Instructions for use BERLIPRIL

Pharmacological properties of the drug Berlipril

Pharmacodynamics. Enalapril maleate is a salt of maleic acid and enalapril. Enalapril hydrolysis occurs in the liver, resulting in the formation of its active metabolite, enalaprilat, which is an ACE inhibitor. ACE converts angiotensin I into angiotensin II, a substance that has a vasoconstrictor effect. Inhibition of ACE leads to a decrease in the formation of angiotensin II in tissues and blood plasma, a decrease in the secretion of aldosterone and an increase in renin activity in the blood plasma. Since ACE breaks down bradykinin, which has a vasodilating effect, the consequence of ACE inhibition is an increase in the activity of the kalikrein-kinin system and, thus, activation of the prostaglandin system. The use of enalapril maleate in patients with hypertension (arterial hypertension) causes a decrease in blood pressure without a compensatory increase in heart rate and a decrease in peripheral vascular resistance. In patients with heart failure, the use of enalapril maleate leads to a decrease in peripheral vascular resistance, resulting in a decrease in afterload on the heart. When treated with enalapril maleate, there is an increase in IOC, an increase in stroke index and exercise tolerance, a decrease in left ventricular hypertrophy, and an improvement in intraglomerular renal blood flow. Enalapril maleate has no effect on the metabolism of glucose and lipoproteins. Pharmacokinetics. After oral administration, up to 60% of the dose is absorbed into the gastrointestinal tract. Concomitant food intake does not affect the absorption of enalaprilat. Bioavailability is about 50–70%. The maximum concentration in the blood plasma is reached after approximately 4 hours. The effective half-life of enalaprilat after repeated oral administration is 11 hours. Effective inhibition of ACE activity occurs 2-4 hours after taking a single dose of enalapril maleate. The onset of antihypertensive action is noted after 1 hour, and the maximum effect is observed 4-6 hours after taking the drug. The duration of action depends on the dose, however, when the drug is used in recommended doses, the antihypertensive and hemodynamic effects persist for at least 24 hours. In volunteers with normal renal function, steady-state concentrations are achieved approximately on the 3rd–4th day with a dosage of 10 mg every 24 hours. In the range therapeutic doses, binding to plasma proteins does not exceed 60%. Metabolites other than enalaprilat are not known. The drug is excreted primarily by the kidneys. Renal clearance is approximately 150 ml/min. The half-life of enalaprilat is 35 hours. The main component in the urine is enalaprilat (40% of the dose taken) and unchanged enalapril maleate (about 20%). If renal function is impaired, the release of enalaprilat decreases according to the degree of dysfunction. Enalaprilat is eliminated during hemodialysis and peritoneal dialysis. Hemodialysis reduces the plasma concentration of enalaprilat by approximately 46%.

Berlipril 20, 20 mg, tablets, 30 pcs.

Use with caution in cases of primary hyperaldosteronism, bilateral renal artery stenosis, stenosis of the artery of a single kidney, hyperkalemia, condition after kidney transplantation, aortic stenosis, mitral stenosis (with hemodynamic impairment), idiopathic hypertrophic subaortic stenosis, connective tissue diseases, coronary artery disease, cerebrovascular diseases, diabetes mellitus, renal failure (proteinuria more than 1 g/day), liver failure, in patients on a diet with limited salt intake or on hemodialysis, when taken simultaneously with immunosuppressants and saluretics, in elderly people (over 65 years of age). In patients with a reduced circulating blood volume (as a result of diuretic therapy, limited salt intake, during hemodialysis, diarrhea, vomiting), there is an increased risk of a sudden and pronounced decrease in blood pressure after using even the initial dose of an ACE inhibitor.

Patients with severe heart failure, coronary artery disease and cerebrovascular disease, in whom a sharp decrease in blood pressure can lead to myocardial infarction, stroke or impaired renal function, should be carefully monitored. Sudden cessation of treatment does not lead to withdrawal syndrome (a sharp rise in blood pressure).

It is recommended to carefully monitor newborns and infants who have been exposed in utero to ACE inhibitors in order to identify a pronounced decrease in blood pressure, oliguria, hyperkalemia, and neurological disorders that may be due to a decrease in renal and cerebral blood flow with a decrease in blood pressure. In oliguria, it is necessary to maintain blood pressure and renal perfusion by administering appropriate fluids and vasoconstrictors.

In patients with reduced renal function, the single dose should be reduced or the intervals between doses should be increased.

Before studying the function of the parathyroid glands, the drug should be discontinued.

During the treatment period, it is not recommended to drink alcohol (alcohol enhances the hypotensive effect).

Caution should be exercised when performing physical exercise in hot weather (risk of dehydration and excessive reduction in blood pressure due to decreased circulating blood volume).

Before performing surgical interventions, it is necessary to warn the surgeon and anesthesiologist about the use of ACE inhibitors.

