Enalapril-n-zdorovya

INSTRUCTION for medical use|consumption| of the medicinal product ENALAPRIL-H-ZDOROVYE

Composition:

Active substances: enalapril, hydrochlorothiazide;

1 tablet contains enalapril maleate 10 mg, hydrochlorothiazide 25 mg;

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

Medicinal form. Tablets.

Main physico-chemical properties: white or white with a creamy shade, 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 C09B A02.

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 reduce potassium loss associated with hydrochlorothiazide administration.

Pharmacodynamics. Enalapril is a highly specific competitive ACE inhibitor, 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 substance; it also reduces aldosterone secretion, resulting in decreased concentrations of angiotensin II and aldosterone in blood. It inhibits the breakdown of bradykinin, a powerful vasodilator peptide. The mechanism by which enalapril lowers blood pressure is primarily related to inhibition of the renin-angiotensin-aldosterone system regulating blood pressure; enalapril may exert antihypertensive effects even in patients with low-renin hypertension.

Pressor (sympathoadrenal) systems are suppressed, while depressor systems (kallikrein-kinin and prostaglandin systems) are activated, and production of vascular endothelial factors increases. As a result of these effects, total peripheral vascular resistance, blood pressure, and pulmonary circulation pressure decrease, while cardiac output increases. Enalapril causes a gradual reduction in systolic and diastolic pressure.

Administration of enalapril in hypertension leads to blood pressure reduction in both supine and upright positions without 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 blood pressure elevation. Effective inhibition of ACE activity is usually achieved within 2–4 hours after oral administration of an individual dose of enalapril. Onset of antihypertensive activity is typically observed within 1 hour, and peak blood pressure reduction occurs 4–6 hours after drug administration. Duration of effect depends on the dose. However, when used at recommended doses, antihypertensive and hemodynamic effects persist 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 some increase in cardiac output and minimal or no changes in heart rate. After enalapril administration, renal blood flow increases; 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 favorable or neutral impact on total cholesterol levels.

The degree of blood pressure reduction observed with the combination of enalapril and hydrochlorothiazide exceeds that achieved with individual components administered separately.

Hydrochlorothiazide is an active diuretic agent whose action is due to reduced reabsorption of sodium and chloride ions in the proximal portion of the convoluted tubules. It also inhibits reabsorption of potassium and bicarbonates. Diuretic effect develops within 1–2 hours, reaches maximum within 4 hours, and lasts up to 12 hours. Diuretic action occurs both in 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 within 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. It is hydrolyzed in the liver to form enalaprilat. Bioavailability is nearly 40%. After oral administration, Cmax of enalapril in plasma occurs within 1 hour, and of enalaprilat within 3–4 hours. Enalaprilat readily penetrates histohematological barriers, except the blood-brain barrier, crosses the placenta, and is excreted in trace amounts into breast milk. Enalaprilat does not undergo biotransformation. Enalaprilat binds to plasma proteins by 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 half-life (T½) of enalaprilat is 11 hours. In renal insufficiency, T½ increases. Enalaprilat is removed from the body during hemodialysis.

Hydrochlorothiazide is rapidly absorbed after oral administration (60–80%). It accumulates in erythrocytes 3–9 times more than in plasma. Protein binding in plasma is 40–70%. Volume of distribution in the terminal elimination phase is 3–6 L/kg (equivalent to 210–420 L at a body weight of 70 kg). Hydrochlorothiazide undergoes minimal metabolism. When plasma levels were assessed for at least 24 hours, plasma half-life ranged from 5.6 to 14.8 hours. Hydrochlorothiazide is rapidly eliminated by the kidneys, T½ is 10 hours, and 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 insufficiency, T½ of enalaprilat and hydrochlorothiazide increases.

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

Clinical characteristics.

Indications. Arterial hypertension in patients for whom combination therapy is indicated.

Contraindications. Hypersensitivity to enalapril and other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide and other sulfonamide derivatives, or any component of the drug; history of angioedema associated with previous ACE inhibitor therapy; hereditary or idiopathic angioedema; severe renal impairment (creatinine clearance less than 30 mL/min or serum creatinine level exceeding 265 µmol/L (3 mg/100 mL)); renal artery stenosis; during hemodialysis; clinical condition following kidney transplantation; severe hepatic dysfunction; anuria, primary hyperaldosteronism; refractory hypokalemia or hyperkalemia; refractory hyponatremia; symptomatic hyperuricemia (gout); pregnancy or planned pregnancy (see "Use in pregnancy or breastfeeding").

