Liprazid 20

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIPRAZID 10 (LIPRAZID 10) LIPRAZID 20 (LIPRAZID 20)

Composition:

Active substances: lisinopril and hydrochlorothiazide;

One tablet of LIPRAZID 10 contains lisinopril (calculated as 100% anhydrous lisinopril) – 10 mg, corresponding to lisinopril dihydrate – 10.89 mg, and hydrochlorothiazide (calculated as 100% dry substance) – 12.5 mg;

One tablet of LIPRAZID 20 contains lisinopril (calculated as 100% anhydrous lisinopril) – 20 mg, corresponding to lisinopril dihydrate – 21.78 mg, and hydrochlorothiazide (calculated as 100% dry substance) – 12.5 mg;

Excipients:
LIPRAZID 10 – mannitol (E 421), maize starch, magnesium stearate, iron oxide yellow (E 172), calcium hydrogen phosphate dihydrate.
LIPRAZID 20 – mannitol (E 421), maize starch, magnesium stearate, iron oxide red (E 172), calcium hydrogen phosphate dihydrate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

LIPRAZID 10 – round, biconvex tablets, cream-colored. Marbling and specks ranging from yellow to brown may be present on the tablet surface.

LIPRAZID 20 – round, biconvex tablets, pink-colored. Marbling and specks of red-brown color may be present on the tablet surface.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Combined preparations of ACE inhibitors. Lisinopril and diuretics. ATC Code C09BA03.

Pharmacological properties.

Pharmacodynamics.

A combination antihypertensive agent containing the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the diuretic hydrochlorothiazide.

Lisinopril inhibits ACE, which converts angiotensin I into angiotensin II. Reduction in angiotensin II levels leads to a direct decrease in aldosterone levels. This results in reduced total peripheral vascular resistance and systemic arterial pressure.

Hydrochlorothiazide is a thiazide diuretic with antihypertensive activity. It reduces electrolyte and water reabsorption in the distal renal tubules, increases diuresis, thereby decreasing total circulating blood volume and reducing elevated arterial pressure. Significant reduction in systolic and diastolic blood pressure occurs within 3–4 days of hydrochlorothiazide administration, while the optimal antihypertensive effect is achieved after 3–4 weeks of treatment.

The combination of lisinopril and hydrochlorothiazide produces a more pronounced hypotensive effect than either component alone.

Non-melanoma skin cancer: Results from two pharmacoepidemiological studies based on data from the Danish National Cancer Registry demonstrated a cumulative dose-dependent association between hydrochlorothiazide (HCTZ) and the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

One study included a population of 71,533 patients with BCC and 8,629 patients with SCC, compared with 1,430,833 and 172,462 control subjects, respectively. Use of high cumulative doses of HCTZ (≥ 50,000 mg cumulative) was associated with an adjusted risk ratio (RR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear cumulative dose-dependent relationship was observed for both BCC and SCC.

Another study showed a possible association between lip cancer (SCC) and HCTZ use: 633 cases of lip cancer (SCC) were compared with 63,067 control subjects using a random sampling strategy. A cumulative dose-dependent association was demonstrated with an adjusted RR of 2.1 (95% CI: 1.7–2.6), increasing to RR 3.9 (3.0–4.9) for high doses (~25,000 mg) and RR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").

Pharmacokinetics.

The bioavailability of lisinopril is approximately 30%. Food intake does not significantly affect lisinopril absorption. A small amount (6–10%) binds to plasma proteins. The initial effect after lisinopril administration develops within 1 hour, and maximum plasma concentration is reached within 6–7 hours after intake. The drug is practically not biotransformed in the body; only about 7% of lisinopril is metabolized in the liver. Lisinopril partially crosses the placental barrier. The majority of the substance is excreted unchanged in urine. The elimination half-life from blood serum is 12 hours. Lisinopril elimination is slowed in elderly patients.

The diuretic effect of hydrochlorothiazide develops within 2 hours after administration, reaches maximum intensity within 3–4 hours, and lasts for 6–12 hours. The bioavailability of hydrochlorothiazide is 65–70%. Approximately 40% binds to plasma proteins. Hydrochlorothiazide crosses the placenta and is excreted in breast milk. It is not metabolized and is excreted by the kidneys.

