Enalozid® mono

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

Composition:

Active substance: enalapril;

1 tablet contains enalapril maleate equivalent to 100% dry substance 5 mg or 10 mg;

Excipients: sodium hydrogencarbonate, lactose monohydrate, maize starch, pregelatinized starch, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets of white or almost white color, with a flat surface, beveled edges, and a score line.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors, single-component. ATC code C09A A02.

Pharmacological Properties.

Pharmacodynamics.

Enalozid® Mono (enalapril maleate) is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline.

Mechanism of action

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to 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 of angiotensin II on renin release) and reduced aldosterone secretion.

ACE is identical to kininase II. Thus, enalapril maleate may also block the breakdown of bradykinin, a potent vasodilator peptide.

The mechanism by which enalapril maleate lowers blood pressure is primarily related to inhibition of the renin-angiotensin-aldosterone system (RAAS); enalapril maleate may exert antihypertensive effects even in patients with low-renin hypertension.

Administration of Enalozid® Mono in arterial hypertension results in reduced blood pressure in patients both in supine and upright positions, without a significant increase in heart rate.

Symptomatic postural hypotension occurs infrequently. In some patients, optimal blood pressure reduction may require several weeks of therapy. Sudden discontinuation of enalapril maleate is not associated with rapid increases in blood pressure.

Effective inhibition of ACE activity is usually achieved within 2–4 hours after a single oral dose of enalapril. The onset of antihypertensive activity is typically observed within 1 hour, and peak blood pressure reduction occurs 4–6 hours after administration. The duration of effect is dose-dependent. However, when used at recommended doses, antihypertensive and hemodynamic effects persist for at least 24 hours.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by decreased peripheral arterial resistance, increased cardiac output, and either slight or no tachycardia. After administration of enalapril maleate, renal blood flow increases; glomerular filtration rate usually remains unchanged. Signs of sodium or water retention were not observed. However, in patients with low baseline glomerular filtration rates, these values increased.

In studies of patients with or without diabetes and kidney disease, administration of enalapril resulted in reduced albuminuria, urinary excretion of IgG, and total urinary protein.

When used concomitantly with thiazide diuretics, the antihypertensive effects of enalapril maleate are at least additive. Enalapril maleate may reduce or prevent the development of thiazide-induced hypokalemia.

In patients with heart failure receiving cardiac glycosides and diuretics, administration of oral or injectable enalapril maleate was associated with reduced peripheral resistance and blood pressure. Cardiac output increased, and heart rate (usually elevated in patients with heart failure) decreased. Pulmonary capillary wedge pressure also decreased. Exercise tolerance improved, and severity of heart failure, assessed by NYHA (New York Heart Association) criteria, was reduced. These effects were sustained during long-term treatment.

In patients with mild to moderate heart failure, enalapril slowed the progression of myocardial dilation and heart failure, as evidenced by reduced left ventricular end-diastolic and end-systolic volumes and improved ejection fraction.

In a multicenter, randomized, double-blind, placebo-controlled trial (SOLVD Prevention), a population with asymptomatic left ventricular dysfunction (left ventricular ejection fraction < 35%) was studied. A total of 4228 patients were randomized to receive placebo (n=2117) or enalapril (n=2111). In the placebo group, heart failure or death occurred in 818 patients (38.6%) compared to 630 patients (29.8%) in the enalapril group (a 29% risk reduction, 95% CI, 21–36%, p < 0.001). Hospitalization due to onset or worsening of heart failure or death occurred in 518 patients (24.5%) in the placebo group and 434 patients (20.6%) in the enalapril group (a 20% risk reduction, 95% CI, 9–30%, p < 0.001). In another multicenter, randomized, double-blind, placebo-controlled trial (SOLVD Treatment), a population with symptomatic congestive heart failure due to systolic dysfunction (ejection fraction < 35%) was studied. A total of 2569 patients receiving standard heart failure therapy were randomized to placebo (n=1284) or enalapril (n=1285). There were 510 deaths (39.7%) in the placebo group compared to 452 (35.2%) in the enalapril group (a 16% risk reduction, 95% CI, 5–26%, p=0.0036). Cardiovascular deaths were 461 in the placebo group versus 399 in the enalapril group (an 18% risk reduction, 95% CI, 6–28%, p < 0.002), primarily due to reduced mortality from progressive heart failure (251 in placebo vs. 209 in enalapril, a 22% risk reduction, 95% CI, 6–35%). Fewer patients died or were hospitalized due to worsening heart failure (736 in placebo vs. 613 in enalapril, a 26% risk reduction, 95% CI, 18–34%, p < 0.0001). Overall, in the SOLVD trials, the drug reduced the risk of myocardial infarction by 23% (95% CI, 11–34%, p < 0.001) and reduced the risk of hospitalization due to unstable angina by 20% (95% CI, 9–29%, p < 0.001).

