Enalapril

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALAPRIL (ENALAPRIL)

Composition:

Active substance: enalapril maleate;

1 tablet contains enalapril maleate 0.01 g (10 mg);

Excipients: lactose monohydrate, maize starch, microcrystalline cellulose, magnesium stearate, colloidal anhydrous silicon dioxide, povidone.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or almost white tablets with a score line.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors. Enalapril. ATC code C09A A02.

Pharmacological properties.

Pharmacodynamics.

Enalapril maleate is the maleic acid 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 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 of angiotensin II on renin release) and decreased aldosterone secretion.

ACE is identical to kininase II. Thus, enalapril may also block the breakdown of bradykinin, a potent vasodilator peptide. However, the significance of this effect for the therapeutic action of the drug remains unclear.

The mechanism by which enalapril reduces blood pressure is primarily related to inhibition of the renin-angiotensin-aldosterone system. Enalapril may exert antihypertensive effects even in patients with low-renin hypertension.

Administration of enalapril in arterial hypertension leads to reduction in blood pressure in both supine and upright positions without significant increase in heart rate.

Symptomatic postural hypotension occurs infrequently. In some patients, optimal blood pressure reduction may require several weeks of therapy. Abrupt discontinuation of enalapril is not associated with rapid rebound increase 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 effect is typically observed within 1 hour, and peak reduction in blood pressure occurs 4–6 hours after administration. Duration of effect depends on the dose. However, when used at recommended doses, the antihypertensive and hemodynamic effects persist for at least 24 hours.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction is usually accompanied by decreased peripheral arterial resistance with increased cardiac output and either minimal or no increase in heart rate. After enalapril administration, renal blood flow usually increases; glomerular filtration rate (GFR) typically remains unchanged. No signs of sodium or water retention have been observed. However, in patients with low baseline GFR, this value usually increases.

In short-term clinical studies in patients with or without diabetes and with kidney disease, enalapril administration was associated with reduced albuminuria, urinary excretion of IgG, and total urinary protein.

When used concomitantly with thiazide diuretics, the antihypertensive effects of enalapril are at least additive. Enalapril 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 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, decreased. These effects were maintained during long-term treatment.

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

In a multicenter, randomized, double-blind, placebo-controlled trial, 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 in the enalapril group (29.8%) (29% risk reduction, 95% CI, 21–36%, p < 0.001). 518 patients in the placebo group (24.5%) and 434 patients in the enalapril group (20.6%) died or were hospitalized due to development or worsening of heart failure (20% risk reduction, 95% CI; 9–30%, p < 0.001). In another multicenter, randomized, double-blind, placebo-controlled trial, a population with symptomatic congestive heart failure due to systolic dysfunction (ejection fraction < 35%) was studied. 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 in the enalapril group (35.2%) (16% risk reduction, 95% CI, 5–26%, p=0.0036). Cardiovascular mortality was 461 in the placebo group versus 399 in the enalapril group (18% risk reduction, 95% CI, 6–28%, p < 0.002), primarily due to reduced mortality from progressive heart failure (251 in the placebo group vs. 209 in the enalapril group, 22% risk reduction, 95% CI, 6–35%). Fewer patients died or were hospitalized due to worsening heart failure (736 in the placebo group vs. 613 in the enalapril group, 26% risk reduction, 95% CI, 18–34%, p < 0.0001). Overall, in the SOLVD trial in patients with left ventricular dysfunction, enalapril reduced the risk of myocardial infarction by 23% (95% CI, 11–34%, p < 0.001) and reduced the risk of hospitalization for unstable angina by 20% (95% CI, 9–29%, p < 0.001).

Clinical pharmacology in children.

Experience with use in children aged 6 years and older with 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 (GFR) > 30 mL/min/1.73 m², patients weighing < 50 kg received 0.625, 2.5, or 20 mg of enalapril daily, and patients weighing ≥ 50 kg received 1.25, 5, 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 (averaging approximately 0.02 mg/kg once daily), did not provide sustained antihypertensive effect. The maximum studied dose was 0.58 mg/kg (up to 40 mg) once daily. The adverse effect profile in children was similar to that in adult patients.

Pharmacokinetics.

Absorption.

After oral administration, enalapril is rapidly absorbed; maximum serum concentration of enalapril is reached within 1 hour after administration. The extent of enalapril absorption after oral tablet administration is approximately 60%. The presence of food in the gastrointestinal tract does not affect the absorption of enalapril. After absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Maximum serum concentration of enalaprilat is observed approximately 4 hours after oral enalapril administration.

