Berlipril 5, tablets 5 mg 30 pcs

Enalapril maleate is a hypotensive agent from the group of ACE inhibitors. Enalapril maleate is a salt of maleic acid and enalapril, a derivative of L-alanine and L-proline. Enalapril is a prodrug: its hydrolysis produces enalaprilate, which directly inhibits ACE.

The mechanism of its action is related to the reduction of angiotensin II formation from angiotensin I, the reduction of which leads to a direct reduction of aldosterone release. At the same time, it decreases RPS, systolic and diastolic BP, and post- and preload on myocardium.

Enalapril dilates the arteries more than the veins, and there is no reflex increase in heart rate. It reduces bradykinin degradation and increases prostaglandin synthesis.

Enalapril hypotensive effect is more pronounced at high plasma renin concentration than at normal or reduced. Decrease of BP within therapeutic limits has no effect on cerebral blood flow, blood flow in cerebral vessels is maintained at a sufficient level even against the background of decreased blood pressure. Enalapril improves coronary and renal blood flow.

On long-term use, enalapril reduces left ventricular myocardial hypertrophy and arterial wall myocytes resistance, prevents the progression of heart failure and slows the development of left ventricular dilatation. It improves the blood supply to the ischemic myocardium. It has a slightly pronounced diuretic effect.

The time of the onset of hypotensive effect when taken orally is 1 hour, reaches a maximum after 4-6 hours and lasts up to 24 hours. In some patients, therapy with enalapril for several weeks is necessary to achieve the optimal level of BP. In chronic heart failure significant clinical effect is observed with long-term treatment with enalapril – 6 months or more.

Indications

Arterial hypertension (including renovascular).
Chronic heart failure.
Prevention of the development of clinically significant heart failure in patients with asymptomatic left ventricular dysfunction.

Pharmacological effect

Enalapril maleate is an antihypertensive drug from the group of ACE inhibitors. Enalapril maleate is a salt of maleic acid and enalapril, a derivative of L-alanine and L-proline. Enalapril is a prodrug: as a result of its hydrolysis, enalaprilat is formed, which directly inhibits ACE.

The mechanism of its action is associated with a decrease in the formation of angiotensin II from angiotensin I, a decrease in the content of which leads to a direct decrease in the release of aldosterone. At the same time, peripheral vascular resistance, systolic and diastolic blood pressure, post- and preload on the myocardium are reduced.

Enalapril dilates arteries to a greater extent than veins, while no reflex increase in heart rate is observed. Reduces the degradation of bradykinin, increases the synthesis of prostaglandins.

The hypotensive effect of enalapril is more pronounced at high plasma renin concentrations than at normal or reduced levels. A decrease in blood pressure within therapeutic limits does not affect cerebral circulation; blood flow in the vessels of the brain is maintained at a sufficient level even against the background of reduced blood pressure. Enalapril improves coronary and renal blood flow.

With long-term use, enalapril reduces hypertrophy of the left ventricular myocardium and myocytes of the walls of resistive arteries, prevents the progression of heart failure and slows down the development of left ventricular dilatation. Improves blood supply to ischemic myocardium. It has a weak diuretic effect.

The onset of the hypotensive effect when taken orally is 1 hour, reaches a maximum after 4-6 hours and lasts up to 24 hours. In some patients, enalapril therapy is necessary for several weeks to achieve an optimal blood pressure level. In chronic heart failure, a significant clinical effect is observed with long-term treatment with enalapril – 6 months or more.

Special instructions

Caution must be exercised in patients with reduced blood volume (including when used simultaneously with diuretics, in conditions of limited salt intake, hemodialysis, diarrhea, vomiting), in whom a sudden and pronounced decrease in blood pressure may develop in response to the use of an ACE inhibitor.

In patients with mild chronic heart failure, with or without chronic renal failure, symptomatic hypotension is usually not observed. The development of arterial hypotension is most likely in patients with more severe chronic heart failure due to the use of high doses of diuretics, hyponatremia, or functional renal failure.

