Ednyt^® (Tablets) Instructions for Use

ATC Code

C09AA02 (Enalapril)

Active Substance

Enalapril

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE inhibitor

Pharmacological Action

Enalapril belongs to drugs affecting the renin-angiotensin-aldosterone system (RAAS) – ACE inhibitors. Enalapril is used for the treatment of essential hypertension (primary arterial hypertension) of any severity and renovascular hypertension, both in monotherapy and in combination with other antihypertensive agents, in particular with diuretics. Enalapril is used for the treatment or prevention of the development of heart failure.

Pharmacodynamics

Enalapril is a derivative of two amino acids, L-alanine and L-proline. After oral administration, Enalapril is rapidly absorbed and hydrolyzed to enalaprilat, which is a highly specific and long-acting ACE inhibitor that does not contain a sulfhydryl group. ACE (peptidyl-dipeptidase A) catalyzes the conversion of angiotensin I to the pressor peptide angiotensin II. After absorption, Enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which results in an increase in plasma renin activity (due to the elimination of negative feedback in response to renin release) and a decrease in aldosterone secretion.

ACE is identical to the enzyme kininase II, therefore Enalapril can also block the degradation of bradykinin, a peptide with a pronounced vasodilatory effect. The significance of this effect in the therapeutic action of enalapril requires clarification.

Although the main mechanism by which Enalapril reduces blood pressure is considered to be the suppression of RAAS activity, which plays an important role in blood pressure regulation, Enalapril exhibits an antihypertensive effect even in patients with hypertension and reduced plasma renin activity.

The use of enalapril in patients with hypertension leads to a reduction in blood pressure both in the standing and lying positions without a significant increase in heart rate. Symptomatic postural hypotension develops infrequently. In some patients, achieving optimal blood pressure reduction may require several weeks of therapy. Interruption of enalapril therapy does not cause a sharp increase in blood pressure.

Effective inhibition of ACE activity usually develops 2-4 hours after a single oral dose of enalapril. The antihypertensive effect develops within 1 hour, and the maximum reduction in blood pressure is observed 4-6 hours after taking the drug. The duration of action is dose-dependent. However, when using the recommended doses, the antihypertensive effect and hemodynamic effects persist for 24 hours.

Antihypertensive therapy with enalapril leads to a significant regression of left ventricular hypertrophy and preservation of its systolic function.

In clinical hemodynamic studies in patients with essential hypertension, the reduction in blood pressure was accompanied by a decrease in total peripheral vascular resistance, an increase in cardiac output, and no change or minor changes in heart rate. After taking enalapril, an increase in renal blood flow is observed without changes in the glomerular filtration rate and the presence of signs of sodium or fluid retention. However, in patients with initially reduced glomerular filtration, its rate usually increased. Long-term use of enalapril in patients with essential hypertension and renal failure may lead to improved renal function, as evidenced by an increase in the glomerular filtration rate.

In short-term clinical studies in patients with renal failure with or without diabetes, a reduction in albuminuria, urinary excretion of IgG, and a decrease in total protein in the urine were observed after taking enalapril.

When enalapril and thiazide diuretics are used concomitantly, a more pronounced antihypertensive effect is observed. Enalapril reduces or prevents the development of hypokalemia caused by taking thiazide diuretics.

Therapy with enalapril is usually not associated with an undesirable effect on the concentration of uric acid in the blood plasma.

Therapy with enalapril is accompanied by a favorable effect on the ratio of lipoprotein fractions in the blood plasma and no effect or a favorable effect on the concentration of total cholesterol.

In patients with heart failure on therapy with cardiac glycosides and diuretics, taking enalapril leads to a decrease in total peripheral vascular resistance and blood pressure. Cardiac output increases, while heart rate, usually elevated in patients with heart failure, decreases. Pulmonary capillary wedge pressure also decreases.

Increases exercise tolerance and reduces the severity of heart failure, as assessed by the New York Heart Association (NYHA) criteria. These effects are manifested during long-term therapy with enalapril.

In patients with mild to moderate heart failure, Enalapril slows the progression of cardiac dilation and heart failure, as evidenced by a reduction in left ventricular end-diastolic and systolic volumes and an improvement in left ventricular ejection fraction.

Clinical data have shown that Enalapril reduces the frequency of ventricular arrhythmias in patients with heart failure, although the main mechanisms and clinical significance of this effect are not known.

Pharmacokinetics

Absorption

After oral administration, Enalapril is rapidly absorbed in the gastrointestinal tract. C_max of enalapril in the blood serum is reached within 1 hour after oral administration. The extent of absorption of enalapril after oral administration is approximately 60%. Food intake does not affect the absorption of enalapril. After absorption, Enalapril is rapidly hydrolyzed to form the active metabolite enalaprilat, a potent ACE inhibitor. C_max of enalaprilat in the blood serum is observed approximately 3-4 hours after oral administration of enalapril. The duration of absorption and hydrolysis of enalapril is similar for various recommended therapeutic doses. In healthy volunteers with normal renal function, C_ss of enalaprilat in the blood serum is reached by the 4th day from the start of enalapril administration.

Distribution

In the range of therapeutic doses, the binding of enalaprilat to blood plasma proteins does not exceed 60%.

Metabolism

There are no data on other significant pathways of enalapril metabolism besides hydrolysis to enalaprilat.

Excretion

Excretion of enalapril is carried out mainly by the kidneys. The main metabolites determined in the urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged Enalapril (approximately 20%). The concentration curve of enalaprilat in the blood plasma has a long terminal phase, apparently due to its binding to ACE. T_1/2 of enalaprilat during course oral administration of the drug is 11 hours.

Pharmacokinetics in special patient groups

Patients with renal failure. The area under the concentration-time curve (AUC) of enalapril and enalaprilat increases in patients with renal failure. In patients with mild to moderate renal failure (creatinine clearance 40-60 ml/min) after taking enalapril at a dose of 5 mg once a day, the equilibrium AUC value of enalaprilat was approximately 2 times higher than in patients with unchanged renal function. In patients with severe renal failure (creatinine clearance not more than 30 ml/min), the AUC value increased approximately 8 times. The effective T_1/2 of enalaprilat after multiple administration of enalapril in patients with severe renal failure increased, and the onset of the equilibrium concentration of enalaprilat was delayed. Enalaprilat can be removed from the systemic circulation by hemodialysis. The clearance during hemodialysis is 62 ml/min.

Patients with hepatic insufficiency. There are no data on the pharmacokinetics of enalapril in patients with hepatic insufficiency.

Elderly patients (over 65 years). There are no data on the pharmacokinetics of enalapril in elderly patients.

Breastfeeding. After a single oral dose of enalapril 20 mg in postpartum patients, the mean C_max of enalapril in breast milk was 1.7 µg/L (from 0.54 to 5.9 µg/L) at 4-6 hours after administration. The mean C_max of enalaprilat was 1.7 µg/L (from 1.2 to 2.3 µg/L) and was observed at various times within 24 hours after administration. Based on the C_max data in breast milk, the estimated maximum intake of enalapril by a fully breastfed infant is 0.16% of the dose calculated based on the mother’s body weight. In a woman who took Enalapril orally at a dose of 10 mg once a day for 11 months, the C_max of enalapril in breast milk was 2 µg/L at 4 hours after administration, and the C_max of enalaprilat was 0.75 µg/L at approximately 9 hours after administration. The mean concentration in breast milk over 24 hours after taking enalapril was 1.44 µg/L for enalapril and 0.63 µg/L for enalaprilat.

In one woman who took Enalapril at a dose of 5 mg once, and in two women who took Enalapril at a dose of 10 mg once, the concentration of enalaprilat in breast milk was below the detectable level (less than 0.2 µg/L) at 4 hours after administration. The concentration of enalapril was not determined in them.

Indications

• Essential hypertension of any severity;
• Renovascular hypertension;
• Heart failure of any severity;

In patients with clinical manifestations of heart failure, the drug Ednyt^® is also indicated for

• Increasing patient survival;
• Slowing the progression of heart failure;
• Reducing the frequency of hospitalizations for heart failure.
• Prevention of the development of clinically significant heart failure. In patients without clinical symptoms of heart failure with left ventricular dysfunction, the drug Ednyt^® is indicated for:
  • Slowing the development of clinical manifestations of heart failure;
  • Reducing the frequency of hospitalizations for heart failure.
• Prevention of coronary ischemia in patients with left ventricular dysfunction. The drug Ednyt^® is indicated for:
  • Reducing the incidence of myocardial infarction;
  • Reducing the frequency of hospitalizations for unstable angina.

ICD codes

Dosage Regimen

Tablets

Take orally, regardless of meal time.

Essential hypertension

The initial dose is 10-20 mg depending on the severity of hypertension and is taken once a day. For mild hypertension, the recommended initial dose is 10 mg once a day. For other degrees of hypertension, the initial dose is 20 mg once a day. The maintenance dose is 1 tablet of 20 mg once a day. The dosage is selected individually for each patient, but the maximum dose should not exceed 40 mg/day.

Renovascular hypertension

Since in patients of this group, blood pressure and renal function may be particularly sensitive to ACE inhibition, therapy is started with a low dose – 5 mg or less. Then the dose is selected according to the needs and condition of the patient. The usual effective dose is 20 mg of the drug Ednyt^® once a day with daily intake. Caution should be exercised when using the drug Ednyt^® in patients who have recently taken diuretics.

Concomitant treatment of hypertension with diuretics

Symptomatic arterial hypotension may develop after the first dose of the drug Ednyt^®. This effect is most likely in patients who are taking diuretics. The drug is recommended to be used with caution, as these patients may have a violation of the water-electrolyte balance. Diuretics should be discontinued 2-3 days before starting therapy with the drug Ednyt^®. If this is not possible, then the initial dose of the drug Ednyt^® should be reduced (to 5 mg or less) to determine the primary effect of the drug on blood pressure. Then the dose should be selected taking into account the need and condition of the patient.

Dosage in patients with renal failure

The interval between doses of the drug Ednyt^® should be increased and/or the dose should be reduced.

* Enalapril is subject to hemodialysis. Dose adjustment on days when hemodialysis is not performed should be based on the level of blood pressure.

Heart failure/asymptomatic left ventricular dysfunction

The initial dose of the drug Ednyt^® in patients with clinically significant heart failure or with asymptomatic left ventricular dysfunction is 2.5 mg. In this case, the use of the drug should be carried out under careful medical supervision to determine the primary effect of the drug on blood pressure: after taking the first dose of the drug, the patient should be under medical supervision for at least 2 hours or at least 1 hour after blood pressure stabilization.

The drug Ednyt^® can be used for the treatment of heart failure with severe clinical manifestations in combination with diuretics and, if necessary, with cardiac glycosides or beta-blockers. In the absence of symptomatic arterial hypotension (resulting from treatment with the drug Ednyt^®) or after its correction, the dose of the drug should be gradually increased to the usual maintenance dose of 20 mg, which is taken either once or divided into 2 doses depending on the patient’s tolerance of the drug. Dose selection can be carried out over 2-4 weeks or in a shorter time if there are residual signs and symptoms of heart failure. This therapeutic regimen effectively reduces mortality rates in patients with clinically significant heart failure.

Both before and after starting treatment with the drug Ednyt^®, regular monitoring of blood pressure and renal function should be carried out (see section “Special Instructions”), since the development of arterial hypotension with subsequent (more rarely) occurrence of acute renal failure as a result of taking the drug has been reported. In patients taking diuretics, the dose of diuretics should be reduced if possible before starting treatment with the drug Ednyt^®. The development of arterial hypotension after taking the first dose of the drug Ednyt^® does not mean that arterial hypotension will reoccur during long-term treatment and does not indicate the need to discontinue the drug.

During treatment with the drug Ednyt^®, the concentration of potassium in the blood serum should also be monitored (see section “Drug Interactions”).

Adverse Reactions

In general, the drug Ednyt^® is well tolerated. The overall frequency of adverse events with the use of enalapril did not exceed that with placebo. In most cases, adverse events were mild, transient, and did not require discontinuation of therapy.

The following adverse events were observed with the use of enalapril, the frequency of adverse events is given according to the following classification: (very common: ≥10%, common: ≥1% and <10%, uncommon: ≥0.1% and < 1%, rare: ≥0.01% and <0.1%, very rare: <0.01%, frequency unknown: cannot be estimated from the available data).

From the hematopoietic system uncommon – anemia (including aplastic and hemolytic); rare – neutropenia, decrease in hemoglobin and hematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune diseases.

From the endocrine system frequency unknown – syndrome of inappropriate antidiuretic hormone secretion.

From metabolism and nutrition uncommon – hypoglycemia.

Mental disorders common – depression; uncommon – confusion, insomnia, drowsiness, increased nervousness; rare – unusual dreams, sleep disorders.

From the nervous system very common – dizziness; common – headache, fainting, taste disturbance; uncommon – paresthesia, systemic dizziness.

From the organ of vision very common – blurred vision.

From the organ of hearing and labyrinthine disorders uncommon – tinnitus.

From the heart common – angina pectoris, chest pain, arrhythmia, tachycardia; uncommon – palpitations, myocardial infarction* (possibly secondary to severe arterial hypotension in high-risk patients).

