Berlipril® 5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BERLIPRIL® 5

Composition:

Active substance: enalapril maleate;

1 tablet contains enalapril maleate 5 mg;

Excipients: lactose monohydrate, light magnesium carbonate, gelatin, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: almost white tablets, slightly biconvex with bevelled edges and a score line on one side.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors, single component. ATC code C09A A02.

Pharmacological Properties.

Pharmacodynamics.

Berlipril® 5 (enalapril maleate) is the maleate 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 to the pressor substance angiotensin II. After absorption, enalapril maleate is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to blockade of the negative feedback mechanism of renin release) and decreased aldosterone secretion.

ACE is identical to kininase II. Thus, Berlipril® 5 may also block the degradation of bradykinin, a potent vasodilator peptide. However, the role of this effect in the therapeutic action of enalapril remains unclear.

The mechanism by which Berlipril® 5 lowers blood pressure is primarily attributed to inhibition of the renin-angiotensin-aldosterone system (RAAS). Berlipril® 5 may exert antihypertensive effects even in patients with low-renin hypertension.

Administration of Berlipril® 5 to patients with arterial hypertension results in a 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. Abrupt discontinuation of Berlipril® 5 has not been associated with a rapid rise in blood pressure.

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

Hemodynamic studies in patients with essential arterial hypertension have shown that blood pressure reduction is accompanied by a decrease in peripheral arterial resistance and an increase in cardiac output, while heart rate remains slightly changed or unchanged. After administration of Berlipril® 5, renal blood flow increases; glomerular filtration rate (GFR) remains unchanged. Signs of sodium and water retention are not observed. However, in patients with low GFR prior to therapy, this parameter usually increases.

In short-term clinical studies in patients with renal disease, both with and without diabetes, administration of enalapril maleate resulted in reduced albuminuria, as well as decreased urinary excretion of IgG and total protein.

When used concomitantly with thiazide diuretics, the antihypertensive effect of Berlipril® 5 is additive. Berlipril® 5 may reduce or prevent thiazide-induced hypokalemia.

In patients with heart failure receiving cardiac glycosides and diuretics, oral or intravenous administration of enalapril maleate resulted in reduced peripheral resistance and decreased blood pressure. Cardiac output increased, while heart rate (typically elevated in heart failure patients) decreased. Pulmonary capillary wedge pressure also decreased. Exercise tolerance and the degree of heart failure, assessed by New York Heart Association (NYHA) criteria, improved. These effects are maintained during long-term treatment.

In patients with mild to moderate heart failure, enalapril slows the progression of cardiac dilation/enlargement and heart failure, as evidenced by reductions in left ventricular end-diastolic and end-systolic volumes and improvement in ejection fraction.

In a multicenter, randomized, double-blind, placebo-controlled trial (SOLVD, Prevention Trial), a population of patients with asymptomatic left ventricular dysfunction (ejection fraction < 35%) was studied. A total of 4228 patients were randomized to receive placebo (n=2117) or enalapril maleate (n=2111). In the placebo group, 818 patients developed heart failure or died (38.6%) compared to 630 patients in the enalapril maleate group (29.8%) (risk reduction: 29%; 95% CI: 21–36%; p < 0.001).

518 patients in the placebo group (24.5%) and 434 in the enalapril maleate group (20.6%) died or were hospitalized due to development of heart failure or complications of existing disease (risk reduction: 20%; 95% CI: 9–30%; p < 0.001).

In another multicenter, randomized, double-blind, placebo-controlled trial (SOLVD, Treatment Trial), a population of patients with clinical signs of congestive heart failure due to systolic dysfunction (ejection fraction < 35%) was studied. A total of 2569 patients receiving standard heart failure therapy were randomized to receive placebo (n=1284) or enalapril (n=1285). In the placebo group, 510 deaths (39.7%) were recorded compared to 452 in the enalapril group (35.2%) (risk reduction: 16%; 95% CI: 5–26%; p=0.0036). Cardiovascular mortality was 461 in the placebo group versus 399 in the enalapril group (risk reduction: 18%; 95% CI: 6–28%; p < 0.002), primarily due to reduced mortality from progressive heart failure (251 cases in the placebo group vs. 209 in the enalapril group; risk reduction: 22%; 95% CI: 6–35%). Fewer patients died or were hospitalized due to worsening heart failure (736 in the placebo group vs. 613 in the enalapril group; risk reduction: 26%; 95% CI: 18–34%; p < 0.0001). Overall, in patients with left ventricular dysfunction in the SOLVD trial, enalapril reduced the risk of myocardial infarction by 23% (95% CI: 11–34%; p < 0.001) and the risk of hospitalization for unstable angina by 20% (95% CI: 9–29%; p < 0.001).