The effective elimination half-life (t½) of enalaprilat after multiple oral doses is 11 hours.

Distribution.

Within the entire therapeutic concentration range, no more than 60% of enalaprilat is protein-bound to serum proteins.

Biological transformation.

Apart from conversion to enalaprilat, there is no evidence of significant further 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), steady-state AUC of enalaprilat is approximately twice higher than in patients with normal renal function after 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increases approximately 8-fold. In these conditions, the effective elimination half-life of enalaprilat is prolonged, and time to steady state is delayed (see section "Dosage and administration").

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, or to any other angiotensin-converting enzyme (ACE) inhibitor.

History of angioedema associated with ACE inhibitor therapy.

Hereditary or idiopathic angioedema.

Enalapril should not be used in combination with aliskiren-containing products in patients with diabetes or renal impairment (eGFR < 60 mL/min/1.73 m²).

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

Enalapril should not be taken within 36 hours of switching to or from sacubitril/valsartan, a drug containing a neprilysin inhibitor (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.

Antihypertensive therapy.

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

Potassium-sparing diuretics, potassium supplements, or other drugs that may increase serum potassium levels.

ACE inhibitors enhance diuretic-induced potassium loss. The use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements or salt substitutes, or other drugs that may increase serum potassium levels (e.g., trimethoprim-containing preparations), especially in patients with renal impairment, may lead to a significant increase in serum potassium levels. If these agents are indicated due to hypokalemia, they should be used with caution and serum potassium levels should be monitored regularly (see section "Special 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 precautions for use"). Hypotensive effects can be minimized by discontinuing the diuretic, increasing dietary salt intake, or initiating therapy with a low dose of enalapril.

Antidiabetic agents.

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may reduce blood glucose levels, increasing the risk of hypoglycemia. This phenomenon is most likely during the first weeks of concomitant therapy and in patients with renal impairment (see sections "Special precautions for use" and "Undesirable effects").

Serum lithium.

Concomitant use of ACE inhibitors and lithium has been associated with reversible increases in serum lithium levels and lithium toxicity. Concurrent 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 precautions for use").

Tricyclic antidepressants/neuroleptics/anesthetics/sedatives.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors.

NSAIDs, including selective COX-2 inhibitors, may reduce the effects of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs, including selective 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 lead to renal dysfunction. These effects are usually reversible.

Acute renal failure may rarely occur, particularly in certain patients with pre-existing renal impairment (e.g., elderly patients or those with reduced blood volume, including those taking diuretics). Therefore, such combinations should be used cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and be closely monitored for 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 limited to specific cases and accompanied by 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 end-organ damage, dual blockade of the RAAS 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 RAAS. Enalapril should not be used with aliskiren in patients with diabetes or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Contraindications" or "Special precautions for use").

Gold preparations.

Nitritoid reactions (symptoms including facial swelling, nausea, vomiting, and arterial hypotension) have rarely been reported 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.

Neprilysin inhibitors.

Concomitant use with neprilysin inhibitors (e.g., sacubitril) may increase the risk of angioedema.

Sympathomimetics.

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol.

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and beta-blockers.

Enalapril can be safely used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, 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 end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to therapy with a single RAAS-acting agent. 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.

Special precautions for use.

Symptomatic hypotension.

Symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving enalapril, symptomatic hypotension occurs more frequently in those with 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 "Undesirable effects"). Symptomatic hypotension has been observed in patients with heart failure, with or without renal impairment. 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 have impaired renal function. Such patients should begin enalapril therapy under medical supervision. Particular caution and monitoring are required when adjusting the dose of enalapril and/or diuretic. Similarly, patients with ischemic heart disease or cerebrovascular disease should be closely monitored, as excessive reduction in blood pressure may lead to myocardial infarction or stroke.

If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, administered intravenous physiological saline. Transient arterial hypotension during enalapril therapy is not a contraindication for continued treatment, which can usually be continued without complications after blood pressure normalization through fluid volume restoration.

In some patients with heart failure and normal or low blood pressure, enalapril may further reduce blood pressure. This response to the drug is expected and generally not a reason to discontinue therapy. If arterial hypotension becomes refractory to treatment, the dose should be reduced and/or diuretic therapy and/or enalapril 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 outflow tract obstruction; their use should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Renal 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. For such patients, regular monitoring of serum potassium and creatinine levels is standard medical practice.