Enalapril should not be co-administered with aliskiren-containing products in patients with diabetes mellitus 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.

Ganglionic blockers or adrenergic blockers combined with enalapril should be administered only under careful patient monitoring.

Lithium-containing medications. Diuretics or ACE inhibitors reduce renal lithium clearance 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, and/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 have additive effects leading to 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 used cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and be under close monitoring of renal function at the initiation and periodically throughout concomitant therapy.

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), 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 warnings and precautions for use").

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

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

Gold preparations. Rare reactions similar to nitrite-like reactions (vasodilatory symptoms including flushing, facial swelling, dizziness, nausea, vomiting, and arterial hypotension) have been observed in patients receiving injectable gold preparations (sodium aurothiomalate) concurrently with ACE inhibitors, including enalapril.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

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 more likely 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 warnings and precautions for use").

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist. In patients with confirmed atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to therapy with a single renin-angiotensin-aldosterone system inhibitor. 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). May enhance sensitivity to the effects of muscle relaxants.

Alcohol (ethanol), barbiturates, narcotic analgesics, antidepressants. May potentiate orthostatic hypotension.

Antidiabetic agents (oral antidiabetic agents and insulin). Thiazide therapy may reduce glucose tolerance. Dose adjustments may be necessary. 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 clinical response to digoxin toxicity (e.g., increased ventricular excitability).

Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormone, stimulant laxatives, or glycyrrhizin (found in licorice). Hydrochlorothiazide may exacerbate electrolyte imbalances, primarily 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 contraindicate concomitant use.

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

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

Medicinal products used for gout treatment (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. In cases of high-dose salicylate intake, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

Methyldopa. Isolated reports of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

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

Anticholinergic agents (e.g., atropine, biperiden) 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 use may lead to 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);
• certain 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 required, 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.

Iodine-containing contrast agents. In cases of diuretic-induced dehydration, the risk of acute renal failure increases, particularly with high-dose contrast agents. Patients require rehydration prior to administration of iodine-containing agents.

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid >3 g/day, and nonselective NSAIDs. Concomitant use of 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 with enalapril use is increased in patients with salt/volume depletion, for example, due to diuretic therapy, salt intake 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, with hyponatremia, or with 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, serum electrolyte levels should be periodically checked.

Particular caution is required when treating patients with ischemic heart disease or cerebrovascular disorders, since excessive reduction in blood pressure 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 an intravenous infusion of 0.9% sodium chloride solution. Transient arterial hypotension after taking the drug is not a contraindication for continuing treatment, which may be resumed 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 to the drug is expected and should not be considered a reason to discontinue treatment. If arterial hypotension becomes refractory to treatment, the dose should be reduced and/or diuretic and/or drug therapy discontinued.

Dual blockade of the renin-angiotensin-aldosterone system. Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited only to individual 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 blockade of the renin-angiotensin-aldosterone system is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single agent acting on the renin-angiotensin-aldosterone system. Enalapril should not be used with aliskiren in patients with diabetes or impaired renal function (eGFR < 60 mL/min/1.73 m²).

Renal function impairment. Renal function impairment caused by enalapril has been reported, especially in patients with severe heart failure or kidney diseases, including renal artery stenosis. If diagnosed promptly and treated appropriately, renal failure associated with enalapril therapy is usually reversible.

In some patients with arterial hypertension without pre-existing renal insufficiency, serum urea and creatinine levels may increase during enalapril treatment combined with diuretics. It may be necessary to reduce the enalapril dose and/or discontinue the diuretic. In such cases, the possibility of renal artery stenosis should be considered.

Hyperkalemia. The combination of enalapril and low-dose diuretics may cause 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 patients and younger adults 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 obstructive outflow pathways; their use should be avoided in cardiogenic shock and hemodynamically significant obstruction.