In two large randomized controlled trials (ONTARGET [Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [Veterans Affairs Nephropathy in Diabetes]), the use of an ACE inhibitor in combination with an angiotensin II receptor blocker (ARB) was evaluated.

The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy. These trials showed a modest beneficial effect on renal and/or cardiovascular outcomes and mortality reduction, but an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy. Given the similar pharmacodynamic properties, these findings are also relevant to other ACE inhibitors and angiotensin II receptor blockers.

Therefore, patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to evaluate the benefits of adding aliskiren to standard therapy with ACE inhibitors or ARBs in patients with type 2 diabetes and chronic kidney disease and/or cardiovascular disease. The trial was prematurely terminated due to an increased risk of adverse events. Cardiovascular death or stroke occurred more frequently in the aliskiren group than in the placebo group, as did other serious adverse events of interest (hyperkalemia, hypotension, and renal dysfunction).

Clinical pharmacology in children.

Experience with the use of the drug in children with arterial hypertension aged 6 years and older is limited. In clinical trials involving 110 children with arterial hypertension aged 6 to 16 years, with body weight ≥ 20 kg and glomerular filtration rate > 30 mL/min/1.73 m², patients with body weight < 50 kg received 0.625 mg, 2.5 mg, or 20 mg of enalapril maleate daily, while patients with body weight ≥ 50 kg received 1.25 mg, 5 mg, or 40 mg of enalapril maleate daily. Once-daily administration of enalapril maleate reduced blood pressure in a dose-dependent manner. The dose-dependent antihypertensive effect was observed across all subgroups (by age, Tanner stage, sex, race). However, with the lowest studied doses of 0.625 mg and 1.25 mg (corresponding to an average of 0.02 mg/kg once daily), adequate antihypertensive efficacy was not demonstrated. The maximum dose studied during the trial was 0.58 mg/kg (up to 40 mg) once daily. The adverse event profile in children was similar to that observed in adult patients.

Pharmacokinetics.

Absorption.

After oral administration, enalapril maleate is rapidly absorbed, with peak serum concentration reached within the first hour. Based on urinary excretion data, the extent of absorption of enalapril maleate after oral tablet administration is approximately 60%. The presence of food in the gastrointestinal tract does not affect the absorption of the oral medicinal product Berlipril® 5. After absorption, orally administered enalapril maleate is rapidly and completely hydrolyzed to enalaprilat, a potent ACE inhibitor. The peak concentration of enalaprilat in serum occurs approximately 4 hours after oral administration of enalapril tablets.

The effective elimination half-life (T½) of enalaprilat after multiple oral doses of enalapril is 11 hours. In patients with normal renal function, steady-state concentrations of enalaprilat in serum are achieved after 4 days of treatment.

Distribution.

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

Biological transformation.

Apart from conversion to enalaprilat, there is no significant evidence of further metabolism of enalapril maleate.

Excretion.

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

Renal impairment.

In patients with renal impairment, exposure to enalapril maleate and enalaprilat is increased. After administration of 5 mg once daily to patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), the steady-state AUC (area under the concentration-time curve) of enalaprilat was approximately twice that in patients with normal renal function. In severe renal impairment (creatinine clearance ≤ 30 mL/min), the AUC increased approximately 8-fold. At this stage of renal impairment, the effective T½ of enalaprilat after multiple dosing of enalapril maleate is prolonged, and the rate of reaching steady-state levels is slowed (see section "Dosage and administration").

Enalaprilat can be removed from systemic circulation by hemodialysis. Dialysis clearance is 62 mL/min.

Children.

Pharmacokinetic studies using multiple doses were conducted in 40 children (boys and girls) with arterial hypertension aged 2 months to 16 years, who received oral enalapril maleate at doses of 0.07 to 0.14 mg/kg/day. No significant differences in enalaprilat pharmacokinetics were observed between children and adults. Results indicated increased AUC (when dose-normalized per body weight) with age; however, this increase in AUC was not observed when doses were normalized per body surface area. At steady state, the mean effective half-life of enalaprilat was 14 hours.

