Enalapril-nl-zdorovya

INSTRUCTION for medical use of the medicinal product ENALAPRIL-HL-ZDOROVYE

Composition:

Active substances: enalapril, hydrochlorothiazide;

1 tablet contains enalapril maleate 10 mg, hydrochlorothiazide 12.5 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, pregelatinized starch, potato starch, magnesium stearate, colloidal anhydrous silicon dioxide, povidone.

Dosage form. Tablets.

Main physical and chemical properties: white or white with a creamy tint, flat cylindrical tablets with a score line and bevel.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Combined preparations of ACE inhibitors. Enalapril and diuretics. ATC code C09BA02.

Pharmacological properties. The drug contains a combination of two antihypertensive agents. The hypotensive effects of the two components complement each other and are maintained for 24 hours. The presence of enalapril helps to reduce potassium loss associated with hydrochlorothiazide administration.

Pharmacodynamics. Enalapril is a highly specific competitive angiotensin-converting enzyme (ACE) inhibitor and a prodrug that is converted in the body into its active metabolite, enalaprilat.

Enalaprilat inhibits ACE activity, thereby preventing the conversion of angiotensin I into angiotensin II—a potent vasoconstrictor—and reduces aldosterone secretion, resulting in decreased plasma concentrations of angiotensin II and aldosterone. It also inhibits the breakdown of bradykinin, a powerful vasodilator peptide. The mechanism by which enalapril lowers blood pressure is primarily related to suppression of the renin-angiotensin-aldosterone system (RAAS), which regulates arterial pressure; enalapril may exert antihypertensive effects even in patients with low-renin hypertension.

The pressor (sympathoadrenal) systems are suppressed, while depressor systems (kallikrein-kinin and prostaglandin systems) are activated, and vascular endothelial factor production is increased. As a result, total peripheral vascular resistance, arterial pressure, and pulmonary circulation pressure decrease, while cardiac output increases. Enalapril causes a gradual reduction in systolic and diastolic blood pressure.

Administration of enalapril to patients with hypertension leads to a reduction in arterial pressure in both supine and upright positions without a significant increase in heart rate. Symptomatic postural hypotension occurs infrequently. In some patients, optimal blood pressure reduction may require several weeks of therapy. Sudden discontinuation of enalapril does not lead to rapid rebound hypertension. Effective inhibition of ACE activity is usually achieved within 2–4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive activity is typically observed within 1 hour, with peak blood pressure reduction occurring 4–6 hours after administration. The duration of effect depends on the dose. However, at recommended doses, antihypertensive and hemodynamic effects are maintained for at least 24 hours after a single oral dose.

In patients with essential hypertension, blood pressure reduction is usually accompanied by decreased peripheral arterial resistance, with a slight increase in cardiac output and minimal or no changes in heart rate. After enalapril administration, renal blood flow increases, while glomerular filtration rate remains unchanged. However, in patients with low glomerular filtration rate before treatment, it usually increases. Antihypertensive therapy with enalapril leads to significant regression of left ventricular hypertrophy while preserving systolic function. Enalapril treatment has been associated with favorable effects on plasma lipoprotein fractions and either favorable or neutral effects on total cholesterol levels.

The degree of blood pressure reduction observed with the combination of enalapril and hydrochlorothiazide exceeds that achieved with either component used alone.

Hydrochlorothiazide is an active diuretic agent whose action is due to reduced reabsorption of sodium and chloride ions in the proximal convoluted tubules. It also inhibits reabsorption of potassium and bicarbonates. The diuretic effect begins within 2 hours, reaches maximum effect within 4 hours, and lasts up to 12 hours. The diuretic effect is evident in both alkalosis and acidosis and does not diminish with prolonged use.

Hydrochlorothiazide increases plasma renin activity. Although enalapril exerts antihypertensive effects even in patients with low-renin hypertension, concomitant administration of hydrochlorothiazide leads to greater blood pressure reduction in these patients.

Hydrochlorothiazide produces diuretic and antihypertensive effects, but prolonged use may lead to metabolic disturbances, which are counteracted by enalapril (e.g., hypokalemia). The combination of an ACE inhibitor with a diuretic enhances antihypertensive action and reduces myocardial load. Maximum therapeutic effect develops after 3–4 weeks of treatment.