Clinical pharmacology in children

Experience with the use of the drug in children aged 6 years and older with arterial hypertension is limited. In a clinical study involving 110 children aged 6 to 16 years with arterial hypertension, body weight ≥ 20 kg, and glomerular filtration rate > 30 mL/min/1.73 m², patients with body weight < 50 kg received 0.625 mg, 2.5 mg, or 20 mg of enalapril daily, while patients with body weight ≥ 50 kg received 1.25 mg, 5 mg, or 40 mg of enalapril daily. Once-daily administration of enalapril reduced diastolic blood pressure in a dose-dependent manner.

The dose-dependent antihypertensive effect of enalapril was consistent across all subgroups (age, Tanner stage, sex, race). However, the lowest studied doses (0.625 mg and 1.25 mg), corresponding on average to 0.02 mg/kg once daily, did not provide sustained antihypertensive effects. The maximum studied dose was 0.58 mg/kg (up to 40 mg) once daily. The adverse reaction profile in children was similar to that in adult patients.

Pharmacokinetics.

Absorption. After oral administration, enalapril is rapidly absorbed, with peak serum concentrations reached within 1 hour. The extent of absorption of enalapril from tablets is approximately 60%. The presence of food in the gastrointestinal tract does not affect the absorption of oral enalapril. After absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat occur approximately 4 hours after oral administration of enalapril.

The effective half-life (T½) of enalaprilat after multiple oral doses is 11 hours.

Distribution. Across the entire therapeutic concentration range, no more than 60% of enalaprilat is bound to serum proteins.

Metabolism. Apart from conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.

Elimination. Enalaprilat is primarily eliminated by the kidneys. The main components in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril (approximately 20%).

Renal impairment. In patients with renal impairment, exposure to enalapril and enalaprilat is increased. In patients with mild to moderate renal dysfunction (creatinine clearance 40–60 mL/min), the steady-state area under the concentration-time curve (AUC) of enalaprilat is approximately twice that in patients with normal renal function after a 5 mg once-daily dose. In severe renal impairment (creatinine clearance ≤30 mL/min), AUC increases approximately 8-fold. At these levels of renal impairment, the effective half-life of enalaprilat is prolonged, and time to steady state is delayed.

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

Clinical characteristics.

Indications.

• Treatment of arterial hypertension.
• Treatment of clinically manifest heart failure.
• Prevention of clinically manifest heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction ≤ 35%).

Contraindications.

• Hypersensitivity to enalapril, to any excipient of the medicinal product, or to any other angiotensin-converting enzyme (ACE) inhibitor.

• History of angioedema associated with previous use of ACE inhibitors.

• Hereditary or idiopathic angioedema.

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

Enalozid® Mono must not be used in combination with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²).

The medicinal product must not be used in combination with neprilysin inhibitors (e.g., sacubitril). Enalozid® Mono must not be administered within 36 hours before or after treatment with sacubitril/valsartan, a product containing a neprilysin inhibitor (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Interaction with other medicinal products and other forms of interaction.

Antihypertensive therapy

Concomitant use of these agents may enhance the hypotensive effect of enalapril. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may additionally reduce blood pressure.

Potassium-sparing diuretics or potassium supplements or other agents that may increase serum potassium levels

ACE inhibitors reduce diuretic-induced potassium loss. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements or salt substitutes, or other agents that may increase serum potassium levels (e.g., trimethoprim-containing products), particularly in patients with renal impairment, may lead to significant increases in serum potassium levels. If use of the above-mentioned medicinal products is indicated due to hypokalemia, they should be used with caution and serum potassium levels should be monitored regularly (see section "Special warnings and precautions for use").

Diuretics (thiazide or loop diuretics)

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

Antidiabetic agents

Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may lead to reduced blood glucose levels and risk of hypoglycemia, most likely during the first weeks of concomitant therapy and in patients with renal impairment (see sections "Special warnings and precautions for use" and "Undesirable effects").

