Berlipril® plus 10/25

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BERLIPRIL® PLUS 10/25

Composition:

Active substances: enalapril maleate, hydrochlorothiazide;

1 tablet contains enalapril maleate 10 mg and hydrochlorothiazide 25 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: flat, light-yellow tablets with bevelled edges on both sides and a score line on one side.

The score line is intended exclusively for breaking the tablet in half to facilitate swallowing and is not intended for dividing the tablet into equal doses.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors and diuretics. ATC code C09BA02.

Pharmacological properties.

Berlipril® Plus 10/25 is a combination drug containing an ACE inhibitor – enalapril, and an antihypertensive diuretic – hydrochlorothiazide.

Pharmacodynamics.

Enalapril maleate

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 to angiotensin II, which has vasoconstrictor activity. After absorption, enalapril is hydrolyzed to enalaprilat, which in turn inhibits ACE. This leads to a reduction in angiotensin II levels in plasma and a subsequent increase in plasma renin activity (due to blockade of the negative feedback mechanism on renin release) and decreased aldosterone secretion. The structure of ACE is identical to kininase II, thus enalapril may block the breakdown of bradykinin – a potent vasodilator. However, the clinical significance of this effect has not been established. The antihypertensive effect of enalapril is primarily related to inhibition of the renin-angiotensin-aldosterone system, but the drug reduces blood pressure even in patients with low-renin hypertension. Administration of enalapril to patients with arterial hypertension results in reduced blood pressure in both supine and upright positions without a significant increase in heart rate. In rare cases, this is accompanied by orthostatic hypotension. In some patients, optimal blood pressure reduction occurs only after several weeks of treatment. Abrupt discontinuation of enalapril therapy does not result in a rapid rise in blood pressure. Adequate inhibition of ACE activity is usually observed within 2–4 hours after a single oral dose of enalapril. The antihypertensive effect begins within 1 hour after administration, but maximal blood pressure reduction occurs after 4–6 hours. The duration of the drug's effect depends on its dose. However, when recommended doses are used, the hypotensive and hemodynamic effects persist for at least 24 hours. In hemodynamic assessments of patients with essential hypertension, blood pressure reduction was associated with decreased peripheral vascular resistance and increased cardiac output, with minimal change in heart rate. After enalapril administration, renal blood flow was enhanced, while glomerular filtration rate remained unchanged. Sodium and water retention were not observed with enalapril use. However, in patients with previously low glomerular filtration rate, this parameter may increase during treatment. In short-term clinical studies conducted in patients with impaired renal function, with or without concomitant diabetes mellitus, a reduction in albuminuria, proteinuria, and urinary IgG excretion was observed after enalapril administration. When used concomitantly with thiazide diuretics, the antihypertensive effect of enalapril is enhanced. Enalapril may prevent or reduce hypokalemia associated with thiazide diuretic use.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers was investigated 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 ONTARGET trial was conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D trial was conducted in patients with type 2 diabetes and diabetic nephropathy. The data from these trials did not show a significant beneficial effect on renal and/or cardiovascular outcomes and related mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was conducted to evaluate the potential benefit of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This trial was terminated early due to an increased risk of adverse reactions. Cardiovascular mortality and stroke occurred more frequently in the aliskiren group than in the placebo group, and reports of serious adverse reactions (hyperkalemia, hypotension, and renal dysfunction) were more frequent in the aliskiren group than in the placebo group.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide-type diuretic that exerts a diuretic effect by inhibiting sodium reabsorption in the cortical segment of the renal tubules. It enhances the excretion of sodium and chloride, and to a lesser extent potassium and magnesium, increasing urine volume and promoting blood pressure reduction. The diuretic effect of the drug usually begins within 2 hours after oral administration, reaches maximum effect within 4 hours, and lasts for 6–12 hours. After reaching a certain dose, further increases in the therapeutic effect of thiazide diuretics cease, while adverse reactions increase. Increasing the dose beyond the recommended amount in the absence of efficacy does not yield the desired result and is associated with numerous adverse reactions.

Non-melanoma skin cancer (NMSC). Epidemiological data have shown an association between cumulative hydrochlorothiazide dose and the development of NMSC. One study included a population of 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 control group participants, respectively. High-dose hydrochlorothiazide use (cumulative ≥ 50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study suggested a possible association between lip cancer (SCC) and hydrochlorothiazide: 633 patients with lip cancer were compared with 63,067 participants in the control group using a risk-set sampling strategy. A dose-response relationship was demonstrated: the adjusted OR was 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high doses (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see also section "Special precautions for use").

