Valsartan 160/hydrochlorothiazide 12.5/amlodipine 10 macleods

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valsartan 160/Hydrochlorothiazide 12.5/Amlodipine 5 Macleods Valsartan 160/Hydrochlorothiazide 12.5/Amlodipine 10 Macleods

Composition:

1 tablet of 160 mg/12.5 mg/5 mg contains:

Active substances: valsartan 160 mg; hydrochlorothiazide 12.5 mg; amlodipine besylate equivalent to amlodipine 5 mg;

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

Coating Instacoat Universal ICG-U-10346 White: hypromellose, polyethylene glycol, talc,

titanium dioxide (E 171);

1 tablet of 160 mg/12.5 mg/10 mg contains:

Active substances: valsartan 160 mg; hydrochlorothiazide 12.5 mg; amlodipine besylate equivalent to amlodipine 10 mg;

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

Coating Instacoat Universal A05G10966 Yellow: hypromellose, polyethylene glycol, talc,

titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets of 160 mg/12.5 mg/5 mg – biconvex, film-coated, oval-shaped, white tablets with "T23" engraved on one side and smooth on the other side;

Tablets of 160 mg/12.5 mg/10 mg – biconvex, film-coated, oval-shaped, light-yellow tablets with "C96" engraved on one side and smooth on the other side.

Pharmacotherapeutic group. Angiotensin II antagonists, other combinations. Valsartan, amlodipine and hydrochlorothiazide. ATC code C09DX01.

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains three antihypertensive agents with complementary mechanisms of blood pressure control 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 demonstrates complementary antihypertensive effects.

Amlodipine

Amlodipine, one of the components of the medicinal product, inhibits transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The antihypertensive mechanism of amlodipine involves direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and decreased arterial blood pressure.

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

Plasma concentrations correlate with effect in both young 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 and effective renal plasma flow, without altering filtration fraction or proteinuria.

Valsartan

Valsartan is a potent and specific orally active antagonist of angiotensin II receptors. Valsartan acts selectively on the AT1 receptor subtype, which mediates the known effects of angiotensin II.

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

In most patients, after a single oral dose, the onset of the hypotensive effect occurs within 2 hours, and maximal reduction in blood pressure 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 generally 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 thiazide diuretic binding and inhibition of NaCl transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of the Na+Cl– transporter, possibly through competition at chloride binding sites, thereby affecting electrolyte reabsorption mechanisms: it directly enhances excretion of sodium and chloride to a roughly equivalent extent, and indirectly, via diuresis, reduces plasma volume, leading to increased plasma renin activity, aldosterone secretion, and urinary potassium excretion, as well as decreased serum potassium levels.

Non-melanoma skin cancer (NMSC)

Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (with 1,430,833 individuals in the control group) and 8,629 cases of squamous cell carcinoma (with 172,462 individuals in the control group). High-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal and squamous cell carcinomas. Another study indicated a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were compared with 63,067 population-based controls using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) 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 studies did not demonstrate significant beneficial effects 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 warnings and precautions for use").

Additionally, the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints), which 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, 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 frequent 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 medicinal product to healthy adult volunteers, maximum plasma concentrations 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 following administration of the medicinal product are similar to those observed when its components are administered as individual agents.

Amlodipine

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

Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies show that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism. 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 concentrations are achieved after 7–8 days of continuous administration. 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 valsartan exposure (as measured by AUC) by approximately 40% and peak plasma concentration (Cmax) by approximately 50%, although valsartan concentrations 8 hours after dosing are similar between fasting and fed conditions. 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 serum albumin.

Metabolism. Valsartan undergoes minimal biotransformation, 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 about 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. Hydrochlorothiazide is rapidly absorbed after oral administration (Tmax approximately 2 hours). The increase in mean AUC is linear and proportional to dose within the therapeutic dose range. No changes in hydrochlorothiazide kinetics are observed upon repeated administration, and accumulation is minimal with once-daily dosing. When administered with food, both increases and decreases in systemic availability of hydrochlorothiazide have been observed compared to fasting conditions. The magnitude of these effects is minor and of limited clinical significance. Absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration.