Pharmacokinetics. Enalapril is well absorbed. Approximately 60% of enalapril is absorbed from the gastrointestinal tract after oral administration. Concomitant food intake does not affect absorption. In the liver, it is hydrolyzed to form the active metabolite enalaprilat. Bioavailability is approximately 40%. After oral administration of enalapril, maximum plasma concentrations (Cmax) are observed at 1 hour for enalapril and at 3–4 hours for enalaprilat. Enalaprilat readily penetrates histohematological barriers except the blood-brain barrier, crosses the placenta, and is excreted in small amounts into breast milk. Enalaprilat does not undergo biotransformation. Protein binding of enalaprilat to plasma proteins is less than 50%. After enalapril administration, 33% of the dose is excreted in feces (6% as enalapril, 27% as enalaprilat), and approximately 60% in urine (20% unchanged, 40% as enalaprilat). Renal clearance is 150 ± 44 mL/min. The elimination half-life (T½) of enalaprilat is 11 hours. In renal impairment, T½ increases. Enalaprilat is removed during hemodialysis.

Hydrochlorothiazide is rapidly absorbed after oral administration (60–80%). The diuretic effect develops within 1–2 hours. Hydrochlorothiazide accumulates in erythrocytes 3–9 times more than in plasma. Protein binding ranges from 40% to 70%. The volume of distribution in the terminal elimination phase is 3–6 L/kg (equivalent to 210–420 L for a 70 kg body weight). Hydrochlorothiazide undergoes minimal metabolism. When plasma levels were measured over at least 24 hours, the plasma half-life ranged from 5.6 to 14.8 hours. Hydrochlorothiazide is rapidly eliminated by the kidneys, with a T½ of 10 hours; nearly 95% of the substance is excreted in urine. Hydrochlorothiazide crosses the placenta and enters breast milk but does not cross the blood-brain barrier.

In patients with severe renal impairment, the half-lives (T½) of enalaprilat and hydrochlorothiazide are prolonged.

Concomitant administration of multiple doses of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of either drug. The combined tablet is bioequivalent to the separate administration of its components.

Clinical characteristics.

Indications. Arterial hypertension in patients who require combination therapy.

Contraindications. Hypersensitivity to enalapril and other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide and other sulfonamide derivatives, or to any other component of the drug; history of angioedema associated with previous ACE inhibitor therapy; hereditary or idiopathic angioedema; patients with severe renal impairment (creatinine clearance less than 30 mL/min or serum creatinine levels exceeding 265 µmol/L (3 mg/100 mL)); renal artery stenosis; contraindicated during hemodialysis; clinical condition following kidney transplantation; severe hepatic dysfunction; anuria, primary hyperaldosteronism; refractory hypokalemia or hyperkalemia; refractory hyponatremia; symptomatic hyperuricemia (gout); pregnancy or women planning to become pregnant (see "Use during pregnancy or breastfeeding"). Enalapril should not be used with drugs containing aliskiren in patients with diabetes or renal impairment (eGFR < 60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

Enalapril and hydrochlorothiazide

Other antihypertensive agents. Concomitant use of β-blockers, methyldopa, or calcium channel blockers may enhance the antihypertensive effect of the drug. Concurrent administration of nitroglycerin and other nitrates or vasodilators may additionally reduce blood pressure.

Ganglion blockers or adrenergic blockers, when combined with enalapril, should be administered only under close patient monitoring.

Lithium-containing preparations. Diuretics or ACE inhibitors reduce renal clearance of lithium and significantly increase the risk of lithium toxicity; therefore, concomitant use is not recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs may attenuate the antihypertensive effects of ACE inhibitors, diuretics, or other antihypertensive agents. In some patients with impaired renal function (e.g., elderly patients or those with dehydration, including those receiving diuretic therapy), concomitant use of NSAIDs, including COX-2 inhibitors, with angiotensin II receptor antagonists and ACE inhibitors may result in additive effects on increased serum potassium levels and further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, such combinations should be initiated cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and be closely monitored for renal function at the start of concomitant therapy and periodically thereafter.

Enalapril

Potassium-sparing diuretics and potassium supplements. ACE inhibitors may potentiate hyperkalemia caused by potassium-sparing diuretics. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), as well as potassium-containing dietary supplements or salt substitutes, may lead to a significant increase in serum potassium levels. If these agents are indicated due to hypokalemia, they should be used with caution and serum potassium levels should be monitored regularly (see section "Special precautions for use").