Enalapril maleate/hydrochlorothiazide

Clinical studies have demonstrated that the combination of enalapril and hydrochlorothiazide produces a greater antihypertensive effect than either drug used alone. Enalapril may prevent or reduce hypokalemia induced by hydrochlorothiazide.

Pharmacokinetics.

Absorption.

Enalapril maleate

After oral administration, enalapril is rapidly absorbed, and maximum serum concentration is observed within 1 hour. Based on urinary enalapril content, the extent of absorption after oral administration in tablet form is approximately 60%. The presence of food in the gastrointestinal tract does not affect enalapril absorption after oral administration. After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Maximum serum levels of enalaprilat are reached 4 hours after oral administration of enalapril in tablet form. The effective half-life of enalaprilat after multiple doses of enalapril is 11 hours. With normal renal function, steady-state serum concentrations of enalaprilat are reached within 4 days of starting treatment.

Distribution. Over the therapeutic concentration range, the extent of enalaprilat binding to human plasma proteins does not exceed 60%.

Metabolism. Enalapril does not undergo significant metabolic transformation except for conversion to enalaprilat.

Elimination. Enalaprilat is primarily eliminated via the kidneys. In urine, enalaprilat accounts for 40% of the administered dose, and unchanged enalapril accounts for approximately 20%.

Renal impairment. Exposure to enalapril and enalaprilat increases in renal impairment. In mild to moderate renal impairment (creatinine clearance 40–60 mL/min), the steady-state AUC (area under the concentration-time curve) of enalaprilat at a dose of 5 mg once daily is approximately twice higher than with normal renal function. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increases approximately eightfold. In such patients, repeated administration of enalapril maleate prolongs the effective half-life of enalaprilat and increases the time to steady-state.

Lactation. Within 4–6 hours after a single 20 mg oral dose administered to five postpartum women, the peak concentration of enalapril maleate in breast milk averaged 1.7 µg/L (range of peaks from 0.54 to 5.9 µg/L). The average peak concentration of enalaprilat was 1.7 µg/L (range 1.2 to 2.3 µg/L); peak concentrations were observed at various times over 24 hours. Based on peak concentration data in breast milk, it is estimated that an infant exclusively breastfed receives no more than 0.16% of the maternal dose adjusted per kg of body weight. In a woman taking 10 mg of enalapril daily for 11 months, a peak concentration of 2 µg/L was observed approximately 4 hours after drug intake, and a peak concentration of enalaprilat of 0.75 µg/L approximately 9 hours after intake. The total daily content of enalaprilat in maternal milk was 0.63 µg/L, and total daily enalapril content was 1.44 µg/L. Four hours after a single 5 mg dose of enalapril in one patient and single 10 mg doses in two patients, enalaprilat levels in milk were below the limit of detection (< 0.2 µg/L); enalapril content was not determined.

Hydrochlorothiazide

After oral administration, hydrochlorothiazide is absorbed to a sufficient extent, with approximately 80% of the administered dose being absorbed. Food intake has only a minor effect on its absorption. Maximum plasma levels are reached within 2–5 hours. Approximately 50–60% of hydrochlorothiazide is bound to albumin, but most of it accumulates in erythrocytes. The average elimination half-life is 5–15 hours. Hydrochlorothiazide is excreted by the kidneys almost unchanged (> 95%).

Preclinical safety data.

Preclinical data do not indicate a particular hazard for humans based on standard safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies.

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

Clinical characteristics.

Indications.

Berlipril® plus 10/25 is indicated for adults in whom blood pressure reduction is inadequate when treated with enalapril maleate monotherapy.

This medicinal product may be used to replace combination therapy with enalapril maleate 10 mg and hydrochlorothiazide 25 mg in patients who are stable on these doses.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients (see section "Composition");
• hypersensitivity to other ACE inhibitors or to sulfonamide-derived drugs;
• severe renal impairment (creatinine clearance ≤ 30 mL/min) and dialysis;
• anuria;
• history of angioedema induced by ACE inhibitor therapy;
• hereditary/inherent predisposition to angioedema;
• renal artery stenosis;
• severe hepatic dysfunction;
• concomitant use of Berlipril® plus 10/25 with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction");
• concomitant use with sacubitril/valsartan therapy: treatment with Berlipril® plus 10/25 should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan;
• pregnancy or women who are planning to become pregnant (see sections "Use in pregnancy or lactation", "Special precautions for use", and "Interaction with other medicinal products and other forms of interaction");
• breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Enalapril maleate/hydrochlorothiazide

Other antihypertensive agents. Concomitant use may enhance the antihypertensive effects of enalapril and hydrochlorothiazide. Combination with nitroglycerin, other nitrates, or vasodilating agents may lead to further significant reduction in blood pressure.

