Berlipril® 10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BERLIPRIL® 10

Composition:

Active substance: enalapril;

1 tablet contains enalapril maleate 10 mg;

Excipients: lactose monohydrate, light magnesium carbonate, sodium starch glycolate (type A), gelatin, colloidal anhydrous silicon dioxide, magnesium stearate, iron oxide (E 172): brown.

Pharmaceutical form. Tablets.

Main physicochemical properties: slightly biconvex tablets with bevelled edges and a score line on one side, pale brown in colour.

Tablets can be divided into equal halves.

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

Pharmacological Properties.

Pharmacodynamics.

Berlipril® (enalapril maleate) is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline.

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the pressor substance angiotensin II. After absorption, enalapril maleate undergoes hydrolysis to form enalaprilat, which inhibits ACE. As a result of this inhibition, plasma angiotensin II concentrations decrease, leading to increased plasma renin activity (due to blockade of the negative feedback mechanism regulating renin release) and reduced aldosterone secretion.

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

Mechanism of action.

The antihypertensive mechanism of action of Berlipril® is primarily related to inhibition of the renin-angiotensin-aldosterone system. Enalapril may reduce blood pressure even in patients with low-renin hypertension.

Pharmacodynamic effects.

Administration of Berlipril® in patients with arterial hypertension leads to reduction in arterial pressure in both supine and upright positions, without a significant increase in heart rate.

Symptomatic orthostatic hypotension rarely occurs. In some patients, optimal blood pressure reduction is achieved only after several weeks of therapy. Abrupt discontinuation of Berlipril® therapy is not associated with a sudden rise in blood pressure.

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

Hemodynamic studies in patients with essential arterial hypertension have demonstrated that blood pressure reduction is accompanied by decreased peripheral arterial resistance and increased cardiac output, while heart rate remains virtually unchanged. After administration of Berlipril®, renal blood flow increases; glomerular filtration rate remains unchanged. Signs of sodium and water retention are not observed. However, in patients with low glomerular filtration rate prior to therapy initiation, this parameter typically increases.

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

When used concomitantly with thiazide diuretics, the antihypertensive effect of Berlipril® is additive. Berlipril® 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 arterial pressure. Cardiac output increased, while heart rate (which is usually elevated in patients with heart failure) 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 and heart failure, as evidenced by reductions in end-diastolic and end-systolic volumes in the left ventricle and improvement in ejection fraction.

Clinical efficacy and safety.

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 symptoms of congestive heart failure due to systolic dysfunction (ejection fraction < 35%) was studied. A total of 2569 patients receiving conventional heart failure therapy were randomized to receive either placebo (n=1284) or enalapril maleate (n=1285). In the placebo group, 510 deaths (39.7%) occurred compared to 452 in the enalapril group (35.2%) (risk reduction: 16%; 95% CI: 5–26%; p=0.0036). Cardiovascular deaths were 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 due to unstable angina by 20% (95% CI: 9–29%; p < 0.001).

In two large-scale 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 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 demonstrated a modest beneficial effect on renal and/or cardiovascular outcomes and mortality reduction, but also 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 therapy 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 angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or both. 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 serious adverse events of interest (hyperkalemia, hypotension, and renal dysfunction).

Children.

Experience with the use of the drug in children with arterial hypertension aged >6 years is limited. In clinical studies involving 110 children aged 6 to 16 years with arterial hypertension, 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 those 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. Dose-dependent antihypertensive effects were observed in all subgroups (by age, Tanner stage, sex, race). However, at 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 plasma concentration observed within 1 hour. After oral administration of enalapril maleate tablets, bioavailability, as determined by urinary recovery, is approximately 60%. The presence of food in the gastrointestinal tract does not affect the absorption of Berlipril® upon oral administration. After absorption, orally administered enalapril maleate undergoes rapid and extensive hydrolysis to enalaprilat, a potent inhibitor of angiotensin-converting enzyme. Peak plasma concentration of enalaprilat is reached 4 hours after oral dosing of enalapril.

The effective elimination half-life (T½) of enalaprilat after repeated oral administration is 11 hours. In individuals with normal renal function, steady-state plasma concentrations of enalaprilat are achieved after four days of therapy.

Distribution. Over the range of therapeutically relevant concentrations in humans, plasma protein binding does not exceed 60%.

