Corsar® trio

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CORSAR® TRIO (CORSARTRIO)

Composition:

Active substances: valsartan, amlodipine besylate, hydrochlorothiazide;

One film-coated tablet contains:

160 mg of valsartan; 6.935 mg of amlodipine besylate, equivalent to 5 mg of amlodipine; 12.5 mg of hydrochlorothiazide;

or 160 mg of valsartan; 13.87 mg of amlodipine besylate, equivalent to 10 mg of amlodipine; 12.5 mg of hydrochlorothiazide;

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

Film coating:

hypromellose, titanium dioxide (E 171), polyethylene glycol.

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group.

Cardiovascular agents. Agents acting on the renin-angiotensin system. Combined angiotensin II inhibitors. Angiotensin II antagonists, other combinations. Valsartan, amlodipine and hydrochlorothiazide.

ATC code C09DX01.

Pharmacological properties.

Pharmacodynamics.

The medicinal product Corzar® Trio contains three antihypertensive agents with complementary mechanisms of action for controlling blood pressure in patients with essential hypertension: amlodipine, belonging to the class of calcium channel blockers; valsartan, belonging to the class of angiotensin II antagonists; and hydrochlorothiazide, belonging to the class of thiazide diuretics. The combination of these three components exhibits mutually complementary antihypertensive effects.

Amlodipine

Amlodipine, contained in the medicinal product Corzar® Trio, inhibits transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The antihypertensive effect of amlodipine is mediated by direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and blood pressure.

In therapeutic doses, amlodipine causes vasodilation in patients with arterial hypertension, leading to reduced blood pressure in both supine and standing positions. This reduction in blood pressure is not accompanied by marked changes in heart rate or plasma catecholamine levels during long-term treatment.

Plasma concentration correlates with effect in both younger and elderly patients.

In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate (GFR) and effective renal plasma flow, without altering filtration fraction or proteinuria.

Valsartan

Valsartan is an orally active, potent, and specific antagonist of angiotensin II receptors. Valsartan acts selectively on the AT1-receptor subtype responsible for the known effects of angiotensin II.

Administration of valsartan to patients with arterial hypertension leads to reduced blood pressure without affecting pulse rate.

In most patients, after a single oral dose, the onset of antihypertensive effect occurs within 2 hours, and maximal blood pressure reduction is achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after dosing. With repeated administration, maximal blood pressure reduction (at all dosage regimens) is usually achieved within 2–4 weeks.

Hydrochlorothiazide

The primary site of action of thiazide diuretics is the distal convoluted tubules of the kidneys. High-affinity binding sites in the renal cortex have been identified as the main site for binding of thiazide diuretics and inhibition of NaCl transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of Na+Cl- cotransporters, possibly through competition at Cl- binding sites, thereby affecting electrolyte reabsorption mechanisms: directly increasing excretion of sodium and chloride to approximately equivalent degrees, and indirectly, via diuresis, reducing plasma volume, which leads to increased plasma renin activity, aldosterone secretion, and potassium excretion in urine, as well as decreased serum potassium levels.

Non-melanoma skin cancer

Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of non-melanoma skin cancer (NMSC). One study included 715,333 cases of basal cell carcinoma (BCC) (with 1,430,843 control subjects) and 8,629 cases of squamous cell carcinoma (SCC) (with 172,462 control subjects). Use of high cumulative doses of hydrochlorothiazide (≥ 50,000 mg) was associated with an adjusted risk ratio of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A cumulative dose-response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and hydrochlorothiazide use: 633 cases of lip cancer (SCC) were compared with 63,067 control subjects using a random 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) for high dose (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest dose (~100,000 mg).

Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomized controlled trials, ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes trial), investigated the concomitant use of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These trials did not demonstrate a significant beneficial effect on renal and/or cardiovascular function or mortality; however, an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings are also relevant for other ACE inhibitors and angiotensin II receptor antagonists.

Therefore, concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy (see section "Special precautions for use").

Additionally, the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints) evaluated the benefits of adding aliskiren to standard therapy (an ACE inhibitor or angiotensin II receptor antagonist) in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the aliskiren group than in the placebo group; furthermore, adverse events and serious adverse events (hyperkalemia, hypotension, and renal impairment) were more common in the aliskiren group than in the placebo group.

Pharmacokinetics.

Linearity

Amlodipine, valsartan, and hydrochlorothiazide exhibit linear pharmacokinetics.

Amlodipine/valsartan/hydrochlorothiazide

After oral administration of the combination of amlodipine, valsartan, and hydrochlorothiazide, peak plasma concentrations 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 in combination are similar to those observed when each is administered as a single agent.

Amlodipine

Absorption

After oral administration of amlodipine alone at therapeutic doses, maximum plasma concentration (Cmax) is reached within 6–12 hours. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

Volume of distribution is approximately 21 L/kg. Approximately 97.5% of circulating drug is bound to plasma proteins.

