Combisart h

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KOMBISARTH N (KOMBISARTH)

Composition:

Active substances: amlodipine, valsartan, hydrochlorothiazide;

1 tablet 5 mg/160 mg/12.5 mg contains: amlodipine besylate 6.94 mg, equivalent to 5 mg of amlodipine; valsartan 160 mg; hydrochlorothiazide 12.5 mg;

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

Coating: film-coating mixture Opadry II White 32F280008 (hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); polyethylene glycol (macrogol));

or

Active substances: amlodipine, valsartan, hydrochlorothiazide;

1 tablet 10 mg/160 mg/12.5 mg contains: amlodipine besylate 13.87 mg, equivalent to 10 mg of amlodipine; valsartan 160 mg; hydrochlorothiazide 12.5 mg;

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

Coating: film-coating mixture Opadry II Orange 32F230000 (hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); polyethylene glycol (macrogol); iron oxide yellow (E 172); iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 5 mg/160 mg/12.5 mg: oval-shaped tablets with a flat surface and beveled edges, coated with a white film coating;

Tablets 10 mg/160 mg/12.5 mg: oval-shaped tablets with a flat surface and beveled edges, coated with a light reddish-brown film coating.

Pharmacotherapeutic group. Angiotensin II antagonists, other combinations.

ATC code C09DX01.

Pharmacological properties.

Pharmacodynamics.

Combisart N contains three antihypertensive agents with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium channel blockers, valsartan belongs to the class of angiotensin II receptor antagonists, and hydrochlorothiazide belongs to the class of thiazide diuretics.

The combination of these three components is characterized by mutually complementary antihypertensive effects.

Amlodipine

Amlodipine, included in Combisart N, inhibits transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The mechanism of amlodipine’s antihypertensive action occurs via direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and blood pressure.

At therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to reduced 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 use.

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 an orally active, potent, and specific angiotensin II receptor antagonist. 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 a reduction in blood pressure without affecting pulse rate.

In most patients, after single oral dosing, onset of the hypotensive effect occurs within 2 hours, and maximum blood pressure reduction is achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after administration. With repeated dosing, maximum 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. It has been confirmed that high-affinity binding sites for thiazide diuretics exist in the renal cortex, which serve as the main site for inhibition of NaCl transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of the Na+Cl– cotransporter, possibly by competing for Cl– binding sites, thereby affecting electrolyte reabsorption: directly increasing excretion of sodium and chloride to approximately equivalent degrees, and indirectly, via diuretic effect, reducing plasma volume, which subsequently increases plasma renin activity, aldosterone secretion, and urinary potassium excretion, as well as lowering 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 71,533 cases of basal cell carcinoma (with 1,430,833 individuals in the control group) and 8,629 cases of squamous cell carcinoma (with 172,462 individuals in the control group). High-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose–response relationship was observed for both basal cell and squamous cell carcinomas. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were matched with 63,067 population 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), 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 any 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 to 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").

Additionally, the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes with Cardiovascular and Renal Disease), 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 dysfunction) 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 Combisart N 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 Combisart N 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 amlodipine bioavailability.

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.

Biological transformation. 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 half-life of approximately 30–50 hours. Steady-state plasma concentrations are reached after 7–8 days of continuous administration. About 10% of unchanged 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 defined by AUC) by approximately 40% and peak plasma concentration (Cmax) by approximately 50%, although valsartan concentrations are similar in fasting and postprandial groups approximately 8 hours after administration. However, this reduction in AUC is not associated with 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 albumins.

Biological transformation. 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 about 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. Absorption of hydrochlorothiazide after oral administration is rapid (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 with repeated administration, and accumulation was minimal with once-daily dosing. When administered with food, both increases and decreases in systemic availability of hydrochlorothiazide were observed compared to fasting administration. 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 albumins. Hydrochlorothiazide also accumulates in erythrocytes at levels 1.8 times higher than in plasma.

Biological transformation. Hydrochlorothiazide is excreted unchanged.

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

Special patient populations

Children (under 18 years of age)

There are no pharmacokinetic data 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, resulting in 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 done cautiously.

Systemic exposure to valsartan is somewhat 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 drug are similarly well tolerated in young and elderly patients, the usual 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, 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 usual 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, exposure (as measured by AUC) to 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 used with caution in patients with hepatic disease.

