Enalozid® 12.5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALOZID® 12.5 (ENALOZID 12.5)

Composition:

Active substances: enalapril, hydrochlorothiazide;

One tablet contains: enalapril maleate, recalculated to 100% substance – 10 mg, hydrochlorothiazide, recalculated to 100% substance – 12.5 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or white with a creamy shade tablets, with a flat surface, beveled edge, with or without a score line.

Pharmacotherapeutic group. Combined preparations of ACE inhibitors. Enalapril and diuretics. ATC code C09BA02.

Pharmacological properties.

Pharmacodynamics.

The medicinal product is a combination of an angiotensin-converting enzyme 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 levels of angiotensin II, resulting in increased plasma renin activity (due to inhibition 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 effect in the therapeutic actions 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 an antihypertensive effect even in patients with low-renin hypertension.

Hydrochlorothiazide (HCTZ) 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 administration with hydrochlorothiazide in such patients results in a greater reduction in blood pressure. The enalapril component in the preparation generally attenuates the potassium decrease induced by hydrochlorothiazide.

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 absorption of enalapril following oral administration is approximately 60–70%.

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 its 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 serum concentrations of enalaprilat are achieved by the 4th day 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 the gastrointestinal absorption of enalapril. The extent of absorption and hydrolysis of enalapril is similar across different doses within the recommended therapeutic range.

Hydrochlorothiazide

During monitoring of plasma levels 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

Repeated concomitant administration of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to the individual components administered simultaneously.

Clinical characteristics.

Indications.

Treatment of 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 to any other component of the medicinal product.
• 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.
• Contraindicated during hemodialysis.
• Clinical condition following kidney transplantation.
• Severe hepatic impairment.
• Anuria, primary hyperaldosteronism.
• Refractory hypokalemia or hyperkalemia.
• Refractory hyponatremia.
• Symptomatic hyperuricemia (gout).
• Pregnancy or women planning to become pregnant (see "Use in pregnancy or breastfeeding").
• Enalapril must not be used concomitantly with aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²).
• 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").

Interaction with other medicinal products and other forms of interaction.

Enalapril maleate and hydrochlorothiazide

Other antihypertensive agents.

Concomitant use of beta-blockers, methyldopa, or calcium channel blockers may enhance the hypotensive effect of the medicinal product. Concomitant use of nitroglycerin and other nitrates or vasodilators may further reduce blood pressure.

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

Lithium-containing preparations.

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 cyclooxygenase-2 (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 on increasing serum potassium levels and worsening 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. Close monitoring of renal function is required at the beginning of concomitant therapy and periodically during treatment.

Enalapril

Potassium-sparing diuretics and potassium supplements.

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 a significant increase in serum potassium levels. Caution should also be exercised when coadministering Enalozid® 12.5 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, the combination of enalapril with the above-mentioned medicinal products is not recommended. If the above-mentioned agents are indicated due to hypokalemia, they should be used cautiously with regular monitoring of serum potassium levels (see section “Special precautions”).

Medicinal products increasing the risk of angioedema.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections “Contraindications” and “Special precautions”).

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

Co-trimoxazole (trimethoprim/sulfamethoxazole)

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

Cyclosporine.

Hyperkalemia may occur when ACE inhibitors are used concomitantly with 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 reduced intravascular volume and increase the risk of arterial hypotension at the initiation of enalapril therapy (see section “Special precautions”). Hypotensive effects may be minimized by discontinuing the diuretic, increasing salt intake, or initiating treatment with low doses of the medicinal product.

Tricyclic antidepressants/antipsychotics/narcotics.

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

Gold preparations.

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

Sympathomimetics.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Alcohol.

Alcohol enhances the hypotensive effect of ACE inhibitors.

Antidiabetic agents.

Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance glucose-lowering effects with an increased risk of hypoglycemia. This effect is likely to occur during the first weeks of concomitant therapy and in patients with impaired renal function.

Acetylsalicylic acid, thrombolytics, beta-blockers.

Enalapril may be used cautiously concomitantly with acetylsalicylic acid (when used as a thrombolytic agent), thrombolytic agents, and beta-blockers.

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist.

In patients with confirmed atherosclerotic disease, heart failure, or diabetes with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been reported to be associated with higher incidences 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 restricted 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).

