Enalapril-astrafarm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALAPRIL-ASTRAPHARM (ENALAPRIL-ASTRAPHARM)

Composition:

Active substance: enalapril;

1 tablet contains enalapril maleate 10 mg, 20 mg;

Excipients:

for 10 mg tablets: lactose monohydrate; potato starch; povidone; magnesium stearate; colouring agent "Azorubine" (carmoisine) (E 122);

for 20 mg tablets: lactose monohydrate; potato starch; povidone; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: pink tablets with specks of more intense colour, flat cylindrical shape with bevelled edges and a score line;

20 mg tablets: white tablets, flat cylindrical shape with bevelled edges and a score line.

Pharmacotherapeutic group.

Angiotensin-converting enzyme inhibitors, single-component.

ATC code C09A A02.

Pharmacological properties.

Pharmacodynamics.

Enalapril-AstraPharm (enalapril maleate) is the maleic acid salt of enalapril, a derivative of two amino acids, L-alanine and L-proline.

Mechanism of action

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the pressor substance angiotensin II.

Following 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 inhibition of the negative feedback of angiotensin II on renin release) and decreased aldosterone secretion.

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

The mechanism by which enalapril lowers blood pressure is primarily related to inhibition of the renin-angiotensin-aldosterone system (RAAS). The drug may exert antihypertensive effects even in patients with low-renin hypertension.

Administration of Enalapril-AstraPharm in arterial hypertension leads to a reduction in blood pressure in patients both in the supine and upright positions, without a significant increase in heart rate.

Symptomatic postural hypotension occurs infrequently. In some patients, optimal blood pressure reduction may require several weeks of therapy. Abrupt discontinuation of Enalapril-AstraPharm has not been associated with a rapid rise in blood pressure.

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

In clinical studies in patients with essential hypertension, blood pressure reduction was generally associated with decreased peripheral vascular resistance, increased cardiac output, and either a slight increase or no change in heart rate. After enalapril administration, renal blood flow usually increases; glomerular filtration rate (GFR) typically remains unchanged. There were no signs of sodium or water retention. However, in patients with low baseline GFR values, these values usually increased.

In clinical trials in patients with renal disease, including those with diabetes mellitus, enalapril administration was associated with reduced albuminuria, urinary IgG excretion, and total urinary protein excretion.

When administered concomitantly with thiazide diuretics, the antihypertensive effects of Enalapril-AstraPharm are at least additive. The drug may reduce or prevent the development of thiazide-induced hypokalemia.

In patients with heart failure receiving cardiac glycosides and diuretics, administration of oral or injectable Enalapril-AstraPharm was associated with reduced peripheral resistance and blood pressure. Cardiac output increased, and heart rate (usually elevated in patients with heart failure) decreased. Pulmonary capillary wedge pressure also decreased. Exercise tolerance improved, and the severity of heart failure, assessed by NYHA (New York Heart Association) criteria, was reduced. These effects were sustained during long-term treatment.

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

Clinical pharmacology in children

Experience with enalapril use in children aged 6 years and older with arterial hypertension is limited. In studies involving children aged 6 to 16 years with arterial hypertension, body weight ≥ 20 kg, and glomerular filtration rate (GFR) > 30 mL/min/1.73 m², patients weighing < 50 kg received 0.625, 2.5, or 20 mg of enalapril daily, and those weighing ≥ 50 kg received 1.25, 5, or 40 mg of enalapril daily. Once-daily administration of enalapril reduced diastolic blood pressure in a dose-dependent manner.

Pharmacokinetics.

Absorption

After oral administration, enalapril is rapidly absorbed, with peak serum concentration (Cmax) of enalapril achieved within 1 hour after oral intake. The extent of enalapril absorption following oral tablet administration is approximately 60%. The presence of food in the gastrointestinal tract does not affect the absorption of oral enalapril. After absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Cmax of enalaprilat is reached approximately 4 hours after oral administration of enalapril.

The effective half-life of enalaprilat after repeated oral dosing is 11 hours.

Distribution

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

Metabolism

Apart from its conversion 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 dysfunction (creatinine clearance 40–60 mL/min), the steady-state area under the concentration-time curve (AUC) of enalaprilat is approximately twice that in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increases by approximately 8-fold. At these levels of renal impairment, the effective elimination half-life of enalaprilat is prolonged, and the time to reach steady-state is increased (see section "Dosage and administration").

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

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to 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.