Serum lithium

Increases in serum lithium levels and lithium toxicity have been reported during concomitant use of ACE inhibitors and lithium. Concomitant use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and increase the risk of lithium intoxication. Concomitant use of enalapril with lithium is not recommended; however, if such a combination is necessary for a patient, careful monitoring of serum lithium levels is required (see section "Special warnings and precautions for use").

Tricyclic antidepressants/neuroleptics/anesthetics/sedatives

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

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors

NSAIDs, including selective COX-2 inhibitors, may reduce the effect of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs, including COX-2 inhibitors.

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors may have an additive effect on increasing serum potassium and may cause renal dysfunction. These effects are usually reversible.

Acute renal failure has been reported rarely, particularly in certain patients with renal impairment (e.g., elderly patients or patients with reduced blood volume, including those taking diuretics). Therefore, such combination therapy should be initiated with caution in patients with renal impairment. Patients should maintain adequate fluid intake and undergo close monitoring of renal function at the start of concomitant therapy and periodically during treatment.

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 restricted to selected cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Clinical trials have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with higher rates of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single RAAS-acting agent.

Enalozid® Mono must not be used in combination with aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Contraindications" and "Special warnings and precautions for use").

Gold preparations

Nitritoid reactions (symptoms including facial swelling, nausea, vomiting, and hypotension) have been reported rarely in patients receiving injectable gold preparations (sodium aurothiomalate) concomitantly with ACE inhibitors, including enalapril.

mTOR inhibitors

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

Neprilysin inhibitors

Concomitant use with neprilysin inhibitors (e.g., sacubitril) may increase the risk of angioedema (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers

Enalapril may be safely administered concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, and β-blockers.

Special precautions for use.

Symptomatic hypotension

Symptomatic hypotension has been observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving enalapril, symptomatic hypotension occurs more frequently in the presence of hypovolemia, which may result, for example, from diuretic therapy, salt restriction, in patients undergoing hemodialysis, as well as in patients with diarrhea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). Symptomatic hypotension has also been observed in patients with heart failure, with or without renal insufficiency. Symptomatic hypotension occurs more frequently in patients with more severe forms of heart failure who are receiving higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should begin treatment with Enalozid® Mono under medical supervision. Particular caution is required when adjusting the dose of Enalozid® Mono and/or diuretic. Similarly, careful monitoring is required in patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In the event of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous physiological saline. Transient arterial hypotension during Enalozid® Mono therapy is not a contraindication for continued treatment, which can usually be resumed without complications after blood pressure normalization through fluid volume restoration.

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

Aortic or mitral stenosis/hypertrophic cardiomyopathy

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

Renal function impairment

In patients with impaired renal function (creatinine clearance < 80 mL/min), the initial dose of enalapril should be adjusted according to creatinine clearance (see section "Dosage and administration") and subsequently based on response to treatment. Regular monitoring of serum potassium and creatinine levels is standard medical practice for such patients.

Renal function impairment has been reported with enalapril use, primarily observed in patients with severe heart failure or kidney disease, including renal artery stenosis. Renal impairment associated with enalapril therapy is usually reversible with timely detection and appropriate management.

In some patients with hypertension who had no pre-existing kidney disease, enalapril in combination with diuretics caused slight and transient increases in blood urea nitrogen and serum creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation increases the likelihood of underlying renal artery stenosis (see section "Special precautions for use": Renovascular hypertension).

Renovascular hypertension

There is an increased risk of arterial hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney treated with ACE inhibitors. Loss of renal function may occur even with minimal changes in serum creatinine levels. Such patients should start treatment with low doses under close medical supervision, with careful dose titration and monitoring of renal function.

Kidney transplantation

There is no experience with the use of Enalozid® Mono in patients who have recently undergone kidney transplantation. Therefore, treatment with Enalozid® Mono is not recommended in these patients.

Hepatic impairment

Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome remains unclear. Patients taking ACE inhibitors who develop jaundice or marked elevations in liver enzymes should discontinue the ACE inhibitor and be placed under appropriate medical observation.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other complicating factors. Enalapril should be used with extreme caution in patients with collagen vascular disease receiving immunosuppressive therapy, allopurinol, or procainamide, or in combination with these complicating factors, especially if renal impairment is already present. Serious infections, sometimes unresponsive to intensive antibiotic therapy, have developed in some of these patients. Periodic monitoring of white blood cell counts is recommended when enalapril is prescribed to such patients, and patients should be advised to report any signs of infection.

