Berlipril^® 5 (Tablets) Instructions for Use

ATC Code

C09AA02 (Enalapril)

Active Substance

Enalapril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin-converting enzyme (ACE) inhibitors

Pharmacological Action

Enalapril maleate is an antihypertensive 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: as a result of its hydrolysis, enalaprilat is formed, which directly inhibits ACE. Its mechanism of 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 aldosterone secretion. This reduces total peripheral vascular resistance, systolic and diastolic blood pressure, and post- and preload on the myocardium.

Enalapril dilates arteries to a greater extent than veins, with no reflex increase in heart rate noted. It reduces the degradation of bradykinin and increases the synthesis of prostaglandins.

The antihypertensive effect of enalapril is more pronounced with a high plasma renin concentration than with a normal or reduced one. A decrease in blood pressure within therapeutic limits does not affect cerebral circulation; blood flow in the cerebral vessels 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-type arteries, prevents the progression of heart failure, and slows the development of left ventricular dilation. It improves blood supply to the ischemic myocardium. It has a weakly pronounced diuretic effect.

The onset of the antihypertensive effect after oral administration 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 blood pressure level. In chronic heart failure, a significant clinical effect is observed with long-term treatment with enalapril – 6 months or more.

Pharmacokinetics

When taken orally, 60% of the drug is absorbed. Food intake does not affect the absorption of enalapril.

Plasma protein binding is 50%. C_max in blood plasma is reached after 1 hour for enalapril, and after 3-4 hours for enalaprilat. Enalaprilat easily passes through histohematic barriers, excluding the blood-brain barrier; a small amount penetrates the placental barrier and into breast milk.

Enalapril is rapidly metabolized in the liver to form the active metabolite enalaprilat, which is a more potent ACE inhibitor than Enalapril. The bioavailability of the drug is 40%.

T_1/2 of enalaprilat is about 11 hours. It is excreted from the body mainly by the kidneys – 60% (20% as enalapril and 40% as enalaprilat), through the intestine – 33% (6% as enalapril and 27% as enalaprilat).

It is removed by hemodialysis (rate 62 ml/min) and peritoneal dialysis.

Indications

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

ICD codes

Dosage Regimen

Tablets

Orally. To select the appropriate dosing regimen, it is advisable to use the most suitable dosage of the drug – 5 mg, 10 mg, or 20 mg. The drug is used both as monotherapy and in combination with other antihypertensive agents.

Arterial hypertension

The initial dose ranges from 5 mg to 20 mg of enalapril maleate once a day, depending on the severity of arterial hypertension.

For mild arterial hypertension, the recommended maintenance dose is 5-10 mg of enalapril maleate once a day; for moderate arterial hypertension – 10-20 mg of enalapril maleate once a day.

For more severe arterial hypertension, the recommended maintenance daily dose of enalapril maleate is 20 mg once a day. The dose is selected individually for each patient but should not exceed 40 mg/day. The maximum daily dose of the drug is 40 mg (in 1 or 2 doses).

Renovascular hypertension

Initial dose – 5 mg of enalapril maleate once a day. After taking the first dose of the drug, careful monitoring of blood pressure is necessary. Then the dose is selected according to the therapeutic effect. The maximum daily dose is 20 mg once a day with daily use. Subsequently, careful observation of the patient is necessary, including mandatory monitoring of renal function.

For patients simultaneously taking diuretics, it is necessary to temporarily discontinue diuretic therapy 2-3 days before prescribing the drug. If this is not possible, the initial dose of enalapril maleate should be no more than 5 mg/day. The drug should be prescribed with caution, as such patients may have fluid deficiency and/or hyponatremia; subsequently, the dosage is selected individually.

Chronic heart failure and asymptomatic left ventricular dysfunction

For chronic heart failure and asymptomatic left ventricular dysfunction, the drug is used as part of combination therapy simultaneously with diuretics and, if necessary, cardiac glycosides or beta-blockers. The initial minimum dose of the drug is 2.5 mg once a day; treatment should be started under careful medical supervision. The increase in the dose of enalapril maleate should be gradual, usually by 2.5-5 mg every 3-4 days according to the individual patient’s response, up to the maximum tolerated doses, but not higher than 40 mg/day for chronic heart failure and 20 mg/day for asymptomatic left ventricular dysfunction, in 1 or 2 doses. The selection of the maintenance dose is carried out over 2-4 weeks.

