Enalapril: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALAPRIL (ENALAPRIL)

Composition:

Active substance: 1 tablet contains enalapril maleate 10 mg (0.01 g);

Excipients: lactose monohydrate, potato starch, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, round-shaped, with a score line and beveled edge.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors, single-component.

ATC code C09A A02.

Pharmacological Properties.

Pharmacodynamics.

Enalapril (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, which inhibits ACE. Inhibition of ACE leads to reduced plasma levels of angiotensin II, resulting in increased plasma renin activity (due to suppression of the negative feedback mechanism between angiotensin II activity and 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 the drug remains unclear.

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

Use of enalapril in arterial hypertension results in reduced blood pressure in patients both in the supine and upright positions, without a significant increase in heart rate.

Symptomatic postural hypotension occurs rarely. In some patients, optimal blood pressure reduction may require several weeks of therapy. Sudden discontinuation of the drug has not been 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. The onset of antihypertensive activity is typically observed within 1 hour, and peak reduction in blood pressure occurs 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 patients with essential hypertension, blood pressure reduction is usually accompanied by a decrease in peripheral arterial resistance with an increase in cardiac output and either a slight increase or no change in heart rate. After administration, renal blood flow increases; glomerular filtration rate remains unchanged. Signs of sodium or water retention have not been observed. However, in patients with low baseline glomerular filtration rates, these values increased.

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

When used concomitantly with thiazide diuretics, the hypotensive effects of enalapril are at least additive. Enalapril 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 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 severity of heart failure, assessed by NYHA (New York Heart Association) criteria, decreased. These effects were maintained during long-term treatment.

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

In patients with left ventricular dysfunction, enalapril use reduces the risk of myocardial infarction and the risk of hospitalization due to unstable angina.

Clinical pharmacology in children

Experience with use in children aged 6 years and older with arterial hypertension is limited. In children with arterial hypertension, once-daily administration of enalapril reduces diastolic blood pressure in a dose-dependent manner.

The adverse effect profile in children does not differ from that in adult patients.

Pharmacokinetics.

Absorption

After oral administration, enalapril is rapidly absorbed, with peak serum concentrations of enalapril achieved within 1 hour. 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. Following absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat occur approximately 4 hours after oral administration of enalapril.

The effective elimination half-life (t½) of enalaprilat following repeated oral administration is 11 hours.

Distribution

Across the entire therapeutic concentration range, no more than 60% of enalaprilat is bound to serum 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 increases. In patients with mild to moderate renal dysfunction (creatinine clearance 40–60 mL/min), the steady-state AUC of enalaprilat is approximately twice higher than in patients with normal renal function after a single 5 mg dose once daily. In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increases 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 delayed (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 ACE inhibitor therapy.
Hereditary or idiopathic angioedema.
Pregnancy or women planning to become pregnant (see section "Use in pregnancy or breastfeeding").

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

Interaction with other medicinal products and other forms of interaction.

Antihypertensive therapy

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

Potassium-sparing diuretics or potassium supplements

ACE inhibitors reduce diuretic-induced potassium loss. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes may lead to a significant increase in serum potassium levels. If these agents are indicated due to hypokalemia, they should be used cautiously with regular monitoring of serum potassium levels (see section “Special precautions for use”).

Diuretics (thiazide or loop diuretics)

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

Antidiabetic agents

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may reduce blood glucose levels, increasing the risk of hypoglycemia. This phenomenon is most likely during the first weeks of combined treatment and in patients with renal impairment (see sections "Special precautions for use", "Undesirable effects").

Serum lithium

Cases of reversible increases in serum lithium levels 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 toxicity. Concomitant use of enalapril and lithium is not recommended; however, if such combination is necessary for a patient, careful monitoring of serum lithium levels is required (see section "Special 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 precautions for use").

Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors

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

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors may have an additive effect on increasing serum potassium and may lead to renal dysfunction. 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 blood volume, including those taking diuretics). Therefore, such combinations should be used cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and be under close monitoring of renal function at the start of concomitant therapy and periodically thereafter.

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. In patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy affecting the RAAS. Enalapril must not be co-administered with aliskiren in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Contraindications" or "Special precautions for use").