From the vessels common – arterial hypotension (including orthostatic hypotension); uncommon – flushing, orthostatic hypotension, stroke* (possibly secondary to severe arterial hypotension in high-risk patients); rare – Raynaud’s syndrome.

From the respiratory system very common – cough; common – dyspnea; uncommon – rhinorrhea, sore throat, hoarseness, bronchospasm/bronchial asthma; rare – pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

From the gastrointestinal tract very common – nausea; common – diarrhea, abdominal pain, taste disturbances; uncommon – intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, stomach irritation, dry oral mucosa, gastric and duodenal ulcer; rare – stomatitis/aphthous ulcers, glossitis; very rare – intestinal angioedema.

From the liver and biliary tract rare – liver failure, hepatitis (hepatocellular or cholestatic), hepatitis (including necrosis), cholestasis (including jaundice).

From the skin and subcutaneous tissues common – skin rash, hypersensitivity reactions/angioedema (angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx); uncommon – increased sweating, pruritus, urticaria, alopecia; rare – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma; frequency unknown – a symptom complex has been reported, which may include all or some of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive test for antinuclear antibodies, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis. Skin rash, photosensitivity and other skin reactions may also occur.

Musculoskeletal system uncommon – muscle cramps.

Urinary system uncommon – renal function disorders, renal failure, proteinuria; rare – oliguria.

Reproductive system and breast uncommon – erectile dysfunction; rare – gynecomastia.

General disorders and administration site conditions very common – asthenia; common – increased fatigue; uncommon – malaise, pyrexia.

Investigations uncommon – hyperkalemia, increased serum creatinine; uncommon – increased blood urea, hyponatremia; rare – increased hepatic enzyme levels, increased serum bilirubin.

* The incidence was comparable to that observed in clinical trials with placebo or another comparative drug.

The following adverse events have been identified during post-marketing surveillance, but a causal relationship with enalapril intake has not been established: urinary tract infection, upper respiratory tract infection, bronchitis, cardiac arrest, atrial fibrillation, herpes zoster, melena, ataxia, pulmonary artery branch thromboembolism and pulmonary infarction, hemolytic anemia, including cases of hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.

If any of the adverse reactions listed in the instructions worsen, or if any other adverse reactions not listed in the instructions occur, the patient should inform the attending physician.

Contraindications

• Hypersensitivity to enalapril, any of the excipients of the drug, or other ACE inhibitors;
• History of angioedema associated with ACE inhibitor use, as well as hereditary or idiopathic angioedema;
• Concomitant use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with angiotensin II receptor antagonists (ARBs) in patients with diabetic nephropathy;
• Age under 18 years (efficacy and safety not established);
• Pregnancy;
• Breastfeeding period;
• Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

With caution

Bilateral renal artery stenosis or stenosis of the artery to a single kidney; status after kidney transplantation; aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; coronary artery disease or cerebrovascular diseases; renal failure; symptomatic arterial hypotension, chronic heart failure, use of the drug in elderly patients (over 65 years); renovascular hypertension; bone marrow depression; systemic connective tissue diseases (systemic lupus erythematosus, scleroderma, and others), immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these aggravating factors; hepatic insufficiency; diabetes mellitus; hyperkalemia; with concomitant use of potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes, and lithium preparations; during low-density lipoprotein apheresis (LDL-apheresis) using dextran sulfate; burdened allergic history or history of angioedema; conditions accompanied by a decrease in circulating blood volume (including during diuretic therapy, salt-restricted diet, hemodialysis, diarrhea, or vomiting); during desensitization with hymenoptera venom allergen; in patients on hemodialysis using high-flux membranes (such as AN69^®); in patients after major surgical interventions or during general anesthesia; in patients of Black race.

Use in Pregnancy and Lactation

Pregnancy

The use of the drug Ednyt^® during pregnancy is contraindicated. If pregnancy is diagnosed, the use of the drug Ednyt^® should be discontinued immediately.

In case of planned pregnancy, ACE inhibitor therapy should be discontinued and the patient switched to alternative antihypertensive therapy with drugs with an established safety profile for use during pregnancy.

Published results from a retrospective epidemiological study of newborns whose mothers took ACE inhibitors in the first trimester of pregnancy noted an increased risk of serious congenital malformations compared to newborns whose mothers did not take ACE inhibitors in the first trimester. The number of birth defects was low, and the results of this study have not been reconfirmed.

