Normopress

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMOPRES (NORMOPRES)

Composition:

Active substances: captopril, hydrochlorothiazide;

One tablet contains captopril 50 mg, hydrochlorothiazide 25 mg;

Excipients: lactose monohydrate; potato starch; microcrystalline cellulose; povidone; talc; stearic acid; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round-shaped tablets with a flat surface, beveled edges and a score line, white or slightly yellowish in color.

Pharmacotherapeutic group. Combined preparations of ACE inhibitors. Captopril and diuretics. ATC code C09BA01.

Pharmacological properties.

Pharmacodynamics.

Normopres is a combined antihypertensive medicinal product containing a fixed-dose combination of captopril and hydrochlorothiazide.

Captopril is an angiotensin-converting enzyme (ACE) inhibitor. It suppresses the formation of angiotensin II, thereby counteracting its vasoconstrictive effects and stimulatory influence on aldosterone secretion in the adrenal glands. It reduces total peripheral vascular resistance and arterial pressure, decreases myocardial preload, and lowers pressure in the right atrium and pulmonary circulation.

Hydrochlorothiazide exerts a moderately expressed diuretic effect by increasing the excretion from the body of sodium, chloride, potassium ions, and water. It reduces sodium ion content in the vascular wall, thereby decreasing its sensitivity to vasoconstrictive stimuli and enhancing the antihypertensive effect of captopril.

Pharmacokinetics.

After oral administration, captopril is actively absorbed in the gastrointestinal tract. Time to reach maximum plasma concentration is approximately 1 hour. Captopril is 25–30% bound to plasma proteins. It is metabolized in the liver. The main metabolites are captopril-cysteine and captopril disulfide dimer. Elimination half-life (T½) is approximately 2–3 hours. 95% of captopril is excreted by the kidneys: 50% as metabolites and up to 50% unchanged.

Hydrochlorothiazide is absorbed in the gastrointestinal tract by 68–78% after oral administration. Its elimination half-life (T½) is approximately 3–4 hours. 20–75% of hydrochlorothiazide is excreted unchanged by the kidneys.

In patients with renal insufficiency, drug elimination is slowed.

Clinical characteristics.

Indications.

Arterial hypertension.

Contraindications.

• Hypersensitivity to captopril, to other ACE inhibitors, to hydrochlorothiazide, other sulfonamide-derived drugs, or to any component of the medicinal product.
• History of angioedema during therapy with other ACE inhibitors.
• Hereditary (idiopathic) angioedema.
• Bilateral renal artery stenosis or stenosis of the artery of a solitary kidney associated with progressive azotemia.
• Status post kidney transplantation.
• Anuria.
• Aortic orifice narrowing or mitral stenosis, or presence of other obstacles to outflow from the left ventricle of the heart.
• Hypertrophic cardiomyopathy with low cardiac output.
• Hyperkalemia.
• Refractory hypokalemia or hypercalcemia.

– Refractory hyponatremia.

• Symptomatic hyperuricemia (gout).
• Primary hyperaldosteronism.
• Porphyria.
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Severe hepatic dysfunction (pre-comatose state, hepatic coma, liver failure).
• Pregnancy or women planning to become pregnant (see section "Use in pregnancy or lactation").
• Lactation period (see section "Use in pregnancy or lactation").
• Concomitant use of aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of this medicinal product with the following drugs may result in:

with diuretics (thiazide or loop diuretics) – risk of developing arterial hypotension due to dehydration caused by high-dose diuretic therapy; the hypotensive effect can be minimized by discontinuing diuretics, increasing fluid and salt intake, and reducing initial captopril doses;

with potassium-sparing diuretics or potassium-containing dietary supplements. ACE inhibitors reduce potassium loss caused by diuretic use. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to hyperkalemia. When co-administered due to existing hypokalemia, they should be used with great caution and with frequent monitoring of serum potassium concentration.

with α- and β-adrenergic blockers, long-acting calcium channel blockers, and other antihypertensive agents, organic nitrates, MAO inhibitors, hypnotics (nitrazepam), tranquilizers (alprazolam) – enhanced hypotensive effect of the medicinal product; combination with these drugs should be used with caution;

with ethanol-containing medicinal products and beverages, barbiturates, narcotics, neuroleptics, tricyclic antidepressants – enhanced hypotensive effect and orthostatic hypotension;

with sympathomimetics, estrogens, methenamine – reduced antihypertensive effect of the medicinal product; careful monitoring of blood pressure parameters in the patient is required;

with nonsteroidal anti-inflammatory drugs (NSAIDs) – reduced antihypertensive effect of the medicinal product and impaired renal function with increased plasma potassium concentration; rarely, acute renal failure may develop, especially in patients with pre-existing renal impairment.

