Berlipril® 20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BERLIPRIL® 20

Composition:

Active substance: enalapril;

1 tablet contains enalapril maleate 20 mg;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: slightly biconvex tablets with bevelled edges and a score line on one side, pale reddish in color.

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 maleic acid 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 of renin release) and reduced aldosterone secretion.

ACE is identical to kininase II. Thus, Berlipril® may also block the breakdown 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 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 of arterial pressure in both supine and upright positions, without significant increase in heart rate.

Symptomatic orthostatic hypotension is rare. In some patients, optimal blood pressure reduction occurs only after several weeks of therapy. Abrupt discontinuation of Berlipril® therapy is not associated with a rapid 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 within 4–6 hours after dosing. Duration of action is dose-dependent. However, at recommended doses, antihypertensive and hemodynamic effects last 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 largely 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 before treatment initiation, this parameter typically increases.

In short-term clinical studies in patients with and without diabetes mellitus 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 digitalis glycosides and diuretics, oral or intravenous administration of enalapril maleate resulted in decreased peripheral resistance and reduced 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/enlargement and heart failure, as evidenced by reductions in left ventricular end-diastolic and end-systolic volumes 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 either 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 a 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%) were recorded, compared to 452 in the enalapril group (35.2%) (risk reduction: 16%; 95% CI: 5–26%; p=0.0036). In the placebo group, 461 cardiovascular deaths were recorded compared to 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%). A number of patients died or were hospitalized due to progression of heart failure (736 patients 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 [The Veterans Affairs Nephropathy in Diabetes]), the use of an ACE inhibitor in combination with an angiotensin II receptor blocker was studied.

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 studies showed a modest beneficial effect on renal and/or cardiovascular outcomes and reduced mortality, but also an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy. Given the similar pharmacodynamic properties, these findings also apply 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. Fatal cardiovascular events 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, 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. Dose-dependent antihypertensive effects were observed in all subgroups (by age, Tanner stage, sex, race). However, with the lowest studied doses of 0.625 mg and 1.25 mg (averaging 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. Following 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® after oral administration. After absorption, orally administered enalapril maleate undergoes rapid and extensive hydrolysis to enalaprilat, a potent inhibitor of angiotensin-converting enzyme. Peak plasma concentrations of enalaprilat are reached within 4 hours after oral administration of enalapril tablets.

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

Distribution. Within the therapeutically relevant concentration range 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), AUC (area under the curve) of enalaprilat during chronic 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), AUC increases approximately 8-fold. At this stage of renal impairment, the effective elimination half-life of enalaprilat after multiple doses 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. Its dialysis clearance is 62 mL/min.

Children

Pharmacokinetic studies with multiple dosing 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-normalized by body weight) with age; however, this increase in AUC was not observed when doses were normalized by body surface area. At steady state, the mean effective accumulation half-life of enalaprilat was 14 hours.

Lactation

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 various times within a 24-hour period. Based on maximum concentrations in breast milk, the maximum infant intake via exclusive breastfeeding is estimated at 0.16% of the maternal dose.

In a woman taking 10 mg enalapril orally daily 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. Total daily amounts of enalapril and enalaprilat in breast milk were 1.44 µg/L and 0.63 µg/L, respectively.

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

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.
• Contraindicated in pregnant women and women planning to become pregnant (see section "Use in pregnancy or breastfeeding").
• Contraindicated to co-administer Berlipril® with medicinal products containing aliskiren in patients with diabetes and renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) (see section "Pharmacological properties", "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 section "Interaction with other medicinal products and other forms of interaction", "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Medicinal products increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications", "Special precautions for use").

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

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

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving enalapril. Potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Caution is advised when using Berlipril® concomitantly with other medicinal products 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® with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, these products should be used with extreme caution and under regular monitoring of serum potassium levels (see section "Special precautions for use").

Cyclosporine

Hyperkalemia may occur with concomitant use of ACE inhibitors and cyclosporine. Serum potassium levels should be monitored (see section "Special precautions for use").

Heparin

Hyperkalemia may occur with concomitant use of ACE inhibitors and heparin. Serum potassium levels should be monitored (see section "Special precautions for use").

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

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, 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 with agents acting on the RAAS (see section "Contraindications", "Adverse reactions", "Special precautions for use").

Diuretics (thiazide-type or loop diuretics)

Prior treatment with high-dose diuretics may lead to hypovolemia and thereby increase the risk of hypotension at the start of enalapril maleate 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 a low dose.

Thrombolytics

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

Other antihypertensive agents

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

Lithium

There have been reports of transient increases in serum lithium concentration and lithium toxicity when used concomitantly with 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 such 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").

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

Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, may attenuate the antihypertensive effect of ACE inhibitors.

The effects of NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors, and ACE inhibitors on increasing serum potassium levels are additive and may lead to worsening 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 reduced fluid volume, including due to diuretic use). Adequate hydration should be ensured, and renal function should be closely monitored periodically after initiation of combination therapy.