The combination of amlodipine/valsartan/hydrochlorothiazide has not been tested for genotoxicity or carcinogenicity, as no signs of interaction between these long-marketed agents have been observed. However, amlodipine, valsartan, 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, administered either as three separate medicinal products or as two medicinal products, one of which is a combination.

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").

• Hepatic impairment, 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 Combisart N with medicinal products containing aliskiren 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 and severe aortic stenosis).

• Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Interaction studies of Combisart N with other medicinal products have not been conducted. Table 1 provides information only on interactions known for each individual active ingredient.

However, it is important to note that Combisart N may enhance the hypotensive effect of other antihypertensive medicinal products.

Table 1

Concomitant use not recommended
Components of Combisart H	Medicinal products and substances with which interactions exist	Effect of interaction
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 thiazide diuretics such as hydrochlorothiazide. Since thiazides reduce renal clearance of lithium, the risk of lithium toxicity may increase with use of Combisart H. 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 with valsartan is required, 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 blood pressure-lowering effects.
Concomitant use requires caution
Components of Combisart H	Medicinal products and substances with which interactions exist	Effect of interaction
Amlodipine	CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir)	Studies in elderly patients have shown that diltiazem inhibits the metabolism of amlodipine, possibly via CYP3A4 (plasma concentration increases by approximately 50%, and the effect of amlodipine is enhanced). It cannot be excluded that stronger CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine 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 reduce plasma concentrations of amlodipine. Clinical monitoring with possible dose adjustment of amlodipine during and after treatment with an inducer is recommended. Amlodipine should be used with caution together with CYP3A4 inducers.
	Simvastatin	Repeated doses of 10 mg amlodipine with 80 mg simvastatin increase simvastatin exposure by 77% compared to simvastatin alone. It is recommended to reduce the daily dose of simvastatin to 20 mg in patients taking amlodipine.
	Dantrolene (infusions)	In animals, fatal ventricular fibrillation and cardiovascular collapse due to 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.
Valsartan and hydrochlorothiazide	Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and nonselective NSAIDs	NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. Moreover, concomitant use of Combisart H and NSAIDs may lead to worsening renal function and increased serum potassium levels. Therefore, monitoring of renal function at the beginning of treatment and adequate patient hydration are recommended.
Valsartan	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 uptake transporter inhibitors (rifampicin, cyclosporine) or efflux transporter inhibitors (ritonavir) may increase systemic exposure to valsartan.
Hydrochlorothiazide	Alcohol, barbiturates, or narcotics	Concomitant use of thiazide diuretics with agents 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	Bioavailability of thiazide diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), 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, possibly induced by functional renal impairment associated with hydrochlorothiazide use.
	Beta-blockers and diazoxide	Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase 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 exacerbate 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	Thiazide-induced hypokalemia or hypomagnesemia may predispose 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 prior to administration.
	Ion-exchange resins	Absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol, potentially leading to subtherapeutic effects. However, separating the dose of hydrochlorothiazide by at least 4 hours before or 4–6 hours after the resin may minimize this 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 with amlodipine/valsartan/hydrochlorothiazide combination, 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, antipsychotics, antiepileptics, etc. 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, particularly class Ia and class III antiarrhythmics, and some antipsychotics.
	Medicinal products used for gout treatment (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.
	Methyldopa	Isolated cases of hemolytic anemia have been reported 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 agents	Thiazides potentiate the antihypertensive effect of other antihypertensive agents (e.g., guanethidine, methyldopa, beta-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 warrant discontinuation.
	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 may lead to hypercalcemia in predisposed patients (e.g., hyperparathyroidism, malignancies, or vitamin D-mediated conditions) due to enhanced 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 renal dysfunction (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

Symptomatic arterial hypotension may occur after initiation of therapy in patients with salt depletion and/or dehydration who are receiving high-dose diuretics. Such conditions should be corrected prior to administration of Combisart H or patients should be closely monitored at the beginning of treatment.

If marked arterial hypotension occurs during treatment with Combisart H, the patient should be placed in a supine position with legs elevated. If necessary, intravenous infusion of physiological saline should be administered. Therapy may be continued after stabilization of blood pressure.

Changes in serum electrolyte levels

Amlodipine/valsartan/hydrochlorothiazide

Serum electrolyte levels should be monitored periodically to detect possible electrolyte imbalance.

