INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALOZID® 25 (ENALOZID 25)

Composition:

Active substances: enalapril maleate, hydrochlorothiazide;

One tablet contains, recalculated to 100% substance: enalapril maleate 10 mg, hydrochlorothiazide 25 mg;

Excipients: lactose monohydrate, potato starch, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets from white to yellowish-white in color, with a flat surface, beveled edges, and a score line.

Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors and diuretics.

ATC code C09B A02.

Pharmacological properties.

Pharmacodynamics.

Enalozid® 25 is a combination of an angiotensin-converting enzyme (ACE) inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to suppression of the negative feedback mechanism on renin release) and reduced aldosterone secretion.

ACE is identical to kininase II. Enalapril may also block the degradation of bradykinin, a potent vasodilator peptide. However, the role of this mechanism in the therapeutic effects of enalapril remains unknown. While the mechanism by which enalapril lowers blood pressure is primarily attributed to inhibition of the renin-angiotensin-aldosterone system, which plays a key role in blood pressure regulation, enalapril may exert antihypertensive effects even in patients with low-renin hypertension.

Hydrochlorothiazide is a diuretic and antihypertensive agent that increases plasma renin activity. The antihypertensive effects of the two components are additive and typically last for 24 hours. Although enalapril alone exerts a hypotensive effect even in patients with low-renin hypertension, concomitant use with hydrochlorothiazide in such patients results in greater blood pressure reduction. The enalapril component of the drug generally attenuates the potassium-lowering effect caused by hydrochlorothiazide.

Non-melanoma skin cancer (NMSC)

Epidemiological data have shown a cumulative dose-dependent association between hydrochlorothiazide use and the development of NMSC. One study included a group of 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,426 individuals in the respective control groups. High cumulative doses of hydrochlorothiazide (≥ 50,000 mg) were associated with an adjusted OR of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study suggested an association between lip cancer (SCC) and hydrochlorothiazide exposure: 633 cases of lip cancer were compared with 63,067 individuals from the control population using a random sampling strategy. A cumulative dose-response relationship was demonstrated, with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high doses (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see section "Special precautions").

Pharmacokinetics.

Enalapril maleate. After oral administration, enalapril is rapidly absorbed, reaching peak serum concentrations within 1 hour. Based on urinary excretion data, the extent of enalapril absorption after oral administration is approximately 60%.

After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent inhibitor of angiotensin-converting enzyme. Peak serum concentrations of enalaprilat are reached 3–4 hours after oral administration of enalapril maleate. Enalapril is primarily eliminated by the kidneys. The main components in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril. Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The serum concentration profile of enalaprilat is characterized by a prolonged terminal phase, likely due to binding to ACE. In individuals with normal renal function, steady-state concentrations of enalaprilat are achieved by day 4 of oral enalapril administration. The effective accumulation half-life of enalaprilat after multiple oral doses of enalapril is 11 hours. Food intake does not affect enalapril absorption in the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril is similar across different doses within the recommended therapeutic range.

Hydrochlorothiazide. During plasma level monitoring for at least 24 hours, the plasma elimination half-life ranged from 5.6 to 14.8 hours. Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. After oral administration, at least 61% of the dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.

Enalapril/hydrochlorothiazide. Concomitant multiple dosing of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of these drugs. The combination tablet is bioequivalent to the individual components administered simultaneously.

Renal impairment

In patients with renal impairment, exposure to enalapril and enalaprilat is increased. In patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), the steady-state AUC of enalaprilat was approximately twice higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), the AUC increased approximately 8-fold. At these levels of renal impairment, the effective elimination half-life of enalaprilat is prolonged, and the time to reach steady-state is delayed.

Enalaprilat can be removed from systemic circulation by hemodialysis. The dialysis clearance of enalaprilat is 62 mL/min.

Clinical characteristics.

Indications.

Treatment of arterial hypertension in patients for whom combination therapy is indicated.