Use of the drug Berlipril

Eating does not affect the absorption of enalapril maleate. The dose of the drug is selected individually depending on the patient’s condition and the effect of the drug on blood pressure. AH (arterial hypertension). The initial dose of Berlipril is 5–20 mg, depending on the degree of hypertension (arterial hypertension) and the patient’s condition; Frequency of administration: 1 time per day. For mild hypertension (arterial hypertension), the initial dose is 5–10 mg (Berlipril 5 or Berlipril 10 are prescribed). In patients with pronounced activation of the renin-angiotensin-aldosterone system (for example, with renal hypertension, electrolyte imbalance, cardiac decompensation or severe hypertension (arterial hypertension)), a significant decrease in blood pressure is possible at the beginning of treatment, in which case constant monitoring of the patient is required and a reduction in the initial dose up to 2.5–5 mg. At the beginning of the use of enalapril maleate, in the case of previous therapy with diuretics in high doses, hypovolemia may develop and, as a consequence, arterial hypotension. It is recommended that such patients begin treatment at a dose not exceeding 5 mg and, if possible, stop taking diuretics 2-3 days before starting therapy. At the beginning of treatment, monitoring of renal function and serum potassium levels is necessary. The usual maintenance daily dose is 20 mg of enalapril maleate, the maximum is 40 mg/day. Heart failure/asymptomatic left ventricular dysfunction. In the treatment of patients with heart failure and asymptomatic left ventricular dysfunction, Berlipril is prescribed in addition to diuretics, digitalis drugs or beta-adrenergic blockers. The initial dose of the drug is 2.5 mg, therapy should be started under the strict supervision of a physician. If symptomatic hypotension does not occur at the beginning of treatment or is short-lived, the dose of the drug should be gradually increased to a maintenance dose (20 mg), which the patient takes once or, depending on tolerability, in 2 doses. This dose titration is recommended during the first 2–4 weeks of therapy. The maximum maintenance dose is 40 mg/day, divided into 2 doses. Recommended dose titration of Berlipril in the treatment of patients with heart failure and asymptomatic left ventricular dysfunction.

Before and after initiating therapy with Berlipril, careful monitoring of blood pressure and renal function should be carried out, as there have been reports of hypotension and, rarely, renal failure. Before starting therapy, the dose of the diuretic used by the patient is reduced, if possible. A hypotensive reaction at the beginning of treatment with Berlipril does not mean that it will occur during long-term treatment and does not exclude its further use. Serum potassium levels and renal function should be regularly monitored. Dosing for renal impairment.

The intervals between doses of enalapril maleate should be increased and/or the dose reduced. Enalapril is dialyzed. On days free from dialysis, the dose depends on the degree of blood pressure reduction. Use in elderly patients. The dose should be adjusted depending on the state of renal function. Use in children. For children who can swallow tablets, the dose should be adjusted individually depending on their condition and the need to lower blood pressure. For patients weighing 20–50 kg, the initial dose is 2.5 mg, the maximum daily dose is 20 mg; for patients with body weight ≥50 kg, the initial dose is 5 mg, the maximum daily dose is 40 mg. Berlipril is prescribed once a day. The indicated maximum daily dose should not be exceeded. There is no data regarding the use of the drug in infants and children with a glomerular filtration rate ≤30 ml/min/1.73 m2, therefore it is not recommended to prescribe the drug to children of this age category.

Berlipril® plus (Berlipril® plus)

Enalapril

During therapy with Berlipril® plus, the patient's condition should be regularly monitored, especially at the beginning of treatment.

As with other ACE inhibitors, one should keep in mind the possibility of developing symptomatic arterial hypotension (even several hours after taking the first dose) in patients with severe chronic heart failure, severe renal impairment, as well as in patients with fluid and electrolyte imbalance. balance, due to previous diuretic therapy, a diet with limited salt intake, diarrhea, vomiting, or in patients on hemodialysis.

In patients with coronary artery disease, severe cerebrovascular diseases, aortic stenosis with hemodynamic disturbances, or other obstructions to the outflow of blood from the left ventricle, a significant decrease in blood pressure can lead to myocardial infarction and/or stroke.

Arterial hypotension with severe consequences is rare and transient. Transient arterial hypotension is not a contraindication to further drug therapy.

Rarely, when treated with ACE inhibitors, a syndrome is observed that begins with cholestatic jaundice, which progresses to sudden hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unclear. Patients who develop jaundice or a marked increase in liver transaminase activity during treatment with ACE inhibitors should discontinue the ACE inhibitors and undergo medical observation.

If a patient with arterial hypertension was treated with diuretics, then, if possible, they should be discontinued 2-3 days before starting treatment with Berlipril® plus (due to the risk of developing arterial hypotension).

Before starting treatment and during therapy, kidney function should be monitored (determine the protein content in the urine using test strips in the first portion of morning urine), because Proteinuria can occur both in patients with existing renal impairment and in those taking relatively high doses of ACE inhibitors.

In patients with diabetes mellitus treated with oral hypoglycemic agents or insulin, blood glucose concentrations should be regularly monitored during the first month of treatment with ACE inhibitors (see section “Drug Interactions”).

During treatment with Berlipril® plus, an increase in potassium levels in the blood serum is possible, especially in patients with chronic renal failure, diabetes mellitus, with simultaneous use of potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, as well as in patients taking other drugs leading to increased potassium levels in the blood serum (heparin); this effect is usually attenuated by thiazide diuretics due to increased potassium excretion. If the simultaneous use of the above drugs is necessary, then regular monitoring of potassium levels in the blood serum is recommended.

There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia in patients receiving treatment with ACE inhibitors. The risk of neutropenia likely depends on the dose and the clinical condition of the patient. Neutropenia may more often occur in patients with reduced renal function, especially if there is a concomitant connective tissue disease (systemic lupus erythematosus, scleroderma) or during treatment with immunosuppressants, allopurinol or procainamide, as well as with a combination of these risk factors. Some of these patients developed severe infectious diseases, which in some cases did not respond to intensive antibiotic therapy.

When using enalapril in such patients, it is advisable to carry out monitoring of blood leukocytes and a complete blood count before treatment, every 2 weeks in the first three months of treatment, and then regularly. The patient should be strongly advised to report to the doctor any symptom of an infectious disease (sore throat, fever); in this case, the leukocyte blood count should be monitored. If neutropenia (less than 1000/mm3) is suspected or detected, which is reversible, Berlipril® plus and other drugs taken simultaneously should be discontinued.