Gold preparations

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

mTOR inhibitors

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

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

Concomitant use of enalapril with acetylsalicylic acid (at cardiologic doses), thrombolytics, and β-blockers is safe.

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 is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with a single agent acting on the renin-angiotensin-aldosterone system. 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, potassium levels, and blood pressure.

Special precautions for use.

Symptomatic hypotension

Symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving enalapril, symptomatic hypotension occurs more frequently in the presence of hypovolemia, which may result, for example, from 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" and "Side effects"). Symptomatic hypotension has also been observed in patients with heart failure, with or without renal insufficiency. Symptomatic hypotension occurs more frequently in patients with more severe forms of heart failure who are receiving higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should initiate enalapril therapy under medical supervision. Monitoring should be especially careful when adjusting the dose of enalapril 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 development of arterial hypotension, the patient should be placed in a supine position and, if necessary, administered physiological saline intravenously. Transient arterial hypotension during enalapril administration is not a contraindication for further use, which can usually be continued without complications after normalization of blood pressure by fluid volume restoration.

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

Aortic or mitral stenosis/hypertrophic cardiomyopathy

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

Renal function impairment

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

Renal function impairment has been reported in association with enalapril use, primarily observed in patients with severe heart failure or kidney disease, including renal artery stenosis. Renal impairment associated with enalapril therapy is usually reversible if detected early and managed appropriately.

In some patients with hypertension who had no pre-existing kidney disease, enalapril in combination with diuretics caused slight and transient increases in blood urea nitrogen and serum creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation increases the likelihood of underlying renal artery stenosis (see section "Special precautions for use": 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 of a solitary functioning kidney treated with ACE inhibitors. Loss of renal function may occur even with minimal changes in serum creatinine levels. Such patients should start therapy with low doses under close medical supervision, with careful titration and monitoring of renal function.

Kidney transplantation

There is no experience with enalapril use in patients who have recently undergone kidney transplantation. Therefore, enalapril therapy is not recommended in such patients.

Hepatic insufficiency

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

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of 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 function is already impaired. Some of these patients developed serious infections, which sometimes did not respond to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended when prescribing enalapril to such patients, and patients should be instructed to report any signs of infection.

Hypersensitivity/angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported rarely during therapy with ACE inhibitors, including enalapril, occurring at various times during treatment. In such cases, enalapril therapy should be discontinued immediately and the patient placed under continuous observation until complete resolution of symptoms is confirmed. Observation may be discontinued only after this. Even when only tongue swelling occurs without respiratory distress, patients may require continued 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 is localized in the tongue, glottis, or larynx, especially in patients with a history of airway surgery, airway obstruction may develop. When the tongue, pharynx, or larynx are involved and airway obstruction is possible, appropriate therapy should be initiated immediately, 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 Black race 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 (e.g., temsirolimus, sirolimus, everolimus) may increase the risk of angioedema.

Anaphylactoid reactions during allergen desensitization with Hymenoptera venom

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

Anaphylactoid reactions during low-density lipoprotein apheresis

Rarely, patients receiving ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate developed life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis.

Patients undergoing hemodialysis

In patients undergoing dialysis with high-flux membranes (e.g., AN 69®) who are also receiving an ACE inhibitor, anaphylactoid reactions have occasionally occurred. Therefore, for such patients, it is recommended to consider using dialysis membranes of another type or an antihypertensive agent from another class.

Hypoglycemia

Patients with diabetes receiving oral antidiabetic agents or insulin who initiate ACE inhibitor therapy should be advised to closely 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 therapy with ACE inhibitors. 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 inhibits 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 therapy with ACE inhibitors, including enalapril, some patients have experienced elevated serum potassium levels. The risk of hyperkalemia is increased in patients with renal insufficiency, impaired renal function, age > 70 years, diabetes mellitus, transient conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of potassium-containing dietary supplements or salt substitutes; and in patients taking other drugs that may increase serum potassium (e.g., heparin). In particular, concomitant use of potassium-sparing diuretics, potassium-containing dietary supplements, or salt substitutes in patients with impaired renal function may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned drugs is considered necessary, they should be used with caution, with 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

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").

Lactose

Enalapril contains lactose and therefore should not be taken by patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome. Enalapril contains less than 100 mg of lactose per tablet.

Ethnic considerations

Like other angiotensin-converting enzyme inhibitors, enalapril is less effective in reducing blood pressure in patients of Black race compared to patients of non-Black race, possibly due to a higher prevalence of low-renin states among the Black population with arterial hypertension.

Use during pregnancy or breastfeeding.

Pregnancy

ACE inhibitors are contraindicated in pregnant women or women who may become pregnant (see section "Contraindications").

Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy initiated.

Epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. It is known that use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

When prescribing enalapril, the patient must be informed of the potential harm to the fetus.

In cases where ACE inhibitors were used during pregnancy, periodic ultrasound examinations should be performed to assess the intra-amniotic space. However, both physicians and patients should be aware that oligohydramnios may develop after irreversible fetal damage has already occurred.

If ACE inhibitors were used during the second trimester of pregnancy, ultrasound evaluation of embryonic kidney function and skull development is recommended.

Infants born to mothers who received ACE inhibitors should be carefully monitored for arterial hypotension, oliguria, and hyperkalemia. Enalapril, which can cross the placenta, may be partially removed from the newborn's body by peritoneal dialysis; theoretically, it may be removed by exchange transfusion, although there is no experience with this procedure.

Breastfeeding

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

Ability to influence reaction rate when driving or operating machinery.

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

Method of Administration and Dosage

Food intake does not affect the absorption of Enalapril tablets.

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

The 10 mg tablet should be swallowed whole without breaking. If a patient requires a dose lower than 10 mg, a lower-dose formulation of the drug should be used.

Arterial Hypertension

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

In patients with highly activated renin-angiotensin-aldosterone system (e.g., renovascular hypertension, disturbances in salt and/or fluid balance, decompensated cardiac function, or severe arterial hypertension), excessive reduction in arterial pressure may occur after the initial dose. Such patients should 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 increase the risk of arterial hypotension at the start of enalapril therapy. For such patients, the recommended initial dose is 5 mg* or lower. If possible, diuretic therapy should be discontinued 2–3 days before starting Enalapril. 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 should be used concomitantly with diuretics and, if necessary, cardiac glycosides or beta-blockers. The initial dose of Enalapril for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg*. Treatment must be initiated under close medical supervision to monitor the initial effects of the drug on arterial pressure. If there is no adverse effect or after appropriate symptomatic hypotension has been managed at the beginning of enalapril therapy for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, which may be administered 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 in patients with clinically manifest heart failure. The maximum dose is 40 mg daily in two divided doses.

Proposed dose titration of Enalapril for 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

** Exercise caution when administering the drug to 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 (see section "Special precautions"), as cases of arterial hypotension and (less commonly) subsequent renal failure have been reported. In patients taking diuretics, the diuretic dose should be reduced, if possible, prior to initiating Enalapril therapy. The development of arterial hypotension after the initial dose of Enalapril does not necessarily indicate that hypotension will persist during long-term therapy and does not imply a need to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Dosing in renal insufficiency

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

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

Elderly patients

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

Children with hypertension aged 6 years and older

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

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 should be taken once daily. Dosage should be adjusted according to clinical needs up to a maximum of 20 mg per day for patients with body weight from 20 to 50 kg and 40 mg per day for patients with body weight ≥ 50 kg (see sections "Special instructions" and "Children").

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

Children.

To be used in children aged 6 years and older.

Enalapril is not recommended for neonates 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 signs of overdose, according to available data, are profound arterial hypotension, which begins approximately 6 hours after drug intake and coincides with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

For treatment of overdose, intravenous infusions of isotonic solution are recommended. If arterial hypotension occurs, the patient should be placed in a supine position. Administration of angiotensin II and/or intravenous catecholamines may be considered. If the drug was recently ingested, measures to eliminate enalapril maleate should be initiated (such as induced emesis, 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, cardiac pacing is indicated. Vital signs, serum electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Adverse Reactions

When enalapril 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 suppression, pancytopenia, lymphadenopathy, autoimmune diseases.

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion.

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

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

Eye disorders: blurred vision.

Cardiovascular system disorders: dizziness, 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 (see section "Special precautions for use"), Raynaud's phenomenon.

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

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

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

Skin and subcutaneous tissue disorders: rash, hypersensitivity/angioedema of the face, extremities, lips, tongue, glottis and/or larynx (see section "Special precautions for use"), 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 symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. Skin reactions such as rash, photosensitization, and other skin disorders may also occur as adverse effects.

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

Reproductive system disorders: impotence, gynecomastia.

General disorders and administration site conditions: asthenia, increased fatigue, muscle cramps, flushing, tinnitus, discomfort, fever.

Laboratory test changes: hyperkalemia, increased serum creatinine, increased blood urea nitrogen, hyponatremia, elevated liver enzymes, increased serum bilirubin.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister. 2 or 10 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Chemical and Pharmaceutical Plant "Chervona Zirka".

Manufacturer's address and place of business.

61010, Ukraine, Kharkiv, 1 Gordienkivska Street.

INSTRUCTION

for medical use of medicinal product

ENALAPRIL

(ENALAPRIL)

Composition:

Active ingredient: 1 tablet contains enalapril maleate 10 mg (0.01 g);

Excipients: lactose monohydrate, potato starch, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round-shaped tablets with a score line and beveled edges.

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

ATC code C09A A02.

Pharmacological properties.

Pharmacodynamics.

Enalapril (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, which inhibits ACE. Inhibition of ACE leads to a decrease 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 reduced aldosterone secretion.

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

The mechanism by which the drug lowers blood pressure is primarily associated with inhibition of the renin-angiotensin-aldosterone system. Enalapril may exert antihypertensive effects even in patients with low-renin hypertension.

Administration of enalapril 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 rarely. In some patients, achieving optimal blood pressure reduction may require several weeks of therapy. Abrupt discontinuation of the drug is not 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 administration. The duration of effect depends on the dose. However, when used at recommended doses, antihypertensive and hemodynamic effects persist for at least 24 hours.

In patients with essential hypertension, blood pressure reduction is usually accompanied by a decrease in peripheral arterial resistance with increased cardiac output and a slight or no increase in heart rate. Renal blood flow increases after administration; glomerular filtration rate remains unchanged. There are no signs of sodium or water retention. However, in patients with low baseline glomerular filtration rate, these levels increase.

In patients with or without diabetes mellitus and kidney disease, enalapril administration was associated with a reduction in albuminuria, urinary IgG excretion, and total urinary protein.

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

In patients with heart failure receiving cardiac glycosides and diuretics, administration of oral or injectable enalapril 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 heart failure severity, assessed by NYHA (New York Heart Association) criteria, decreased. These effects persist during long-term treatment.

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

In patients with left ventricular dysfunction, enalapril reduces the risk of myocardial infarction and hospitalization due to unstable angina.

Clinical pharmacology in children

Experience in children aged 6 years and older with arterial hypertension is limited. In children with arterial hypertension, once-daily administration of enalapril reduces diastolic blood pressure in a dose-dependent manner.

The adverse effect profile in children does not differ from that in adult patients.

Pharmacokinetics.

Absorption

After oral administration, enalapril is rapidly absorbed, with maximum serum concentration of enalapril achieved within 1 hour. The extent of enalapril absorption after oral tablet administration is approximately 60%. The presence of food in the gastrointestinal tract does not affect the absorption of oral enalapril. After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Maximum serum concentration of enalaprilat is observed approximately 4 hours after oral enalapril administration.

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

Distribution

Within 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.

Excretion

Enalaprilat is primarily excreted by the kidneys. The main urinary components are enalaprilat, accounting for about 40% of the dose, and unchanged enalapril (about 20%).

Renal impairment

In patients with renal insufficiency, exposure to enalapril and enalaprilat increases. In patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), the steady-state AUC of enalaprilat is approximately twice higher than in patients with normal renal function after a 5 mg dose once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increases approximately 8-fold. At this level of renal impairment, the effective half-life of enalaprilat is prolonged, and time to steady state is delayed (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, to any excipient, or to any other ACE inhibitor.
History of angioedema associated with ACE inhibitor use.
Hereditary or idiopathic angioedema.
Pregnancy or women planning to become pregnant (see section "Use in pregnancy or lactation").

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

Interaction with other medicinal products and other forms of interaction.

Antihypertensive therapy

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

Potassium-sparing diuretics or potassium supplements

ACE inhibitors enhance diuretic-induced potassium loss. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), as well as potassium-containing dietary supplements or salt substitutes, may lead to a significant increase in serum potassium levels. If these agents are indicated due to hypokalemia, they should be used cautiously with regular monitoring of serum potassium levels (see section "Special precautions for use").

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 for use"). Hypotensive effects can be minimized by discontinuing the diuretic, increasing salt intake, or starting therapy with a low dose of enalapril.

Antidiabetic agents

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

Serum lithium

When ACE inhibitors and lithium are used concomitantly, reversible increases in serum lithium levels and lithium toxicity have been reported. 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 with lithium is not recommended, but if such combination is necessary for a patient, careful monitoring of serum lithium levels should be performed (see section "Special precautions for use").

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 for use").

Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors

Nonsteroidal anti-inflammatory drugs (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 has an additive effect on increasing serum potassium and may lead to impaired renal function. These effects are usually reversible.

Acute renal failure is occasionally possible, especially in certain patients with impaired renal function (e.g., elderly patients or patients with reduced circulating blood volume, including those taking diuretics). Therefore, such combinations should be used cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and be under close 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 limited to specific cases with careful monitoring of blood pressure, renal function, and electrolyte levels. In patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with a higher incidence of arterial hypotension, loss of consciousness, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy targeting the renin-angiotensin-aldosterone system. Enalapril should not be used with aliskiren in patients with diabetes or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Contraindications" or "Special precautions for use").

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) and concomitant ACE inhibitors, including enalapril.

mTOR inhibitors

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

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

Concomitant use of enalapril with acetylsalicylic acid (in cardiologic doses), thrombolytics, and β-blockers is safe.

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 is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy targeting the renin-angiotensin-aldosterone system. 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, potassium levels, and blood pressure.

Special precautions for use.

Symptomatic hypotension

Symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. In hypertensive patients receiving enalapril, symptomatic hypotension occurs more frequently in patients with hypovolemia, such as those undergoing diuretic therapy, salt restriction, hemodialysis, or patients with diarrhea or vomiting (see sections "Interaction with other medicinal products" and "Adverse reactions"). Symptomatic hypotension has also been observed in patients with heart failure, with or without renal insufficiency. Symptomatic hypotension occurs more frequently in patients with more severe forms of heart failure who are taking higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should start enalapril therapy under medical supervision. Monitoring should be especially careful when adjusting the dose of enalapril and/or diuretic. Similarly, patients with ischemic heart disease and cerebrovascular disease should be closely 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 horizontal position and, if necessary, given intravenous physiological saline. Transient arterial hypotension during enalapril administration is not a contraindication for further use, which can usually continue without complications after blood pressure normalization through fluid volume restoration.

In some patients with heart failure and normal or low blood pressure, enalapril may further reduce blood pressure. This response to the drug is expected and usually not a reason to discontinue treatment. If arterial hypotension becomes resistant to treatment, the dose should be reduced and/or diuretic and/or enalapril 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 cases of cardiogenic shock and hemodynamically significant obstruction.

Renal impairment

In patients with impaired renal function (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 treatment response. Regular monitoring of potassium and serum creatinine levels is standard medical practice for such patients.

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

In some hypertensive patients without pre-existing kidney disease, enalapril combined with diuretics caused a slight and transient increase 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 for use": 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 of a single functioning kidney treated with ACE inhibitors. Loss of renal function may occur even with minimal changes in serum creatinine levels. Such patients should start treatment with low doses under careful medical supervision with cautious titration and monitoring of renal function.