The combination of these medicinal products should be used with caution. Before initiating therapy, fluid and electrolyte balance should be normalized, and renal function should be monitored periodically during treatment. When high doses of salicylates are used, hydrochlorothiazide may potentiate their toxic effects on the central nervous system;

with medicinal products that increase serum potassium concentration (heparin, cyclosporine, potassium-sparing diuretics – amiloride, spironolactone, triamterene), potassium-containing medicinal products and supplements – marked increase in plasma potassium concentration; concomitant use of these medicinal products is not recommended; if co-administration is necessary due to existing hypokalemia, they should be used with great caution and with frequent monitoring of serum potassium concentration;

with allopurinol, procainamide, immunosuppressive (azathioprine), and cytostatic agents – concomitant use with ACE inhibitors may increase the risk of leukopenia, especially if the latter are used at doses exceeding recommended levels;

with diazoxide – enhanced hyperglycemic, hyperuricemic, and hypotensive effects; periodic monitoring of blood glucose and uric acid levels may be required;

with anesthetics, non-depolarizing muscle relaxants, anesthetic induction agents (tubocurarine chloride, gallamine triethiodide) – enhanced effects of the above-mentioned medicinal products; dose adjustment and fluid-electrolyte balance correction may be necessary before surgery;

with lithium-containing medicinal products – concomitant use of ACE inhibitors and lithium may cause transient elevation of serum lithium levels and lithium intoxication. Concurrent use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and increase the risk of lithium intoxication. Therefore, concomitant use of captopril with lithium is not recommended. If such a combination is necessary, careful monitoring of serum lithium levels is required;

with cardiac glycosides – increased toxicity of digitalis preparations (arrhythmias) due to hypokalemia caused by hydrochlorothiazide;

with carbamazepine – increased risk of developing hyponatremia; periodic monitoring of electrolyte levels may be required;

with amphotericin B, carbenoxolone, glucocorticosteroids, corticotropin, stimulant laxatives – enhanced electrolyte imbalance, particularly development of hypokalemia;

with metformin – metabolic acidosis in patients with impaired renal function;

with methyldopa – in isolated cases, hemolytic anemia;

with antidiabetic agents, oral anticoagulants, gout-treatment agents – reduced efficacy of the above-mentioned medicinal products; dose adjustment may be required;

with medicinal products whose effects are influenced by changes in plasma potassium levels, including:

• class IA antiarrhythmic agents (quinidine, hydroquinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide);
• neuroleptics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, ciampamine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• other agents: bepridil, cisapride, difemanyl, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinpocetine – risk of developing torsades de pointes arrhythmia due to possible hypokalemia and hypomagnesemia; periodic monitoring of plasma potassium levels and electrocardiography (ECG) is required;

with pressor amines (noradrenaline) – treatment with the medicinal product should be discontinued one week before planned surgery;

with antacids, food, cholestyramine, colestipol – reduced absorption and decreased bioavailability of the medicinal product;

with probenecid – reduced excretion of captopril;

with iodine-containing contrast agents – increased risk of acute renal failure, especially with administration of high doses, due to dehydration caused by hydrochlorothiazide. Fluid balance should be normalized before iodine administration.

Use of the medicinal product may result in a positive urine test for acetone.

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

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

Cyclosporine. Concomitant use with cyclosporine may exacerbate hyperuricemia and increase the risk of complications such as gout.

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

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid >3 g/day, and non-selective NSAIDs. Concomitant use of NSAIDs may reduce the antihypertensive effect of hydrochlorothiazide and enhance its effect on serum potassium levels.