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

Hydrochlorothiazide

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

Treatment with Combisart H should be initiated only after correction of hypokalemia and any coexisting hypomagnesemia. Thiazide diuretics may cause hypokalemia or exacerbate 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 drug 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 may exacerbate pre-existing hyponatremia. Hyponatremia may be accompanied by neurological symptoms (nausea, progressive disorientation, apathy). Treatment with hydrochlorothiazide should be initiated only after correction of existing hyponatremia. In cases of severe or rapidly developing hyponatremia during treatment with Combisart H, the drug should be discontinued until normalization of serum sodium. 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, especially potassium, sodium, and magnesium.

Renal impairment

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

When using Combisart H, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended in patients with impaired renal function.

Combisart H is contraindicated in patients with severe renal impairment, anuria, or those undergoing dialysis.

Dosage adjustment of Combisart H is not required in patients with mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m²).

Renal artery stenosis

Combisart H 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 Combisart H 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 (plasma concentration–time) is higher in patients with hepatic impairment; dosage recommendations are lacking. For patients with mild to moderate hepatic impairment not associated with cholestasis, the maximum recommended dose of valsartan is 80 mg. Therefore, Combisart H is not indicated for this patient group.

Angioedema

Angioedema, including laryngeal and glottal edema that may lead to airway obstruction, and/or swelling of the face, lips, pharynx, and/or tongue, has been observed in patients taking valsartan. Some of these patients had a history of angioedema with other drugs, including angiotensin-converting enzyme (ACE) inhibitors. Administration of Combisart H should be discontinued immediately if angioedema occurs; re-administration is not recommended.

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

Due to inhibition of the renin-angiotensin-aldosterone system, renal dysfunction may be expected in susceptible patients. In patients with severe heart failure, in whom renal function may depend on renin-angiotensin-aldosterone system 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. Such 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–IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine, despite only a minor difference 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 drug should be prescribed with caution in patients with heart failure and coronary artery disease, particularly at the maximum dose of Combisart H – 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 drug 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 be switched to alternative antihypertensive agents with established safety profiles in pregnancy. If pregnancy occurs, ARB therapy should be discontinued immediately and alternative therapy initiated if needed.

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, Combisart H 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 Combisart H 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, leading to periodic and mild increases in serum calcium levels in the absence of known calcium metabolism disorders. Treatment with Combisart H should be discontinued if hypercalcemia develops during therapy. Serum calcium levels should be monitored periodically during thiazide therapy. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued before parathyroid function testing.

Intestinal angioedema

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

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during treatment with Combisart H, discontinuation of therapy is recommended. If resumption of diuretic therapy is considered necessary, protection of exposed skin from sunlight or artificial UV radiation is recommended.

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

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 usually occur within hours to the first week after initiation of therapy. Untreated acute angle-closure glaucoma may lead to irreversible vision loss.

Hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, immediate medical or surgical treatment should be considered. Risk factors for angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

General

The drug should be prescribed with caution in patients with a history of hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies or asthma.

The medicinal product contains lactose; therefore, it should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Elderly patients (aged 65 years and older)

The drug should be prescribed with caution, particularly with frequent monitoring of blood pressure, in elderly patients, especially at the maximum dose of Combisart H – 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 higher incidences of hypotension, hyperkalemia, and renal dysfunction (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 necessary, 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 be 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, are recommended. 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 usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening pulmonary function, and hypotension. If ARDS is suspected, Combisart H 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 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 is available and if the condition poses greater risk to the mother and fetus.

Valsartan

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

Hydrochlorothiazide

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

Hydrochlorothiazide crosses the placenta. The pharmacological mechanism of action of hydrochlorothiazide 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 be associated with other adverse reactions observed in adults.

Amlodipine/valsartan/hydrochlorothiazide

There is no experience with the use of Combisart H in pregnant women. Available data on the components of the drug suggest that the use of Combisart H is contraindicated.

Breastfeeding period

Amlodipine is excreted in breast milk. The infant's exposure, expressed as a percentage of maternal dose, 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 detected in breast milk in small amounts. Thiazides in high doses causing strong diuresis may interfere with breast milk production.

The use of Combisart H is contraindicated during breastfeeding.

Fertility

There are no clinical studies on the effect of Combisart H on 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

Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. Unfavorable effects on male fertility were observed in one rat study.

Ability to affect reaction speed when driving or operating machinery

Patients taking Combisart H may experience dizziness or weakness after taking the drug and should therefore take this into account when driving or operating potentially hazardous machinery.