ACE inhibitors can cause fetal or neonatal morbidity and mortality when used in the second and third trimesters of pregnancy. The use of ACE inhibitors during these periods was associated with adverse effects on the fetus and newborn, manifested as arterial hypotension, renal failure, hyperkalemia and/or skull hypoplasia in the newborn. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, but it is unclear whether these cases were related to the action of ACE inhibitors. The development of oligohydramnios may occur due to decreased fetal renal function. This complication can lead to limb contractures, deformation of the skull bones, including the facial part, and fetal lung hypoplasia.

Newborns whose mothers took the drug Ednyt^® during pregnancy should be thoroughly examined for arterial hypotension, oliguria, and hyperkalemia. If oliguria develops, special attention should be paid to maintaining blood pressure and renal perfusion. Enalapril crosses the placental barrier and can be partially removed from the newborn’s systemic circulation by peritoneal dialysis. Theoretically, Enalapril can also be removed by exchange transfusion.

Breastfeeding period

Enalapril and enalaprilat pass into breast milk in trace amounts. If it is necessary to use the drug during breastfeeding, the patient should stop breastfeeding.

Use in Hepatic Impairment

Use with caution in patients with hepatic insufficiency.

Use in Renal Impairment

Use with caution in patients with renal failure, as well as in patients with bilateral renal artery stenosis, stenosis of the artery to a single kidney, and after kidney transplantation.

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

The drug should be used with caution in elderly patients (over 65 years of age).

Special Precautions

Symptomatic arterial hypotension

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated hypertension. In hypertensive patients taking Enalapril, arterial hypotension develops more often against the background of dehydration, occurring, for example, as a result of diuretic therapy, salt restriction, in patients on hemodialysis, as well as in patients with diarrhea or vomiting. Symptomatic arterial hypotension has also been observed in patients with heart failure, with or without renal impairment. Arterial hypotension develops more often in patients with more severe heart failure with hyponatremia or renal impairment, who are using higher doses of “loop” diuretics. In these patients, enalapril treatment should be initiated under medical supervision, which should be particularly careful when changing the dose of enalapril and/or the diuretic. Similarly, patients with coronary artery disease or cerebrovascular diseases should be monitored, in whom an excessive decrease in blood pressure may lead to myocardial infarction or stroke. If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, 0.9% sodium chloride solution should be administered. Transient arterial hypotension when taking enalapril is not a contraindication to further use and dose increase of the drug, which can be continued after volume replenishment and normalization of blood pressure.

In some patients with heart failure and normal or low blood pressure, Enalapril may cause an additional decrease in blood pressure. This reaction to the drug is expected and is not a reason to discontinue treatment. In cases where arterial hypotension becomes stable, the dose should be reduced and/or treatment with the diuretic and/or enalapril should be discontinued.

Aortic or mitral stenosis/hypertrophic obstructive cardiomyopathy

Like all vasodilating drugs, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

Renal impairment

In some patients, arterial hypotension developing after initiation of ACE inhibitor treatment may lead to further deterioration of renal function. In some cases, acute renal failure has been reported, usually reversible. In patients with renal impairment, dose reduction and/or frequency of administration may be required. In some patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney, an increase in blood urea and serum creatinine was observed. The changes were usually reversible, and the values returned to baseline after discontinuation of therapy. This pattern of changes is most likely in patients with renal impairment.

In some patients without signs of kidney disease prior to treatment, Enalapril in combination with diuretics caused usually minor and transient increases in blood urea and serum creatinine. In such cases, dose reduction and/or discontinuation of the diuretic and/or enalapril may be required.

In patients with impaired renal function (creatinine clearance (CrCl) <80 ml/min), the initial dose and/or frequency of enalapril administration should be reduced depending on the CrCl value; in such cases, renal function (plasma creatinine and potassium concentrations) should be regularly monitored during the first few weeks of treatment; if plasma urea and creatinine concentrations increase in patients without signs of kidney disease prior to enalapril therapy, appropriate examination is recommended (may be a sign of previously unrecognized renal artery stenosis in the patient).

Kidney transplantation

There is no experience with use in patients after kidney transplantation, therefore treatment with enalapril is not recommended in patients after kidney transplantation.