MEDICINAL PRODUCTS whose effects are influenced by changes in serum potassium levels. Periodic monitoring of serum potassium levels and ECG is recommended when hydrochlorothiazide is used concomitantly with medicinal products whose effects are influenced by changes in serum potassium levels (e.g., cardiac glycosides and antiarrhythmic agents), and with agents that may cause polymorphic ventricular tachycardia (torsades de pointes), since hypokalemia is a contributing factor to the development of torsades de pointes.

The medicinal product may be used for treatment of acute myocardial infarction in combination with acetylsalicylic acid (cardiologic doses), thrombolytic agents, β-adrenergic blockers, and/or nitrates.

Other antihypertensive agents. Concomitant administration of captopril with other antihypertensive agents (e.g., β-blockers and long-acting calcium channel blockers) is safe; co-administration of such agents may enhance the hypotensive effect of captopril. Concomitant use of nitroglycerin, other nitrates, or other agents should be applied with caution.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions, such as arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to monotherapy with agents acting on the RAAS.

Special precautions for use

Before starting treatment with the drug, diuretic therapy should be reduced or discontinued. Prior to initiating angiotensin-converting enzyme (ACE) inhibitors, circulating blood volume (CBV) should be corrected, and the decision on the lowest effective optimal dose of the drug should be made.

During treatment, periodic monitoring of electrolyte levels (particularly potassium), plasma urea and creatinine concentrations, and peripheral blood count is recommended.

A low-sodium diet is recommended during treatment with the drug.

Alcoholic beverages are not recommended during treatment with the drug.

The drug should be used with caution in patients with disturbances of water-electrolyte balance (due to intensive diuretic therapy, diarrhea, vomiting, or low-sodium diet) and in patients undergoing hemodialysis, as arterial hypotension may develop. Water-electrolyte balance should be corrected before initiating treatment.

The drug should be used with caution in patients with severe cardiac dysfunction and in elderly patients (aged 65 years and older). Administration of the drug to these patient groups is possible only under strict monitoring of arterial pressure, renal function, and water-electrolyte status.

In case of hypotension, the patient should be placed in a horizontal position (supine), and if necessary, CBV should be expanded by intravenous administration of 0.9% sodium chloride solution.

Special precautions related to the presence of captopril in the drug

The drug should be used with caution in patients with impaired renal function (creatinine clearance less than 40 mL/min). Initial doses of captopril should be adjusted according to creatinine clearance and subsequently based on the patient's response to treatment. Regular monitoring of renal function parameters (at the beginning and periodically during treatment) is required, including determination of plasma potassium and creatinine levels.

The drug should be used with caution in patients with uncomplicated arterial hypertension, as symptomatic arterial hypotension may occur in individual cases. The risk of its development increases in patients with water-electrolyte imbalance (due to intensive diuretic therapy, diarrhea, vomiting, or low-sodium diet) and in patients undergoing hemodialysis. Symptomatic hypotension has also been observed in patients with heart failure. Treatment of such patients should be initiated under medical supervision with low doses, and doses should be carefully titrated. This also applies to patients with ischemic heart disease or cerebrovascular disease, in whom a significant decrease in arterial pressure may lead to myocardial infarction or impaired cerebral circulation (stroke).

Captopril should be avoided in the development of cardiogenic shock and significant hemodynamic disturbances.

The drug should be used with caution in patients with renovascular hypertension, as concomitant use with ACE inhibitors increases the risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under medical supervision with low doses, and doses should be carefully titrated.

It is evident that combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and leads to decreased renal function (including acute renal failure). Therefore, dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If dual blockade therapy is necessary, it should be conducted under medical supervision with frequent monitoring of renal function, electrolytes, and arterial pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

The drug should be used with caution in patients with diabetes mellitus who are receiving oral antidiabetic agents or insulin, and regular monitoring of blood glucose levels should be performed, especially during the first month of treatment.

Very rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and rapidly progressing to hepatic necrosis and (sometimes) resulting in fatal outcomes. The mechanism of this syndrome is not established. Patients receiving ACE inhibitors who develop jaundice or marked elevation of liver enzymes should discontinue ACE inhibitor therapy and seek medical advice.