Before carrying out a planned surgical intervention, the anesthesiologist should be informed that the patient is receiving Berlipril® plus, since there is a risk of developing arterial hypotension during surgery under general anesthesia. If it is impossible to cancel ACE inhibitors, the blood volume should be carefully monitored.

It should be borne in mind that when treated with Berlipril® plus in patients who are indicated for hemodialysis or other types of blood filtration, the development of anaphylactoid reactions (facial swelling, hyperemia, marked decrease in blood pressure, shortness of breath) may develop due to the use of high-flow filter membranes ability, consisting of polyacrylonitrile (high-flow membranes). It is recommended to use other types of filter membranes for dialysis or alternative antihypertensive therapy using a drug from a different pharmacotherapeutic group.

During the period of desensitizing therapy to wasp or bee venom, patients receiving the drug Berlipril® plus may develop hypersensitivity reactions that pose a threat to life. To avoid corresponding reactions, therapy with ACE inhibitors should be temporarily interrupted before each session of desensitizing therapy.

In case of development of angioedema of the lips, face, neck (usually in the first weeks of treatment with ACE inhibitors), Berlipril® plus should be immediately discontinued and treatment with an antihypertensive drug from another pharmacotherapeutic group should be continued. However, in rare cases, severe angioedema involving the tongue, glottis or larynx can also develop after long-term use of ACE inhibitors and can be fatal. In this case, it is necessary to take emergency treatment measures, including, at a minimum (but not necessarily limited to): immediate subcutaneous injection of 0.3-0.5 ml of epinephrine (adrenaline) solution 1:1000 or slow intravenous administration of epinephrine 1 mg/ml (diluted according to instructions!) under careful monitoring of ECG and blood pressure. The patient should be hospitalized and monitored for at least 12-24 hours (until the corresponding symptoms disappear completely).

Hydrochlorothiazide

In patients with kidney disease, thiazides may worsen azotemia. In patients with impaired renal function, hydrochlorothiazide may accumulate. With the progression of renal failure, characterized by an increase in the level of total nitrogen in the blood without an increase in protein nitrogen, discontinuation of the drug Berlipril® plus should be considered.

Each patient when taking diuretics requires systematic monitoring of the concentration of electrolytes in the blood plasma.

Thiazides can cause water and electrolyte imbalance (hypokalemia, hyponatremia and hypochloremic alkalosis). Precursor symptoms are: dryness of the oral mucosa, thirst, weakness, stupor, drowsiness, anxiety, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, nausea or vomiting.

When using thiazide diuretics, signs of potassium deficiency may be detected, but simultaneous use of enalapril helps reduce hypokalemia caused by diuretics. The highest risk of developing hypokalemia exists in patients with liver cirrhosis, increased diuresis, as well as insufficient oral intake of table salt, simultaneous use of GCS or corticotropin (ACTH) (see section “Drug Interactions”).

In hot weather, dilutional hyponatremia may occur in patients with edema. Chloride deficiency is usually mild and does not require treatment.

Thiazides can reduce the excretion of calcium by the kidneys and cause a transient increase in serum calcium without visible disturbances in its metabolism. Severe hypercalcemia may be a sign of latent hyperparathyroidism. Thiazides should be discontinued before testing the function of the parathyroid glands (see section “Drug Interactions”).

Thiazides increase the excretion of magnesium by the kidneys (risk of developing hypomagnesemia).

When treated with thiazides, the development of impaired glucose tolerance is possible. Dosage adjustments of insulin or oral hypoglycemic agents may be necessary. When treated with thiazides, latent diabetes mellitus can manifest itself (see section “Drug interactions”).

A relationship has been established between an increase in the concentration of cholesterol and triglycerides and the use of thiazide diuretics. Treatment with thiazides may cause hyperuricemia and/or exacerbation of gout.

Hydrochlorothiazide may cause a positive result during doping control.

Enalapril/hydrochlorothiazide combination

The combination of ACE inhibitors with thiazide diuretics does not eliminate the risk of hypokalemia, so potassium levels in the blood should be regularly monitored.

Impact on the ability to drive vehicles and operate machinery

The effect of Berlipril® plus on the ability to drive vehicles and operate machinery has not been specifically studied, therefore, during treatment with Berlipril® plus, caution should be exercised when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Contraindications to the use of the drug Berlipril

Hypersensitivity to enalapril maleate, to other ACE inhibitors or to any of the components of the drug. A history of angioedema, which developed as a result of the use of ACE inhibitors, as well as hereditary idiopathic angioedema (Quincke's edema, swelling of the face, lips, tongue, larynx and/or vocal cords). Narrowing of the renal arteries (bilateral or solitary kidney); condition after kidney transplant. Narrowing of the heart valve openings or the presence of other obstructions to the outflow of blood from the left ventricle. Primary increase in aldosterone levels in the blood. Primary liver disease or dysfunction. During pregnancy and breastfeeding. There is no experience using the drug in children.