Increased sensitivity/angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported rarely during ACE inhibitor therapy, including enalapril, occurring at various times during treatment. In such cases, enalapril therapy should be discontinued immediately, and the patient should be placed under continuous observation until complete resolution of symptoms is confirmed. Observation may only be discontinued after this point. Even in cases of tongue swelling without respiratory distress, patients may require prolonged monitoring, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal cases due to laryngeal angioedema or tongue swelling have been reported very rarely. When swelling involves the tongue, glottis, or larynx, especially in patients with a history of airway surgery, airway obstruction may develop. If the tongue, pharynx, or larynx are involved, airway obstruction may occur, and appropriate therapy should be initiated immediately, 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 Black ethnicity receiving ACE inhibitors compared to patients of other ethnicities.

Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").

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

Concomitant use of ACE inhibitors and neprilysin inhibitors may increase the risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Anaphylactoid reactions during allergen desensitization with insect venom

Rarely, anaphylactoid reactions, potentially life-threatening, have occurred in patients receiving ACE inhibitors during allergen desensitization with insect venom. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before desensitization.

Anaphylactoid reactions during LDL apheresis

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

Patients undergoing hemodialysis

In patients undergoing dialysis with high-flux membranes (e.g., AN 69®) and concurrently receiving an ACE inhibitor, anaphylactoid reactions have occasionally occurred. Therefore, for such patients, consideration should be given to using dialysis membranes of a different type or an antihypertensive agent from another class.

Hypoglycemia

Patients with diabetes receiving oral antidiabetic agents or insulin who initiate ACE inhibitor therapy should be advised to monitor blood glucose levels carefully, especially during the first few months of concomitant therapy (see section "Interaction with other medicinal products and other forms of interaction").

Cough

Cough has been reported during ACE inhibitor therapy. The cough is typically non-productive and persistent, and resolves after discontinuation of the drug. Cough due 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 inhibits the formation of angiotensin II secondary to compensatory renin release. If arterial hypotension develops that can be explained by these interaction mechanisms, it should be corrected by increasing fluid volume.

Hyperkalemia

During treatment with ACE inhibitors, including enalapril, elevated serum potassium levels have been observed in some patients. The risk of hyperkalemia is increased in patients with renal insufficiency, impaired renal function, age > 70 years, diabetes mellitus, transient conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of potassium-containing dietary supplements or salt substitutes; and in patients taking other medications that may increase serum potassium (e.g., heparin, trimethoprim-containing preparations). In particular, the use of potassium-sparing diuretics, potassium-containing dietary supplements, or salt substitutes in patients with impaired renal function may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned agents is considered necessary, they should be used with caution and with regular monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Lithium

Combination of lithium and enalapril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant therapy with ACE inhibitor and angiotensin receptor antagonist

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacological properties").

If dual blockade is necessary, therapy should be conducted under specialist supervision with continuous monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy (see section "Interaction with other medicinal products and other forms of interaction").

Lactose

The medicinal product Enalozid® Mono contains lactose and therefore should not be administered to patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Ethnic considerations

Like other angiotensin-converting enzyme inhibitors, enalapril is less effective in reducing blood pressure in patients of Black ethnicity compared to patients of other ethnicities, possibly due to a higher prevalence of low-renin states among hypertensive patients of Black ethnicity.

Children

There is limited experience with the effective and safe use of the medicinal product in children aged 6 years and older with arterial hypertension, but no experience with other indications. There is also limited pharmacokinetic data in children from 2 months of age (see sections "Pharmacological properties" and "Dosage and administration"). Enalozid® Mono is not recommended for the treatment of children for conditions other than arterial hypertension.

Enalozid® Mono is not recommended for use in neonates and children with glomerular filtration rate <30 mL/min/1.73 m² due to lack of data (see section "Dosage and administration").

Pregnancy

The medicinal product should not be used by pregnant women or women planning to become pregnant.

If pregnancy is confirmed, treatment with ACE inhibitors should be discontinued immediately and, if possible, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding.