Kidney transplantation

There is no experience with enalapril use in patients who have recently undergone kidney transplantation. Therefore, enalapril therapy 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 significant elevation of liver enzymes should discontinue the ACE inhibitor and receive appropriate medical monitoring.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia is rare. Enalapril should be used with extreme caution in patients with collagen vascular diseases undergoing immunosuppressive therapy, treatment with allopurinol or procainamide, or in combination with these complicating factors, especially if renal function is already impaired. Some of these patients developed severe infections, sometimes unresponsive to intensive antibiotic therapy. Periodic monitoring of white blood cell count 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. In such cases, enalapril therapy should be immediately discontinued, and the patient should be under continuous observation until complete resolution of symptoms. Observation may only be discontinued after complete resolution. Even if only tongue swelling occurs without respiratory distress, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal outcomes due to laryngeal angioedema or tongue swelling have been reported. If swelling occurs in the tongue, glottis, or larynx, especially in patients with a history of airway surgery, airway obstruction may develop. When involvement of the tongue, pharynx, or larynx may cause airway obstruction, immediate appropriate therapy should be initiated, which may include subcutaneous injection 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 taking ACE inhibitors compared to patients of other races.

Patients with a history of angioedema not related 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.

Anaphylactoid reactions during allergen desensitization with hymenoptera venom

Occasionally, anaphylactoid reactions, potentially life-threatening, have occurred in patients receiving ACE inhibitors during allergen desensitization with hymenoptera venom. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting desensitization.

Anaphylactoid reactions during low-density lipoprotein apheresis

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

Patients undergoing hemodialysis

Anaphylactoid reactions have occasionally occurred in patients undergoing dialysis with high-flux membranes (e.g., AN 69®) while taking an ACE inhibitor. Therefore, for such patients, it is recommended to consider using a different type of dialysis membrane or an antihypertensive agent from another class.

Hypoglycemia

Patients with diabetes mellitus taking oral antidiabetic agents or insulin and starting ACE inhibitor therapy should be advised to carefully monitor blood glucose levels, especially during the first few 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. 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 interaction mechanisms, it can be corrected by increasing fluid volume.

Hyperkalemia

During treatment with ACE inhibitors, including enalapril, increased serum potassium levels have been observed in some patients. The risk of hyperkalemia is increased in patients with renal failure, impaired renal function, age > 70 years, diabetes mellitus, transient conditions (particularly dehydration), acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of potassium-containing dietary supplements or salt substitutes; and patients taking other drugs that may increase serum potassium (e.g., heparin). In particular, concomitant use of potassium-sparing diuretics, potassium-containing dietary supplements, or salt substitutes in patients with impaired renal function may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned drugs is considered necessary, they should be used cautiously with 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 an ACE inhibitor and an angiotensin receptor antagonist

Combining 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").

Lactose

Enalapril contains lactose and therefore should not be used in patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome. Enalapril contains less than 100 mg of lactose per tablet.

Ethnic characteristics

Like other angiotensin-converting enzyme inhibitors, enalapril is less effective in reducing blood pressure in patients of African descent compared to patients of non-African descent, possibly due to a higher prevalence of low-renin states among African populations with arterial hypertension.

Use in pregnancy or lactation.

Pregnancy

ACE inhibitors are contraindicated in pregnancy or in women planning pregnancy (see section "Contraindications").

Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be immediately discontinued and, if possible, alternative therapy initiated.

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increase in risk cannot be excluded. It is known that ACE inhibitor use during the second and third trimesters of pregnancy may lead to fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

Patients should be informed about the potential harm to the fetus when enalapril is prescribed.

If ACE inhibitors were used during the second trimester of pregnancy, ultrasound assessment of embryonic kidney function and skull ossification is recommended.

Breastfed infants whose mothers took ACE inhibitors should be carefully monitored for arterial hypotension, oliguria, and hyperkalemia. Enalapril, capable of crossing the placenta, can be partially removed from the newborn's body by peritoneal dialysis; theoretically, it could be removed by exchange transfusion, although there is no experience with this procedure.

Lactation

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

Effect on ability to drive and operate 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 tablets.

Dosage should be individually adjusted according to each patient's condition (see section "Special precautions for use") and blood pressure response.

