockade. Amlodipine If little time has passed since ingestion of the medicinal product, induction of emesis or gastric lavage should be considered. Administration of activated charcoal immediately or 2 hours after amlodipine administration significantly reduced amlodipine absorption in healthy volunteers. Amlodipine is unlikely to be removed by hemodialysis. Valsartan Valsartan is unlikely to be removed by hemodialysis. Hydrochlorothiazide Hydrochlorothiazide overdose is accompanied by electrolyte deficiency (hypokalemia, hypochloremia) and hypovolemia due to excessive diuresis. The most common symptoms of overdose are nausea and somnolence. Hypokalemia may lead to muscle cramps and/or exacerbation of arrhythmia associated with concomitant use of cardiac glycosides or certain antiarrhythmic medicinal products. The fraction of hydrochlorothiazide removed by hemodialysis is not established. Adverse reactions. The safety profile of amlodipine/valsartan/hydrochlorothiazide combination, presented below, is based on clinical studies and the known safety profile of its individual components: amlodipine, valsartan and hydrochlorothiazide. All adverse reactions listed by system organ class (MedDRA) and frequency are presented for the amlodipine/valsartan/hydrochlorothiazide combination and separately for each component: 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 unknown (cannot be estimated from available data). Frequency of adverse reactions associated with amlodipine/valsartan/hydrochlorothiazide combination: Eye disorders: uncommon – vision disorders. Ear and labyrinth disorders: uncommon – vertigo. Respiratory, thoracic and mediastinal disorders: uncommon – cough, dyspnea, throat irritation. Gastrointestinal disorders: common – dyspepsia; uncommon – abdominal discomfort, upper abdominal pain, bad breath, diarrhea, dry mouth, nausea, vomiting. Renal and urinary disorders: common – polyuria; uncommon – increased serum creatinine, acute renal failure. Metabolism and nutrition disorders: common – hypokalemia; uncommon – anorexia, hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia. Nervous system disorders: common – dizziness, headache; uncommon – coordination disorder, postural dizziness, effort dizziness, dysgeusia, lethargy, paresthesia, peripheral neuropathy, neuropathy, somnolence, syncope. Psychiatric disorders: uncommon – insomnia/sleep disturbance. Cardiac disorders: uncommon – tachycardia. Vascular disorders: common – arterial hypotension; uncommon – orthostatic hypotension, phlebitis, thrombophlebitis. Skin and subcutaneous tissue disorders: uncommon – pruritus, hyperhidrosis. Musculoskeletal and connective tissue disorders: uncommon – back pain, joint swelling, muscle spasms, muscle weakness, myalgia, limb pain. Reproductive system and breast disorders: uncommon – impotence. General disorders and administration site conditions: common – weakness, edema; uncommon – abasia, gait disturbance, asthenia, discomfort, malaise, non-cardiac chest pain. Laboratory investigations: uncommon – increased blood urea nitrogen, increased blood uric acid, decreased blood potassium, increased body weight. Frequency of adverse reactions associated with amlodipine: Eye disorders: uncommon – vision disorders, visual disturbances. Ear and labyrinth disorders: uncommon – tinnitus. Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea, rhinitis; very rare – cough. Gastrointestinal disorders: common – nausea, vomiting, abdominal discomfort, upper abdominal pain; uncommon – altered defecation frequency, diarrhea, dry mouth, dyspepsia; very rare – gastritis, gingival hyperplasia, pancreatitis. Hepatobiliary disorders: very rare – hepatitis, intrahepatic cholestasis, jaundice, increased liver enzymes, including increased serum bilirubin (more associated with cholestasis). Renal and urinary disorders: uncommon – micturition disorder, nocturia, polyuria. Metabolism and nutrition disorders: very rare – hyperglycemia. Nervous system disorders: common – dizziness, headache, somnolence; uncommon – dysgeusia, paresthesia, syncope, tremor, hypoesthesia; very rare – hypertension, peripheral neuropathy, neuropathy; frequency unknown – extrapyramidal syndrome. Psychiatric disorders: uncommon – depression, insomnia/sleep disturbance, mood changes; rare – shyness. Cardiac disorders: common – palpitations; very rare – arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction. Vascular disorders: common – flushing; uncommon – arterial hypotension; very rare – vasculitis. Blood and lymphatic system disorders: very rare – leukopenia, thrombocytopenia, sometimes with purpura. Immune system disorders: very rare – hypersensitivity. Skin and subcutaneous tissue disorders: uncommon – pruritus, rash, purpura, alopecia, exanthema, hyperhidrosis, skin color change; very rare – urticaria, angioedema, erythema multiforme, photosensitivity reactions (see section "Special