Side effects of the drug Berlipril

To assess the frequency of side effects, the following classification is used: very often: 1/10; often: 1/100, but ≤1/10; sometimes: 1/1000, but ≤1/100; rare: 1/10,000, but ≤1/1000; very rare: 1/10,000, including isolated cases. From the hematopoietic and lymphatic systems : sometimes - anemia (aplastic or hemolytic); rarely - neutropenia, decreased hemoglobin and hematocrit, thrombocytopenia, agranulocytosis, suppression of bone marrow function, pancytopenia, enlarged lymph nodes, autoimmune diseases. Metabolism : sometimes - hypoglycemia. From the side of the central nervous system : often - headache, depression; sometimes - confusion, drowsiness, insomnia, nervousness, paresthesia, dizziness; rarely - frightening dreams, sleep disturbance. From the side of the organ of vision : very often - blurred vision. From the cardiovascular system : very often - dizziness; often - hypotension (including orthostatic), syncope, myocardial infarction or cerebral stroke (as a result of a significant drop in blood pressure in patients with high risk factors), chest pain, cardiac arrhythmia, angina pectoris, tachycardia; sometimes - increased heartbeat; rarely - Raynaud's syndrome. From the respiratory system : very often - dry cough; often - dyspnea; sometimes - rhinorrhea, sore throat, hoarseness, bronchospasm/asthma; rarely - pulmonary infiltrates, rhinitis, allergic alveolitis/eosilophilic pneumonia. From the gastrointestinal tract : very often - nausea; often - diarrhea, abdominal pain, change in taste; sometimes - intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, lack of appetite, stomach irritation, dry mouth, peptic ulcer; rarely - stomatitis/aphthous ulcers, glossitis. From the liver and biliary system : rarely - liver failure, hepatocellular or cholestatic hepatitis (including hepatonecrosis), cholestasis (including jaundice). From the skin and subcutaneous fat : often - skin rash, angioedema (lips, face, vocal cords and/or larynx, and/or extremities); sometimes - sweating, itching, urticaria, alopecia; rarely - erythema multiforme, photosensitivity or other skin manifestations. Isolated cases of severe forms of skin reactions have been described - pemphigus, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, as well as toxic epidermal necrolysis. Skin reactions may be accompanied by fever, myalgia, myositis, arthralgia, arthritis, vasculitis, serositis, increased ESR, eosinophilia and leukocytosis and/or increased titers of antinuclear antibodies. In some cases, psoriasis-like skin changes, photosensitivity, increased sweating, skin hyperemia, alopecia, onycholysis, and increased symptoms of Raynaud's syndrome were noted. From the kidneys and urinary tract : sometimes - impaired renal function, renal failure, proteinuria; rarely - oliguria. From the reproductive system : sometimes - impotence; rarely - gynecomastia. General disorders : very often - asthenia; often - increased fatigue; sometimes - muscle cramps, hot flashes, tinnitus, discomfort, chills. Laboratory data : often - hyperkalemia, increased serum creatinine levels; sometimes - increased urea levels in the blood serum, hyponatremia; rarely - proteinuria, increased levels of liver enzymes, bilirubin levels in the blood serum.

Special instructions for the use of the drug Berlipril

For patients with a lack of fluid in the body (due to the use of diuretics, diarrhea, vomiting), the use of enalapril maleate should be carried out under strict medical supervision in order to prevent the development of hypotension. Particular caution is required when using it in patients with arterial or mitral stenosis, and hypertrophic cardiomyopathy. The drug is not used in patients in shock, with signs of circulatory failure and significant hemodynamic impairment due to an obstruction in the left ventricular outflow tract. There have been reports of the development of renal failure when using enalapril maleate in patients with severe heart failure, and renal dysfunction was reversible with timely diagnosis and treatment. Prescribing enalapril maleate to patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney poses a particular danger due to a possible sharp decrease in blood pressure or the development of renal failure, which can only be manifested by a slight increase in serum creatinine levels. Treatment of such patients should begin with low doses of the drug, carefully titrating the dose and monitoring renal function. Enalapril maleate is not recommended for use in patients who have recently undergone kidney transplantation due to lack of experience with its use. Enalapril maleate is discontinued if the patient develops jaundice or a significant increase in the level of liver enzymes due to the possible development of cholestasis and acute hepatonecrosis, sometimes with fatal outcome. Caution should be exercised when prescribing enalapril maleate to patients with collagenosis, when used simultaneously with immunosuppressants, allopurinol, procainamide due to the possible development of neutropenia/agranulocytosis, thrombocytopenia and anemia. When performing hemodialysis using polyacrylonitrile metalsulfonate membranes - high-flux membranes, for example "AN 69" and the simultaneous use of enalapril, there is a risk of developing anaphylactic reactions, so this combination should be avoided when using other membranes when performing hemodialysis. If it is necessary to perform lipidpheresis, as well as during desensitization for insect bites, life-threatening anaphylactic reactions may develop in the case of simultaneous use of an ACE inhibitor. In such a situation, it is necessary to temporarily replace the ACE inhibitor with an antihypertensive drug of another group. Patients with diabetes mellitus who are simultaneously taking oral hypoglycemic agents and enalapril maleate require careful monitoring of blood glucose levels. When using enalapril maleate, a dry cough may occur, which completely disappears after discontinuation of the drug. Before preparing for surgery, the anesthesiologist should be informed that the patient is using enalapril maleate. During treatment with enalapril, hyperkalemia may develop, especially in patients with heart and/or renal failure, so potassium levels in the blood should be periodically monitored. The drug Berlipril contains lactose, so it should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency in the body or glucose-galactose malabsorption syndrome. Use during pregnancy and lactation. Enalapril maleate should not be used in the first trimester of pregnancy and during breastfeeding. If pregnancy is planned or diagnosed, you should switch to treatment with alternative drugs as soon as possible. In the II–III trimester of pregnancy, enalapril maleate is contraindicated due to its toxic effect on the fetus (deterioration of renal function, oligohydramnios, delayed ossification of the skull bones) and infants (renal failure, hypotension, hyperkalemia). If a pregnant woman took enalapril maleate in the second and third trimesters of pregnancy, an ultrasound scan of the fetus is recommended to check renal function and the condition of the skull bones, and the child after birth requires careful monitoring to detect hypotension, oliguria and hyperkalemia. During treatment with the drug, breastfeeding should be stopped. Children. Due to the lack of sufficient information about the effectiveness and safety of the drug Berlipril for chronic heart failure and asymptomatic left ventricular dysfunction, the drug is recommended only for children with hypertension (arterial hypertension). This provision also applies to infants and children with a glomerular filtration rate ≤30 ml/min/1.73 m2. More detailed information regarding dosing of the drug in children is given in the APPLICATION section. The ability to influence the speed of reaction when driving vehicles or working with machinery : dizziness and general weakness are possible. At the beginning of treatment, when the drug is discontinued, as well as when taking alcohol at the same time, a negative effect on the ability to drive vehicles and work with potentially dangerous mechanisms is possible.