Biotransformation

Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.

Elimination

Amlodipine is eliminated from plasma in a biphasic manner, with a terminal elimination half-life of approximately 30–50 hours. Steady-state plasma levels are achieved after 7–8 days of continuous dosing. Approximately 10% of the original amlodipine and 60% of its metabolites are excreted in urine.

Valsartan

Absorption

After oral administration of valsartan alone, peak concentrations are reached within 2–4 hours. Mean absolute bioavailability is 23%. Food intake reduces the area under the plasma concentration-time curve (AUC) of valsartan by approximately 40% and Cmax by approximately 50%, although valsartan concentrations 8 hours after dosing are similar in fasting and postprandial groups. However, this reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered regardless of food intake.

Distribution

The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating limited tissue distribution. Valsartan is highly bound to serum proteins (94–97%), primarily to albumin.

Biotransformation

Valsartan undergoes minimal transformation, with only about 20% of the dose 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 drug. After intravenous administration, plasma clearance of valsartan is approximately 2 L/hour, and renal clearance is 0.62 L/hour (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption

Hydrochlorothiazide is rapidly absorbed after oral administration (Tmax approximately 2 hours). The increase in mean AUC is linear and dose-proportional within the therapeutic dose range. No changes in hydrochlorothiazide kinetics were observed upon repeated dosing, and accumulation was minimal with once-daily administration. Concomitant intake with food resulted in both increased and decreased systemic availability of hydrochlorothiazide compared to fasting, but the magnitude of these effects is small and of limited clinical significance. Absolute bioavailability of hydrochlorothiazide after oral administration is 60–80%.

Distribution

Apparent volume of distribution is 4–8 L/kg. Hydrochlorothiazide in circulating blood is bound to plasma proteins (40–70%), primarily to albumin. Hydrochlorothiazide also accumulates in erythrocytes at concentrations 1.8 times higher than in plasma.

Biotransformation

Hydrochlorothiazide is excreted unchanged.

Elimination.

More than 95% of the absorbed dose is excreted unchanged in urine. Renal clearance involves both passive filtration and active secretion in renal tubules. Elimination half-life is 6–15 hours.

Special patient populations

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 younger and elderly patients. In elderly patients, amlodipine clearance tends to be reduced, leading to increased AUC and elimination half-life. Mean systemic AUC of valsartan is 70% higher in elderly patients than in younger patients; therefore, dose escalation in these patients should be cautious.

Systemic exposure to valsartan is slightly higher in elderly patients compared to younger patients, but this difference is not clinically significant.

Limited data suggest that systemic clearance of hydrochlorothiazide is reduced in both healthy elderly volunteers and elderly hypertensive patients compared to younger healthy volunteers.

Since all three components of the drug are similarly well tolerated in younger and elderly patients, the standard dosing regimen is recommended for elderly patients.

Renal impairment

Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected for a drug with renal clearance accounting for only 30% of total plasma clearance, no correlation was observed between renal function and systemic exposure to valsartan. Therefore, patients with mild to moderate renal impairment can be treated with the standard initial dose.

Hepatic impairment

In patients with hepatic impairment, amlodipine clearance is reduced, leading to an increase in AUC by approximately 40–60%. On average, AUC of valsartan is twice as high in patients with mild to moderate chronic liver disease compared to healthy adult volunteers (matched for age, sex, and body weight). The drug should be administered with caution in patients with hepatic disease.

The combination of valsartan/amlodipine/hydrochlorothiazide has not been tested for genotoxicity and carcinogenicity, as no signs of interaction between these long-marketed agents have been observed. However, valsartan, amlodipine, and hydrochlorothiazide have each been individually tested for genotoxicity and carcinogenicity, and negative results were obtained.

Clinical characteristics.

Indications.

Treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with the combination of amlodipine, valsartan and hydrochlorothiazide, who are taking three separate medications or two medications, one of which is a combination product.

Contraindications.

• Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, or to any excipient of the medicinal product;
• Pregnancy or planning for pregnancy (see section "Use in pregnancy or breastfeeding");
• Impaired liver function, biliary cirrhosis or cholestasis;
• Severe renal impairment (eGFR < 30 mL/min/1.73 m²), anuria, or patients on dialysis;
• Concomitant use of the medicinal product Corsar® Trio with agents containing aliskiren in patients with diabetes or renal impairment (eGFR < 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 following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Studies on the interaction of the combination valsartan/amlodipine/hydrochlorothiazide with other medicinal products have not been conducted. The information provided below refers only to interactions known for each individual active substance.

However, it is important to note that the medicinal product Corsar® Trio may potentiate the hypotensive effect of other antihypertensive agents.

Concomitant use not recommended

Valsartan and hydrochlorothiazide

Lithium

Reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium with ACE inhibitors, angiotensin II receptor antagonists (including valsartan), or with thiazide diuretics such as hydrochlorothiazide.