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

Metabolism. Hydrochlorothiazide is excreted unchanged.

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

Special patient populations

Children (under 18 years of age)

No pharmacokinetic data are available 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, 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 should be performed cautiously in these patients.

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 patients with arterial hypertension compared to younger healthy volunteers.

Since all three components of the medicinal product are similarly well tolerated in both young and elderly patients, the standard dosage regimen is recommended.

Renal impairment

Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected for a drug with only 30% of total plasma clearance being renal clearance, no correlation was observed between renal function and systemic exposure to valsartan.

Therefore, patients with mild to moderate renal impairment may use the medicinal product at the standard initial dose.

Hepatic impairment

In patients with hepatic impairment, amlodipine clearance is reduced, resulting in an increase in AUC by approximately 40–60%. On average, exposure to valsartan (as measured by AUC) is about 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 medicinal product should be used with caution in patients with hepatic disease.

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

Clinical characteristics.

Indications.

Treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with a combination of amlodipine, valsartan, and hydrochlorothiazide, administered either as three separate medicinal products or as two medicinal products, one of which is a combination product.

Contraindications.

• Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, or to any of the excipients.

• Pregnancy or planned pregnancy (see "Use in pregnancy or breastfeeding").

• Impaired liver function, biliary cirrhosis, or cholestasis.

• Severe renal impairment (glomerular filtration rate (GFR) <30 mL/min/1.73 m²), anuria, or patients on dialysis.

• Concomitant use of the medicinal product with aliskiren-containing products in patients
  with diabetes mellitus 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, severe aortic stenosis).

• Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Interaction studies between the fixed-combination product and other medicinal products have not been conducted. Table 1 provides information only on interactions known for each individual active substance.

However, it is important to consider that the medicinal product may enhance the hypotensive effect of other antihypertensive agents.