Clinical characteristics.

Indications.

Arterial hypertension when monotherapy with hydrochlorothiazide or lisinopril has not achieved the desired reduction in blood pressure.

Contraindications.

• Hypersensitivity to lisinopril, hydrochlorothiazide, other components of the drug, or to other angiotensin-converting enzyme (ACE) inhibitors;
• Hypersensitivity to sulfonamide derivatives;
• History of angioedema associated with previous use of ACE inhibitors;
• Hereditary or idiopathic angioedema (Quincke's edema) in history;
• Mitral or aortic stenosis, hypertrophic cardiomyopathy with significant hemodynamic disturbances;
• Acute myocardial infarction with unstable hemodynamics;
• Cardiogenic shock;
• Severe renal failure (creatinine clearance < 30 mL/min), serum creatinine level ≥ 220 μmol/L, anuria;
• Bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney;
• State after kidney transplantation;
• Mechanical obstruction of urinary tract;
• Fluid and electrolyte disturbances (treatment-resistant hyperkalemia/hypokalemia, refractory hyponatremia, hypovolemia);
• Severe forms of diabetes mellitus;
• Severe hepatic insufficiency, hepatic encephalopathy;
• Primary hyperaldosteronism;
• Acute gout attack;
• Porphyria;
• Use with aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²);
• Use of high-flux membranes made of polyacrylonitrile-sodium-2-methylallylsulfonate (e.g., AN 69) during hemodialysis;
• Pregnancy or women who are planning to become pregnant (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Other antihypertensive agents: possible enhancement of hypotensive effect. Concomitant use with nitroglycerin and other organic nitrates or vasodilators may further reduce blood pressure. Ganglionic blockers or adrenergic neuron blockers may be used in combination with lisinopril-containing drugs only under strict medical supervision.

Combination with aliskiren-containing drugs should be avoided.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors (including lisinopril), angiotensin II receptor blockers (ARBs), or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and deterioration of renal function (including acute kidney injury), compared to use of a single RAAS-blocking agent (see sections "Contraindications" and "Special precautions").

Lithium preparations: reversible increase in serum lithium levels and development of its toxic effects. Thiazide diuretics and ACE inhibitors reduce renal clearance of lithium and significantly increase the risk of lithium toxicity. Therefore, concomitant use of lisinopril/hydrochlorothiazide with lithium is not recommended; however, if such combination is necessary, careful monitoring of serum lithium levels is required.

Other diuretics: additive antihypertensive effect may occur. In patients already receiving diuretics, especially those recently initiated on diuretic therapy, administration of lisinopril may sometimes cause excessive reduction in blood pressure. Diuretic therapy should be discontinued 2–3 days before starting treatment with the combination drug lisinopril/hydrochlorothiazide to prevent symptomatic hypotension. If this is not possible, treatment should be initiated with lisinopril alone.

Potassium-sparing diuretics, potassium-containing dietary supplements, or potassium-containing salt substitutes: increased risk of hyperkalemia. The potassium loss caused by thiazide diuretics is usually counterbalanced by the potassium-sparing effect of lisinopril. However, concomitant use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels, particularly in patients with impaired renal function or diabetes mellitus. If concomitant use of lisinopril/hydrochlorothiazide and any of these agents is necessary, they should be used cautiously with frequent monitoring of serum potassium levels.

Medicinal products inducing ventricular tachycardia of the "torsade de pointes" type: due to the risk of hypokalemia, the risk of cardiac arrhythmias, including ventricular tachycardia of the "torsade de pointes" type, increases when hydrochlorothiazide is used concomitantly with drugs whose effects are influenced by changes in serum potassium levels:

• Class I antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Others (e.g., bepridil, cizapride, diphenadine, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinca alkaloids).