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.
Severe renal impairment (creatinine clearance ≤ 30 mL/min).
Refractory hypokalemia.
Symptomatic hyperuricemia (gout).
Anuria.
Angioedema associated with previous administration of ACE inhibitors, in medical history.
Hereditary or idiopathic angioedema.
Hypersensitivity to drugs which are sulfonamide derivatives.
Pregnancy or women who are planning to become pregnant (see "Use in pregnancy or lactation").
Severe hepatic impairment.
Concomitant use of Enalosid® 25 with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant use with sacubitril/valsartan therapy. The medicinal product must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse events (hypotension, hyperkalemia, and worsening of renal function, including acute renal failure) compared to use of a single RAAS-acting agent (see sections "Contraindications" and "Special precautions for use").

Other antihypertensive agents. Concomitant use of these agents may enhance the hypotensive effect of enalapril and hydrochlorothiazide. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may further reduce blood pressure.

Lithium. Reversible increases in serum lithium concentration and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may additionally increase lithium levels and increase the risk of lithium toxicity when an ACE inhibitor is administered. Concomitant use of Enalosid® 25 with lithium-containing medicinal products is not recommended; however, if such a combination is necessary, serum lithium levels should be closely monitored (see section "Special precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may attenuate the antihypertensive effects of ACE inhibitors, diuretics, and/or other antihypertensive agents. For this reason, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors, or diuretics may be diminished when NSAIDs, including selective COX-2 inhibitors, are administered.

Concomitant use of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors may additionally increase serum potassium levels and may lead to renal dysfunction. These effects are usually reversible. Rarely, renal failure may develop, particularly in patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those receiving diuretic therapy). Therefore, such combination therapy should be used with caution in patients with impaired renal function.

Enalapril maleate

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving enalapril therapy. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. Caution should also be exercised when Enalosid® 25 is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic, similar to amiloride. Therefore, combination of enalapril with the above-mentioned medicinal products is not recommended. If concomitant use of such agents is indicated due to hypokalemia, treatment should be administered with caution and serum potassium levels should be frequently monitored (see section "Special precautions for use").

MEDICINAL PRODUCTS THAT INCREASE THE RISK OF ANGIOEDEMA.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema (see sections "Contraindications" and "Special precautions for use").

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

Co-trimoxazole (trimethoprim/sulfamethoxazole)

In patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly, the risk of developing hyperkalemia is increased (see section "Special precautions for use").

Cyclosporine. Hyperkalemia may occur with concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin

Hyperkalemia may occur with concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.

Diuretics (thiazide or loop diuretics). Prior treatment with high-dose diuretics may lead to dehydration and risk of hypotension at the initiation of enalapril therapy. The hypotensive effect may be attenuated by discontinuing the diuretic, increasing fluid volume, or increasing salt intake.

Tricyclic antidepressants/neuroleptics/anesthetics. Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may lead to additional reduction in blood pressure (see section "Special precautions for use").

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

Antidiabetic agents. Results from epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may lead to reduced blood glucose levels with a risk of hypoglycemia. This effect is likely to occur during the first weeks of concomitant therapy and in patients with impaired renal function (see section "Special precautions for use").

Alcohol. Alcohol potentiates the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytic agents, and β-blockers. Enalapril may be used with caution concomitantly with acetylsalicylic acid (in cardiologic doses), thrombolytic agents, and β-adrenoblockers.

Gold preparations. Nitritoid reactions (facial flushing, nausea, vomiting, and arterial hypotension) have been reported in patients receiving injectable gold preparations (sodium aurothiomalate) concomitantly with an ACE inhibitor, including enalapril.

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist. 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 arterial hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to therapy with a single renin-angiotensin-aldosterone system (RAAS)-acting agent. Dual blockade (e.g., combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases and accompanied by careful monitoring of renal function, potassium levels, and blood pressure.

Hydrochlorothiazide

Non-depolarizing muscle relaxants. Thiazides may enhance sensitivity to tubocurarine.

Alcohol, barbiturates, or narcotic analgesics. May potentiate the development of orthostatic hypotension.

Antidiabetic agents (oral agents and insulin). Dose adjustment of antidiabetic agents may be necessary (see "Special precautions for use").

