Berlipril 10, tablets 10 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 results in enalaprilate, which directly inhibits ACE. Its mechanism of 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 OPPS, systolic and diastolic BP, 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.

Long-term use of 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

Active ingredient

Composition

Active ingredient:

Enalapril maleate – 10 mg.

Auxiliary substances:

lactose monohydrate – 165.75 mg,

gelatin – 6 mg,

magnesium carbonate – 25 mg,

colloidal silicon dioxide – 3 mg,

sodium carboxymethyl starch – 8 mg,

magnesium stearate – 2 mg,

dye iron oxide brown (E172) – 0.25 mg.

How to take, the dosage

Ingestion. Tablets are taken regardless of the time of meals, without chewing, with plenty of liquid.

In order to choose the appropriate dosing regimen, it is reasonable to use the most appropriate dosage of the drug – 5 mg, 10 mg or 20 mg (Berlipril® 5, Berlipril® 10 or Berlipril® 20, respectively). The drug is used both as monotherapy and in combination with other hypotensive agents.

Arterial hypertension

The starting dose is 5 mg to 20 mg of enalapril maleate once daily depending on the severity of arterial hypertension.

In mild arterial hypertension: the recommended maintenance dose is 5-10 mg of enalapril maleate once daily; in moderate arterial hypertension, 10-20 mg of enalapril maleate once daily.

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

Renovascular hypertension

The initial dose is 5 mg of enalapril maleate once daily. After the first dose of the drug, close monitoring of BP is necessary. Then the dose is adjusted according to the therapeutic effect. The maximum daily dose is 20 mg once daily with daily administration. Thereafter, the patient should be closely monitored, including obligatory control of renal function.

Patients taking diuretics at the same time should temporarily discontinue diuretic therapy for 2-3 days before prescribing the drug. If this is not possible, the initial dose of enalapril maleate should not exceed 5 mg/day. The drug is recommended to be administered with caution, since fluid deficiency and/or hyponatremia may be observed in such patients; further on, the dosage should be adjusted individually.

Chronic heart failure and asymptomatic left ventricular dysfunction

In chronic heart failure and asymptomatic left ventricular dysfunction, Berlipril® is used in combination therapy simultaneously with diuretics and, if necessary, with cardiac glycosides or beta-adrenoblockers. The initial minimum dose of the drug is 2.5 mg once daily, treatment should be started under close medical supervision. The dose of enalapril maleate should be increased gradually, usually by 2.5-5 mg every 3-4 days according to the individual patient’s response to maximum tolerated doses, but not more than 40 mg/day in chronic heart failure and 20 mg/day in asymptomatic left ventricular dysfunction, in 1 or 2 doses. The maintenance dose is adjusted over a period of 2-4 weeks.

Treatment with enalapril is prolonged; in chronic heart failure and asymptomatic left ventricular dysfunction the effect can be fully assessed not earlier than 6 months after the start of therapy. In cases of very pronounced BP decrease, the maintenance dose of the drug is gradually reduced.

In elderly patients a more pronounced hypotensive effect and prolongation of drug duration of action are more often observed due to decreased elimination rate of enalapril, so the recommended starting dose of enalapril maleate for elderly patients is not more than 2.5 mg. The maintenance daily dose should be adjusted according to serum creatinine concentration.

Interaction

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

The use of potassium-containing food supplements, potassium-containing salt substitutes and/or the use of potassium-saving diuretics as well as heparin may lead to significant increase in the concentration of serum potassium ions, especially in patients with impaired renal function and/or diabetes. If concomitant use of the above drugs with enalapril is necessary, regular monitoring of serum potassium ion concentrations should be performed.

When using berlipril® concomitantly with thiazide diuretics the hypokalemia caused by the latter is usually reduced by enalapril.

Previous therapy with high doses of diuretics may lead to hypovolemia and risk of hypotension at the beginning of enalapril therapy. The excessive hypotensive effect of enalapril can be reduced either by withdrawal of the diuretic or by increasing the blood pressure or table salt intake and by starting enalapril therapy at a low dose. Concomitant use of thiazide-type diuretics and ACE inhibitors may lead to hypovolemia and thus increase the risk of hypotension.

The concomitant use of Berlipril® and lithium preparations is not recommended due to the risk of lithium intoxication. Serum lithium concentrations should be monitored closely if this combination is indicated.

