Enap

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENAP® (ENAP®)

Composition:

Active substance: enalapril maleate;

One tablet contains 2.5 mg or 5 mg or 10 mg or 20 mg of enalapril maleate;

Excipients: tablets of 2.5 mg and 5 mg: sodium hydrogencarbonate, lactose monohydrate, maize starch, hydroxypropylcellulose, talc, magnesium stearate;

tablets of 10 mg and 20 mg: sodium hydrogencarbonate, lactose monohydrate, maize starch, talc, magnesium stearate, iron oxide red (E 172), iron oxide yellow (E 172) – only for 20 mg tablets.

Pharmaceutical form. Tablets.

Main physicochemical properties:

2.5 mg tablets: white, round, biconvex tablets with bevelled edges;

5 mg tablets: white, round, flat tablets with bevelled edges and a notch on one side;

10 mg tablets: reddish-brown, round, flat tablets with bevelled edges and a notch on one side, with white specks on the surface and throughout the tablet mass;

20 mg tablets: light orange, round, flat tablets with bevelled edges and a notch on one side, with white specks on the surface and throughout the tablet mass.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme inhibitors. ATC code C09AA02.

Pharmacological properties.

Pharmacodynamics.

Enalapril maleate – 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 results in decreased plasma levels of angiotensin II, leading to increased plasma renin activity (due to removal 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 degradation 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). Enalapril may exert its antihypertensive effect even in patients with low-renin hypertension.

Administration of Enap® in arterial hypertension results in reduction of 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 Enap® has not been associated with rapid rebound increase 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 drug administration. The duration of effect depends on the dose. However, when used at recommended doses, antihypertensive and hemodynamic effects are maintained for at least 24 hours.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction is usually accompanied by a decrease in peripheral vascular resistance, with an increase in cardiac output and either a slight increase or no change in heart rate. After enalapril administration, renal blood flow increases, while glomerular filtration rate remains unchanged. There is no evidence of sodium or water retention. However, in patients with initially low glomerular filtration rates, these values usually increase.

In short-term clinical studies in patients with impaired renal function, with or without diabetes, enalapril administration was associated with reduced albuminuria, urinary excretion of IgG, and total urinary protein.

When administered concomitantly with thiazide diuretics, the hypotensive effects of Enap® 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 Enap® was associated with reduced peripheral resistance and blood pressure. Cardiac output increased, while 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, was reduced. These effects were maintained during long-term treatment.

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

Antihypertensive therapy with Enap**®** leads to significant regression of left ventricular hypertrophy with preservation of left ventricular systolic function.

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

Pharmacokinetics.

Absorption

Enalapril is rapidly absorbed from the gastrointestinal tract, reaching peak serum concentration within 1 hour. The extent of absorption is approximately 60%, and food intake does not affect absorption. After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentration of enalaprilat is reached 4 hours after oral administration of enalapril. The effective half-life for accumulation of enalaprilat after multiple doses of enalapril is 11 hours. In patients with normal renal function, steady-state serum concentrations of enalaprilat are achieved within four days of treatment.

Distribution

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

Metabolism

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

Elimination

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. After administration of 5 mg once daily in patients with mild to moderate renal impairment (creatinine clearance 0.6–1 ml/sec), the steady-state AUC of enalaprilat was approximately twice higher than in patients with normal renal function. In severe renal impairment (creatinine clearance 0.5 ml/sec), the AUC increased 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.

Enalaprilat can be removed from the systemic circulation by hemodialysis. The dialysis clearance of enalaprilat is 1.03 ml/sec.

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 or to any of the other components of the medicinal product, or to other ACE inhibitors.
• History of angioedema associated with previous treatment with ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation").
• Enap® should not be used with medicinal products containing aliskiren in patients with diabetes mellitus or with renal impairment (eGFR < 60 mL/min/1.73 m²).
• Concomitant use in combination with neprilysin inhibitors (e.g., sacubitril) – due to increased risk of angioedema. The medicinal product should not be administered within 36 hours after the last dose of sacubitril/valsartan – a medicinal product containing a neprilysin inhibitor, or after switching from it to another medicinal product (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving enalapril. 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. Caution should also be exercised when combining enalapril with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of enalapril with the above-mentioned medicinal products is not recommended. If the above-mentioned 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 intravascular 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 initiating therapy with a low dose of enalapril.

Other antihypertensive medicinal products

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

Antidiabetic medicinal products

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic medicinal products (e.g., insulin, oral hypoglycemic agents) may lead to 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 for use", "Undesirable effects").

