Enap, tablets 2,5mg 60 pcs

An antihypertensive drug, ACE inhibitor. The mechanism of action is associated with inhibition of ACE activity, which leads to reduction of angiotensin II formation.

Enalapril is a derivative of two amino acids: L-alanine and L-proline. After absorption, enalapril taken orally is hydrolyzed to enalarylate, which inhibits ACE.

The mechanism of its action is associated with decrease of angiotensin I angiotensin II formation from angiotensin I which decrease in plasma leads to increase of plasma renin activity (due to elimination of negative feedback on renin production) and decrease of aldosterone secretion.

As ACE is identical to the enzyme kininase II, enalapril can also block the degradation of bradykinin, a peptide with a potent vasopressor effect. The significance of this effect in the mechanism of action of enalapril has not been definitively established.

The antihypertensive effect of enalapril is primarily associated with inhibition of RAAS activity, which plays an important role in BP regulation. Despite this fact, enalapril has antihypertensive effect even in patients with arterial hypertension and low concentration of renin.

Enalapril decreases BP regardless of body position (both lying and standing) without a significant increase in HR. Symptomatic orthostatic hypotension is rare. In some patients, it may take several weeks of therapy to achieve optimal BP reduction. Abrupt withdrawal of enalapril has not been accompanied by a rise in BP.

Effective inhibition of ACE activity usually occurs 2-4 hours after a single oral administration of enalapril. Time of onset of antihypertensive action when taken orally is usually 1 h and reaches a maximum of 4-6 h. Duration of action depends on the dose. When used in recommended doses, the antihypertensive effect and hemodynamic effects are maintained for at least 24 h.

In patients with essential hypertension, a decrease in BP is accompanied by a decrease in PPS and an increase in cardiac output, while HR does not change or changes insignificantly. Renal blood flow increases, but glomerular filtration rate does not change. However, in patients with a baseline low glomerular filtration rate, it usually increased.

In patients with diabetic/nondiabetic nephropathy, albuminuria/proteinuria and renal IgG excretion decreased with enalapril.

In patients with chronic heart failure (CHF) on therapy with cardiac glycosides and diuretics
use of enalapril is accompanied by decreased RRPS and BP, increased cardiac output, and decreased HR (usually HR is increased in patients with chronic heart failure).

The pulmonary capillary congestion pressure also decreases. With long-term use enalapril increases exercise tolerance and reduces the severity of heart failure (assessed by criteria of NYHA).

Enalapril in patients with mild to moderate heart failure slows its progression and also slows development of left ventricular dilatation. In patients with left ventricular dysfunction enalapril decreases risk of major ischemic outcomes (including incidence of myocardial infarction and number of hospitalizations for unstable angina).

Indications

– essential hypertension;

– chronic heart failure (as part of combined therapy);

– prevention of the development of clinically significant heart failure in patients with asymptomatic left ventricular dysfunction (as part of combined therapy);

Prevention of coronary ischemia in patients with left ventricular dysfunction to reduce the incidence of myocardial infarction and decrease the rate of hospitalizations for unstable angina.

Active ingredient

Composition

1 tablet enalapril maleate 2.5 mg

Excipients:

sodium bicarbonate – 1.3 mg,

lactose monohydrate – 64.9 mg,

corn starch – 11.2 mg,

Hyprolose – 1.25 mg,

talc – 3 mg,

magnesium stearate – 0.85 mg.

How to take, the dosage

The drug is taken orally, regardless of meals, preferably at the same time of the day. The tablets should be swallowed with a small amount of liquid.

Arterial hypertension

The initial dose is 5 to 20 mg once daily, depending on the severity of arterial hypertension. In mild arterial hypertension, the recommended starting dose is 5 to 10 mg/day.

In patients with marked activation of the RAAS (e.g., with renovascular hypertension, electrolyte loss and/or dehydration, decompensated heart failure or severe arterial hypertension) an excessive decrease of BP at the beginning of treatment is possible. In such situations, it is recommended to start therapy with a low initial dose of 5 mg/day or less, under medical supervision.

Pre-existing high-dose diuretic therapy may lead to dehydration and increased risk of hypotension at the start of Enap® therapy; the recommended starting dose is 5 mg/day. Treatment with diuretics should be discontinued 2-3 days before the beginning of Enap® use. Caution should be exercised when using Enap®, renal function and serum potassium should be monitored.

The usual maintenance dose is 20 mg once daily.

The dose is adjusted individually; if necessary, the dose can be increased to a maximum daily dose of 40 mg.

Chronic heart failure and left ventricular dysfunction

The starting dose is 2.5 mg once daily, and treatment should be started under close medical supervision.

The drug Enap® for treatment of heart failure may be used simultaneously with diuretics and/or beta-adrenoblockers, if necessary with cardiac glycosides. In case of absence of symptomatic arterial hypotension at the beginning of therapy or after its correction the dose should be increased gradually (by 2.5-5 mg every 3-4 days) up to usual maintenance dose – 20 mg/day, which is prescribed either once or in 2 intakes depending on drug tolerance. The dose is adjusted over a 2-4 week period. The maximum daily dose is 40 mg in 2 doses.

WeekDose in mg/dayWeek 11-3 days: 2.5 mg/day* in 1 dose
Day 4-7 days: 5 mg/day in 2 dosesWeek 210 mg in 1-2 dosesWeek 3 and 420 mg in 1-2 doses

*Special precautions should be taken in patients with impaired renal function who take diuretics.

With regard to the risk of arterial hypotension and renal failure (much rarer), BP and renal function should be carefully monitored before and after starting Enap®. In patients taking diuretics, the doses of the latter, if possible, should be reduced before starting Enap® administration. The development of arterial hypotension after the first dose does not mean that the arterial hypotension will continue with long-term use, and does not indicate the need to discontinue the drug.

In patients with impaired renal function, the intervals between doses should be increased and/or the dose of Enap® reduced.

CCB Initial daily dose from 80 mL/min to 30 mL/min5 mg to 10 mL/min to 10 mL/min2.5 to 5 mg less than 10 mL/min2.5 mg on dialysis days*

* Enalaprilat is excreted by hemodialysis. In the interval between hemodialysis sessions, the dose of the drug should be adjusted under control of BP.

Elderly patients are more likely to have greater antihypertensive effects and longer duration of action due to slower elimination rate of enalapril, so the recommended starting dose is 1.25 mg.

In elderly patients, the dose is adjusted according to renal function.

Interaction

The risk of arterial hypotension, hyperkalemia and renal function disorders (including acute renal failure) is higher in case of dual RAAS blockade, i.e. in case of simultaneous use of angiotensin II receptor antagonists, ACE inhibitors or aliskiren, compared to the use of one of the above groups. It is recommended to monitor BP, renal function and water-electrolyte balance if concomitant use of the drugs is necessary.

The concomitant use of enalapril with aliskiren in patients with diabetes mellitus or impaired renal function (CKD)

The ACE inhibitors decrease potassium loss due to diuretics. Concomitant use of enalapril and potassium-saving diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations or potassium-containing table salt substitutes, as well as use of other drugs that increase potassium content in blood plasma (e.g. heparin) may lead to hyperkalemia. If concomitant use is necessary, caution should be exercised and serum potassium content should be monitored regularly.

Pre-existing high-dose diuretic therapy may lead to decreased RBC and increased risk of arterial hypotension during initiation of enalapril therapy. Excessive antihypertensive effects can be reduced by withdrawal of the diuretic, increased water or table salt intake, and by starting enalapril therapy at a low dose.

The concomitant use of beta-adrenoblockers, alpha-adrenoblockers, ganglioblockers, methyldopa, slow calcium channel blockers, nitroglycerin or other nitrates with enalapril may further decrease BP.

When concomitant use of ACE inhibitors with lithium preparations, a transient increase in serum lithium concentration and development of lithium intoxication have been observed. The use of thiazide diuretics may lead to an additional increase in serum concentrations of lithium and risk of lithium intoxication when concomitant use of ACE inhibitors. Concomitant use of enalapril with lithium is not recommended. If such a combination is necessary, serum lithium concentrations should be carefully monitored.

The concomitant use of some anesthetics, tricyclic antidepressants and antipsychotics (neuroleptics) with ACE inhibitors may lead to additional BP reduction.

The concomitant use of NSAIDs (including selective COX-2 inhibitors) may impair the antihypertensive effect of ACE inhibitors or angiotensin II receptor antagonists. NSAIDs and ACE inhibitors have an additive effect in increasing serum potassium, which may lead to reversible deterioration of renal function, especially in patients with existing renal impairment.

In rare cases, acute renal failure may develop, especially in patients with impaired renal function (e.g., elderly patients or patients with severe hypovolemia, including with the use of diuretics). Before initiating therapy, it is necessary to replenish the blood circulatory volume. During the treatment it is recommended to monitor renal function.

Epidemiological studies suggest that concomitant use of ACE inhibitors and hypoglycemic agents (insulin and hypoglycemic agents for oral administration) may increase hypoglycemic effect with risk of hypoglycemia. More often hypoglycemia develops in the first weeks of therapy in patients with impaired renal function.

Ethanol increases antihypertensive effect of ACE inhibitors.

Sympathomimetics may decrease the antihypertensive effect of ACE inhibitors.

The simultaneous use of enalapril with acetylsalicylic acid (as an antiplatelet agent), thrombolytics and beta-adrenoblockers is safe.

Withdraws the effect of drugs containing theophylline.

The simultaneous use of allopurinol, cytostatics and immunosuppressants (including methotrexate, cyclophosphamide) with ACE inhibitors may increase the risk of leukopenia. Concomitant use with allopurinol increases the risk of allergic reactions, especially in patients with impaired renal function.

The concomitant use of cyclosporine with ACE inhibitors may increase the risk of hyperkalemia.

Antacids may decrease the bioavailability of ACE inhibitors.

In the use of ACE inhibitors, including enalapril, a symptom complex including facial hyperemia, nausea, vomiting, arterial hypotension has been described in patients receiving intravenous gold (sodium aurothiomalate) preparations.

There have been no clinically significant pharmacokinetic interactions of enalapril with hydrochlorothiazide, furosemide, digoxin, timolol, methyldopa, warfarin, indomethacin, sulindac and cimetidine.

Concomitant use with propranolol decreases serum concentrations of enalaprilat, but this effect is clinically insignificant.

Special Instructions

Arterial hypotension

Symptomatic arterial hypotension rarely develops in patients with uncomplicated arterial hypertension. Arterial hypotension with all clinical manifestations may occur after the first administration of Enap® in patients with hypovolemia, as a result of diuretic therapy, salt-free diet, diarrhea, vomiting or hemodialysis.

The development of symptomatic arterial hypotension is more likely in patients with severe heart failure due to high-dose diuretics, hyponatremia or renal dysfunction.

In these patients the treatment should be started under medical supervision until the dose of Enap® and/or diuretic is optimally adjusted. The same tactics may be applied to patients with CHD or cerebrovascular disease in whom an abrupt excessive decrease of BP may lead to development of myocardial infarction or cerebral circulation disorder.

In case of severe arterial hypotension, the patient should be transferred to a horizontal position with a low head rest and, if necessary, 0.9% sodium chloride solution should be infused intravenously.

Transient arterial hypotension is not a contraindication for further treatment with Enap® . After BP and OBC stabilization, therapy can be continued.

In some patients with heart failure and normal or low BP, additional BP lowering with Enap® is possible. This effect is predictable and is not a reason to discontinue therapy. If arterial hypotension is accompanied by clinical symptoms, the doses should be reduced and/or the diuretic and/or Enap® should be stopped.

Aortic or mitral stenosis, GOCMP

As with all vasodilators, ACE inhibitors should be used with caution in patients with valve obstruction and left ventricular outflow tract hypertrophy. Patients with cardiogenic shock and hemodynamically significant left ventricular obstruction should not be prescribed.

In patients with renal impairment (CK®), the renal function should be adjusted first taking into account the CK and then the clinical response to treatment. In such patients, serum potassium and creatinine concentrations should be monitored regularly.

In patients with severe heart failure and renal disease, including renal artery stenosis, renal failure may develop when treated with Enap®. The changes were usually reversible after discontinuation of Enap®.

In some patients with arterial hypertension who were not found to have renal disease prior to treatment, a slight and transient increase in serum urea and creatinine concentrations has been observed with Enap® administration. In such cases, it may be necessary to reduce the dose of Enap® and/or discontinue the diuretic. This situation indicates the possibility of occult renal artery stenosis.

Renovascular hypertension

In patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure. Only minor changes in serum creatinine concentration may indicate decreased renal function. In such patients, treatment should be started with low doses under close medical supervision. The dose should be titrated carefully and renal function should be monitored.