Tricyclic antidepressants, antipsychotic agents, anesthetics: concomitant use with ACE inhibitors may lead to further reduction in blood pressure.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid at doses ≥ 3 g/day, nonselective NSAIDs: prolonged use of NSAIDs reduces the antihypertensive and diuretic effects of ACE inhibitors and thiazides. Concomitant use of NSAIDs and ACE inhibitors has an additive effect on increasing serum potassium levels, which may lead to worsening of renal function. These effects are usually reversible. In individual cases, acute kidney injury may occur, particularly in patients with pre-existing renal impairment, e.g., elderly patients or those with dehydration. NSAIDs may enhance the effect of hydrochlorothiazide on serum potassium levels, reduce the natriuretic effect of thiazides, and increase the risk of NSAID-induced renal impairment.

Trimethoprim, heparin: concomitant use of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalemia and renal dysfunction.

Hypoglycemic agents (insulin, oral hypoglycemic drugs): epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic drugs may enhance glucose-lowering effects with an increased risk of hypoglycemia. The likelihood of this effect is particularly high during the first weeks of combination therapy and in patients with impaired renal function. Dose adjustment of antidiabetic drugs may be required.

Gold preparations: nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness, arterial hypotension, which may be severe) after gold injection (e.g., sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitors.

Sympathomimetics: the antihypertensive effect of ACE inhibitors may be reduced.

Estrogens, corticosteroids: possible reduction in antihypertensive effect of ACE inhibitors due to fluid retention.

Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH), or stimulant laxatives: hydrochlorothiazide may exacerbate electrolyte imbalance, especially hypokalemia.

Calcium salts and vitamin D: thiazide diuretics may reduce calcium excretion and increase plasma calcium levels. Serum calcium levels should be monitored and doses of calcium/vitamin D supplements adjusted accordingly.

Cardiac glycosides: increased risk of glycoside toxicity (including ventricular irritability) due to thiazide-induced hypokalemia and hypomagnesemia.

Cholestyramine and colestipol: possible delay or reduction in hydrochlorothiazide absorption by up to 85% in the presence of anion-exchange resins. Therefore, sulfonamide diuretics should be taken at least 1 hour before or 4–6 hours after these agents.

Antacid agents: bioavailability of lisinopril may be reduced; therefore, the drug should be taken 1–2 hours before or 1–2 hours after antacid administration.

Non-depolarizing muscle relaxants (e.g., tubocurarine chloride): hydrochlorothiazide enhances the effect of these agents and increases sensitivity to tubocurarine.

Sotalol: thiazide-induced hypokalemia may increase the risk of sotalol-induced arrhythmias.

Allopurinol: concomitant use of ACE inhibitors and allopurinol increases the risk of renal damage and may lead to an increased risk of leukopenia. The risk of hypersensitivity reactions is also increased.

Other gout treatments (probenecid, sulfinpyrazone): dose increase of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels.

Cyclosporine: concomitant use of ACE inhibitors and cyclosporine increases the risk of renal damage and hyperkalemia. Concomitant use of diuretics may increase the risk of hyperuricemia and gout-like complications.

Lovastatin: concomitant use of ACE inhibitors and lovastatin increases the risk of hyperkalemia.

Aldesleukin: enhanced hypotensive effect of ACE inhibitors.

Agents suppressing bone marrow function: increased risk of neutropenia and/or agranulocytosis.

Cytostatics, immunosuppressants, procainamide: concomitant use with ACE inhibitors may lead to an increased risk of leukopenia.

Cytotoxic agents (e.g., cyclophosphamide, methotrexate): thiazides may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Pressor amines (e.g., norepinephrine, epinephrine): possible reduction in response to pressor amines, but not to the extent of contraindicating their use.

Barbiturates, diazepam, narcotic drugs: possible potentiation of arterial and orthostatic hypotension.

Anticholinergic agents (e.g., atropine, biperiden): increased bioavailability of thiazide diuretics due to reduced gastrointestinal motility and delayed gastric emptying.

Salicylates: at high doses, hydrochlorothiazide may enhance the central nervous system toxicity of salicylates.

Methyldopa: isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide.

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

Beta-blockers, diazoxide: possible enhancement of their hyperglycemic effect due to thiazides.

Amantadine: hydrochlorothiazide may increase the risk of amantadine adverse reactions.

