Enalapril

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

Composition:

Active substance: enalapril;

1 tablet contains enalapril maleate (recalculated to 100 % substance) – 10 mg;

Excipients: lactose monohydrate; potato starch; microcrystalline cellulose; povidone; colloidal anhydrous silicon dioxide; talc; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: intact, regular round cylinders, with flat upper and lower surfaces, beveled edges, with a score line for division, white or almost white in color.

Pharmacotherapeutic group.

Angiotensin-converting enzyme inhibitors, single-component.

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, which is hydrolyzed in the liver to form enalaprilat, the active angiotensin-converting enzyme (ACE) inhibitor.

Inhibition of ACE leads to reduced formation of angiotensin II in tissues and blood plasma, decreased aldosterone secretion, and increased plasma renin activity. As a result of ACE inhibition, activity of the kallikrein-kinin system increases, bradykinin accumulates, and prostaglandin system is consequently activated. Administration of enalapril maleate to patients with arterial hypertension leads to reduction in arterial blood pressure without compensatory increase in heart rate (HR), and reduces peripheral vascular resistance. In patients with heart failure, enalapril maleate reduces peripheral vascular resistance, thereby decreasing cardiac afterload. Treatment with enalapril maleate results in increased cardiac output, improved stroke index and exercise tolerance, reduced left ventricular hypertrophy, and improved intraglomerular renal hemodynamics. Enalapril maleate has no effect on glucose and lipoprotein metabolism.

Pharmacokinetics.

Following oral administration, enalapril maleate is rapidly absorbed, with approximately 60% of the administered dose being bioavailable. Food does not affect its absorption. Peak plasma concentration of enalaprilat is reached approximately 4 hours after administration. The effective half-life of enalaprilat after repeated oral dosing is 11 hours. Effective inhibition of angiotensin-converting enzyme activity occurs within 2–4 hours after a single dose of enalapril maleate. Antihypertensive effect begins within 1 hour, with maximum effect observed 4–6 hours after dosing. Duration of action is dose-dependent; however, at recommended doses, antihypertensive and hemodynamic effects last for at least 24 hours. In volunteers with normal renal function, enalaprilat serum concentrations reach steady-state levels approximately 4 days after initiation of therapy. Within the range of therapeutically relevant concentrations, plasma protein binding in humans does not exceed 60%. Apart from conversion to enalaprilat, no significant further metabolism of enalapril maleate has been reported. Enalaprilat is primarily excreted by the kidneys. The main components in urine are enalaprilat (40% of the administered dose) and unchanged enalapril maleate (about 20%).

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 previous ACE inhibitor therapy.
• Hereditary or idiopathic angioedema.
• Use of enalapril with aliskiren-containing products in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²).
• Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation").

Enalapril must not be used in combination with neprilysin inhibitors (e.g., sacubitril). Enalapril should not be administered within 36 hours before or after sacubitril/valsartan, a product 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 antihypertensive medicinal products may enhance the hypotensive effect of enalapril. Concurrent administration with nitroglycerin, other nitrates, or other vasodilators may further reduce blood pressure.

Potassium-sparing diuretics or potassium supplements

ACE inhibitors reduce diuretic-induced potassium loss. The use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, salt substitutes containing potassium, or other agents that may increase serum potassium levels (e.g., trimethoprim-containing products) may lead to significant increases in serum potassium, particularly in patients with impaired renal function. If these agents are indicated due to hypokalemia, they should be used cautiously with regular monitoring of serum potassium levels (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 hypotension at the start of enalapril therapy (see section "Special precautions for use"). Hypotensive effects can be minimized by discontinuing diuretic therapy, increasing salt intake, or initiating enalapril at a low dose.

Antidiabetic agents

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may result in decreased blood glucose levels and an increased 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", "Adverse reactions").

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 and lithium is not recommended; however, if such combination is necessary, 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 lead to additional reduction in blood pressure (see section "Special 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 efficacy of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be diminished 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 impairment. These effects are usually reversible.

Acute renal failure, although rare, may occur, particularly in certain patients with pre-existing renal impairment (e.g., elderly patients or patients with reduced blood volume, including those on diuretics). Therefore, such combination should be used cautiously in patients with renal dysfunction. Patients should maintain adequate fluid intake and be closely monitored for renal function at the initiation 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 a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single RAAS-acting agent. Enalapril must not be used with aliskiren in patients with diabetes or renal impairment (GFR < 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 hypotension) have been rarely reported in patients receiving injectable gold preparations (sodium aurothiomalate) concomitantly with ACE inhibitors, including enalapril.

mTOR inhibitors

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

Neprilysin inhibitors

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

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers

Enalapril can be safely used concomitantly with acetylsalicylic acid (at cardioprotective doses), thrombolytics, and β-blockers.