Amlodipine may mildly or moderately affect 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

Combisart N 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 Combisart N is 1 tablet daily, preferably in the morning.

Prior to switching to Combisart N, the patient's condition should be adequately controlled with unchanged doses of the individual monocomponent drugs currently being used. The dose of Combisart N must be based on the doses of the individual components of the combination being used at the time of transition.

The maximum recommended dose of Combisart N is 10 mg/320 mg/25 mg.

Special Patient Populations

Renal Impairment

Since hydrochlorothiazide is a component of the drug, Combisart N 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 valsartan is a component of the drug, Combisart N 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, Combisart N is not indicated for this patient group. Dose recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established. When switching hypertensive patients with hepatic impairment to Combisart N, the lowest available dose of amlodipine should be used.

Heart Failure and Coronary Artery Disease

Experience with the use of Combisart N, particularly at maximum doses, in patients with heart failure and coronary artery disease is limited. The drug should be used with caution in such patients, especially at the maximum dose of Combisart N (10 mg/320 mg/25 mg).

Elderly Patients (aged 65 years and older)

The drug should be prescribed with caution to elderly patients, particularly with frequent monitoring of blood pressure, especially when using the maximum dose of Combisart N (10 mg/320 mg/25 mg), due to limited data in this population. When switching elderly patients to Combisart N, the lowest available dose of amlodipine should be used.

Pediatric Population

There are insufficient data on the use of Combisart N 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 drug is not administered to this age group.

Overdose

Symptoms

There are no data on overdose with Combisart N. The main symptom of overdose is likely to be pronounced arterial hypotension with dizziness. Amlodipine overdose may lead to marked peripheral vasodilation and possibly reflex tachycardia. Cases of severe and potentially prolonged systemic hypotension, including shock with fatal outcome, have been reported.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, 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 evident arterial hypotension following overdose with Combisart N requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the lower limbs, monitoring of circulating blood volume and diuresis. Vasoconstrictor agents 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 since 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 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 Combisartu N described below is based on clinical studies of the medicinal product and the known safety profile of its individual components: amlodipine, valsartan, and hydrochlorothiazide.

Summary of safety profile

The safety of Combisartu N 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 only rarely required treatment discontinuation. In this active-controlled clinical study, the most common reasons for discontinuation with Combisartu N 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 drug's components.

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

Adverse reactions listed in Table 2 by system organ classes (MedDRA) and frequency are presented for Combisartu N (amlodipine/valsartan/hydrochlorothiazide) as well as separately for amlodipine, valsartan, and hydrochlorothiazide.

Very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000; frequency not known (cannot be estimated from the available data).

Table 2

System organ classes (MedDRA)	Adverse reactions	Frequency
		Combisart N	Amlodipine	Valsartan	Hydrochlor- 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
	Hyperglycemia	--	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 disturbances	Uncommon	Uncommon	--	Rare
	Mood changes	--	Uncommon	--
	Apathy	--	Rare	--	--
Nervous system disorders	Coordination disorders	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	--	--
	Respiratory distress, pulmonary edema, pneumonitis	--	--	--	Very rare
	Rhinitis	--	Uncommon	--	--
	Throat irritation	Uncommon	--	--	--
	Acute respiratory distress syndrome (ARDS)	--	--	--	Very rare
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 elevated serum bilirubin levels	--	Very rare*	Unknown	--
	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 spasms	Uncommon	Uncommon	--	Unknown
	Muscle weakness	Uncommon	--	--	--
	Myalgia	Uncommon	Uncommon	Unknown	--
	Limb pain	Uncommon	--	--	--
	Ankle swelling	--	Common	--	--
Renal and urinary disorders	Elevated serum creatinine levels	Uncommon	--	Unknown	--
	Urination disorders		Uncommon
	Nocturia	--	Uncommon	--	--
	Polyuria	Common	Uncommon	--	--
	Renal dysfunction	--	--	--	Unknown
	Acute renal failure	Uncommon	--	--	Unknown
	Renal 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	Elevated lipid levels		--		Very common
	Elevated blood urea nitrogen	Uncommon	--	--	--
	Elevated blood uric acid	Uncommon	--	--	--
	Glucosuria				Rare
	Decreased blood potassium levels	Uncommon	--	--	--
	Elevated 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, there is a cumulative dose-response relationship between hydrochlorothiazide use and the development of NMSC.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a pack.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business operations.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua