ENALAPRIL TABLET. 10MG No. 20СТМ2151 ACC

Instructions ENALAPRIL TABLETS 10MG No. 20 STM 2151 AKTS

Composition

active ingredient: 1 tablet contains enalapril maleate 10 mg (0.01 g);

excipients: lactose monohydrate, potato starch, povidone, calcium stearate.

Dosage form

Pills.

main physicochemical properties: white or almost white tablets, round in shape with a score and a bevel.

Pharmacotherapeutic group

Angiotensin-converting enzyme inhibitors, monocomponent.

ATX code C09A A02.

Pharmacological properties

Pharmacodynamics.

Enalapril (enalapril maleate) is the maleic acid salt of enalapril, a derivative of two amino acids: L-alanine and L-proline.

Mechanism of action

Angiotensin-converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE causes a decrease in plasma angiotensin II levels, which leads to an increase in plasma renin activity (due to inhibition of the negative feedback between angiotensin II activity and renin release) and a decrease in aldosterone secretion.

ACE is identical to kininase II. Thus, enalapril may also block the cleavage of bradykinin, a potent vasodepressor peptide. However, the significance of this phenomenon for the therapeutic effect of the drug remains unclear.

The mechanism by which the drug lowers blood pressure is primarily associated with inhibition of the renin-angiotensin-aldosterone system. Enalapril may have an antihypertensive effect even in patients with low-renin hypertension.

The use of Enalapril in case of arterial hypertension causes a decrease in blood pressure in patients in horizontal and vertical positions without a significant increase in heart rate.

Symptomatic postural hypotension is rare. In some patients, achieving optimal blood pressure control may require several weeks of therapy. Abrupt withdrawal of the drug has not been associated with a rapid increase in blood pressure.

Effective inhibition of ACE activity is usually achieved 2-4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive activity is usually observed after 1 hour, and the peak reduction in blood pressure is achieved 4-6 hours after taking the drug. The duration of the effect is dose-dependent. However, when used in recommended doses, the antihypertensive and hemodynamic effects were maintained for at least 24 hours.

In patients with essential hypertension, the reduction in blood pressure is usually accompanied by a decrease in peripheral arterial resistance with an increase in cardiac output and little or no increase in heart rate. Renal blood flow increases after administration; glomerular filtration rate is not affected. There is no evidence of sodium or water retention. However, in patients with low initial glomerular filtration rates, these levels are increased.

In patients with or without diabetes mellitus and renal disease, reductions in albuminuria, urinary IgG excretion, and total urinary protein were observed after enalapril administration.

When co-administered with thiazide diuretics, the hypotensive effects of Enalapril are at least additive. Enalapril may reduce or prevent the development of thiazide-induced hypokalemia.

In patients with heart failure receiving cardiac glycosides and diuretics, oral or injectable enalapril was associated with a decrease in peripheral resistance and blood pressure. Cardiac output increased and heart rate (usually increased in patients with heart failure) decreased. Pulmonary end-capillary pressure also decreased. Exercise tolerance improved and the severity of heart failure, as assessed by NYHA (New York Heart Association) criteria, decreased. These effects were maintained during long-term treatment.

In patients with mild to moderate heart failure, enalapril slowed the progression of myocardial dilatation/enlargement and heart failure, as evidenced by reduced left ventricular end-diastolic and systolic volumes and improved ejection fraction.

In patients with left ventricular dysfunction, enalapril reduces the risk of myocardial infarction and the risk of hospitalization for unstable angina.

Clinical pharmacology in children

Experience in children aged 6 years and older with hypertension is limited. In children with hypertension, enalapril administered once daily reduces the lower limit of blood pressure in a dose-dependent manner.

The side effect profile in children does not differ from that in adult patients.

Pharmacokinetics.

After oral administration, enalapril is rapidly absorbed, with peak serum concentrations occurring within 1 hour. The extent of absorption of enalapril from oral tablets is approximately 60%. The presence of food in the gastrointestinal tract does not affect the absorption of oral enalapril. After absorption, oral enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat occur approximately 4 hours after an oral dose of enalapril.

The effective elimination half-life (T½) of enalaprilat after multiple oral administration is 11 hours.

Distribution

Within the entire therapeutic concentration range, no more than 60% of enalaprilat binds to serum proteins.

Biotransformation

With the exception of conversion to enalaprilat, there is no further evidence of significant metabolism of enalapril.

Breeding

Enalaprilat is excreted primarily by the kidneys. The major components in the urine are enalaprilat, which accounts for approximately 40% of the dose, and unchanged enalapril (approximately 20%).

Kidney dysfunction

In patients with renal insufficiency, exposure to enalapril and enalaprilat is increased. In patients with mild to moderate renal impairment (creatinine clearance 40-60 ml/min), the AUC of enalaprilat at steady state was approximately 2-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal insufficiency (creatinine clearance ≤ 30 ml/min), the AUC increased approximately 8-fold. At this level of renal insufficiency, the effective half-life of enalaprilat is prolonged and the time to steady state is delayed (see section 4.2).

Enalaprilat can be removed from the general circulation by hemodialysis. The dialysis clearance of enalaprilat is 62 ml/min.

Indication

• Treatment of arterial hypertension.
• Treatment of clinically significant heart failure.
• Prevention of clinically significant heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction ≤ 35%).

Contraindication

• Hypersensitivity to enalapril, to any of the excipients or to any other ACE inhibitor.
• History of angioedema associated with the use of ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Pregnant women or women planning to become pregnant (see section “Use during pregnancy or breastfeeding”).

Enalapril should not be used with aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).

Interaction with other medicinal products and other types of interactions

Hypotensive therapy

Concomitant use of these drugs may enhance the hypotensive effect of enalapril. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may further reduce blood pressure.

Potassium-sparing diuretics or potassium supplements

ACE inhibitors increase the potassium loss caused by diuretics. The use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), as well as the use of dietary supplements or salt substitutes containing potassium, can lead to a significant increase in serum potassium. If the above agents are indicated in connection with hypokalemia, they should be used with caution, with regular determination of serum potassium (see section "Special instructions").

Diuretics (thiazide or loop diuretics)

Previous treatment with high doses of diuretics may lead to volume depletion and an increased risk of hypotension at the start of enalapril therapy (see section 4.4). Hypotensive effects may be reduced by discontinuing the diuretic, increasing salt intake, or initiating therapy with a low dose of enalapril.

Antidiabetic drugs

Epidemiological studies have shown that the concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may lead to a decrease in blood glucose levels with a risk of hypoglycemia. This phenomenon is most likely during the first weeks of concomitant administration and in patients with renal insufficiency (see sections "Special warnings and precautions for use", "Adverse reactions").

Serum lithium

Reversible increases in serum lithium levels and toxicity have been reported with concomitant use of ACE inhibitors and lithium. Concomitant use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and increase the risk of lithium toxicity. The use of enalapril with lithium is not recommended, but if the combination proves necessary for the patient, careful monitoring of serum lithium levels should be performed (see section 4.4).

Tricyclic antidepressants/neuroleptics/anesthetics/hypnotics

Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the hypotensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors.

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors has an additive effect on serum potassium and may lead to deterioration of renal function. These effects are usually reversible.

Acute renal failure may occur rarely, especially in some patients with impaired renal function (e.g. elderly patients or patients with reduced circulating blood volume, including those taking diuretics). Therefore, this combination should be administered with caution to patients with impaired renal function. Patients should be adequately hydrated and renal function should be closely monitored at the beginning of concomitant therapy and periodically during such treatment.

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

Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to isolated cases with close monitoring of blood pressure, renal function, and electrolytes. In patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual blockade of the renin-angiotensin-aldosterone system is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a single agent acting on the renin-angiotensin-aldosterone system. Enalapril with aliskiren should not be used in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections “Contraindications” or “Special warnings and precautions for use”).

Gold preparations

Nitritoid reactions (symptoms including facial swelling, nausea, vomiting and hypotension) have been reported rarely in patients treated with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitors, including enalapril.

tTOR inhibitors

Concomitant use with mTOR inhibitors (such as temsirolimus, sirolimus, everolimus) may increase the risk of angioedema (see section "Special warnings and precautions for use").

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and β-blockers

Concomitant administration of enalapril with acetylsalicylic acid (in cardiological doses), thrombolytics, and β-blockers is safe.

Concomitant therapy with an ACE inhibitor and angiotensin receptor antagonist

In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a renin-angiotensin-aldosterone system agent alone. Dual blockade (e.g., by combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases and accompanied by careful monitoring of renal function, potassium levels, and blood pressure.

Application features

Symptomatic hypotension

If hypotension develops, the patient should be placed in a horizontal position and, if necessary, intravenous saline should be administered. Transient hypotension while taking Enalapril is not a contraindication for further administration, which can usually be continued without complications after normalization of blood pressure by restoring fluid volume.

In some patients with heart failure with normal or low blood pressure, enalapril may further reduce blood pressure. This is an expected reaction to the drug and is not usually a reason for discontinuation of treatment. If hypotension becomes refractory to treatment, the dose should be reduced and/or the diuretic and/or enalapril should be discontinued.

Aortic or mitral stenosis/hypertrophic cardiomyopathy

As with all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and outflow tract obstruction; they should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Kidney dysfunction

In patients with renal impairment (creatinine clearance < 80 ml/min), the initial dose of enalapril should be titrated according to creatinine clearance (see section 4.2) and then adjusted according to response to treatment. Regular monitoring of potassium and creatinine levels is standard medical practice in such patients.

Renal impairment has been reported in association with enalapril, primarily in patients with severe heart failure or renal disease, including renal artery stenosis. With timely recognition and appropriate treatment, renal impairment associated with enalapril therapy is usually reversible.

In some hypertensive patients with no known pre-existing renal disease, enalapril and diuretics have been associated with small and transient increases in blood urea and serum creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation increases the likelihood of pre-existing renal artery stenosis (see section 4.4: Renovascular hypertension).

Renovascular hypertension

There is an increased risk of hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with minimal changes in serum creatinine. In such patients, treatment should be initiated at low doses under close medical supervision with careful titration and monitoring of renal function.

Kidney transplantation

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

Liver failure

Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome remains unclear. Patients taking ACE inhibitors who develop jaundice or marked elevations of liver enzymes should discontinue the ACE inhibitor and receive appropriate medical attention.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. Neutropenia has been reported rarely in patients with normal renal function and in the absence of other complicating factors. Enalapril should be used with great caution in patients with collagen vascular disease who are receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing renal impairment. Some of these patients have developed serious infections, sometimes unresponsive to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended when enalapril is prescribed to such patients, and patients should report any signs of infection.

Hypersensitivity/angioedema

Very rarely, fatal outcomes have been reported from angioedema of the larynx or tongue. If the swelling is localized to the tongue, glottis or larynx, especially in patients with a history of airway surgery, airway obstruction may occur. When there is involvement of the tongue, pharynx or larynx and this may cause airway obstruction, appropriate therapy should be initiated immediately, which may include subcutaneous administration of epinephrine 1:1000 (0.3-0.5 ml) and/or measures to maintain a patent airway.

Angioedema was more common in black patients treated with ACE inhibitors than in patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of developing angioedema while receiving an ACE inhibitor (see also section 4.3).

Concomitant use of ACE inhibitors with mTOR inhibitors (e.g. temsirolimus, sirolimus, everolimus) may increase the risk of angioedema.

Anaphylactoid reactions during hyposensitization with a hymenoptera venom allergen

Rarely, patients receiving ACE inhibitors during hymenoptera venom allergen desensitization have developed anaphylactoid reactions, which may be life-threatening. Such reactions can be avoided by temporarily stopping the ACE inhibitor before the desensitization begins.

Anaphylactoid reactions during low-density lipoprotein apheresis

Rarely, patients receiving ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily stopping ACE inhibitors before each apheresis.

Patients on hemodialysis

Anaphylactoid reactions have occasionally been reported in patients dialysed with high-flux membranes (e.g. AN 69®) and concomitantly treated with an ACE inhibitor. Therefore, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent in such patients.

Hypoglycaemia Diabetic patients taking oral antidiabetic agents or insulin and initiating therapy with an ACE inhibitor should be advised to monitor their blood sugar levels closely, particularly during the first few months of concomitant use (see section 4.5). Cough

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

Surgical operations/anesthesia

During major surgery or anesthesia with drugs that cause hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If hypotension develops, which can be explained by these mechanisms of interaction, it is corrected by increasing the volume of fluid.

Hyperkalemia

During treatment with ACE inhibitors, including enalapril, some patients have experienced increases in blood potassium levels. The risk of hyperkalemia is increased in patients with renal insufficiency, with impaired renal function, age > 70 years, with diabetes mellitus, with transient conditions, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride); with the use of potassium-containing food supplements or salt substitutes; and in patients taking other drugs that may increase blood potassium (e.g. heparin). In particular, the use of potassium-sparing diuretics, food supplements or salt substitutes containing potassium in patients with impaired renal function may lead to a significant increase in blood potassium levels. Hyperkalemia may cause serious, sometimes fatal arrhythmias. If concomitant use of enalapril and any of the above-mentioned drugs is considered necessary, they should be used with caution and with regular monitoring of serum potassium (see section 4.5).

Lithium

The combination of lithium and enalapril is generally not recommended (see section “Interaction with other medicinal products and other types of interactions”).

Concomitant therapy with an ACE inhibitor and angiotensin receptor antagonist

The combination of an ACE inhibitor with an angiotensin II receptor antagonist should be limited to individually defined cases, accompanied by careful monitoring of renal function, potassium levels and blood pressure (see section “Interaction with other medicinal products and other types of interactions”).

Lactose

Ethnic features

As with other angiotensin-converting enzyme inhibitors, enalapril is less effective in lowering blood pressure in black patients than in non-black patients, possibly because of a higher prevalence of low-renin states in the black population with hypertension.

Use during pregnancy or breastfeeding

Pregnancy

ACE inhibitors are contraindicated in pregnant women or women planning to become pregnant (see Contraindications).

Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if possible, alternative therapy should be started.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy is inconclusive; however, a small increase in risk cannot be excluded. It is known that the use of ACE inhibitors during the second and third trimesters of pregnancy may induce fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

When prescribing enalapril, the patient should be informed of the potential harm to the fetus.

In cases where ACE inhibitors were used during pregnancy, periodic ultrasound examinations should be performed to assess the intraamniotic space. However, both physicians and patients need to be aware that oligoamnios may develop after irreversible fetal damage has occurred.

If ACE inhibitors have been used in the second trimester of pregnancy, ultrasound examination of fetal renal function and fetal skull is recommended.

Infants whose mothers have taken ACE inhibitors should be closely monitored for hypotension, oliguria, and hyperkalemia. Enalapril, which has the ability to cross the placenta, can be partially removed from the newborn by peritoneal dialysis; theoretically, it can be removed by exchange transfusion, although there is no experience with the latter procedure.

Breast-feeding

Limited pharmacokinetic data indicate very low concentrations in breast milk (see section 5.2). Although these concentrations are considered to be clinically insignificant, the use of Enalapril is not recommended during breast-feeding of premature infants and infants in the first few weeks after birth because of the hypothetical risk of cardiovascular and renal effects and because of insufficient experience in this regard. In older infants, the use of Enalapril during breast-feeding may be considered if treatment is necessary for the mother and the infant is observed for any adverse effects.

The ability to influence the reaction speed when driving or working with other mechanisms

When driving vehicles or operating other mechanisms, the possible development of dizziness or increased fatigue should be taken into account.

Method of administration and doses

Food intake does not affect the absorption of Enalapril tablets.

The dosage should be individualized according to each patient's condition (see section "Special warnings and precautions for use") and blood pressure response.