Treatment with enalapril is long-term; for chronic heart failure and asymptomatic left ventricular dysfunction, the effect can be fully assessed no earlier than 6 months after the start of therapy. In cases of an excessive decrease in blood pressure, the maintenance dose of the drug is gradually reduced.

In elderly patients, a more pronounced antihypertensive effect and a prolongation of the drug’s duration of action are more often observed, which is associated with a decrease in the rate of enalapril excretion, so the recommended initial dose of enalapril maleate for elderly patients is no more than 2.5 mg. The maintenance daily dose should be selected depending on the serum creatinine concentration.

Adverse Reactions

Possible adverse effects when using the drug are listed below in descending order of frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including individual reports.

From the hematopoietic system uncommon – anemia (including aplastic and hemolytic); rare – neutropenia, decreased hemoglobin concentration and hematocrit in serum, eosinophilia, thrombocytopenia, lymph node enlargement, pancytopenia, agranulocytosis, bone marrow depression, autoimmune diseases.

From metabolism and nutrition: uncommon – hypoglycemia.

From the nervous system: common – headache, depression; uncommon – confusion, insomnia, increased excitability, paresthesia, vertigo, tinnitus; rare – change in dream character, sleep disorders.

From the organ of vision rare – blurred vision.

From the cardiovascular system: very common – dizziness; common – hypotension (including orthostatic hypotension), syncope, chest pain, heart rhythm disorders, angina pectoris; uncommon – orthostatic hypotension, palpitation sensation, myocardial infarction or cerebral stroke, possibly due to a sharp drop in blood pressure in high-risk patients; rare – Raynaud’s syndrome.

From the respiratory system: very common – non-productive dry cough; uncommon – rhinorrhea, sore throat and hoarseness, bronchospasm/bronchial asthma; rare – dyspnea, rhinitis, pulmonary infiltrates, allergic alveolitis/eosinophilic pneumonia.

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

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

From the skin and subcutaneous tissues: common – skin rash, urticaria, hypersensitivity reactions/angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx; uncommon – increased sweating, skin itching, urticaria, alopecia; rare – 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 adverse events: 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: uncommon – renal function impairment, proteinuria, renal failure; rare – oliguria.

From the reproductive system and mammary glands uncommon – erectile dysfunction; rare – gynecomastia.

General disorders: very common – asthenia; common – fatigue; uncommon – muscle cramps, flushing, tinnitus, fever.

Laboratory parameters common – hyperkalemia, increased serum creatinine concentration; uncommon – increased serum urea concentration, hyponatremia; rare – 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 facial flushing, nausea, vomiting, and arterial hypotension.

Contraindications

• History of angioedema while taking ACE inhibitors;
• Hereditary or idiopathic angioedema;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity 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 hemodynamic impairment), idiopathic hypertrophic subaortic stenosis, systemic connective tissue diseases, coronary artery disease, cerebrovascular diseases, diabetes mellitus, renal failure (creatinine clearance <80 ml/min), hepatic failure, in patients on a salt-restricted diet or on hemodialysis, with simultaneous use with immunosuppressants and saluretics, in patients over 65 years of age, with bone marrow depression; conditions accompanied by a decrease in circulating blood volume, including diarrhea, vomiting.

Use in Pregnancy and Lactation

The use of Berlipril^® during pregnancy is contraindicated. Patients planning pregnancy should be switched to alternative treatment with a confirmed safety profile for use in pregnant women. Upon confirmation of pregnancy, the use of the drug should be immediately discontinued, and, if necessary, alternative therapy should be initiated. The use of ACE inhibitors in the II and III trimesters of pregnancy was accompanied by a negative impact on the fetus, including the development of arterial hypotension, renal failure, hyperkalemia and/or hypoplasia of the skull bones in the newborn. The development of oligohydramnios is possible, apparently due to a decrease in fetal renal function. This complication can lead to limb contractures, deformation of the skull bones, including its facial part, and pulmonary hypoplasia. When using the drug, the patient should be informed about the potential risk to the fetus.