Lactation.

Four to six hours after a single oral dose of 20 mg in five postpartum women, the mean maximum concentration of enalapril in breast milk was 1.7 µg/L (range: 0.54–5.9 µg/L).

The mean maximum concentration of enalaprilat in breast milk was 1.7 µg/L (range: 1.2–2.3 µg/L); peak concentrations were observed at various times within 24 hours. Based on the maximum concentration in breast milk, the maximum dose received by an exclusively breastfed infant is 0.16% of the maternal dose.

The maximum concentration of enalapril in breast milk of a woman who had taken enalapril 10 mg daily for 11 months was 2 µg/L, measured 4 hours after dose administration, and the maximum concentration of enalaprilat was 0.75 µg/L, measured approximately 9 hours after dose administration. The total amount of enalapril and enalaprilat in breast milk measured over 24 hours was 1.44 µg/L and 0.63 µg/L, respectively.

Enalaprilat concentration in breast milk could not be determined (< 0.2 µg/L) 4 hours after a single 5 mg dose of enalapril in one mother and 10 mg doses in two mothers; enalapril concentrations were not detected.

Preclinical safety data.

Preclinical data do not indicate any special hazard for humans based on standard studies of safe pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, and toxic effects on reproductive function.

Reproductive toxicity studies suggest that enalapril maleate does not affect fertility or reproductive system function in rats and has no teratogenic effect. In a study where the drug was administered to rats before mating and throughout pregnancy and lactation, increased offspring mortality was observed. It has been demonstrated that the drug crosses the placenta and is excreted in milk. Fetal toxicity (harmful effects on the fetus and/or fetal death) of drugs belonging to the class of ACE inhibitors has been proven when administered during the second and third trimesters of pregnancy.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to enalapril maleate, other ACE inhibitors, or to any of the excipients.
• 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 lactation").

Concomitant use of Berlipril® 5 with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).

Enalapril must not be used in combination with sacubitril/valsartan due to an increased risk of angioedema. Enalapril must not be administered within 36 hours before or after sacubitril/valsartan, a medicinal product containing a neprilysin inhibitor (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Medicinal products increasing the risk of angioedema.

Neprilysin inhibitors.

Concomitant use of enalapril with sacubitril/valsartan is contraindicated, as dual inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of enalapril therapy. Enalapril therapy must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Racecadotril, mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus), and vildagliptin.

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

Other antihypertensive agents.

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

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 therapy. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels.

Caution should be exercised when co-administering Berlipril® 5 with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of Berlipril® 5 with the above-mentioned agents is not recommended. If concomitant use is necessary, it should be done with caution and with regular monitoring of serum potassium levels (see section "Special precautions for use").

Cyclosporine.

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

Heparin.

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

Diuretics (thiazide-type or loop diuretics).

Prior treatment with high-dose diuretics may lead to reduced intravascular volume and increase the risk of arterial hypotension at the start of enalapril therapy (see section "Special precautions for use"). The hypotensive effect can be minimized by discontinuing the diuretic, correcting fluid or salt depletion, or initiating enalapril therapy at low doses.

Thrombolytics.

An increased risk of angioedema has been reported in patients receiving alteplase concomitantly with ACE inhibitors, including enalapril (see section "Special precautions for use").

Antidiabetic agents.

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

Metformin.

Concomitant use of ACE inhibitors with metformin may increase the risk of lactic acidosis (possibly due to impaired renal function). Therefore, metformin should be used cautiously in patients at risk, and careful monitoring of renal function is required.

Lithium-containing medicines.

Increases in serum lithium levels and lithium toxicity have been reported during concomitant use of ACE inhibitors and lithium-containing medicines. 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 is required (see section "Special precautions for use").

Tricyclic antidepressants/neuroleptics/anesthetics/opioids.

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").

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

Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, may attenuate the effects of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be reduced 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 levels and may lead to deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may develop, particularly in patients with pre-existing renal impairment (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 and be closely monitored for renal function 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 angiotensin II receptor antagonist) should be restricted to selected cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with higher incidences of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single RAAS-acting agent.

