EVRISDI

INSTRUCTIONS FOR MEDICAL USE OF ENALAPRIL

Composition

active substance: enalapril; 1 tablet contains enalapril maleate (in terms of 100% substance) – 10 mg; excipients: lactose, monohydrate; potato starch; microcrystalline cellulose; povidone; colloidal anhydrous silicon dioxide; talc; calcium stearate.

Pharmaceutical Form

Tablets.

Main Physico-Chemical Properties

Whole regular round cylinders, the upper and lower surfaces of which are flat, the edges of the surfaces are beveled, with a notch for division, from white or almost white color.

Pharmacotherapeutic Group

Angiotensin-converting enzyme inhibitors, monocomponent.

ATC Code

C09A A02.

Pharmacological Properties

Pharmacodynamics

Enalapril maleate is a salt of maleic acid of enalapril, a derivative of two amino acids, L-alanine and L-proline, which is hydrolyzed in the liver to form enalaprilat, which is an inhibitor of angiotensin-converting enzyme (ACE).

Inhibition of ACE leads to a decrease in the formation of angiotensin II in tissues and plasma, additional decrease in aldosterone secretion, and an increase in plasma renin activity. As a result of ACE inhibition, there is an increase in the activity of the kallikrein-kinin system, accumulation of bradykinin, and, as a consequence, activation of the prostaglandin system. The use of enalapril maleate in patients with arterial hypertension leads to a decrease in arterial pressure without a compensatory increase in heart rate, a decrease in peripheral vascular resistance. In patients with heart failure, the use of enalapril maleate causes a decrease in peripheral vascular resistance, resulting in a decrease in post-load on the heart. During treatment with enalapril maleate, an increase in cardiac output, an increase in stroke index, and an increase in exercise tolerance are observed, a decrease in left ventricular hypertrophy, and an improvement in intrarenal hemodynamics in the kidneys. Enalapril maleate does not affect glucose and lipoprotein metabolism.

Pharmacokinetics

After oral administration, enalapril maleate is rapidly absorbed, 60% of the administered dose is absorbed. Food intake does not affect its absorption. The peak concentration of enalaprilat in plasma is reached approximately 4 hours after administration. The effective half-life of enalaprilat after multiple oral administration is 11 hours. Effective inhibition of ACE activity occurs within 2-4 hours after administration of a single dose of enalapril maleate. The onset of antihypertensive action is observed within 1 hour, and the maximum effect is observed within 4-6 hours after administration of the drug. The duration of action depends on the dose, but at the recommended dosage, antihypertensive and hemodynamic effects persist for at least 24 hours. In volunteers with normal renal function, the concentration of enalaprilat in serum reaches its steady state approximately 4 days after the start of administration. Within the range of therapeutically significant concentrations in humans, binding to plasma proteins does not exceed 60%. In addition to conversion to enalaprilat, there is no significant metabolism of enalapril maleate. Enalaprilat is excreted mainly by the kidneys. The main component in urine is 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 ACE inhibitor.

- History of angioedema associated with the use of ACE inhibitors.

- Hereditary or idiopathic angioedema.

- Use of enalapril with drugs containing aliskiren in patients with diabetes or with impaired renal function (GFR < 60 ml/min/1.73 m2).

- Pregnancy or planning of pregnancy (see section "Use during pregnancy or breastfeeding").

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

Interactions with Other Medicinal Products and Other Forms of Interaction

Hypotensive therapy

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

Potassium-sparing diuretics or potassium supplements

ACE inhibitors increase the diuretic-induced loss of potassium. The use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride) and/or the use of potassium-containing salt substitutes or other products that may increase potassium levels in the blood (e.g., trimethoprim-containing products) should be undertaken with caution, especially in patients with impaired renal function, as they may lead to significant increases in potassium levels in the blood. If the above-mentioned products are indicated due to hypokalemia, they should be used with caution, regularly monitoring potassium levels in the blood (see section "Special warnings and precautions for use").

Diuretics (thiazide or loop diuretics)

Prior treatment with high doses of diuretics may lead to a decrease in circulating blood volume and an increased risk of hypotension at the start of enalapril therapy (see section "Special warnings and precautions for use"). Hypotensive effects can be reduced by discontinuing the diuretic, increasing salt intake, or using a low dose of enalapril at the start of therapy.