Lithium. Cases of reversible increases in serum lithium levels and lithium toxicity have been reported with concomitant use of ACE inhibitors. Thiazide diuretics may further increase the risk of lithium toxicity already present with ACE inhibitor therapy. Therefore, the combined enalapril/hydrochlorothiazide preparation is not recommended to be used concomitantly with lithium-containing medications; if such therapy is necessary, serum lithium levels should be closely monitored (see section "Special precautions for use").

Nonsteroidal anti-inflammatory drugs (NSAIDs). Prolonged use of NSAIDs may reduce the antihypertensive effect of ACE inhibitors or diminish the diuretic, natriuretic, and antihypertensive effects of diuretics. Combination of NSAIDs (including COX-2 inhibitors) with ACE inhibitors may have an additive effect leading to increased serum potassium levels and may result in worsening of renal function. These effects are usually reversible. Acute renal failure may rarely occur, particularly in patients with impaired renal function, such as elderly patients or those with reduced circulating blood volume, including due to intensive diuretic therapy.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Clinical trial data indicate that dual blockade of the RAAS, associated with concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren, leads to increased frequency of adverse reactions such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single agent affecting the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Metformin.

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

Enalapril maleate

Medicinal products increasing the risk of angioedema.

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

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (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 significant increases in serum potassium levels.

Caution should be exercised when prescribing Berlipril® plus 10/25 concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of Berlipril® plus 10/25 with the above-mentioned agents is not recommended. If concomitant use is indicated, they should be administered with caution and with regular monitoring of serum potassium levels (see section "Special precautions for use").

Cyclosporine.

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

Heparin.

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

Diuretics (thiazide and loop diuretics). Prior treatment with high doses of diuretics may lead to dehydration and risk of arterial hypotension during initial stages of enalapril therapy (see sections "Special precautions for use" and "Dosage and administration"). Hypotensive effects may be minimized by discontinuing diuretics or increasing dietary salt and fluid intake.

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

Tricyclic antidepressants/neuroleptics/anesthetics. Concomitant use of certain anesthetic agents, tricyclic antidepressants, and neuroleptic agents with ACE inhibitors may cause significant reduction in blood pressure (see section "Special precautions for use").

Sympathomimetic agents. Sympathomimetic agents may attenuate the antihypertensive effect of ACE inhibitors.

Antidiabetic agents. Epidemiological data indicate that concomitant use of ACE inhibitors and antidiabetic agents (insulin or oral hypoglycemic agents) may be associated with significant reduction in blood glucose levels and increased risk of hypoglycemia. This is most likely during the first weeks of such therapy and in patients with impaired renal function (see section "Adverse reactions").

Ethanol. Ethanol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid and beta-blockers. Concomitant use of enalapril with acetylsalicylic acid (in cardiologic doses) and beta-blockers poses no risk.

Gold preparations. Rare nitritoid reactions (e.g., facial flushing, nausea, vomiting, arterial hypotension) have been reported with concomitant use of ACE inhibitors, including enalapril, with injectable gold preparations (sodium aurothiomalate).

Hydrochlorothiazide

Non-depolarizing muscle relaxants. May enhance the response to tubocurarine.

Ethanol/barbiturates/narcotic analgesics. May potentiate orthostatic hypotension.

Antidiabetic agents (oral agents and insulin). Dose adjustment of antidiabetic agents may be required (see section "Adverse reactions").

Cholestyramine and colestipol. In the presence of these ion-exchange resins, absorption of hydrochlorothiazide is impaired. After single-dose administration, cholestyramine and colestipol bind hydrochlorothiazide, reducing its gastrointestinal absorption by 85% and 43%, respectively.

Agents that prolong the QT interval (e.g., quinidine, procainamide, amiodarone, sotalol). Increases the risk of bidirectional torsades de pointes (torsades de pointes tachycardia).

Cardiac glycosides based on digitalis. Hypokalemia may increase cardiac sensitivity to toxic effects of digitalis or cause exaggerated response to these toxic effects (e.g., increased ventricular excitability).

Corticosteroids, corticotropin (ACTH), amphotericin B (when administered parenterally). Concomitant use with hydrochlorothiazide may lead to electrolyte disturbances, particularly hypokalemia.

Potassium-wasting diuretics (e.g., furosemide), carbenoxolone, or laxative abuse. Hydrochlorothiazide may potentiate potassium and/or magnesium loss.

Vasopressor amines (e.g., noradrenaline). The effect of vasopressor amines may be reduced.

Calcium salts. Serum calcium levels may increase when used concomitantly with thiazide agents due to reduced calcium excretion.