Renal dysfunction has been reported with enalapril use, primarily observed in patients with severe heart failure or kidney disease, including renal artery stenosis. When detected early and appropriately managed, renal impairment associated with enalapril therapy is usually reversible.

In some patients with arterial hypertension who had no pre-existing kidney disease, enalapril combined with diuretics has caused usually mild 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 titration and monitoring of renal function.

Kidney transplantation.

There is no experience with the use of enalapril in patients who have recently undergone kidney transplantation. Therefore, the use of this drug 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 receiving ACE inhibitors who develop jaundice or marked elevations in liver enzymes should discontinue the ACE inhibitor and be placed under appropriate medical monitoring.

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 who are receiving immunosuppressive therapy, allopurinol, or procainamide, or in combination with these complicating factors, especially if renal impairment is already present. Some of these patients have developed serious infections, which sometimes did not respond to intensive antibiotic therapy. 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 during therapy with ACE inhibitors, including enalapril, 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. Even when swelling is limited to the tongue without respiratory distress, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal outcomes due to laryngeal angioedema or tongue swelling have been reported very rarely. If swelling occurs in the area of the tongue, glottis, or larynx, particularly in patients with a history of airway surgery, airway obstruction may develop. When the tongue, pharynx, or larynx are involved and airway obstruction is possible, 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 African descent receiving ACE inhibitors compared to patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing angioedema during ACE inhibitor therapy (see also 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 low-density lipoprotein apheresis.

Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during low-density lipoprotein 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, it is recommended to consider using dialysis membranes of another type or an antihypertensive agent from another class.

Hypoglycemia.

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

Cough.

Cough has been reported during therapy with ACE inhibitors. The cough is usually 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 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.

Hyperkalemia.

During therapy 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 impairment, impaired renal function, age over 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 receiving other drugs that may increase serum potassium (e.g., heparin, trimethoprim-containing preparations). In particular, concomitant use of potassium-sparing diuretics, dietary supplements, or salt substitutes containing potassium 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 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").

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 an ACE inhibitor and an angiotensin receptor antagonist.

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

Lactose.

Enalapril contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medication. Enalapril contains less than 100 mg of lactose per tablet.

Children.

There is limited experience with the effective and safe use of the drug in children aged 6 years and older with arterial hypertension.

Ethnic characteristics.

As with other ACE inhibitors, enalapril is less effective in lowering blood pressure in patients of African descent compared to other racial groups, possibly because low renin levels are more common in this population of patients with arterial hypertension.

Use during pregnancy or breastfeeding.

Pregnancy.

The drug 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 must be discontinued immediately, and, if necessary, replaced with another medicinal product permitted during pregnancy.

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

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

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

Breastfeeding period.

Limited pharmacokinetic data indicate very low concentrations in breast milk (see section "Pharmacokinetics"). Although such concentrations are considered clinically insignificant, the use of enalapril is not recommended during breastfeeding of preterm infants and newborns during the first few weeks after birth due to the theoretical risk of cardiovascular and renal effects and the lack of sufficient experience in this regard. In the case of older infants, the use of enalapril during breastfeeding may be considered if treatment is necessary for the mother and the infant is monitored for any adverse effects.

Ability to affect reaction speed when driving or operating machinery.

When driving or operating machinery, the possible development of dizziness or fatigue should be taken into account.

Dosage and Administration

Food intake does not affect the absorption of Enalapril tablets.

If the prescribed dose is less than 5 mg, enalapril preparations with such dosing options should be used.

Dosage must be individually adjusted according to each patient's condition (see section "Special Instructions") and response in blood pressure.

Arterial Hypertension.

The dosage 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). Enalapril should be 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., 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 initial 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-dose diuretics may lead to fluid depletion and increase the risk of arterial hypotension at the beginning 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 Enalapril. 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 treatment of clinically manifest heart failure, Enalapril is used in combination with diuretics and, if necessary, cardiac glycosides or beta-blockers. The initial dose of Enalapril for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. The drug must be administered under close medical supervision to assess its initial effect on blood pressure. If there is no adverse effect or after appropriate symptomatic hypotension has been managed at the beginning of enalapril therapy for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, administered either once daily or divided into two doses, depending on patient tolerance. Dose titration should be performed over 2–4 weeks. This therapeutic regimen effectively reduces mortality rates in patients with clinically manifest heart failure. The maximum dose is 40 mg per day in two divided doses.