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

Patients undergoing hemodialysis. In patients undergoing dialysis with high-permeability membranes (e.g., AN 69) and concurrently receiving ACE inhibitor therapy, anaphylactoid reactions have occurred in some cases. Therefore, for such patients, it is recommended to use other types of dialysis membranes or antihypertensive agents from another drug 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 impairment. Very rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to hepatic necrosis, sometimes with fatal outcomes. The mechanism of this syndrome is unknown. Patients receiving ACE inhibitors who develop jaundice or significant increases in liver enzymes should discontinue the drug and seek 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, sometimes unresponsive to intensive antibiotic therapy.

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

Hyperkalemia. During treatment with ACE inhibitors, including enalapril, elevated 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, transient conditions (e.g., dehydration), acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of potassium-containing dietary supplements or salt substitutes; and in patients taking other drugs that may increase serum potassium levels (e.g., heparin). In particular, concomitant use of potassium-sparing diuretics, dietary supplements, or potassium-containing salt substitutes in patients with impaired renal function may lead to significant increases 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 receiving oral antidiabetic drugs or insulin require careful glycemic monitoring, especially during the first month of ACE inhibitor therapy.

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

Very rarely, fatal angioedema of the larynx or tongue has been reported. 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 non-Caucasian race taking 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 angioedema 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, potentially life-threatening, have occurred in patients receiving ACE inhibitors during allergen desensitization with Hymenoptera venom. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor 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. Such reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis.

Cough. Cough has been reported during treatment with ACE inhibitors. The cough is usually non-productive and persistent and resolves after discontinuation of the drug. Cough associated with ACE inhibitor therapy 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 that can be explained by these interaction mechanisms, it is corrected by increasing fluid volume.

Racial factor. As reported for other ACE inhibitors, enalapril may be less effective in reducing blood pressure in hypertensive patients of non-Caucasian race 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, especially 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 the combined tablets.

Hepatic impairment. Thiazides should be used with caution in patients with hepatic dysfunction 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 treatment may provoke the manifestation of latent diabetes.

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

Increased cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, with hydrochlorothiazide at a dose of 12.5 mg, minimal or no effects have 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 performing parathyroid function tests.

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

Although there are no available data from controlled clinical trials in patients receiving enalapril and hydrochlorothiazide combination, as with patients receiving diuretic therapy, serum electrolyte levels should be regularly measured at appropriate intervals.

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

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

In hot weather, hyponatremia due to plasma dilution 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 certain laboratory tests:

• the drug may reduce plasma protein-bound iodine levels;
• 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 yield 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 use.

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 immediate discontinuation of the drug. 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 developing 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 taking hydrochlorothiazide. 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 patients 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 who have previously had non-melanoma skin cancer.

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

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 alternative therapy initiated if possible. Epidemiological findings regarding the teratogenic risk of ACE inhibitors 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 (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). When prescribing enalapril, patients must 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, an ultrasound examination 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 can 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. Data from animal studies are insufficient.

Hydrochlorothiazide crosses the placental barrier. When used during the second and third trimesters of pregnancy, hydrochlorothiazide 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 of enalapril 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 theoretical 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. When driving a car or operating machinery, caution should be exercised due to the possibility of adverse reactions affecting the nervous system, including dizziness or drowsiness.

Method of Administration and Dosage.

Arterial Hypertension. Tablets with fixed combination of enalapril maleate and hydrochlorothiazide are prescribed to patients in whom arterial pressure is not sufficiently controlled by enalapril alone.

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

Dosage regimen should be individually determined by a physician depending on the patient's condition and severity of arterial hypertension. Treatment should be initiated with low doses with gradual dose escalation. The drug should be administered orally, independently of food intake. The established daily dose should be taken in the morning with a large amount of liquid.

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

Prior Diuretic Therapy. Symptomatic hypotension may occur at the beginning of enalapril therapy. It is more frequently observed in patients in whom prior 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 by 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, for example, every 2 months, once the patient's condition has stabilized.

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

Special Populations. In patients with reduced fluid/salt volume, the initial dose of enalapril is 5 mg (administered at corresponding dosage) or lower. Titration of monocomponents is recommended for such patients.

Dosing in Elderly Patients. The drug should be administered to elderly patients at the same doses as in younger patients. In case of physiological renal insufficiency, enalapril dose adjustment by 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. Administration of the drug should be discontinued and the patient should be carefully examined. 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 severe arterial hypotension, occurring within 6 hours after drug intake and associated with blockade of the renin-angiotensin system and stupor. Symptoms related to overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, pulmonary hyperventilation, tachycardia, increased heart rate, 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 I and/or intravenous administration of catecholamines may be considered.