Biotransformation. Apart from conversion to enalaprilat, there are no data on further significant metabolism of enalapril maleate.

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

Renal impairment. In patients with renal impairment, systemic exposure to enalapril maleate and enalaprilat is increased. In patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), the AUC (area under the curve) of enalaprilat during continuous administration of 5 mg/day is approximately twice higher than in patients with normal renal function. In severe renal impairment (creatinine clearance ≤30 mL/min), the AUC increases approximately 8-fold. At this stage of renal impairment, the effective elimination half-life of enalaprilat after repeated administration of enalapril maleate is prolonged, and attainment of steady-state levels is delayed (see section "Dosage and Administration").

Enalaprilat can be removed from blood by hemodialysis. The dialysis clearance rate is 62 mL/min.

Children.

Pharmacokinetic studies using multiple doses were conducted in 40 children (boys and girls) aged 2 months to 16 years with arterial hypertension, who received oral enalapril maleate at doses ranging from 0.07 to 0.14 mg/kg/day. No major differences in enalaprilat pharmacokinetics were observed between children and adults. Results indicate increased AUC (when dose is 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 elimination half-life of enalaprilat was 14 hours.

Breastfeeding.

Four to six hours after a single 20 mg oral dose 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 varying times within a 24-hour period. Based on maximum concentration values in breast milk, the maximum infant intake via exclusive breastfeeding is estimated at 0.16% of the maternal dose.

In a woman who had taken enalapril 10 mg daily orally for 11 months, the maximum concentration of enalapril in breast milk was 2 µg/L, measured 4 hours after dosing, and the maximum concentration of enalaprilat was 0.75 µg/L, measured approximately 9 hours after dosing. The total daily amount of enalapril and enalaprilat in breast milk 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 enalapril dose in one mother and after a 10 mg dose in two mothers; enalapril concentrations were not quantified.

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, to any of the excipients, or to other angiotensin-converting enzyme inhibitors (ACE inhibitors).
• History of angioedema associated with previous therapy with ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Pregnancy and planned pregnancy (see section "Use in pregnancy or breastfeeding").
• Concomitant use of Berlipril®10 with medicinal products containing aliskiren in patients with diabetes mellitus and renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Pharmacological properties. Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with sacubitril/valsartan: treatment with Berlipril® should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also 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.

Medicinal products that increase the risk of angioedema.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Concomitant administration 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").

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 a significant increase in serum potassium levels. Caution is required when Berlipril® is co-administered with other agents that increase serum potassium levels, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of Berlipril® with the above-mentioned agents is not recommended. If concomitant use is indicated, they should be administered with caution and under regular monitoring of serum potassium levels (see section "Special precautions for use").

Cyclosporine.

Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin.

Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels is recommended.

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

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors with angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse events (such as hypotension, hyperkalemia, and impaired renal function, including acute renal failure) compared to monotherapy affecting the RAAS (see sections "Contraindications", "Adverse reactions", "Special precautions for use").

Diuretics (thiazide-type or loop diuretics).

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

Thrombolytics.

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

Other antihypertensive agents.

Concomitant use of these agents may enhance the hypotensive effect of enalapril. Concurrent use with nitroglycerin and other nitrates or vasodilators may also lead to further reduction in blood pressure.

Lithium.

Cases of transient increases in serum lithium concentration and lithium toxicity have been reported with concomitant use of ACE inhibitors. Concomitant use of thiazide diuretics and ACE inhibitors may increase serum lithium levels and thus the risk of lithium toxicity. Therefore, concomitant use of enalapril maleate and lithium is not recommended; if this combination is necessary, careful monitoring of serum lithium levels is advised (see section "Special precautions for use").

Tricyclic antidepressants/neuroleptics/anesthetics and anesthetic agents.

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

Non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors.

Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of ACE inhibitors.

Concomitant use of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists or ACE inhibitors may enhance the effects on increasing serum potassium levels and may lead to worsening of renal function. These effects are usually reversible. In isolated cases, acute renal failure may occur, particularly in patients with impaired renal function (e.g., elderly patients or those with hypovolemia, including due to diuretic therapy).

Therefore, this combination should be prescribed with caution in patients with impaired renal function. Adequate hydration and monitoring of renal function are required both at the start of treatment with these agents and periodically after their discontinuation.