Instructions for use BERLIPRIL

Symptomatic hypotension

In uncomplicated arterial hypertension, hypotension is rare.

With a lack of fluid in the body, for example, due to diuretic therapy, a salt-depleted diet, dialysis, diarrhea or vomiting in patients suffering from arterial hypertension, symptomatic hypotension develops more often during treatment with Berlipril®. Symptomatic hypotension has been observed in patients with heart failure, with or without renal failure. This may particularly apply to patients with severe heart failure whose severity of the disease is reflected in high doses of loop diuretics, hyponatremia or limited renal function. Treatment of such patients - if a new dose of Berlipril® and/or a diuretic is to be selected - should be started under medical supervision, and this control should always be carefully continued in the future. The same applies to patients with coronary heart disease or cerebrovascular disease, in whom an excessive drop in blood pressure can lead to myocardial infarction or cerebral stroke.

If hypotension develops, the patient should be placed in a horizontal position and, if necessary, given an intravenous infusion of sodium chloride solution. A transient hypotonic reaction is not a contraindication for further treatment, which can usually be carried out without problems after normalization (by replenishing the circulating blood volume) of blood pressure.

In some patients with heart failure whose blood pressure is normal or low, Berlipril may further reduce systemic blood pressure. This far from unexpected effect is usually not a reason to discontinue the drug. If the decrease in blood pressure becomes symptomatic, i.e. will be accompanied by symptoms, it may be necessary to reduce the dose of Berlipril® and/or diuretic and/or discontinue Berlipril®.

Aortic or mitral stenosis/hypertrophic cardiomyopathy

As with other vasodilators, special caution is recommended when using ACEIs in patients who have left ventricular valve obstruction and outflow tract obstructions. In case of shock accompanied by circulatory failure and a hemodynamically obvious obstruction in the outflow tract, the use of these drugs should be avoided.

Renal dysfunction

In patients with limited renal function (creatinine clearance <80 ml/min), the initial dose of enalapril maleate should be adjusted depending on the patient's creatinine clearance. The maintenance dose is selected depending on the patient's response to treatment. In these patients, monitoring of serum potassium and creatinine is routine as part of their usual medical management.

In particular, renal failure has been reported in association with the use of enalapril maleate in patients with severe heart failure or underlying renal disease, including renal artery stenosis. With timely diagnosis and appropriate treatment, renal failure during therapy with enalapril maleate is usually reversible.

In some hypertensive patients who do not have kidney disease, the combination of enalapril maleate with a diuretic may result in an increase in serum urea and creatinine levels. In such cases, it may be necessary to reduce the dose of enalapril maleate and/or discontinue the diuretic. In this case, one must think about possible stenosis of the renal arteries as the cause of these phenomena.

Renovascular hypertension

In patients with bilateral renal artery stenosis or renal artery stenosis of a single functioning kidney, treatment with ACE inhibitors poses a particular risk of a drop in blood pressure or the development of kidney failure. Loss of renal function may occur, often resulting in only mild changes in serum creatinine. Treatment of these patients should be started with low doses and under strict medical supervision, carefully titrating the dose and monitoring 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 drug is not recommended.

Liver failure

During treatment with ACE inhibitors, a syndrome has occasionally been observed, starting with cholestatic jaundice and progressing to fulminant hepatic necrosis (sometimes fatal). The pathogenesis of this syndrome is unclear. In the case of patients who develop jaundice or a clear increase in liver enzyme levels during treatment with ACEIs, discontinuation of the ACEI and appropriate treatment are necessary.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and without special risk factors, neutropenia rarely occurs. In patients suffering from collagenosis with vascular involvement, as well as those being treated with immunosuppressants, allopurinol, procainamide, or in patients with several of these risk factors, enalapril maleate should be used with extreme caution, especially if there is limited renal function. Some of these patients developed severe infections that in some cases did not respond to intensive antibiotic therapy. If these patients are taking enalapril maleate, they are advised to have their white blood cell count regularly monitored and are encouraged to report any signs of any infection to their doctor.

Hypersensitivity/angioedema

Angioedema involving the face, extremities, lips, tongue, vocal folds and/or larynx has been reported in patients treated with ACE inhibitors, including Berlipril®. They may appear at any time during treatment. In these cases, Berlipril® should be discontinued immediately. To ensure complete reversal of symptoms before discharge from the hospital, the patient must be closely monitored. In cases where swelling of the face and lips was limited, symptoms in most cases reversed without treatment. However, antihistamines were beneficial in reducing symptoms.

