Enalapril n-farmex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALAPRIL H-PHARMEX (ENALAPRIL H-PHARMEX)

Composition:

Active substances: enalapril, hydrochlorothiazide;

One 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.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets of white or off-white color, flat cylindrical in shape, with a score line and beveled edges.

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

Pharmacological properties.

The medicinal product contains a combination of two antihypertensive agents. The antihypertensive 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 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 reducing aldosterone secretion, resulting in decreased blood concentrations of angiotensin II and aldosterone. It also inhibits the breakdown of bradykinin, a powerful vasodilatory peptide. The mechanism by which enalapril lowers blood pressure is primarily attributed to suppression of the renin-angiotensin-aldosterone system, which regulates arterial 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 the production of vascular endothelial factors increases. 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 hypertensive patients reduces arterial pressure in both supine and upright positions without significantly increasing heart rate. Symptomatic postural hypotension occurs infrequently. In some patients, optimal blood pressure reduction may require several weeks of therapy. Abrupt discontinuation of enalapril does not lead to a rapid rebound increase in blood pressure. Effective inhibition of ACE activity is typically achieved within 2–4 hours after oral administration of an individual dose of enalapril. The onset of antihypertensive activity is usually observed within 1 hour, with peak blood pressure reduction occurring 4–6 hours after administration. The duration of effect depends on the dose. 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 arterial peripheral resistance, with a slight 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 beneficial effects on plasma lipoprotein fractions and a favorable influence 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 results from reduced reabsorption of sodium and chloride ions in the proximal convoluted tubules. It also inhibits potassium and bicarbonate reabsorption. The diuretic effect begins within 2 hours, reaches its maximum at 4 hours, and lasts up to 12 hours. The diuretic effect occurs under both alkalotic and acidotic conditions 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 use of hydrochlorothiazide results in greater blood pressure reduction in these patients.

Hydrochlorothiazide exerts 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. The maximum therapeutic effect develops after 3–4 weeks of treatment.

Pharmacokinetics. Enalapril is well absorbed. After oral administration, approximately 60% of enalapril is absorbed from the gastrointestinal tract. Concomitant food intake does not affect absorption. In the liver, enalapril is hydrolyzed to form enalaprilat. Bioavailability is nearly 40%. After oral administration, Cmax of enalapril in plasma occurs within 1 hour, while Cmax of enalaprilat occurs within 3–4 hours. Enalaprilat readily crosses histohematological barriers, except the blood-brain barrier, crosses the placenta, and is excreted in small 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 impairment, T½ increases. Enalaprilat is removed from the body during hemodialysis.

Hydrochlorothiazide is rapidly absorbed after oral administration (60–80%). The diuretic effect develops within 1–2 hours and lasts longer. Hydrochlorothiazide accumulates in erythrocytes at concentrations 3–9 times higher than in plasma. 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 for 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 drug is excreted in urine. Hydrochlorothiazide crosses the placenta and is excreted into breast milk, but does not cross the blood-brain barrier.

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

Repeated concomitant administration of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of these drugs. The use of a fixed-dose combination tablet is bioequivalent to the separate administration of its components.

Clinical characteristics.

Indications.

Arterial hypertension in patients for whom combination therapy is indicated.

Contraindications.

Hypersensitivity to ACE inhibitors, thiazide diuretics, other sulfonamide derivatives, or other components of the drug.

History of angioedema associated with administration of an ACE inhibitor.

Hereditary or idiopathic angioedema.

Severe renal impairment (creatinine clearance ≤ 30 mL/min) and treatment with hemodialysis. Clinical condition following kidney transplantation, anuria, primary hyperaldosteronism, renal artery stenosis.

Severe hepatic dysfunction.

Refractory hypokalemia or hypercalcemia, refractory hyponatremia, symptomatic hyperuricemia (gout).

Concomitant use of enalapril with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).

Contraindicated in pregnant women or women planning to become pregnant (see section "Use during pregnancy or breastfeeding").

Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Enalapril maleate/hydrochlorothiazide

Other antihypertensive agents. Concomitant use may potentiate the antihypertensive effects of enalapril and hydrochlorothiazide. Combination with nitroglycerin, other nitro compounds, or vasodilators may lead to further significant reduction in arterial blood pressure.

Lithium. Cases of reversible increase in serum lithium levels and lithium toxicity have been reported with concomitant use of ACE inhibitors. Thiazide diuretics may further increase the risk of lithium toxicity already present with ACE inhibitors. Therefore, the drug is not recommended for concomitant use with lithium-containing preparations; if such therapy is necessary, serum lithium levels should be carefully monitored.

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs may attenuate the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Chronic use of NSAIDs may reduce the antihypertensive effect of ACE inhibitors. Combination of NSAIDs (including COX-2 inhibitors) with ACE inhibitors or angiotensin II receptor antagonists may result in an additive effect leading to increased serum potassium levels and may impair renal function. These effects are usually reversible. In rare cases, acute renal failure may develop, particularly in patients with pre-existing renal impairment, e.g., elderly patients or those with reduced circulating blood volume, including due to intensive diuretic therapy. Therefore, such combinations should be used with caution in patients with impaired renal function. Patients should maintain adequate fluid intake and undergo careful monitoring of renal function at the start of concomitant therapy and periodically during treatment.

Angiotensin receptor antagonists. Literature reports indicate that in patients with confirmed atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single renin-angiotensin-aldosterone system inhibitor. Dual blockade (e.g., combination of an ACE inhibitor with an angiotensin II receptor antagonist) should be restricted to individually defined cases with careful monitoring of renal function, potassium levels, and blood pressure.

Enalapril maleate

Potassium-sparing diuretics or potassium supplements. ACE inhibitors reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium-containing supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. If concomitant use of these agents is indicated due to hypokalemia, they should be used with caution and serum potassium levels should be monitored regularly.

Diuretics (thiazide and loop diuretics). Prior treatment with high-dose diuretics may lead to dehydration and increase the risk of arterial hypotension at the beginning of enalapril therapy. Hypotensive effects can be minimized by discontinuing diuretics, increasing salt and fluid intake, or initiating enalapril at low doses.

Tricyclic antidepressants, neuroleptics, anesthetics, narcotic analgesics. Marked reduction in arterial blood pressure may occur with concomitant use of these agents with ACE inhibitors.

Sympathomimetic agents. Possible attenuation of the effect of ACE inhibitors.

Antidiabetic agents. Epidemiological data suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin or oral agents) may be associated with a significant reduction in blood glucose levels and an increased risk of hypoglycemia. This is most likely during the first weeks of such treatment and in patients with impaired renal function. In diabetic patients taking oral antidiabetic agents or insulin, blood glucose levels should be closely monitored for hypoglycemia, especially during the first month of ACE inhibitor therapy.

Ethanol. Enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytic agents. Concomitant use of enalapril with acetylsalicylic acid (at cardiologic doses) is not hazardous. However, an increased risk of angioedema has been reported in patients receiving alteplase who were concurrently taking ACE inhibitors, including enalapril.

Gold preparations. Rare nitroid reactions (flushing, nausea, vomiting, arterial hypotension) have been reported with concomitant use of ACE inhibitors, including enalapril, and injectable gold preparations (sodium aurothiomalate).

mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). Patients receiving concomitant mTOR inhibitors may be at increased risk of angioedema.

Trimethoprim/sulfamethoxazole combination. Patients receiving trimethoprim/sulfamethoxazole combination drugs may be at increased risk of hyperkalemia.

Hydrochlorothiazide

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

Non-depolarizing muscle relaxants (e.g., tubocurarine). Possible potentiation of the muscle relaxant effect.

Ethanol, barbiturates, narcotic analgesics, antidepressants. Possible potentiation of orthostatic arterial hypotension.