Carbamazepine: risk of hyponatremia. Electrolyte levels should be monitored.

Iodine-containing contrast agents: in cases of diuretic-induced dehydration, the risk of acute kidney injury increases, especially with high doses of iodine-containing agents. Rehydration should be performed before administration of iodine-containing contrast agents.

Tissue plasminogen activators, immunosuppressants such as mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus): possible increased risk of angioedema.

Alcohol: possible enhancement of the hypotensive effect of any antihypertensive agent.

Effect on laboratory test results: due to effects on calcium metabolism, thiazides may influence assessment of parathyroid gland function.

The drug may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers, and/or nitrates under medical supervision.

Lisinopril-containing drugs should be used cautiously in patients with acute myocardial infarction within 6–12 hours after administration of streptokinase due to the risk of arterial hypotension.

Special precautions for use.

Non-melanoma skin cancer.

An increased risk of non-melanoma skin cancer (NMSC) with increasing cumulative dose of HCTZ has been identified in two pharmacoepidemiological studies. The photosensitizing effect of HCTZ may represent a possible mechanism in the development of this pathology.

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

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

Patients with a prior history of NMSC may also require reassessment of HCTZ use.

Symptomatic arterial hypotension.

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated hypertension and is more likely in patients with hypovolemia or electrolyte imbalance (including hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia), e.g., during diuretic therapy, low-salt diet, dialysis, diarrhea, vomiting, or in severe forms of renin-dependent hypertension. Such patients should have regular monitoring of serum electrolytes. Patients at increased risk of symptomatic hypotension should have initiation and dose adjustment of therapy under close medical supervision. Particular caution is required in patients with ischemic heart disease or cerebrovascular disease, in whom excessive blood pressure reduction may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of sodium chloride physiological solution. Transient arterial hypotension during treatment is not a contraindication for further use of the drug. After normalization of blood pressure and restoration of effective blood volume, therapy with lisinopril/hydrochlorothiazide may be resumed at a reduced dose or with one of the components separately.

In some patients with heart failure and normal or low blood pressure, lisinopril may further reduce systemic arterial pressure. This effect is expected and usually not a reason to discontinue treatment. If hypotension becomes symptomatic, dose reduction or discontinuation of the combination drug lisinopril/hydrochlorothiazide may be necessary.

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

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors (including lisinopril), angiotensin II receptor blockers (ARBs), or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of RAAS by combining ACE inhibitors with ARBs or aliskiren is not recommended.

If dual RAAS blockade is considered absolutely necessary, it should occur only under close specialist supervision and with frequent, careful monitoring of renal function, blood electrolyte levels (especially potassium), and blood pressure.

ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Prior diuretic therapy.

Symptomatic arterial hypotension may occur after the initial dose of the combination drug lisinopril/hydrochlorothiazide. This is more likely in patients with dehydration and/or salt depletion due to prior diuretic therapy. Diuretic therapy should be discontinued 2–3 days before starting lisinopril/hydrochlorothiazide combination. If this is not possible, treatment should be initiated with lisinopril alone at a dose of 5 mg.

Aortic and/or mitral valve stenosis/hypertrophic cardiomyopathy.

Like other ACE inhibitors, lisinopril is not recommended for use in patients with mitral valve sten游戏副本

Administration and Dosage

The drug should be prescribed considering the doses of lisinopril or hydrochlorothiazide previously used in monotherapy. The dose should be individually adjusted depending on the therapeutic effect.

The initial recommended dose (calculated as lisinopril) is 5–10 mg once daily. The dose should then be adjusted according to the achieved clinical response. Stable therapeutic effect usually develops within 2–4 weeks of treatment. The recommended maintenance dose is 20 mg once daily. The maximum daily dose (calculated as lisinopril) is 40 mg.

If administration of the drug at doses of 2.5 mg or 5 mg (calculated as lisinopril) is required, dosage forms allowing such dosing should be used.

Children

The safety and efficacy of lisinopril/hydrochlorothiazide in children have not been established; therefore, the drug is contraindicated in patients under 18 years of age.

Overdose

Data on human overdose are limited.