Simultaneous use with antipyretics and pain relievers may decrease the effectiveness of the drug.

Enalapril weakens the effect of drugs containing theophylline.

Enalapril hypotensive effect is increased by diuretics, as well as by hypotensive drugs from other groups, including beta-adrenoblockers, methyldopa, nitroglycerin and other nitrates, slow calcium channel blockers, hydralazine, prazosin, and some anesthetic drugs, ethanol, tricyclic antidepressants, antipsychotic drugs.

ACE inhibitors may increase hematotoxicity of immunosuppressants, allopurinol, cytostatics.

Drugs that inhibit medullary hematopoiesis increase the risk of neutropenia and agranulocytosis.

ACE inhibitors increase the bioavailability of digoxin, increasing its concentration in blood. Therefore, if ACE inhibitors and cardiac glycosides are concomitantly prescribed, the dose of the latter should be slightly reduced to avoid the development of undesirable effects or the effect of relative overdose.

Neuroleptics may increase the hypotensive effect of enalapril.

Sympathomimetics may decrease the hypotensive effect of enalapril.

The simultaneous use of antacids and adsorbents may decrease the bioavailability of ACE inhibitors by up to 50%, as well as delay and decrease their hypotensive effect; therefore, an interval of at least 2 hours between doses should be observed.

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

Epidemiological studies have shown that concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may further contribute to lower blood glucose concentrations, leading to hypoglycemia. This phenomenon is most often observed during the first weeks of concomitant use of the above mentioned drugs, as well as in patients with renal insufficiency. In patients with diabetes receiving hypoglycemic agents for oral administration and/or insulin, regular monitoring of blood glucose concentration is necessary, especially carefully – during the first month of concomitant use with ACE inhibitors.

Special Instructions

Caution should be exercised in patients with decreased RBC (including concomitant use with diuretics, with restriction of table salt intake, hemodialysis, diarrhea, vomiting) in whom a sudden and pronounced decrease of BP may develop in response to ACE inhibitor use.

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

In these patients, treatment should be initiated under physician supervision until optimal adjustment of the dose of berlipril® and/or diuretic. The same tactics may apply to patients with CHD and cerebrovascular disease in whom an excessive drop in BP may 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 intravenous infusion of saline solution should be initiated.

Transient arterial hypotension is not a contraindication to continue treatment with enalapril after BP stabilization. In case of repeated pronounced BP decrease, the dose should be reduced or the drug should be discontinued. Before and during ACE inhibitor therapy, dynamic monitoring of BP, several biochemical and electrolyte blood parameters (concentration of hemoglobin, potassium ions, sodium ions, creatinine, urea, hepatic enzymes in serum) and urine for protein is necessary.

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

In cases of impaired renal function (CK < 80 ml/min), careful monitoring of serum potassium and creatinine concentrations is necessary. In patients with renal impairment 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 artery stenosis of the single kidney, increased serum urea and creatinine concentrations were observed. The changes were usually reversible and returned to normal after discontinuation of treatment.

In some patients who were not found to have renal disease prior to treatment, minor and transient increases in serum urea and creatinine concentrations were observed when enalapril was used concomitantly with diuretics. In such cases, a dose reduction and/or withdrawal of enalapril and/or diuretic may be required.

There is an increased risk of arterial hypotension and renal failure in patients with bilateral renal artery stenosis or artery stenosis of the single kidney who are on therapy with ACE inhibitors. Only moderate changes in serum creatinine concentration may indicate reduced renal function. In these patients, treatment should be started with low doses under close medical supervision, precise gradual adjustment of the individual dose, and monitoring of serum creatinine concentrations.

The use of Berlipril® in patients who have recently undergone renal transplantation is not known. Therefore it is not recommended to treat these patients.

The use of Berlipril® in patients with hepatic impairment 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 fulminant liver necrosis. If symptoms of jaundice or increased liver enzyme activity occur in patients taking ACE inhibitors, therapy with the drug should be discontinued and appropriate evaluation should be performed.

There have been reports of life-threatening anaphylactic reactions in patients treated with ACE inhibitors during desensitization with venom of hymenoptera (Geminoptera). Such reactions can be avoided by temporarily discontinuing the ACE inhibitor prior to desensitization. The use of ACE inhibitors in patients receiving immunotherapy with bee venom should be avoided.

