Enalapril-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Enalapril-Darnitsa (Enalapril-Darnitsa)

Composition:

active substance: enalapril;

1 tablet contains enalapril maleate 10 mg;

excipients: microcrystalline cellulose, potato starch, lactose monohydrate, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored, flat cylindrical tablets with beveled edges and a score line.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors.

ATC code C09AA02.

Pharmacological Properties

Pharmacodynamics

Enalapril maleate is the maleic acid salt of enalapril, a derivative of two amino acids: L-alanine and L-proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the vasoconstrictor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to removal of the negative feedback on renin release) and decreased aldosterone secretion.

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

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

Administration of enalapril to patients with arterial hypertension results in a reduction of blood pressure in both supine and standing positions, without increasing heart rate.

Symptomatic postural hypotension is infrequent. In some patients, optimal blood pressure reduction may require several weeks of therapy. Abrupt discontinuation of enalapril has not been associated with a rapid increase in blood pressure.

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

In hemodynamic studies of enalapril in patients with arterial hypertension, blood pressure reduction was accompanied by decreased peripheral arterial resistance with increased cardiac output and sometimes with minimal change in heart rate. After enalapril administration, renal blood flow increased; glomerular filtration rate remained unchanged. There was no evidence of sodium or water retention. However, in patients with low glomerular filtration rate before treatment, the rate usually increased.

In short-term clinical studies in patients with or without diabetes and with kidney disease, administration of enalapril resulted in a reduction of proteinuria, urinary excretion of immunoglobulin G, and total urinary protein.

When administered concomitantly with thiazide-like diuretics, the antihypertensive effects of enalapril at least complement those of diuretics. Enalapril may reduce or prevent thiazide-induced hypokalemia. In patients with heart failure who are receiving cardiac glycosides and diuretics, enalapril reduces peripheral resistance and arterial blood pressure. Cardiac output increases, and heart rate (which is usually elevated in heart failure patients) decreases. Pulmonary capillary wedge pressure is reduced. Enalapril therapy improves exercise tolerance and reduces the severity of heart failure according to New York Heart Association criteria. These effects persist throughout long-term enalapril therapy. In patients with mild to moderate heart failure, enalapril slows the progression of cardiac dilation and dysfunction (reduction in left ventricular end-diastolic and end-systolic pressure and improvement in ejection fraction).

In patients with left ventricular dysfunction, enalapril reduces the risk of serious ischemic complications, the incidence of myocardial infarction, and the number of hospitalizations due to unstable angina.

There is limited experience regarding the efficacy and safety of enalapril use in children with arterial hypertension aged 6 years and older. A clinical study included 110 children aged 6 to 16 years with arterial hypertension, body weight ≥ 20 kg, and glomerular filtration rate > 0.5 mL/s/1.73 m². Children weighing < 50 kg received 0.625 mg and 2.5 mg or 20 mg of enalapril once daily, while children weighing ≥ 50 kg received 1.25 mg and 5 mg or 40 mg of enalapril once daily. Blood pressure reduction was dose-dependent; the effect was consistent across all dose subgroups (by age, Tanner stage, sex, race). Study results indicate that the lowest doses—0.625 mg and 1.25 mg, corresponding to an average dose of 0.02 mg/kg/day—do not ensure therapeutic efficacy. The maximum dose is 0.58 mg/kg (40 mg) once daily. The adverse event profile in children was similar to that in adult patients.

Pharmacokinetics

Absorption.

Enalapril is rapidly absorbed from the gastrointestinal tract, with peak serum concentrations occurring within one hour. The extent of absorption is approximately 60%, and food intake does not affect absorption. After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat occur 4 hours after oral administration of enalapril. The effective half-life for accumulation of enalaprilat after multiple doses of enalapril is 11 hours. In individuals with normal renal function, steady-state serum concentrations of enalaprilat are reached within 4 days of therapy.

Distribution.

Within the entire therapeutic concentration range, 60% of enalaprilat is protein-bound in plasma.

Metabolism.

Apart from hydrolysis to enalaprilat, there is no evidence of significant metabolism of enalapril.

Excretion.

Enalaprilat is primarily eliminated by the kidneys. The main components in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril (approximately 20%).