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

Enalapril and enalaprilat are excreted in 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 newborn’s circulation by peritoneal dialysis; theoretically – by exchange blood transfusion.

Use in Hepatic Impairment

The drug should be prescribed with caution in hepatic failure.

Use in Renal Impairment

The drug should be prescribed with caution in renal failure, bilateral renal artery stenosis, stenosis of the artery of a single kidney, condition after kidney transplantation.

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

The drug should be prescribed with caution to elderly patients (over 65 years of age).

Special Precautions

Caution is necessary in patients with reduced circulating blood volume (including with simultaneous use with diuretics, under conditions of salt restriction, during 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 arterial hypotension is usually not observed. The development of arterial hypotension is most likely in patients with a more severe degree of chronic heart failure due to the use of high doses of diuretics, hyponatremia, or functional renal failure. In these patients, treatment should be started under medical supervision until the optimal dose of Berlipril^® and/or the diuretic is adjusted. A similar approach can be applied to patients with coronary artery disease and cerebrovascular diseases, in whom an excessive decrease in blood pressure can lead to myocardial infarction or cerebral stroke. In case of severe arterial hypotension, the patient should be placed in a horizontal position and, if necessary, intravenous infusion of saline should be started.

Transient arterial hypotension is not a contraindication for continuing treatment with enalapril after blood pressure stabilization. In case of 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 (hemoglobin concentration, potassium ions, sodium ions, creatinine, urea, liver enzymes in serum), as well as urine for protein is necessary.

Like all vasodilators, ACE inhibitors should be prescribed with caution to patients with left ventricular hypertrophy and valvular obstruction and refrain from their use 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 administration of the drug.

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

In some patients who had no kidney disease before starting treatment, a slight and transient increase in serum urea and creatinine concentrations was observed when Enalapril was used simultaneously with diuretics. In such cases, a reduction in dose and/or discontinuation of enalapril and/or the diuretic may be required.

There is an increased risk of developing arterial hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney who are on therapy with ACE inhibitors. A decrease in renal function may be indicated only by moderate changes in serum creatinine concentration. In these patients, treatment should be started with low doses under careful medical supervision, with precise gradual selection of the individual dose and monitoring of serum creatinine concentration.

There is no experience with the use of the drug in patients who have recently undergone kidney transplantation. Therefore, treatment of such patients with this drug is not recommended.

The use of the drug in patients with hepatic failure usually does not require dose adjustment. Rarely, the use of ACE inhibitors is associated with a syndrome beginning with the development of cholestatic jaundice up to the development of fulminant liver necrosis. If symptoms of jaundice or increased activity of liver enzymes appear in patients taking ACE inhibitors, therapy with the drug should be discontinued and an appropriate examination should be performed.

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

Neutropenia, agranulocytosis, thrombocytopenia, anemia may develop during therapy with ACE inhibitors. With normal renal function and no other complications, neutropenia occurs rarely.

ACE inhibitors are prescribed only in emergency cases in patients with systemic connective tissue diseases, during immunosuppressive therapy, in cases of simultaneous use of allopurinol or procainamide, as well as when all the listed factors are combined, 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 still used in such patients, periodic monitoring of the white blood cell count is recommended, and patients should be appropriately instructed to immediately report any signs of infection to their doctor.

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

Reports of angioedema (Quincke’s edema) of the face, extremities, lips, tongue, glottis and/or larynx have been recorded in patients receiving ACE inhibitors, including Berlipril^®, at various periods of treatment. In such cases, treatment with the drug should be stopped immediately and appropriate medical supervision should be provided until the corresponding symptoms completely disappear. Even in cases where only difficulty swallowing without difficulty breathing occurs, patients should be under medical supervision for a long time, since therapy with antihistamines and corticosteroids may be insufficient. Angioedema of the larynx or tongue can be fatal. Edema of the tongue, vocal folds, or larynx can lead to airway obstruction; appropriate therapy should be carried out as soon as possible, including subcutaneous administration of 0.1% adrenaline solution (0.3-0.5 ml) and/or measures to ensure airway patency.