Increased sensitivity to the effects of muscle relaxants may occur.

Alcohol, barbiturates, narcotic analgesics.

Potentiation of orthostatic hypotension may occur.

Antidiabetic agents (oral antidiabetics and insulin).

Thiazide therapy may reduce glucose tolerance. Dose adjustments may be required. Metformin should be used with caution due to the risk of lactic acidosis associated with possible renal impairment caused by hydrochlorothiazide.

Cholestyramine and colestipol resins.

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

QT interval-prolonging agents (e.g., procainamide, amiodarone, sotalol).

Increased risk of torsades de pointes tachycardia.

Cardiac glycosides.

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

Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormone, stimulant laxatives, or glycyrrhizin (found in licorice).

Hydrochlorothiazide may potentiate electrolyte imbalance, primarily hypokalemia.

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

Pressor amines (e.g., adrenaline).

Thiazides may reduce the response to pressor amines, but not sufficiently to preclude concomitant use.

Cytoplastic agents (e.g., cyclophosphamide, methotrexate).

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic medicinal products 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.

When high doses of salicylates are used, hydrochlorothiazide may potentiate their toxic effects on the central nervous system.

Methyldopa.

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

Cyclosporine.

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

Anticholinergic agents (e.g., atropine, biperiden).

Increase bioavailability of thiazide diuretics due to reduced gastrointestinal motility and delayed gastric emptying.

Alcohol (ethanol), barbiturates, narcotics, or antidepressants.

May lead to enhanced orthostatic hypotension.

Other antihypertensive agents.

Additive effect.

Cardiac glycosides (digitalis).

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., cardiac glycosides and antiarrhythmic agents), as well as with the following agents (including antiarrhythmics) that may cause torsades de pointes tachycardia, with hypokalemia being a risk factor for its development (ventricular tachycardia):

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

Calcium salts.

Thiazide diuretics may increase serum calcium levels due to reduced calcium excretion. When calcium supplementation is necessary, the dose should be adjusted with monitoring of serum calcium levels.

Effect on laboratory test results.

Due to effects on calcium metabolism, thiazides may influence the assessment of parathyroid gland function (see section “Special precautions”).

Carbamazepine.

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

Iodinated contrast agents.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid >3 g/day, and nonselective NSAIDs.

When used concomitantly, NSAIDs may attenuate the antihypertensive effect of hydrochlorothiazide and enhance its effect on serum potassium levels.

Beta-blockers and diazoxide.

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may enhance 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. Among patients receiving Enalozid® 12.5, arterial hypotension occurs more frequently in patients with disturbances in water-electrolyte balance, for example, due to diuretic therapy, salt restriction, dialysis, diarrhea, or vomiting. In such cases, regular monitoring of serum electrolyte levels is required. 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. Such patients should begin 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, as 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 intravenous 0.9% sodium chloride solution. Transient arterial hypotension during treatment is not a contraindication for continuing therapy, which may be resumed after normalization of blood pressure and restoration of fluid volume.

In some patients with heart failure and normal or reduced blood pressure, the drug may further reduce blood pressure. This reaction should not be considered a reason to discontinue treatment. In cases where arterial hypotension becomes resistant to treatment, the dose should be reduced and/or diuretic therapy and/or Enalozid® 12.5 should be discontinued.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to specific cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with target 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 concomitantly with aliskiren in patients with diabetes mellitus or impaired renal function (eGFR < 60 mL/min/1.73 m²) (see sections "Contraindications" or "Special precautions for use").

Renal function impairment.

Renal function impairment due to enalapril has been reported, particularly in patients with severe heart failure or kidney disease, 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, administration of enalapril together with a diuretic may lead to increased serum urea and creatinine levels. Dose reduction of enalapril and/or discontinuation of the diuretic may be required. In such cases, the possibility of renal artery stenosis should be considered.

Hyperkalemia.

Combination of enalapril with 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 administered simultaneously are similar in elderly patients and younger adults with arterial hypertension.

Use in children.

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

Enalapril.

Aortic or mitral stenosis / hypertrophic cardiomyopathy.

Like all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction or outflow tract obstruction; their use should be avoided in cases of cardiogenic shock and hemodynamically significant obstruction.

Renovascular hypertension.

Patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney who are taking ACE inhibitors have an increased risk of developing arterial hypotension. Even minor changes in serum creatinine levels may worsen renal function. Treatment of these patients should be initiated with low doses, with careful dose titration and monitoring of renal function.

Patients undergoing hemodialysis.

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

Renal transplantation.

There is no experience with the use of Enalozid® 12.5 in patients with recently transplanted kidneys. Therefore, treatment with the drug is not recommended for these patients.

Hepatic function impairment.

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

Neutropenia/agranulocytosis.

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

When using enalapril in these patients, periodic monitoring of leukocyte count is recommended, and the patient should inform the physician about any signs of infection.

Serum potassium.

ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. The effect is usually insignificant in patients with normal renal function. The risk of hyperkalemia is increased in patients with renal insufficiency, impaired renal function, patients aged > 70 years, patients with diabetes mellitus, transient states, particularly dehydration, acute heart decompensation, metabolic acidosis, and with concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of dietary supplements or salt substitutes containing potassium, as well as in patients taking other drugs that may increase serum potassium levels (e.g., heparin, cotrimoxazole, also known as trimethoprim/sulfamethoxazole, and particularly aldosterone antagonists or ARAs). In particular, concomitant use of potassium-sparing diuretics, trimethoprim or cotrimoxazole (also known as trimethoprim/sulfamethoxazole), potassium-containing dietary supplements or salt substitutes in patients with impaired renal function may lead to significant elevation of 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 (see section "Interaction with other medicinal products and other forms of interaction").

Hypoglycemia.

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin require careful glycemic monitoring, especially during the first month of treatment with ACE inhibitors.

Increased sensitivity / angioedema.

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been observed in some patients treated with angiotensin-converting enzyme inhibitors, including Enalozid® 12.5. It may occur at any time during treatment. In such cases, use of Enalozid® 12.5 must be discontinued immediately, and the patient should be placed under continuous observation to ensure complete resolution of symptoms. Even if only tongue swelling is observed without respiratory distress, the patient may require prolonged observation, 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 who have previously experienced angioedema unrelated to ACE inhibitor use may have an increased risk of developing it when using ACE inhibitors.

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., swelling of the airways or tongue, with or without respiratory impairment) (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. Before initiating treatment in patients taking Enalozid® 12.5, a careful benefit-risk assessment should be performed.

Anaphylactoid reactions during desensitization therapy.

Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during allergen desensitization therapy 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 related to 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.

Enalapril may be less effective in lowering blood pressure in patients of non-Caucasian race with hypertension 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, as well as when creatinine clearance is 30 mL/min or lower (i.e., moderate or severe renal insufficiency).

Enalozid® 12.5 tablets should not be prescribed to patients with renal insufficiency (creatinine clearance < 80 mL/min) until titration of individual components of the drug indicates the need for doses present in the combined tablets.

Hepatic function impairment.

Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as even minor deviations 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.

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

Thiazides may reduce calcium excretion in urine and cause periodic slight elevation of serum calcium. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before performing tests for parathyroid function.

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

Although there are no data from controlled clinical trials regarding patients receiving Enalozid® 12.5, as with patients receiving diuretic therapy, serum electrolyte levels should be regularly measured.

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

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

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

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

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

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

Increased sensitivity.

In patients predisposed to allergies or with a history of bronchial asthma, hypersensitivity reactions to hydrochlorothiazide may occur.

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

Non-melanoma skin cancer.

Results of two recent pharmacoepidemiological studies (based on Danish nationwide data sources, including the Danish Cancer Registry and the Danish Register of Prescribed Medications) showed a cumulative dose-dependent association between hydrochlorothiazide use and the occurrence of basal cell carcinoma and squamous cell carcinoma. The photosensitizing effect of hydrochlorothiazide may be the cause of these conditions. Patients taking hydrochlorothiazide alone or in combination with other medicinal products should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions or changes in existing ones and to report any suspicious skin lesions.

Suspicious skin lesions should undergo histological examination by biopsy.

Patients should be advised to limit exposure to sunlight and UV radiation and to use appropriate protection when exposed to sunlight and UV radiation to minimize the risk of skin cancer.