Gold preparations.

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

Sympathomimetic agents.

Sympathomimetic agents may reduce the antihypertensive effect of ACE inhibitors.

Antidiabetic medicinal products.

Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance hypoglycemic effects, increasing the risk of hypoglycemia. Such cases appear to occur particularly during the first weeks of combination therapy and in patients with impaired renal function (see sections "Special precautions for use", "Adverse reactions").

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 with caution in patients at risk, and careful monitoring of renal function is required.

Alcohol.

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, β-blockers.

Enalapril can be safely used concomitantly with acetylsalicylic acid (at doses used in cardiology) and β-blockers.

Special precautions for use.

Symptomatic arterial hypotension.

In patients with uncomplicated arterial hypertension, arterial hypotension is rare. In patients with depleted fluid volume, for example due to diuretic therapy, low-salt diet, haemodialysis, diarrhoea or vomiting, symptomatic arterial hypotension occurs more frequently during treatment with Berlipril® (see sections "Interaction with other medicinal products and other forms of interaction", "Undesirable effects"). Arterial hypotension may also occur in patients with heart failure, with or without concomitant renal impairment. This most commonly occurs in patients with severe heart failure receiving high doses of loop diuretics, hyponatraemia, or functional renal impairment. Such patients should start therapy with Berlipril® under medical supervision with careful dose titration of Berlipril® and/or diuretic. The same approach should be applied to patients with ischaemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke. In case of development of arterial hypotension, the patient should be placed in a supine position and, if necessary, intravenous infusion of sodium chloride solution should be administered. Transient arterial hypotension during treatment with Berlipril® is not a contraindication for further therapy, which may be continued after normalization of blood pressure through restoration of circulating blood volume. In some patients with heart failure and normal or low blood pressure, additional blood pressure reduction may occur under the influence of Berlipril®. This effect is fully expected and usually does not require discontinuation of the drug. If arterial hypotension becomes symptomatic, dose reduction and/or discontinuation of the diuretic and/or Berlipril® may be necessary.

Aortic or mitral stenosis/Hypertrophic cardiomyopathy.

Like all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction or outflow tract obstruction. They should be avoided in 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 maleate should be adjusted according to the patient's creatinine clearance (see section "Dosage and administration"), and the maintenance dose should be adjusted based on the patient's response to treatment. In such patients, monitoring of serum potassium and creatinine levels should be part of routine medical observation.

In particular, cases of renal failure have been reported during enalapril maleate therapy, predominantly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. Such enalapril maleate-associated renal failure is reversible if diagnosed promptly and managed appropriately.

In some patients with arterial hypertension without prior overt renal disease, combination of enalapril maleate with a diuretic may lead to increased serum urea and creatinine levels. In such cases, dose reduction of enalapril maleate and/or discontinuation of the diuretic may be required. In such situations, renal artery stenosis should be considered as a possible cause of these findings (see section "Special precautions for use: Renovascular hypertension").

Renovascular hypertension.

In patients with bilateral renal artery stenosis or stenosis of the renal artery of a single functioning kidney, treatment with ACE inhibitors carries a high risk of reduced arterial pressure or development of renal failure. This may result in loss of renal function, which may manifest only as minor changes in serum creatinine levels. Treatment of such patients should be initiated with low doses under close medical supervision, with careful dose titration and monitoring of renal function.

Kidney transplantation.

There is no experience with the use of Berlipril® in patients who have recently undergone kidney transplantation; therefore, treatment of such patients with this medicinal product is not recommended.

Hepatic function impairment.

Rarely, a syndrome has been observed during ACE inhibitor therapy, beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis (sometimes) with fatal outcome. The pathogenesis of this syndrome is unclear. In patients who develop jaundice or marked elevation of liver enzymes during ACE inhibitor therapy, treatment with ACE inhibitors should be discontinued and appropriate therapy initiated.

Neutropenia/Agranulocytosis.