Gold preparations

In isolated cases, nitritoid reactions (symptoms include flushing, nausea, vomiting, and arterial hypotension) have been reported 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 section "Special precautions for use").

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 renal function should be closely monitored.

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 fluid volume depletion, such as due to diuretic therapy, low-salt diet, haemodialysis, diarrhoea or vomiting, symptomatic arterial hypotension occurs more frequently during treatment with Berlipril® (see section "Interaction with other medicinal products and other forms of interaction", "Adverse reactions"). Arterial hypotension may also occur in patients with heart failure, with or without concomitant renal impairment. This is most commonly observed in patients with severe heart failure receiving high doses of loop diuretics, hyponatraemia or functional renal impairment. Such patients should begin Berlipril® therapy 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 hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of sodium chloride solution. Transient arterial hypotension during Berlipril® therapy is not a contraindication for continued treatment, which may be resumed 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 generally not a reason to discontinue the drug. If arterial hypotension becomes symptomatic, dose reduction and/or discontinuation of the diuretic and/or Berlipril® may be required.

Aortic or mitral valve stenosis / hypertrophic cardiomyopathy.

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

Renal function impairment.

In patients with reduced 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 follow-up.

In particular, there have been reports of renal failure during enalapril maleate therapy, predominantly in patients with severe heart failure or pre-existing 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 this situation, 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 hypotension or development of renal failure. Renal function deterioration may occur, which may be reflected only by 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 beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis (sometimes fatal) has been observed during ACE inhibitor therapy. 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 in combination with these complicating factors, especially if renal function is already impaired. Some of these patients developed severe infections, 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 angiotensin-converting enzyme (ACE) inhibitor therapy, including Berlipril®. These events may occur at any time during treatment. In such cases, Berlipril® should be discontinued immediately and the patient should be closely monitored until complete resolution of symptoms is confirmed prior to discharge from hospital. Even in cases of isolated tongue swelling without respiratory compromise, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal cases due to laryngeal and tongue oedema have also been reported. Angioedema of the tongue, epiglottis or larynx carries an increased risk of airway obstruction, particularly in patients who have undergone airway surgery. In cases of tongue, vocal cord or laryngeal involvement with risk of airway obstruction, immediate appropriate treatment should be initiated, e.g., subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 ml), and/or measures to secure airway patency.

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

Patients with a history of angioedema not related to ACE inhibitors 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 section "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Concomitant therapy with ACE inhibitors and racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) or vildagliptin increases the risk of angioedema (e.g. airway or tongue swelling with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Patients receiving ACE inhibitors should be particularly cautious when initiating treatment with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) or vildagliptin.

Concomitant use of ACE inhibitors with alteplase (used in thrombolytic therapy) has been associated with an increased risk of angioedema.

Anaphylactoid reactions during desensitization therapy for Hymenoptera venom.

Rarely, life-threatening anaphylactoid reactions have been observed during desensitization therapy for Hymenoptera venom in patients concurrently receiving ACE inhibitors. 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 ACE inhibitors. If LDL apheresis is indicated, ACE inhibitors should 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 concurrently receiving ACE inhibitors. In such patients, use of alternative dialysis membranes or antihypertensive agents from another class should be considered.

Patients with diabetes mellitus.

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin and additionally prescribed ACE inhibitors should have careful monitoring of blood glucose levels, 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 chronic cough.

Surgery/anaesthesia.

During major surgery or anaesthesia with agents causing hypotension, enalapril maleate inhibits angiotensin II formation secondary to compensatory renin release. If hypotension occurs due to these mechanisms, it may be corrected by increasing fluid volume.

Serum potassium levels.

ACE inhibitors may cause hyperkalaemia due to inhibition of aldosterone release. This effect is usually mild in patients with normal renal function. However, hyperkalaemia may occur in patients with renal impairment and in those taking potassium-containing supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), heparin, cyclosporine, and particularly aldosterone antagonists or angiotensin receptor blockers. Potassium-sparing diuretics, trimethoprim, co-trimoxazole and potassium-containing supplements should be used with caution in patients receiving ACE inhibitors (see "Dual blockade of the renin-angiotensin-aldosterone system (RAAS)" in this section above).

Serum potassium levels and renal function should be monitored (see "Renal function impairment" in this section above).

Risk factors for hyperkalaemia include: age over 70 years, diabetes mellitus, hypoaldosteronism, and concomitant conditions such as dehydration, acute heart failure, metabolic acidosis.

Hyperkalaemia may lead to severe arrhythmias, sometimes fatal.

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 by combination therapy with 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 close medical supervision with periodic monitoring of renal function, electrolyte levels and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy.

Lactose.

The medicinal product contains lactose. This medicinal product should not be used in patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome.

Sodium.