Pregnancy or planned pregnancy (see section "Use in pregnancy or breast-feeding").

Do not use Enalapril-Astrafarm with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 ml/min/1.73 m²).

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

Interaction with other medicinal products and other forms of interaction.

Antihypertensive therapy

Concomitant use of antihypertensive medicinal products may enhance the hypotensive effect of enalapril. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may additionally reduce blood pressure.

Potassium-sparing diuretics or potassium supplements

ACE inhibitors may potentiate diuretic-induced potassium loss. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, salt substitutes containing potassium, or other medicinal products that may increase serum potassium levels (e.g., trimethoprim-containing products) may lead to significant increases in serum potassium, particularly in patients with impaired renal function.

Diuretics (thiazide or loop diuretics)

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

Antidiabetic agents

Concomitant use of ACE inhibitors and antidiabetic medicinal products (insulin, oral hypoglycemic agents) has been reported to decrease blood glucose levels, increasing the risk of hypoglycemia. This phenomenon is most likely during the first weeks of concomitant therapy and in patients with renal impairment (see sections "Special warnings and precautions for use", "Undesirable effects").

Lithium

Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of ACE inhibitors and lithium. Concomitant use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and increase the risk of lithium intoxication. Concomitant use of enalapril and lithium is not recommended; however, if such combination is necessary, careful monitoring of serum lithium levels is required (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 reduction in blood pressure (see section "Special warnings and precautions for use").

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

NSAIDs, including selective COX-2 inhibitors, may reduce the 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.

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors may have an additive effect on increasing serum potassium and may lead to renal impairment. These effects are usually reversible.

Acute renal failure may rarely occur, particularly in certain patients with pre-existing renal impairment (e.g., elderly patients or patients with reduced plasma volume, including those taking diuretics). Therefore, such combination should be initiated cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and be under close monitoring of renal function at the initiation of concomitant therapy and periodically during treatment.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be restricted to selected cases and accompanied by careful monitoring of blood pressure, renal function, and electrolyte levels. Clinical trials have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual blockade of the RAAS is associated with higher incidences of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single agent acting on the RAAS.

Enalapril-Astrafarm must not be used with aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 ml/min/1.73 m²) (see sections "Contraindications" and "Special warnings and precautions for use").

Gold preparations

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

mTOR inhibitors

Concomitant use with mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may increase the risk of angioedema (see section "Special 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 "Interaction with other medicinal products and other forms of interaction").

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers

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

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist

In patients with confirmed atherosclerotic disease, heart failure, or diabetes with end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been associated with higher incidences of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single RAAS-acting agent. Dual blockade (e.g., combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually determined cases and accompanied by careful monitoring of renal function, serum potassium levels, and blood pressure.

Special precautions for use.

Symptomatic hypotension

Symptomatic hypotension was rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving Enalapril-AstraPharm, symptomatic hypotension develops more frequently in the presence of hypovolemia, which may occur, for example, due to diuretic therapy, salt restriction, in patients undergoing hemodialysis, as well as in patients with diarrhea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction", "Side effects"). Symptomatic hypotension has also been observed in patients with heart failure, with or without renal impairment. Symptomatic hypotension occurs more frequently in patients with more severe forms of heart failure who are receiving higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should begin treatment under medical supervision. Particular caution and monitoring are required when adjusting the dose of Enalapril-AstraPharm and/or diuretic. Similarly, patients with ischemic heart disease or cerebrovascular disease should be closely monitored, as excessive reduction in blood pressure may lead to myocardial infarction or stroke.

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

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

Aortic or mitral stenosis / hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction or outflow tract obstruction; they should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Renal impairment

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

Renal dysfunction has been reported in association with enalapril use, primarily observed in patients with severe heart failure or kidney disease, including renal artery stenosis. When detected early and appropriately managed, enalapril-related renal failure is usually reversible.

In some patients with arterial hypertension who had no pre-existing kidney disease prior to treatment initiation, enalapril in combination with diuretics has caused usually mild and transient increases in blood urea nitrogen and serum creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation increases the likelihood of underlying renal artery stenopenia (see section "Special precautions for use": Renovascular hypertension).

Renovascular hypertension

There is an increased risk of arterial 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 kidney function may occur even with minimal changes in serum creatinine levels. Such patients should start treatment with low doses under close medical supervision, with careful titration and monitoring of renal function.

Kidney transplantation

There is no experience with the use of Enalapril-AstraPharm in patients who have recently undergone kidney transplantation. Therefore, this medication is not recommended for such patients.