Proteinuria may develop in patients with impaired renal function or those receiving relatively high doses of captopril (more than 150 mg/day). Protein excretion exceeding 1 g/day was recorded in approximately 0.7% of patients receiving captopril. Nephrotic syndrome was diagnosed in 20% of patients with proteinuria. In most cases, proteinuria resolved within 6 months after discontinuation of the drug. Changes in renal function parameters, such as blood urea nitrogen and creatinine levels, were rare. In patients with impaired renal function, urine protein content should be determined before treatment and monitored periodically during therapy.

Cases of neutropenia, agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. The drug should be prescribed with extreme caution to patients with collagen diseases, those undergoing immunosuppressive therapy, those receiving allopurinol or procainamide, and especially in combination of these conditions, particularly in the presence of impaired renal function. In some such patients, severe infections develop that are not always responsive to intensive antibiotic therapy. When using the drug in such patients, periodic monitoring of blood leukocyte count and differential count (before treatment, every 2 weeks during the first 3 months of therapy, and periodically thereafter) is required, and patients should be warned to report any signs of infection (fever, enlarged lymph nodes, sore throat). If neutropenia develops (neutrophil count < 1000/mm³), the drug should be discontinued. After discontinuation of therapy, neutrophil count rapidly returns to normal in most patients.

In some patients receiving ACE inhibitors, including captopril, increased serum potassium levels may occur. Patients at risk of hyperkalemia include those with renal failure, diabetes mellitus, individuals receiving potassium-sparing diuretics, potassium-containing dietary supplements, and patients receiving other drugs that increase serum potassium levels. If concomitant use of these drugs during ACE inhibitor therapy is necessary, regular monitoring of serum potassium levels is required.

Cases of angioedema of the face, extremities, lips, tongue, glottis, and larynx have been reported in some patients receiving ACE inhibitors, particularly during the first weeks of treatment. In individual cases, angioedema may develop even after prolonged ACE inhibitor therapy. Isolated fatal cases due to laryngeal or lingual angioedema have been reported. In case of angioedema development, captopril should be immediately discontinued and appropriate treatment initiated. The patient should be hospitalized and monitored for at least 12–24 hours until complete resolution of symptoms. Patients of non-black race are at higher risk of developing angioedema.

In patients undergoing surgery or anesthesia with agents that lower arterial pressure, captopril may block the compensatory renin-mediated increase in angiotensin II formation. Arterial hypotension resulting from this mechanism should be corrected by administration of additional fluid volume.

During ACE inhibitor therapy, patients may develop a persistent non-productive cough, which resolves after discontinuation of treatment.

In patients receiving ACE inhibitors during allergen desensitization with Hymenoptera venom, development of persistent anaphylactoid reactions is possible. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy.

In patients receiving ACE inhibitors during hemodialysis with high-flux membranes, development of persistent anaphylactoid reactions is possible. These reactions can be avoided by replacing dialysis membranes with another type or using antihypertensive agents of another class.

In patients receiving ACE inhibitors during low-density lipoprotein apheresis, development of persistent anaphylactoid reactions is possible. These reactions can be avoided by replacing dialysis membranes with another type or using antihypertensive agents of another class.

Cross-sensitivity is possible with drugs containing ACE inhibitors.

ACE inhibitors, including captopril, are less effective in reducing arterial pressure in patients of black race compared to patients of other races due to predominant low renin fractions.

Concomitant use of the drug with lithium is not recommended due to increased toxicity of lithium.

Special precautions related to the presence of hydrochlorothiazide in the drug

As with other antihypertensive drugs, symptomatic arterial hypotension may occur in some patients.

During thiazide therapy, glucose tolerance may decrease. Modification of antidiabetic drug doses, including insulin, may be required. Latent diabetes mellitus may manifest during thiazide therapy.

Thiazides may reduce renal calcium excretion and cause slight transient elevation of serum calcium levels. Significant hypercalcemia may indicate latent hyperparathyroidism.

Hypersensitivity reactions may develop in patients receiving thiazides, particularly in those with a history of allergy or bronchial asthma, as well as in patients without previous history of these conditions. Reports of systemic lupus erythematosus exacerbation or activation during thiazide therapy have been received.

