Enalapril-zdorovya

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALAPRIL-ZDOROVIYA

Composition:

Active substance: 1 tablet contains enalapril maleate 5 mg or 10 mg or 20 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, copovidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:
5 mg tablets are white or almost white, biconvex;
10 mg or 20 mg tablets are white or almost white, flat cylindrical with bevelled edges, imprinted with «ZT» by embossing on one side, or without imprint.

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-proproline.

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

ACE is identical to kininase II. Thus, the drug 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 the drug reduces arterial pressure is primarily attributed to inhibition of the renin-angiotensin-aldosterone system. The drug may exert antihypertensive effects even in patients with low-renin hypertension.

In arterial hypertension, administration of the drug leads to a reduction in arterial pressure in both supine and upright positions without a significant increase in heart rate. Symptomatic postural hypotension occurs infrequently. In some patients, optimal blood pressure reduction may require several weeks of therapy. Sudden discontinuation of the drug has not been associated with rapid rebound hypertension.

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

Hemodynamic studies in patients with essential hypertension have shown that blood pressure reduction is generally associated with decreased peripheral arterial resistance, increased cardiac output, and either a slight increase or no change in heart rate. Following administration of the drug, renal blood flow typically increases; glomerular filtration rate usually remains unchanged. There is no evidence of sodium or water retention. However, in patients with low baseline glomerular filtration rates, these values generally increased.

In patients with or without diabetes mellitus and kidney disease, enalapril administration has been associated with reduced albuminuria, urinary excretion of IgG, and total urinary protein.

When used concomitantly with thiazide diuretics, the antihypertensive effects of the drug are at least additive. The drug 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 has been associated with reduced peripheral resistance and blood pressure, increased cardiac output, and decreased heart rate (which is usually elevated in patients with heart failure). Pulmonary capillary wedge pressure also decreases. Exercise tolerance improves and severity of heart failure, assessed by NYHA (New York Heart Association) criteria, is reduced. These effects are sustained during long-term therapy.

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

Experience with use in children aged 6 years and older with arterial hypertension is limited. Data indicate that once-daily administration of enalapril reduces 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 of 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 is not different from that in adult patients.

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

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

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

Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.

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%).

In patients with renal impairment, exposure to enalapril and enalaprilat is increased. In patients with mild to moderate renal dysfunction (CLcr 40–60 mL/min), the steady-state AUC of enalaprilat is approximately twice that in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (CLcr ≤ 30 mL/min), AUC increases approximately 8-fold. At these levels of renal impairment, the effective T½ of enalaprilat is prolonged, and the time to steady state is delayed.

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

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to the components of the drug or to any other angiotensin-converting enzyme (ACE) inhibitor.
• History of angioedema associated with previous use of ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Pregnancy or women planning to become pregnant (see section "Use during pregnancy or breastfeeding").

Concomitant use of enalapril with drugs containing aliskiren is not recommended in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²).

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 further reduce arterial 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), as well as potassium-containing dietary supplements or salt substitutes, may lead to a significant increase in serum potassium levels. If these agents are indicated due to hypokalemia, they should be used cautiously with regular monitoring of serum potassium levels.

Diuretics (thiazide or loop diuretics). Prior treatment with high-dose diuretics may lead to reduced intravascular volume and increase the risk of arterial hypotension at the initiation of enalapril therapy. Hypotensive effects can be minimized by discontinuing the diuretic, increasing dietary salt intake, or starting enalapril at a low dose.

Antidiabetic agents. Epidemiological data suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may reduce blood glucose levels and increase the risk of hypoglycemia. This phenomenon is most likely during the first weeks of combined therapy and in patients with renal impairment.

Serum lithium. Concurrent use of ACE inhibitors and lithium has been associated with reversible increases in serum lithium levels and lithium toxicity. Concomitant use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and increase the risk of lithium intoxication. Concomitant use of enalapril and lithium is not recommended; however, if such combination is necessary, careful monitoring of serum lithium levels is required.