Hepatic impairment

Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome remains unclear. Patients taking ACE inhibitors who develop jaundice or marked elevation of liver enzymes should discontinue the ACE inhibitor and be placed under appropriate medical observation.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia occurred rarely in patients with normal renal function and without other complicating factors. Enalapril should be prescribed with extreme caution to patients with collagen vascular disease receiving immunosuppressive therapy, allopurinol, procainamide, or a combination of these complicating factors, especially if renal impairment is already present. Serious infections, sometimes unresponsive to intensive antibiotic therapy, have developed in some of these patients. Periodic monitoring of white blood cell counts is recommended when enalapril is prescribed to such patients, and patients should be advised to report any signs of infection.

Hypersensitivity/angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported during treatment with ACE inhibitors, including Enalapril-AstraPharm, occurring at various times during therapy. In such cases, the drug should be discontinued immediately, and the patient should be placed under continuous observation until complete resolution of symptoms. Observation may only be discontinued after this. Even when swelling is limited to the tongue without respiratory compromise, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal outcomes due to laryngeal angioedema or tongue swelling have been reported very rarely. When swelling occurs in the area of the tongue, glottis, or larynx, especially in patients with a history of airway surgery, airway obstruction may develop. When angioedema involves the tongue, pharynx, or larynx, potentially causing airway obstruction, immediate appropriate therapy should be initiated, which may include subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL) and/or measures to ensure airway patency.

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

Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing angioedema during ACE inhibitor therapy (see also section "Contraindications").

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

Concomitant use of ACE inhibitors and neprilysin inhibitors may increase the risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Anaphylactoid reactions during allergen desensitization with Hymenoptera venom

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

Anaphylactoid reactions during low-density lipoprotein apheresis

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

Patients undergoing hemodialysis

In patients undergoing dialysis using high-flux membranes (e.g., AN 69®) and concurrently receiving an ACE inhibitor, anaphylactoid reactions have occasionally occurred. Therefore, for such patients, consideration should be given to using dialysis membranes of another type or an antihypertensive agent from another class.

Hypoglycemia

Patients with diabetes mellitus who are taking oral antidiabetic agents or insulin and initiate therapy with an ACE inhibitor should be advised to closely monitor their blood glucose levels, especially during the first several months of concomitant use (see section "Interaction with other medicinal products and other forms of interaction").

Cough

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

Surgery/anesthesia

During major surgical procedures or anesthesia with agents causing arterial hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If arterial hypotension develops that can be explained by these interaction mechanisms, it is corrected by increasing fluid volume.

Hyperkalemia

During treatment with ACE inhibitors, including enalapril, elevated serum potassium levels have been observed in some patients. The risk of hyperkalemia is increased in patients with renal impairment, impaired kidney function, age over 70 years, diabetes mellitus, transient conditions (e.g., dehydration), acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements or salt substitutes, and in patients taking other medications that may increase serum potassium (such as heparin, trimethoprim-containing preparations).

In particular, concomitant use of potassium-sparing diuretics, dietary supplements, or potassium-containing salt substitutes in patients with impaired renal function may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned medications is considered necessary, they should be used with caution and serum potassium levels should be monitored regularly (see section "Interaction with other medicinal products and other forms of interaction").

Lithium

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

Concomitant therapy with 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, serum potassium, and blood pressure (see section "Interaction with other medicinal products and other forms of interaction").

Lactose

Enalapril-AstraPharm contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medication. Enalapril-AstraPharm contains less than 200 mg of lactose per tablet.

Use during pregnancy or breastfeeding.

Pregnancy

The drug is contraindicated in pregnant women or women planning to become pregnant (see section "Contraindications"). If pregnancy is confirmed during treatment with this drug, its use should be discontinued immediately, and if necessary, replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on the risk of teratogenicity associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, although a small increased risk cannot be excluded. Except when continuation of the drug is considered necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is detected, ACE inhibitor use should be discontinued immediately, and alternative therapy initiated if necessary.

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

If ACE inhibitor use occurred during the second trimester of pregnancy, ultrasound examination of the kidneys and skull is recommended.

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

Breastfeeding period

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Food intake does not affect the absorption of Enalapril-Astrafarm tablets. Since the tablet is not scored and cannot be divided, in cases where a dose lower than 5 mg is prescribed, enalapril formulations allowing such dosing should be used.