Cholestyramine and colestipol resins. Absorption of hydrochlorothiazide is reduced in the presence of anion-exchange resins. A single dose of cholestyramine or colestipol resin binds hydrochlorothiazide and reduces its absorption from the gastrointestinal tract by 85% and 43%, respectively.

Prolongation of QT interval (quinidine, procainamide, amiodarone, sotalol). Increased risk of ventricular tachyarrhythmias.

Digitalis glycosides. Hypokalemia may activate or exacerbate cardiac reactions to the toxic effects of digitalis (e.g., increased ventricular excitability).

Corticosteroids, ACTH. Exacerbates electrolyte imbalance, particularly hypokalemia.

Potassium-wasting diuretics (e.g., furosemide), carbenoxolone, or laxative abuse. Hydrochlorothiazide may increase potassium and/or magnesium losses.

Pressor amines (e.g., adrenaline). The effect of pressor amines may be reduced (see section "Interaction with other medicinal products and other forms of interaction").

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

Special precautions for use.

Enalapril maleate and hydrochlorothiazide

Hypotension and electrolyte/water imbalance. Symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. Symptomatic hypotension occurs more frequently in patients with disturbances in fluid balance who are receiving Enalozid® 25, for example, due to diuretic therapy, a low-salt diet, diarrhea, or vomiting. Such patients require regular periodic monitoring of serum electrolyte levels. Particular attention should be paid to the treatment of patients with ischemic heart disease or cerebrovascular disorders, as a significant reduction in arterial pressure may lead to myocardial infarction or stroke.

Symptomatic hypotension has been observed in patients with arterial hypertension and heart failure, with or without renal insufficiency.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of sodium chloride physiological solution. Transient hypotension is not a contraindication for further use of the drug. If, after normalization of circulating blood volume, arterial pressure increases, therapy may be resumed at usual doses.

Renal function impairment. Enalozid® 25 should not be prescribed to patients with impaired renal function (creatinine clearance ˂80 ml/min ˃30 ml/min) until titration of the individual components of the drug reaches the dosage of this medicinal form.

During enalapril therapy combined with diuretics, some patients with arterial hypertension but no signs of kidney disease prior to treatment developed increased blood urea and creatinine levels. In such cases, treatment with Enalozid® 25 should be discontinued, and the possibility of renal artery stenosis should be considered.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). In patients receiving concomitant angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or aliskiren, the risk of developing arterial hypotension, hyperkalemia, and renal function impairment (including acute renal failure) increases. Therefore, dual blockade of the RAAS (concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren) is not recommended (see "Interaction with other medicinal products and other forms of interaction"). If dual blockade is considered absolutely necessary, it should be performed under physician supervision with careful regular monitoring of renal function, fluid-electrolyte balance, and arterial pressure. Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

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

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

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist. Combination of an ACE inhibitor with an angiotensin receptor antagonist should be limited to individually determined cases under careful monitoring of renal function, potassium levels, and arterial pressure (see section "Interaction with other medicinal products and other forms of interaction").

Enalapril maleate

Aortic stenosis/hypertrophic cardiomyopathy. ACE inhibitors (like all other vasodilators) should be used with caution in patients with left ventricular outflow tract obstruction. ACE inhibitors should be avoided in cases of cardiogenic shock and hemodynamically significant obstruction.

Renal failure. Cases of renal failure associated with enalapril use have been reported, primarily in patients with severe heart failure or underlying kidney disease, including renal artery stenosis. With timely diagnosis and appropriate treatment, enalapril-associated renal failure is usually reversible (see "Method of administration and dosage").

Renovascular hypertension. In patients treated with ACE inhibitors who have bilateral renal artery stenosis or stenosis of the artery of a single kidney, there is an increased risk of hypotension and renal function impairment. Renal function impairment may occur even with minor changes in serum creatinine levels. In such patients, treatment should be initiated at low doses under medical supervision, with cautious dose escalation and monitoring of renal function.