Renal impairment.

In patients with renal impairment, exposure to enalapril and enalaprilat is increased. In patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), steady-state AUC of enalaprilat is approximately twice higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increases approximately 8-fold. In these conditions, the effective half-life of enalaprilat is prolonged, and attainment of steady-state is delayed.

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

Children and adolescents.

A multiple-dose pharmacokinetic study was conducted in 40 boys and girls aged 2 months to 16 years with arterial hypertension who received 0.07–0.14 mg/kg enalapril maleate orally once daily. There were no differences in the pharmacokinetic parameters of enalaprilat in children compared to adults. Data indicated an increase in AUC (normalized to dose per body weight) with increasing age; however, no increase in AUC was observed when data were normalized by body surface area. At steady state, the mean effective half-life for accumulation of enalaprilat is 14 hours.

Lactation.

After administration of a single 20 mg oral dose to five postpartum women, the mean peak level of enalapril in breast milk was 1.7 µg/L (range 0.54–5.9 µg/L) at 4–6 hours. The mean peak level of enalaprilat was 1.7 µg/L (range 1.2–2.3 µg/L); peaks occurred at various times over a 24-hour period. Using data on peak levels in breast milk, the maximum infant intake by exclusively breastfed infants was estimated to be approximately 0.16% of the maternal dose, adjusted for body weight. Women who took enalapril orally at 10 mg daily for 11 months had peak enalapril levels in milk of 2 µg/L at 4 hours after dose administration, and peak enalaprilat levels of 0.75 µg/L approximately 9 hours after drug intake. Total amounts of enalapril and enalaprilat measured in breast milk over a 24-hour period were 1.44 µg/L and 0.63 µg/L, respectively. Enalaprilat levels in milk could not be detected (< 0.2 µg/L) 4 hours after administration of a single 5 mg dose of enalapril to one mother and 10 mg to two mothers.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to enalapril, to any excipient, or to any other angiotensin-converting enzyme (ACE) inhibitor.
• History of angioedema associated with previous use of ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Contraindicated in pregnant women and women planning to become pregnant (see "Use in pregnancy or breastfeeding").
• Concomitant use of enalapril with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

Potassium-sparing diuretics, potassium supplements. ACE inhibitors reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to hyperkalemia. When co-administered in the presence of hypokalemia, these agents should be used with great caution and serum potassium concentrations should be monitored frequently.

Diuretics (thiazide or loop diuretics). Prior treatment with high-dose diuretics may lead to reduced blood volume and increase the risk of excessive hypotension. The hypotensive effect can be minimized by discontinuing diuretic therapy, increasing salt and fluid intake, or initiating enalapril therapy at a low dose.

Other antihypertensive medicinal products. Concomitant use of enalapril with other antihypertensive agents may enhance the antihypertensive effect of enalapril. Enalapril may be used together with any other medicinal product for the treatment of arterial hypertension. Concurrent use with nitroglycerin, other nitrates, or other vasodilating agents may additionally lower blood pressure.

Lithium. Concomitant use of ACE inhibitors and lithium may cause transient elevation of serum lithium levels and lithium toxicity. Concurrent use of ACE inhibitors with thiazide diuretics may further increase serum lithium levels and increase the risk of lithium toxicity. Concomitant use of enalapril and lithium is not recommended. If such combination is necessary for a patient, careful monitoring of serum lithium levels is required.

Tricyclic antidepressants/neuroleptics/anesthetics/opioids. Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may result in additional reduction in blood pressure.

Nonsteroidal anti-inflammatory drugs (NSAIDs). Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the effect 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. Chronic use of NSAIDs may reduce the antihypertensive effect of ACE inhibitors. ACE inhibitors and NSAIDs, including selective cyclooxygenase-2 inhibitors, have an additive effect on increasing serum potassium levels, which may lead to renal dysfunction and/or heart failure. This effect is usually reversible. Rarely, acute renal failure may occur, particularly in patients with pre-existing renal impairment (elderly patients or patients with reduced blood volume, including those taking diuretics). Patients should be adequately hydrated and renal function should be monitored after initiation of combination therapy and periodically during treatment.