Dosage must be individually adjusted according to each patient's condition (see section "Special Instructions") and the blood pressure response.

Arterial Hypertension

The dosage ranges from an initial dose of 5 mg to a maximum of 20 mg, depending on the severity of arterial hypertension and the patient's condition (see below). Enalapril-Astrafarm is taken once daily. For mild arterial hypertension, the recommended initial dose is 5–10 mg.

In patients with highly activated RAAS (e.g., those with renovascular hypertension, disturbances in salt and/or fluid balance, decompensated cardiac function, or severe arterial hypertension), excessive reduction in arterial blood pressure after the initial dose may occur. Such patients should start with a dose of 5 mg or lower, and treatment initiation should be under medical supervision.

Prior treatment with high doses of diuretics may lead to fluid depletion and increase the risk of arterial hypotension at the start of enalapril therapy. For 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-Astrafarm. Renal function and serum potassium levels should be monitored.

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

Heart Failure/Asymptomatic Left Ventricular Dysfunction

For treatment of clinically manifest heart failure, Enalapril-Astrafarm should be used concomitantly with diuretics and, if necessary, with cardiac glycosides or β-blockers. The initial dose for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. Treatment should be initiated under close medical supervision to monitor the initial effects of the drug on blood pressure. If no adverse effects occur, or after appropriate management of symptomatic hypotension occurring at the beginning of treatment with Enalapril-Astrafarm, the dose should be gradually increased to the usual maintenance dose of 20 mg, administered either once daily or divided into two doses, depending on patient tolerance. Dose titration should be performed over 2–4 weeks. This therapeutic regimen has been shown to effectively reduce mortality rates in patients with clinically manifest heart failure. The maximum dose is 40 mg per day in two divided doses.

Table 1

Proposed dose titration of Enalapril-Astrafarm for patients with heart failure/asymptomatic left ventricular dysfunction

Week	Dose, mg/day
Week 1	Days 1–3: 2.5 mg/day* once daily Days 4–7: 5 mg/day in two divided doses
Week 2	10 mg/day in one or two divided doses
Weeks 3 and 4	20 mg/day in one or two divided doses

* The drug should be used with caution in patients with impaired renal function or those taking diuretics (see section "Special precautions").

Careful monitoring of blood pressure and renal function should be performed both before and during treatment with Enalapril-AstraPharm (see section "Special precautions"), as cases of arterial hypotension and (less frequently) subsequent renal failure have been reported. In patients taking diuretics, the diuretic dose should be reduced if possible prior to initiating treatment with Enalapril-AstraPharm. The development of arterial hypotension after the initial dose of Enalapril-AstraPharm does not imply that hypotension will persist during long-term therapy and does not indicate the necessity to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Table 2

Dosing in renal impairment

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

Renal status	Creatinine clearance (CC), ml/min	Initial dose, mg/day
Mild impairment	30 < CC < 80 ml/min	5–10 mg
Moderate impairment	10 < CC ≤ 30 ml/min	2.5 mg
Severe impairment. Such patients are usually on hemodialysis	CC ≤ 10 ml/min	2.5 mg on dialysis days*

*See section "Special instructions": Patients undergoing hemodialysis.

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

Geriatric patients

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

Children with hypertension aged 6 years and older

Experience with enalapril in children with hypertension is limited (see sections "Pharmacodynamics", "Pharmacokinetics", "Special instructions").

For children who can swallow tablets, the dose should be individually adjusted according to the patient's condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg for patients with body weight from 20 to 50 kg and 5 mg for patients with body weight ≥ 50 kg. Enalapril-Astrafarm is taken once daily. Dosage should be adjusted as needed up to a maximum of 20 mg daily for patients with body weight from 20 to 50 kg and 40 mg daily for patients with body weight ≥ 50 kg (see sections "Special instructions", "Children").

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

Children.

Use in children aged 6 years and older.

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

Overdose.

Limited data are available on overdose. The main signs of overdose, according to available data, include marked hypotension starting approximately 6 hours after drug intake, coinciding with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Plasma enalaprilat levels reported to exceed therapeutic maximum levels by 100 and 200 times were observed after ingestion of 300 mg and 440 mg of enalapril, respectively.

For treatment of overdose, intravenous infusion of isotonic saline solution is recommended. In case of hypotension, the patient should be placed in a supine position. Administration of angiotensin II and/or intravenous catecholamines may be considered. If the drug was recently ingested, measures to eliminate enalapril maleate should be initiated (such as induced vomiting, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis (see section "Special instructions": patients undergoing hemodialysis). In cases of bradycardia resistant to therapeutic interventions, treatment with a cardiac pacemaker is indicated. Vital signs, serum electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Adverse Reactions.