Since thiazides reduce renal clearance of lithium, the risk of lithium toxicity may increase with the use of Corsar® Trio. Therefore, careful monitoring of serum lithium levels is recommended during concomitant therapy.

Valsartan

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

If concomitant use of a medicinal product affecting potassium levels is required with valsartan, frequent monitoring of plasma potassium levels is recommended.

Amlodipine

Grapefruit or grapefruit juice

The use of amlodipine with grapefruit or grapefruit juice is not recommended, as it may lead to an increased antihypertensive effect in some patients.

Concomitant use requires caution

Amlodipine

CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir)

Studies in elderly patients have shown that diltiazem inhibits amlodipine metabolism, possibly involving CYP3A4 (plasma concentration increases by approximately 50% and amlodipine effect is enhanced). It cannot be excluded that stronger CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may increase amlodipine plasma concentration more markedly 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 (anticonvulsants 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 decreased plasma concentrations of amlodipine. Clinical monitoring with possible dose adjustment of amlodipine is recommended during and after treatment with an inducer.

Amlodipine should be used with caution when coadministered 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. The daily dose of simvastatin should be reduced to 20 mg in patients taking amlodipine.

Dantrolene (infusions)

In animal studies, fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed after intravenous administration of verapamil and dantrolene. 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 during treatment of malignant hyperthermia.

Tacrolimus

There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid tacrolimus toxicity, concomitant use of amlodipine in patients treated with tacrolimus requires monitoring of tacrolimus blood levels and, if necessary, dose adjustment of tacrolimus.

Valsartan and hydrochlorothiazide

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

NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. Additionally, concomitant use of Corsar® Trio with NSAIDs may lead to impaired renal function and increased serum potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate hydration of the patient are recommended.

Inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir)

In vitro studies using human liver tissue have shown 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.

Hydrochlorothiazide

Alcohol, barbiturates, or narcotic drugs

Concomitant use of thiazide diuretics with substances that also lower blood pressure (e.g., those causing central nervous system sympathetic inhibition or direct vasodilation) may potentiate orthostatic hypotension.

Amantadine

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

Anticholinergic drugs and other medicinal products affecting gastrointestinal motility

Bioavailability of thiazide-type diuretics may be increased by anticholinergic drugs (e.g., atropine, biperiden), likely due to reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may decrease the bioavailability of thiazide diuretics.

Antidiabetic agents (e.g., insulin and oral antidiabetic agents)

Thiazide diuretics may alter glucose tolerance, necessitating re-evaluation of insulin and oral hypoglycemic agent dosing.

Metformin

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

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 enhance the hyperglycemic effect of diazoxide.

Carbamazepine

Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Patients should be warned of the possibility of hyponatremic reactions and monitored accordingly.

Cyclosporine

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

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

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Cardiac glycosides

Hypokalemia or hypomagnesemia induced by thiazides may predispose to digitalis-induced cardiac arrhythmias.

Iodine-containing contrast agents

In cases of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine-containing agents. Rehydration should be performed prior to 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, to minimize interaction, hydrochlorothiazide should be administered at least 4 hours before or 4–6 hours after the resin.

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 agents 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 may be enhanced when used concomitantly with antidepressants, neuroleptics, antiepileptic agents. Corsar® Trio should be prescribed with caution during long-term treatment with these agents.

Medicinal products that may cause torsades de pointes

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

Medicinal products used for the treatment of gout (probenecid, sulfinpyrazone, allopurinol)

Dose adjustment of uricosuric agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be required.

Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.

Metildopa

There have been isolated reports of hemolytic anemia with concomitant use of hydrochlorothiazide and methyldopa.

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

Thiazides, including hydrochlorothiazide, potentiate the effects of curare derivatives.

Other antihypertensive medicinal products

Thiazide diuretics potentiate the antihypertensive effects of other antihypertensive agents (e.g., guanethidine, methyldopa, β-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin II 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 contraindicate their use.

Vitamin D and calcium salts

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may potentiate increased serum calcium levels.

Concomitant use of thiazide diuretics may lead to hypercalcemia (e.g., in patients with hyperparathyroidism, malignancies, or vitamin D-mediated conditions) due to increased tubular reabsorption of calcium.

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

Clinical data have shown that dual RAAS blockade through concomitant use of ACE inhibitors, angiotensin receptor antagonists (ARAs), or aliskiren is associated with an increased risk of adverse reactions such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to monotherapy with a RAAS-acting agent.

Special precautions for use.

The safety and efficacy of amlodipine in hypertensive crisis have not been studied.

Patients with sodium deficiency and/or dehydration

Excessive hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of the amlodipine/valsartan/hydrochlorothiazide combination (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.