Patients undergoing hemodialysis. Enalapril is contraindicated in patients requiring dialysis due to renal failure. Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux membranes (such as AN 69®) while receiving concomitant ACE inhibitor therapy. For these patients, alternative dialysis membranes or antihypertensive drugs from other classes should be used.

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

Hepatic insufficiency. Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant necrotic hepatitis, sometimes with fatal outcomes. The mechanism of this syndrome is unknown. Patients receiving ACE inhibitors who develop jaundice or a significant increase in liver enzymes should discontinue the ACE inhibitor and receive appropriate medical supervision.

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 without other complicating factors. Enalapril should be prescribed with extreme caution to patients with collagen vascular diseases undergoing immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if renal function impairment already exists. Some patients developed severe infections that, in some cases, did not respond to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended when prescribing enalapril to such patients, and patients should be instructed to report any signs of infection.

Serum potassium. ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. This effect is usually mild in patients with normal renal function. Risk factors for hyperkalemia include renal failure, diabetes mellitus, patients over 70 years of age, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), dietary supplements or salt substitutes containing potassium, and use of other drugs associated with increased serum potassium levels (e.g., heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, particularly aldosterone antagonists or ARAs). Use of potassium supplements, potassium-sparing diuretics, trimethoprim or co-trimoxazole (also known as trimethoprim/sulfamethoxazole), and potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium levels. Hyperkalemia may cause serious and even fatal arrhythmias.

If concomitant use of Enalozid® 25 and the above-mentioned agents is considered necessary, they should be used with caution and under frequent monitoring of serum potassium levels.

Hypoglycemia. Patients with diabetes mellitus who are taking oral antidiabetic agents or insulin and start taking an ACE inhibitor should be advised to carefully monitor their blood glucose levels, especially during the first month of combination therapy (see section "Interaction with other medicinal products and other forms of interaction").

Hypersensitivity/angioedema. Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported during treatment with ACE inhibitors, including enalapril maleate. In such cases, treatment with the drug should be immediately discontinued and careful monitoring of the patient's condition should be initiated to control clinical symptoms. Even in cases where only tongue swelling is observed without respiratory distress, prolonged monitoring of the patient is required, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal cases of angioedema associated with laryngeal or tongue swelling have been reported very rarely. In patients with swelling of the tongue, glottis, or larynx, airway obstruction may occur, especially in patients with a history of surgical treatment of the airways.

In cases where swelling is localized in the tongue, glottis, or larynx and may lead to airway obstruction, subcutaneous injection of 1:1000 adrenaline solution (0.3–0.5 ml) should be administered immediately, and other appropriate therapeutic measures should be taken.

Patients who previously experienced angioedema unrelated to ACE inhibitor use may be more prone to developing angioedema during ACE inhibitor therapy.

Angioedema occurs more frequently in patients of African descent receiving ACE inhibitors compared to patients of European descent. However, overall, it is considered that patients of African descent have an increased risk of developing angioedema.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Treatment with sacubitril/valsartan may be initiated only 36 hours after the last dose of enalapril. Treatment with enalapril may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction").

Racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin should be prescribed with caution to patients already taking an ACE inhibitor. A thorough benefit-risk assessment should be performed before initiating treatment in patients taking Enalozid® 25.

Anaphylactoid reactions during desensitization with hymenoptera venom.

Severe anaphylactoid reactions have been reported rarely in patients receiving ACE inhibitors during desensitization with hymenoptera venom allergens. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting desensitization.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis session.

Cough. Cases of cough have been observed during ACE inhibitor therapy. The cough is usually non-productive and persistent and resolves after discontinuation of the drug. Cough induced by ACE inhibitors should be considered in the differential diagnosis of cough.

Surgery/anesthesia. During major surgical procedures or anesthesia with agents causing hypotension, enalaprilat blocks the formation of angiotensin II secondary to compensatory renin release. If hypotension occurs due to this mechanism, it can be corrected by increasing fluid volume.