Concomitant use of Berlipril® 5 with aliskiren is not recommended in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Contraindications" and "Special precautions for use").

Gold-containing medicines.

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

Sympathomimetics.

Sympathomimetic agents may reduce the antihypertensive effects of ACE inhibitors.

Alcohol.

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid and beta-blockers.

Concomitant use of enalapril with acetylsalicylic acid (at cardioprotective doses) and beta-blockers is safe.

Special precautions for use.

Symptomatic hypotension.

Symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving Berlipril® 5, symptomatic hypotension occurs more frequently in the presence of hypovolemia, which may result, for example, from diuretic therapy, dietary 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", "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 receiving higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should begin treatment with Berlipril® 5 under medical supervision. Particular caution is required when adjusting the dose of Berlipril® 5 and/or diuretics. Similarly, patients with ischemic heart disease or cerebrovascular disease should be closely monitored, as excessive reduction in arterial pressure may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, administered intravenous physiological saline. Transient arterial hypotension is not a contraindication for further use, which may be continued after normalization of arterial pressure through volume repletion.

In some patients with heart failure and normal or low arterial pressure, Berlipril® 5 may further reduce arterial pressure. This response to the drug is expected and usually does not require discontinuation of therapy. If arterial hypotension becomes pronounced, the dose should be reduced and/or diuretic therapy and/or Berlipril® 5 should be discontinued.

Aortic or mitral stenosis/hypertrophic cardiomyopathy.

Like all vasodilators, ACE inhibitors should be used with particular caution in patients with obstruction of the left ventricular outflow tract or obstructive outflow. They 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 based on the patient's response to treatment. Routine monitoring of serum potassium and creatinine levels is standard medical practice for such patients.

In particular, there have been reports of renal failure during treatment with enalapril maleate, predominantly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. Such enalapril-related renal failure is reversible if diagnosed and treated promptly.

In some patients with arterial hypertension who had no evidence of renal disease prior to treatment initiation, enalapril maleate in combination with diuretics has caused 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 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 to a single functioning kidney when 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 close medical supervision, with careful dose titration and monitoring of renal function.

Renal transplantation.

There is no experience with the use of Berlipril® 5 in patients who have recently undergone kidney transplantation. Therefore, the use of Berlipril® 5 is not recommended.

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 receiving ACE inhibitors who develop jaundice or a marked increase in liver enzymes should discontinue the ACE inhibitor and remain under medical supervision.

Neutropenia/agranulocytosis.

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other complicating factors, neutropenia is rare. Enalapril maleate should be used with extreme caution in patients with collagen vascular disease, those receiving immunosuppressive therapy, allopurinol, procainamide, or a combination of these complicating factors, especially if renal function is already impaired. Serious infections, sometimes refractory to intensive antibiotic therapy, have occurred in some of these patients. Periodic monitoring of white blood cell counts is recommended when enalapril maleate is prescribed to such patients, and patients should be instructed to report any signs of infection.

Hypersensitivity/angioedema.

Cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported during treatment with ACE inhibitors, including Berlipril® 5, occurring at various times during therapy. In such cases, treatment with Berlipril® 5 should be discontinued immediately, and the patient should be placed under continuous observation until complete resolution of symptoms is ensured. Observation may be discontinued only after all such symptoms have disappeared. Even in cases of isolated tongue swelling without respiratory compromise, prolonged observation is required, 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 involves the tongue, glottis, or larynx, especially in patients with a history of airway surgery, airway obstruction may develop. In cases of involvement of the tongue, vocal cords, or larynx with risk of airway obstruction, appropriate treatment should be initiated immediately, e.g., subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL), and/or measures to secure airway patency should be taken.

Angioedema occurs more frequently in patients of non-Caucasian 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 when treated with an ACE inhibitor (also see section "Contraindications").

Concomitant use of ACE inhibitors and sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of Berlipril® 5. Therapy with Berlipril® 5 should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

The risk of angioedema (e.g., airway or tongue swelling with or without respiratory compromise) may be increased when ACE inhibitors are used concomitantly with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin (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 ACE inhibitors.

An increased risk of angioedema has been observed with concomitant use of ACE inhibitors and alteplase (thrombolytic therapy).