Symptomatic arterial hypotension may occur in patients with sodium deficiency and/or dehydration who are receiving high-dose diuretics. It is recommended to correct such conditions before initiating treatment with the medicinal product Corzar® Trio or to closely monitor the patient at the beginning of therapy.

If marked arterial hypotension occurs during treatment with Corzar® Trio, the patient should be placed in a supine position with the legs elevated. Intravenous infusion of physiological saline may be necessary if required. Treatment may be continued after stabilization of blood pressure.

Changes in serum electrolyte levels

Amlodipine/valsartan/hydrochlorothiazide

In a controlled study of the amlodipine/valsartan/hydrochlorothiazide combination, the opposing effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium levels approximately balanced each other in many patients. In other patients, one of these effects may predominate.

Periodic monitoring of serum electrolytes at appropriate intervals is necessary to detect possible electrolyte imbalances.

Regular assessment of serum electrolytes and potassium levels should be performed at appropriate intervals to prevent possible electrolyte imbalances, particularly in patients with risk factors such as impaired renal function, concomitant medication use, or a history of electrolyte imbalance.

Valsartan

Concomitant use with potassium-containing supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase potassium levels (e.g., heparin) is not recommended. If necessary, potassium levels should be monitored.

Angioedema of the intestine

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

Hydrochlorothiazide

Hypokalemia has been reported during treatment with thiazide diuretics, including hydrochlorothiazide.

Treatment with Corzar® Trio should be initiated only after correction of hypokalemia and any coexisting hypomagnesemia. Thiazide diuretics may cause or exacerbate existing hypokalemia and should therefore be used with caution in patients with conditions involving potassium loss, such as salt-wasting nephropathy and prerenal (cardiogenic) renal dysfunction. If hypokalemia develops during hydrochlorothiazide therapy, treatment with Corzar® Trio should be discontinued until stable correction of potassium balance is achieved.

Treatment with thiazide diuretics, including hydrochlorothiazide, may lead to or exacerbate existing hyponatremia and hypochloremic alkalosis. Hyponatremia associated with neurological symptoms (nausea, progressive disorientation, apathy) may occur. Treatment with hydrochlorothiazide should only be initiated after correction of existing hyponatremia. If severe or rapidly developing hyponatremia occurs during treatment with Corzar® Trio, the drug should be discontinued until serum sodium levels normalize. Thiazides, including hydrochlorothiazide, increase urinary magnesium excretion, which may lead to hypomagnesemia. Thiazide diuretics reduce calcium excretion, potentially leading to hypercalcemia.

All patients receiving thiazide diuretics should undergo periodic monitoring of electrolyte levels, particularly potassium, sodium, and magnesium.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer with increasing cumulative dose of hydrochlorothiazide was observed in two pharmacoepidemiological studies. The photosensitizing effect of hydrochlorothiazide may be the mechanism underlying this pathology.

Patients taking hydrochlorothiazide alone or in combination with other medicinal products should be informed about the risk of developing non-melanoma skin cancer, especially with long-term use, the need for regular skin examinations, and the necessity to promptly report any new skin lesions or suspicious skin neoplasms, as well as changes in skin lesions or moles.

To reduce the risk of skin cancer, patients should be informed about preventive measures such as limiting exposure to sunlight and UV radiation, and, when exposure is unavoidable, ensuring adequate skin protection. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy material.

Patients with a history of non-melanoma skin cancer may also require reassessment of hydrochlorothiazide use.

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide is contraindicated in patients who previously experienced ARDS after taking hydrochlorothiazide.

Renal function impairment

Thiazide diuretics may accelerate azotemia in patients with chronic kidney disease.

Dose adjustment of Corzar® Trio is not required in patients with mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m²).

The medicinal product is contraindicated in patients with severe renal impairment, anuria, and those undergoing dialysis.

Periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended in patients with renal impairment receiving Corzar® Trio.

Renal artery stenosis

Corzar® Trio should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney, as serum urea and creatinine levels may increase.

Renal transplantation

There is currently no information on the safety of Corzar® 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 increased in patients with hepatic impairment; dosing recommendations have not been established. For patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. Therefore, Corzar® Trio is not indicated for this patient group.

Angioedema

Angioedema, including laryngeal and glottic edema that may lead to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling, has been reported in patients treated with valsartan. Some of these patients had a history of angioedema with other drugs, including ACE inhibitors. Treatment with Corzar® Trio should be immediately discontinued if angioedema occurs; re-administration is not recommended.

Heart failure and coronary artery disease/post-myocardial infarction state

Due to RAAS inhibition, renal function impairment may be expected in sensitive patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists may lead to oliguria and/or progressive azotemia (rarely) with acute renal failure and/or fatal outcomes. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.

In the long-term, placebo-controlled PRAISE-2 study in patients with NYHA class III and IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine, despite minimal differences in the development 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 lead to fatal outcomes.