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anaemia have been reported in patients receiving ACE inhibitor therapy. Neutropenia is rare in patients with normal renal function and without special risk factors. Enalapril should be used with extreme caution in patients with collagen vascular disease receiving immunosuppressive therapy, allopurinol, procainamide, or a combination of these complicating factors, especially if renal impairment already exists. In some of these patients, severe infections have occurred, which were sometimes refractory to intensive antibiotic therapy. If enalapril maleate is used in such patients, regular monitoring of blood leukocyte count is recommended, and patients should be instructed to inform their physician of any signs of infection.

Hypersensitivity/Angioedema.

Cases of angioedema involving the face, extremities, lips, tongue, vocal cords, and/or larynx have been reported in patients receiving ACE inhibitors, including Berlipril®. These events may occur at any time during therapy. In such cases, Berlipril® should be discontinued immediately, and careful monitoring should be maintained until complete resolution of symptoms is confirmed before discharge from hospital. Even when only tongue swelling occurs without respiratory compromise, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal cases have also been reported in association with laryngeal and tongue oedema. With swelling of the tongue, epiglottis, or larynx, there is an increased risk of airway obstruction, particularly in patients who have undergone airway surgery. If the tongue, vocal cords, or larynx are involved with signs of airway obstruction, immediate appropriate treatment should be initiated, for example, subcutaneous administration of adrenaline 1:1000 (0.3–0.5 mL), and/or measures to secure airway patency.

Angioedema occurs more frequently in patients of Black ethnicity compared to other ethnic groups during ACE inhibitor therapy.

Patients with a history of angioedema not related to ACE inhibitors may have an increased risk of developing angioedema during ACE inhibitor therapy (also see section "Contraindications").

Concomitant use of ACE inhibitors with 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®. Therapy with Berlipril® 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").

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

Caution is required at the initiation of 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 concomitant ACE inhibitor therapy. These reactions can be avoided by temporarily discontinuing ACE inhibitors before starting desensitization therapy.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis.

Rarely, life-threatening anaphylactoid reactions have occurred during low-density lipoprotein (LDL) apheresis with dextran sulfate in patients receiving concomitant ACE inhibitor therapy. If LDL apheresis is indicated, ACE inhibitors should also be temporarily replaced with other antihypertensive or heart failure medications.

Patients undergoing haemodialysis.

Anaphylactoid reactions have been reported in patients undergoing dialysis with high-flux membranes (e.g., "AN 69®") while receiving concomitant ACE inhibitor therapy. In such patients, consideration should be given to using dialysis membranes of a different type or an antihypertensive agent from another class.

Patients with diabetes mellitus.

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

Cough.

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

Surgery/anaesthesia.

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

Serum potassium.

ACE inhibitors may cause hyperkalaemia as they suppress aldosterone release. The effect is usually mild in patients with normal renal function. However, hyperkalaemia may occur in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim, 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 levels 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 hyperkalaemia include age (>70 years), diabetes mellitus, hypoaldosteronism, transient conditions such as dehydration, acute heart decompensation, and metabolic acidosis. Hyperkalaemia may cause serious, sometimes fatal, arrhythmias.

Lithium.

Lithium preparations are generally not recommended to be combined with enalapril (see section "Interaction with other medicinal products and other forms of interaction").

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

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

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

In patients with diabetic nephropathy, concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended.

Lactose.

Berlipril® contains lactose and therefore should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome. The lactose content in 1 tablet of Berlipril® is less than 200 mg per tablet.

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 in other indications is lacking. Pharmacokinetic data in children from 2 months of age are limited (see sections "Pharmacodynamics", "Pharmacokinetics", "Dosage and administration"). Berlipril® 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 for use in children with glomerular filtration rate < 30 mL/min/1.73 m² (see section "Dosage and administration").

Pregnancy.

Initiation of ACE inhibitor therapy during pregnancy is not recommended.

For women of childbearing potential requiring long-term ACE inhibitor therapy, alternative antihypertensive therapy with an established safety profile during pregnancy should be considered (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

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.

Like other ACE inhibitors, enalapril is less effective in lowering blood pressure in Black patients compared to non-Black patients, possibly due to the higher prevalence of low renin levels in the Black hypertensive population.

Use during pregnancy or breastfeeding.

Pregnancy.

The use of this medicinal product is contraindicated in pregnant women and women planning pregnancy.

If pregnancy is confirmed during therapy with this medicinal product, treatment should be discontinued immediately and alternative therapy initiated if necessary.