When Enalapril-Astrafarm was used, adverse effects were mostly mild, transient, and did not require discontinuation of therapy in most cases.

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

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion.

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

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

Eye disorders: blurred vision.

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

Respiratory system disorders: cough, dyspnea, rhinorrhea, sore throat and 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 intestine.

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

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

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

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

Reproductive system disorders: impotence, gynecomastia.

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

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

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 2, 6, 9, or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and location of business activity.

6 Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.

INSTRUCTION

for medical use of medicinal product

ENALAPRIL-ASTRAPHARM

(ENALAPRIL-ASTRAPHARM)

Composition:

Active ingredient: enalapril;

1 tablet contains enalapril maleate 10 mg or 20 mg;

Excipients:

for 10 mg tablets: lactose monohydrate; potato starch; povidone; magnesium stearate; colorant "Azorubine" (carmoisine) (E 122);

for 20 mg tablets: lactose monohydrate; potato starch; povidone; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: pink tablets with specks of more intense coloration, flat cylindrical in shape with beveled edges and a score line;

20 mg tablets: white tablets, flat cylindrical in shape with beveled edges and a score line.

Pharmacotherapeutic group.

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

ATC code C09A A02.

Pharmacological properties.

Pharmacodynamics.

Enalapril-Astrafarm (enalapril maleate) is the maleic acid salt of enalapril, a derivative of two amino acids, L-alanine and L-proline.

Mechanism of action

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the pressor substance angiotensin II.

After absorption, enalapril is hydrolyzed to enalaprilat, an inhibitor of ACE.

ACE inhibition leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to inhibition of the negative feedback between angiotensin II activity and renin release) and decreased aldosterone secretion.

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

The mechanism by which enalapril lowers blood pressure is primarily related to inhibition of the renin-angiotensin-aldosterone system (RAAS). The drug may exert antihypertensive effects even in patients with low-renin hypertension.

Administration of Enalapril-Astrafarm in arterial hypertension leads to a reduction in blood pressure in both supine and upright positions without a significant increase in heart rate.

Symptomatic postural hypotension occurs infrequently. In some patients, optimal blood pressure reduction may require several weeks of therapy. Sudden discontinuation of Enalapril-Astrafarm is not associated with a rapid rise in blood pressure.

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

In clinical studies in patients with essential hypertension, blood pressure reduction was usually accompanied by decreased peripheral arterial resistance with increased cardiac output and either slight or no increase in heart rate. Renal blood flow usually increases after enalapril administration; glomerular filtration rate (GFR) usually remains unchanged. No signs of sodium or water retention were observed. However, in patients with low baseline GFR, these values usually increased.

In clinical trials in patients with kidney disease, including diabetic patients, enalapril administration was associated with reduced albuminuria, urinary IgG excretion, and total urinary protein.

When used concomitantly with thiazide diuretics, the antihypertensive effects of Enalapril-Astrafarm are at least additive. The drug may reduce or prevent thiazide-induced hypokalemia.

In patients with heart failure receiving cardiac glycosides and diuretics, oral or injectable Enalapril-Astrafarm was associated with reduced peripheral resistance and blood pressure. Cardiac output increased, and heart rate (usually elevated in heart failure patients) decreased. Pulmonary capillary wedge pressure also decreased. Exercise tolerance improved and severity of heart failure, assessed by NYHA (New York Heart Association) criteria, decreased. These effects were sustained during long-term treatment.

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

Clinical pharmacology in children

Experience with enalapril use in children aged 6 years and older with arterial hypertension is limited. In studies involving children aged 6 to 16 years with arterial hypertension, body weight ≥ 20 kg, and glomerular filtration rate (GFR) > 30 mL/min/1.73 m², patients weighing < 50 kg received 0.625, 2.5, or 20 mg of enalapril daily, and patients weighing ≥ 50 kg received 1.25, 5, or 40 mg of enalapril daily. Once-daily administration of enalapril reduced diastolic blood pressure in a dose-dependent manner.

Pharmacokinetics.

Absorption

After oral administration, enalapril is rapidly absorbed, with peak serum concentration (Cmax) reached within 1 hour. The extent of enalapril absorption after oral tablet administration is approximately 60%. Food in the gastrointestinal tract does not affect the absorption of oral enalapril. After absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Cmax of enalaprilat is observed approximately 4 hours after oral enalapril administration.