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

In case of bradycardia resistant to therapeutic measures, therapy with a cardiac pacemaker is indicated.

Hydrochlorothiazide. The most common symptoms are manifestations of hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis. If digitalis is 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, elevated blood urea nitrogen (mainly due to renal failure).

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

Adverse Reactions. The most common adverse reactions were dizziness and increased fatigue, which usually resolved with dose reduction and rarely required discontinuation of the drug.

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

Adverse reactions reported during use of either enalapril alone or hydrochlorothiazide alone, or during clinical trials or post-marketing experience, are included.

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: syncope, insomnia, drowsiness, paresthesia, dizziness, vertigo, fatigue, malaise, nervousness, paresis (due to hypokalemia).

Respiratory System: dyspnea, allergic alveolitis.

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

Hematological System: decreased hemoglobin and hematocrit levels, as well as reduced platelet and leukocyte counts; rarely – neutropenia, thrombocytopenia, bone marrow suppression.

Renal and Urinary Tract: impaired renal function, renal failure, proteinuria.

Reproductive System: decreased libido.

Metabolic Disorders: gout.

Auditory and Vestibular System: tinnitus.

Other: a symptom complex has been reported that may include several or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, and 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"). Intestinal angioedema has been very rarely reported with ACE inhibitors, including enalapril.

Laboratory Test Changes: hyperglycemia, hyperuricemia, hypokalemia. Increased levels of blood urea nitrogen and serum creatinine, as well as elevated liver enzymes and/or bilirubin in serum have been observed. These symptoms are usually reversible upon discontinuation of the drug. Cases of hyperkalemia, hypochloremic alkalosis, hypomagnesemia, hypercalcemia, and increased levels of cholesterol and triglycerides in blood have also been reported. Effects on laboratory test results:

• the drug may decrease plasma protein-bound iodine levels;
• the drug may increase free bilirubin concentration in serum;
• due to its effect on calcium metabolism, thiazides may affect assessment of parathyroid gland function; therefore, drug treatment should be discontinued before evaluating parathyroid function.

Additional adverse reactions observed with individual components of the drug and which may be potential adverse effects of the drug.

Enalapril

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

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

Nervous System/Psychiatric: depression, confusion, sleep disorders, abnormal dreams, asthenia.

Respiratory System: pulmonary infiltrates, bronchospasm/asthma, sore throat, hoarseness, rhinorrhea.

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

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

Hematological System: aplastic and hemolytic anemia, hyponatremia.

Immune System: urticaria, anaphylactic shock, autoimmune disorders.

Metabolic Disorders: hypoglycemia.

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

Hydrochlorothiazide

Cardiovascular System: arrhythmia.

Hepatobiliary System: jaundice (intrahepatic, cholestatic), liver necrosis, cholestasis, cholecystitis.

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

Metabolic Disorders: glucosuria, hypochloremic alkalosis (which may induce hepatic encephalopathy or hepatic coma), hyperuricemia (which may provoke gout attacks in patients with asymptomatic disease), hypoglycemia, reduced glucose tolerance (which may lead to manifestation of latent diabetes mellitus).

Hematological System: leukopenia, agranulocytosis, thrombocytopenia, aplastic and hemolytic anemia.

Immune System: anaphylactic reaction, urticaria.

Skin and Mucous Membranes: photosensitivity, necrotizing angiitis (vasculitis), toxic epidermal necrolysis.

Ocular System: xanthopsia, transient visual disturbances, choroidal effusion.

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

Nervous System/Psychiatric: restlessness, disorientation, mood changes, exhaustion.

Laboratory Test Changes: electrolyte imbalance (including hyponatremia).

Benign, Malignant and Uncertain 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 cramps, cramps, thirst sensation, sexual disorders.

Shelf Life. 4 years.

Storage Conditions. Store in original packaging at temperature not exceeding 25 ºC. Keep out of reach of children.

Packaging. Tablets, 20 or 30 in blisters, in a box.

Prescription Category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's Address and Place of Business. 22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.