The 10 mg tablet should be swallowed whole, without breaking. If a patient requires a dose less than 10 mg, a preparation with a lower dosage should be used.

Arterial hypertension

The dosage ranges from an initial 5 mg* (*use appropriate dosage form) to a maximum of 20 mg depending on the degree of arterial hypertension and patient status (see below). Enalapril is taken once daily. For mild hypertension, the recommended initial dose is 5*-10 mg.

In patients with highly activated renin-angiotensin-aldosterone system (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 an initial dose of 5 mg* or lower, and treatment initiation should be under medical supervision.

Prior treatment with high-dose diuretics may lead to fluid deficiency and risk of arterial hypotension at the start of enalapril therapy. For such patients, an initial dose of 5 mg* or lower is recommended. Diuretic therapy should be discontinued, if possible, 2–3 days before starting enalapril. 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 should be used concomitantly with diuretics and, if necessary, digitalis preparations or beta-blockers. The initial dose of enalapril for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg*, and treatment should be initiated under careful 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 beginning of enalapril treatment for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, which may be administered once daily or divided into two doses depending on patient tolerance. Dose titration is recommended over 2–4 weeks. This therapeutic regimen effectively reduces mortality rates in patients with clinically manifest heart failure. The maximum dose is 40 mg daily in two divided doses.

Proposed enalapril dose titration 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 2 divided doses
Week 2	10 mg/day in 1 or 2 doses
Weeks 3 and 4	20 mg/day in 1 or 2 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 (see section "Special precautions"), as cases of arterial hypotension and (less frequently) worsening renal failure have been reported. Patients receiving diuretics should, if possible, have their diuretic dose reduced prior to initiating Enalapril therapy. The occurrence of arterial hypotension after the initial dose of Enalapril does not necessarily indicate that hypotension will persist during prolonged treatment, and is not an indication to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Dosing in renal impairment

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

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

***See section «Special precautions»: patients undergoing hemodialysis.

Enalapril is removed by hemodialysis. Dose 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 aged 6 years and older

Clinical experience with enalapril in children with arterial hypertension is limited (see sections «Special precautions», «Pharmacodynamics», «Pharmacokinetics»).

For children able to swallow tablets, the dose should be individually adjusted according to patient status, blood pressure response to treatment, and patient 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 should be taken once daily. Dosage should be adjusted according to individual needs 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 precautions» and «Children»).

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

Children.

To be used in children aged 6 years and older.

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

Overdose.

Data regarding overdose are limited. The main signs of overdose, according to available data, are marked arterial hypotension, beginning approximately 6 hours after drug intake and coinciding with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Treatment of overdose includes intravenous infusion of isotonic saline solution. If arterial hypotension occurs, the patient should be placed in a supine position. Infusion of angiotensin II and/or intravenous administration of catecholamines may be considered. If the drug was recently ingested, measures to eliminate enalapril maleate should be undertaken (such as induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis (see section «Special precautions»: Patients undergoing hemodialysis). In cases of bradycardia resistant to therapeutic measures, pacemaker therapy is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be closely monitored.

Adverse reactions.

When enalapril 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 diseases.

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion.

Metabolic disorders: hypoglycemia (see section «Special precautions»).

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

Eye disorders: blurred vision.

Cardiovascular disorders: dizziness, hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia, orthostatic hypotension, palpitations, myocardial infarction or stroke, possibly due to excessive blood pressure reduction in high-risk patients (see section «Special precautions»), Raynaud’s phenomenon.

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

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

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

There have been reports of a complex syndrome developing, 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, photosensitization, and other skin reactions may also occur as adverse effects.

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

Reproductive system disorders: impotence, gynecomastia.

General disorders and administration site conditions: asthenia, increased fatigue, muscle cramps, hot flushes, tinnitus, discomfort, fever.

Laboratory test abnormalities: hyperkalemia, increased serum creatinine, increased blood urea nitrogen, hyponatremia, elevated liver enzymes, increased serum bilirubin.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister. 2 or 10 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Chemical and Pharmaceutical Plant "Krasnaya Zvezda".

Manufacturer's address.

Gordienkovskaya St., Kharkiv, 61010, Ukraine.