The medicinal product should be prescribed with caution to patients with heart failure and coronary artery disease, particularly at the maximum dose of Corzar® Trio – 320 mg/10 mg/25 mg, as data on use in this patient group are limited.

Aortic and mitral valve stenosis

As with other vasodilators, the medicinal product should be prescribed with particular caution in patients with low-grade aortic and mitral valve stenosis.

Pregnancy

Treatment with angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. If continued ARB therapy is necessary, patients planning pregnancy should switch to alternative antihypertensive agents with an established safety profile in pregnancy. If pregnancy occurs, ARB therapy should be discontinued immediately and, if necessary, alternative therapy initiated.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist – valsartan – as the renin-angiotensin system is not activated in these patients. Therefore, Corzar® Trio is not recommended for this patient group.

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels. Dose adjustments of insulin or oral hypoglycemic agents may be necessary in patients with diabetes mellitus.

Since Corzar® Trio contains hydrochlorothiazide, it is contraindicated in systemic hyperuricemia. Hydrochlorothiazide may increase serum uric acid levels due to reduced uric acid clearance and may precipitate hyperuricemia and acute gout attacks in susceptible patients.

Thiazides may reduce calcium excretion in urine and may cause transient and slight increases in serum calcium levels in the absence of known calcium metabolism disorders.

Corzar® Trio is contraindicated in patients with hypercalcemia. It may be used in such patients only after correction of existing hypercalcemia. If hypercalcemia develops during treatment, Corzar® Trio should be discontinued.

Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before parathyroid function testing.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during treatment with Corzar® Trio, treatment should be discontinued. If reinitiation of diuretic therapy 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, a sulfonamide, has been associated with an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or the first week after starting treatment. Untreated acute angle-closure glaucoma may lead to irreversible vision loss.

The medicinal product should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, immediate medical or surgical treatment should be considered. Risk factors for angle-closure glaucoma may include a history of allergic reactions to sulfonamides or penicillin.

General

The medicinal product should be prescribed with caution in patients who have previously experienced hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies or asthma.

Elderly patients (aged 65 years and older)

Corzar® Trio should be prescribed with caution, including frequent blood pressure monitoring, in elderly patients, particularly at maximum doses (320 mg/10 mg/25 mg), as data on use in this patient group are limited.

Dual blockade of the RAAS

Dual blockade of the RAAS by combining ACE inhibitors, ARBs, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure).

Therefore, dual RAAS blockade by combining ACE inhibitors, ARBs, or aliskiren is not recommended.

If dual blockade therapy is considered absolutely necessary, it should be conducted only under close medical supervision with continuous monitoring of blood pressure, renal function, and electrolyte levels. ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Use during pregnancy or breastfeeding.

Pregnancy.

Amlodipine

Studies on the safety of amlodipine use during pregnancy have not been conducted. Reproductive toxicity was observed in animal studies with high doses of amlodipine. Use during pregnancy is recommended only if no safer alternative medicinal product is available and if the condition poses a greater risk to the pregnant woman and fetus.

Valsartan

The medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with valsartan, therapy should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during pregnancy.

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy, particularly in the first trimester, is limited. Data from animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. The pharmacological mechanism of action of hydrochlorothiazide suggests that its use during the second and third trimesters of pregnancy may impair fetoplacental perfusion and cause fetal and neonatal adverse reactions such as jaundice, electrolyte imbalances, and thrombocytopenia, and may also be associated with other adverse reactions observed in adults.

Amlodipine/valsartan/hydrochlorothiazide

There is no experience with the use of Corzar® Trio in pregnant women. Available data on the components of the medicinal product indicate that the use of Corzar® Trio during pregnancy is contraindicated.

Period of breastfeeding.

Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant has been estimated with an interquartile range of 3–7%, maximum 15%. The effect of amlodipine on the infant is unknown. Information on the use of valsartan during breastfeeding is lacking. Hydrochlorothiazide is detected in breast milk in small amounts. High-dose thiazides causing strong diuresis may interfere with breast milk production.

The use of Corzar® Trio is contraindicated during breastfeeding.

Fertility

There are no clinical studies on fertility related to the use of the amlodipine/valsartan/hydrochlorothiazide combination.

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. An adverse effect on male fertility was observed in one rat study.

Ability to affect reaction speed when driving or operating machinery.

Dizziness or weakness may occur in patients taking Corzar® Trio; therefore, patients should take this into account when driving or operating potentially hazardous 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 treatment, their reaction time may be impaired.

Method of Administration and Dosage

Method of Administration

The medicinal product Corzar® Trio can be administered independently of food intake. The tablets should be swallowed whole with water, at the same time each day, preferably in the morning.

Dosage

The recommended dose of the medicinal product Corzar® Trio is 1 tablet per day, preferably in the morning.