Anaphylactoid reactions during desensitization therapy for hymenoptera venom.

Rarely, life-threatening anaphylactoid reactions have been observed during desensitization therapy for hymenoptera venom in patients receiving ACE inhibitors. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting desensitization therapy.

Anaphylactoid reactions during low-density lipoprotein apheresis.

Rarely, life-threatening anaphylactoid reactions have been observed when ACE inhibitors are used concomitantly with low-density lipoprotein apheresis (LDL apheresis) using dextran sulfate. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting apheresis.

Patients undergoing hemodialysis.

In patients undergoing dialysis with high-flux membranes (e.g., "AN 69®") and concomitantly receiving ACE inhibitors, anaphylactoid reactions have occasionally occurred. Therefore, such patients should be treated with dialysis membranes of another type or with antihypertensive agents from another class.

Hypoglycemia.

Patients with diabetes mellitus receiving treatment with oral antidiabetic agents or insulin and additionally prescribed ACE inhibitors should carefully monitor blood glucose levels, especially during the first month of combined therapy (see section "Interaction with other medicinal products and other forms of interaction").

Cough.

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

Surgeries/anesthesia.

During extensive surgical procedures or anesthesia with agents causing arterial hypotension, enalapril maleate 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.

Serum potassium.

ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. The effect is usually minor in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole (also known as trimethoprim/sulfamethoxazole), heparin, cyclosporine, and especially aldosterone antagonists or angiotensin receptor blockers. Potassium-sparing diuretics, trimethoprim, co-trimoxazole, and potassium supplements should be used with caution in patients receiving ACE inhibitors (for angiotensin receptor blockers, see "Dual blockade of the RAAS" in this section).

Serum potassium and renal function should be monitored (see "Renal function impairment" in this section and section "Interaction with other medicinal products and other forms of interaction").

Additional risk factors for hyperkalemia include age (>70 years), diabetes mellitus, hypoaldosteronism, transient conditions such as dehydration, acute heart decompensation, and metabolic acidosis. Hyperkalemia may cause serious, sometimes fatal, arrhythmias.

Lithium-containing preparations.

Combination of lithium and enalapril is generally not recommended.

Dual blockade of the RAAS.

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS with combined therapy using ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

If dual blockade is considered absolutely necessary, therapy should be conducted under close medical supervision with periodic monitoring of renal function, electrolyte levels, and arterial pressure.

Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.

Lactose.

Berlipril® 5 contains lactose; therefore, it should not be administered to patients with rare hereditary disorders of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome. Berlipril® 5 contains less than 200 mg of lactose per tablet.

Sodium.

This medicinal product contains less than 1 mmol of sodium (23 mg lactose) per tablet, i.e., it can be considered sodium-free.

Use in children.

Data on the efficacy and safety of enalapril maleate in children aged 6 years and older with arterial hypertension are limited, and experience with other indications is lacking. Pharmacokinetic data in children aged 2 months and older are limited (see sections "Pharmacodynamics", "Pharmacokinetics", and "Dosage and administration"). Berlipril® 5 is indicated only for children with arterial hypertension and is not recommended for other indications.

Due to lack of appropriate information, enalapril is not recommended in children with glomerular filtration rate < 30 mL/min/1.73 m² (see section "Dos游戏副本 and administration").

Pregnancy.

Initiation of ACE inhibitor therapy during pregnancy is not recommended.

For women of childbearing potential who require long-term ACE inhibitor therapy, alternative antihypertensive treatment with an established safety profile during pregnancy should be considered.

If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy (see sections "Contraindications", "Use during pregnancy or breastfeeding").

Ethnic differences.

As with other ACE inhibitors, the antihypertensive effect of enalapril may be less pronounced in patients of non-Caucasian race compared to patients of other races, possibly due to a higher prevalence of low renin levels in this racial group.

Use during pregnancy or breastfeeding.

Pregnancy.

The use of the drug is contraindicated in pregnant women or women planning pregnancy.

If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and alternative treatment initiated if necessary.

Epidemiological data on teratogenic risk associated with ACE inhibitor use in the first trimester of pregnancy are inconclusive, although a slight increase in risk cannot be excluded. For women of childbearing potential requiring long-term ACE inhibitor therapy, alternative antihypertensive treatment with proven safety during pregnancy should be considered.