Antidiabetic drugs

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic drugs (insulin, oral hypoglycemic agents) may cause a decrease in blood glucose levels with a risk of developing hypoglycemia. This phenomenon is most likely to occur during the first weeks of concomitant use and in the presence of renal impairment in the patient (see sections "Special warnings and precautions for use" and "Adverse reactions").

Lithium levels in the blood

When ACE inhibitors and lithium are used concomitantly, reversible increases in lithium levels in the blood and toxicity have been reported. Concurrent use of ACE inhibitors and thiazide diuretics may further increase lithium levels in the blood and increase the risk of lithium intoxication. Concomitant use of enalapril and lithium is not recommended, but if such a combination is necessary for the patient, careful monitoring of lithium levels in the blood is required (see section "Special warnings and precautions for use").

Tricyclic antidepressants/neuroleptics/anesthetics/sedatives

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

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

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

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors may result in an additive effect on increasing potassium levels in the blood and may lead to impaired renal function. These phenomena are usually reversible.

Rarely, acute renal failure may occur, especially in some patients with impaired renal function (e.g., elderly patients or patients with reduced circulating blood volume, including those taking diuretics). Therefore, such a combination should be introduced with caution in patients with impaired renal function. Patients should consume sufficient amounts of fluid and be under close monitoring of renal function at the start of concomitant therapy and periodically during such 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 only individual cases with close monitoring of blood pressure, renal function, and electrolyte levels. During several studies, it was reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual blockade of RAAS was associated with a higher frequency of hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to the use of one drug affecting RAAS. Enalapril should not be used with aliskiren in patients with diabetes or with impaired renal function (GFR < 60 ml/min/1.73 m2) (see sections "Contraindications" or "Special warnings and precautions for use").

Gold preparations

Rarely, nitritoid reactions (symptoms including facial swelling, nausea, vomiting, and hypotension) have been reported in patients treated with injectable gold preparations (sodium aurothiomalate) and concomitantly with an ACE inhibitor, including enalapril.

mTOR inhibitors

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

Neprilysin inhibitors

Concomitant use with neprilysin inhibitors (e.g., sacubitril) may increase the risk of angioedema (see sections "Special warnings and precautions for use" and "Interactions 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 beta-blockers

Enalapril can be safely used concomitantly with acetylsalicylic acid (in cardiological doses), thrombolytics, and beta-blockers.

Special Warnings and Precautions for Use

Symptomatic Hypotension

Symptomatic hypotension has rarely been observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension treated with enalapril, symptomatic hypotension develops more frequently in the presence of hypovolemia, which occurs, for example, due to diuretic therapy, restriction of salt intake, in patients undergoing hemodialysis, as well as in patients with diarrhea or vomiting (see sections "Interactions with other medicinal products and other forms of interaction" and "Adverse reactions"). Symptomatic hypotension has also been observed in patients with heart failure, which was accompanied by or not accompanied by renal failure. Symptomatic hypotension developed more frequently in patients with more severe forms of heart failure, who were treated with higher doses of loop diuretics, with hyponatremia or impaired renal function. Such patients should start treatment with enalapril under medical supervision. When changing the dose of enalapril and/or diuretic, monitoring should be especially careful. Similarly, patients with ischemic heart disease or cerebrovascular disease should be monitored, in whom excessive blood pressure reduction may lead to myocardial infarction or stroke.

If arterial hypotension develops, the patient should be placed in a horizontal position and, if necessary, intravenous administration of physiological solution should be performed. Transient arterial hypotension during enalapril administration is not a contraindication to further administration, which can be continued usually without complications after normalization of blood pressure by restoring fluid volume.

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

Aortic or Mitral Stenosis/Hypertrophic Cardiomyopathy

As with all vasodilators, ACE inhibitors should be prescribed with caution to patients with outflow obstruction from the left ventricle and outflow tract obstruction; their use should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Impaired Renal Function

Patients with impaired renal function (creatinine clearance < 80 ml/min) should have the initial dose of enalapril adjusted according to creatinine clearance (see section "Posology and method of administration") and further adjusted according to the response to treatment. For such patients, standard medical practice is regular monitoring of potassium levels and creatinine levels in the blood.

Impaired renal function has been reported in association with enalapril use, which was mostly observed in patients with severe heart failure or with kidney disease, including stenosis of the renal artery. Renal failure associated with enalapril therapy is usually reversible upon timely detection and appropriate treatment.