Angioedema involving the larynx can be fatal. If the tongue, vocal folds or larynx are involved and there is a risk of airway obstruction, appropriate treatment should be started immediately (for example, subcutaneous injection of 0.3-0.5 ml of epinephrine [dilution 1:

• 1.000]) and/or take measures to ensure airway patency.

A higher incidence of angioedema has been reported with ACEI therapy in black patients compared with non-black patients.

Patients with a history of angioedema not caused by ACEIs may have an increased risk of developing it when taking ACEIs.

Anaphylactoid reactions during desensitization therapy directed against insect venoms

Rarely, life-threatening anaphylactic reactions have been observed during desensitization therapy directed against insect venom and simultaneous use of ACE inhibitors. If specific immunotherapy (desensitization) directed against insect venom is indicated, then ACE inhibitors must be temporarily replaced with other drugs for the treatment of arterial hypertension or heart failure.

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

During LDL apheresis with dextran sulfate, life-threatening anaphylactoid reactions have occurred rarely during concomitant use of ACE inhibitors. If LDL apheresis is indicated, then ACE inhibitors should be temporarily replaced with other drugs for the treatment of arterial hypertension or heart failure.

Patients undergoing hemodialysis treatment

Anaphylactoid reactions have been reported when using high-flux membranes (eg, "AN 69") during dialysis and concomitant use of ACE inhibitors. Therefore, in such patients it is necessary to use either a different membrane or an antihypertensive agent of a different class of substances.

Patients suffering from diabetes mellitus

In patients with diabetes mellitus who are being treated with oral hypoglycemic drugs or insulin, blood sugar levels should be carefully monitored during the first month of treatment with ACE inhibitors.

Cough

Cough has been reported in association with the use of ACEIs. The absence of sputum is typical, the cough is persistent and disappears after discontinuation of treatment. Cough caused by ACEI therapy should also be considered in the differential diagnosis of cough.

Surgery/anesthesia

In patients undergoing major surgery or anesthesia with drugs that lower blood pressure, enalapril maleate inhibits, in response to compensatory secretion of renin, the production of angiotensin II. If hypotension develops on this basis, it can be corrected by replenishing the volume of circulating blood.

Hyperkalemia

Increases in serum potassium concentrations have been observed in some patients treated with ACE inhibitors, including enalapril maleate. Risk factors for developing hyperkalemia are:

• renal failure, diabetes mellitus, simultaneous treatment with potassium-sparing diuretics, taking potassium supplements or potassium-containing salt substitutes, as well as simultaneous treatment with other drugs that can lead to an increase in serum potassium levels (eg, heparin). If the simultaneous use of the above substances is indicated, then regular monitoring of serum potassium levels is recommended.

Lithium

In general, lithium preparations are not recommended to be combined with enalapril maleate.

Use in pediatric patients

Regarding the use of Berlipril® in children over 6 years of age with arterial hypertension, data regarding efficacy and tolerability are limited. There is no information regarding other indications. There is limited information on pharmacokinetics for children older than 2 months. Berlipril® is recommended for children only with arterial hypertension.

Enalapril maleate is not recommended for newborns and pediatric patients whose glomerular filtration rate is <30 ml/min/1.73 m2, since there is no information about this.

Pregnancy and lactation

Enalapril maleate should not be used during pregnancy. If long-term therapy with enalapril maleate is necessary, patients planning pregnancy should switch to alternative treatment with antihypertensive drugs that have a proven safety profile during pregnancy.

If pregnancy is diagnosed, then enalapril maleate should be stopped immediately and, if necessary, treatment with alternative agents should be started.

Berlipril® is contraindicated in the 2nd and 3rd trimesters of pregnancy. Berlipril® is not recommended for use during lactation.

Ethnic differences

The severity of the hypotensive effect of enalapril maleate - as in the case of other ACEIs - in black patients, obviously, may be less than in non-black patients; this is presumably due to the fact that black patients with hypertension often have reduced plasma renin levels.

Other

This medicine contains lactose. Patients suffering from rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not take this drug.

Impact on the ability to drive vehicles and maintain machines

When actively participating in street traffic or servicing machines, be aware that dizziness or weakness may occur.

Drug interactions Berlipril

Potassium-sparing diuretics and potassium supplements. Enalapril maleate reduces potassium loss caused by diuretics. Its simultaneous use with spironolactone, triamterene, amiloride, potassium preparations or potassium-containing salt substitutes can lead to a significant increase in serum potassium levels. Diuretics. The use of diuretics in high doses prior to the initiation of enalapril maleate therapy may lead to the development of hypotension. The hypotensive effect can be reduced by stopping the diuretic, compensating for the lack of fluid and/or salts in the body, or starting Berlipril therapy using a low dose. Other antihypertensive drugs . Combination use with antihypertensive drugs of other groups, nitroglycerin and/or other nitrates or vasodilators may enhance the antihypertensive effect of enalapril maleate. Lithium. The simultaneous use of enalapril maleate and lithium preparations is not recommended due to increased lithium levels in the blood serum. If this combination is necessary, serum lithium levels should be carefully monitored. Tricyclic antidepressants/neuroleptics/anesthetics and anesthetics. The antihypertensive effect of enalapril maleate may be enhanced. NSAIDs. When used in combination, the antihypertensive effect of enalapril maleate may be weakened. There may be a synergistic effect on serum potassium levels, leading to hyperkalemia and reversible deterioration of renal function. AKI may develop, especially in patients with signs of dehydration or in the elderly. Sympathomimetics. The antihypertensive effect of enalapril maleate may be weakened. Hypoglycemic agents. It is possible to enhance the effect of insulin and oral hypoglycemic drugs when used simultaneously with enalapril maleate, up to the development of hypoglycemia. This is especially possible in the first weeks of combination therapy, as well as in patients with impaired renal function. With simultaneous consumption of alcohol, the effect of enalapril maleate is enhanced. Acetylsalicylic acid/thrombolytic agents/β-adrenergic receptor blockers . There are no contraindications for the combination of enalapril maleate with these drugs.