Table 1

Concomitant use not recommended
Components of the medicinal product	Medicinal products and substances with which interactions exist	Effect of interaction
Valsartan and hydrochlorothiazide	Lithium	Reversible increases in serum lithium concentration and lithium toxicity have been reported during concomitant use of lithium with ACE inhibitors, angiotensin II receptor antagonists (including valsartan), or thiazides such as hydrochlorothiazide. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may increase with use of the medicinal product. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use of these medicinal products.
Valvalsartan	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 with valsartan is necessary, frequent monitoring of plasma potassium levels is recommended.
Amlodipine	Grapefruit or grapefruit juice	Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as bioavailability may increase in some patients, leading to enhanced antihypertensive effect.
Concomitant use requires caution
Components of the medicinal product	Medicinal products and substances with which interactions exist	Effect of interaction
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 the effect of amlodipine 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 [e.g., 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 reduce plasma concentrations of amlodipine. Clinical monitoring with possible dose adjustment of amlodipine during and after discontinuation of the inducer is 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. The daily dose of simvastatin should be reduced to 20 mg in patients taking amlodipine.
	Dantrolene (infusions)	Lethal cases due to ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals 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, use of amlodipine in patients receiving tacrolimus requires monitoring of tacrolimus blood levels and, if necessary, dose adjustment of tacrolimus.
Valvalsartan 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 the medicinal product and NSAIDs may lead to worsening renal function and increased serum potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate patient hydration are recommended.
Valvalsartan	Uptake transporter inhibitors (rifampicin, cyclosporine) or efflux transporter inhibitors (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 uptake transporter inhibitors (rifampicin, cyclosporine) or efflux transporter inhibitors (ritonavir) may increase systemic exposure to valsartan.
Hydrochlorothiazide	Alcohol, barbiturates, or narcotic agents	Concomitant administration of thiazide diuretics with substances that also lower blood pressure (e.g., those reducing central sympathetic activity or causing direct vasodilation) may enhance orthostatic hypotension.
	Amantadine	Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine.
	Anticholinergic agents and other medicinal products affecting gastrointestinal motility	Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide diuretics, likely due to reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics.
	Antidiabetic agents (e.g., insulin and oral antidiabetics) Metformin	Thiazides may alter glucose tolerance. Recalibration of insulin and oral hypoglycemic agent doses may be necessary. Metformin should be used with caution due to the risk of lactic acidosis induced by possible functional renal impairment associated with hydrochlorothiazide use.
	Beta-blockers and diazoxide	Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may enhance the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
	Carbamazepine	Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Patients should be warned about the possibility of hyponatremic reactions and monitored accordingly.
	Cyclosporine	Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and complications of gouty type.
	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	Thiazide-induced hypokalemia or hypomagnesemia may occur as adverse effects predisposing to digoxin-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 iodine doses. 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, staggering the dose of hydrochlorothiazide and the resin so that hydrochlorothiazide is administered at least 4 hours before or 4–6 hours after the resin may potentially minimize the interaction.
	Medicinal products affecting potassium levels (potassium-wasting diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylate derivatives) and antiarrhythmic agents	The hypokalemic effect of hydrochlorothiazide may be enhanced by potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylate derivatives, and antiarrhythmic agents. If such agents are prescribed concomitantly with amlodipine/valsartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended.
	Medicinal products affecting sodium levels	The hyponatremic effect of diuretics may be enhanced by antidepressants, antipsychotics, antiepileptics, etc., when used concomitantly. Caution is required during prolonged 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, including class Ia and class III antiarrhythmics, and certain antipsychotics.
	Medicinal products used to treat gout (probenecid, sulfinpyrazone, and allopurinol)	Dose adjustment of uricosuric agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.
	Methyldopa	Isolated reports of hemolytic anemia have occurred during concomitant use of hydrochlorothiazide and methyldopa.
	Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)	Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.
	Other antihypertensive agents	Thiazides potentiate the antihypertensive effect of other antihypertensive agents (e.g., guanethidine, methyldopa, beta-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 warrant discontinuation of 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 in predisposed patients (e.g., hyperparathyroidism, malignancies, or vitamin D-mediated states) due to increased tubular reabsorption of calcium.

Dual blockade of the RAAS with angiotensin II receptor antagonists, ACE inhibitors, or aliskiren

Clinical data have shown that dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse reactions, such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy with a drug acting on the RAAS.

Special precautions for use.

The safety and efficacy of amlodipine 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 the Medicinal Product (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 after initiation of therapy in patients with salt depletion and/or dehydration, particularly those receiving high-dose diuretics. It is recommended to correct such conditions prior to initiating therapy or to closely monitor patients at the beginning of treatment.

If pronounced arterial hypotension occurs during treatment with the medicinal product, the patient should be placed in a supine position with elevated lower limbs. Intravenous infusion of physiological saline may be administered if necessary. Therapy may be continued after stabilization of blood pressure.

Serum electrolyte level changes

Amlodipine/valsartan/hydrochlorothiazide

In a controlled study of the medicinal product, the opposing effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium levels approximately balance each other in many patients. In others, one or the other effect may predominate.

Serum electrolyte levels should be monitored periodically to detect potential electrolyte imbalances.

Periodic monitoring 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 agents that may increase potassium levels (e.g., heparin) is not recommended. If necessary, potassium levels should be monitored.

Hydrochlorothiazide

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

Treatment with the medicinal product should only be initiated after correction of hypokalemia and any coexisting hypomagnesemia. Thiazide diuretics may cause hypokalemia or exacerbate pre-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 dysfunction. If hypokalemia develops during hydrochlorothiazide therapy, 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 worsening of pre-existing hyponatremia. Hyponatremia may be accompanied by neurological symptoms (nausea, progressive disorientation, apathy). Therapy with hydrochlorothiazide should only be initiated after correction of existing hyponatremia. In cases of severe or rapidly developing hyponatremia during treatment with the medicinal product, administration should be discontinued until serum sodium levels normalize. Thiazides, including hydrochlorothiazide, increase urinary excretion of magnesium, potentially leading to hypomagnesemia. Thiazide diuretics reduce calcium excretion, which may lead to hypercalcemia.