Use of ACE inhibitors during the second and third trimesters of pregnancy may result in fetotoxic effects (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

In the mother, there is a risk of oligohydramnios, which may lead to reduced fetal renal function, limb contractures, craniofacial deformities, and pulmonary hypoplasia.

If ACE inhibitors were used during the second trimester of pregnancy, ultrasound examination of the fetal kidneys and skull is recommended.

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

Breastfeeding period.

Limited pharmacokinetic data confirm the presence of ACE inhibitors in breast milk at low concentrations (see section "Pharmacokinetics"). Although low concentrations of ACE inhibitors are not clinically significant, Berlipril® is not recommended during breastfeeding of premature infants and newborns in the first weeks of life due to the risk of cardiovascular and renal effects on the infant and insufficient clinical experience. In other cases, treatment of breastfeeding women with the drug may be considered only if clearly necessary and should be conducted under medical supervision to monitor for adverse effects in the infant.

Fertility.

Studies on the effects of Berlipril® on human fertility have not been conducted.

Results of reproductive toxicity studies indicate that enalapril does not affect fertility or reproductive characteristics in rats.

Ability to affect reaction speed when driving or operating machinery.

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

Method of administration and dosage.

Food intake does not affect the absorption of Berlipril® 5 tablets. The tablet may be divided into equal parts.

The dosage should be individually adjusted depending on the patient's condition (see section "Special precautions for use") and the drug's effect on arterial pressure.

Arterial hypertension.

The initial dose of Berlipril® 5 ranges from 5 to 20 mg, depending on the severity of hypertension and the patient's condition. Berlipril® 5 should be taken once daily.

For mild arterial hypertension, the recommended initial dose is 5–10 mg. In patients with pronounced activation of the RAAS (e.g., with renovascular hypertension, disturbances in salt and/or fluid balance, decompensated cardiac function, or severe arterial hypertension), excessive reduction of arterial pressure may occur after the initial dose. Such patients should be started on a dose of 5 mg or lower, and treatment initiation should be performed under medical supervision.

Prior treatment with high doses of diuretics may lead to fluid depletion and an increased risk of arterial hypotension at the beginning of enalapril therapy. For such patients, an initial dose of 5 mg or lower is recommended. If combination therapy is required, diuretic treatment should be discontinued 2–3 days before initiating Berlipril® 5. Renal function and serum potassium levels should be monitored.

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

Heart failure/asymptomatic left ventricular dysfunction.

For the treatment of symptomatic heart failure, Berlipril® 5 is used concomitantly with diuretics and, if necessary, cardiac glycosides or beta-blockers. The initial dose of Berlipril® 5 in patients with clinically evident heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. The drug should be initiated under close medical supervision to assess its initial effect on arterial pressure. In the absence of adverse effects or after appropriate management of symptomatic hypotension occurring at the beginning of Berlipril® 5 therapy, the dose should be gradually increased to the usual maintenance dose of 20 mg, administered either once daily or divided into two doses, depending on individual tolerability. This dose titration should be performed during the first 2–4 weeks of treatment. This therapeutic regimen has been shown to effectively reduce mortality in patients with clinically evident heart failure. The maximum daily dose is 40 mg, which should be divided into two doses.

Recommended dose titration of Berlipril® 5 in patients with heart failure/asymptomatic left ventricular dysfunction.

Table 1

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

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

Careful monitoring of blood pressure and renal function (see section "Special precautions") should be performed both before and after initiation of treatment with Berlipril® 5, 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 treatment with Berlipril® 5. The development of arterial hypotension at the beginning of treatment with Berlipril® 5 does not imply that hypotension will persist during long-term therapy, nor does it indicate the necessity to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Dosing in renal impairment.

In general, the interval between doses of enalapril should be increased and/or the dose of the drug should be reduced.

Table 2

Renal status	Creatinine clearance (CrCL), mL/min	Initial dose, mg/day
Mild to moderate to severe renal impairment	30 < CrCL < 80	5–10
Severe renal impairment	10 < CrCL ≤ 30	2.5
Renal failure	CrCL ≤ 10	2.5 (on dialysis days**)

**see section "Special instructions: Patients undergoing hemodialysis". Enalaprilat is dialyzable. Adjust the dose on non-dialysis days according to the degree of blood pressure reduction.