Immunosuppressants, systemic corticosteroids, procainamide. May cause decreased white blood cell count, leukopenia.

Cytostatic agents (e.g., cyclophosphamide, fluorouracil, methotrexate). Thiazides may reduce renal excretion of cytostatic agents and enhance their myelosuppressive effects.

Agents for treatment of gout (e.g., allopurinol, benzbromarone). Dose adjustment of these agents may be required, as hydrochlorothiazide increases serum uric acid levels.

Clinical laboratory tests.

Hydrochlorothiazide may interfere with the bentiromide test. Thiazide diuretics may reduce serum protein-bound iodine concentration in the absence of other signs of thyroid dysfunction.

Special precautions for use.

Enalapril maleate and hydrochlorothiazide

Arterial hypotension and fluid/electrolyte imbalance.

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension. The risk of its development is increased when Berlipril® plus 10/25 is used in patients with disturbances of water and electrolyte balance, salt-restricted diet, dialysis, diarrhea, or vomiting (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). In such patients, regular monitoring of serum electrolyte concentrations is recommended. Particular attention should be paid to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction of arterial pressure may lead to myocardial infarction or acute cerebrovascular accident. Symptomatic arterial hypotension has been observed in patients with heart failure, with or without concomitant renal impairment.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, infused with physiological saline. Transient arterial hypotension is not a contraindication for further treatment, which may be continued after normalization of blood pressure with infusion therapy.

Renal function impairment.

Berlipril® plus 10/25 should not be prescribed to patients with renal impairment (creatinine clearance < 80 mL/min and > 30 mL/min) until the necessity of using this combination has been established during dose titration of enalapril (see section "Dosage and administration").

In some patients without apparent kidney pathology, increased blood urea and creatinine concentrations have been observed, particularly when enalapril is used concomitantly with diuretics (see Enalapril maleate, Renal function impairment, Hydrochlorothiazide in section "Special precautions for use"). If this occurs, treatment with Berlipril® plus 10/25 should be discontinued. In such cases, renal artery stenosis should be considered (see Enalapril maleate, Vasorenal hypertension in section "Special precautions for use").

Concomitant use of Berlipril® plus 10/25 and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see section "Contraindications").

Hyperkalemia.

Hyperkalemia cannot be excluded when enalapril is used in combination with diuretics at low doses (see Enalapril maleate, Serum potassium in section "Special precautions for use").

Lithium.

Concomitant use of enalapril and diuretics with lithium-containing medications is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Enalapril maleate

Stenosis of the aortic orifice/hypertrophic cardiomyopathy.

Like other vasodilators, ACE inhibitors should be used with caution in patients with impaired outflow from the left ventricle, as well as in cardiogenic shock and stenosis causing significant hemodynamic effects.

Renal function impairment.

Cases of renal failure have been reported during enalapril treatment, mainly in patients with severe heart failure or kidney disease, including renal artery stenosis. With timely diagnosis and adequate treatment, this renal failure is reversible (see Enalapril maleate-hydrochlorothiazide, Renal function impairment; Hydrochlorothiazide, Renal function impairment in section "Special precautions for use" and section "Dosage and administration").

Vasorenal arterial hypertension.

The use of ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the renal artery of a single functioning kidney increases the risk of arterial hypotension and renal failure. In such cases, renal function impairment may occur with only minor changes in serum creatinine concentration. These patients should be treated under constant medical supervision with regular monitoring of renal function.

Kidney transplantation.

There is no clinical experience with enalapril use in patients who have recently undergone kidney transplantation; therefore, the drug is not recommended for this patient group.

Patients undergoing hemodialysis.

Enalapril is not indicated for patients with renal impairment requiring dialysis. Cases of anaphylactic reactions during hemodialysis with high-flux membranes (e.g., AN 69®) have been reported in patients taking ACE inhibitors. If such a procedure is necessary, it is recommended to use dialysis membranes of another type or to use an antihypertensive agent from another class.

Hepatic impairment.

Rarely, the use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is not fully understood. Patients who develop jaundice or a significant increase in liver enzymes during treatment with ACE inhibitors should discontinue the ACE inhibitor and receive appropriate treatment (see Hydrochlorothiazide, Hepatic impairment in section "Special precautions for use").

Neutropenia/agranulocytosis.

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and without other predisposing factors. Enalapril should be used with caution in patients with vascular disorders due to collagen diseases, those receiving immunosuppressive agents, allopurinol, procainamide, or a combination of these factors, especially in patients with prior kidney damage. Severe infections resistant to antibiotic therapy have occurred in some patients. During enalapril use in such patients, periodic monitoring of the leukocyte formula is recommended, and all patients should be advised to report any signs of infection to their physician.