Epidemiological data on the risk of teratogenicity associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, although a small increased risk cannot be excluded. For women of childbearing potential requiring long-term ACE inhibitor therapy, alternative antihypertensive therapy with an established safety profile during pregnancy should be considered.

ACE inhibitor therapy during the second and third trimesters of pregnancy causes fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

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

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

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

Lactation.

Limited pharmacokinetic data confirm the presence of ACE inhibitors in breast milk in low concentrations (see section "Pharmacokinetics"). Although such concentrations are considered clinically insignificant, Berlipril® is not recommended during breastfeeding of preterm infants and newborns during the first few weeks of life due to a theoretical risk of cardiovascular and renal effects and limited experience. In cases of older newborns, Berlipril® therapy in breastfeeding women may be considered only if treatment is essential for the mother and the infant is monitored for any adverse effects.

Fertility.

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

Reproductive toxicity studies indicate that enalapril has no effect on fertility or reproductive performance in rats.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

The dosage of the drug should be individually adjusted depending on the patient's condition (see section "Special Instructions") and its effect on arterial blood pressure.

Food intake does not affect the absorption process of Berlipril®.

Arterial Hypertension

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

For mild arterial hypertension, the recommended initial dose is 5–10 mg.

In patients with pronounced activation of the renin-angiotensin-aldosterone system (e.g., renovascular hypertension, disturbances in salt and/or fluid balance, decompensated heart failure, or severe arterial hypertension), a significant decrease in arterial pressure may occur after the initial dose. In such patients, treatment should be initiated at a dose of 5 mg or lower, under close medical supervision.

In patients previously treated with high-dose diuretics, fluid deficiency may develop, increasing the risk of arterial hypotension at the beginning of enalapril therapy. For such patients, an initial dose of 5 mg or lower is recommended. If possible, diuretic therapy should be discontinued 2–3 days before starting treatment with Berlipril®. Renal function and serum potassium levels should be monitored.

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

Heart Failure/Asymptomatic Left Ventricular Dysfunction

In the treatment of symptomatic heart failure (HF), Berlipril® should be administered in addition to diuretics and, if necessary, digitalis preparations or beta-blockers. The initial dose of Berlipril® for patients with symptomatic heart failure or asymptomatic left ventricular dysfunction (ALVD) is 2.5 mg. To assess the initial effect of the drug on arterial pressure, treatment should be initiated under close medical supervision. If symptomatic hypotension does not occur or is easily managed after initiating Berlipril® therapy in heart failure, the dose should be gradually increased to the standard maintenance dose of 20 mg, taken once daily or, depending on patient tolerance, divided into two doses. Such dose titration is recommended to be performed over 2–4 weeks of therapy. The maximum dose is 40 mg of enalapril per day, which should be divided into two doses.

Recommended Dose Titration of Berlipril® in Patients with Heart Failure/Asymptomatic Left Ventricular Dysfunction

Week	Dosage, 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 once daily or in two divided doses
Weeks 3 and 4	20 mg/day once daily or in two divided doses

* Special caution should be exercised in patients with impaired renal function and in patients taking diuretic medicinal products (see section "Special precautions").

Careful monitoring of blood pressure and renal function should be performed before and after initiation of therapy with Berlipril® (see section "Special precautions"), as cases of hypotension and (less frequently) subsequent renal failure have been reported. Prior to starting treatment with Berlipril®, the dose of concomitantly administered diuretics should be reduced, if possible. The occurrence of hypotension at the beginning of Berlipril® therapy does not indicate its development during long-term treatment and does not preclude further use of the medicinal product. Monitoring of serum potassium levels and renal function should also be performed.

Dosing in renal insufficiency.

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

Creatinine clearance (CCr), mL/min	Initial dose, mg/day
30 < CCr < 80 mL/min	5–10 mg
10 < CCr ≤ 30 mL/min	2.5 mg
CCr ≤ 10 mL/min	2.5 mg on dialysis days*

*see section "Special instructions". Patients undergoing hemodialysis.

Enalaprilat is dialyzable. The dose on non-dialysis days should be adjusted according to the degree of blood pressure reduction.

Elderly patients.

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

Children with hypertension aged > 6 years.