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

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

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

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical interventions 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). Very rare severe cases of acute respiratory toxicity, including ARDS, have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. 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 taking hydrochlorothiazide.

Special warnings regarding excipients.

Enalozid® 12.5 contains lactose. This medicinal product should not be used in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

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

Women planning pregnancy should be informed about the potential harm to the fetus and should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy initiated.

Epidemiological conclusions regarding the risk of teratogenicity after exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a slight increase in risk cannot be excluded. It is known that use of ACE inhibitors 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).

If ACE inhibitors are 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 already occurred.

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

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

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy, particularly during the first trimester, is limited. Data from animal studies are insufficient.

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

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

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

Hydrochlorothiazide is contraindicated during pregnancy.

Breastfeeding

According to some pharmacokinetic data, very low concentrations of the drug pass into breast milk (see section "Pharmacokinetics"). Although such concentrations are considered clinically insignificant, use of the drug is not recommended during breastfeeding of newborns due to the hypothetical risk of cardiovascular and renal effects, as well as insufficient experience with such use. If use is absolutely necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving vehicles or operating machinery.

When driving vehicles or operating machinery, caution should be exercised and the possibility of adverse reactions of the nervous system, including dizziness or drowsiness, should be taken into account.

Dosage and Administration

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 (with creatinine clearance of 30 mL/min or less), thiazides may be insufficiently effective.

If creatinine levels are in the range of >30 to <80 mL/min, Enalozid® 12.5 should be administered only after prior dose determination of each component.

The recommended initial dose of enalapril maleate 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 starting therapy with Enalozid® 12.5 to avoid a sudden drop in blood pressure. Symptomatic arterial hypotension may occur at the beginning of Enalozid® 12.5 therapy and is more commonly observed in patients in whom prior diuretic therapy has caused disturbances in water-electrolyte balance.

Children. Safety and efficacy of the drug in pediatric patients 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 marked arterial hypotension occurring within 6 hours after drug intake, 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, rapid heartbeat, dizziness, anxiety, and cough. Plasma enalapril levels exceeding 100 and 200 times the maximum levels achieved with therapeutic doses were recorded after ingestion of 300 mg and 440 mg of enalaprilat, respectively. In case of arterial hypotension, administration of angiotensin II and/or intravenous catecholamines may be required.

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

In cases of bradycardia resistant to pharmacological therapy, treatment with a cardiac pacemaker is indicated.

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

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

Adverse Reactions

The most commonly reported adverse reactions were dizziness and increased fatigue, which usually resolved upon dose reduction and rarely required discontinuation of the medicinal product.

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

The following adverse reactions have been reported, particularly during use of enalapril or hydrochlorothiazide alone, during clinical trials, or following marketing of the product.

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, somnolence, 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.

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

Kidneys and urinary tract: impaired renal function, renal failure, proteinuria.

Reproductive system: decreased libido.

Metabolic disorders: gout.

Ears and vestibular system: tinnitus.

Other: a symptom complex that may include fever, serositis, vasculitis, myalgia/myositis, and arthralgia/arthritis; positive antinuclear antibody (ANA) test, increased erythrocyte sedimentation rate (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 angiotensin-converting enzyme (ACE) inhibitors, including enalapril.

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

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

Additional adverse reactions observed with individual components of the drug, which may represent potential adverse effects of Enalozid® 12.5

Enalapril.

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

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

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

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

Cardiovascular system: cardiac rhythm disturbances, 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, erythema multiforme, exfoliative dermatitis, pemphigus.

Blood 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 (SIADH), 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 precipitate hepatic encephalopathy or hepatic coma), hyperuricemia (which may trigger gout attacks in patients with asymptomatic disease), hypoglycemia, reduced glucose tolerance (which may lead to manifestation of latent diabetes mellitus).

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

Immune system: anaphylactic reaction, urticaria.

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

Eyes: xanthopsia, transient visual disturbances, choroidal effusion (frequency unknown).

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

Respiratory tract, mediastinum and thoracic cavity: acute respiratory distress syndrome (ARDS) (see section "Special precautions").

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

Laboratory test changes: electrolyte imbalance (including hyponatremia).

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

Benign, malignant and unspecified neoplasms (including cysts and polyps).

Frequency "unknown": non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Description of selected adverse reactions

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: 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 per carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer’s address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.