Berlipril® 10 (Berlipril® 10)

Symptomatic hypotension

Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. In patients with arterial hypertension taking Berlipril® 10, arterial hypotension develops more often against the background of dehydration, which occurs, for example, as a result of diuretic therapy, limiting the intake of table salt, in patients on dialysis, as well as in patients with diarrhea or vomiting. Symptomatic hypotension has been observed in patients with heart failure with or without renal failure. Hypotension most often develops in patients with more severe heart failure and associated use of high doses of loop diuretics, hyponatremia or impaired renal function. In these patients, the use of Berlipril® 10 should be started under medical supervision, which should also be careful when changing the dose of Berlipril® 10 and/or diuretic. Similarly, patients with coronary heart disease or cerebrovascular disease should be monitored, in whom an excessive decrease in blood pressure may lead to the development of myocardial infarction or stroke.

If arterial hypotension develops, the patient should be placed in a horizontal position and, if necessary, a 0.9% sodium chloride solution should be administered intravenously. Transient arterial hypotension when using the drug Berlipril®10 is not a contraindication to further use of the drug, which can be continued after replenishment of fluid volume and normalization of blood pressure.

In some patients with heart failure with normal or low blood pressure, Berlipril® 10 may cause an additional decrease in blood pressure. This reaction to taking the drug is expected and is not a reason to stop treatment. In cases where arterial hypotension becomes clinically significant, the dose should be reduced and/or discontinued use of the diuretic and/or Berlipril® 10.

Aortic or mitral stenosis/hypertrophic obstructive cardiomyopathy

As with all vasodilators, ACE inhibitors should be prescribed with caution to patients with left ventricular valvular stenosis and left ventricular outflow tract obstruction and should be avoided in cases of cardiogenic shock and hemodynamically significant obstruction.

Renal dysfunction

In cases of impaired renal function (creatinine clearance <80 ml/min), careful monitoring of potassium and creatinine levels in the blood plasma is necessary. In patients with impaired renal function, it may be necessary to reduce the dose of the drug and/or increase the intervals between doses. The development of renal failure has been reported when enalapril was prescribed, mainly in patients with severe heart failure or kidney disease, including renal artery stenosis. With timely diagnosis and appropriate treatment, renal failure during enalapril therapy is usually reversible.

In some patients initially without signs of renal pathology, an increase in the concentrations of urea and creatinine in the blood plasma was noted, especially with the simultaneous use of diuretics. A dose reduction of enalapril and/or discontinuation of the diuretic may be necessary. In this situation, it is necessary to exclude the presence of renal artery stenosis.

Renovascular hypertension

There is an increased risk of hypotension and renal failure when using ACE inhibitors in patients with bilateral renal artery stenosis or arterial stenosis of a solitary kidney. Even a small change in plasma creatinine may be a sign of decreased kidney function. The use of Berlipril® 10 in patients in this group should be started under close medical supervision, with low doses, the dose should be titrated carefully, and renal function should be monitored.

Kidney transplant

Since there is no experience with the use of Berlipril® 10 in patients who have recently undergone kidney transplantation, the use of Berlipril® 10 in patients in this category is not recommended.

Liver failure

In rare cases, the use of ACE inhibitors has been associated with the development of a syndrome starting with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome has not been studied. If jaundice appears or a significant increase in the activity of liver enzymes during the use of ACE inhibitors, the use of the drug should be discontinued, and the patient should be under appropriate medical supervision.

Hypersensitivity/Angioedema

There have been reports of angioedema (Quincke's edema) of the face, extremities, lips, tongue, vocal folds and/or larynx in patients taking ACE inhibitors, including the drug Berlipril®10, during different periods of treatment. In very rare cases, the development of intestinal edema has been reported. In such cases, treatment with Berlipril® 10 should be stopped immediately, and proper medical supervision should be carried out until the corresponding symptoms disappear completely.

Even in cases where only difficulty swallowing occurs without difficulty breathing, patients should be under medical supervision for a long time, since therapy with antihistamines and corticosteroids may not be sufficient. In very rare cases, angioedema of the larynx or tongue has been fatal. Swelling of the tongue, vocal folds and/or larynx can lead to airway obstruction (especially in patients who have undergone airway surgery), appropriate therapy including subcutaneous injection of 0.1% epinephrine solution (0.3-0.5 ml) and /or measures to ensure airway patency should be carried out as soon as possible.

In patients of the Negroid race, the incidence of angioedema when using ACE inhibitors is higher than in representatives of other races.

Patients with a history of angioedema not associated with the use of ACE inhibitors have an increased risk of its occurrence when using ACE inhibitors.

In rare cases, intestinal edema (angioedema of the intestine) develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal levels of C1-esterase. Diagnosis is made using abdominal computed tomography, ultrasound, or surgery. Symptoms disappeared after stopping the ACE inhibitors. The possibility of developing intestinal edema must be taken into account when carrying out the differential diagnosis of abdominal pain in patients taking ACE inhibitors.

Anaphylactoid reactions during desensitization with an allergen from Hymenoptera venom

There are reports of rare development of life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during the procedure of desensitization with hymenoptera venom (heminoptera). Such reactions can be avoided if the use of the ACE inhibitor is temporarily discontinued before desensitization begins. The use of ACE inhibitors should be avoided in patients receiving bee venom immunotherapy.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions have been observed in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate. If LDL apheresis is used, ACE inhibitors should be temporarily replaced with drugs from other pharmacotherapeutic groups for the treatment of arterial hypertension or heart failure.