Antidiabetic agents (oral agents, insulin). Possible attenuation of glucose-lowering effect due to hydrochlorothiazide (reduced glucose tolerance may occur with thiazide therapy). Dose adjustments may be necessary. Metformin should be used with caution due to the risk of lactic acidosis secondary to possible functional renal impairment caused by hydrochlorothiazide.

Cholestyramine and colestipol. In the presence of these ion-exchange resins, absorption of hydrochlorothiazide is impaired. After single-dose administration, cholestyramine and colestipol bind hydrochlorothiazide, reducing its gastrointestinal absorption by 85% and 43%, respectively. Sulfonamide-derived diuretics should be administered at least 1 hour before or 4–6 hours after cholestyramine or colestipol.

Agents that prolong the QT interval. Increased risk of cardiac arrhythmias, including ventricular tachycardia (e.g., torsades de pointes):

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

Cardiac glycosides derived from digitalis. Hypokalemia may increase cardiac sensitivity to toxic effects of digitalis or cause hyperreactivity to these toxic effects (e.g., increased ventricular excitability).

Corticosteroids, corticotropin (ACTH), carbenoxolone, amphotericin (for parenteral administration), stimulant laxatives. Concomitant use with hydrochlorothiazide may lead to electrolyte disturbances, particularly hypokalemia.

Potassium-wasting diuretics (e.g., furosemide), carbenoxolone, or stimulant laxatives in case of abuse. Hydrochlorothiazide may enhance potassium and/or magnesium loss.

Vasopressor amines (e.g., noradrenaline). The effect of vasopressor amines may be reduced.

Calcium salts and vitamin D. Thiazide diuretics reduce calcium excretion and may increase plasma calcium levels. Serum calcium levels should be monitored and the dose of calcium/vitamin D supplements adjusted accordingly.

Immunosuppressants, systemic corticosteroids, procainamide. Possible decrease in white blood cell count, leukopenia.

Cytostatic agents (e.g., cyclophosphamide, fluorouracil, methotrexate). Possible increased bone marrow toxicity, including granulocytopenia, due to reduced renal excretion of these agents caused by hydrochlorothiazide.

Antigout agents (e.g., allopurinol, benzbromarone, probenecid, sulfinpyrazone). Dose increases of these agents may be necessary because hydrochlorothiazide increases serum uric acid levels. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.

Disulfiram. Increases plasma concentration of hydrochlorothiazide and reduces its hyperuricemic effect.

Antihypertensive drugs. When used concomitantly with hydrochlorothiazide, a reduction in the dose of antihypertensive drugs may be necessary to prevent excessive reduction in blood pressure.

Carbamazepine. Development of hyponatremia. Electrolyte levels should be monitored; if necessary, diuretics from other classes may be used.

Anticholinergic agents (e.g., atropine, biperiden). Increase bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Salicylates. At high doses, hydrochlorothiazide may potentiate the toxic effects of salicylates on the central nervous system.

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

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

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

Amantadine. Hydrochlorothiazide increases the risk of adverse reactions to amantadine.

Iodine-containing contrast agents. In cases of diuretic-induced dehydration, the risk of acute renal failure increases, especially with high doses of iodine-containing agents. Rehydration should be performed prior to administration.

Clinical laboratory tests. Hydrochlorothiazide may affect the results of the bentiromide test. Thiazide diuretics may reduce serum levels of protein-bound iodine in the absence of other signs of thyroid dysfunction.

Special precautions for use.

Symptomatic arterial hypotension and fluid 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 the presence of disturbances in water-electrolyte balance, a low-salt diet, dialysis, diarrhea, or vomiting. Arterial hypotension has been observed in patients with heart failure, with or without concomitant renal impairment. The risk is higher in patients with more severe heart failure, associated with the use of high doses of loop diuretics, hyponatremia, or impaired renal function. In such patients, treatment should be initiated under strict medical supervision, and serum electrolyte concentrations should be monitored regularly during therapy. These recommendations also apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or acute cerebrovascular accident. In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, infused with 0.9% sodium chloride solution. Transient arterial hypotension is not a contraindication for further treatment, which may be continued after normalization of blood pressure with infusion therapy.