Hepatic insufficiency

In rare cases, the use of ACE inhibitors has been accompanied by a syndrome that began with cholestatic jaundice or hepatitis and progressed to fulminant hepatic necrosis, sometimes fatal. The mechanism of development of this syndrome is not understood. If jaundice appears or a significant increase in liver transaminase activity occurs during the use of ACE inhibitors, the drug should be discontinued and appropriate therapy prescribed. The patient should be under medical supervision.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been observed in patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and without other complicating factors. Enalapril should be used with particular caution in patients with systemic connective tissue diseases (systemic lupus erythematosus, scleroderma, and others) receiving immunosuppressive therapy, allopurinol or procainamide, or with a combination of these complicating factors, especially in the presence of pre-existing renal impairment. In some of these patients, serious infections developed, which in some cases did not respond to intensive antibiotic therapy. If Enalapril is used in such patients, regular monitoring of white blood cell and lymphocyte counts is recommended, and patients should be warned to report any signs of infection.

Hypersensitivity reactions/angioedema

Rare cases of angioedema of the face, extremities, lips, tongue, vocal folds, and/or larynx have been observed with the use of ACE inhibitors, including Enalapril, occurring at various times during treatment. In such cases, enalapril should be discontinued immediately and the patient’s condition carefully monitored to control and correct clinical symptoms. Even in cases where only tongue swelling is observed without the development of respiratory distress, patients may require prolonged observation, as therapy with antihistamines and corticosteroids may be insufficient. Very rarely, fatalities due to angioedema associated with laryngeal edema or tongue swelling have been reported. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction, especially in patients who have undergone respiratory tract surgery. In cases where the edema is localized in the area of the tongue, vocal folds, or larynx and may cause airway obstruction, appropriate treatment should be immediately prescribed, which may include subcutaneous administration of 0.1% epinephrine (adrenaline) solution (0.3-0.5 ml) and/or ensuring airway patency (intubation or tracheostomy).

In very rare cases, intestinal edema (angioedema of the intestine) has developed during therapy with ACE inhibitors. In this case, patients experienced abdominal pain, as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was established using computed tomography of the abdomen, ultrasound, or during surgery. Symptoms resolved after discontinuation of the ACE inhibitor. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

In Black patients taking ACE inhibitors, angioedema has been observed more frequently than in patients of other races.

Patients with a history of angioedema not associated with ACE inhibitor use may be at increased risk of developing angioedema during ACE inhibitor therapy.

An increased risk of angioedema has been observed in patients taking ACE inhibitors and mTOR inhibitors concomitantly.

Anaphylactoid reactions during desensitization with hymenoptera venom allergen

In rare cases, patients taking ACE inhibitors have developed life-threatening anaphylactoid reactions during desensitization with hymenoptera venom allergen. Adverse reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting desensitization.

Anaphylactoid reactions during LDL-apheresis

In patients taking ACE inhibitors during LDL-apheresis using dextran sulfate, life-threatening anaphylactoid reactions have rarely been observed. The development of these reactions can be avoided by temporarily discontinuing the ACE inhibitor before each LDL-apheresis procedure.

Patients on hemodialysis

Anaphylactoid reactions have been observed in patients on hemodialysis using high-flux membranes (such as AN69^®) and simultaneously receiving ACE inhibitor therapy. In these patients, dialysis membranes of a different type or antihypertensive agents of other classes should be used.

Cough

The occurrence of cough has been reported during therapy with ACE inhibitors. Typically, the cough is non-productive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-associated cough should be considered in the differential diagnosis of cough.

Surgery/general anesthesia

During major surgery or general anesthesia using agents that cause an antihypertensive effect, enalaprilat blocks the formation of angiotensin II caused by compensatory renin release. If a pronounced decrease in blood pressure develops, explained by such a mechanism, it can be corrected by increasing the circulating blood volume.

Hyperkalemia

The risk of hyperkalemia is observed in renal failure, diabetes mellitus, as well as with the concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salts. The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salts, especially in patients with impaired renal function, can lead to a significant increase in serum potassium concentration. Hyperkalemia can lead to serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and the above-mentioned drugs is necessary, caution should be exercised and serum potassium concentration should be regularly monitored.

List of conditions/diseases/risk factors for hyperkalemia: elderly age (over 65 years); some concomitant conditions (decreased blood volume, decompensated chronic heart failure, metabolic acidosis); other drugs that contribute to increased plasma potassium concentration (such as heparin, tacrolimus, cyclosporine, drugs containing co-trimoxazole [trimethoprim + sulfamethoxazole]).

Hypoglycemia

Patients with diabetes mellitus taking oral hypoglycemic agents or insulin should be informed about the need for regular monitoring of blood glucose concentration (hypoglycemia) before starting ACE inhibitors, especially during the first month of concomitant use of these drugs.