precautions for use". Photosensitivity), exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema; frequency unknown – necrotizing vasculitis and toxic epidermal necrolysis. Musculoskeletal and connective tissue disorders: common – ankle swelling; uncommon – arthralgia, back pain, muscle spasms, myalgia. Reproductive system and breast disorders: uncommon – gynecomastia, impotence. General disorders and administration site conditions: common – weakness, edema; uncommon – pain, asthenia, discomfort, malaise, non-cardiac chest pain. Laboratory investigations: uncommon – increase/decrease in body weight. Frequency of adverse reactions associated with valsartan: Ear and labyrinth disorders: uncommon – vertigo. Respiratory, thoracic and mediastinal disorders: uncommon – cough. Gastrointestinal disorders: uncommon – abdominal discomfort, upper abdominal pain. Hepatobiliary disorders: frequency unknown – increased liver enzymes, including increased serum bilirubin. Renal and urinary disorders: frequency unknown – increased serum creatinine, renal failure and renal dysfunction. Vascular disorders: frequency unknown – vasculitis. Blood and lymphatic system disorders: frequency unknown – decreased hemoglobin and hematocrit, neutropenia, thrombocytopenia, sometimes with purpura. Immune system disorders: frequency unknown – hypersensitivity. Skin and subcutaneous tissue disorders: frequency unknown – rash, pruritus, bullous dermatitis, angioedema. Musculoskeletal and connective tissue disorders: frequency unknown – myalgia. General disorders and administration site conditions: uncommon – weakness. Laboratory investigations: frequency unknown – increased blood potassium. Frequency of adverse reactions associated with hydrochlorothiazide: Eye disorders: rare – vision disorders; frequency unknown – acute angle-closure glaucoma, choroidal effusion. Respiratory, thoracic and mediastinal disorders: very rare – acute respiratory distress syndrome (ARDS) (see section "Special precautions for use"), pulmonary edema, pneumonitis. Gastrointestinal disorders: common – decreased appetite, nausea, vomiting; rare – constipation, diarrhea, abdominal discomfort, upper abdominal pain; very rare – pancreatitis. Hepatobiliary disorders: rare – intrahepatic cholestasis, jaundice. Renal and urinary disorders: rare – renal failure and renal dysfunction; frequency unknown – renal dysfunction, acute renal failure. Metabolism and nutrition disorders: very common – hypokalemia; common – hyperuricemia, hypomagnesemia, hyponatremia; rare – hypercalcemia, hyperglycemia, worsening of metabolic signs of diabetes; very rare – hyperchloremic alkalosis. Nervous system disorders: rare – dizziness, headache, paresthesia. Psychiatric disorders: rare – depression, insomnia/sleep disturbance. Cardiac disorders: rare – arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation). Vascular disorders: common – orthostatic hypotension. Blood and lymphatic system disorders: rare – thrombocytopenia, sometimes with purpura; very rare – leukopenia, neutropenia, agranulocytosis, bone marrow failure; frequency unknown – aplastic anemia. Immune system disorders: very rare – hypersensitivity. Skin and subcutaneous tissue disorders: common – rash, urticaria; rare – purpura, photosensitivity reactions (see section "Special precautions for use". Photosensitivity); very rare – skin reactions similar to lupus erythematosus, reactivation of cutaneous form of lupus erythematosus, necrotizing vasculitis and toxic epidermal necrolysis; frequency unknown – erythema multiforme. Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency unknown – non-melanoma skin cancer (basal cell and squamous cell carcinoma). Musculoskeletal and connective tissue disorders: frequency unknown – muscle spasms. Reproductive system and breast disorders: common – impotence. General disorders and administration site conditions: frequency unknown – prostration, asthenia. Laboratory investigations: very common – increased lipid levels; rare – glucosuria. Description of selected adverse reactions. Non-melanoma skin cancer: Based on available epidemiological data, a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer is observed (see section "Special precautions for use"). Reporting suspected adverse reactions. Reporting suspected adverse reactions after medicinal product registration is an important procedure. This allows continuous monitoring of the benefit-risk ratio for the respective medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system. Shelf life. 3 years. Storage conditions. Store in original packaging at temperature not exceeding 25 °C. Keep out of reach of children. Packaging. 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. Prescription status. Prescription only. Manufacturer. JSC "Pharmaceutical Company "Darnitsa". Manufacturer's location and address of business activity. Ukraine, 02093, Kyiv, Borispilska St., 13.