Stenosis of the aortic or mitral valve/hypertrophic cardiomyopathy. Like other vasodilating agents, ACE inhibitors should be used with caution in patients with impaired outflow from the left ventricle, as well as in cardiogenic shock and hemodynamically significant stenosis.

Renal function impairment. Enalapril N-Pharmex should not be prescribed to patients with renal impairment (creatinine clearance < 80 mL/min and > 30 mL/min) until the necessity of using a drug with this composition has been established during enalapril dose titration.

In patients with impaired renal function, the initial enalapril dose should be determined based on creatinine clearance and subsequently adjusted according to the patient's response to treatment. In such patients, serum potassium and creatinine levels should be monitored regularly. Cases of renal failure during enalapril therapy have been reported, primarily in patients with severe heart failure or renal disease, including renal artery stenosis. With timely diagnosis and adequate treatment, this renal failure is reversible.

In some patients without apparent kidney pathology, increased blood urea and creatinine concentrations have been observed, especially when enalapril is used concomitantly with diuretics. If this occurs, treatment with Enalapril N-Pharmex should be discontinued. In such cases, renal artery stenosis should be considered.

Concomitant use of Enalapril N-Pharmex and aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (eGFR < 60 mL/min/1.73 m²). In particular, the possibility of renal artery stenosis should be considered.

The use of thiazide diuretics is not always appropriate in the treatment of patients with impaired renal function. They are ineffective when creatinine clearance is 30 mL/min or lower (e.g., in patients with moderate or severe renal impairment). In patients with kidney disease, thiazide diuretics may exacerbate azotemia. Cumulative effects of the drug may occur in patients with impaired renal function. If progressive renal failure becomes evident (increased non-protein nitrogen fraction), the prescribed treatment should be carefully reviewed and hydrochlorothiazide discontinued if necessary.

Vasorenal hypertension. The use of ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the renal artery of a single functioning kidney increases the risk of developing arterial hypotension and renal failure. In such cases, renal dysfunction may be accompanied by only minor changes in serum creatinine concentration. These patients should be treated under continuous medical supervision with a low dose, which should be gradually and cautiously increased, with monitoring of renal function.

Renal transplantation. There is no clinical experience with the use of the drug in patients who have recently undergone kidney transplantation; therefore, the drug is not recommended for this patient group.

Hepatic impairment. Rarely, the use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is not fully understood. Patients who develop jaundice or a significant increase in liver enzymes during ACE inhibitor therapy should discontinue the ACE inhibitor and receive appropriate treatment. Thiazide diuretics should be used with caution in patients with hepatic impairment or progressive liver disease, as even minor changes in fluid and electrolyte balance may precipitate hepatic coma.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other predisposing factors. Enalapril should be used with caution in patients with collagen vascular diseases, immunosuppressive therapy, allopurinol, procainamide, or a combination of these factors, especially in patients with renal impairment. Some patients developed severe infections unresponsive to antibiotic therapy. During enalapril use in such patients, periodic monitoring of the leukocyte count is recommended, and all patients should be advised to report any signs of infection.

Hypersensitivity reactions/angioedema. Angioedema of the face, extremities, lips, tongue, epiglottis, or larynx has been reported during therapy with ACE inhibitors, including enalapril. This swelling may develop at any time during treatment. In such cases, the drug should be discontinued immediately, and the patient should remain under medical supervision until all symptoms have completely resolved. Even if angioedema affects only the tongue without concomitant respiratory distress, prolonged observation is necessary, as antihistamines and corticosteroids may be insufficient. Rarely, fatal outcomes due to laryngeal and lingual angioedema have been reported. Angioedema involving the tongue, epiglottis, or larynx carries an increased risk of airway obstruction, particularly in patients who have recently undergone airway surgery. In such cases, immediate measures are required, including subcutaneous injection of 1:1000 epinephrine solution (0.3–0.5 mL) and/or securing airway patency. The patient should remain under medical supervision until complete resolution of symptoms. Angioedema occurs more frequently in patients of African descent compared to other patients receiving ACE inhibitors. Patients with a history of angioedema of other etiology have an increased risk of this complication when using ACE inhibitors.