Diuretics (thiazide or loop diuretics). Prior treatment with high-dose diuretics may lead to reduced circulating blood volume and increase the risk of arterial hypotension at the initiation of enalapril therapy (see section "Special precautions for use"). Hypotensive effects can be minimized by discontinuing the diuretic, increasing salt intake, or initiating treatment with low doses of the drug.

Tricyclic antidepressants/antipsychotics/narcotics. Concomitant use of anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may lead to further reduction in blood pressure.

Gold preparations. Rare reactions resembling nitrite-like reactions (vasodilation symptoms, including flushing, facial swelling, dizziness, nausea, vomiting, and arterial hypotension) have been observed in patients receiving intravenous gold preparations (sodium aurothiomalate) concomitantly with ACE inhibitors, including enalapril.

Sympathomimetics. Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Alcohol. Alcohol enhances the hypotensive effect of ACE inhibitors.

Antidiabetic agents. Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect, increasing the risk of hypoglycemia. This effect is likely to occur during the first weeks of concomitant therapy and in patients with impaired renal function.

Acetylsalicylic acid, thrombolytics, β-blockers. Enalapril may be used cautiously together with acetylsalicylic acid (when used as a thrombolytic agent), thrombolytic agents, and β-blockers.

mTOR inhibitors. Concomitant use with mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may increase the risk of angioedema (see section "Special precautions for use").

Concomitant therapy with ACE inhibitor and angiotensin receptor antagonist. In patients with confirmed atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been reported to be associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to therapy with a single RAAS-acting agent. Dual blockade (e.g., combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually determined cases and accompanied by careful monitoring of renal function, potassium levels, and blood pressure.

Hydrochlorothiazide

The following medicinal products may interact with thiazide diuretics when used concomitantly:

Non-depolarizing muscle relaxants (e.g., tubocurarine). Potentiation of sensitivity to the effects of muscle relaxants may occur.

Alcohol (ethanol), barbiturates, narcotic analgesics, antidepressants. Orthostatic hypotension may be potentiated.

Antidiabetic agents (oral antidiabetics and insulin). Thiazide therapy may reduce glucose tolerance. Dose adjustments may be required. Metformin should be used with caution due to the risk of lactic acidosis associated with possible renal impairment caused by hydrochlorothiazide.

Cholestyramine and colestipol resins. Anion-exchange resins may reduce the absorption of hydrochlorothiazide. Single doses of cholestyramine or colestipol resins reduce gastrointestinal absorption of hydrochlorothiazide by 85% and 43%, respectively.

QT interval prolongation (e.g., procainamide, amiodarone, sotalol). Increased risk of torsades de pointes tachycardia.

Cardiac glycosides. Hypokalemia may increase cardiac sensitivity or enhance the clinical response to digitalis toxicity (e.g., increased ventricular excitability).

Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormone, stimulant laxatives, or glycyrrhizin (found in licorice). Hydrochlorothiazide may potentiate electrolyte imbalances, predominantly hypokalemia.

Potassium-wasting diuretics (e.g., furosemide), carbenoxolone, or laxative abuse. Hydrochlorothiazide may cause increased loss of potassium and/or magnesium.

Pressor amines (e.g., adrenaline). Thiazides may reduce the response to pressor amines, but not sufficiently to preclude concomitant use.

Cytoxic agents (e.g., cyclophosphamide, methotrexate). Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic drugs and enhance their myelosuppressive effect.

Prostaglandin synthase inhibitors. In some patients, their use may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.

Medicinal products used for the treatment of gout (probenecid, sulfinpyrazone, and allopurinol). Dose adjustments of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid concentration. Increased doses of probenecid or sulfinpyrazone may be necessary. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

Salicylates. When high doses of salicylates are administered, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

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

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

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

Other antihypertensive agents. Additive effect.

Digitalis glycosides. Hypokalemia or hypomagnesemia induced by thiazide therapy may lead to the development of digitalis-induced cardiac arrhythmias.

Medicinal products affected by changes in serum potassium levels. Periodic monitoring of serum potassium levels and ECG is recommended when losartan/hydrochlorothiazide is used concomitantly with medicinal products affected by changes in serum potassium levels (e.g., digitalis glycosides and antiarrhythmic agents), as well as with the following agents (including antiarrhythmics) that may cause torsades de pointes tachycardia, with hypokalemia being a predisposing factor:

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Some antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other agents (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).

Calcium salts. Thiazide diuretics may increase serum calcium levels due to reduced excretion. If calcium supplementation is necessary, the dose should be adjusted under monitoring of serum calcium levels.