Lithium preparations

Concomitant use of lithium preparations and enalapril is not recommended.

Dual blockade of the RAAS

Arterial hypotension, syncope, stroke, hyperkalemia, and renal function disorders (including acute renal failure) have been reported in susceptible patients, especially when combination therapy with drugs affecting the RAAS is used. Dual blockade of the RAAS by combined use of ACE inhibitors with ARBs or aliskiren is not recommended.

Concomitant use of enalapril with aliskiren and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate renal impairment or with severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Use in Elderly Patients

Data from clinical studies on the efficacy and safety of enalapril were similar in elderly and younger patients with hypertension.

Race

As with the use of other ACE inhibitors, Enalapril appears to be less effective in lowering blood pressure in Black patients than in patients of other races, which may be explained by the higher prevalence of conditions with low plasma renin activity in the Black patient population with hypertension.

Lactose

The drug contains lactose monohydrate, therefore it should not be taken by patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Ethanol

Consumption of alcoholic beverages is not recommended during therapy with enalapril, as ethanol enhances the antihypertensive effect of ACE inhibitors.

Thiazide Diuretics

When used concomitantly with thiazide diuretics, there is a potential risk of developing hypokalemia – regular monitoring of plasma potassium concentration should be performed.

Effect on Ability to Drive and Operate Machinery

The effect of the drug Ednyt^® on the ability to drive vehicles and operate machinery has not been studied. However, some adverse events (e.g., dizziness) that were observed when taking the drug Ednyt^® may affect the ability to drive vehicles and operate machinery.

Overdose

Information on overdose is limited.

Symptoms marked decrease in blood pressure (begins approximately 6 hours after drug intake) up to the development of collapse, disturbance of water-electrolyte balance, renal failure, increased respiratory rate, tachycardia, palpitation sensation, bradycardia, dizziness, anxiety, cough, stupor. Serum enalaprilat concentrations exceeding those observed with therapeutic doses by 100 and 200 times occurred after intake of 300 mg and 440 mg of enalapril, respectively.

Treatment in case of a marked decrease in blood pressure, the patient should be placed in a horizontal position with the head low. As therapy, intravenous administration of 0.9% sodium chloride solution is necessary, with intravenous administration of catecholamines if required. If the drug was taken recently, gastric lavage and oral administration of activated charcoal are indicated. Enalaprilat can be removed from the systemic circulation by hemodialysis. Patients with bradycardia resistant to therapy are indicated for pacemaker implantation. Constant monitoring of vital functions, serum creatinine and electrolyte concentrations is indicated.

Drug Interactions

Other Antihypertensive Agents

An additive effect may be observed with the concomitant use of enalapril and other antihypertensive therapy. When enalapril is used concomitantly with other antihypertensive agents, especially with diuretics, an enhancement of the antihypertensive effect may be observed. Concomitant use of enalapril with beta-blockers, methyldopa, or slow calcium channel blockers increases the severity of the antihypertensive effect. Concomitant use of enalapril with alpha-, beta-blockers and ganglionic blockers should be carried out under careful medical supervision.

Concomitant use of enalapril with nitroglycerin, other nitro preparations or other vasodilators enhances the antihypertensive effect.

Potassium-Sparing Diuretics, Potassium Preparations, Potassium-Containing Salt Substitutes, Other Drugs Capable of Increasing Plasma Potassium Concentration

Concomitant use of enalapril with potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes, other drugs capable of increasing plasma potassium content (including angiotensin II receptor antagonists, heparin, tacrolimus, cyclosporine; drugs containing co-trimoxazole [trimethoprim + sulfamethoxazole]) may lead to a significant increase in plasma potassium concentration. If it is necessary to use enalapril with the above-mentioned drugs, regular monitoring of plasma potassium concentration should be performed.

Non-Potassium-Sparing (Thiazide and “Loop”) Diuretics

The use of diuretics in high doses can lead to hypovolemia (due to a decrease in circulating blood volume), and the addition of enalapril to therapy can lead to a marked decrease in blood pressure. The excessive antihypertensive effect of enalapril can be reduced either by discontinuing the diuretic, or by increasing the circulating blood volume or consuming table salt, as well as by reducing the dose of enalapril. When enalapril is used concomitantly with non-potassium-sparing (thiazide or “loop”) diuretics, hypokalemia caused by the action of diuretics is generally attenuated due to the effect of enalapril.