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 with thiazide diuretics may further increase serum lithium levels and increase the risk of lithium intoxication. Concomitant use of enalapril with lithium is not recommended; however, 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 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 effect of diuretics and other antihypertensive medicinal products. Therefore, the antihypertensive effect of angiotensin II receptor antagonists (ARBs) or ACE inhibitors may be attenuated by NSAIDs, including selective COX-2 inhibitors.

Concomitant use of NSAIDs, including COX-2 inhibitors, with ARBs or ACE inhibitors results in 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 renal impairment (e.g., elderly patients or patients with reduced intravascular volume, including those taking diuretics). Therefore, such combination should be used cautiously in patients with renal impairment. Patients should maintain adequate fluid intake; renal function should be closely monitored at the start 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 ARB II) should be restricted to specific cases only, with careful monitoring of blood pressure, renal function, and electrolyte levels. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with higher rates of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single agent affecting the RAAS. Concomitant use of ACE inhibitors and ARBs II should not be used in patients with diabetic nephropathy.

Enap® should not be used with aliskiren in patients with diabetes mellitus or with 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 concomitantly an ACE inhibitor, including enalapril.

Medicinal products increasing the risk of angioedema

Concomitant use with neprilysin inhibitors (e.g., sacubitril) is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

mTOR inhibitors

Concomitant use with racécadotril, mTOR inhibitors (such as temsirolimus, sirolimus, everolimus), and vildagliptin may lead to an increased 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

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

Co-trimoxazole (trimethoprim/sulfamethoxazole)

In patients concomitantly receiving co-trimoxazole (trimethoprim/sulfamethoxazole), the risk of hyperkalemia is increased (see section "Special precautions for use").

Cyclosporine

Hyperkalemia may occur with concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin

Hyperkalemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium levels is recommended.

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 "Undesirable 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 have impaired renal function. Such patients should begin therapy with Enap® under medical supervision. Particular caution is required when adjusting the dose of the drug and/or diuretic. Similarly, patients with ischemic heart disease or cerebrovascular disorders should be closely monitored, as excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In the event of arterial hypotension, the patient should be placed in a supine position and, if necessary, administered intravenous physiological saline. Transient arterial hypotension following enalapril administration is not a contraindication to continued treatment, 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, enalapril may further reduce blood pressure levels. 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 valve stenosis/hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction or obstructive pathway, and 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 < 1.33 mL/sec), the initial dose of enalapril should be adjusted according to creatinine clearance (see section "Dosage and administration") and subsequently based on the 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. When detected early and managed appropriately, renal impairment associated with enalapril therapy is usually reversible.

In some patients with arterial hypertension who had no pre-existing kidney disease, 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 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 kidney function may occur even with minimal changes in serum creatinine levels. Such patients should start treatment with low doses under strict medical supervision, with careful dose titration and monitoring of renal function.

Kidney transplantation

There is no experience with the use of Enap® in patients who have recently undergone kidney transplantation. Therefore, Enap® is not recommended for these 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 elevations in 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 is rare in patients with normal renal function and no other complicating factors. Enalapril should be administered with extreme caution to patients with collagen vascular diseases receiving immunosuppressive therapy, allopurinol, or procainamide, or in combination with these complicating factors, especially if renal function is already impaired. Serious infections, sometimes unresponsive to intensive antibiotic therapy, have developed in some of these patients. Periodic monitoring of leukocyte count is recommended when enalapril is prescribed to such patients. Patients should be advised to report any signs of infection.

Hypersensitivity/angioedema

Cases of angioedema involving the face, extremities, lips, tongue, glottis, and/or larynx have been reported during various periods of treatment with ACE inhibitors, including enalapril. In such cases, enalapril therapy should be discontinued immediately, and the patient should be placed under continuous observation until complete resolution of symptoms is confirmed. Observation may be discontinued only after this. Even in cases of tongue swelling 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 very rarely reported. When swelling involves the tongue, glottis, or larynx—particularly in patients with a history of airway surgery—airway obstruction may develop. If the tongue, pharynx, or larynx are involved and airway obstruction is possible, 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 Black patients 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 section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan should not be initiated within 36 hours after the last dose of enalapril. Enalapril therapy should not be initiated within 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema, such as airway or tongue swelling, with or without respiratory compromise (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Anaphylactoid reactions during allergen desensitization with hymenoptera venom

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

Anaphylactoid reactions during LDL apheresis

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

Patients undergoing hemodialysis

In patients undergoing dialysis with 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 receiving oral antidiabetic agents or insulin who initiate ACE inhibitor therapy should be advised to closely monitor blood glucose levels, particularly 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 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 that cause arterial hypotension, enalapril inhibits the formation of angiotensin II secondary to compensatory renin release. If arterial hypotension develops and can be explained by these interaction mechanisms, it can be corrected by increasing fluid volume.