Special precautions for use.

Symptomatic hypotension

Symptomatic hypotension has rarely 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, dietary 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 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 have impaired renal function. Such patients should begin enalapril therapy under medical supervision. Particular caution is 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.

In the event of arterial hypotension, the patient should be placed in a supine position and, if necessary, given intravenous physiological saline. Transient arterial hypotension during enalapril therapy is not a contraindication to 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 does not warrant discontinuation of therapy. If arterial hypotension becomes refractory to treatment, the dose should be reduced and/or diuretic and/or enalapril therapy discontinued.

Aortic or mitral stenosis/hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be administered 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 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 the 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, predominantly 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 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 to a single functioning kidney when 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 enalapril use in patients who have recently undergone kidney transplantation. Therefore, enalapril is not recommended for these patients.

Hepatic insufficiency

Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant 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 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 who are receiving immunosuppressive therapy, allopurinol, or procainamide, or in combination with these complicating factors, especially if renal function is already impaired. 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.

Hypersensitivity/angioedema

Cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported with ACE inhibitors, including enalapril, occurring at various times during therapy. 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 in cases of tongue swelling without respiratory distress, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal outcomes due to laryngeal angioedema or tongue swelling have been reported very rarely. When swelling occurs in the area of the tongue, glottis, or larynx, particularly in patients with a history of airway surgery, airway obstruction may develop. If the tongue, pharynx, or larynx is involved and airway obstruction is possible, immediate appropriate therapy should be initiated, 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 Hymenoptera venom

Rarely, patients receiving ACE inhibitors during allergen desensitization with Hymenoptera venom have developed anaphylactoid reactions that may be life-threatening. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before desensitization.

Anaphylactoid reactions during low-density lipoprotein apheresis

Rarely, anaphylactoid reactions, which may be life-threatening, have occurred in patients receiving ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate. These 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®) who are also 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 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 treatment 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 that cause 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 can 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 impairment, reduced 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 blocker

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 renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

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.

Children

There is limited experience with the effective and safe use of enalapril 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"). Enalapril is not recommended for treating children for conditions other than arterial hypertension.

Enalapril is not recommended for newborns 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 in pregnant women or women planning to become pregnant.

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

Ethnic considerations

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

Lactose

The product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this product, its use should 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 have been used during the second trimester of pregnancy, ultrasound examination of the kidneys and skull is recommended.

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

Breastfeeding

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

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

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

Dosage and Administration

Food intake does not affect the absorption of Enalapril tablets.

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

When enalapril is prescribed at doses less than 5 mg, a formulation of enalapril allowing such dosing should be used.

Arterial Hypertension

The dosage ranges from an initial 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 hypertension, the recommended initial dose is 5–10 mg.

In patients with highly activated RAAS (e.g., renovascular hypertension, disturbances in salt and/or fluid balance, decompensated cardiac function, or severe arterial hypertension), excessive reduction in arterial 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 doses of diuretics may lead to fluid depletion and increase the risk of arterial hypotension at the start of enalapril therapy. For these patients, an initial dose of 5 mg or lower is recommended. If possible, diuretic treatment 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 should be used concomitantly with diuretics and, if necessary, cardiac glycosides or β-blockers. The initial dose of enalapril 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 effect of the drug on arterial pressure. In the absence of adverse effects or after appropriate management of symptomatic hypotension occurring at the beginning of enalapril therapy, 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 tolerability. Dose titration should be performed over 2–4 weeks. This therapeutic regimen has been shown to effectively reduce mortality rates in patients with clinically manifest heart failure. The maximum dose is 40 mg per day, given in two divided doses.

Proposed dose titration of Enalapril in patients with heart failure/asymptomatic left ventricular dysfunction

Table 1

* 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) worsening renal failure have been reported. In patients taking diuretics, the diuretic dose should be reduced, if possible, prior to initiating therapy with Enalapril. The occurrence of arterial hypotension after the initial dose of Enalapril 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.

Dosing in renal impairment

Generally, the dosing interval of enalapril should be prolonged and/or the dose reduced (see Table 2).

Table 2

* 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 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. Enalapril should be taken once daily. Dosage should be adjusted as needed up to a maximum of 20 mg daily for patients with body weight from 20 to 50 kg and 40 mg for patients with body weight ≥ 50 kg (see sections "Special instructions" and "Children").