Before switching to Corzar® Trio, the patient's condition should be controlled with stable doses of monotherapy agents taken concomitantly. The dose of Corzar® Trio should correspond to the doses of the individual components of the combination being used at the time of the switch.

The maximum recommended dose of Corzar® Trio is 320 mg/10 mg/25 mg.

Special Patient Groups

Renal Impairment

Since hydrochlorothiazide is a component of the product, Corzar® Trio is contraindicated in patients with anuria and severe renal impairment (creatinine clearance < 30 mL/min/1.73 m²).

No dose adjustment is required in patients with mild to moderate renal impairment.

*Hepatic Impair 1.73 m².

No dose adjustment is required in patients with mild to moderate renal impairment.

Hepatic Impairment

Since valsartan is a component of the product, Corzar® Trio is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment not associated with cholestasis, the maximum recommended dose of valsartan is 80 mg; therefore, Corzar® Trio is not recommended for this patient group. Dosage recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established.

When administering Corzar® Trio to patients with hepatic insufficiency, the lowest dose of one of the drug components—amlodipine—should be used.

Heart Failure and Coronary Artery Disease

Experience with the use of Corzar® Trio, particularly at maximum doses, in patients with heart failure and coronary artery disease is limited. The product should be used with caution in such patients, especially at the maximum dose of Corzar® Trio—320 mg/10 mg/25 mg.

Elderly Patients (aged 65 years and older)

The product should be prescribed with caution to elderly patients, particularly with frequent monitoring of blood pressure, especially at maximum doses (320 mg/10 mg/25 mg), as data on use in this patient group are limited.

When administering Corzar® Trio to elderly patients, the lowest dose of one of the drug components—amlodipine—should be used.

Children

Corzar® Trio should not be used in children under 18 years of age due to lack of data on safety and efficacy.

Overdose.

Symptoms

There are no data on overdose with Corzar® Trio. The main symptom of overdose is possible pronounced arterial hypotension with dizziness. Overdose of amlodipine may lead to marked peripheral vasodilation and possibly reflex tachycardia. Severe and potentially prolonged systemic hypotension, including shock with fatal outcome, has been reported. Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may develop with delay (24–48 hours after ingestion) and may require mechanical ventilation. Provocative factors may include early resuscitation measures (including fluid overload) aimed at supporting perfusion and cardiac output.

Treatment

Amlodipine/Valsartan/Hydrochlorothiazide

Clinically evident arterial hypotension due to overdose of Corzar® Trio requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the lower limbs, monitoring of circulating blood volume and diuresis. Vasoconstrictors may be appropriate to restore vascular tone and blood pressure, provided there are no contraindications to their use. Intravenous calcium gluconate may be effective in reversing the effects of calcium channel blockade.

Amlodipine

If only a short time has passed since ingestion, induction of emesis or gastric lavage should be considered. Administration of activated charcoal immediately or 2 hours after amlodipine intake significantly reduces its absorption.

It is unlikely that amlodipine is removed by hemodialysis.

Valsartan

It is unlikely that valsartan is removed by hemodialysis.

Hydrochlorothiazide

Overdose of hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia due to excessive diuresis. The most common symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of arrhythmias associated with concomitant use of cardiac glycosides or certain antiarrhythmic drugs.

The extent to which hydrochlorothiazide is removed by hemodialysis has not been established.

Adverse Reactions

The safety profile of the combination valsartan/amlodipine/hydrochlorothiazide described below is based on clinical studies of the medicinal product and the well-known safety profiles of its individual components: amlodipine, valsartan, and hydrochlorothiazide.

Summary of Safety Profile

The safety of the combination valsartan/amlodipine/hydrochlorothiazide was evaluated at the maximum dose of 320 mg/10 mg/25 mg in a controlled short-term (8-week) clinical study involving 2271 patients, of whom 582 received valsartan in combination with amlodipine and hydrochlorothiazide. Adverse reactions were generally mild and transient, and rarely required discontinuation of therapy. In this active-controlled clinical study, the most common reasons for discontinuation with the combination valsartan/amlodipine/hydrochlorothiazide were dizziness and hypotension (0.7%).

In the 8-week controlled clinical study, no significant new or unexpected adverse effects were observed with triple therapy compared to the known effects of monotherapy or dual therapy with the individual components of the drug.

In the 8-week controlled clinical study, laboratory test changes observed with the combination valsartan/amlodipine/hydrochlorothiazide were minor and consistent with the pharmacological mechanisms of action of the individual monotherapies. The presence of valsartan in the triple combination attenuates the hypokalemic effect of hydrochlorothiazide.