Hyperkalemia

Elevated serum potassium levels have been observed in some patients receiving ACE inhibitors, including enalapril. The risk of hyperkalemia is increased in patients with renal impairment, hypoaldosteronism, impaired renal function, patients aged >70 years, patients with diabetes mellitus, transient conditions such as dehydration, acute heart decompensation, metabolic acidosis, and in patients concurrently receiving 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 or cotrimoxazole, also known as trimethoprim/sulfamethoxazole, and particularly aldosterone antagonists or angiotensin receptor blockers). In particular, the 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. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, 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 ACE inhibitor and angiotensin receptor antagonist

Combining an ACE inhibitor with an ARB II should be limited to individually determined cases, accompanied by careful monitoring of renal function, serum potassium, and blood pressure (see section "Interaction with other medicinal products and other forms of interaction").

Use in children

Experience with efficacy and safety of use in children over 6 years of age with hypertension is limited, and experience for other indications is lacking. Limited pharmacokinetic data are available for use in children over 2 months of age (see sections "Dosage and administration", "Pharmacodynamics", and "Pharmacokinetics").

Enalapril is not recommended for children for indications other than arterial hypertension.

Due to lack of safety data, enalapril is not recommended for neonates and pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m².

Pregnancy/breastfeeding

Initiation of ACE inhibitors during pregnancy is not recommended. Pregnant women or women planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately, and alternative therapy should be initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Pregnancy

ACE inhibitors are contraindicated in pregnant women and 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 discontinued immediately, and alternative therapy initiated if possible.

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

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

Newborns of mothers who received ACE inhibitors should be closely monitored for arterial hypotension, oliguria, and hyperkalemia (see sections "Contraindications" and "Special precautions for use").

Breastfeeding

Limited pharmacokinetic data indicate very low concentrations in breast milk. Although such concentrations are considered clinically insignificant, Enap® is not recommended during breastfeeding of preterm infants and newborns during the first few weeks after birth due to a theoretical risk of cardiovascular and renal effects and insufficient experience with such use. For older infants, Enap® use 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.

Dosage and Administration

The tablets should be taken whole with a small amount of water, regardless of food intake. The medication should be taken daily at the same time. Do not take two doses simultaneously.

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 2.5 mg to a maximum of 20 mg once daily, depending on the degree of arterial hypertension and the patient's condition. 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 may occur after the initial dose. Such patients should start with a dose of 5 mg or lower, and treatment should begin 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. Whenever possible, diuretic therapy should be discontinued 2–3 days before starting Enap®. For patients who cannot discontinue diuretics before starting Enap®, the initial dose should be 2.5 mg as a single dose. 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 daily, administered either as a single dose or divided into two doses.

Heart Failure/Asymptomatic Left Ventricular Dysfunction

For treatment of clinically manifest heart failure, enalapril should be administered concomitantly with diuretics, and, if necessary, with cardiac glycosides or beta-blockers. The initial dose of Enap® for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. The drug should be administered under close medical supervision to monitor its initial effects on blood pressure. If there is no adverse effect or after appropriate management of symptomatic hypotension occurring at the beginning of enalapril therapy, the dose should be gradually increased to the usual maintenance dose of 20 mg, taken 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 in patients with clinically manifest heart failure. The maximum dose is 40 mg daily, divided into two doses.

Table 1.

Proposed dose titration of enalapril in 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 and in those taking diuretics (see section "Special precautions").

Careful monitoring of blood pressure and renal function should be performed both before and after initiation of enalapril therapy (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 starting Enap® therapy. The development of arterial hypotension after the initial dose of enalapril does not imply that hypotension will persist during long-term treatment and does not indicate the necessity to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Dosing in renal insufficiency

In patients with renal insufficiency, the dosing intervals of enalapril should be prolonged and/or the doses reduced.

Table 2.

Renal status	Creatinine clearance (CrCL), mL/min	Initial dose, mg/day
Mild renal impairment	30 < CrCL < 80 mL/min	5–10 mg
Moderate renal 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 made according to 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

Clinical experience with the use of Enap**®** in children with hypertension is limited (see sections "Pharmacodynamics", "Pharmacokinetics", and "Special instructions").