Children.

To be used in children aged 6 years and older.

Enalapril is not recommended for neonates 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 reported in available data include profound hypotension, beginning approximately 6 hours after drug intake 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 after ingestion of 300 mg and 440 mg of enalapril, respectively.

For treatment of overdose, intravenous infusion of isotonic saline solution is recommended. If 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 (such as induction of emesis, gastric lavage, administration 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, treatment with a cardiac pacemaker is indicated. Vital signs, serum electrolyte concentrations, and serum creatinine levels should be closely monitored.

Adverse reactions.

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

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion.

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

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

Eye disorders: blurred vision, visual disturbances.

Cardiovascular disorders: arterial hypotension (including orthostatic hypotension), syncope, chest pain, rhythm disturbances, 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 and warnings"), Raynaud's phenomenon.

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

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

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

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

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

Renal and urinary disorders: renal function impairment, renal failure, proteinuria, oliguria.

Reproductive system disorders: impotence, gynaecomastia.

General disorders: asthenia, increased fatigue, muscle cramps, hot flushes, tinnitus, discomfort, fever.

Laboratory findings: hyperkalaemia, increased serum creatinine, increased blood urea, hyponatraemia, increased liver enzymes, increased serum bilirubin.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 2 blisters in a carton.

Prescription category. Prescription only.

Manufacturer.

JSC "Lubnifarm".

Manufacturer's address and place of business.

16 Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.

INSTRUCTION

for medical use of medicinal product

Enalapril

(Enalapril)

Composition:

Active substance: enalapril;

1 tablet contains enalapril maleate (calculated as 100 % substance) – 10 mg;

Excipients: lactose monohydrate; potato starch; microcrystalline cellulose; povidone; colloidal anhydrous silicon dioxide; talc; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: intact, regular, round cylinders with flat upper and lower surfaces, bevelled edges, scored for division, white or almost white in colour.

Pharmacotherapeutic group.

Angiotensin-converting enzyme (ACE) inhibitors, single component.

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, which is hydrolysed in the liver to form enalaprilat, the active metabolite and inhibitor of angiotensin-converting enzyme (ACE).

Inhibition of ACE leads to reduced formation of angiotensin II in tissues and plasma, reduced aldosterone secretion, and increased plasma renin activity. Inhibition of ACE also increases the activity of the kallikrein-kinin system, accumulation of bradykinin, and subsequent activation of the prostaglandin system. Administration of enalapril maleate to patients with arterial hypertension reduces blood pressure without compensatory increase in heart rate (HR) or peripheral vascular resistance. In patients with heart failure, enalapril maleate reduces peripheral vascular resistance, thereby decreasing cardiac afterload. Enalapril maleate treatment increases cardiac output, stroke index, and exercise tolerance, reduces left ventricular hypertrophy, and improves intraglomerular renal haemodynamics. Enalapril maleate has no effect on glucose and lipoprotein metabolism.

Pharmacokinetics.

After oral administration, enalapril maleate is rapidly absorbed, with approximately 60 % of the administered dose being bioavailable. Food does not affect its absorption. Peak plasma concentration of enalaprilat occurs approximately 4 hours after administration. The effective half-life of enalaprilat after repeated oral dosing is about 11 hours. Effective inhibition of ACE activity occurs 2–4 hours after a single dose of enalapril maleate. Antihypertensive effect begins within 1 hour, with maximum effect achieved 4–6 hours after administration. Duration of action is dose-dependent; however, with recommended dosing, antihypertensive and haemodynamic effects last at least 24 hours. In volunteers with normal renal function, enalaprilat serum concentrations reach steady state levels approximately 4 days after initiation of therapy. Plasma protein binding in the therapeutic concentration range does not exceed 60 %. Apart from conversion to enalaprilat, there is no significant further metabolism of enalapril maleate. Enalaprilat is primarily excreted by the kidneys. The main urinary components are enalaprilat (40 % of the administered dose) and unchanged enalapril maleate (about 20 %).

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, any excipient, or any other ACE inhibitor.
• History of angioedema associated with ACE inhibitor therapy.
• Hereditary or idiopathic angioedema.
• Use of enalapril with aliskiren-containing products in patients with diabetes or renal impairment (eGFR < 60 mL/min/1.73 m²).
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding").