Hypoglycemic Agents

Epidemiological studies have shown that the concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect of the latter with a risk of hypoglycemia. This phenomenon is generally most frequently observed during the first weeks of combination therapy, as well as in patients with impaired renal function. In diabetic patients taking oral hypoglycemic agents or insulin, blood glucose concentration should be regularly monitored, especially during the first month of concomitant use with ACE inhibitors.

Lithium Preparations

Like other drugs affecting sodium excretion, ACE inhibitors may reduce the renal excretion of lithium, therefore, when lithium preparations and ACE inhibitors are used concomitantly, serum lithium concentration should be regularly monitored. Concomitant use of ACE inhibitors leads to an enhancement of the cardiotoxic and neurotoxic effects of lithium.

Tricyclic Antidepressants/Antipsychotics/General Anesthetics/Narcotic Drugs

Enhancement of the antihypertensive effect of ACE inhibitors (further decrease in blood pressure with concomitant use) and an increased risk of orthostatic hypotension.

Ethanol

Ethanol enhances the antihypertensive effect of ACE inhibitors.

Acetylsalicylic Acid, Thrombolytics and Beta-Blockers

Enalapril can be used concomitantly with acetylsalicylic acid (as an antiplatelet agent), thrombolytics and beta-blockers.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the effect of diuretics and other antihypertensive agents. Consequently, the antihypertensive effect of angiotensin II receptor antagonists (ARBs) or ACE inhibitors may be attenuated when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those taking diuretics) receiving therapy with NSAIDs, including selective COX-2 inhibitors, concomitant use of ARBs or ACE inhibitors may cause further deterioration of renal function, including the development of acute renal failure. These effects are usually reversible, therefore concomitant use of these drugs should be carried out with caution in patients with impaired renal function. Patients should receive adequate fluid intake; careful monitoring of renal function is recommended, both at the beginning and during therapy.

Dual Blockade of the RAAS

Dual blockade of the RAAS using ARBs, ACE inhibitors or aliskiren (a renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and renal function disorders (including acute renal failure) compared to monotherapy. Regular monitoring of blood pressure, renal function and blood electrolyte concentrations is necessary in patients taking Enalapril and other drugs affecting the RAAS concomitantly. Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate renal impairment or severe renal failure (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Gold Preparations

A symptom complex (nitrate-like reactions), including facial flushing, nausea, vomiting and arterial hypotension, has been observed in rare cases with the concomitant use of parenteral gold preparations (sodium aurothiomalate) and ACE inhibitors, including Enalapril.

mTOR (mammalian Target of Rapamycin) Inhibitors (e.g., temsirolimus, sirolimus, everolimus)

An increased risk of angioedema has been observed in patients taking ACE inhibitors and mTOR inhibitors concomitantly.

Co-trimoxazole (trimethoprim + sulfamethoxazole)

Patients receiving ACE inhibitors and co-trimoxazole (trimethoprim + sulfamethoxazole) concomitantly may have an increased risk of hyperkalemia.

Dipeptidyl Peptidase Type IV (DPP-IV) Inhibitors (gliptins), e.g., sitagliptin, saxagliptin, vildagliptin, linagliptin

When used concomitantly with ACE inhibitors, the risk of developing angioedema may be increased.

Racecadotril (an enkephalinase inhibitor used to treat acute diarrhea)

When used concomitantly with ACE inhibitors, the risk of developing angioedema may be increased.

Estramustine

When used concomitantly with ACE inhibitors, the risk of developing angioedema may be increased.

Other Drugs

No clinically significant pharmacokinetic drug interaction was observed between enalapril and the following drugs: hydrochlorothiazide, furosemide, digoxin, timolol, methyldopa, warfarin, indomethacin, sulindac and cimetidine. When enalapril and propranolol are used concomitantly, the serum concentration of enalaprilat decreases, but this effect is not clinically significant.

Theophylline

Enalapril attenuates the effect of drugs containing theophylline.

Estrogens

When used concomitantly, estrogens attenuate the antihypertensive effect of enalapril due to fluid retention.

Baclofen

Enhances the antihypertensive effect of ACE inhibitors. Blood pressure should be carefully monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.

Allopurinol, Procainamide, Cytostatics, Immunosuppressants, Corticosteroids (for systemic use)

Concomitant use with ACE inhibitors may increase the risk of developing neutropenia/agranulocytosis.

Antacids

When used concomitantly, a decrease in the bioavailability of ACE inhibitors is possible.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.