For children who can swallow tablets, the dose should be individually prescribed based on the patient's condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg once daily for patients with body weight from 20 kg to 50 kg and 5 mg once daily for patients with body weight ≥ 50 kg. Dosage should be adjusted according to need up to a maximum dose of 20 mg/day for patients with body weight from 20 to 50 kg and 40 mg/day for patients with body weight ≥ 50 kg (0.58 mg of drug/kg body weight) (see section "Special instructions").

Enap® 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.

Enap**®** 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 on overdose in humans are available. The main signs of overdose reported are profound hypotension starting approximately 6 hours after drug intake, coinciding with blockade of the RAAS, 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 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. If hypotension occurs, the patient should be placed in a supine position. If possible, angiotensin II and/or catecholamines should be administered intravenously. If the drug has been recently ingested, measures to eliminate enalapril maleate are recommended (such as induced vomiting, gastric lavage, administration of absorbents, and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis (see section "Special instructions"). In case of bradycardia resistant to therapeutic interventions, treatment with a cardiac pacemaker is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Side effects

Adverse reactions are classified by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not known (isolated reports).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders:

• Uncommon: anaemia (including aplastic and haemolytic);
• Rare: neutropenia, decreased haemoglobin, decreased haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune disorders.

Endocrine system disorders:

• Not known: syndrome of inappropriate antidiuretic hormone secretion.

Mental disorders:

• Common: depression;
• Uncommon: confusion, nervousness, insomnia;
• Rare: abnormal dreams, sleep disturbances.

Nervous system disorders:

• Very common: dizziness;
• Common: headache, fainting, taste disturbance;
• Uncommon: somnolence, paraesthesia, vertigo.

Eye disorders:

• Very common: blurred vision.

Ear and labyrinth disorders:

• Uncommon: tinnitus.

Cardiac disorders:

• Common: chest pain, arrhythmia, angina pectoris, tachycardia;
• Uncommon: palpitations, myocardial infarction or cerebrovascular stroke, possibly secondary to excessive arterial hypotension in high-risk patients**.

Vascular disorders:

• Common: hypotension (orthostatic hypotension);
• Uncommon: flushing;
• Rare: Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders:

• Very common: cough;
• Common: dyspnoea;
• Uncommon: rhinorrhoea, sore throat and hoarseness, pharyngitis, bronchospasm/asthma;
• Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders:

• Very common: nausea;
• Common: diarrhoea, abdominal pain, taste disturbance;
• Uncommon: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcer;
• Rare: stomatitis/aphthous ulcers, glossitis;
• Very rare: angioedema of the gastrointestinal tract when used concomitantly with ACE inhibitors, including enalapril.

Hepatobiliary disorders:

• Rare: hepatic failure, hepatitis – hepatocellular or cholestatic, hepatonecrosis, cholestasis, including jaundice.

Skin and subcutaneous tissue disorders:

• Common: rash, increased sensitivity/angioedema of the face, limbs, lips, tongue, glottis and/or larynx*;
• Uncommon: sweating, pruritus, urticaria, alopecia;
• Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A syndrome complex including some or all of the following symptoms has been reported: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibodies, elevated ESR, eosinophilia and leukocytosis. Skin rashes, photosensitivity or other dermatological manifestations may occur.

Musculoskeletal and connective tissue disorders:

• Uncommon: muscle cramps.

Renal and urinary disorders:

• Uncommon: renal dysfunction, renal failure, proteinuria;
• Rare: oliguria.

Reproductive system and breast disorders:

• Uncommon: impotence;
• Rare: gynaecomastia.

General disorders:

• Very common: asthenia;
• Common: increased fatigue;
• Uncommon: discomfort, fever.

Laboratory findings:

• Common: hyperkalaemia, increased serum creatinine;
• Uncommon: increased blood urea, hyponatraemia;
• Rare: increased liver enzymes, increased serum bilirubin.

These changes are usually reversible and normalize after discontinuation of enalapril. Since the introduction of the drug into widespread clinical use, isolated cases of neutropenia, thrombocytopenia and bone marrow suppression have been reported, where a relationship to Enap® could not be excluded.

*See section "Special warnings and precautions for use"

**The frequency rate was comparable to that in placebo and active control groups in clinical trials.

Treatment should be discontinued if severe adverse reactions occur.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25°C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging.

Tablets of 2.5 mg, 5 mg or 20 mg: 10 tablets in a blister; 2 blisters in a cardboard box.

Tablets of 10 mg: 10 tablets in a blister; 2, 6 or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.