An increased risk of angioedema (e.g., airway or tongue swelling with or without respiratory distress) has been observed with concomitant use of ACE inhibitors and mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) or alteplase (thrombolytic therapy).

Anaphylactic reactions during desensitization therapy for Hymenoptera venom. Rarely, anaphylactoid reactions, potentially life-threatening, have occurred during desensitization therapy for Hymenoptera venom in patients receiving ACE inhibitors. These reactions can be avoided by temporarily discontinuing ACE inhibitors before starting desensitization therapy.

Anaphylactic reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactic reactions have been observed in patients receiving ACE inhibitors during LDL apheresis with dextrin sulfate. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis procedure.

Hemodialysis. Anaphylactic reactions have been reported during hemodialysis with high-flux membranes (e.g., AN 69) in patients receiving ACE inhibitors. If such a procedure is necessary, it is recommended to use dialysis membranes of another type or switch to an antihypertensive agent from another class.

Metabolic and endocrine effects. Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should be warned about the need for careful blood glucose monitoring to prevent hypoglycemia, especially during the first month of concomitant therapy with ACE inhibitors.

Thiazide diuretics, including hydrochlorothiazide, may impair glucose tolerance. Diabetic patients may require adjustment of antidiabetic medication, including insulin. Thiazide diuretics may unmask latent diabetes mellitus. Use of thiazide diuretics may lead to increased serum cholesterol and triglyceride levels, and in some patients, hyperuricemia or gout may develop. This hyperuricemic effect is likely dose-dependent. Additionally, enalapril may increase serum uric acid levels and thus potentiate the hyperuricemic effect of hydrochlorothiazide. Diuretics may reduce calcium excretion in urine, leading to mild, transient increases in plasma calcium levels. Marked hypercalcemia may indicate latent hyperparathyroidism. Pathological changes in parathyroid glands with hypercalcemia and hypophosphatemia have been observed in some patients during prolonged thiazide therapy. Thiazide use should be discontinued before evaluating parathyroid function.

Hydrochlorothiazide may increase serum free bilirubin concentration (due to displacement from albumin binding). Thiazides may reduce protein-bound iodine levels in plasma without signs of thyroid dysfunction.

As with any diuretic, periodic monitoring of serum electrolytes is necessary.

Cough. A non-productive cough has been reported with ACE inhibitor use, which resolves after discontinuation of the drug; this should be considered in differential diagnosis of cough etiology.

Surgery/anesthesia. During surgical procedures or anesthesia with agents that lower blood pressure, enalapril inhibits angiotensin II formation due to compensatory renin release. If arterial hypotension occurs via this mechanism, it can be corrected with infusion therapy.

Electrolyte disturbances. Increased serum potassium levels have been observed in some patients receiving ACE inhibitors, including enalapril. Risk factors for hyperkalemia include renal impairment, reduced kidney function, age over 70 years, diabetes mellitus, intercurrent illnesses such as dehydration, acute heart failure decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements, potassium-containing salt substitutes, or other agents that increase serum potassium (e.g., heparin). Concomitant use of potassium supplements, potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes in patients with impaired renal function may lead to significant increases in serum potassium. Hyperkalemia may cause severe arrhythmias, including fatal outcomes. If concomitant use of these agents with enalapril is necessary, treatment should be administered with caution and regular monitoring of serum potassium levels.