In these patients, treatment should begin under the supervision of a physician until the optimal dose adjustment of Berlipril® and/or diuretic. Similar tactics can be applied to patients with coronary artery disease and cerebrovascular diseases, in whom an excessive drop in blood pressure can lead to myocardial infarction or cerebral stroke. If severe arterial hypotension develops, the patient should be placed in a horizontal position and, if necessary, an IV infusion of saline should be started.

Transient arterial hypotension is not a contraindication for continuing treatment with enalapril after stabilization of blood pressure. In case of a repeated pronounced decrease in blood pressure, the dose should be reduced or the drug discontinued. Before starting and during treatment with ACE inhibitors, dynamic monitoring of blood pressure, some biochemical and electrolyte blood parameters (concentration of hemoglobin, potassium ions, sodium ions, creatinine, urea, liver enzymes in the blood serum), as well as urine for the presence of protein is necessary.

As with all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular hypertrophy and valvular obstruction and should be avoided in cases of cardiogenic shock and hemodynamically significant obstruction.

In cases of impaired renal function (creatinine clearance <80 ml/min), careful monitoring of serum potassium and creatinine concentrations is necessary. In patients with renal failure, it may be necessary to reduce the dose and/or frequency of dosing.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, increases in serum urea and creatinine concentrations were observed. The changes were usually reversible and returned to normal after cessation of treatment.

In some patients who did not have renal disease before treatment, slight and transient increases in serum urea and creatinine concentrations were observed when enalapril was used concomitantly with diuretics. In such cases, it may be necessary to reduce the dose and/or discontinue enalapril and/or diuretic.

There is an increased risk of developing arterial hypotension and renal failure in patients with bilateral renal artery stenosis or arterial stenosis of a solitary kidney who are treated with ACE inhibitors. Only moderate changes in serum creatinine concentration may indicate a decrease in renal function. In these patients, treatment should begin with small doses under close medical supervision, precise gradual selection of the individual dose and monitoring of serum creatinine concentrations.

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.

The use of Berlipril® in patients with liver failure usually does not require dose adjustment. Rarely, taking ACE inhibitors is associated with a syndrome ranging from the development of cholestatic jaundice to the development of fulminant liver necrosis. If symptoms of jaundice or increased liver enzyme activity occur in patients taking ACE inhibitors, discontinue drug therapy and conduct appropriate evaluation.

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

Neutropenia, agranulocytosis, thrombocytopenia, and anemia can develop during therapy with ACE inhibitors. With normal renal function and the absence of other complications, neutropenia rarely occurs.

ACE inhibitors are prescribed only in emergency cases when the patient has systemic connective tissue diseases, during immunosuppressive therapy, in cases of simultaneous use of allopurinol or procainamide, as well as in a combination of all of these factors, especially against the background of existing renal failure.

Some of these patients developed severe infections, which in some cases did not respond to intensive antibiotic therapy. If enalapril is used in such patients, periodic monitoring of the white blood cell count is recommended, and patients should be appropriately instructed to promptly report any signs of infection to the physician.

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

There have been reports of angioedema (Quincke’s edema) of the face, extremities, lips, tongue, glottis and/or larynx in patients receiving ACE inhibitors, incl. Berlipril®, during different periods of treatment. In such cases, treatment with Berlipril 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. Angioedema of the larynx or tongue can be fatal. Swelling of the tongue, vocal folds or larynx can lead to airway obstruction; appropriate therapy, including subcutaneous injection of 0.1% epinephrine solution (0.3-0.5 ml) and/or measures to ensure airway conduction, 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. Like other ACE inhibitors, enalapril appears to be less effective in lowering blood pressure in black patients than in others, possibly due to the high prevalence of low renin in this population of patients with hypertension.

During the treatment period, it is not recommended to drink alcoholic beverages, because alcohol enhances the hypotensive effect of the drug.

In patients undergoing surgery or general anesthesia with the use of drugs that lower blood pressure, 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®.