Effect on laboratory test results. Due to their effect on calcium metabolism, thiazides may influence the assessment of parathyroid gland function.

Carbamazepine. Due to the risk of symptomatic hyponatremia, clinical and biological monitoring is required.

Iodinated contrast agents. In cases of diuretic-induced dehydration, the risk of acute renal failure is increased, particularly with high-dose contrast agents. Patients require rehydration prior to administration of iodinated contrast agents.

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid >3 g/day, and nonselective NSAIDs. When used concomitantly, NSAIDs may attenuate the antihypertensive effect of hydrochlorothiazide and enhance its effect on serum potassium levels.

β-blockers and diazoxide. Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.

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

Special precautions for use.

Enalapril and hydrochlorothiazide

Arterial hypotension and electrolyte imbalance. Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension. The risk of its development during enalapril therapy is increased in patients with fluid imbalance, e.g., due to diuretic therapy, salt restriction, dialysis, or presence of diarrhea or vomiting. Regular monitoring of serum electrolyte levels is required for such patients. Symptomatic arterial hypotension occurred more frequently in patients with more severe forms of heart failure who were receiving higher doses of loop diuretics, had hyponatremia, or impaired renal function. These patients should start treatment under medical supervision.

Patients should be examined for clinical signs of fluid and electrolyte imbalance, such as dehydration, hyponatremia, hypochloremic alkalosis (which may induce hepatic encephalopathy or hepatic coma), hypomagnesemia, or hypokalemia, which may occur due to diarrhea or vomiting. In such patients, periodic monitoring of serum electrolyte levels is recommended.

Particular caution is required when treating patients with ischemic heart disease or cerebrovascular disorders, as excessive reduction in blood pressure may lead to myocardial infarction or stroke.

If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, receive intravenous 0.9% sodium chloride solution. Transient arterial hypotension during treatment is not a contraindication, and therapy may be continued after normalization of blood pressure and restoration of fluid volume.

In some patients with heart failure and normal or low blood pressure, the drug may further reduce blood pressure. This response is expected and should not be considered a reason to discontinue treatment. In cases where arterial hypotension becomes refractory to treatment, the dose should be reduced and/or diuretic and/or drug therapy discontinued.

Dual blockade of the RAAS. Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to specific cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Data indicate that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy affecting the RAAS. Enalapril should not be used concomitantly with aliskiren in patients with diabetes or impaired renal function (eGFR < 60 mL/min/1.73 m²).

Renal function impairment. Cases of renal dysfunction caused by enalapril have been reported, particularly in patients with severe heart failure or kidney disease, including renal artery stenosis. If diagnosed promptly and treated appropriately, enalapril-related renal failure is usually reversible.

In some patients with arterial hypertension but no pre-existing renal insufficiency, administration of enalapril together with a diuretic may lead to increased serum urea and creatinine levels. Dose reduction of enalapril and/or discontinuation of the diuretic may be required. In such cases, the possibility of renal artery stenosis should be considered.

Hyperkalemia. The combination of enalapril and low-dose diuretics may lead to hyperkalemia.

Lithium. Concomitant use of enalapril and lithium is generally not recommended.

Elderly patients. The efficacy and tolerability of enalapril maleate and hydrochlorothiazide used simultaneously are similar in elderly and younger adult patients with arterial hypertension.

Enalapril

Aortic or mitral stenosis/hypertrophic cardiomyopathy. Like all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction or outflow tract obstruction; their use should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Renovascular hypertension. Patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney who are taking ACE inhibitors have an increased risk of developing arterial hypotension. Even minor changes in serum creatinine may lead to worsening renal function. Treatment in these patients should begin under strict medical supervision, starting with low doses and careful dose titration with monitoring of renal function.

Patients undergoing hemodialysis. In patients undergoing dialysis with high-flux membranes (e.g., AN 69) and concomitant ACE inhibitor therapy, anaphylactoid reactions have occurred in some cases. Therefore, for such patients, it is recommended to use dialysis membranes of another type or antihypertensive agents from another class.

Kidney transplantation. There is no experience with the use of the drug in patients who have recently undergone kidney transplantation. Therefore, treatment with the drug is not recommended for them.

Hepatic function impairment. Very rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. Patients receiving ACE inhibitors who develop jaundice or significant elevation of liver enzymes should discontinue the drug and receive appropriate medical care.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitor therapy. Neutropenia rarely occurs in patients with normal renal function and without special risk factors. Enalapril should be used with extreme caution in patients with collagenosis, immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these risk factors, especially if renal function impairment has previously been established. Some of these patients may develop severe infections, which sometimes do not respond to intensive antibiotic therapy.