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

Distribution

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

Metabolism

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

Elimination

Enalaprilat is primarily eliminated via the kidneys. The main urinary components 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 increases. In patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), the steady-state area under the concentration-time curve (AUC) of enalaprilat was approximately twice that in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increased approximately eightfold. In such cases, the effective half-life of enalaprilat is prolonged, and the time to reach steady state is increased (see section "Dosage and administration").

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

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to enalapril, any excipient, or any other ACE inhibitor.

History of angioedema associated with ACE inhibitor use.

Hereditary or idiopathic angioedema.

Pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding").

Enalapril-Astrafarm should not be used with aliskiren-containing products in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²).

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

Interaction with other medicinal products and other forms of interaction.

Antihypertensive therapy

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

Potassium-sparing diuretics or potassium supplements

ACE inhibitors may enhance diuretic-induced potassium loss. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium levels (e.g., trimethoprim-containing drugs) may lead to significant increases in serum potassium, especially in patients with impaired renal function.

Diuretics (thiazide or loop diuretics)

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

Antidiabetic agents

Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemics) has been reported to cause decreased blood glucose levels with risk of hypoglycemia. This phenomenon is most likely during the first weeks of concomitant therapy and in patients with renal impairment (see sections "Special precautions", "Adverse reactions").

Lithium

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

Tricyclic antidepressants/neuroleptics/anesthetics/sedatives

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

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

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the effects of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs, including selective COX-2 inhibitors.

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors may have additive effects on increasing serum potassium and may lead to impaired renal function. These effects are usually reversible.

Acute renal failure may rarely occur, particularly in patients with impaired renal function (e.g., elderly patients or those with reduced circulating blood volume, including those on diuretics). Therefore, such combinations should be used cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and undergo careful monitoring of renal function at the start and periodically during concomitant therapy.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be restricted to specific cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Clinical trials have shown that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with higher rates of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy targeting the RAAS.

Enalapril-Astrafarm should not be used with aliskiren in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Contraindications", "Special precautions").

Gold preparations

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

mTOR inhibitors

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

Neprilysin inhibitors

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

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers

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

Concomitant therapy with ACE inhibitor and 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 higher rates of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy targeting the RAAS. 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.

Special precautions.

Symptomatic hypotension

Symptomatic hypotension rarely occurred in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving Enalapril-Astrafarm, symptomatic hypotension occurred more frequently in patients with hypovolemia, e.g., due to diuretic therapy, salt restriction, hemodialysis, or in patients with diarrhea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions"). Symptomatic hypotension has also been observed in patients with heart failure, with or without renal impairment. Symptomatic hypotension occurred more frequently in patients with more severe heart failure who were receiving high doses of loop diuretics, had hyponatremia, or impaired renal function. Such patients should initiate therapy under medical supervision. Monitoring should be especially careful when adjusting doses of Enalapril-Astrafarm and/or diuretics. Similarly, patients with ischemic heart disease or cerebrovascular disease should be carefully monitored, as excessive blood pressure reduction may lead to myocardial infarction or stroke.

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

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

Aortic or mitral stenosis/hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be used cautiously in patients with left ventricular outflow tract obstruction or outflow tract obstruction. Their use should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Renal impairment

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

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

In some patients with arterial hypertension without prior kidney disease, enalapril combined with diuretics caused usually mild and transient increases in blood urea nitrogen and serum creatinine. In such cases, dose reduction and/or diuretic discontinuation may be necessary. This situation increases the likelihood of existing renal artery stenosis (see section "Special precautions": Renovascular hypertension).

Renovascular hypertension

There is an increased risk of arterial hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney treated with ACE inhibitors. Loss of renal function may occur even with minimal changes in serum creatinine. Such patients should start treatment with low doses under careful physician supervision, with cautious dose titration and monitoring of renal function.

Kidney transplantation

There is no experience with Enalapril-Astrafarm use in patients who have recently undergone kidney transplantation. Therefore, this drug is not recommended for such patients.

Hepatic impairment

Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome remains unclear. Patients receiving ACE inhibitors who develop jaundice or marked increases in liver enzymes should discontinue ACE inhibitor therapy and be appropriately monitored.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia rarely occurred in patients with normal renal function and no other complicating factors. Enalapril should be used with extreme caution in patients with collagen vascular disease receiving immunosuppressive therapy, allopurinol, or procainamide, or in combination with these complicating factors, especially if renal impairment is already present. Some of these patients developed serious infections that sometimes did not respond to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended when enalapril is prescribed to such patients, and patients should report any signs of infection.