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

If the patient is able to swallow tablets, the dose should be individually adjusted according to the patient's 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 recommended initial dose is 5 mg. Berlipril® should be administered 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® is not recommended for children with glomerular filtration rate (GFR) < 30 mL/min/1.73 m² due to lack of relevant data.

Method of administration: for oral use.

Children.

Berlipril® is contraindicated in children under 6 years of age. Data on the efficacy and safety of enalapril maleate in children over 6 years of age with hypertension are limited, and experience with use for other indications is lacking. Pharmacokinetic data on the use of the drug in children older than 2 months are limited. Berlipril® is indicated only for children with hypertension, but it is not recommended for other indications.

Due to lack of relevant data, Berlipril® is not recommended for use in children with glomerular filtration rate (GFR) < 30 mL/min/1.73 m².

Overdose.

Information on human overdose is limited. The most likely signs of overdose observed to date include profound arterial hypotension, beginning approximately 6 hours after drug intake and corresponding to blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. After administration of 300 mg and 440 mg of enalapril maleate, serum enalaprilat concentrations were measured at 100 and 200 times higher, respectively, than those observed with therapeutic doses.

For the treatment of overdose, intravenous infusion of sodium chloride solution is recommended. If arterial hypotension occurs, the patient should be placed in a supine position.

Infusion of angiotensin II and/or intravenous administration of catecholamines may also be considered. If the drug was recently ingested, measures should be taken to remove enalapril maleate (e.g., induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat is removed from systemic circulation by hemodialysis (see section "Special instructions": Patients undergoing hemodialysis). In cases of refractory bradycardia, cardiac pacing is indicated. Vital signs, serum electrolytes, and creatinine levels should be continuously monitored.

Adverse Reactions

To assess the frequency of adverse events occurring during enalapril administration, the following classification is used: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000; very rare: < 1/10,000; and not known: cannot be estimated from available data.

Blood and lymphatic system disorders:
Uncommon – anaemia (including aplastic and haemolytic anaemia);
Rare – neutropenia, decreased haemoglobin and haematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune disorders.

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

Metabolism and nutrition disorders:
Uncommon – hypoglycaemia (see section "Special Warnings and Precautions for Use");
Not known – lactic acidosis (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Nervous system and psychiatric disorders:
Common – headache, depression;
Uncommon – confusion, drowsiness, insomnia, nervousness, paraesthesia, dizziness;
Rare – sleep disturbances, abnormal dreams.

Eye disorders:
Very common – blurred vision.

Cardiovascular system disorders:
Very common – dizziness;
Common – arterial hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia;
Uncommon – orthostatic hypotension, palpitations, myocardial infarction or cardiovascular events (incidence comparable to placebo group and active control groups in clinical trials), likely due to secondary reduction in blood pressure in patients with high risk factors (see section "Special Warnings and Precautions for Use");
Rare – Raynaud's syndrome.

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

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

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

Skin and subcutaneous tissue disorders:
Common – rash, hypersensitivity reactions/angioedema of the face, limbs, lips, tongue, vocal cords and/or larynx (see section "Special Warnings and Precautions for Use");
Uncommon – sweating, pruritus, urticaria, alopecia;
Rare – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

There have been reports of a syndrome complex that may include one or more of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody (ANA) test, elevated erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. Skin rash, photosensitization, or other dermatological manifestations may also occur.

Renal and urinary disorders:
Uncommon – renal failure, impaired renal function, proteinuria;
Rare – oliguria.

Reproductive system and breast disorders:
Uncommon – impotence;
Rare – gynaecomastia.

General disorders and administration site conditions:
Very common – asthenia;
Common – increased fatigue;
Uncommon – muscle cramps, hot flushes, tinnitus, discomfort, malaise.

Investigations:
Common – hyperkalaemia, increased serum creatinine levels;
Uncommon – increased serum urea levels, hyponatraemia;
Rare – increased liver enzyme levels, increased serum bilirubin levels.

Reporting suspected adverse reactions after medicine authorization is highly important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions.

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 status.
Prescription only.

Manufacturer.
Berlin-Chemie AG.

Manufacturer's address.
Glinkiker Weg 125, 12489 Berlin, Germany.

Marketing Authorization Holder.
Berlin-Chemie AG.

Address of Marketing Authorization Holder.
Glinkiker Weg 125, 12489 Berlin, Germany.