Serum potassium.

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

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

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

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

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

If dual RAAS blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision with careful monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

Patients with diabetes mellitus.

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should be warned about the need for careful monitoring of blood glucose levels to avoid hypoglycemia, especially during the first month of concomitant use (see Hydrochlorothiazide, Metabolic and endocrine effects in section "Special precautions for use" and section "Interaction with other medicinal products and other forms of interaction").

Hypersensitivity reactions/angioedema.

Cases of angioedema of the face, extremities, lips, tongue, epiglottis, and larynx have been reported with ACE inhibitors, including enalapril maleate. Such swelling may develop at any time during treatment.

In such cases, Berlipril® plus 10/25 should be discontinued immediately, and the patient should remain under medical supervision until all symptoms have completely resolved. Even if angioedema affects only the tongue without respiratory distress, prolonged observation is required, as antihistamines and corticosteroids may be insufficient.

Rare fatal cases due to laryngeal and lingual angioedema have been reported. With swelling of the tongue, epiglottis, or larynx, there is an increased risk of airway obstruction, especially in patients who have recently undergone airway surgery. In such cases, immediate measures are required, including subcutaneous injection of epinephrine 1:1000 solution (0.3–0.5 mL) and/or securing airway patency.

Angioedema occurs more frequently in patients of African descent compared to Caucasian patients taking ACE inhibitors.

Overall, patients of African descent are considered to have a higher risk of developing angioedema.

Patients with a history of angioedema of other etiology are at increased risk for this complication when prescribed ACE inhibitors (also see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy should not be initiated earlier than 36 hours after the last dose of Berlipril® plus 10/25. Berlipril® plus 10/25 therapy 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., airway or tongue swelling with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is required when initiating racecadotril, mTOR inhibitors (sirolimus, everolimus, temsirolimus), or vildagliptin in patients already taking ACE inhibitors.

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

Anaphylactic reactions during desensitization to hymenoptera venom.

Rarely, life-threatening anaphylactic reactions have been observed in patients taking ACE inhibitors during desensitization to hymenoptera venom. These reactions can be avoided by temporarily discontinuing the ACE inhibitor before each desensitization procedure.

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

Rarely, life-threatening anaphylactic reactions have been observed in patients taking ACE inhibitors during LDL apheresis with dextrin sulfate. These reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis procedure.

Cough.

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

Surgery/anesthesia.

During surgical procedures or anesthesia with agents that lower blood pressure, enalapril blocks angiotensin II formation due to compensatory renin release. If arterial hypotension occurs due to this mechanism, it can be corrected with infusion therapy (see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy.

Berlipril® plus 10/25 should not be used in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with Berlipril® plus 10/25, the drug should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy (see sections "Contraindications" and "Use during pregnancy or lactation").

Ethnic differences.

As with other ACE inhibitors, the antihypertensive effect of enalapril may be less pronounced in patients of African descent compared to patients of other races, possibly due to a higher prevalence of low renin levels in this population.

Hydrochlorothiazide

Renal function impairment.

The use of thiazide diuretics is not always appropriate in the treatment of patients with impaired renal function. They are ineffective when creatinine clearance is 30 mL/min or less (e.g., in patients with moderate to severe renal impairment) (see Enalapril maleate-hydrochlorothiazide, Renal function impairment; Enalapril maleate, Renal function impairment in section "Special precautions for use" and section "Dosage and administration").

Hepatic impairment.

Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, as minor changes in fluid and electrolyte balance may precipitate hepatic coma (see Enalapril maleate, Hepatic impairment in section "Special precautions for use").

Metabolic and endocrine effects.

Thiazide diuretics may impair glucose tolerance. In patients with diabetes mellitus, adjustment of antidiabetic medication doses, including insulin, may be required (see Enalapril maleate, Patients with diabetes mellitus in section "Special precautions for use").

The use of thiazide diuretics may lead to increased cholesterol and triglyceride levels, and in some patients, hyperuricemia and/or gout may develop. This hyperuricemic effect is likely dose-dependent. Additionally, enalapril may increase blood uric acid levels and thus potentiate the hyperuricemic effect of hydrochlorothiazide. As with any diuretic use, periodic monitoring of serum electrolytes is required.

Thiazide diuretics, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypokalemia, hyponatremia, hypochloremic alkalosis). Early signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, somnolence, restlessness, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea and vomiting. Although hypokalemia may occur with thiazide diuretics, concomitant use of enalapril reduces this effect. The risk of hypokalemia is higher in patients with liver cirrhosis, those with markedly increased diuresis, inadequate electrolyte intake, and those receiving corticosteroids or adrenocorticotropic hormone (ACTH) (see section "Interaction with other medicinal products and other forms of interaction").