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

Renal impairment

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

Periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended in patients with renal impairment during treatment with the medicinal product.
The medicinal product is contraindicated in patients with severe renal impairment, anuria, or those undergoing dialysis.

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

Renal artery stenosis

The medicinal product 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.

Kidney transplantation

There is currently no information on the safety of using the medicinal product 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 the AUC (area under the plasma concentration-time curve) is higher in patients with hepatic impairment; dosage recommendations are lacking. For patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. For this reason, the medicinal product is not indicated for this patient group.

Angioedema

Angioedema, including laryngeal and glottal edema that may lead to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling, has been observed in patients taking valsartan. Some of these patients had a history of angioedema with other medications, including angiotensin-converting enzyme (ACE) inhibitors. The medicinal product should be discontinued immediately if angioedema occurs; re-administration is not recommended.

Intestinal angioedema

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

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

Due to suppression of the renin-angiotensin-aldosterone system (RAAS), renal dysfunction 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 a long-term, placebo-controlled study of amlodipine (PRAISE-2) in patients with NYHA (New York Heart Association) 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 mortality.

The medicinal product should be prescribed with caution in patients with heart failure and coronary artery disease, particularly at the maximum dose of 10 mg/320 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 administered 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 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 must 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, Valmisar NA is not recommended for this patient group.

Systemic lupus erythematosus

There are reports that thiazide diuretics, including hydrochlorothiazide, may 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.

Since the medicinal product 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 urinary calcium excretion and may cause transient, mild increases in serum calcium levels in the absence of known calcium metabolism disorders. 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. 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 the medicinal product, therapy should be discontinued. If resumption of diuretic therapy is considered necessary, protection of exposed skin areas from sunlight or artificial UV radiation is recommended.

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

The use of hydrochlorothiazide, a sulfonamide, has been associated with an allergic reaction leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include sudden onset of decreased visual acuity or eye pain and typically occur within hours or the first week after initiation of treatment. Untreated angle-closure glaucoma may lead to irreversible vision loss.

First-line management requires immediate discontinuation of hydrochlorothiazide. If intraocular pressure remains uncontrolled, immediate medical or surgical treatment should be considered. Risk factors for developing angle-closure glaucoma may include a history of sulfonamide or penicillin allergy (see section "Adverse reactions").

General

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

Elderly patients (aged 65 years and older)

The medicinal product should be prescribed with caution, including frequent monitoring of blood pressure, in elderly patients, particularly at the maximum dose of 10 mg/320 mg/25 mg, as data on use in this patient group are limited.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension and may lead to increased incidences of hypotension, hyperkalemia, and renal impairment (including acute renal failure).

Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended.

If dual blockade is required, it should be performed under close specialist supervision with continuous monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

Non-melanoma skin cancer

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

Patients taking hydrochlorothiazide should be informed about the risk of NMSC. These patients should be advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. Preventive measures to minimize skin cancer risk, such as limiting exposure to sunlight and ultraviolet radiation and using adequate protection when exposed to sunlight, should be considered. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsies. The use of hydrochlorothiazide should also be reconsidered in patients with a history of NMSC.

Acute respiratory toxicity

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

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 at high doses. Use during pregnancy is recommended only if no safer alternative agent is available and if the condition poses greater risk to the mother and fetus.

Valsartan

The medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, therapy must be discontinued immediately and, if necessary, replaced with a 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 imbalance, 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 the medicinal product in pregnant women. Available data on the components of the medicinal product suggest that its use is contraindicated.

Breastfeeding period

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

The use of the medicinal product is contraindicated during breastfeeding.