In patients of Black race, the frequency 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 levels in this population of patients with arterial hypertension.

During treatment, it is not recommended to consume alcoholic beverages, as alcohol enhances the hypotensive effect of the drug.

In patients undergoing surgery or general anesthesia using drugs that lower blood pressure, Enalapril can block the formation of angiotensin II under the influence of compensatory renin release. If arterial hypotension is assumed to develop by this mechanism, it can be corrected by increasing the circulating blood volume. Before surgical interventions (including dental procedures), the surgeon/anesthesiologist must be warned about the use of the drug Berlipril^®.

In rare cases, patients taking ACE inhibitors during LDL apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. 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.

In patients on dialysis using high-flux membranes (e.g., AN69^®), anaphylactoid reactions have been observed while using ACE inhibitors. Therefore, for such patients, it is recommended to either use a different type of dialysis membrane or use antihypertensive drugs from another group.

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

Some patients taking ACE inhibitors, including Enalapril, experience an increase in the concentration of potassium ions in the blood serum. The risk group for the development of hyperkalemia includes patients suffering from renal failure or diabetes mellitus, taking potassium-sparing diuretics or potassium-containing salt substitutes, and other drugs that increase the concentration of potassium ions in the blood serum (e.g., heparin). If the use of the above drugs 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 Black individuals compared to persons of other races, possibly due to low renin levels in hypertensive patients in this population.

Sudden discontinuation of treatment with enalapril does not lead to the development of a “withdrawal” syndrome (a sharp increase in blood pressure).

Effect on the ability to drive vehicles and mechanisms

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

Drug Interactions

With simultaneous use with NSAIDs, including selective COX-2 inhibitors, a decrease in the hypotensive effect of ACE inhibitors, including enalapril, is possible. In some patients with impaired renal function, simultaneous use of NSAIDs and ACE inhibitors may lead to further deterioration of renal function. These changes are usually reversible.

The use of potassium-containing dietary supplements, potassium-containing salt substitutes and/or 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 simultaneous use of the above drugs with enalapril is necessary, regular monitoring of the concentration of potassium ions in the blood serum should be carried out.

With simultaneous use of the drug Berlipril^® and thiazide diuretics, hypokalemia caused by the latter is usually reduced under the influence of enalapril.

Prior therapy with high doses of diuretics can lead to hypovolemia and the risk of developing hypotension at the beginning of therapy with enalapril. The excessive hypotensive effect of enalapril can be reduced either by discontinuing the diuretic, or by increasing the circulating blood volume or consuming table salt, and also provided that treatment with enalapril is started at a low dose. Simultaneous use of thiazide diuretics and ACE inhibitors can lead to hypovolemia and thus increase the risk of developing arterial hypotension.

Simultaneous use of the drug 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 lithium concentration in the blood serum is necessary.

Simultaneous 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, including beta-blockers, methyldopa, nitroglycerin and other nitrates, slow calcium channel blockers, hydralazine, prazosin, as well as some anesthetics, ethanol, tricyclic antidepressants, antipsychotics.

ACE inhibitors may enhance the hematotoxicity of immunosuppressants, allopurinol, cytostatics.

Drugs that cause bone marrow suppression 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 somewhat reduced to avoid the development of undesirable effects or an effect of relative overdose.

Neuroleptics can enhance the hypotensive effect of enalapril.

Sympathomimetics can weaken the hypotensive effect of enalapril.

Simultaneous use of antacids, 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 drug doses of at least 2 hours should be observed.

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

Epidemiological studies have shown that simultaneous use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may additionally contribute to a decrease in blood glucose concentration, leading to the development of hypoglycemia. This phenomenon is most often noted 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 concentration is necessary, especially careful – during the first month of simultaneous use with ACE inhibitors.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.