Hyponatremia may occur in patients with edema during hot weather. Chloride deficiency is usually mild and does not require therapeutic intervention. Thiazide diuretics may reduce calcium excretion in urine and cause reversible, mild elevation of serum calcium levels in the absence of disorders affecting calcium metabolism. Marked hypercalcemia may occur in patients with occult hyperparathyroidism. Thiazide diuretics should be discontinued before parathyroid function tests. Thiazide diuretics may increase magnesium excretion in urine, potentially leading to hypomagnesemia.

Anti-doping test.

Hydrochlorothiazide contained in this medicinal product may cause false-positive results in anti-doping tests.

Hypersensitivity.

Hypersensitivity reactions may occur in patients with or without a history of bronchial asthma. There have also been reports of an increased risk of exacerbation or activation of systemic lupus erythematosus.

Choroidal effusion, acute myopia, and angle-closure glaucoma.

Hydrochlorothiazide, being a sulfonamide, has been associated with an idiosyncratic reaction leading to choroidal effusion with visual disturbances, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute decrease in visual acuity or eye pain. These symptoms usually occur within hours to one week after starting treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss.

The primary measure is rapid discontinuation of hydrochlorothiazide. If intraocular pressure is uncontrolled, immediate therapeutic or surgical intervention may be necessary. A history of allergy to sulfonamides or penicillins may be a risk factor for developing angle-closure glaucoma.

Non-melanoma skin cancer (NMSC).

In two epidemiological studies based on data from the Danish national cancer registry, increasing cumulative doses of hydrochlorothiazide were associated with an increased risk of NMSC (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). The photosensitizing effects of hydrochlorothiazide may be a possible mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to limit exposure to sunlight and UV radiation and use appropriate protection when such exposure occurs. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy specimens. Patients with a history of NMSC may also require reevaluation of hydrochlorothiazide use (see also section "Adverse reactions").

Acute respiratory toxicity.

Rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide use. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, Berlipril® plus 10/25 should be discontinued and appropriate treatment initiated.

Hydrochlorothiazide should not be used in patients who previously developed ARDS after taking hydrochlorothiazide.

Lactose.

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

Sodium.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, which can be considered "sodium-free."

Use during pregnancy or lactation.

Pregnancy. Berlipril® plus 10/25 should not be used in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with Berlipril® plus 10/25, the drug should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

ACE inhibitors

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are not conclusive, although a slight risk cannot be excluded. Women planning pregnancy should switch from ACE inhibitor therapy to alternative antihypertensive agents with an established safety profile during pregnancy, except when ACE inhibitor therapy is considered necessary. When pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately, and alternative therapy initiated if needed.

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, arterial hypotension, hyperkalemia). Oligohydramnios—likely due to reduced fetal renal function—may lead to limb contractures, craniofacial deformities, or pulmonary hypoplasia. In cases of fetotoxic effects during ACE inhibitor therapy in the second and third trimesters, patients should undergo ultrasound examination to assess fetal renal function and skull condition. Newborns whose mothers used ACE inhibitors should be monitored for possible arterial hypotension.

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy is limited, especially during the first trimester. Experimental animal data are insufficient. Hydrochlorothiazide crosses the placental barrier. Due to its mechanism of action, hydrochlorothiazide may impair fetoplacental blood flow and adversely affect the fetus and, consequently, the newborn, causing jaundice, electrolyte disturbances, and thrombocytopenia during the second and third trimesters.

Hydrochlorothiazide is not indicated for the treatment of gestational edema, pregnancy-induced hypertension, or preeclampsia, as it may reduce plasma volume and cause placental hypoperfusion without providing therapeutic benefit.

Hydrochlorothiazide is also not recommended for the treatment of primary arterial hypertension in pregnant women, except in rare cases when other drugs cannot be used.

Lactation. Berlipril® plus 10/25 is contraindicated during lactation.

Enalapril and hydrochlorothiazide pass into human breast milk. The use of thiazide diuretics during lactation in nursing mothers has been associated with reduced or ceased milk production. Due to the potential for serious adverse reactions in infants from both active components of this medicinal product, its use should be discontinued during lactation. Otherwise, women are advised to discontinue breastfeeding.