Gold. Rarely, reactions similar to nitrite reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported in patients receiving gold injections (sodium aurothiomalate) and concomitant ACE inhibitors, including enalapril.

Antidiabetic medicinal products. Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin or oral antidiabetic agents) may cause hypoglycemia. This effect is more likely during the first weeks of combination therapy and in patients with renal impairment.

Ethanol. Ethanol enhances the hypotensive effect of ACE inhibitors.

Sympathomimetics. Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

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

An increased risk of angioedema has been reported in patients receiving alteplase who were concurrently taking ACE inhibitors.

Cyclosporine. Cyclosporine should be used with caution when administered concomitantly with enalapril, and renal function should be monitored.

Dual blockade of the renin-angiotensin-aldosterone system. Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to specific cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual blockade of the renin-angiotensin-aldosterone system was associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single agent affecting the renin-angiotensin-aldosterone system. Concomitant use of enalapril and aliskiren is contraindicated in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²).

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist. In patients with confirmed atherosclerotic disease, heart failure, or diabetes with end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to therapy with agents affecting the renin-angiotensin-aldosterone system alone. Dual blockade (e.g., combining an ACE inhibitor with an angiotensin II receptor antagonist) should be restricted to individually determined cases and accompanied by careful monitoring of renal function, potassium levels, and blood pressure.

mTOR inhibitors. Concomitant use with mTOR inhibitors (such as temsirolimus, sirolimus, everolimus) increases the risk of angioedema.

Trimethoprim/sulfamethoxazole combination. Patients receiving concomitant trimethoprim/sulfamethoxazole combination therapy have an increased risk of hyperkalemia.

Special precautions for use.

Symptomatic hypotension. Symptomatic hypotension is very rare in patients with uncomplicated arterial hypertension. It is more likely to occur in patients with arterial hypertension who have reduced blood volume, for example due to diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Symptomatic hypotension may occur in patients with heart failure, with or without concomitant renal impairment. It is more likely to occur in patients with more severe forms of heart failure due to high-dose loop diuretics, hyponatremia, or impaired renal function. Such patients should be started on therapy under medical supervision, and careful monitoring is required, even if the dose of enalapril and/or diuretic is adjusted. This also applies to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

If hypotension develops, the patient should be placed in a supine position and, if necessary, plasma volume should be increased by intravenous infusion of 0.9% sodium chloride solution. Transient hypotension is not a contraindication for enalapril therapy. After normalization of blood pressure and plasma volume, patients usually tolerate subsequent doses well.

In some patients with heart failure and normal or low blood pressure, enalapril may cause additional blood pressure reduction. This effect is predictable and usually not a reason to discontinue treatment. If hypotension becomes refractory to treatment, dose reduction and/or discontinuation of diuretics and/or enalapril may be necessary.

Stenosis of the aortic or mitral valve/ hypertrophic cardiomyopathy. As with all vasodilating drugs, ACE inhibitors should be used with extreme caution in patients with left ventricular outflow tract obstruction and should be avoided in cases of cardiogenic shock and hemodynamically significant left ventricular outflow tract obstruction with generalized atherosclerosis. In such patients, excessive reduction in blood pressure may lead to hypoperfusion and ischemia of the heart, brain, or kidneys.

Renal function impairment. Patients with impaired renal function (creatinine clearance < 1.33 mL/s) require dose adjustment according to creatinine clearance, and subsequently according to treatment response. Serum creatinine and potassium levels should be monitored regularly.

In patients with severe heart failure or kidney disease, including renal artery stenosis, renal failure may occur during enalapril therapy. If detected early and managed appropriately, it is usually reversible.

In some patients without kidney disease, mild and transient increases in serum urea and creatinine levels may occur when enalapril is administered concomitantly with diuretics. Dose reduction of ACE inhibitors and/or discontinuation of diuretics may be necessary. This situation may indicate the presence of renal artery stenosis.

Renovascular hypertension. In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney who are taking ACE inhibitors, transient hypotension or renal failure may occur. Loss of kidney function may occur with minimal changes in serum creatinine. Such patients should be started on therapy under medical supervision with low doses; careful titration and monitoring of renal function are required during treatment.