Fertility

There are no clinical studies related to the use of the medicinal product and fertility.

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 the maximum recommended human dose based on 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 the medicinal product; 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 while taking amlodipine, their reaction time may be impaired.

Method of Administration and Dosage

Method of Administration

The medication can be administered 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 the medication is 1 tablet daily, preferably in the morning.

Prior to switching to this medication, the patient's condition should be stabilized on unchanged doses of individual monotherapeutic agents, which should be taken simultaneously. The dose of this medication 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 the medication is 10 mg/320 mg/25 mg.

Special Patient Populations

Renal Impairment

Since the medication contains hydrochlorothiazide, it is contraindicated in patients with anuria and severe renal impairment (glomerular filtration rate [GFR] <30 mL/min/1.73 m²).

Dose adjustment is not required in patients with mild to moderate renal impairment.

Hepatic Impairment

Since the medication contains valsartan, it 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, this medication is not indicated for this patient group. Dosage recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established. When switching hypertensive patients with hepatic impairment to this medication, the lowest available dose of amlodipine should be used.

Heart Failure and Coronary Artery Disease

Experience with the use of this medication, particularly at maximum doses, in patients with heart failure and coronary artery disease is limited. Caution is recommended when administering the medication, especially the maximum dose of 10 mg/320 mg/25 mg, to patients with heart failure and coronary artery disease.

Elderly Patients (aged 65 years and older)

Caution, including frequent monitoring of blood pressure, is recommended when prescribing this medication to elderly patients, particularly the maximum dose of 10 mg/320 mg/25 mg, due to limited data in this patient group. When switching elderly patients to this medication, the lowest available dose of amlodipine should be used.

Pediatric Population

There are no adequate data on the use of this medication in pediatric patients (patients under 18 years of age) for the indication of arterial hypertension.

Children

Safety and efficacy in children have not been established; therefore, the medication should not be used in this age group.

Overdose

Symptoms

There are no data on overdose with the medication. The main symptom of overdose is possible severe arterial hypotension with dizziness. Amlodipine overdose may lead to marked peripheral vasodilation and possibly reflex tachycardia. Severe and potentially prolonged systemic hypotension has been reported, including shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema have been reported as a consequence of amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

Treatment

Amlodipine/Valsartan/Hydrochlorothiazide

Clinically significant arterial hypotension due to overdose 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 administration of calcium gluconate may be effective in reversing calcium channel blockade effects.

Amlodipine

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

Amlodipine is unlikely to be removed by hemodialysis.

Valsartan

Valsartan is unlikely to be removed by hemodialysis.

Hydrochlorothiazide

Hydrochlorothiazide overdose 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 arrhythmia, particularly when digoxin or certain antiarrhythmic drugs are used concomitantly.

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

Adverse reactions

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

Summary of safety profile

The safety of the medicinal product was evaluated at the maximum dose of 10 mg/320 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 due to the study medication 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 medicinal product.

In the 8-week controlled clinical study, laboratory parameter changes observed with the use of the medicinal product were minor and consistent with the pharmacological mechanisms of action of the monotherapeutic agents. The presence of valsartan in the triple combination attenuates the hypokalemic effect of hydrochlorothiazide.

Adverse reactions listed in Table 2 by organ system classes (MedDRA) and frequency are presented for the medicinal product (amlodipine/valsartan/hydrochlorothiazide) and separately for amlodipine, valsartan, and hydrochlorothiazide.

Very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10000 to <1/1000; very rare: <1/10000; not known (cannot be estimated from the available data).