Patients undergoing hemodialysis using high permeability membranes

in patients undergoing dialysis using high-permeability membranes (eg, AN69®) while receiving ACE inhibitors. Therefore, in this category of patients, it is recommended either to use a different type of dialysis membrane or to use antihypertensive drugs from other pharmacotherapeutic groups.

Neutropenia/agranulocytosis

Neutropenia, agranulocytosis, thrombocytopenia and anemia may develop during therapy with ACE inhibitors. With normal renal function and the absence of other complicating factors, neutropenia rarely occurs. Enalapril should be used with extreme caution in patients with collagen disease, those on immunosuppressive therapy, those taking allopurinol or procainamide, or a combination of these complicating factors, especially in the presence of impaired renal function. Some patients in this category developed serious infectious diseases, which in some cases did not respond to intensive antibiotic therapy. When using Berlipril® 10 in such patients, regular monitoring of the white blood cell count is recommended, and during treatment, all patients should be instructed to report to the doctor any signs of a possible infection.

Cough

Cough has been reported during treatment with ACE inhibitors. Usually the cough is non-productive and persistent and stops after discontinuation of the drug. The development of a dry cough due to therapy with ACE inhibitors should be taken into account in the differential diagnosis of cough.

Surgical interventions/General anesthesia

In patients undergoing surgery and/or general anesthesia with the use of blood pressure-lowering drugs, enalapril may block the formation of angiotensin II under the influence of compensatory renin release. If it is assumed that arterial hypotension develops by this mechanism, it can be corrected by increasing the volume of blood volume. Before surgical interventions (including dental procedures), it is necessary to warn the surgeon/anesthesiologist about the use of Berlipril® 10.

Diabetes

Patients with diabetes mellitus taking oral hypoglycemic agents and/or insulin concomitantly with Berlipril® 10 should be instructed to carefully monitor plasma glucose levels to detect hypoglycemia, especially during the first month of concomitant use with Berlipril® 10.

Hyperkalemia

In some patients taking ACE inhibitors, incl. enalapril, an increase in potassium levels in the blood plasma was observed. Risk factors for the development of hyperkalemia include: renal failure and deterioration of renal function, age over 70 years, diabetes mellitus, hypoaldosteronism, intercurrent diseases and conditions, including dehydration, acute cardiac decompensation, metabolic acidosis, simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone , triamterene or amiloride), potassium-containing dietary supplements or potassium-containing table salt substitutes, or other drugs that increase plasma potassium levels (for example, heparin, co-trimoxazole (trimethoprim + sulfamethoxazole)), use of potassium-containing dietary supplements, potassium-sparing diuretics or potassium-containing diuretics substitutes for table salt, especially in patients with impaired renal function. Hyperkalemia can cause serious, sometimes fatal, heart rhythm problems. If necessary, simultaneous use of the drug Berlipril®10 and the drugs listed above should be exercised with caution. It is recommended to regularly monitor the potassium content in the blood plasma.

Lithium preparations

The simultaneous use of lithium and enalapril is not recommended (see section “Interaction with other drugs”).

Double blockade of the RAAS

There is evidence that the simultaneous use of ACE inhibitors with angiotensin II receptor antagonists or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure).

The simultaneous use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal failure (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

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

In cases where the simultaneous use of two drugs acting on the RAAS is necessary, their use should be carried out under the supervision of a physician and with regular monitoring of renal function, blood pressure and electrolyte levels in the blood plasma.

Ethnic differences

Like other ACE inhibitors, enalapril may be less effective in lowering blood pressure in blacks compared to other races, possibly due to the higher prevalence of low-renin status in hypertensive patients in this population.

Use in elderly patients

Clinical studies of the efficacy and safety of enalapril were similar in older and younger patients with hypertension.

Alcohol

During the treatment period it is not recommended to drink alcoholic beverages. Alcohol enhances the antihypertensive effect of ACE inhibitors.

Galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome

The drug Berlipril® 10 contains lactose, therefore its use in patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome is contraindicated.

Overdose of the drug Berlipril

There is only limited information regarding overdose in humans. The most likely sign of overdose is severe arterial hypotension, occurring approximately 6 hours after taking the tablets, and simultaneous blockade of the renin-angiotensin-aldosterone system with the development of a stuporous state. With an overdose of ACE inhibitors, circulatory failure, loss of electrolytes, renal failure, hyperventilation, tachycardia, increased heart rate, bradycardia, dizziness, fear and cough may develop. Treatment: IV infusion of sodium chloride solution is recommended. If there is a sharp decrease in blood pressure, the patient must be placed in a horizontal position with the lower limbs raised. Infusion of angiotensin II and/or catecholamines is advisable. If the tablets have been taken recently, the stomach should be rinsed and sorbents should be used. Enalaprilat is removed by dialysis. For resistant bradycardia, the use of an artificial pacemaker is indicated. It is necessary to constantly monitor the level of electrolytes and creatinine in the blood serum. Treatment of angioedema . The development of angioedema of the face, lips, tongue, larynx, and extremities can occur at any time during therapy. In these cases, the drug should be discontinued and the patient observed. If swelling on the face and lips is limited, the use of antihistamines is necessary. Swelling of the tongue, glottis and larynx can be life-threatening and requires emergency treatment, such as subcutaneous injection of 0.3–0.5 mg epinephrine (1:1000 dilution) and/or airway management .