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

Sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually appear within hours or the first week after initiation of treatment.

Untreated acute angle-closure glaucoma may lead to irreversible vision loss. The primary treatment is prompt discontinuation of the drug. 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.

The drug may affect the results of the following laboratory tests:

• The drug may decrease plasma protein-bound iodine levels;
• Treatment with the drug should be discontinued before laboratory evaluation of parathyroid function;
• The drug may increase free bilirubin concentration in serum.

The drug should be used with caution in patients with impaired liver function or progressive liver disease, as thiazide diuretics may cause water-electrolyte imbalance, which may lead to rapid development of hepatic coma. Administration of the drug to these patients is possible only under strict monitoring of arterial pressure, renal function, and water-electrolyte status.

The drug should be used with caution in patients with impaired renal function, as thiazide diuretics may cause azotemia. Accumulation of the drug is also possible. In progressive kidney disease characterized by elevated blood urea nitrogen levels, the necessity of continuing therapy should be carefully evaluated, and treatment should be discontinued if necessary.

The antihypertensive effect of hydrochlorothiazide may be enhanced after sympathectomy.

In patients receiving hydrochlorothiazide, gout exacerbation may occur due to increased uric acid concentration, latent diabetes mellitus may clinically manifest, and systemic lupus erythematosus may exacerbate.

Cases of photosensitivity reactions have been reported during thiazide diuretic therapy. If photosensitivity reactions occur during treatment, the drug should be discontinued. If the physician considers re-prescribing the diuretic necessary, protection of skin areas exposed to sunlight or artificial UV radiation is recommended.

Hydrochlorothiazide may cause water-electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Symptoms include dry mouth, thirst; weakness, fatigue, drowsiness, restlessness; muscle pain or cramps, muscle weakness; arterial hypotension; oliguria; tachycardia; and gastrointestinal disturbances such as nausea and vomiting. Although concomitant use with captopril reduces the risk of hydrochlorothiazide-induced hypokalemia, patients at increased risk of hypokalemia include those with liver cirrhosis, high diuresis, inadequate oral electrolyte replacement, and individuals receiving glucocorticoid or adrenocorticotropic hormone therapy. In hot weather, hyponatremia, usually mild and not requiring treatment, may occur in patients prone to edema.

Hydrochlorothiazide may cause hypercalcemia; therefore, the drug should be discontinued before assessing parathyroid function.

Hydrochlorothiazide may increase cholesterol and triglyceride levels, decrease magnesium and iodine-binding thyroglobulins in blood (without signs of thyroid dysfunction).

Hydrochlorothiazide may cause a positive doping test.

Non-melanoma skin cancer. Results of two recent pharmacoepidemiological studies (based on Danish nationwide information sources, including the Danish Cancer Registry and the Danish National Prescription Registry) showed a cumulative dose-dependent association between hydrochlorothiazide use and the development of basal cell carcinoma and squamous cell carcinoma. The photosensitizing effect of hydrochlorothiazide may be responsible for the development of these conditions. Patients receiving hydrochlorothiazide alone or in combination with other drugs should be informed about the risk of non-melanoma skin cancer and advised to regularly examine their skin for new lesions or changes in existing ones and to report any suspicious skin lesions.

Suspicious skin lesions should undergo histological examination by biopsy. Patients should be advised to limit exposure to sunlight and UV radiation and to use appropriate protection when exposed to sunlight or UV radiation to minimize the risk of skin cancer.

The appropriateness of hydrochlorothiazide use should also be carefully reconsidered in patients with a history of skin cancer (see section "Adverse reactions").

Acute respiratory toxicity

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

The drug contains lactose; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Use during pregnancy or breastfeeding

The drug is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment, the drug should be immediately discontinued and replaced with another drug approved for use in pregnant women.

The drug should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

During treatment with the drug, patients should refrain from driving or operating machinery, as dizziness and drowsiness may occur, particularly at the beginning of therapy.

Dosage and Administration

The medicinal product should be taken orally, 1 hour before meals, as its absorption is reduced when food is present in the stomach.