Kidney transplantation. There is no experience with the use of enalapril in patients who have recently undergone kidney transplantation; therefore, enalapril is not recommended for such patients.

Hepatic impairment. Rarely, treatment with ACE inhibitors may lead to a syndrome beginning with cholestatic jaundice, progressing to fulminant necrotizing hepatitis, and (sometimes) resulting in death. The mechanism of this syndrome is unclear. If jaundice or a marked increase in liver enzymes occurs during treatment with ACE inhibitors, therapy should be immediately discontinued, careful monitoring should be initiated, and treatment should be administered as necessary.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other complications. Enalapril should be used with extreme caution in patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) who are receiving concomitant therapy with antidepressants, allopurinol, or procainamide, or a combination of these factors, especially if renal impairment has already occurred. Serious infections, sometimes unresponsive to intensive antibiotic therapy, may develop in some of these patients. If enalapril is administered to such patients, periodic blood leukocyte counts are recommended. Patients should immediately inform their physician of any signs of infection.

Hypersensitivity/angioedema. Rarely, angioedema of the face, extremities, lips, tongue, glottis, and/or larynx may occur during treatment with ACE inhibitors, including enalapril. This may occur at any time during treatment. In such cases, treatment should be completely discontinued and appropriate monitoring should be initiated to ensure complete resolution of all symptoms.

Even if only tongue swelling occurs without airway compromise, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient. Very rarely, fatal cases due to laryngeal and tongue angioedema have been reported.

In cases of angioedema of the tongue, glottis, or larynx, which may cause airway obstruction, especially in patients with a history of surgery, epinephrine (0.3–0.5 mL of 1:1000 epinephrine solution for subcutaneous injection) should be administered immediately and airway access should be ensured.

Patients with a history of angioedema unrelated to ACE inhibitor therapy have an increased risk of developing angioedema during ACE inhibitor treatment.

Angioedema occurs more frequently in patients of non-Caucasian race taking ACE inhibitors compared to patients of other races.

Anaphylactoid reactions during allergen desensitization to wasp or bee venom.
Rarely, life-threatening reactions resembling allergic (pseudoanaphylactic) reactions may occur in patients taking ACE inhibitors during desensitization to wasp or bee venom. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each desensitization session.

Anaphylactoid reactions during low-density lipoprotein apheresis.
Rarely, life-threatening reactions resembling allergic (pseudoanaphylactic) reactions may occur in patients taking ACE inhibitors during low-density lipoprotein apheresis with dextrin sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Patients undergoing hemodialysis. Cases of hypersensitivity reactions resembling allergic (pseudoanaphylactic) reactions have been reported in patients undergoing dialysis with polyacrylonitrile membranes (e.g., AN 69) while concurrently taking ACE inhibitors. For such patients, consideration should be given to using alternative types of dialysis membranes or a different class of antihypertensive agents.

Hypoglycemia. Patients with diabetes mellitus who are taking oral antidiabetic agents or insulin require careful glycemic monitoring, especially during the first few months of concomitant treatment with ACE inhibitors.

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.

Surgery/anesthesia. In patients undergoing major surgery or anesthesia with agents causing arterial hypotension, enalapril may block the formation of angiotensin II due to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, correction with increased blood volume is required.

Hyperkalemia. During treatment with ACE inhibitors, including enalapril, serum potassium levels may increase in some patients. Risk factors for hyperkalemia include renal impairment or reduced renal function, age over 70 years, diabetes mellitus, hypoaldosteronism, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium levels (e.g., heparin). Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to a significant increase in serum potassium levels. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of the above-mentioned drugs is considered necessary, regular monitoring of serum potassium levels is recommended.

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 (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic/racial characteristics. As with all ACE inhibitors, enalapril is less effective in lowering blood pressure in patients of non-Caucasian race compared to Caucasian patients, possibly due to a higher prevalence of low-renin states among non-Caucasian patients with arterial hypertension.

Special warnings regarding inactive ingredients. Enalapril-Darnitsia contains lactose; therefore, the drug should not be used in 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 during pregnancy or in women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be immediately discontinued and replaced with another drug approved for use in pregnant women.