When using enalapril in these patients, periodic monitoring of leukocytes is recommended, and patients should be warned to inform their physician about any signs of infection.

Hyperkalemia. During ACE inhibitor therapy, including enalapril, increased serum potassium levels have been observed in some patients. The risk of hyperkalemia is increased in patients with renal insufficiency, impaired renal function, age > 70 years, diabetes mellitus, transient states (e.g., dehydration), acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of dietary supplements or salt substitutes containing potassium; and in patients taking other drugs that may increase serum potassium levels (e.g., heparin). In particular, the use of potassium-sparing diuretics, dietary supplements, or salt substitutes containing potassium in patients with impaired renal function may lead to a significant increase in serum potassium levels. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned drugs is considered necessary, they should be used with caution, with regular monitoring of serum potassium levels.

Hypoglycemia. Patients with diabetes mellitus receiving oral antidiabetic drugs or insulin require careful glycemic control, especially during the first month of ACE inhibitor therapy.

Increased sensitivity/angioedema. In patients treated with ACE inhibitors, angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has occurred in some cases. It may occur at any time during treatment. In such cases, the drug must be discontinued immediately, and continuous monitoring of the patient is required to ensure complete resolution of symptoms. Even if only tongue swelling is observed without respiratory distress, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal angioedema of the larynx or tongue has been reported very rarely. If swelling of the tongue, glottis, or larynx occurs, airway obstruction is likely, especially in patients who have undergone surgery on the respiratory organs. In these cases, emergency treatment is required, which may include subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL) and/or measures to ensure airway patency.

Angioedema occurs more frequently in patients of African descent receiving ACE inhibitors compared to patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing it when using ACE inhibitors.

Concomitant use of ACE inhibitors with mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may increase the risk of angioedema.

Anaphylactoid reactions during desensitization therapy. Rarely, anaphylactoid reactions, which may be life-threatening, have occurred in patients receiving ACE inhibitors during allergen desensitization with Hymenoptera venom. Such reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before starting hyposensitization.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactoid reactions may occur during LDL apheresis with dextran sulfate in patients receiving ACE inhibitors. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis.

Cough. Cough has been reported during ACE inhibitor therapy. It is usually non-productive and persistent and resolves after discontinuation of the drug. ACE inhibitor-related cough should be considered in the differential diagnosis of cough.

Surgery/anesthesia. During major surgical procedures or anesthesia with agents causing arterial hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If arterial hypotension develops due to these interaction mechanisms, it can be corrected by increasing fluid volume.

Racial factor. As reported for other ACE inhibitors, enalapril may be less effective in lowering blood pressure in hypertensive patients of African descent compared to patients of other races, possibly due to lower plasma renin levels in these patients.

Hydrochlorothiazide

Renal function impairment. Thiazides may be insufficiently effective as diuretics in patients with impaired renal function or when creatinine clearance is ≤30 mL/min (i.e., moderate to severe renal insufficiency).

The drug should not be prescribed to patients with renal insufficiency (creatinine clearance < 80 mL/min) until titration of individual drug components indicates the necessity of doses present in combination tablets.

Hepatic function impairment. Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as even minor disturbances in fluid and electrolyte balance may lead to hepatic coma.

Metabolic and endocrine effects. Thiazide therapy may alter glucose tolerance. Adjustment of antidiabetic drug doses, including insulin, may be required. Thiazide therapy may provoke the manifestation of latent diabetes.

Thiazides may reduce serum sodium, magnesium, and potassium levels.

Elevated cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, with low-dose use (12.5 mg), minimal or no effect has been reported.

Thiazides may reduce calcium excretion in urine and cause occasional slight increases in serum calcium. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before thyroid function tests.

Thiazide diuretic therapy may cause hyperuricemia and/or exacerbation of gout in some patients. However, enalapril may increase urinary uric acid levels and thus may attenuate the hyperuricemic effect of hydrochlorothiazide.

Although there are no available data from controlled clinical trials for patients receiving enalapril and hydrochlorothiazide combination, they, like patients receiving diuretic therapy, should have serum electrolyte levels measured regularly at appropriate intervals due to the risk of fluid and electrolyte imbalance.

Thiazides (including hydrochlorothiazide) may cause fluid and electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Dangerous signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargic sleep, drowsiness, fatigue, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting).