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

Anaphylactoid reactions have been observed in patients undergoing dialysis using high-flow membranes (eg, AN69®) while receiving ACE inhibitors. Therefore, for such patients, it is recommended either to use a different type of dialysis membrane or to use a different group of antihypertensive drugs.

In patients with diabetes mellitus taking oral hypoglycemic agents or insulin, blood glucose concentrations should be carefully monitored during the first month of treatment with enalapril.

In some patients taking ACE inhibitors, incl. enalapril, there is an increase in the concentration of potassium ions in the blood serum. The risk group for developing hyperkalemia includes patients suffering from renal failure or diabetes mellitus, taking potassium-sparing diuretics or potassium-containing salt substitutes, or other drugs that increase the concentration of potassium ions in the blood serum (for example, heparin). If the use of the above medications during treatment with Berlipril® is necessary, regular monitoring of the concentration of potassium ions in the blood serum is recommended. Like other ACE inhibitors, enalapril may be less effective in lowering blood pressure in blacks compared to other races, possibly due to lower renin levels in hypertensive patients in this population.

Sudden cessation of treatment with enalapril does not lead to the development of withdrawal syndrome (a sharp rise in blood pressure).

Impact on the ability to drive vehicles and operate machinery

Caution must be exercised when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions (dizziness may occur due to a sharp decrease in blood pressure, especially after taking the initial dose of enalapril in patients taking diuretics).

Active ingredient

Enalapril

Composition

Active ingredient:

enalapril maleate – 5 mg.

Excipients:

lactose monohydrate – 171 mg,

magnesium hydroxycarbonate – 25 mg,

gelatin – 6 mg,

colloidal silicon dioxide – 3 mg,

sodium carboxymethyl starch – 8 mg,

magnesium stearate – 2 mg.

Pregnancy

The use of Berlipril® during pregnancy is contraindicated.

Patients planning pregnancy should be switched to an alternative treatment with a proven safety profile for use in pregnant women. If pregnancy is confirmed, use of Berlipril should be discontinued immediately and, if necessary, alternative therapy should be initiated.

The use of ACE inhibitors in the second and third trimesters of pregnancy was accompanied by negative effects on the fetus, including the development of arterial hypotension, renal failure, hyperkalemia and/or hypoplasia of the skull bones in the newborn. Oligohydramnios may develop, apparently due to decreased fetal renal function.

This complication can lead to contracture of the limbs, deformation of the bones of the skull, including its facial part, and hypoplasia of the lungs. When using the drug Berlipril®, it is necessary to inform the patient about the potential risk to the fetus.

If it is impossible to discontinue the drug Berlipril® during pregnancy, careful monitoring of newborns whose mothers took Berlipril® is necessary to identify a possible decrease in blood pressure, oliguria and hyperkalemia, monitor the state of renal function, as well as the skull bones of the newborn using ultrasound.

Enalapril and enalaprilat are excreted into breast milk in trace amounts, but their safety has not been studied. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Enalapril can be removed from the neonatal circulation using peritoneal dialysis; theoretically – through exchange blood transfusion.

Contraindications

A history of angioedema while taking ACE inhibitors.
Hereditary or idiopathic angioedema.
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.
Pregnancy.
Breastfeeding period.
Age up to 18 years (efficacy and safety have not been established).
Increased sensitivity to enalapril and other ACE inhibitors or components of the drug.

With caution: primary hyperaldosteronism, bilateral renal artery stenosis, stenosis of the artery of a single kidney, condition after kidney transplantation, hyperkalemia, aortic stenosis, mitral stenosis (with impaired hemodynamic parameters), idiopathic hypertrophic subaortic stenosis, systemic connective tissue diseases, coronary artery disease, cerebrovascular diseases, diabetes mellitus, renal failure (CC < 80 mg/min), liver failure, in patients on a salt-restricted diet or on hemodialysis, when used simultaneously with immunosuppressants and saluretics, in patients over 65 years of age, when bone marrow hematopoiesis is suppressed; conditions accompanied by a decrease in blood volume, incl. diarrhea, vomiting.