Tricyclic antidepressants/neuroleptics/anesthetics/sedatives. Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may lead to additional reduction in arterial blood pressure.

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 an additive effect on increasing serum potassium levels and may lead to impaired renal function. These effects are usually reversible.

Acute renal failure has been reported rarely, particularly in certain patients with pre-existing renal impairment (e.g., elderly patients or patients with reduced intravascular volume, including those taking diuretics). Therefore, such combinations should be used cautiously in patients with renal impairment. Patients should maintain adequate hydration and be closely monitored for renal function at the initiation of combination 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 under strict 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 monotherapy 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).

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

Sympathomimetics. Sympathomimetic agents 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.

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 monotherapy 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, serum potassium levels, and blood pressure.

Special precautions for use.

Symptomatic hypotension. Symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. In hypertensive patients receiving enalapril, symptomatic hypotension occurs more frequently in patients 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. Symptomatic hypotension has also been observed in patients with heart failure, with or without concomitant renal insufficiency. Symptomatic hypotension occurs more frequently in patients with more severe forms of heart failure who are receiving higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should begin treatment under medical supervision. Particular caution is required when adjusting the dose of the drug and/or diuretic. Similarly, patients with ischemic heart disease or cerebrovascular disease should be closely monitored, as excessive reduction in arterial pressure may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, administered intravenous physiological saline solution. Transient arterial hypotension during treatment with the drug is not a contraindication for continued use, which can usually be resumed without complications after normalization of blood pressure through fluid volume restoration.

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

Aortic or mitral stenosis/hypertrophic cardiomyopathy. As with all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction or outflow tract obstruction; their use should be avoided in cases of cardiogenic shock and hemodynamically significant obstruction.

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

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

In some hypertensive patients without pre-existing kidney disease, enalapril in combination with diuretics has usually caused slight and transient increases in blood urea nitrogen and serum creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation may indicate the presence of renal artery stenosis.

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 when treated with ACE inhibitors. Loss of kidney function may occur even with minimal changes in serum creatinine levels. For such patients, treatment should be initiated 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 the drug in patients who have recently undergone kidney transplantation. Therefore, treatment with the drug is not recommended in 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 elevation of liver enzymes should discontinue the ACE inhibitor and be placed under appropriate medical monitoring.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia is rare. Enalapril should be used with extreme caution in patients with collagen vascular diseases receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or in combination with these complicating factors, especially if renal impairment already exists. Some of these patients developed serious infections, which sometimes did not respond to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended when prescribing enalapril to such patients, and patients should be instructed to report any signs of infection.

Hypersensitivity/angioedema. Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported during therapy with ACE inhibitors, including enalapril, occurring at various times during treatment. In such cases, treatment with the drug should be immediately discontinued and the patient placed under continuous medical observation until complete resolution of symptoms is confirmed. Observation may only be discontinued thereafter. Even when only tongue swelling occurs 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 is localized in the tongue, glottis, or larynx, especially 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, 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 when treated with an ACE inhibitor.

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

Anaphylactoid reactions during LDL apheresis. Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate. 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) while concurrently receiving an ACE inhibitor, anaphylactoid reactions have occasionally occurred. Therefore, for such patients, consideration should be given to using dialysis membranes of a different type or an antihypertensive agent from another drug class.

Hypoglycemia. Patients with diabetes mellitus who are taking oral antidiabetic agents or insulin and begin therapy with an ACE inhibitor should be advised to closely monitor their blood glucose levels, especially during the first few months of concomitant use.

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. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgical procedures/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, increased serum potassium levels have been observed in some patients. The risk of hyperkalemia is increased in patients with renal insufficiency, impaired renal function, age > 70 years, diabetes mellitus, transient conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of potassium-containing dietary supplements or salt substitutes; and in patients taking other drugs that may increase serum potassium (e.g., heparin). 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 drugs is considered necessary, they should be used with caution and with regular monitoring of serum potassium levels.

Lithium. Combination of lithium and enalapril is generally not recommended.