Although hypokalemia may occur during thiazide diuretic therapy, concomitant therapy with enalapril may reduce diuretic-induced hypokalemia. The risk of hypokalemia may be increased in patients with liver cirrhosis, those with high diuresis, inadequate oral electrolyte intake, and those receiving concomitant corticosteroid or adrenocorticotropic hormone therapy.

In hot weather, hyponatremia due to hemodilution may occur in patients prone to edema. Chloride deficiency is usually mild and does not require treatment.

Thiazides increase magnesium excretion in urine, which may lead to hypomagnesemia.

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

• the drug may reduce protein-bound iodine levels in plasma;
• treatment with the drug should be discontinued before laboratory testing to assess parathyroid function;
• the drug may increase free bilirubin concentration in serum;
• hydrochlorothiazide may give a positive result in anti-doping tests.

Hypersensitivity. Hypersensitivity reactions to hydrochlorothiazide may occur in patients prone to allergies or with a history of bronchial asthma.

Exacerbation or activation of systemic lupus erythematosus has been observed during thiazide diuretic therapy.

Drugs containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug.

Untreated acute angle-closure glaucoma may lead to irreversible vision loss. The primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, emergency medical or surgical treatment may be required. A history of allergy to sulfonamides or penicillin may be a risk factor for acute angle-closure glaucoma.

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

Non-melanoma skin cancer. An increased risk of non-melanoma skin cancer [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative exposure to hydrochlorothiazide has been observed in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for non-melanoma skin cancer. Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer and should regularly check their skin for new lesions and promptly report any suspicious skin changes. Preventive measures, such as limited exposure to sunlight and UV radiation and adequate protection when exposed, should be recommended to minimize the risk of skin cancer. Suspicious skin lesions should be promptly investigated, including histological examination of biopsies. The use of hydrochlorothiazide may also be reconsidered in patients with a history of previous non-melanoma skin cancer.

The drug contains lactose. If a patient has established intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.

Use during pregnancy or breastfeeding. ACE inhibitors are contraindicated in pregnant women and women planning pregnancy (see section "Contraindications").

Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy initiated. Epidemiological conclusions regarding teratogenic risk after ACE inhibitor exposure during the first trimester of pregnancy are inconclusive; however, a slight increase in risk cannot be excluded. It is known that ACE inhibitor use during the second and third trimesters of pregnancy may cause fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). When prescribing enalapril, the patient should be informed about the potential harm to the fetus.

If ACE inhibitors were taken during pregnancy, periodic ultrasound examinations should be performed to assess the intra-amniotic space. However, both physicians and patients should be aware that oligohydramnios may develop after irreversible fetal damage has occurred.

If ACE inhibitors were used during the second trimester of pregnancy, ultrasound evaluation of embryonic kidney and skull function is recommended.

Newborns whose mothers took ACE inhibitors should be carefully monitored for arterial hypotension, oliguria, and hyperkalemia. Enalapril, which can cross the placenta, can be partially removed from the newborn's body by peritoneal dialysis; theoretically, it could be removed by exchange transfusion, although there is no experience with this procedure.

Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal study data are insufficient.

Hydrochlorothiazide crosses the placental barrier. Use during the second and third trimesters of pregnancy may impair fetoplacental circulation and cause jaundice in the fetus or newborn, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used to treat edema, arterial hypertension, or preeclampsia in pregnant women, as instead of beneficial effects on disease course, it increases the risk of plasma volume reduction and worsens uteroplacental blood flow.

Hydrochlorothiazide should not be used to treat essential arterial hypertension in pregnant women.

Hydrochlorothiazide should not be used during pregnancy.

Breastfeeding. Limited pharmacokinetic data indicate very low concentrations in breast milk. Although such concentrations are considered clinically insignificant, the use of the drug is not recommended during breastfeeding of newborns due to the hypothetical risk of cardiovascular and renal effects and insufficient experience with such use.

Hydrochlorothiazide passes into breast milk; its use during breastfeeding is contraindicated. If its use is absolutely necessary, breastfeeding must be discontinued.

Ability to affect reaction speed when driving or operating machinery. Caution is required when driving or operating machinery due to the possibility of adverse reactions affecting the nervous system, including dizziness or drowsiness.

Dosage and Administration.

Arterial hypertension. Tablets with the fixed combination of enalapril maleate and hydrochlorothiazide are intended for patients whose blood pressure is not adequately controlled by enalapril alone.