In any patient receiving diuretics, plasma electrolyte levels should be monitored periodically. Thiazide diuretics, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypokalemia, hyponatremia, hypochloremic alkalosis). Early signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, drowsiness, dizziness, restlessness, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Although hypokalemia may occur with hydrochlorothiazide use, concomitant enalapril use reduces this effect. The risk of hypokalemia is higher in patients with liver cirrhosis, those with markedly increased diuresis, insufficient electrolyte intake, or those receiving corticosteroids or adrenocorticotropic hormone. Since the risk of hypokalemia cannot be excluded with this drug, serum potassium levels should be monitored regularly during treatment. Hyponatremia of dilution may occur in edematous patients during hot weather. Chloride deficiency is usually mild and does not require therapeutic intervention. Thiazide diuretics may reduce urinary calcium excretion and cause reversible, mild increases in serum calcium in the absence of disorders affecting calcium metabolism. Marked hypercalcemia may occur in latent hyperparathyroidism. Thiazide use should be discontinued before parathyroid function testing. Thiazide diuretics may increase magnesium excretion in urine, potentially leading to hypomagnesemia.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Clinical data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual RAAS blockade with concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision with careful monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

Antidoping test. Hydrochlorothiazide contained in the drug may cause false-positive results in antidoping tests.

Lithium. The drug is not recommended for concomitant use with lithium due to increased lithium toxicity.

Ethnic differences. As with other ACE inhibitors, the antihypertensive effect of enalapril may be less pronounced in patients of African descent compared to other patients, possibly due to a higher prevalence of low renin levels in this population.

Laboratory tests. The drug may reduce protein-bound iodine levels in plasma. Treatment should be discontinued before laboratory evaluation of parathyroid function, as the drug may increase serum free bilirubin concentration.

Hypersensitivity. Hypersensitivity reactions may occur in patients with a history of bronchial asthma. There have also been reports of an increased risk of exacerbation or activation of systemic lupus erythematosus.

The drug contains lactose, which should be considered in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Acute angle-closure glaucoma. Hydrochlorothiazide, a sulfonamide, has been associated with idiosyncratic reactions leading to acute transient myopia and acute angle-closure glaucoma. Symptoms include acute reduction in visual acuity or eye pain. These typically occur within hours to one week after starting treatment. Acute angle-closure glaucoma may lead to permanent vision loss if not treated promptly.

The primary measure is rapid discontinuation of hydrochlorothiazide. If intraocular pressure is uncontrolled, immediate therapeutic or surgical intervention may be necessary. A history of allergy to sulfonamides or penicillins may be a risk factor for angle-closure glaucoma.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy. If pregnancy is detected, the drug should be discontinued immediately, except in cases where its use is considered life-saving for the mother.

Epidemiological data on teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. Except when continuation of the drug is deemed necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is diagnosed, ACE inhibitor use should be discontinued immediately, and alternative therapy initiated if needed.

ACE inhibitors used by women during the second and third trimesters of pregnancy may cause fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) or neonatal toxicity (renal failure, hypotension, hyperkalemia).

If ACE inhibitors were used during the second trimester of pregnancy, ultrasound examination of the kidneys and skull is recommended.

Newborns whose mothers received ACE inhibitors should be closely monitored for arterial hypotension.

Daily use of diuretics during pregnancy is not recommended, as both mother and fetus are exposed to unnecessary risks of complications, including fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions observed in adult patients.

If use of the drug during pregnancy is considered necessary, periodic ultrasound examinations should be performed to assess the intra-amniotic space. If oligohydramnios is detected, the drug should be discontinued, except when its use is considered life-saving for the mother. However, both physicians and patients should be aware that oligohydramnios may develop after irreversible fetal damage has occurred.

Newborns whose mothers received the drug should be closely monitored for arterial hypotension, oliguria, and hyperkalemia. Enalapril, which can cross the placenta, may be partially removed from the newborn's body by peritoneal dialysis; theoretically, it may also be removed by exchange transfusion.

Enalapril and hydrochlorothiazide pass into breast milk. If use of the drug is considered necessary, breastfeeding should be discontinued.

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy is limited. Experimental animal data are insufficient. Hydrochlorothiazide crosses the placental barrier. In the second and third trimesters, it may impair fetoplacental blood flow and adversely affect the fetus and, consequently, the newborn, causing jaundice, electrolyte disturbances, and thrombocytopenia.

Hydrochlorothiazide is not indicated for the treatment of gestational edema, pregnancy-induced hypertension, or preeclampsia, as it may reduce plasma volume and placental hypoperfusion without providing a beneficial effect on disease course.