Pregnancy

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

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

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

Newborns whose mothers received ACE inhibitors should be closely monitored for signs of arterial hypotension (see sections "Contraindications", "Special precautions for use").

Breastfeeding

Limited pharmacokinetic data indicate very low concentrations in breast milk. Although these concentrations are considered clinically insignificant, use of Enalozid® Mono during breastfeeding is not recommended in preterm infants and newborns during the first few weeks after birth due to the risk of cardiovascular and renal effects and insufficient experience with use. In older infants, use of Enalozid® Mono during breastfeeding may be considered if treatment is necessary for the mother, provided the infant is monitored for any adverse effects.

Ability to affect reaction speed when driving or operating machinery.

When driving or operating machinery, it should be noted that dizziness or fatigue may occasionally occur.

Method of Administration and Dosage

Food intake does not affect the absorption of Enalozid® Mono tablets. If a dose lower than 5 mg is prescribed, the tablet may be divided.

Dosage should be individually adjusted according to each patient's condition (see section "Special Warnings and Precautions for Use") and response in blood pressure.

Arterial Hypertension

The dosage of the drug ranges from an initial dose of 5 mg to a maximum of 20 mg, depending on the degree of arterial hypertension and the patient's condition (see below). Enalozid**®** Mono is taken once daily. For mild arterial hypertension, the recommended initial dose is 5–10 mg.

In patients with a highly activated renin-angiotensin-aldosterone system (e.g., those with renovascular hypertension, disturbances in salt and/or fluid balance, decompensated cardiac function, or severe arterial hypertension), excessive reduction in blood pressure may occur after the first dose. Such patients should start with a dose of 5 mg or lower, and treatment initiation should be under medical supervision.

Prior treatment with high doses of diuretics may lead to fluid depletion and increase the risk of arterial hypotension at the start of enalapril therapy. For such patients, an initial dose of 5 mg or lower is recommended. If possible, diuretic therapy should be discontinued 2–3 days before starting Enalozid**®** Mono. Renal function and serum potassium levels should be monitored.

The usual maintenance dose is 20 mg once daily. The maximum maintenance dose is 40 mg per day.

Heart Failure/Asymptomatic Left Ventricular Dysfunction

For the treatment of clinically manifest heart failure, Enalozid**®** Mono should be used in combination with diuretics and, if necessary, cardiac glycosides or beta-blockers. The initial dose of Enalozid**®** Mono for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. Treatment should be initiated under close medical supervision to monitor the initial effects on blood pressure. In the absence of adverse effects, or after appropriate management of symptomatic hypotension occurring at the beginning of treatment with Enalozid**®** Mono for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, which may be administered once daily or divided into two doses, depending on patient tolerance. Dose titration should be performed over 2–4 weeks. This therapeutic regimen has been shown to effectively reduce mortality in patients with clinically manifest heart failure. The maximum dose is 40 mg per day, given in two divided doses.

Proposed dose titration regimen for Enalozid® Mono in patients with heart failure/asymptomatic left ventricular dysfunction

Week	Dose, mg/day
Week 1	days 1–3: 2.5 mg/day* once daily days 4–7: 5 mg/day in two divided doses
Week 2	10 mg/day in one or two doses
Weeks 3 and 4	20 mg/day in one or two doses

*For patients with renal impairment or those taking diuretics, special precautions should be considered (see section "Special Warnings and Precautions").

Careful monitoring of blood pressure and renal function should be performed both before and during treatment with Enalozid**®** Mono (see section "Special Warnings and Precautions"), as cases of hypotension and (less frequently) subsequent renal failure have been reported. For patients receiving diuretics, the diuretic dose should be reduced, if possible, prior to initiating therapy with Enalozid**®** Mono. The occurrence of hypotension after the initial dose of Enalozid**®** Mono does not necessarily predict sustained hypotension during continued treatment and is not an indication to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Dosage in Renal Impairment

The dosing interval of enalapril should be prolonged and/or the dose reduced.

Renal status	Creatinine clearance (CrCL), mL/min	Initial dose (mg/day)
Mild renal impairment	30<CrCL<80 mL/min	5-10 mg
Moderate renal impairment	10<CrCL≤30 mL/min	2.5 mg
Severe impairment (such patients are usually on hemodialysis)	CrCL ≤10 mL/min	2.5 mg on dialysis days⃰

⃰See section "Special precautions": Patients undergoing hemodialysis.