In some patients with hypertension who had no kidney disease before starting treatment, enalapril, in combination with diuretics, caused a usually minor and transient increase in blood urea and creatinine levels in the blood. In such cases, it may be necessary to reduce the dose and/or discontinue the diuretic. This situation increases the likelihood of existing renal artery stenosis (see section "Special warnings and precautions for use" Renovascular hypertension).

Renovascular Hypertension

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

Kidney Transplantation

There is no experience with the use of enalapril in patients who have recently undergone kidney transplantation. Therefore, such patients are not recommended to be treated with enalapril.

Liver Dysfunction

Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant necrosis of the liver and (sometimes) fatal outcome. The mechanism of this syndrome remains unexplained. Patients who are taking ACE inhibitors and develop jaundice or significant elevations in liver enzymes should discontinue the ACE inhibitor and be kept under medical surveillance.

Neutropenia/Agranulocytosis

In patients who have taken ACE inhibitors, neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported. In patients with normal renal function and in the absence of other complicating factors, neutropenia occurred rarely. Enalapril should be prescribed with great caution to patients with collagen vascular disease who are receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is already impaired renal function. In some of these patients, serious infections have developed, which have not responded to intensive antibiotic therapy. When enalapril is prescribed to such patients, periodic monitoring of the white blood cell count is recommended, and patients should report any signs of infection.

Hypersensitivity/Angioedema

When ACE inhibitors, including enalapril, are used, isolated cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been described, which occurred at various times during treatment. In these cases, enalapril treatment should be discontinued immediately, and constant monitoring of the patient should be established to ensure complete disappearance of symptoms. Only after that can monitoring be stopped. Even when edema is limited to the tongue, without respiratory distress, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatalities have been reported due to angioedema of the larynx or tongue. When edema involves the tongue, glottis, or larynx, especially in patients with a history of surgical interventions on the respiratory tract, airway obstruction may develop. When there is involvement of the tongue, pharynx, or larynx, and this may cause airway obstruction, appropriate therapy should be started immediately, which may include subcutaneous administration of a 1:1000 adrenaline solution and/or measures to ensure airway patency.

In black patients who have used ACE inhibitors, angioedema has occurred more frequently compared to patients of other races.

Patients with a history of angioedema not associated with ACE inhibitors may have an increased risk of its occurrence when treated with an ACE inhibitor (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 "Interactions with other medicinal products and other forms of interaction").

Anaphylactoid Reactions During Desensitization with Hymenoptera Venom

Rarely, in patients who have received ACE inhibitors during desensitization with Hymenoptera venom, anaphylactoid reactions have developed, which could be life-threatening. Such reactions can be avoided if ACE inhibitor administration is temporarily discontinued before starting desensitization.

Anaphylactoid Reactions During Low-Density Lipoprotein Apheresis

Rarely, in patients who have taken ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate, anaphylactoid reactions have occurred, which were life-threatening. Such reactions can be avoided by temporarily discontinuing ACE inhibitor administration before each apheresis.

Patients Undergoing Hemodialysis

In patients undergoing dialysis using high-flux membranes (e.g., AN 69) and concomitantly taking an ACE inhibitor, anaphylactoid reactions have sometimes developed. Therefore, for such patients, it is recommended to consider the use of dialysis membranes of a different type or a hypotensive agent of a different group.

Hypoglycemia

Patients with diabetes who are taking oral antidiabetic drugs or insulin and start treatment with an ACE inhibitor should be advised to carefully monitor blood glucose levels, especially during the first few months of concomitant use (see section "Interactions with other medicinal products and other forms of interaction").

Cough

Cough has been reported during treatment with ACE inhibitors. Usually, the cough is non-productive and persistent and disappears after discontinuation of the drug. Cough due to ACE inhibitor treatment should be considered in the differential diagnosis of cough.

Surgery/Anesthesia

During major surgical operations or anesthesia using drugs that cause hypotension, enalapril blocks the formation of angiotensin II, secondary to compensatory renin release. If hypotension develops in this situation, which can be explained by these mechanisms of interaction, it is corrected by increasing fluid volume.