Symptoms: symptoms of ACE inhibitor overdose may include arterial hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, restlessness, and cough.

Symptoms of hydrochlorothiazide overdose include those caused by decreased serum electrolyte levels (e.g. hypokalemia, hypochloremia, hyponatremia), as well as dehydration resulting from excessive diuresis. Tachycardia, arrhythmia, arterial hypotension, cardiovascular shock, weakness, confusion and disturbances of consciousness, depressed consciousness (including coma), dizziness, muscle spasms, seizures, paresthesia, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, increased blood urea nitrogen (mainly in renal failure), and renal failure may occur.

In patients receiving cardiac glycosides, hypokalemia may increase the risk of cardiac arrhythmias.

Treatment: symptomatic and supportive care; there is no specific antidote. Treatment with the drug should be discontinued and careful monitoring of the patient should be initiated. Therapeutic measures depend on the nature and severity of symptoms.

The recommended treatment for overdose is intravenous administration of physiological saline (sodium chloride solution). In case of arterial hypotension, the patient should be placed in a supine position with legs elevated. If necessary, infusion of angiotensin II and/or intravenous administration of catecholamines may be required.

If drug ingestion was recent, measures aimed at enhancing elimination and preventing further absorption should be undertaken (e.g. induction of emesis, gastric lavage, administration of enterosorbents and sodium sulfate). Lisinopril may be removed from systemic circulation by hemodialysis; however, polyacrylonitrile metal sulfonate high-flux membranes (e.g., AN 69) should be avoided.

Bradycardia or significant vagal reaction may be alleviated by intravenous administration of atropine. In cases of therapy-resistant bradycardia, cardiac pacing is indicated.

In the event of angioneurotic edema, adequate emergency treatment is required (administration of epinephrine (0.3–0.5 mL of 1:1000 epinephrine solution) subcutaneously, glucocorticoids, antihistamines, and securing airway patency via intubation or tracheotomy).

Vital functions, serum electrolyte concentrations, and creatinine levels should be continuously monitored.

Side effects.

Side effects associated with lisinopril.

Blood and lymphatic system disorders: decreased hemoglobin and hematocrit levels, myelosuppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia, lymphadenopathy, autoimmune disorders.

Nervous system and psychiatric disorders: dizziness, headache, mood changes, paresthesia, vertigo, taste disturbances, sleep disorders, confusion, olfactory disturbances, imbalance, disorientation, tinnitus, decreased visual acuity, depressive symptoms, syncope, hallucinations.

Cardiovascular system: arterial hypotension (especially after the first dose in patients with sodium deficiency, dehydration, or heart failure), orthostatic effects (including hypotension), flushing, chest pain/discomfort, myocardial infarction or cerebrovascular stroke, possibly secondary to excessive arterial hypotension in high-risk patients; palpitations, tachycardia, bradycardia, Raynaud's phenomenon. When lisinopril is administered to patients with acute myocardial infarction, second- to third-degree AV block, severe arterial hypotension and/or renal dysfunction may occur, particularly within the first 24 hours; in rare cases, cardiogenic shock.

Musculoskeletal system: muscle spasms have been reported.

Respiratory system, thoracic organs, and mediastinum: cough, rhinitis, bronchitis, dyspnea, bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia. Upper respiratory tract infections have been reported.

Gastrointestinal tract and hepatobiliary system: diarrhea, constipation, vomiting, nausea, abdominal pain, dyspepsia, dry mouth, glossitis, decreased appetite, pancreatitis, intestinal angioedema, hepatocellular or cholestatic hepatitis, jaundice, hepatic failure.

Very rare cases of unfavorable progression of hepatitis leading to hepatic failure have been reported. Patients receiving a combination of lisinopril and hydrochlorothiazide who develop jaundice or marked elevations of serum liver enzymes should discontinue this combination and receive appropriate medical monitoring.

Skin and subcutaneous tissue: rash, pruritus, urticaria, skin hyperemia, alopecia, psoriasis, hypersensitivity reactions/angioedema: angioedema of the face, extremities, lips, tongue, vocal cords, and/or larynx; hyperhidrosis, pemphigoid reactions, toxic epidermal necrolysis, Stevens-Johnson syndrome, polymorphic erythema, cutaneous pseudolymphoma.