The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "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 in other indications is lacking. Pharmacokinetic data in children from 2 months of age are limited. Berlipril® is indicated only for children with arterial hypertension, but 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 "Dosage and administration").

Pregnancy.

ACE inhibitor therapy should not be initiated during pregnancy.

For women of childbearing potential who require 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.

As with 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 who may become pregnant.

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

Epidemiological data on teratogenic risk 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 who require 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 observed for signs of arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Breastfeeding.

Limited pharmacokinetic data confirm the presence of ACE inhibitors in breast milk in low concentrations (see section "Pharmacokinetics"). Although these concentrations are considered clinically insignificant, Berlipril® is not recommended during breastfeeding of preterm infants and newborns during the first weeks of life due to a theoretical risk of cardiovascular and renal effects and insufficient experience. In older infants, 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.

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

Ability to drive and use machines.

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

Method of administration and dosage

The dose of the drug should be individually adjusted depending on the patient's condition (see section "Special precautions") and the effect of the drug 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. in renovascular hypertension, disturbances in salt and/or fluid balance, decompensated heart function, or severe arterial hypertension), a significant decrease in arterial blood pressure may occur after the initial dose. In such patients, treatment should be initiated with a dose of 5 mg or a lower dose under strict medical supervision.

In patients previously treated with high-dose diuretics, fluid deficiency may develop and increase the risk of arterial hypotension at the beginning of enalapril therapy. For these 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®. Kidney function and serum potassium levels should be monitored.

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

Heart failure/asymptomatic left ventricular dysfunction

For treatment of 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 blood 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. This dose titration should be performed over 2–4 weeks of therapy. The maximum daily dose is 40 mg of enalapril, which should be divided into two doses.

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

* 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®, if possible, reduce the dose of diuretics being taken by the patient. The occurrence of hypotension at the beginning of Berlipril® therapy does not indicate its development during long-term treatment and does not preclude continued use of the medicinal product. Monitoring of serum potassium levels and renal function should also be performed.

Dosing in renal impairment

In general, the dosing intervals should be prolonged and/or the dose reduced.

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

Enalaprilat is dialyzable. Adjust the dose on days when dialysis is not performed depending on the degree of blood pressure reduction.

Elderly patients

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

Children with hypertension aged > 6 years

Clinical data on the use of Berlipril® in pediatric patients with hypertension are limited (see sections "Special precautions", "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. The recommended initial dose is 2.5 mg for children with body weight from 20 to <50 kg and 5 mg for patients with body weight ≥ 50 kg. Berlipril® should be administered once daily. The dose should be adjusted 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 precautions").

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

Route 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 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 and is not recommended for other indications.

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

Overdose.

Information on overdose in humans is limited. The most likely signs of overdose reported to date include marked hypotension, beginning approximately 6 hours after drug intake and coinciding with blockade of the renin-angiotensin system, and stupor. Symptoms associated with ACE inhibitor overdose 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 100 and 200 times higher, respectively, than those observed with therapeutic doses.

Treatment of overdose should include intravenous infusion of sodium chloride solution. If 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 to remove enalapril maleate should be taken (e.g., induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat is removed from systemic circulation by hemodialysis (see section "Special precautions": Patients undergoing hemodialysis). In cases of refractory bradycardia, cardiac pacing is indicated. Vital signs, serum electrolytes, and creatinine levels should be closely monitored.

Adverse Reactions

To assess the frequency of adverse events occurring during enalapril use, the following classification is applied: 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 frequency 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 depression, pancytopenia, lymphadenopathy, autoimmune disorders.

Endocrine system disorders:
Frequency not known – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders:
Uncommon – hypoglycaemia (see section "Special precautions and warnings");
Frequency 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 – headache, depression, syncope, taste disturbances;
Uncommon – confusion, drowsiness, insomnia, nervousness, paraesthesia, dizziness;
Rare – sleep disorders, abnormal dreams.

Eye disorders:
Very common – blurred vision.

Ear and labyrinth disorders:
Uncommon – tinnitus.

Cardiac and vascular disorders:
Common – arterial hypotension (including orthostatic hypotension), chest pain, arrhythmias, angina pectoris, tachycardia;
Uncommon – orthostatic hypotension, flushing, palpitations, myocardial infarction or cerebrovascular events (incidence comparable to placebo and active control groups in clinical trials), likely secondary to reduced blood pressure in patients with risk factors (see section "Special precautions and warnings");
Rare – Raynaud's syndrome.

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

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

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

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

Frequency not known: Cases have been reported of a symptom complex including 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.

Musculoskeletal and connective tissue disorders:
Uncommon – muscle cramps.

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 – malaise, fever.

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

Reporting suspected adverse reactions after product authorization is highly important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required 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 a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.
Blister packs of 10 tablets; 3 blisters per cardboard box.

Prescription status.
Prescription only.

Manufacturer.
Berlin-Chemie AG.

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

Marketing Authorization Holder.
Berlin-Chemie AG.

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