The dosage should be individually adjusted depending on the clinical condition.

The initial dose is ½ tablet (25 mg of captopril and 12.5 mg of hydrochlorothiazide) once daily.

If necessary, the maintenance dose may subsequently be increased to 1 tablet (50 mg of captopril and 25 mg of hydrochlorothiazide) once daily.

Maximum therapeutic effect develops within 6–8 weeks after initiation of treatment. Dose adjustments should be made at 6-week intervals, unless clinical manifestations require more rapid changes. If blood pressure reduction is insufficient, additional captopril and hydrochlorothiazide may be added to the treatment regimen as monotherapy agents. In such cases, the daily dose of captopril should not exceed 150 mg and that of hydrochlorothiazide should not exceed 50 mg.

Patients with renal impairment.

Since captopril and hydrochlorothiazide are primarily eliminated via the kidneys, their plasma levels may increase in patients with impaired renal function. Dose reduction is recommended: in patients with creatinine clearance between 30 and 80 mL/min, the initial dose is ½ tablet (25 mg captopril and 12.5 mg hydrochlorothiazide) once daily, taken in the morning.

Children.

There is no data available on the use of this medicinal product in children.

Overdose.

Captopril

Symptoms: sudden drop in arterial blood pressure, tachycardia, headache, loss of appetite, taste disturbances, skin allergic reactions, neutropenia. In severe cases, seizures, paresis, shock, stupor, cardiac arrhythmias, bradycardia, renal failure, and electrolyte imbalance may occur. If these symptoms occur, the drug should be discontinued immediately and medical advice should be sought.

The patient should be placed in a horizontal position and gastric lavage should be performed.

In cases of severe overdose, the patient must be urgently hospitalized for intensive detoxification measures, including hemodialysis, and interventions aimed at increasing circulating blood volume and normalizing cardiovascular, respiratory, and nervous system functions, as well as restoring kidney function. Hemodialysis using high-flux membranes made of polyacrylonitrile-metal sulfate (AN69) and hemofiltration should be avoided due to the risk of anaphylactoid reactions. Peritoneal dialysis is ineffective.

Treatment: Symptomatic therapy aimed at normalizing arterial blood pressure and relieving other symptoms.

Hydrochlorothiazide

Symptoms: weakness, nausea, vomiting, diarrhea. These symptoms usually resolve quickly upon dose reduction or discontinuation of the drug. In some cases, following ingestion of high doses, the following symptoms have been reported: tachycardia, arterial hypotension, shock, dizziness, confusion, mental disturbances, muscle spasms, paresthesia, exhaustion, polyuria, oliguria, anuria, hypokalemia, hyponatremia, hypochloremia, alkalosis, elevated blood urea nitrogen levels (in patients with renal insufficiency). Severe manifestations of overdose may include significant disturbances in water-electrolyte balance and development of coma due to direct pathological effects of hydrochlorothiazide on the central nervous system, as well as weakness, nausea, vomiting, and thirst.

Treatment: To remove the drug from the stomach, induction of emesis, gastric lavage, and administration of adsorbents are recommended. In cases of severe overdose manifestations, the patient must be urgently hospitalized in a specialized medical facility for intensive detoxification procedures (including hemodialysis), correction of water-electrolyte imbalances, normalization of cardiovascular, respiratory, and central nervous system functions, and restoration of kidney function. There is no specific antidote. In cases of arterial hypotension and shock, administration of fluids and electrolytes (potassium, sodium, magnesium) is recommended. Monitoring of fluid and electrolyte balance and kidney function is required until the patient's condition normalizes.

Adverse reactions.

Captopril

Blood and lymphatic system disorders: eosinophilia, pancytopenia (especially in patients with impaired renal function), thrombocytopenia, anemia (including aplastic and hemolytic), leukopenia, neutropenia, agranulocytosis.

Metabolism and nutrition disorders: anorexia, hypoglycemia, hyperkalemia, hyponatremia.

Nervous system disorders: headache, drowsiness, taste disturbances, dizziness, paresthesia, cerebral ischemia (including stroke and syncope), asthenia.

Psychiatric disorders: sleep disturbances, confusion, depression.