Enalapril should not be used in combination with neprilysin inhibitors (e.g., sacubitril). Enalapril should not be administered within 36 hours of switching from or to sacubitril/valsartan, a neprilysin inhibitor-containing product (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions and warnings").

Interaction with other medicinal products and other forms of interaction.

Antihypertensive therapy

Concomitant use of antihypertensive agents may enhance the hypotensive effect of enalapril. Concurrent administration with nitroglycerin, other nitrates, or other vasodilators may further reduce blood pressure.

Potassium-sparing diuretics or potassium supplements

ACE inhibitors may enhance diuretic-induced potassium loss. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, salt substitutes, or other agents that may increase serum potassium (e.g., trimethoprim-containing preparations), especially in patients with renal impairment, may lead to significant increases in serum potassium levels. If such agents are indicated due to hypokalaemia, they should be used cautiously with regular monitoring of serum potassium levels (see section "Special precautions and warnings").

Diuretics (thiazide or loop diuretics)

Prior treatment with high-dose diuretics may lead to reduced circulating volume and increased risk of arterial hypotension at the start of enalapril therapy (see section "Special precautions and warnings"). Hypotensive effects can be minimized by discontinuing diuretic therapy, increasing salt intake, or initiating enalapril at a low dose.

Antidiabetic agents

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may cause decreased blood glucose levels with risk of hypoglycaemia. This phenomenon is most likely during the first weeks of combined therapy and in patients with renal impairment (see sections "Special precautions and warnings", "Adverse reactions").

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 the risk of lithium intoxication. Concomitant use of enalapril and lithium is not recommended; however, if such combination is necessary, close monitoring of serum lithium levels is required (see section "Special precautions and warnings").

Tricyclic antidepressants/neuroleptics/anesthetics/sedatives

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

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

NSAIDs, including selective COX-2 inhibitors, may reduce the efficacy 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 additive effects on increasing serum potassium and may lead to renal impairment. These effects are usually reversible.

Acute renal failure is rarely possible, particularly in patients with pre-existing renal impairment (e.g., elderly patients or those with reduced circulating volume, including those on diuretics). Therefore, such combinations should be used cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and be under close monitoring of renal function at the start and periodically during concomitant therapy.

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. Clinical trials have shown 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, hyperkalaemia, and worsening renal function (including acute renal failure) compared to monotherapy. 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 and warnings").

Gold preparations

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

mTOR inhibitors

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

Neprilysin inhibitors

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

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers

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

Special precautions and warnings.

Symptomatic hypotension

Symptomatic hypotension is rare in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving enalapril, symptomatic hypotension is more likely in those with hypovolaemia, such as those on diuretic therapy, salt restriction, haemodialysis, or with diarrhoea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Symptomatic hypotension has also been observed in patients with heart failure, with or without renal impairment. It occurs more frequently in patients with more severe heart failure, those on high-dose loop diuretics, with hyponatraemia, or renal impairment. Such patients should be started on enalapril under medical supervision. Monitoring should be especially careful when adjusting the dose of enalapril and/or diuretic. Similarly, patients with ischaemic heart disease or cerebrovascular disease should be closely monitored, as excessive blood pressure reduction may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, given intravenous saline. Transient arterial hypotension during enalapril therapy is not a contraindication for continued use, which can usually be resumed without complications after blood pressure normalizes with fluid volume restoration.

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

Aortic or mitral stenosis/hypertrophic cardiomyopathy

As with all vasodilators, ACE inhibitors should be used cautiously in patients with left ventricular outflow tract obstruction or obstructive pathway; their use should be avoided in cardiogenic shock or haemodynamically significant obstruction.

Renal impairment

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

Renal impairment has been reported with enalapril use, particularly in patients with severe heart failure or renal disease, including renal artery stenosis. Renal failure associated with enalapril therapy is usually reversible with timely recognition and appropriate treatment.

In some hypertensive patients without pre-existing renal disease, enalapril combined with diuretics may cause mild and transient increases in blood urea and serum creatinine. In such cases, dose reduction or discontinuation of the diuretic may be necessary. This situation may indicate underlying renal artery stenosis (see section "Special precautions and warnings" Renovascular hypertension).

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are at increased risk of arterial hypotension and renal failure when treated with ACE inhibitors. Loss of renal function may occur even with minimal increases in serum creatinine. Such patients should be started on low doses under careful medical supervision with cautious dose titration and monitoring of renal function.