Hydrochlorothiazide is also not recommended for the treatment of primary arterial hypertension in pregnant women, except in rare cases when other drugs cannot be used.

Breastfeeding. Enalapril N-Pharmex is contraindicated during breastfeeding.

In humans, enalapril and hydrochlorothiazide pass into breast milk. Use of thiazide diuretics during breastfeeding in mothers has been associated with reduced or ceased milk production. Due to the potential for serious adverse reactions in infants to both active components of this drug, its use should be discontinued during breastfeeding. Otherwise, women are advised to discontinue breastfeeding.

Enalapril

Pharmacokinetic data confirm that enalapril passes into breast milk in very low concentrations. Although minimal concentrations of ACE inhibitors are not clinically significant, due to the risk of adverse reactions in infants (effects on the cardiovascular system and renal function) and the lack of sufficient clinical experience with Enalapril N-Pharmex, enalapril therapy is not recommended in patients breastfeeding premature infants or during the first weeks of life. In older infants, enalapril use by the mother may be considered only in cases of extreme necessity and under medical supervision for adverse reactions in the infant.

Hydrochlorothiazide

Hydrochlorothiazide passes into breast milk in small amounts. In high doses, thiazides significantly increase diuresis and thereby suppress lactation.

Fertility. Studies on the effect of Enalapril N-Pharmex on fertility have not been conducted.

Enalapril

Toxicity studies on reproductive function in animals suggest that Enalapril N-Pharmex may affect fertility and reproductive system function.

Hydrochlorothiazide

In animal studies on reproductive toxicity of hydrochlorothiazide, no adverse effects on fertility in either sex were observed.

Ability to affect reaction speed when driving or operating machinery.

During the initial period of drug use (duration individually determined by the physician), driving and operating machinery are prohibited. Subsequently, the extent of restriction is determined individually by the physician.

Dosage and Administration

The drug is not indicated for initial treatment of arterial hypertension. At the initial stages of arterial hypertension treatment, optimal doses of individual drugs should be selected. If necessary, the patient may be prescribed a fixed-dose combination drug instead of monotherapy.

The standard daily dose is 1 tablet per day. The tablet should be taken independently of food intake, in the morning, with a sufficient amount of liquid, for example, a glass of water.

When switching patients from enalapril monotherapy to the combination drug, especially in patients with fluid and electrolyte disturbances (e.g., after vomiting, diarrhea, or treatment with diuretics), severe heart failure, or severe arterial hypertension, including renal origin, a significant decrease in arterial pressure may occur. Therefore, such patients should be under medical supervision for approximately 8 hours after administration of the first dose.

Renal impairment. The use of the drug is contraindicated when creatinine clearance is < 30 mL/min. When creatinin clearance is 30–80 mL/min, the drug may be used only after prior dose titration of each component. For such patients, the recommended initial dose of enalapril is 5–10 mg.

Elderly patients. Data on the relationship between the efficacy and safety of the drug and patient age are lacking. Renal function should be taken into account when using the drug.

Children.

The safety and efficacy of the drug in children have not been established.

Overdose

The most common sign of enalapril overdose is marked arterial hypotension, occurring approximately 6 hours after tablet ingestion, accompanied by blockade of the renin-angiotensin-aldosterone system and stupor. Acute circulatory failure, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, fear, and cough may also occur. There have been reports of oral ingestion of 300 mg and 400 mg of enalapril maleate, resulting in serum enalapril levels increased by 100 and 200 times, respectively, compared to levels typically observed with therapeutic doses.

The most common signs of hydrochlorothiazide overdose are symptoms caused by decreased serum electrolyte levels (hypokalemia, hypochloremia, hyponatremia), as well as dehydration due to excessive diuresis. Tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, disturbances of consciousness, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and increased blood urea nitrogen (mainly in renal failure) may occur. In patients receiving cardiac glycosides, hypokalemia may lead to increased cardiac arrhythmias.