The following adverse effects may occur during treatment with the medicinal product Corsar® Trio (valsartan/amlodipine/hydrochlorothiazide) as well as with amlodipine, valsartan, and hydrochlorothiazide used as monotherapy. The frequencies are categorized as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

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

Blood and lymphatic system disorders: agranulocytosis, bone marrow depression (very rare – hydrochlorothiazide), decreased hemoglobin and hematocrit levels (frequency not known – valsartan), hemolytic anemia (very rare – hydrochlorothiazide), leukopenia (very rare – amlodipine, hydrochlorothiazide), neutropenia (frequency not known – valsartan), thrombocytopenia, sometimes with purpura (very rare – amlodipine, frequency not known – valsartan, rare – hydrochlorothiazide), aplastic anemia (frequency not known – hydrochlorothiazide).

Immune system disorders: hypersensitivity (very rare – amlodipine, hydrochlorothiazide, frequency not known – valsartan).

Metabolism and nutrition disorders: anorexia (uncommon – Corsar® Trio), hypercalcemia (uncommon – Corsar® Trio, rare – hydrochlorothiazide), hyperglycemia (very rare – amlodipine), hyperlipidemia (uncommon – Corsar® Trio), hyperuricemia (uncommon – Corsar® Trio, common – hydrochlorothiazide), hyperchloremic alkalosis (very rare – hydrochlorothiazide), hypokalemia (common – Corsar® Trio, very common – hydrochlorothiazide), hypomagnesemia (common – hydrochlorothiazide), hyponatremia (uncommon – Corsar® Trio, common – hydrochlorothiazide), worsening of metabolic signs of diabetes (rare – hydrochlorothiazide).

Psychiatric disorders: depression (uncommon – amlodipine, rare – hydrochlorothiazide), insomnia/sleep disturbances (uncommon – Corsar® Trio, amlodipine, rare – hydrochlorothiazide), mood changes (uncommon – amlodipine), nervousness (rare – amlodipine).

Nervous system disorders: coordination disturbances (uncommon – Corsar® Trio), dizziness (common – Corsar® Trio, amlodipine, rare – hydrochlorothiazide), postural dizziness, effort dizziness (uncommon – Corsar® Trio), dysgeusia (uncommon – Corsar® Trio, amlodipine), extrapyramidal disorder (frequency not known – amlodipine), headache (common – Corsar® Trio, amlodipine, rare – hydrochlorothiazide), hypertension (very rare – amlodipine), lethargy (uncommon – Corsar® Trio), paresthesia (uncommon – Corsar® Trio, amlodipine, rare – hydrochlorothiazide), peripheral neuropathy, neuropathy (uncommon – Corsar® Trio, very rare – amlodipine), somnolence (uncommon – Corsar® Trio, common – amlodipine), syncope (uncommon – Corsar® Trio, amlodipine), tremor (uncommon – amlodipine), hypoesthesia (uncommon – amlodipine).

Eye disorders: acute angle-closure glaucoma (frequency not known – hydrochlorothiazide), visual disturbances (uncommon – Corsar® Trio, amlodipine, rare – hydrochlorothiazide), visual disorders (uncommon – amlodipine), choroidal effusion (frequency not known – hydrochlorothiazide).

Ear and labyrinth disorders: tinnitus (uncommon – amlodipine), vertigo (uncommon – Corsar® Trio, valsartan).

Cardiac disorders: palpitations (common – amlodipine), tachycardia (uncommon – Corsar® Trio), arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation) (very rare – amlodipine, rare – hydrochlorothiazide), myocardial infarction (very rare – amlodipine).

Vascular disorders: flushing (common – amlodipine), hypotension (common – Corsar® Trio, uncommon – amlodipine), orthostatic hypotension (uncommon – Corsar® Trio, common – hydrochlorothiazide), phlebitis, thrombophlebitis (uncommon – Corsar® Trio), vasculitis (very rare – amlodipine, frequency not known – valsartan).

Respiratory, thoracic and mediastinal disorders: cough (uncommon – Corsar® Trio, valsartan, very rare – amlodipine), dyspnea (uncommon – Corsar® Trio, amlodipine), acute respiratory distress syndrome (ARDS) (very rare – hydrochlorothiazide), respiratory distress, pulmonary edema, pneumonitis (very rare – hydrochlorothiazide), rhinitis (uncommon – amlodipine), throat irritation (uncommon – Corsar® Trio).

Gastrointestinal disorders: abdominal discomfort, upper abdominal pain (uncommon – Corsar® Trio, valsartan, common – amlodipine, rare – hydrochlorothiazide), unpleasant breath odor (uncommon – Corsar® Trio), altered defecation frequency (uncommon – amlodipine), constipation (rare – hydrochlorothiazide), decreased appetite (common – hydrochlorothiazide), diarrhea (uncommon – Corsar® Trio, amlodipine, rare – hydrochlorothiazide), dry mouth (uncommon – Corsar® Trio, amlodipine), dyspepsia (common – Corsar® Trio, uncommon – amlodipine), gastritis (very rare – amlodipine), gingival hyperplasia (very rare – amlodipine), nausea (uncommon – Corsar® Trio, common – amlodipine, hydrochlorothiazide), pancreatitis (very rare – amlodipine, hydrochlorothiazide), vomiting (uncommon – Corsar® Trio, amlodipine, common – hydrochlorothiazide), intestinal angioedema (very rare – valsartan).