There have been reports of a complex reaction including one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody test, elevated erythrocyte sedimentation rate (ESR), eosinophilia, leukocytosis, rash, photosensitivity reactions, or other dermatological manifestations.

Urinary system: renal dysfunction, uremia, acute renal failure, oliguria/anuria.

Endocrine system: inappropriate secretion of antidiuretic hormone.

Reproductive system and mammary glands: impotence, gynecomastia.

Metabolic disorders: hypoglycemia, gout.

General disorders and administration site conditions: increased fatigue, asthenia.

Laboratory test results: increased serum levels of urea, creatinine, bilirubin, and liver enzymes; hyperkalemia, hyponatremia, proteinuria.

Side effects associated with hydrochlorothiazide.

Blood and lymphatic system disorders: leukopenia, neutropenia/agranulocytosis, thrombocytopenia with or without purpura, hemolytic and aplastic anemias, decreased hematocrit, myelosuppression, lymphadenopathy.

Immune system disorders: hypersensitivity reactions, including anaphylactic reactions, anaphylactic shock, angioedema (including facial, lip, tongue, laryngeal, extremity edema, and intestinal angioedema).

Metabolism and nutrition disorders: decreased appetite/anorexia, hyperuricemia (which may precipitate gout attacks in patients with asymptomatic disease), gout; electrolyte imbalance, including hyponatremia, hypokalemia, hypochloremic alkalosis (which may trigger hepatic encephalopathy/coma), hypomagnesemia, hypercalcemia; hyperglycemia, glucosuria, impaired glucose tolerance (which may lead to manifestation of latent diabetes mellitus); increased plasma levels of urea, creatinine, liver enzymes, bilirubin, cholesterol, lipids, and triglycerides.

Psychiatric disorders: restlessness, depression, sleep disturbances, drowsiness, confusion, disorientation, mood changes, nervousness.

Nervous system disorders: dizziness, headache, paresthesia, convulsions, apathy, fatigue, weakness, asthenia.

Eye disorders: transient blurred vision/decreased visual acuity, xanthopsia, conjunctivitis, choroidal effusion, acute myopia, and secondary acute angle-closure glaucoma.

Ear and labyrinth disorders: vertigo, tinnitus, ear pain.

Cardiovascular system: arrhythmias, orthostatic hypotension, arterial hypotension, tachycardia; necrotizing angiitis (vasculitis, cutaneous vasculitis).

Respiratory system, thoracic organs, and mediastinum: acute respiratory distress syndrome (ARDS), including pneumonitis and pulmonary edema (see section "Special precautions for use").

Gastrointestinal disorders: nausea, vomiting, diarrhea, constipation, dry mouth, thirst, stomatitis/aphthous ulcers, glossitis, taste disturbances, heartburn, gastric irritation/pain/spasm in the epigastric region, pancreatitis, sialadenitis.

Hepatobiliary system: development of hepatic encephalopathy or hepatic coma, hepatocellular or cholestatic jaundice, cholecystitis.

Skin and subcutaneous tissue: skin rash, photosensitivity reactions, pruritus, urticaria, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis, lupus-like skin reactions/exacerbation of systemic lupus erythematosus, alopecia.

Musculoskeletal and connective tissue disorders: muscle cramps or pain, muscle weakness, arthralgia/arthritis.

Renal and urinary disorders: renal dysfunction, interstitial nephritis, renal failure.

Neoplasms: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) (see sections "Pharmacodynamics" and "Special precautions for use").

Other: decreased libido/impotence, increased body temperature.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets per blister, 3 blisters per carton; 60 tablets per container, 1 container per carton; 90 tablets per container, 1 container per carton.

Prescription category. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borschagivskiy Chemical and Pharmaceutical Plant".

Limited Liability Company "AGROFARM".

Manufacturer's address and place of business.

Ukraine, 03134, Kyiv, Miru St., 17.

Ukraine, 08200, Kyiv region, Irpin, Centralna St., 113-A.