Kidney transplantation

There is no experience with Enap® in patients who have recently had a kidney transplant. Therefore, treatment with Enap® in these patients is not recommended.

Hepatic dysfunction

In rare cases therapy with ACE inhibitors has been accompanied by the development of syndrome starting with cholestatic jaundice and hepatitis up to fulminant liver necrosis. The mechanism of this syndrome is unknown. If jaundice or significant increase in hepatic enzyme activity occurs, treatment with ACE inhibitor should be stopped immediately, the patient should be closely monitored, and treatment should be given if necessary.

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, thrombocytopenia and anemia have been described in patients using ACE inhibitors. In patients with normal renal function in the absence of other complications neutropenia is rare. Enap® should be used with great caution in patients with connective tissue diseases (including systemic lupus erythematosus, scleroderma) concomitantly receiving immunosuppressive therapy, allopurinol or procainamide, as well as in combination of these factors, especially in existing renal function disorders. These patients may develop severe infections that are not amenable to intensive antibiotic therapy. If patients do take Enap® , it is advisable to periodically monitor the white blood cell count. The patient should be warned that in case of any signs of infection it is necessary to see a doctor immediately.

Hypersensitivity/angioedema

In patients treated with ACE inhibitors, including Enap® , there have been reports of angioedema of the face, limbs, lips, vocal folds and/or larynx at any time after treatment initiation. Enap® should be discontinued immediately and the patient should be monitored until the symptoms have completely disappeared. Even in case of tongue edema, when only difficulty in swallowing without respiratory distress syndrome occurs, patients may require long-term monitoring, as use of antihistamines and GCS may be insufficient.

The angioedema of the larynx or tongue may be fatal in very rare cases. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction, especially after a history of airway surgery. If swelling of the tongue, vocal folds or larynx is present, appropriate therapy is indicated, which may include: intravenous injection of 0.1% epinephrine (adrenaline) solution (0.3 ml-0.5 ml) and/or measures to restore airway patency (intubation or tracheostomy).

The incidence of angioedema is higher among patients of the Negro race receiving ACE inhibitor therapy than among patients of other racial backgrounds.

Patients with a history of angioedema unrelated to ACE inhibitors have an increased risk of developing angioedema with any ACE inhibitor.

Anaphylactoid reactions during Hymenoptera venom desensitization

Patients who have taken ACE inhibitors during Hymenoptera venom desensitization have rarely developed life-threatening anaphylactoid reactions. To prevent such reactions, the ACE inhibitor should be temporarily discontinued during desensitization procedures.

Anaphylactoid reactions during LDL apheresis

Patients who have taken ACE inhibitors during LDL apheresis with dextran sulfate have rarely developed life-threatening anaphylactoid reactions. The drug should be temporarily replaced with drugs of another group.

Hemodialysis

Because of the increased risk of anaphylactoid reactions, the drug should not be used in patients on hemodialysis using high flow polyacrylonitrile membranes (AN69®). If hemodialysis is necessary, it is advisable to use a different type of dialysis membrane or another group of antihypertensive medications.

Hypoglycemia

In diabetic patients receiving oral hypoglycemic drugs or insulin, blood glucose concentrations should be carefully monitored during the first month of treatment with ACE inhibitor.

Cough

The use of Enap® may result in a dry, non-productive, prolonged cough that disappears after discontinuation of the ACE inhibitor, which should be considered in the differential diagnosis of cough with an ACE inhibitor.

Surgery/general anesthesia

Before surgical interventions (including dental procedures), the surgeon/anesthesiologist should be warned about the use of Enap®. In major surgical procedures or general anesthesia with agents causing arterial hypotension, ACE inhibitors may block angiotensin II formation in response to compensatory renin release. If a pronounced decrease in BP develops, explained by such a mechanism, it can be corrected by administration of plasma substitutes.

Hyperkalemia

May develop during treatment with ACE inhibitors, including Enap®. Risk factors of hyperkalemia development are renal insufficiency, elderly age (over 70), diabetes mellitus, some concomitant conditions (decreased circulatory blood pressure, decompensated acute heart failure, metabolic acidosis), concomitant use of potassium-saving diuretics (spironolactone, eplerenone, triamterene, amiloride), as well as potassium drugs or potassium-containing substitutes and use of other drugs that increase potassium content in blood plasma (e.g., heparin).