Kidney transplantation

There is no experience with enalapril use in patients who have recently undergone kidney transplantation. Therefore, enalapril is not recommended for 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 increases in liver enzymes should discontinue the ACE inhibitor and be placed under appropriate medical supervision.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anaemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no complicating factors. Enalapril should be used with extreme caution in patients with collagen vascular disease, those on immunosuppressive therapy, allopurinol, or procainamide, or a combination of these factors, especially if renal impairment is present. Some of these patients have developed serious infections that were sometimes unresponsive to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended in such patients, and they should be advised to report any signs of infection.

Hypersensitivity/angioedema

Angioedema of the face, limbs, lips, tongue, glottis, and/or larynx has been reported during ACE inhibitor therapy, including enalapril, at various times during treatment. Enalapril should be discontinued immediately and the patient placed under continuous observation until complete resolution of symptoms. Even isolated tongue swelling without respiratory compromise may require prolonged observation, as antihistamines and corticosteroids may be insufficient.

Fatal outcomes due to laryngeal or tongue angioedema have been very rarely reported. If swelling involves the tongue, glottis, or larynx, especially in patients with a history of airway surgery, airway obstruction may occur. If involvement of the tongue, pharynx, or larynx is suspected, immediate appropriate therapy should be initiated, including subcutaneous injection of 1:1000 adrenaline solution (0.3–0.5 mL) and/or measures to secure airway patency.

Angioedema occurs more frequently in patients of African descent receiving ACE inhibitors compared to other ethnic groups.

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 (e.g., 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 Hymenoptera venom

Rarely, patients receiving ACE inhibitors during allergen desensitization with Hymenoptera venom have developed anaphylactoid reactions that may be life-threatening. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before desensitization.

Anaphylactoid reactions during low-density lipoprotein apheresis

Rarely, patients taking ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily discontinuing ACE inhibitors before each apheresis session.

Patients on haemodialysis

Patients on haemodialysis using high-flux membranes (e.g., AN 69®) and concomitantly taking an ACE inhibitor may occasionally develop anaphylactoid reactions. Therefore, alternative dialysis membranes or antihypertensive agents from another class should be considered for such patients.

Hypoglycaemia

Patients with diabetes receiving oral antidiabetic agents or insulin and starting ACE inhibitor therapy 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 ACE inhibitor therapy. It is usually non-productive and persistent, resolving after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of chronic cough.

Surgery/anesthesia

During major surgery or anaesthesia with agents causing arterial hypotension, enalapril inhibits angiotensin II formation secondary to compensatory renin release. If arterial hypotension develops due to these mechanisms, it can be corrected by fluid volume expansion.

Hyperkalaemia

During treatment with ACE inhibitors, including enalapril, some patients may develop increased serum potassium levels. The risk of hyperkalaemia is higher in patients with renal failure, impaired renal function, age > 70 years, diabetes, transient conditions (e.g., dehydration, acute heart decompensation), metabolic acidosis, or 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 (e.g., heparin, trimethoprim-containing preparations). In particular, concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes in patients with renal impairment may lead to significant increases in serum potassium. Hyperkalaemia 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 cautiously 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, hyperkalaemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If dual blockade is necessary, therapy should be supervised by specialists 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.

Children

There is limited experience with effective and safe use in children over 6 years of age with arterial hypertension, but no experience in other indications. There are also limited pharmacokinetic data in children over 2 months of age (see sections "Pharmacological properties" and "Dosage and administration"). Enalapril is not recommended for treating children with conditions other than arterial hypertension.

Enalapril is not recommended for newborns 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 during pregnancy or by women planning pregnancy.

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

Ethnic characteristics

As with other ACE inhibitors, enalapril is less effective in lowering blood pressure in patients of African descent compared to other ethnic groups, possibly due to a higher prevalence of low renin levels in this population with arterial hypertension.

Lactose

The product contains lactose and should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use in pregnancy or breastfeeding.

Pregnancy

The medicinal product should not be used during pregnancy or by women planning pregnancy. If pregnancy is confirmed during treatment, therapy should be discontinued immediately and replaced with a pregnancy-approved alternative.

ACE inhibitors used during the second and third trimesters may cause foetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) or neonatal toxicity (renal failure, arterial hypotension, hyperkalaemia).

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

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

Breastfeeding

Limited pharmacokinetic data indicate very low concentrations in breast milk (see section "Pharmacokinetics"). Although such concentrations are considered clinically insignificant, enalapril is not recommended during breastfeeding of premature infants or newborns in the first weeks of life due to theoretical cardiovascular and renal risks and insufficient experience. For older infants, enalapril use during breastfeeding may be considered if necessary for the mother, provided the infant is monitored for adverse effects.