Enalapril

Pharmacokinetic data show very low concentrations of enalapril in breast milk. Although low concentrations of ACE inhibitors are not clinically significant, due to the risk of adverse reactions in infants (effects on the cardiovascular system and renal function) and the lack of clinical experience with Berlipril® plus 10/25, enalapril therapy in patients should not be used in cases of preterm infants or during the first weeks of life if the infant is breastfed. Enalapril use by the mother during breastfeeding at a later age is acceptable only in cases of extreme necessity and under medical supervision for adverse reactions in the infant.

Hydrochlorothiazide

Hydrochlorothiazide passes into breast milk in small amounts. At high doses, thiazides significantly increase diuresis and thereby suppress lactation.

Fertility. Studies on the effect of Berlipril® plus 10/25 on fertility have not been conducted.

Enalapril

Results from reproductive toxicity studies in rats suggest that enalapril does not affect fertility or reproductive system function.

Hydrochlorothiazide

Reproductive toxicity studies of hydrochlorothiazide in mice and rats did not show any adverse effects on fertility in either sex.

Ability to affect reaction speed when driving or operating machinery.

In some patients, use of Berlipril® plus 10/25 may alter reaction speed, impairing the ability to drive or operate machinery or work in conditions requiring stable balance. This is most likely at the beginning of treatment, during dose escalation, or when changing medications, as well as when alcohol is consumed during treatment. It should be remembered that Berlipril® plus 10/25 may be associated with dizziness and fatigue.

Method of Administration and Dosage

Berlipril® Plus 10/25 is not indicated for initial treatment of essential hypertension. At the initial stages, optimal doses of its individual components should be titrated. If necessary, a fixed-dose combination drug containing both active substances may be prescribed instead of monotherapy.

The standard dose is 1 tablet per day. The tablet should be taken independently of food intake, in the morning, with a sufficient amount of liquid, for example, one glass of water.

When switching patients from enalapril maleate monotherapy to Berlipril® Plus 10/25, especially in patients with fluid and electrolyte disturbances (e.g., after vomiting, diarrhea, or diuretic therapy), severe heart failure, or severe arterial hypertension including renal origin, a significant decrease in arterial pressure may occur. Therefore, such patients should be under medical supervision for approximately 8 hours after the first dose.

Dosing in Renal Impairment (Creatinine Clearance – 30–80 mL/min)

Berlipril® Plus 10/25 is contraindicated in patients with severe renal impairment. It may be prescribed to patients with creatinine clearance >30 and <80 mL/min, but only after individual dose titration of the active components. In such patients, the recommended initial dose of enalapril maleate in monotherapy is 5–10 mg.

Elderly Patients. Data on the relationship between efficacy and safety of the drug and patient age are lacking. Renal function should be taken into account when administering the drug.

Children.

The drug should not be used in children due to insufficient information on its efficacy and safety in this patient group.

Overdose.

There are no specific guidelines for the treatment of patients with overdose of Berlipril® Plus 10/25. Management is symptomatic and supportive. Administration of Berlipril® Plus 10/25 should be discontinued and the patient should be thoroughly examined.

Treatment. Possible measures to manage overdose include induced emesis, administration of activated charcoal, and laxatives if the drug was recently ingested, as well as correction of dehydration, electrolyte imbalances, and arterial hypotension using standard methods.

Enalapril Maleate. The most common sign of overdose reported to date is marked arterial hypotension, beginning approximately 6 hours after tablet ingestion, associated with blockade of the renin-angiotensin-aldosterone system and stupor. In cases of ACE inhibitor overdose, the following symptoms may develop: acute circulatory failure, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. There have been reports of oral ingestion of 300 mg and 400 mg of enalapril maleate, resulting in serum enalaprilat levels 100 and 200 times higher, respectively, than levels typically observed with therapeutic doses.

Treatment. For management of overdose, intravenous infusion of 0.9% sodium chloride solution is recommended. If arterial hypotension occurs, the patient should be placed in a supine position. Intravenous infusion of angiotensin II and/or catecholamine-group agents may be considered. If enalapril maleate was ingested recently, measures to remove it from the body are indicated: induced emesis, gastric lavage, administration of adsorbents, and sodium sulfate. Enalaprilat can be removed from systemic circulation by hemodialysis. In cases of persistent bradycardia, cardiac pacing is indicated, with continuous monitoring of vital signs, serum creatinine concentration, and serum electrolyte levels.

Hydrochlorothiazide. The most common signs of overdose are symptoms caused by decreased electrolyte levels (hypokalemia, hypochloremia, hyponatremia), as well as dehydration resulting from excessive diuresis. In patients receiving cardiac glycosides, hypokalemia may lead to increased cardiac arrhythmias.

Side effects

During clinical trials or after marketing of the medicinal product, the following adverse reactions have been reported for Berlipril® Plus 10/25, as well as for enalapril or hydrochlorothiazide used separately.