Neutropenia, agranulocytosis, thrombocytopenia, anemia may develop against the background of ACE inhibitor therapy. Neutropenia is rare in normal renal function and in the absence of other complications.

The ACE inhibitors are indicated only in urgent cases if the patient has systemic connective tissue disease, during immunosuppressive therapy, in cases of concomitant use of allopurinol or procainamide, and in a combination of all of these factors, especially in the presence of renal failure.

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

The occurrence of cough during treatment with ACE inhibitors has been reported. The cough is usually 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, vocal cleft and/or larynx in patients treated with ACE inhibitors, including Berlipril®, during various periods of treatment. In such cases, treatment with Berlipril® should be discontinued immediately, and appropriate medical monitoring should be carried out until the symptoms have completely disappeared. Even if only difficulty in swallowing without difficulty in breathing occurs, patients should be kept under medical supervision for an extended period of time, as therapy with antihistamines and corticosteroids may not be sufficient.

The angioedema of the larynx or tongue can be fatal. Tongue, vocal fold or laryngeal edema can lead to airway obstruction, appropriate therapy including intravenous injection of 0.1% adrenaline solution (0.3-0.5 ml) and/or measures to ensure airway conduction should be given as soon as possible.

The incidence of angioedema with ACE inhibitors is higher in patients of the Negro race than in other races. Like other ACE inhibitors, enalapril appears to be less effective in lowering blood pressure in non-Hispanic patients than in other races, possibly because of the high prevalence of low renin levels in this population of patients with arterial hypertension.

Persons should not drink alcoholic beverages during treatment because alcohol increases the hypotensive effect of the drug.

In patients undergoing surgery or general anesthesia with blood pressure lowering drugs, enalapril may block angiotensin II formation due to compensatory renin release. If arterial hypotension is assumed to develop by this mechanism, it may be corrected by increasing the BOD. The surgeon/anesthesiologist should be advised of the use of Berlipril® prior to surgical procedures (including dental procedures).

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.

In patients on dialysis using high throughput membranes (e.g., AN69®), anaphylactoid reactions have been observed with ACE inhibitors. Therefore, either the use of a different type of dialysis membrane or the use of a different group of hypotensive drugs is recommended for these patients.

In diabetic patients 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, including enalapril, elevated serum potassium ion concentrations are observed. The risk of hyperkalemia includes patients with renal insufficiency or diabetes, patients taking potassium-saving diuretics or potassium-containing salt substitutes, other drugs that increase the concentration of potassium ions in blood serum (e.g., heparin).

If the use of the above medications during treatment with Berlipril® is necessary, regular monitoring of serum potassium ion concentrations is recommended. As with other ACE inhibitors, enalapril may be less effective in reducing BP in non-Hispanic races than in other races, possibly due to the low renin levels in patients with arterial hypertension in this population.

Sudden discontinuation of enalapril does not result in withdrawal (a rapid rise in BP).

Effect on driving and operating machinery

Perhaps caution should be exercised when driving motor vehicles and engaging in potentially hazardous activities requiring increased concentration and rapid psychomotor reactions (dizziness due to rapid BP decrease is possible, especially after taking the initial dose of enalapril in patients taking diuretics).

Contraindications

With caution: Primary hyperaldosteronism, bilateral renal artery stenosis, artery stenosis of the single kidney, post renal transplantation condition, hyperkalemia, aortic stenosis, mitral stenosis (with impaired hemodynamics), idiopathic hypertrophic subaortic stenosis, systemic connective tissue disease, CHD, cerebrovascular disease, diabetes, renal failure (CK < 80 mg/min), hepatic insufficiency, in patients on a diet with restriction of table salt or on hemodialysis, in concurrent use with immunosuppressants and saluretics, in patients older than 65 years, inhibition of bone marrow hematopoiesis; conditions accompanied with reduction of BOD, includingincluding diarrhea and vomiting.

Side effects

Possible side effects of Berlipril® are listed below in descending order of frequency:

Hematopoietic system disorders: infrequent – anemia (including aplastic and hemolytic); rare – neutropenia, decreased serum hemoglobin concentration and hematocrit, eosinophilia, thrombocytopenia, increased lymph nodes, pancytopenia, agranulocytosis, inhibition of bone marrow hematopoiesis, autoimmune diseases.