Treatment is symptomatic and supportive. In case of overdose, administration of the drug should be discontinued and the patient should be placed under medical supervision. In the event of arterial hypotension, the patient should be placed in a horizontal position and, if necessary, infused with 0.9% sodium chloride solution. Intravenous infusion of angiotensin II and/or catecholamine-group drugs may be considered. If the drug was recently ingested, induced vomiting, gastric lavage, and administration of adsorbents and laxatives are indicated. Enalapril can be removed by hemodialysis. In case of persistent bradycardia, a cardiac pacemaker should be used, and continuous monitoring of vital functions and serum electrolyte levels should be performed.

Adverse reactions.

Infections and infestations: sialadenitis.

Blood and lymphatic system disorders: anemia (including aplastic and hemolytic), leukopenia, neutropenia, decreased hemoglobin levels, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune diseases.

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: hypoglycemia, hyperglycemia, glucosuria, hyperuricemia, loss of appetite, anorexia, gout, metabolic alkalosis.

Nervous system disorders: headache, confusion, unconsciousness, sleep disturbances, somnolence, insomnia, unusual dreams, increased excitability, disorientation, mood changes, nervousness, restlessness, paresthesia, vertigo, dizziness, depression.

Sensory organ disorders: transient visual disturbances, xanthopsia, tinnitus, acute attack of closed-angle glaucoma.

Cardiovascular system disorders: arterial hypotension (including orthostatic), loss of consciousness, cardiac arrhythmias, angina pectoris, tachycardia, flushing, palpitations, myocardial infarction or stroke, likely secondary to severe arterial hypotension in high-risk patients, Raynaud's syndrome.

Respiratory system disorders: cough, dyspnea, rhinorrhea, pharyngitis, sore throat or hoarseness, bronchospasm/asthma, pulmonary infiltrates, respiratory distress syndrome (including pneumonitis and pulmonary edema), rhinitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders: nausea, diarrhea, abdominal pain, altered taste perception, intestinal obstruction, pancreatitis, vomiting, dyspeptic disorders, constipation, gastric irritation, dry mouth, thirst, peptic ulcers, flatulence, stomatitis/aphthous stomatitis, glossitis, angioneurotic edema of the intestine.

Hepatobiliary disorders: liver failure, hepatic necrosis (sometimes fatal), hepatitis (hepatocellular or cholestatic), cholestasis (including with jaundice), cholecystitis (particularly in patients diagnosed with cholelithiasis).

Skin and subcutaneous tissue disorders: rash (including exanthema), hypersensitivity/angioedema (there have been reports of facial, limb, lip, tongue, epiglottis and/or larynx swelling), anaphylactic reactions (including anaphylactic shock), increased sweating, pruritus, urticaria, alopecia, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), exfoliative dermatitis, bullous dermatoses, erythroderma, purpura, cutaneous lupus erythematosus, necrotizing vasculitis.

A symptom complex has been described, including fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive ANA (antinuclear antibodies) titer, elevated ESR (erythrocyte sedimentation rate), eosinophilia, leukocytosis. Skin rashes, photosensitivity, and other skin reactions are also possible.

Musculoskeletal and connective tissue disorders: muscle cramps, arthralgia.

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

Reproductive system and breast disorders: sexual dysfunction, impotence, gynecomastia.

General disorders: asthenia, increased fatigue, chest pain, malaise, weakness, increased body temperature.

Investigations: electrolyte disturbances (including hypokalemia, hyperkalemia, hyponatremia, hypomagnesemia, hypercalcemia), increased liver enzyme activity, increased bilirubin levels, increased serum cholesterol and triglycerides, reversible increase in serum levels of substances excreted by the kidneys (creatinine, urea, uric acid).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk profile of the medicinal product.

Healthcare professionals should report any suspected adverse reactions in accordance with current legislation.

Shelf life. 4 years from the date of manufacture of the bulk product.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

No. 20 (20×1): 20 tablets in a blister, 1 blister per carton.

Prescription category. Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's address and place of business.

100, Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.