Elderly patients.

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

Children.

Clinical data on the use of Berlipril® 5 in children with arterial hypertension are limited (see sections "Pharmacological properties", "Special instructions").

For children who can swallow tablets, the dose should be individually adjusted based on their condition, degree of blood pressure reduction, and body weight. For children with body weight from 20 to 50 kg, the recommended initial dose is 2.5 mg; for patients with body weight ≥ 50 kg, the initial dose is 5 mg. Berlipril® 5 is taken once daily. The dose should be titrated according to the patient's needs. The maximum daily dose should not exceed 20 mg for patients with body weight from 20 kg to 50 kg and 40 mg for patients with body weight above 50 kg (see section "Special instructions").

Berlipril® 5 is not recommended for neonates and children with glomerular filtration rate < 30 mL/min/1.73 m² due to lack of relevant data.

Children.

Berlipril**®** 5 can be administered to children aged 6 years and older.

Berlipril**®** 5 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. According to available information, the main signs of overdose include profound arterial hypotension, beginning approximately 6 hours after drug intake and coinciding with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Plasma levels of enalaprilat exceeding 100 and 200 times the maximum levels achieved with therapeutic doses have been reported following ingestion of 300 mg and 440 mg of enalapril, respectively.

For treatment of overdose, intravenous administration of isotonic saline solution is recommended. In case of arterial hypotension, the patient should be placed in a supine position with legs elevated. Additionally, infusion of angiotensin II and/or catecholamines may be administered. If the drug was recently ingested, measures aimed at eliminating enalapril maleate should be taken (e.g., induction of emesis or gastric lavage, administration of adsorbents 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.

Adverse Reactions

Adverse effects that may occur during enalapril administration are classified according to frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100),
rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be determined from available data).

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

Endocrine system disorders.
Not known: syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Metabolism and nutrition disorders.
Uncommon: hypoglycemia.
Not known: lactic acidosis (see section "Interaction with other medicinal products and other forms of interaction").

Nervous system and psychiatric disorders.
Very common: dizziness.
Common: depression, headache, syncope, taste disturbance.
Uncommon: confusion, somnolence, insomnia, nervousness, paresthesia, vertigo.
Rare: abnormal dreams, sleep disorders.

Eye disorders.
Very common: blurred vision.

Ear and labyrinth disorders.
Uncommon: tinnitus.

Cardiac and vascular disorders.
Common: hypotension (including orthostatic hypotension), chest pain, arrhythmia, angina pectoris, tachycardia.
Uncommon: orthostatic hypotension, flushing, palpitations, myocardial infarction or stroke (in clinical trials, incidence rates were comparable to those in placebo and active control groups), possibly due to excessive blood pressure reduction in high-risk patients.
Rare: Raynaud's syndrome.

Respiratory, thoracic and mediastinal disorders.
Very common: cough.
Common: dyspnea.
Uncommon: rhinorrhea, sore throat, hoarseness, bronchospasm/asthma.
Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders.
Very common: nausea.
Common: diarrhea, abdominal pain.
Uncommon: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers.
Rare: stomatitis/aphthous ulcers, glossitis.
Very rare: intestinal angioedema.

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

Skin and subcutaneous tissue disorders.
Common: rash, hypersensitivity/angioedema (including face, extremities, lips, tongue, glottis and/or larynx) (see section "Special precautions for use").
Uncommon: increased sweating, pruritus, urticaria, alopecia.
Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

Not known: there have been reports of a complex syndrome which may include some or all of the following manifestations: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, increased antinuclear antibody titer, elevated erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. Skin rashes, photosensitization, or other dermatological manifestations may also 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: gynecomastia.

General disorders and administration site conditions.
Very common: asthenia.
Common: increased fatigue.
Uncommon: discomfort, fever.

Laboratory test abnormalities.
Common: hyperkalemia, increased serum creatinine concentration.
Uncommon: increased blood urea concentration, hyponatremia.
Rare: increased liver enzyme levels, elevated serum bilirubin concentration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system of the State Expert Centre of the Ministry of Health of Ukraine.

Shelf life. 3 years.

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

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

Blister pack containing 10 tablets; 3 blisters per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's address and location of business activity.

Glienicker Weg 125, 12489 Berlin, Germany.