The 10 mg tablet should be swallowed whole and not broken. If the patient requires treatment with doses of less than 10 mg, the lower dosage should be used.

Arterial hypertension

The dose of the drug ranges from an initial 5 mg* (*use in the appropriate dosage) to a maximum of 20 mg depending on the degree of arterial hypertension and the patient's condition (see below). Enalapril should be taken once a day. In mild arterial hypertension, the recommended initial dose is 5*-10 mg.

In patients with a strongly activated renin-angiotensin-aldosterone system (e.g. renovascular hypertension, salt and/or fluid imbalance, cardiac decompensation or severe hypertension), an excessive decrease in blood pressure may occur after the initial dose. In such patients, a starting dose of 5 mg* or lower is recommended and initiation of treatment should be under medical supervision.

Previous treatment with high doses of diuretics may lead to fluid depletion and a risk of hypotension at the start of enalapril therapy. In such patients, a starting dose of 5 mg* or less is recommended. If possible, diuretic treatment should be discontinued 2-3 days before starting treatment with Enalapril. Renal function and serum potassium should be monitored.

The usual maintenance dose is 20 mg once daily. The maximum maintenance dose is 40 mg daily.

For the treatment of clinically significant heart failure, Enalapril should be used together with diuretics and, if necessary, digitalis or beta-blockers. The initial dose of Enalapril for patients with clinically significant heart failure or asymptomatic left ventricular dysfunction is 2.5 mg*, while the use of the drug should be carried out under careful medical supervision in order to establish the initial effect of the drug on blood pressure. In the absence of effect or after appropriate correction of symptomatic hypotension that occurred at the beginning of treatment with Enalapril for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, which should be administered once or divided into two doses, depending on what is better tolerated by the patient. The dose selection is recommended to be carried out within 2-4 weeks. Such a therapeutic regimen effectively reduces mortality rates in patients with clinically significant heart failure. The maximum dose is 40 mg per day in two doses.

Suggested Enalapril Dose Titration for Patients with Heart Failure/Asymptomatic Left Ventricular Dysfunction

** The drug should be used with caution in patients with impaired renal function or those taking diuretics (see section "Special warnings and precautions for use").

Both before and after the initiation of treatment with Enalapril, blood pressure and renal function should be closely monitored (see section 4.4), as hypotension and (rarely) subsequent renal failure have been reported. Patients taking diuretics should have their dose reduced if possible before initiating treatment with Enalapril. The development of hypotension after the initial dose of Enalapril does not mean that hypotension will persist with continued treatment and does not indicate the need to discontinue the drug. Serum potassium and renal function should also be monitored.

Dosage in renal failure

In general, the interval between enalapril doses should be increased and/or the dosage of the drug reduced.

***See section “Special warnings and precautions for use”: patients on hemodialysis.

Enalapril is removed by hemodialysis. Dosage adjustment on days when hemodialysis is not performed should be made depending on the level of blood pressure.

Elderly patients

The dose should be adjusted depending on renal function (see section "Special warnings and precautions for use").

Children with hypertension aged 6 years and older

Clinical experience with Enalapril in children with arterial hypertension is limited (see sections "Special warnings and precautions for use", "Pharmacodynamics", "Pharmacokinetics").

For children who can swallow tablets, the dose should be individualized according to the patient's condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg* for patients weighing 20 to 50 kg and 5 mg* for patients weighing ≥ 50 kg. Enalapril should be taken once daily. The dosage should be adjusted as needed to a maximum of 20 mg per day for patients weighing 20 to 50 kg and 40 mg for patients weighing ≥ 50 kg (see sections 4.4 and 4.4).

Enalapril is not recommended for neonates and children with glomerular filtration rate < 30 mL/min/1.73 m2 due to lack of data.

Children

Use for children aged 6 and over.

Enalapril is not recommended for neonates and children with glomerular filtration rate < 30 mL/min/1.73 m2 due to lack of data.

Overdose

There are limited data on overdose of the drug. The main signs of overdose, according to the available data, are pronounced arterial hypotension.