Metabolism and nutrition: infrequent – hypoglycemia.

Nervous system disorders: frequently – headache, depression; infrequent – mental confusion, insomnia, hyperexcitability, paresthesias, vertigo, tinnitus; rarely – change of the nature of dreams, sleep disorders.

VIight: rarely – blurred vision.

Cardiovascular system disorders: very common – dizziness; common – hypotension (including orthostatic hypotension), syncope, chest pain, heart rhythm disorders, angina; infrequent – orthostatic hypotension, palpitations, myocardial infarction or cerebral stroke, possibly caused by a sudden drop in BP in high-risk patients; rare – Raynaud syndrome.

Respiratory system: very common – non-productive dry cough; infrequent – rhinorrhea, sore throat and hoarseness of voice, bronchospasm/bronchial asthma; rare – shortness of breath, rhinitis, pulmonary infiltrates, allergic alveolitis/eosinophilic pneumonia.

The digestive system: very frequently – nausea; frequently – diarrhea, abdominal pain, change in taste perception; infrequently – intestinal obstruction, pancreatitis, lack of appetite, dry oral mucosa, change in taste perception, peptic ulcer; rarely – stomatitis/aftosal ulcers, glossitis; very rarely – angioedema of the bowel.

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

Skin and subcutaneous tissue disorders: Frequent – skin rash, urticaria, hypersensitivity reactions/angioneurotic edema of the face of extremities, lips, tongue, vocal folds and/or larynx; infrequent – increased sweating, skin itching, urticaria, alopecia; rare – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vesicularis, 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. There may be skin rash, photosensitization, or other skin manifestations.

Recreational and urinary tract disorders: infrequent – renal dysfunction, proteinuria, renal failure; rarely – oliguria.

Gender and mammary gland disorders: infrequent – erectile dysfunction; rarely – gynecomastia.

General disorders: very common – asthenia; common – fatigue; infrequent – muscle cramps, blood rushes to the face, tinnitus, fever.

Laboratory measures: frequently – hyperkalemia, increased concentration of serum creatinine; infrequently – increased concentration of serum urea, hyponatremia; rarely – increase of liver enzymes activity, hyperbilirubinemia.

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

Overdose

Symptoms: approximately 6 h after oral administration – a marked decrease in BP, up to the development of collapse, myocardial infarction, acute cerebral circulation disorder or thromboembolic complications, disruption of water-electrolyte balance, renal failure, rapid breathing, tachycardia, palpitations, bradycardia, dizziness, anxiety, feelings of fear, muscle cramps, cough, stupor. Plasma concentrations of enalaprilat 100-200 times higher than therapeutic doses were observed after oral administration of 300 mg and 440 mg of enalapril maleate, respectively.

Treatment:The use of the drug should be stopped immediately; treatment measures should be aimed at elimination of enalapril and enalaprilat and correction of arterial hypotension. The patient should be transferred to a horizontal position with a low headboard. In mild cases gastric lavage and activated charcoal administration are indicated, in more severe cases – intravenous infusion of saline, plasma substitutes, if necessary – administration of angiotensin II or catecholamines; hemodialysis (elimination rate of enalaprilat – 62 ml/min). In patients with bradycardia resistant to therapy, a pacemaker is indicated.

Pregnancy use

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

The use of ACE inhibitors in II and III trimesters of pregnancy has been associated with adverse effects on the fetus, including the development of arterial hypotension, renal failure, hyperkalemia and/or hypoplasia of the skull bone in the neonate. Oligohydramnios may develop, apparently due to decreased fetal renal function. This complication may lead to limb contractures, deformities of the skull bones, including its facial part, hypoplasia of the lungs. When using Berlipril®, the patient should be informed about the potential risk to the fetus.

If Berlipril® cannot be withdrawn during pregnancy, closely monitor newborns whose mothers have taken Berlipril® to detect possible decreased BP, oliguria, and hyperkalemia, to monitor renal function, and to monitor the neonatal skull bones by ultrasound examination.

Enalapril and enalaprilate are excreted into breast milk in trace amounts, but their safety has not been studied. Breast-feeding should be stopped if it is necessary to use the drug during lactation.

Enalapril can be removed from the neonatal circulation by peritoneal dialysis; theoretically, by exchange blood transfusion.

Similarities