The fixed combination of enalapril maleate and hydrochlorothiazide should not be used for initial therapy and is generally recommended after individual dose adjustment of each component. However, if clinically appropriate, direct transition from monotherapy to the fixed combination may be considered.

The dosage regimen should be individually determined by the physician depending on the patient's condition and severity of arterial hypertension. Treatment should be initiated with low doses, gradually increasing the dosage. The drug is administered orally, independent of food intake. The prescribed daily dose should be taken in the morning with a large amount of fluid.

The usual dose is 1 tablet once daily. If necessary, the dose may be increased to 2 tablets once daily.

Prior diuretic therapy: Symptomatic hypotension may occur at the beginning of enalapril therapy. This is more commonly observed in patients whose previous diuretic therapy has caused disturbances in water-electrolyte balance. Diuretic therapy should be discontinued 2–3 days before initiating treatment with this drug.

Dosing in renal impairment

Creatinine clearance above 30 mL/min. For patients with renal impairment and creatinine clearance ≥ 30 mL/min, dose adjustment of enalapril via titration is required before switching to the fixed combination. Loop diuretics are preferred over thiazides in such patients. The dose of enalapril and hydrochlorothiazide should be the lowest possible. Periodic monitoring of potassium and creatinine levels is required, e.g., every 2 months, once the patient's condition has stabilized.

Creatinine clearance below 30 mL/min. The use of this drug is contraindicated.

Special populations. For patients with reduced fluid/salt volume, the initial dose of enalapril should be up to 5 mg (administered at the appropriate dosage). Dose titration of individual components is recommended for such patients.

Dosing in elderly patients. The drug should be administered to elderly patients at the same doses as for younger patients. In cases of physiological renal impairment, enalapril dose adjustment via titration is required before switching to the fixed combination.

Children. Safety and efficacy of the drug in children have not been established.

Overdose. Treatment is symptomatic and supportive. Drug administration should be discontinued and the patient should be carefully monitored. Recommended measures include: induction of emesis if the drug was recently ingested, as well as correction of dehydration, electrolyte imbalance, and arterial hypotension using standard procedures.

Enalapril maleate. The main manifestation of overdose is marked arterial hypotension occurring within 6 hours after drug intake, accompanied by blockade of the RAAS and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, pulmonary hyperventilation, tachycardia, palpitations, dizziness, anxiety, and cough. Plasma enalapril levels exceeding 100 and 200 times the maximum levels achieved with therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalaprilat, respectively. In case of arterial hypotension, infusion of angiotensin II and/or intravenous administration of catecholamines may be considered.

Recommended treatment for overdose is intravenous administration of 0.9% sodium chloride solution. Enalapril can be removed from systemic circulation by hemodialysis.

In cases of bradycardia resistant to therapeutic interventions, treatment with a cardiac pacemaker is indicated.

Hydrochlorothiazide. The most common signs and symptoms are manifestations of hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis. If digitalis preparations are also administered, hypokalemia may exacerbate cardiac arrhythmias. Other manifestations of overdose may include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, disturbances of consciousness, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen levels (primarily due to renal failure).

Continuous monitoring of vital signs, electrolyte concentrations, and serum creatinine levels is required.

Side effects

The most commonly reported side effects were dizziness and increased fatigue, which usually resolved with dose reduction and rarely required discontinuation of the drug.

Other side effects (1–2%) included: muscle cramps, nausea, asthenia, orthostatic effects including arterial hypotension, headache, cough, and impotence.

The following adverse reactions have been reported either during use of enalapril or hydrochlorothiazide alone, during clinical trials, or following market release of the drug.

Cardiovascular system: non-orthostatic hypotension, palpitations, tachycardia, chest pain.

Gastrointestinal tract: pancreatitis, diarrhea, vomiting, dyspepsia, abdominal pain, peptic ulcers, flatulence, constipation, dry mouth, aphthous ulcers.

Nervous system/psychiatric disorders: syncope, insomnia, somnolence, paresthesia, dizziness, vertigo, fatigue, malaise, nervousness, paresis (due to hypokalemia).

Respiratory system: dyspnea, allergic alveolitis.

Skin and appendages: Stevens-Johnson syndrome, rash, pruritus, increased sweating, diaphoresis, photosensitivity, or other dermatological reactions.

Blood and lymphatic system: decreased hemoglobin and hematocrit levels, reduced platelet and leukocyte counts; rarely neutropenia, thrombocytopenia, and bone marrow suppression.