The following classification is used to assess the frequency of adverse reactions:

Very common: ≥ 1/10;
Common: ≥ 1/100, < 1/10;
Uncommon: ≥ 1/1000, < 1/100;
Rare: ≥ 1/10,000, < 1/1000;
Very rare: < 1/10,000;
Not known: frequency cannot be estimated from the available data.

Infections and infestations

Rare: sialadenitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Not known: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Blood and lymphatic system disorders

Uncommon: anaemia, including aplastic and haemolytic.
Rare: neutropenia, decreased haemoglobin levels, decreased haematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, leucopenia, pancytopenia, lymphadenopathy, autoimmune disorders.

Endocrine disorders

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

Gastrointestinal and metabolic disorders

Common: hypokalaemia, hypercholesterolaemia, hypertriglyceridaemia, hyperuricaemia.
Uncommon: hypoglycaemia (see section "Special warnings and precautions for use"), hypomagnesaemia, gout.
Rare: hyperglycaemia, glucosuria.
Very rare: metabolic alkalosis, hypercalcaemia (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

Very common: dizziness.
Common: headache, depression, loss of consciousness, taste disturbances.
Uncommon: confusion, somnolence, insomnia, increased excitability, paraesthesia, vertigo, decreased libido.
Rare: unusual dreams, sleep disturbances, paralysis (due to hypokalaemia).

Eye disorders

Very common: blurred vision.
Uncommon: xanthopsia.
Not known: choroidal effusion, acute angle-closure glaucoma.

Ear and labyrinth disorders

Uncommon: tinnitus.

Cardiac and vascular disorders

Common: arterial hypotension, including orthostatic, cardiac arrhythmias, angina pectoris, tachycardia.
Uncommon: flushing, palpitations, myocardial infarction or cerebrovascular accident, likely due to severe arterial hypotension in patients at risk (see section "Special warnings and precautions for use").
Rare: Raynaud's syndrome, necrotizing vasculitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders

Very common: cough.
Common: dyspnoea.
Uncommon: rhinorrhoea, sore throat or hoarseness, bronchospasm/asthma.
Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.
Very rare: acute respiratory distress syndrome (ARDS) (see section "Special warnings and precautions for use").

Gastrointestinal disorders

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

Hepatobiliary disorders

Rare: liver failure, liver necrosis (sometimes fatal), hepatitis, cholestatic jaundice, cholecystitis, particularly in patients with diagnosed cholelithiasis.

Skin and subcutaneous tissue disorders

Common: rash (exanthema), hypersensitivity/angioedema (cases of angioedema of the face, extremities, lips, tongue, larynx and/or glottis have been reported) (see section "Special warnings and precautions for use").
Uncommon: increased sweating, pruritus, urticaria, alopecia, photosensitivity.
Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus and lupus-like reactions, bullous dermatosis, erythroderma, anaphylactic reactions.
Not known: a symptom complex including fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive ANA (antinuclear antibodies) titre, elevated ESR, eosinophilia, leukocytosis. Skin rashes, photosensitivity and other skin reactions may also occur.

Musculoskeletal and connective tissue disorders

Common: muscle cramps.
Uncommon: arthralgia.

Renal and urinary disorders

Uncommon: impaired renal function, renal failure, proteinuria.
Rare: oliguria, interstitial nephritis.

Reproductive system and breast disorders

Uncommon: impotence.
Rare: gynaecomastia.

General disorders and administration site conditions

Very common: asthenia.
Common: increased fatigue, chest pain.
Uncommon: malaise, pyrexia (fever).

Investigations

Common: hyperkalaemia, increased serum creatinine levels.
Uncommon: increased blood urea nitrogen, hyponatraemia.
Rare: increased liver enzyme activity, increased serum bilirubin levels.

Description of selected adverse reactions

Non-melanoma skin cancer: epidemiological studies have shown an association between cumulative dose of hydrochlorothiazide and non-melanoma skin cancer (NMSC) (see also sections "Pharmacodynamics" and "Special warnings and precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life: 3 years. Do not use after the expiry date.

Storage conditions: Store at temperatures not exceeding 30 °C. To protect from moisture, keep the medicinal product in the original packaging. Keep out of reach and sight of children.

Packaging: 10 tablets in a blister; 2 or 3 blisters per cardboard box.

Prescription status: Prescription only.

Manufacturer

BERLIN-CHEMIE AG, Germany.

Manufacturer's address

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing Authorisation Holder

Berlin-Chemie AG.

Address of the Marketing Authorisation Holder

Glienicker Weg 125, 12489 Berlin, Germany.