Pregnancy

ACE inhibitors should not be initiated during pregnancy. If continued therapy with ACE inhibitors is not considered essential, women planning pregnancy should be switched to alternative antihypertensive therapy with a safety profile established for use during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately, and alternative therapy should be initiated if possible.

Ethnic differences. As with other ACE inhibitors, enalapril is less effective in lowering blood pressure in patients of African descent compared to patients of other races. This may be explained by the higher prevalence of low-renin activity systems among hypertensive patients of African descent.

Hydrochlorothiazide

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

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

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

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

Thiazides may reduce calcium excretion in urine and cause occasional slight increases in serum calcium.

Marked hypercalcemia may be a manifestation of occult hyperparathyroidism. Thiazide use should be discontinued before testing parathyroid function.

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

Patients receiving diuretic therapy should have their serum electrolyte levels measured regularly at appropriate intervals.

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

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

In hot weather, hyponatremia 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.

Hypersensitivity

Hypersensitivity reactions may occur in patients taking thiazides, with or without a history of allergy or bronchial asthma. Cases of exacerbation or reactivation of systemic lupus erythematosus have been reported.

Special warnings regarding inactive components of the drug. This drug should not be used in patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

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

Medicinal products 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 several hours or weeks after starting the drug.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, medical or surgical intervention may be necessary. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Acute respiratory toxicity

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

Non-melanoma skin cancer

According to two epidemiological studies included in the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), has been associated with cumulative exposure to high doses of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC. They should be advised to regularly check their skin for new lesions and immediately report any suspicious skin changes. Preventive measures, such as limiting exposure to sunlight and ultraviolet radiation and using appropriate protective measures, are recommended to minimize the risk of skin cancer. Suspicious skin lesions should be promptly investigated, including histological examination by biopsy. The continued appropriateness of hydrochlorothiazide use should also be re-evaluated in patients with a history of NMSC (see section "Adverse reactions").

Use during pregnancy or breastfeeding.

Enalozid® 25 should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use should be immediately discontinued and replaced with another medicinal product approved for use during pregnancy.

Breastfeeding.

Enalapril and thiazide diuretics pass into breast milk. Use of Enalozid® 25 during breastfeeding is not recommended.

Ability to affect reaction speed when driving or operating machinery.

Some of the adverse effects listed in the "Adverse reactions" section may affect the ability to drive or operate machinery.

Method of Administration and Dosage

For arterial hypertension.

The initial dose of the drug is 1 tablet once daily. If the desired effect is not achieved, the daily dose may be increased to 2 tablets once daily. The maximum dose is 2 tablets per day.

For renal impairment.

In patients with impaired kidney function, including moderate to severe renal insufficiency (creatinine clearance of 30 mL/min or less), thiazides may be insufficiently effective.

If creatinine clearance is in the range of >30 to <80 mL/min, Enalozid® 25 should be administered only after prior dose determination of each component.

The recommended initial dose of enalapril maleate when used separately in mild renal impairment is 5 to 10 mg.

Prior diuretic therapy.

If a patient is already receiving diuretics, it is recommended to discontinue or reduce the diuretic dose at least 2–3 days before initiating therapy with Enalozid® 25 to avoid a sudden drop in arterial pressure. Symptomatic arterial hypotension may occur at the beginning of Enalozid® 25 therapy and is more commonly observed in patients whose prior diuretic therapy has caused disturbances in water-electrolyte balance.

Children.

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

Overdose.

Treatment – symptomatic and supportive. Administration of the drug should be discontinued and the patient should be thoroughly examined.

In case of accidental overdose, if the drug was taken recently, it is necessary to perform gastric lavage, induce vomiting, administer activated charcoal and laxatives, and correct fluid and electrolyte imbalances and arterial hypotension using standard measures.

Enalapril maleate. Symptoms of enalapril overdose include marked arterial hypotension, which begins approximately 6 hours after drug intake and is associated with blockade of the renin-angiotensin system and stupor.

Symptoms related to overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Plasma enalaprilat levels up to 100 and 200 times higher than maximum therapeutic levels have been recorded after ingestion of 300 mg and 440 mg of enalapril maleate, respectively.