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

The drug contains lactose, which should be taken into account in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy. The drug is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, treatment must be immediately discontinued and, if necessary, replaced with another medicinal product approved for use during pregnancy.

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

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

Newborns whose mothers received ACE inhibitors should be closely monitored for the development of arterial hypotension.

Breastfeeding. Limited pharmacokinetic data indicate very low concentrations in breast milk. Although such concentrations are considered clinically insignificant, the use of the drug is not recommended during breastfeeding of preterm infants and newborns during the first few weeks of life due to a hypothetical risk of cardiovascular and renal effects, as well as insufficient experience in this regard. In the case of older infants, use of the drug during breastfeeding may be considered if treatment is necessary for the mother, provided the infant is monitored for any adverse effects.

Ability to affect reaction rate when driving or operating machinery. When driving 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 tablets. Since the tablet is not scored, if a dose lower than 5 mg is required, enalapril-containing products allowing such dosing should be used.

Dosage must be individually adjusted according to each patient's condition and response in arterial pressure.

Arterial Hypertension. The dosage ranges from an initial dose of 5 mg to a maximum of 20 mg, depending on the severity of arterial hypertension and the patient's condition (see below). The drug 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 arterial pressure may occur after the initial dose. Such patients should receive an initial 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 therapy should be discontinued 2–3 days before starting enalapril treatment. 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, the drug should be used concomitantly with diuretics and, if necessary, digitalis preparations or beta-blockers. The initial dose for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. Treatment initiation must be 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 treatment, 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 has been shown to effectively reduce mortality rates in patients with clinically manifest heart failure. The maximum dose is 40 mg per day in two divided doses.

Proposed 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.

Careful monitoring of blood pressure and renal function should be performed both before and during treatment with the drug, as cases of arterial hypotension and (less commonly) subsequent renal failure have been reported. In patients taking diuretics, the diuretic dose should be reduced, if possible, prior to initiating treatment with the drug. The development of arterial hypotension after the initial dose of the drug does not necessarily indicate that hypotension will persist during long-term therapy and does not imply the need 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 dosage of the drug reduced.

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

Geriatric patients. Dosage should be adjusted according to renal function.

Children with hypertension aged 6 years and older. Clinical experience with the use of the drug in children with hypertension is limited. For children able to swallow tablets, the dose should be individually prescribed based on 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. The drug should be taken once daily. Dosage should be adjusted according to 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.

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

Children. |established|, therefore, use in children aged 6 years and older.

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

Overdose. Data regarding 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, 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 ingestion of 300 mg and 440 mg of enalapril, respectively.

For the treatment of overdose, intravenous infusion of isotonic saline solution 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 undertaken (such as induced vomiting, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis. In cases of bradycardia resistant to therapeutic interventions, treatment with a cardiac pacemaker is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Side effects

When using the drug, adverse reactions were mostly mild, transient, and did not require discontinuation of therapy.

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

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

Metabolic disorders: hypoglycemia.

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

Eye disorders: blurred vision.

Cardiovascular disorders: dizziness, hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia, palpitations, myocardial infarction or stroke, possibly due to excessive blood pressure reduction in patients at high risk, Raynaud's phenomenon.

Respiratory system disorders: cough, dyspnea, rhinorrhea, sore throat and hoarseness, bronchospasm/asthma, lung infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

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

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

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

A complex syndrome has been reported, which may include 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 reactions such as rash, photosensitivity, and other skin-related adverse effects may also occur.

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

Reproductive system disorders: impotence, gynecomastia.

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

Laboratory test abnormalities: hyperkalemia, increased serum creatinine, increased blood urea, hyponatremia, increased 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: 5 mg tablets, pack size 20 (10×2), 30 (10×3) in blisters in a box; 10 mg or 20 mg tablets, pack size 20 (10×2), 20 (20×1) in blisters in a box.

Prescription category: Prescription only.

Manufacturer: LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and place of business: Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenko Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenko Street, 100.

(Limited Liability Company "FARMEKS GROUP")