Women of childbearing potential who are prescribed ACE inhibitor therapy should be informed of the negative effects of these drugs on the fetus and the need for immediate medical consultation upon confirmation of pregnancy.

Breastfeeding.

Some pharmacokinetic data indicate very low concentrations in breast milk (see section "Pharmacokinetics"). 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 after birth due to the hypothetical risk of cardiovascular and renal effects, as well as limited experience with such use. For older infants, enalapril use during breastfeeding may be considered if treatment is necessary for the mother, provided the infant is monitored for any adverse effects.

Ability to influence reaction speed when driving or operating machinery.

It should be noted that dizziness or hypotension may occasionally occur, which may affect reaction speed when driving or operating machinery.

Dosage and Administration.

Tablets should be taken whole, with a small amount of water, regardless of food intake. Enalapril-Darnitsya should be taken at the same time each day, and the prescribed dose must not be exceeded.

The 10 mg tablet may be divided; if a 5 mg dose is prescribed, ½ tablet should be used.

In patients with a highly activated renin-angiotensin-aldosterone system (e.g., with renovascular hypertension, disturbances in salt and/or fluid balance, decompensated heart failure, or severe arterial hypertension), excessive lowering of arterial pressure may occur after the initial dose. Such patients should be started on a low initial dose of 5 mg or less, and treatment initiation should be under medical supervision.

Essential hypertension.

The initial dose for adults is 5 mg, 10 mg, or 20 mg once daily, depending on the severity of hypertension. For mild hypertension, the recommended initial dose is 5–10 mg daily. For moderate to severe hypertension, the initial dose is 20 mg once daily. The maintenance dose is 10 mg twice daily. Dosage should be individually adjusted for each patient, but must not exceed 40 mg daily.

Renovascular hypertension.

In adult patients of this group, therapy should be initiated with a low starting dose, for example 5 mg (½ tablet), under medical supervision. If a dose lower than 5 mg is required, an appropriate dosage form of enalapril allowing such dosing should be used. Dosage should then be individually titrated for each patient. A daily dose of 20 mg of Enalapril-Darnitsya is expected to be effective in most patients. Caution is advised when treating patients who have recently received diuretics.

Concomitant antihypertensive diuretic therapy.

Arterial hypotension may occur after the first dose of the drug. This effect is most likely in patients receiving diuretic therapy. In such cases, Enalapril-Darnitsya should be prescribed cautiously, as these patients may have fluid and/or sodium depletion.

The usual maintenance dose is 20 mg once daily. The maximum maintenance dose is 40 mg daily. Diuretic therapy should be discontinued 2–3 days before starting enalapril treatment. If this is not possible, the initial dose should be reduced to 5 mg or less, using an appropriate dosage form of enalapril allowing such dosing, to assess the initial effect of the drug on arterial pressure. Renal function and serum potassium levels should be monitored. Dosage should then be individually adjusted for each patient.

Renal impairment.

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

*See section "Special precautions. Patients undergoing hemodialysis."

**Enalapril is removed by hemodialysis. Dosage adjustment on days when hemodialysis is not performed should be made according to the arterial pressure level.

Heart failure/asymptomatic left ventricular dysfunction.

The initial dose of enalapril for adult patients with heart failure is 2.5 mg (use an appropriate dosage form of enalapril that allows such dosing). The drug should be administered under strict medical supervision in order to monitor its initial effect on arterial pressure. Enalapril-Darnytsia can be used for the treatment of symptomatic heart failure, in combination with diuretics and, if necessary, cardiac glycosides and beta-blockers. In the absence of adverse effects or after appropriate management of symptomatic hypotension caused by enalapril therapy, the dose should be gradually increased to the target dose of 20 mg, which may be administered either once daily or divided into two doses, depending on patient tolerability. Dose titration may be performed over 2–4 weeks or over a shorter period. This therapeutic regimen effectively reduces mortality rates in patients with clinically evident heart failure.

The maximum daily dose of enalapril is 40 mg, which should be divided into two doses.

Dose titration of enalapril in patients with heart failure/asymptomatic left ventricular dysfunction

*If enalapril is prescribed in doses less than 5 mg, an appropriate dosage form of enalapril allowing such dosing should be used. Enalapril-Darnitsia should be administered with caution to patients with impaired renal function or those taking diuretics.