For the treatment of overdose, intravenous administration of physiological saline is recommended.

If arterial hypotension occurs, the patient should be placed in a supine position with legs elevated. If necessary, infusion of angiotensin II and/or intravenous administration of catecholamines may be considered. If the drug was taken recently, measures should be taken to remove enalapril maleate from the body (induction of vomiting, gastric lavage, use of adsorbents and sodium sulfate). Enalapril can be removed from systemic circulation by hemodialysis. In cases of bradycardia resistant to treatment, cardiac pacing is indicated. Vital signs, serum electrolyte levels, and serum creatinine should be continuously monitored.

Hydrochlorothiazide. The most commonly observed symptoms are those caused by electrolyte loss (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis.

When digoxin-containing drugs are taken concomitantly, hypokalemia may exacerbate arrhythmias.

Adverse Reactions

Infections and infestations: sialadenitis.

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

Immune system disorders: anaphylactic reactions.

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolic and nutritional disorders: hypokalemia, gout, fluid and electrolyte imbalance (including hyponatremia), increased blood cholesterol and triglycerides, hypoglycemia, hyperuricemia, hypomagnesemia, hyperglycemia, hypercalcemia.

Nervous system disorders/psychiatric disorders: headache, depression, syncope, taste disturbances, insomnia, nervousness, restlessness, somnolence, paresthesia, vertigo, confusion, abnormal dreams, sleep disorders, paresis (due to hypokalemia), decreased libido.

Eye disorders: loss of visual acuity, transient loss of visual acuity, xanthopsia, choroidal effusion (frequency unknown).

Ear and labyrinth disorders: tinnitus.

Cardiac disorders: dizziness, hypotension, orthostatic hypotension, tachycardia, palpitations, arrhythmia, angina pectoris, Raynaud's syndrome, flushing, myocardial infarction/stroke (possibly due to excessive hypotension in high-risk patients).

Respiratory, thoracic and mediastinal disorders: sore throat and hoarseness, rhinitis, rhinorrhea, cough, dyspnea, pulmonary infiltrates, allergic alveolitis/eosinophilic pneumonia, bronchospasm, asthma, respiratory distress (including pneumonitis and pulmonary edema), acute respiratory distress syndrome (ARDS) (see section "Special precautions for use").

Gastrointestinal disorders: anorexia, dry mouth, stomatitis/aphthous ulcers, glossitis, nausea, vomiting, pancreatitis, diarrhea, dyspepsia, abdominal pain, flatulence, constipation, angioneurotic intestinal edema, ileus, gastric irritation, peptic ulcers.

Hepatobiliary disorders: liver failure, hepatic necrosis (may be fatal), hepatitis (hepatocellular or cholestatic), jaundice, cholecystitis (particularly in patients with pre-existing gallstone disease).

Skin and subcutaneous tissue disorders: rash (exanthema), hypersensitivity, angioedema, including angioedema of the face, extremities, lips, tongue, glottis and/or larynx, purpura, diaphoresis, pruritus, alopecia, urticaria, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, cutaneous lupus erythematosus, erythroderma, bullous eruption, toxic epidermal necrolysis, exfoliative dermatitis. A syndrome complex has been reported that may include several or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody (ANA) test, elevated ESR, eosinophilia, leukocytosis. Skin rash, photosensitivity, or other dermatological reactions may occur.

Benign, malignant and unspecified neoplasms (including cysts and polyps)1: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)1.

Musculoskeletal and connective tissue disorders: muscle cramps, muscle spasms, arthralgia.

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

Reproductive system and breast disorders: gynecomastia, impotence.

Investigations: hyperkalemia, hyponatremia, increased blood urea nitrogen (BUN), increased serum creatinine, increased liver enzymes and/or serum bilirubin.

General disorders and administration site conditions: asthenia, chest pain, fever, increased fatigue, discomfort.

1 Non-melanoma skin cancer: epidemiological data indicate an association between cumulative hydrochlorothiazide dose and NMSC (see section "Special precautions for use" and "Pharmacological properties").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister. 2 or 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address of the place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.