Hyperkalemia

During treatment with ACE inhibitors, including enalapril, hyperkalemia has been observed in some patients. The risk of hyperkalemia is increased in patients with renal impairment, impaired renal function, age > 70 years, diabetes, transient conditions, such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); the use of potassium-containing salt substitutes or other products that may increase potassium levels in the blood; and in patients taking other drugs that may cause hyperkalemia (e.g., heparin, trimethoprim-containing products). In particular, the use of potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes in patients with impaired renal function may lead to significant increases in potassium levels in the blood. Hyperkalemia can 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, regularly monitoring potassium levels in the blood (see section "Interactions with other medicinal products and other forms of interaction").

Lithium

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

Concomitant Use of ACE Inhibitor and Angiotensin Receptor Antagonist

There are data that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Therefore, dual blockade of RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If dual blockade is necessary, therapy should be carried out under the supervision of specialists and with constant monitoring of renal function, electrolyte levels, and blood pressure indicators. 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 with arterial hypertension aged 6 years and older, but there is no experience with its use for other indications. There is also limited data on pharmacokinetics in children aged 2 months and older (see sections "Pharmacodynamics", "Pharmacokinetics", "Special warnings and precautions for use"). Enalapril is not recommended for the treatment of children with diseases other than arterial hypertension.

Enalapril is not recommended for use in newborns and children with a glomerular filtration rate of < 30 ml/min/1.73 m2 due to the lack of data (see section "Posology and method of administration").

Pregnancy

The drug should not be used in pregnant women or women planning to become pregnant.

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

Ethnic Characteristics

As with other ACE inhibitors, enalapril is less effective in reducing blood pressure in black patients than in patients of other races, possibly due to the fact that low renin levels are more common in this population of patients with arterial hypertension.

Lactose

The drug contains lactose, so it should not be prescribed to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use During Pregnancy or Breastfeeding

Pregnancy

The drug should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be discontinued immediately and replaced with another drug approved for use in pregnant women.

ACE inhibitors used during the II and III trimesters of pregnancy may cause fetotoxicity (renal dysfunction, oligohydramnios, delayed ossification of the skull bones) or neonatal toxicity (renal failure, hypotension, hyperkalemia).

If ACE inhibitors were used during the II trimester of pregnancy, it is recommended to perform ultrasound examination of the kidneys and skull.

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

Breastfeeding

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

Ability to Affect the Speed of Reaction When Driving Vehicles and Other Mechanisms

When driving a vehicle or working with other mechanisms, one should take into account the possible development of dizziness or increased fatigue.

Posology and Method of Administration

Food intake does not affect the absorption of enalapril tablets.

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

If enalapril is prescribed in a dose of less than 5 mg, a preparation of enalapril with such dosing should be used.

Arterial Hypertension

The dose of the drug is 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 is taken once a day. For mild arterial hypertension, the recommended initial dose is 5-10 mg.

In patients with highly activated RAAS (e.g., with renovascular hypertension, impaired salt and/or fluid balance, decompensated heart failure, or severe arterial hypertension), excessive blood pressure reduction may occur after the initial dose. Such patients are recommended to start with an initial dose of 5 mg or lower, and the start of treatment should be under medical supervision.

Prior treatment with high doses of diuretics may lead to a deficit of fluid and an increased risk of hypotension at the start of enalapril therapy. For such patients, an initial dose of 5 mg or lower is recommended. If possible, diuretic treatment should be discontinued 2-3 days before starting enalapril treatment. Renal function and potassium levels in the blood should be monitored.

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

Heart Failure/Asymptomatic Left Ventricular Dysfunction

For the treatment of clinically manifest heart failure, enalapril should be used in combination with diuretics and, if necessary, digitalis preparations or beta-blockers. The initial dose of enalapril for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, and treatment should be started under close medical supervision to establish the initial effect of the drug on blood pressure. If there is no effect or after appropriate correction of symptomatic hypotension that develops at the start of enalapril treatment for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, which is taken once or divided into 2 doses, depending on the patient's tolerance. Dose titration is recommended to be carried out over 2-4 weeks. A similar therapeutic regimen effectively reduces mortality in patients with clinically manifest heart failure. The maximum dose is 40 mg per day in 2 divided doses.

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

* With caution, the drug should be used in patients with impaired renal function or those taking diuretics (see section "Special warnings and precautions for use").