Hypersensitivity/angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported during treatment with ACE inhibitors, including Enalapril-Astrafarm. In such cases, the drug should be discontinued immediately, and the patient should be closely observed until complete symptom resolution. Observation should continue even if only tongue swelling occurs without respiratory compromise, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal outcomes due to laryngeal angioedema or tongue swelling have been very rarely reported. If swelling occurs in the tongue, glottis, or larynx, especially in patients with a history of airway surgery, airway obstruction may develop. If swelling involves the tongue, pharynx, or larynx, potentially causing airway obstruction, appropriate therapy should be initiated immediately, including subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL) and/or measures to ensure airway patency.

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

Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing angioedema when treated with an ACE inhibitor (see also section "Contraindications").

Concomitant use of ACE inhibitors with mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) may increase the risk of angioedema.

Concomitant use of ACE inhibitors and neprilysin inhibitors may increase the risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Anaphylactoid reactions during allergen desensitization with Hymenoptera venom

Anaphylactoid reactions, potentially life-threatening, have been rarely reported in patients receiving ACE inhibitors during allergen desensitization with Hymenoptera venom. Such reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before desensitization.

Anaphylactoid reactions during low-density lipoprotein apheresis

Anaphylactoid reactions, potentially life-threatening, have been rarely reported in patients receiving ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate. Such reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Patients undergoing hemodialysis

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

Hypoglycemia

Patients with diabetes receiving oral antidiabetic agents or insulin who initiate ACE inhibitor therapy should be advised to carefully monitor blood glucose levels, especially during the first few months of concomitant therapy (see section "Interaction with other medicinal products and other forms of interaction").

Cough

Cough has been reported during ACE inhibitor therapy. 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

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

Hyperkalemia

During ACE inhibitor therapy, including enalapril, increased serum potassium levels have been observed in some patients. The risk of hyperkalemia is increased in patients with renal impairment, impaired renal function, age over 70 years, diabetes, transient conditions (particularly dehydration), acute heart decompensation, metabolic acidosis, concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements or salt substitutes, or other drugs that may increase serum potassium (e.g., heparin, trimethoprim-containing drugs). In particular, concomitant use of potassium-sparing diuretics, dietary supplements, or potassium-containing salt substitutes in patients with renal impairment may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned drugs is considered necessary, they should be used with caution and regular monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Lithium

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

Concomitant therapy with ACE inhibitor and angiotensin receptor antagonist

Combining an ACE inhibitor with an angiotensin receptor antagonist should be restricted 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").

Lactose

Enalapril-Astrafarm contains lactose; therefore, patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medication. Enalapril-Astrafarm contains less than 200 mg of lactose per tablet.

Use during pregnancy or breastfeeding.

Pregnancy

The drug is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this drug, therapy should be discontinued immediately and, if necessary, replaced with another medication approved for use during pregnancy.

Epidemiological data on teratogenic risk from ACE inhibitor use during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. Except when continuation of therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. ACE inhibitor use should be discontinued immediately upon pregnancy detection and, if necessary, alternative therapy initiated.

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

If ACE inhibitors are used during the second trimester of pregnancy, renal and skull ultrasound examinations are recommended.

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

Breastfeeding period

Limited data indicate very low concentrations of enalapril in breast milk (see section "Pharmacokinetics"). Although these concentrations are considered clinically insignificant, Enalapril-Astrafarm is not recommended during breastfeeding of premature infants or newborns in the first few weeks after birth due to the theoretical risk of cardiovascular and renal effects and insufficient experience. In older infants, Enalapril-Astrafarm use during breastfeeding may be considered if therapy is necessary for the mother, provided the infant is monitored for any adverse effects.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and administration.

Food intake does not affect the absorption of Enalapril-Astrafarm tablets. Since the tablet is not scored, if a dose less than 5 mg is required, enalapril preparations allowing such dosing should be used.

Dosage should be individualized based on each patient's condition (see section "Special precautions") and blood pressure response.

Arterial hypertension

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

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

Prior treatment with high-dose diuretics may lead to fluid depletion and risk of arterial hypotension at the start of enalapril therapy. For such patients, an initial dose of 5 mg or lower is recommended. If possible, diuretic therapy should be discontinued 2–3 days before starting Enalapril-Astrafarm. Renal function and serum potassium levels should be checked.