Table 2

System organ classes (MedDRA)	Adverse reactions	Frequency
		Valmisar NA	Amlodipine	Valsartan	Hydrochloro- thiazide
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)	--	--	--	Unknown
Blood and lymphatic system disorders	Agranulocytosis, bone marrow depression	--	--	--	Very rare
	Decreased hemoglobin and hematocrit levels	--	--	Unknown	--
	Hemolytic anemia	--	--	--	Very rare
	Leukopenia	--	Very rare	--	Very rare
	Neutropenia	--	--	Unknown	--
	Thrombocytopenia, sometimes with purpura	--	Very rare	Unknown	Rare
	Aplastic anemia	--	--	--	Unknown
Immune system disorders	Hypersensitivity	--	Very rare	Unknown	Very rare
Metabolism and nutrition disorders	Anorexia	Uncommon	--	--	--
	Hypercalcemia	Uncommon	--	--	Rare
	Hypoglycemia	--	Very rare	--	Rare
	Hyperlipidemia	Uncommon	--	--	--
	Hyperuricemia	Uncommon	--	--	Common
	Hyperchloremic alkalosis	--	--	--	Very rare
	Hypokalemia	Common	--	--	Very common
	Hypomagnesemia	--	--	--	Common
	Hyponatremia	Uncommon	--	--	Common
	Worsening of metabolic signs of diabetes	--	--	--	Rare
Psychiatric disorders	Depression	--	Uncommon	--	Rare
	Insomnia/sleep disturbance	Uncommon	Uncommon	--	Rare
	Mood changes	--	Uncommon	--
	Apathy	--	Rare	--	--
Nervous system disorders	Coordination disturbance	Uncommon	--	--	--
	Dizziness	Common	Common	--	Rare
	Postural dizziness, effort dizziness	Uncommon	--	--	--
	Dysgeusia	Uncommon	Uncommon	--	--
	Extrapyramidal syndrome	--	Unknown	--	--
	Headache	Common	Common	--	Rare
	Hypertonia	--	Very rare	--	--
	Lethargy	Uncommon	--	--	--
	Paresthesia	Uncommon	Uncommon	--	Rare
	Peripheral neuropathy, neuropathy	Uncommon	Very rare	--	--
	Somnolence	Uncommon	Common	--	--
	Syncope	Uncommon	Uncommon	--	--
	Tremor	--	Uncommon	--	--
	Hypoesthesia	--	Uncommon	--	--
Eye disorders	Visual disturbance	Uncommon	Uncommon	--	Rare
	Visual disorders	--	Uncommon	--	--
	Acute angle-closure glaucoma	--	--	--	Unknown
	Choroidal effusion	--	--	--	Unknown
Ear and labyrinth disorders	Tinnitus	--	Uncommon	--	--
	Vertigo	Uncommon	--	Uncommon	--
Cardiac disorders	Palpitations	--	Common	--	--
	Tachycardia	Uncommon	--	--	--
	Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation)	--	Very rare	--	Rare
	Myocardial infarction	--	Very rare	--	--
Vascular disorders	Flushing	--	Common	--	--
	Arterial hypotension	Common	Uncommon	--	--
	Orthostatic hypotension	Uncommon	--	--	Common
	Phlebitis, thrombophlebitis	Uncommon	--	--	--
	Vasculitis	--	Very rare	Unknown	--
Respiratory, thoracic and mediastinal disorders	Cough	Uncommon	Very rare	Uncommon
	Dyspnea	Uncommon	Uncommon	--	--
	Acute respiratory distress syndrome (ARDS), respiratory failure, pulmonary edema, pneumonitis	--	--	--	Very rare
	Rhinitis	--	Uncommon	--	--
	Throat irritation	Uncommon	--	--	--
Gastrointestinal disorders	Abdominal discomfort, upper abdominal pain	Uncommon	Common	Uncommon	Rare
	Unpleasant breath odor	Uncommon	--	--	--
	Change in defecation frequency	--	Uncommon	--	--
	Constipation	--	--	--	Rare
	Decreased appetite	--	--	--	Common
	Diarrhea	Uncommon	Uncommon	--	Rare
	Dry mouth	Uncommon	Uncommon	--	--
	Dyspepsia	Common	Uncommon	--	--
	Gastritis	--	Very rare	--	--
	Gingival hyperplasia	--	Very rare	--	--