Enalapril is removed by hemodialysis. Dose adjustment on days when hemodialysis is not performed should be based on blood pressure levels.

Geriatric patients

Dosage should be adjusted according to renal function (see section "Special precautions").

Children with hypertension aged 6 years and older

There is limited clinical experience with the use of Enalozid® Mono in the treatment of hypertension in children (see sections "Pharmacological properties" and "Special precautions").

For children who can swallow tablets, the dose should be individually adjusted according to the patient's condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg for patients with body weight from 20 to 50 kg and 5 mg for patients with body weight ≥ 50 kg. Enalozid**®** Mono is taken once daily. Dosage should be adjusted according to clinical need up to a maximum of 20 mg per day for patients with body weight from 20 to 50 kg and 40 mg per day for patients with body weight ≥ 50 kg (see sections "Special precautions" and "Children").

Enalozid**®** Mono is not recommended for neonates and children with glomerular filtration rate < 30 mL/min/1.73 m² due to lack of data.

Children.

Use in children aged 6 years and older.

The medicinal product Enalozid® Mono is not recommended for neonates and children with glomerular filtration rate < 30 mL/min/1.73 m² due to lack of data.

Overdose.

There is limited data on overdose. The main symptoms reported include profound hypotension, which begins approximately 6 hours after drug intake and coincides with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Plasma levels of enalaprilat exceeding the maximum therapeutic levels by 100 and 200 times have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively.

For the treatment of overdose, intravenous infusion of isotonic saline solution is recommended. In case of hypotension, the patient should be placed in a supine position. Administration of angiotensin II and/or intravenous catecholamines may be considered. If the drug was recently ingested, measures to eliminate enalapril maleate should be undertaken (e.g., induced vomiting, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis (see section "Special precautions": Patients undergoing hemodialysis). In cases of bradycardia resistant to therapeutic measures, pacemaker therapy is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be closely monitored.

Adverse Reactions

The undesirable effects listed below have been observed during clinical trials and post-marketing surveillance with enalapril at the following frequencies: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: uncommon – anaemia (including aplastic and haemolytic); rare – neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune disorders.

Endocrine system disorders: frequency not known – syndrome of inappropriate antidiuretic hormone secretion.

Metabolic and nutritional disorders: uncommon – hypoglycaemia.

Nervous system and psychiatric disorders: common – depression, headache; uncommon – confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo; rare – sleep disorders, abnormal dreams.

Eye disorders: very common – blurred vision.

Cardiac and vascular disorders: very common – dizziness; common – hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia; uncommon – orthostatic hypotension, palpitations, myocardial infarction or stroke*, possibly due to excessive reduction in blood pressure in high-risk patients (see section "Special precautions"); rare – Raynaud's phenomenon.

Respiratory system disorders: very common – cough; common – dyspnoea; uncommon – rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma; rare – pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia, pharyngitis.

Gastrointestinal disorders: very common – nausea; common – diarrhoea, abdominal pain, taste disturbances; uncommon – intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers; rare – stomatitis/aphthous ulcers, glossitis; very rare – angioneurotic oedema of the intestine.

Hepatobiliary disorders: rare – hepatic failure, hepatitis – hepatocellular or cholestatic; hepatitis including necrosis; cholestasis, including jaundice.

Skin and subcutaneous tissue disorders: common – rash, increased sensitivity/angioedema (face, extremities, lips, tongue, glottis and/or larynx); uncommon – increased sweating, pruritus, urticaria, alopecia; rare – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A complex of symptoms including some or all of the following has been reported: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibodies test, elevated erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. Skin reactions such as rash, photosensitivity, and other dermatological reactions may also occur as adverse reactions.

Renal and urinary disorders: uncommon – renal dysfunction, renal failure, proteinuria; rare – oliguria.

Reproductive system and breast disorders: uncommon – impotence; rare – gynaecomastia.

General disorders and administration site conditions: very common – asthenia; common – fatigue; uncommon – muscle cramps, flushing, tinnitus, discomfort, fever.

Laboratory test abnormalities: common – hyperkalaemia, increased serum creatinine; uncommon – increased blood urea, hyponatraemia; rare – increased liver enzymes, increased serum bilirubin.

*The frequency of events was comparable between placebo and active control groups during clinical trials.

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 the reach and sight of children.

Packaging.

10 tablets per blister. 2 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.