Both before and after starting enalapril treatment, close monitoring of blood pressure and renal function (see section "Special warnings and precautions for use") is required, as hypotension and (less frequently) subsequent renal failure have been reported. Patients taking diuretics should, if possible, have their dose reduced before starting enalapril treatment. The development of hypotension after the initial dose of enalapril does not mean that hypotension will persist during long-term treatment and does not indicate the need to discontinue the drug. Potassium levels in the blood and renal function should also be monitored.

Dosing in Renal Impairment

Generally, the interval between enalapril administrations should be increased and/or the dose of the drug should be reduced (see Table 2).

* See section "Special warnings and precautions for use": Patients undergoing hemodialysis.

Enalapril is removed by hemodialysis. Dose adjustment on days when hemodialysis is not performed should be carried out depending on blood pressure.

Elderly Patients

The dose should be adjusted according to the patient's renal function (see section "Special warnings and precautions for use").

Children with Arterial Hypertension Aged 6 Years and Older

Experience with the clinical use of enalapril in children with arterial hypertension is limited (see sections "Pharmacodynamics", "Pharmacokinetics", "Special warnings and precautions for use").

Children who can swallow tablets should have the dose individualized 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 a body weight of 20-50 kg and 5 mg for patients with a body weight ≥ 50 kg. Enalapril is taken once a day. Dosing should be adjusted according to the needs up to a maximum of 20 mg per day for patients with a body weight of 20-50 kg and 40 mg for patients with a body weight ≥ 50 kg (see sections "Special warnings and precautions for use" and "Children").

Children

Enalapril is used in children aged 6 years and older.

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

Overdose

There are limited data on overdose of the drug. The main signs of overdose, according to available data, are pronounced hypotension, which begins approximately 6 hours after administration of the drug and coincides with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, accelerated heart rate, bradycardia, dizziness, anxiety, and cough. Enalaprilat levels in plasma that exceed 100 and 200 times the maximum levels achieved with therapeutic doses have been reported after administration of 300 mg and 440 mg of enalapril, respectively.

For the treatment of overdose, intravenous infusions of isotonic solution are recommended. If hypotension develops, the patient should be placed in a horizontal position. The need for infusions of angiotensin II and/or intravenous administration of catecholamines may be considered. If the drug was taken recently, measures to eliminate enalapril maleate (such as inducing vomiting, gastric lavage, taking absorbents, and sodium sulfate) are recommended. Enalaprilat can be removed from the systemic circulation by hemodialysis (see section "Special warnings and precautions for use": Patients undergoing hemodialysis). In the case of bradycardia resistant to therapy, treatment with a pacemaker is indicated. Constant monitoring of vital signs, electrolyte levels, and creatinine levels in the blood is required.

Adverse Reactions

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

From the endocrine system: syndrome of inappropriate secretion of antidiuretic hormone.

Metabolic disorders: hypoglycemia (see section "Special warnings and precautions for use").

From the nervous system and psyche: depression, headache, confusion, drowsiness, insomnia, nervousness, paresthesia, vertigo, sleep disorders, abnormal dreams, dizziness.

From the organs of vision: blurred vision, visual disturbances.

From the cardiovascular system: hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmias, angina pectoris, tachycardia, orthostatic hypotension, accelerated heart rate, myocardial infarction, or stroke, possibly due to excessive blood pressure reduction in patients at high risk (see section "Special warnings and precautions for use"), Raynaud's phenomenon.

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

From the digestive tract: nausea, diarrhea, abdominal pain, change in taste, intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers/oral aphthous ulcers, glossitis, angioedema of the intestine.

From the hepatobiliary system: liver failure, hepatocellular or cholestatic hepatitis, hepatitis, including necrosis, cholestasis (including jaundice).

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

There have been reports of the development of a complex syndrome that included some or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive test for antinuclear antibodies, increased erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. As adverse effects, rash, photosensitization, and other skin reactions may also occur.

From the urinary system: impaired renal function, renal failure, proteinuria, oliguria.

From the reproductive system: impotence, gynecomastia.

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

Laboratory indicators: hyperkalemia, increased creatinine in the blood, increased urea in the blood, hyponatremia, increased liver enzymes, increased bilirubin in the blood.

Shelf Life

3 years.

Storage Conditions

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

Keep out of the reach of children.

Packaging

10 tablets in a blister pack; 2 blister packs in a carton.

Release Category

Prescription only.

Manufacturer

Lubnypharm LLC.

Manufacturer's Location and Address

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