Side Effects

Possible side effects when using the drug Berlipril® are listed below in descending frequency of occurrence:

Very common (≥1/10).
Often (≥1/100, <1/10). Uncommon (≥1/1000, <1/100). Rarely (≥1/10,000, <1/1000). Very rare (<1/10,000), including isolated reports.

From the hematopoietic system: infrequently – anemia (including aplastic and hemolytic); rarely – neutropenia, decreased concentration of hemoglobin and hematocrit in the blood serum, eosinophilia, thrombocytopenia, enlarged lymph nodes, pancytopenia, agranulocytosis, inhibition of bone marrow hematopoiesis, autoimmune diseases.

From the side of metabolism and nutrition: infrequently – hypoglycemia.

From the nervous system: often – headache, depression; infrequently – confusion, insomnia, increased excitability, paresthesia, vertigo, tinnitus; rarely – changes in the nature of dreams, sleep disorders.

From the side of the organ of vision: rarely – blurred vision.

From the cardiovascular system: very often – dizziness; often – hypotension (including orthostatic hypotension), syncope, chest pain, cardiac arrhythmias, angina pectoris; uncommon – orthostatic hypotension, palpitations, myocardial infarction or cerebral stroke, possibly caused by a sharp drop in blood pressure in high-risk patients; rarely – Raynaud’s syndrome.

From the respiratory system: very often – unproductive dry cough; uncommon – rhinorrhea, sore throat and hoarseness, bronchospasm/bronchial asthma; rarely – shortness of breath, rhinitis, pulmonary infiltrates, allergic alveolitis/eosinophilic pneumonia.

From the digestive system: very often – nausea; often – diarrhea, abdominal pain, changes in taste perception; uncommon – intestinal obstruction, pancreatitis, lack of appetite, dry oral mucosa, changes in taste perception, peptic ulcer; rarely – stomatitis/aphthous ulcers, glossitis; very rarely – angioedema of the intestine.

From the liver and biliary tract: rarely – liver failure, hepatitis (hepatocellular or cholestatic), hepatic necrosis, cholestasis (including jaundice).

From the skin and subcutaneous tissues: often – skin rash, urticaria, hypersensitivity reactions/angioedema of the face, limbs, lips, tongue, vocal folds and/or larynx; uncommon – increased sweating, itching, urticaria, alopecia; rarely – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A symptom complex has been reported that may be accompanied by some and/or all of the following side effects: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, increased antinuclear antibody titer, increased erythrocyte sedimentation rate, eosinophilia and leukocytosis. Skin rash, photosensitivity, or other skin manifestations may occur.

From the kidneys and urinary tract: infrequently – impaired renal function, proteinuria, renal failure; rarely – oliguria.

From the genital organs and mammary glands: infrequently – erectile dysfunction; rarely – gynecomastia.

General disorders: very often – asthenia; often – fatigue; uncommon – muscle cramps, flushing of the face, tinnitus, fever.

Laboratory indicators: often – hyperkalemia, increased serum creatinine concentration; uncommon – increased serum urea concentration, hyponatremia; rarely – increased activity of liver enzymes, hyperbilirubinemia.

In rare cases, with the simultaneous use of ACE inhibitors (including enalapril) and intravenous administration of gold preparations (sodium aurothiomalate), a symptom complex has been described, including redness of the facial skin, nausea, vomiting and arterial hypotension.

Interaction

When used simultaneously with NSAIDs, including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), the hypotensive effect of ACE inhibitors, incl. enalapril. In some patients with impaired renal function, concomitant use of NSAIDs and ACE inhibitors may lead to a further deterioration of renal function. These changes are usually reversible.

The use of potassium-containing dietary supplements, potassium-containing salt substitutes and/or the use of potassium-sparing diuretics, as well as heparin, can lead to a significant increase in the concentration of potassium ions in the blood serum, especially in patients with impaired renal function and/or diabetes mellitus. If it is necessary to use the drugs listed above simultaneously with enalapril, regular monitoring of the concentration of potassium ions in the blood serum should be carried out.