Hepatobiliary disorders: increased liver enzymes, including increased serum bilirubin (very rare* – amlodipine, frequency not known – valsartan), hepatitis (very rare – amlodipine), intrahepatic cholestasis, jaundice (very rare – amlodipine, rare – hydrochlorothiazide).

Skin and subcutaneous tissue disorders: alopecia (uncommon – amlodipine), angioedema (very rare – amlodipine, frequency not known – valsartan), bullous dermatitis (frequency not known – valsartan), skin reactions resembling lupus erythematosus, reactivation of cutaneous lupus erythematosus (very rare – hydrochlorothiazide), erythema multiforme (very rare – amlodipine, frequency not known – hydrochlorothiazide), exanthema (uncommon – amlodipine), hyperhidrosis (uncommon – Corsar® Trio, amlodipine), photosensitivity reactions (very rare – amlodipine, rare – hydrochlorothiazide), pruritus (uncommon – Corsar® Trio, amlodipine, frequency not known – valsartan), purpura (uncommon – amlodipine, rare – hydrochlorothiazide), rash (uncommon – amlodipine, frequency not known – valsartan, common – hydrochlorothiazide), skin discoloration (uncommon – amlodipine), urticaria and other forms of rash (very rare – amlodipine, common – hydrochlorothiazide), necrotizing vasculitis and toxic epidermal necrolysis (frequency not known – amlodipine, very rare – hydrochlorothiazide), exfoliative dermatitis (very rare – amlodipine), Stevens-Johnson syndrome (very rare – amlodipine), Quincke's edema (very rare – amlodipine).

Musculoskeletal and connective tissue disorders: arthralgia (uncommon – amlodipine), back pain (uncommon – Corsar® Trio, amlodipine), joint swelling (uncommon – Corsar® Trio), muscle cramps (uncommon – Corsar® Trio, amlodipine, frequency not known – hydrochlorothiazide), muscle weakness (uncommon – Corsar® Trio), myalgia (uncommon – Corsar® Trio, amlodipine, frequency not known – valsartan), limb pain (uncommon – Corsar® Trio), ankle swelling (common – amlodipine).

Renal and urinary disorders: increased serum creatinine (uncommon – Corsar® Trio, frequency not known – valsartan), urinary disorders (uncommon – amlodipine), nocturia (uncommon – amlodipine), polyuria (common – Corsar® Trio, uncommon – amlodipine), renal dysfunction (frequency not known – hydrochlorothiazide), acute kidney injury (uncommon – Corsar® Trio, frequency not known – hydrochlorothiazide), kidney failure and impaired kidney function (frequency not known – valsartan, rare – hydrochlorothiazide).

Reproductive system and breast disorders: impotence (uncommon – Corsar® Trio, amlodipine, common – hydrochlorothiazide), gynecomastia (uncommon – amlodipine).

General disorders: abasia, gait disturbances (uncommon – Corsar® Trio), asthenia (uncommon – Corsar® Trio, amlodipine, frequency not known – hydrochlorothiazide), discomfort, malaise (uncommon – Corsar® Trio, amlodipine), weakness (common – Corsar® Trio, amlodipine, uncommon – valsartan), non-cardiac chest pain (uncommon – Corsar® Trio, amlodipine), edema (common – Corsar® Trio, amlodipine), pain (uncommon – amlodipine), chills (frequency not known – hydrochlorothiazide).

Investigations: increased lipid levels (very common – hydrochlorothiazide), increased blood urea nitrogen (uncommon – Corsar® Trio), increased serum uric acid (uncommon – Corsar® Trio), glucosuria (rare – hydrochlorothiazide), decreased serum potassium (uncommon – Corsar® Trio), increased serum potassium (frequency not known – valsartan), increased body weight (uncommon – Corsar® Trio, amlodipine), decreased body weight (uncommon – amlodipine).

*More associated with cholestasis.

Non-melanoma skin cancer: Based on available epidemiological data, a cumulative dose-response relationship has been observed between hydrochlorothiazide use and the development of non-melanoma skin cancer (NMSC).

Reporting of Suspected Adverse Reactions

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

Shelf Life

2 years.

Storage Conditions

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

Keep out of the reach of children.

Packaging

10 tablets in a blister. 3 blisters in a carton.

Prescription Status

Prescription only.

Manufacturer

JSC "Farmak".

Manufacturer's Address and Location of Business Activity

74 Kyrylivska Street, Kyiv, 04080, Ukraine.

Marketing Authorization Holder: JSC "Farmak".

Address of Marketing Authorization Holder: 63 Kyrylivska Street, Kyiv, 04080, Ukraine.