Eye disorders: blurred vision.

Cardiac and vascular disorders: tachycardia or tachyarrhythmia, angina, palpitations, cardiogenic shock, cardiac arrest, arterial hypotension, Raynaud's syndrome, flushing, pallor, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: dry, irritating (non-productive) cough, dyspnea, bronchospasm, rhinitis, laryngitis, allergic alveolitis/eosinophilic pneumonia, chest pain.

Gastrointestinal disorders: dry mouth, nausea, vomiting, epigastric discomfort, abdominal pain, diarrhea, constipation, stomatitis/aphthous ulcers, glossitis, peptic ulcer, pancreatitis, gastric irritation, decreased appetite, acidosis.

Hepatobiliary disorders: hepatic dysfunction and cholestasis (including jaundice), hepatitis (including necrosis), elevated liver enzymes, hyperbilirubinemia.

Immune system, skin and subcutaneous tissue disorders: pruritus with or without rash, rash, alopecia, angioedema of the face, eyelids, tongue; interstitial angioedema, peripheral edema, urticaria, Stevens-Johnson syndrome, polymorphic erythema, photosensitivity, erythroderma, pemphigoid reactions, exfoliative dermatitis, autoimmune disorders, fever.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Renal and urinary disorders: impaired renal function (including renal failure), proteinuria, polyuria, oliguria, increased urinary frequency, nephrotic syndrome.

Reproductive system and breast disorders: impotence, gynecomastia.

General disorders: fatigue, lymphadenopathy, weakness.

Laboratory findings: increased blood urea nitrogen (BUN) and serum creatinine, decreased hemoglobin and hematocrit, increased erythrocyte sedimentation rate (ESR), increased antinuclear antibody levels, may cause false-positive urine ketone tests.

Hydrochlorothiazide

Infections and infestations: sialadenitis.

Blood and lymphatic system disorders: leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow depression.

Metabolism and nutrition disorders: anorexia, hyperglycemia, glucosuria, decreased glucose tolerance which may precipitate latent diabetes mellitus; hyperuricemia, which may trigger gout attacks in patients with asymptomatic disease; electrolyte imbalance, particularly hypochloremic alkalosis, which may induce hepatic encephalopathy and coma; acidosis; hypokalemia; hyponatremia; hypomagnesemia; hypercalcemia; increased cholesterol and triglyceride levels.

Nervous system disorders: headache, drowsiness, convulsions, paresthesia, vertigo, dizziness.

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

Eye disorders: xanthopsia, transient blurred vision, acute myopia, acute angle-closure glaucoma;
frequency unknown – choroidal effusion.

Cardiac and vascular disorders: postural hypotension, cardiac arrhythmia, necrotizing vasculitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders: respiratory distress, including pneumonitis and pulmonary edema;
very rare – acute respiratory distress syndrome (ARDS) (see section "Special precautions").

Gastrointestinal disorders: loss of appetite, thirst, dry mouth, nausea, vomiting, gastric irritation, diarrhea, constipation, pancreatitis.

Hepatobiliary disorders: jaundice (intrahepatic cholestatic jaundice), cholecystitis.

Immune system, skin and subcutaneous tissue disorders: photosensitivity reactions, rash, eczema, purpura, lupus-like syndrome, exacerbation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions, anaphylactic shock, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders: muscle pain, muscle spasm.

Renal and urinary disorders: impaired renal function, renal failure, interstitial nephritis.

Reproductive system and breast disorders: sexual dysfunction.

General disorders: fever, weakness, exhaustion.

Dose-dependent adverse effects of hydrochlorothiazide (particularly electrolyte imbalances) may be intensified during dose titration.

Benign, malignant and unspecified neoplasms (including cysts and polyps). Frequency unknown: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Description of selected adverse reactions.

Non-melanoma skin cancer: epidemiological studies have shown an association between cumulative dose of hydrochlorothiazide and the occurrence of non-melanoma skin cancer (cumulative dose-effect relationship) (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister pack.

10 tablets in a blister pack; 2 blisters per carton.

Prescription category. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and place of business.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Website: www.vitamin.com.ua