Proposed enalapril dose titration regimen for patients with heart failure/asymptomatic left ventricular dysfunction.

* The drug should be used with caution in patients with impaired renal function or those taking diuretics (see section "Special precautions").

Careful monitoring of blood pressure and renal function should be performed both before and during treatment with Enalapril (see section "Special precautions"), as cases of arterial hypotension and (less frequently) subsequent renal failure have been reported. In patients taking diuretics, the diuretic dose should be reduced, if possible, prior to initiating Enalapril therapy. The development of arterial hypotension after the initial dose of Enalapril does not necessarily predict sustained hypotension during long-term therapy and is not an indication to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Dosage in renal insufficiency.

In general, the dosing interval of Enalapril should be prolonged and/or the dose reduced.

* See section "Special instructions": patients undergoing hemodialysis.

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

Elderly patients.

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

Children with hypertension aged 6 years and older.

Clinical experience with enalapril in children with hypertension is limited (see sections "Pharmacodynamics", "Pharmacokinetics", "Special instructions").

For children who can swallow tablets, the dose should be individually prescribed based on patient condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg for patients with body weight 20–50 kg and 5 mg for patients with body weight ≥50 kg. Enalapril is administered once daily. Dosage should be titrated according to need up to a maximum of 20 mg daily for patients with body weight 20–50 kg and 40 mg for patients with body weight ≥50 kg (see sections "Special instructions" and "Children").

Enalapril is not recommended for newborns and children with glomerular filtration rate <30 mL/min/1.73 m² due to lack of data.

Children.

To be used in children aged 6 years and older.

Enalapril is not recommended for newborns and children with glomerular filtration rate <30 mL/min/1.73 m² due to lack of data.

Overdose.

Data on overdose are limited. The main signs of overdose, according to available data, include profound arterial hypotension starting approximately 6 hours after drug administration and coinciding with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Plasma enalaprilat levels up to 100 and 200 times higher than the maximum levels achieved with therapeutic doses have been reported following administration of 300 mg and 440 mg of enalapril, respectively.

For treatment of overdose, intravenous infusion of isotonic saline is recommended. If arterial hypotension occurs, 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 initiated (e.g., induced emesis, gastric lavage, use of adsorbents and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis (see section "Special instructions": patients undergoing hemodialysis). In cases of bradycardia resistant to therapeutic interventions, pacemaker therapy is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Adverse Reactions

When enalapril is used, adverse effects are mostly mild, transient in nature, and do not usually require discontinuation of therapy.

Blood system disorders: anaemia (including aplastic and haemolytic); neutropenia, decreased haemoglobin, decreased haematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune diseases.

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion.

Metabolic disorders: hypoglycaemia (see section "Special precautions").

Nervous and psychiatric system disorders: depression, headache; confusion, drowsiness, insomnia, nervousness, paraesthesia, vertigo; sleep disorders, abnormal dreams.

Eye disorders: blurred vision.

Cardiovascular system disorders: dizziness; hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia; orthostatic hypotension, rapid heartbeat, myocardial infarction or stroke, possibly due to excessive blood pressure reduction in patients at high risk (see section "Special precautions"), Raynaud's phenomenon.

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

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

Hepatobiliary system disorders: liver failure, hepatocellular or cholestatic hepatitis, hepatitis including necrosis, cholestasis (including jaundice).

Skin and subcutaneous tissue disorders: rash, increased sensitivity/angioedema of the face, extremities, lips, tongue, glottis and/or larynx (see section "Special precautions"); increased sweating, pruritus, urticaria, alopecia; erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A complex syndrome has been reported, comprising some or all of the following manifestations: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. Skin rash, photosensitization, and other skin reactions may also occur as adverse effects.

Renal and urinary system disorders: impaired renal function, renal failure, proteinuria; oliguria.

Reproductive system disorders: impotence; gynaecomastia.

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

Laboratory test abnormalities: hyperkalaemia, increased serum creatinine; increased blood urea, hyponatraemia; elevated liver enzymes, increased serum bilirubin.

Shelf life.

3 years.

Storage conditions.

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

Packaging.

10 tablets in a blister; 1, 2, 3, 5, or 9 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhym-Kharkiv".

PJSC "Tekhnolog".

Manufacturer's address and place of business.

Ukraine, 61115, Kharkiv region, Kharkiv, Severyna Pototskoho Street, 36.

Ukraine, 20300, Cherkasy region, Uman, Stara Prorizna Street, 8.