Renal and urinary system: impaired kidney function, renal failure, proteinuria.

Reproductive system: decreased libido.

Metabolic and nutritional disorders: gout.

Auditory and vestibular system: tinnitus.

Other: a symptom complex has been reported that may include one or more of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated ESR, eosinophilia, leukocytosis.

Hypersensitivity reactions: angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been rarely reported (see section "Special precautions"). Very rare cases of intestinal angioedema have been reported with angiotensin-converting enzyme (ACE) inhibitors, including enalapril.

Laboratory test changes: hyperglycemia, hyperuricemia, hypokalemia. Increases in blood urea nitrogen, serum creatinine, and liver enzymes and/or bilirubin in serum have been observed. These effects are usually reversible upon discontinuation of the drug. Cases of hyperkalemia, hypochloremic alkalosis, hypomagnesemia, hypercalcemia, and increased cholesterol and triglyceride levels have also been reported. Effects on the following laboratory parameters:

• the drug may reduce plasma protein-bound iodine levels;
• the drug may increase free bilirubin concentration in serum;
• due to effects on calcium metabolism, thiazides may interfere with assessment of parathyroid function; therefore, treatment should be discontinued prior to evaluation of parathyroid function.

Additional adverse reactions observed with individual components of the drug that may represent potential side effects of the combination product.

Enalapril

Gastrointestinal tract: ileus, anorexia, taste disturbances, stomatitis, glossitis, nausea.

Hepatobiliary system: liver failure, hepatitis (hepatocellular or cholestatic), cholecystitis, hepatic necrosis, cholestasis.

Nervous system/psychiatric disorders: depression, confusion, sleep disorders, abnormal dreams, asthenia.

Respiratory system: pulmonary infiltrates, bronchospasm/asthma, throat pain, hoarseness, rhinorrhea.

Cardiovascular system: cardiac rhythm disturbances, angina pectoris, orthostatic hypotension, myocardial infarction or stroke (possibly due to excessive hypotension in high-risk patients), Raynaud's phenomenon.

Skin and mucous membranes: photosensitivity, alopecia, erythroderma, toxic epidermal necrolysis, multiform erythema, exfoliative dermatitis, pemphigus.

Blood and lymphatic system: aplastic anemia, hemolytic anemia, hyponatremia.

Immune system: urticaria, anaphylactic shock, autoimmune disorders.

Metabolic and nutritional disorders: hypoglycemia.

Other: blurred vision, lymphadenopathy, oliguria, syndrome of inappropriate antidiuretic hormone secretion (SIADH), muscle cramps.

Hydrochlorothiazide

Cardiovascular system: arrhythmia.

Hepatobiliary system: jaundice (intrahepatic cholestatic), hepatic necrosis, cholestasis, cholecystitis.

Gastrointestinal tract: anorexia, gastric irritation, sialadenitis, taste disturbances, nausea.

Metabolic and nutritional disorders: glucosuria, hypochloremic alkalosis (which may precipitate hepatic encephalopathy or hepatic coma), hyperuricemia (which may trigger gout attacks in patients with asymptomatic hyperuricemia), hypoglycemia, reduced glucose tolerance (which may lead to manifestation of latent diabetes mellitus).

Blood and lymphatic system: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia.

Immune system: anaphylactic reaction, urticaria.

Skin and mucous membranes: photosensitivity, necrotizing angiitis (vasculitis), toxic epidermal necrolysis.

Eye disorders: xanthopsia, transient visual disturbances, choroidal effusion.

Respiratory system: acute respiratory distress syndrome (including pneumonia and pulmonary edema).

Nervous system/psychiatric disorders: restlessness, disorientation, mood changes, exhaustion.

Laboratory test changes: electrolyte imbalance (including hyponatremia).

Benign and malignant neoplasms (including cysts and polyps): frequency unknown – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma). Based on available epidemiological data, a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer has been observed.

Other: fever, interstitial nephritis, muscle spasms, cramps, thirst, sexual dysfunction.

Shelf life. 4 years.

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

Keep out of reach of children.

Packaging. Tablets, 20 or 30 in a blister pack in a box.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY “CORPORATION “ZDOROV’YA”.

Limited Liability Company “FARMEKS GROUP”.

Manufacturer’s address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY “CORPORATION “ZDOROV’YA”)

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(Limited Liability Company “FARMEKS GROUP”)