Ability to affect reaction speed when driving or operating machinery.

When driving or operating machinery, consider the possible occurrence of dizziness or increased fatigue.

Dosage and administration.

Food intake does not affect the absorption of Enalapril tablets.

Dosage should be individualized according to the patient's condition (see section "Special precautions and warnings") and blood pressure response.

When enalapril dosing below 5 mg is required, a formulation allowing such dosing should be used.

Arterial hypertension

Dosage ranges from an initial 5 mg to a maximum of 20 mg, depending on the severity of hypertension and patient status (see below). Enalapril is taken once daily. For mild hypertension, the recommended initial dose is 5–10 mg.

In patients with highly activated RAAS (e.g., renovascular hypertension, salt and/or fluid imbalance, decompensated heart failure, or severe hypertension), excessive blood pressure reduction may occur after the initial dose. Such patients should start with a dose of 5 mg or lower, under medical supervision.

Prior treatment with high-dose diuretics may lead to fluid depletion and 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 enalapril. Renal function and serum potassium should be monitored.

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

Heart failure/asymptomatic left ventricular dysfunction

For treatment of clinically manifest heart failure, enalapril should be used concomitantly with diuretics and, if necessary, digitalis or β-blockers. The initial dose of enalapril for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, administered under careful medical supervision to assess the initial effect on blood pressure. In the absence of effect or after appropriate management of symptomatic hypotension occurring at the start of enalapril therapy for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, administered 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 in patients with clinically manifest heart failure. The maximum dose is 40 mg daily in two divided doses.

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

Table 1

* 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) worsening renal failure have been reported. Patients receiving diuretics should, whenever possible, have their diuretic dose reduced prior to initiating Enalapril therapy. The occurrence of arterial hypotension after the initial dose of Enalapril does not imply that hypotension will persist during long-term therapy and is not an indication to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Dosing in renal insufficiency

In general, the dosing interval of enalapril should be prolonged and/or the dose of the drug reduced (see Table 2).

Table 2

* 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.

Elderly patients

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

Children with arterial hypertension from 6 years of age

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

For children who can swallow tablets, the dose should be individually prescribed 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. Enalapril should be taken once daily. Dose adjustment should be based on clinical need up to a maximum of 20 mg daily for patients with body weight from 20 to 50 kg and 40 mg for patients with body weight ≥ 50 kg (see sections "Special precautions" and "Children").

Children.

To be used in children from 6 years of age.

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, are profound arterial hypotension, beginning approximately 6 hours after drug intake 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, rapid heartbeat, bradycardia, dizziness, anxiety, and cough. Plasma levels of enalaprilat exceeding 100 and 200 times the maximum levels achieved with therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively.

For treatment of overdose, intravenous infusion of isotonic saline solution is recommended.

If arterial hypotension occurs, the patient should be placed in a supine position. Infusion of angiotensin II and/or intravenous administration of catecholamines may be considered. If the drug was recently ingested, measures to eliminate enalapril maleate (such as induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate) are recommended. Enalaprilat may be removed from systemic circulation by hemodialysis (see section "Special precautions": Patients undergoing hemodialysis). In cases of bradycardia resistant to pharmacological therapy, treatment with a cardiac pacemaker is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Adverse reactions.

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

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion.

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

Nervous system and psychiatric disorders: depression, headache, confusion, somnolence, insomnia, nervousness, paresthesia, vertigo, sleep disturbances, abnormal dreams, dizziness.

Eye disorders: blurred vision, visual disturbances.

Cardiovascular system disorders: arterial 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 high-risk patients (see section "Special precautions"), Raynaud's phenomenon.

Respiratory system disorders: cough, dyspnea, rhinorrhea, sore throat and hoarseness, bronchospasm/asthma, pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia, pharyngitis, bronchitis, interstitial pneumonitis.

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

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

Skin and subcutaneous tissue disorders: rash; hypersensitivity/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, including 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, photosensitivity, and other skin reactions may also occur as adverse effects.

Urinary system disorders: impaired renal function, renal failure, proteinuria, oliguria.

Reproductive system disorders: impotence, gynecomastia.

General disorders: asthenia, fatigue, muscle cramps, hot flushes, tinnitus, discomfort, fever.

Laboratory findings: hyperkalemia, increased serum creatinine, increased blood urea, hyponatremia, elevated liver enzymes, increased serum bilirubin.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Lubnypharm".

Manufacturer's address and place of business.

16 Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.