	Nausea	Uncommon	Common	--	Common
	Pancreatitis	--	Very rare	--	Very rare
	Vomiting	Uncommon	Uncommon	--	Common
	Angioneurotic intestinal edema	--	--	Very rare	--
Hepatobiliary disorders	Elevated liver enzymes, including increased serum bilirubin levels	--	Very rare*	Unknown	--
and biliary system	Hepatitis	--	Very rare	--	--
	Intrahepatic cholestasis, jaundice	--	Very rare	--	Rare
Skin and subcutaneous tissue disorders	Alopecia	--	Uncommon	--	--
	Angioedema	--	Very rare	Unknown	--
	Bullous dermatitis	--	--	Unknown	--
	Skin reactions resembling lupus erythematosus, reactivation of cutaneous lupus erythematosus	--	--	--	Very rare
	Multiform erythema	--	Very rare	--	Unknown
	Exanthema	--	Uncommon	--	--
	Hyperhidrosis	Uncommon	Uncommon	--	--
	Photosensitivity reactions	--	Very rare	--	Rare
	Pruritus	Uncommon	Uncommon	Unknown	--
	Purpura	--	Uncommon	--	Rare
	Rash	--	Uncommon	Unknown	Common
	Skin color changes	--	Uncommon	--	--
	Urticaria	--	Very rare	--	Common
	Necrotizing vasculitis and toxic epidermal necrolysis	--	Unknown	--	Very rare
	Exfoliative dermatitis	--	Very rare	--	--
	Stevens-Johnson syndrome	--	Very rare	--	--
	Quincke's edema	--	Very rare	--	--
Musculoskeletal and connective tissue disorders	Arthralgia	--	Uncommon	--	--
	Back pain	Uncommon	Uncommon	--	--
	Joint swelling	Uncommon	--	--	--
	Muscle cramps	Uncommon	Uncommon	--	Unknown
	Muscle weakness	Uncommon	--	--	--
	Myalgia	Uncommon	Uncommon	Unknown	--
	Limb pain	Uncommon	--	--	--
	Ankle swelling	--	Common	--	--
Renal and urinary disorders	Increased serum creatinine levels	Uncommon	--	Unknown	--
	Urination disorders		Uncommon
	Nocturia	--	Uncommon	--	--
	Polyuria	Common	Uncommon	--	--
	Kidney dysfunction	--	--	--	Unknown
	Acute kidney failure	Uncommon	--	--	Unknown
	Kidney failure and impaired kidney function	--	--	Unknown	Rare
Reproductive system and breast disorders	Impotence	Uncommon	Uncommon	--	Common
	Gynecomastia	--	Uncommon	--	--
General disorders and administration site conditions	Akinesia, gait disturbance	Uncommon	--	--	--
	Asthenia	Uncommon	Uncommon	--	Unknown
	Discomfort, malaise	Uncommon	Uncommon	--	--
	Weakness	Common	Common	Uncommon	--
	Non-cardiac chest pain	Uncommon	Uncommon	--	--
	Edema	Common	Common	--	--
	Chills	--	--	--	Unknown
	Pain	--	Uncommon	--	--
Investigations	Increased lipid levels		--		Very common
	Increased blood urea nitrogen	Uncommon	--	--	--
	Increased blood uric acid levels	Uncommon	--	--	--
	Glucosuria				Rare
	Decreased blood potassium levels	Uncommon	--	--	--
	Increased blood potassium levels	--	--	Unknown	--
	Increased body weight	Uncommon	Uncommon	--	--
	Decreased body weight	--	Uncommon	--	--

*More associated with cholestasis.

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

Reporting of suspected adverse reactions

Reporting of adverse reactions after the authorization of a medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging. Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 1, 3, or 9 blisters per cardboard pack.

Prescription status. Prescription-only.

Manufacturer. Macleods Pharmaceuticals Limited.

Manufacturer's address and site of operations.

Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.