With the simultaneous use of Berlipril® and thiazide diuretics, hypokalemia caused by taking the latter is usually reduced by the action of enalapril.

Previous therapy with high doses of diuretics may lead to hypovolemia and the risk of hypotension when initiating enalapril therapy. The excessive hypotensive effect of enalapril can be reduced either by discontinuing the diuretic, or by increasing the volume of blood volume or consuming table salt, as well as by starting treatment with enalapril from a low dose. Concomitant use of thiazide diuretics and ACE inhibitors may lead to hypovolemia and thus increase the risk of arterial hypotension.

The simultaneous use of Berlipril® and lithium preparations is not recommended due to the risk of developing lithium intoxication. If it is necessary to use this combination, careful monitoring of the concentration of lithium in the blood serum is necessary.

Concomitant use with antipyretics and analgesics may reduce the effectiveness of the drug.

Enalapril weakens the effect of drugs containing theophylline.

The hypotensive effect of enalapril is enhanced by diuretics, as well as antihypertensive drugs of other groups, incl. beta-blockers, methyldopa, nitroglycerin and other nitrates, slow calcium channel blockers, hydralazine, prazosin, as well as some anesthesia drugs, ethanol, tricyclic antidepressants, antipsychotics.

ACE inhibitors can enhance the hematotoxicity of immunosuppressants, allopurinol, and cytostatics.

Drugs that suppress bone marrow hematopoiesis increase the risk of developing neutropenia and agranulocytosis.

ACE inhibitors increase the bioavailability of digoxin, increasing its concentration in the blood. In this regard, when prescribing ACE inhibitors and cardiac glycosides simultaneously, the dose of the latter should be slightly reduced to avoid the development of undesirable effects or the effect of a relative overdose.

Antipsychotics may enhance the hypotensive effect of enalapril.

Sympathomimetics may reduce the hypotensive effect of enalapril.

The simultaneous use of antacids and adsorbents can lead to a decrease in the bioavailability of ACE inhibitors by almost 50%, as well as to a slowdown and weakening of their hypotensive effect, so an interval between doses of at least 2 hours should be observed.

Enalapril can be used simultaneously with acetylsalicylic acid (in cardiac doses less than 300 mg/day), thrombolytics and beta-blockers.

Epidemiological studies have shown that the simultaneous use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may further reduce blood glucose concentrations, leading to the development of hypoglycemia. This phenomenon is most often observed during the first weeks of simultaneous use of the above drugs, as well as in patients with renal failure. In patients with diabetes mellitus receiving oral hypoglycemic agents and/or insulin, regular monitoring of blood glucose concentrations is necessary, especially careful during the first month of simultaneous use with ACE inhibitors.

Overdose

Symptoms: approximately 6 hours after ingestion – a pronounced decrease in blood pressure, up to the development of collapse, myocardial infarction, acute cerebrovascular accident or thromboembolic complications, water and electrolyte imbalance, renal failure, increased breathing, tachycardia, palpitations, bradycardia, dizziness, anxiety, fear, muscle cramps, cough, stupor.

Enalaprilat plasma concentrations 100-200 times higher than after therapeutic doses were observed after oral administration of 300 mg and 440 mg of enalapril maleate, respectively.

Treatment: use of the drug should be stopped immediately; therapeutic measures should be aimed at eliminating enalapril and enalaprilat and correcting arterial hypotension.

The patient is transferred to a horizontal position with a low headboard. In mild cases, gastric lavage and activated charcoal are indicated; in more severe cases, intravenous infusion of saline, plasma substitutes, and, if necessary, administration of angiotensin II or catecholamines; hemodialysis (enalaprilat excretion rate – 62 ml/min). In patients with bradycardia resistant to therapy, pacemaker placement is indicated.

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

3 years

Manufacturer

Berlin-Chemie AG, Germany