Arterial pressure and renal function should be carefully monitored both before and after initiation of therapy with this medicinal product in patients with heart failure (see section "Special precautions for use"). Development of arterial hypotension after the initial dose does not imply that hypotension will persist during long-term treatment, and does not indicate the need to discontinue the drug. During enalapril therapy, serum potassium levels should also be monitored (see section "Interaction with other medicinal products and other types of interactions").

Elderly patients.

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

Children with hypertension aged 6 years and older.

Clinical experience with the use of this medicinal product in children with arterial hypertension is limited.

Enalapril-Darnitsia can be used in children aged 6 years and older. Dosage depends on the patient's condition, degree of reduction in arterial pressure, and the child's body weight. For patients with body weight from 20 to 50 kg, the initial dose is 2.5 mg of enalapril per day; for patients with body weight ≥50 kg, the initial dose is 5 mg per day. The maximum studied dose in children is 0.58 mg/kg (up to 40 mg) once daily (see section "Children").

The maximum daily dose should not exceed 20 mg for patients with body weight from 20 to 50 kg and 40 mg for patients with body weight above 50 kg.

Enalapril-Darnitsia is not recommended for use in neonates and children with glomerular filtration rate <30 ml/min/1.73 m² due to lack of data.

Children .

The medicinal product is indicated only for children with arterial hypertension and is not recommended for use in children for other indications.

Enalapril-Darnitsia is indicated for use in children aged 6 years and older.

Due to lack of data, enalapril is not recommended for treatment of children with glomerular filtration rate <30 ml/min/1.73 m².

Overdose.

Data on overdose in humans are limited.

Symptoms. The most likely manifestation of overdose is hypotension, beginning 6 hours after tablet ingestion, along with blockade of the renin-angiotensin system and stupor. Symptoms characteristic of overdose include cardiovascular shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, rapid heartbeat, bradycardia, dizziness, fear, and cough. Serum enalapril levels exceed by 100 and 200 times the levels observed after therapeutic doses following ingestion of 300 mg and 440 mg of enalapril, respectively.

Treatment. Intravenous infusion of 0.9% sodium chloride solution is recommended. If arterial hypotension occurs, the patient should be placed in a supine position. If necessary, infusion of angiotensin II and/or intravenous administration of catecholamines should be initiated. If ingestion was recent, measures aimed at removing enalapril should be taken (induced emesis, gastric lavage, administration of adsorbents and sodium sulfate).

Enalapril can be removed from systemic circulation by hemodialysis.

In case of bradycardia resistant to therapeutic measures, treatment with a cardiac pacemaker is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Adverse Reactions

Eye disorders: blurred vision.

Ear and labyrinth disorders: tinnitus, vertigo.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, rhinorrhea, pharyngitis, dysphonia, sore throat, hoarseness, bronchospasm/asthma, pulmonary 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 gastrointestinal tract.

Hepatobiliary disorders: liver failure; hepatitis – hepatocellular or cholestatic; hepatic necrosis; cholestasis, including jaundice.

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

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: hypoglycemia.

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

Cardiovascular disorders: arterial hypotension (including orthostatic hypotension), syncope, chest pain, cardiac arrhythmia, angina pectoris, tachycardia, palpitations, myocardial infarction or cerebrovascular stroke (possibly secondary to excessive arterial hypotension in high-risk patients), Raynaud's syndrome.

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

Skin and subcutaneous tissue disorders: rash, increased sensitivity/angioedema: angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported; excessive sweating, pruritus, urticaria, alopecia, polymorphic erythema, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A symptom complex has been reported, which may include: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated erythrocyte sedimentation rate (ESR), eosinophilia, leukocytosis. Skin rash, photosensitivity, or other dermatological manifestations may occur.

Reproductive system and breast disorders: impotence, gynecomastia.

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

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

If severe adverse reactions occur, treatment should be discontinued.

Shelf life.

2 years.

Storage conditions.

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

Packaging.

10 tablets in a blister pack. 2, 3, or 9 blister packs in a carton.

Prescription category.

Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's name and address of place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.