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

Heart failure/asymptomatic left ventricular dysfunction

For treatment of clinically manifest heart failure, Enalapril-Astrafarm should be used concomitantly with diuretics and, if necessary, digitalis preparations or β-blockers. The initial dose for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, and treatment should be initiated under close medical supervision to assess the initial effect on blood pressure. In the absence of effect or after appropriate correction of symptomatic hypotension occurring at the start of heart failure treatment with Enalapril-Astrafarm, the dose should be gradually increased to the usual maintenance dose of 20 mg, administered once daily or divided into two doses depending on patient tolerance. Dose titration should be performed over 2–4 weeks. This therapeutic regimen effectively reduces mortality in patients with clinically manifest heart failure. The maximum dose is 40 mg daily in two divided doses.

Table 1

Recommended dose titration of Enalapril-Astrafarm in patients with heart failure/asymptomatic left ventricular dysfunction

Week	Dose, mg/day
Week 1	days 1 to 3: 2.5 mg/day* once daily days 4 to 7: 5 mg/day in 2 divided doses
Week 2	10 mg/day in 1 or 2 divided doses
Weeks 3 and 4	20 mg/day in 1 or 2 divided doses

* The drug should be used with caution in patients with impaired renal function or those receiving diuretics (see section "Special precautions").

Careful monitoring of blood pressure and renal function should be performed both before and during treatment with Enalapril-Astrafarm (see section "Special precautions"), as cases of arterial hypotension and (less frequently) worsening renal failure have been reported. In patients receiving diuretics, the diuretic dose should be reduced, if possible, prior to initiating treatment with Enalapril-Astrafarm. The occurrence of arterial hypotension after the initial dose of Enalapril-Astrafarm does not necessarily indicate that hypotension will persist during long-term therapy, and does not imply the need to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Table 2

Dosing in renal insufficiency

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

Renal status	Creatinine clearance (CC), mL/min	Initial dose, mg/day
Mild impairment	30 < CC < 80 mL/min	5–10 mg
Moderate impairment	10 < CC ≤ 30 mL/min	2.5 mg
Severe impairment. Such patients are usually on hemodialysis	CC ≤ 10 mL/min	2.5 mg on dialysis days*

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

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

Geriatric patients

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

Children with arterial hypertension from 6 years of age

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

For children who can swallow tablets, the dose should be individually adjusted according to the patient's condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg for patients weighing 20 to 50 kg and 5 mg for patients weighing ≥ 50 kg. Enalapril-Astrafarm is taken once daily. Dosage should be adjusted as needed up to a maximum of 20 mg daily for patients weighing 20 to 50 kg and 40 mg for patients weighing ≥ 50 kg (see sections "Special precautions" and "Children").

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

Children.

Indicated for children aged 6 years and older.

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

Overdose.

Data on overdose are limited. The main reported signs of overdose include profound arterial hypotension, beginning approximately 6 hours after drug intake and coinciding with blockade of the renin-angiotensin system, and stupor. Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include circulatory shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Plasma enalaprilat levels up to 100 and 200 times higher than the maximum levels achieved with therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively.

For treatment of overdose, intravenous infusion of isotonic saline solution is recommended. If arterial hypotension occurs, the patient should be placed in a supine position. Infusion of angiotensin I and/or intravenous administration of catecholamines may be considered. If the drug was recently ingested, measures to eliminate enalapril maleate should be initiated (e.g., induced emesis, gastric lavage, activated charcoal, and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis (see section "Special precautions": Patients undergoing hemodialysis). In cases of therapy-resistant bradycardia, treatment with a cardiac pacemaker may be indicated. Vital signs, serum electrolyte concentrations, and serum creatinine levels should be closely monitored.

Adverse reactions.

When Enalapril-Astrafarm is used, adverse effects are mostly mild, transient, and do not require discontinuation of therapy.

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

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

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

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

Eye disorders: blurred vision.

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

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

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

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

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

A complex syndrome has been reported, including some or all of the following manifestations: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. Skin rashes, photosensitivity, and other skin reactions may also occur as adverse effects.

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

Reproductive system disorders: impotence, gynecomastia.

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

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

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 2, 6, 9, or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and location of operations.

6 Kyivska St., Vishneve, Kyiv-Sviatoshyn district, Kyiv region, 08132, Ukraine.