The use of potassium preparations, potassium-saving diuretics, and potassium-containing salt substitutes may lead to a significant increase in serum potassium content, especially in patients with impaired renal function. Hyperkalemia may lead to serious cardiac rhythm disturbances, sometimes with fatal outcome. Simultaneous use of the above mentioned drugs should be conducted with caution under control of serum potassium content.

Lithium

The concomitant use of lithium salts and Enap® is not recommended.

Ethnicity

Enap®, like other ACE inhibitors, has less antihypertensive effect in non-Hispanic patients compared to other races.

Special information about excipients

Enap® contains lactose, therefore the drug is contraindicated in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Impact on ability to drive and operate machinery

Impact on ability to drive and operate machinery. When using Enap® it is necessary to be careful when driving vehicles and performing other potentially dangerous activities requiring high concentration and quick psychomotor reactions (dizziness may occur due to rapid decrease of BP, especially after the initial dose of Enap® in patients taking diuretics).

Contraindications

– history of angioedema associated with the use of ACE inhibitors;

– hereditary Quincke’s edema or idiopathic angioedema;

– concomitant use with aliskiren in patients with diabetes mellitus or impaired renal function (CKD)

– porphyria;

– pregnancy;

– period of lactation (breastfeeding);

– age less than 18 years (efficacy and safety not established);

– lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;

– hypersensitivity to enalapril and other components of the drug;

– hypersensitivity to other ACE inhibitors.

The drug should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery of the sole kidney; with primary hyperaldosteronism; hyperkalemia; after kidney transplantation; with aortic and/or mitral stenosis (with hemodynamic disorders); hypertrophic obstructive cardiomyopathy (HACMI); with decreased RBC volume (incl.In the case of diarrhea, vomiting); with systemic connective tissue diseases (incl. Scleroderma, systemic lupus erythematosus); CHD; with suppression of medullary hematopoiesis; cerebrovascular disease (incl. in patients with cerebrovascular insufficiency); with diabetes mellitus; with renal insufficiency (proteinuria – more than 1 g/day); with hepatic insufficiency; with patients maintaining salt restriction diet or undergoing hemodialysis; concomitantly with immunosuppressants and diuretics; with elderly patients (over 65 years).

Side effects

Classification of the frequency of side effects (WHO): very common (≥1/10), common (≥1/100 and

Hematopoietic system: infrequent – anemia (including aplastic and hemolytic), rare – neutropenia, decreased hemoglobin and hematocrit, thrombocytopenia, agranulocytosis, suppression of bone marrow hematopoiesis, pancytopenia, lymphoadenopathy, autoimmune diseases.

Metabolism disorders: infrequently – hypoglycemia.

Nervous system disorders:very often – dizziness; often – headache, depression; infrequently – confusion, insomnia, somnolence, paresthesia, increased excitability, vertigo; rarely – changes in the nature of dreams, sleep disorders.

Sensory organs:often – change in taste perception; infrequently – tinnitus; very rarely – blurred vision.

Cardiovascular system disorders:often – marked decrease in BP (including orthostatic hypotension), syncope, chest pain, heart rhythm disorders, angina pectoris; infrequently – palpitations, myocardial infarction or stroke (due to sharp decrease of BP in high-risk patients); rarely – Raynaud’s syndrome.

In the respiratory system:very frequently – cough; infrequently – rhinorrhea, sore throat and hoarseness, bronchospasm/bronchial asthma; rarely – shortness of breath, lung infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Digestive system disorders: very common – nausea; common – diarrhea, abdominal pain, flatulence; infrequent – ileitis, intestinal obstruction, pancreatitis, vomiting, constipation, anorexia, dry oral mucosa, peptic ulcer; rare – disorders of liver function and biliary excretion, hepatitis (hepatocellular or cholestatic), including hepatic necrosis, cholestatic jaundice, stomatitis/aphthous ulcers, glossitis; very rare – angioedema of the intestine.

Skin disorders:often – skin rash; infrequently – increased sweating, itching, alopecia; rarely – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vesicles, erythroderma.

A symptom complex has been described that may include fever, myalgia/myositis, arthralgia/arthritis, serositis, vasculitis, elevated CRP, leukocytosis and eosinophilia, and a positive antinuclear antibody test. There may be skin rash, photosensitization reactions, or other skin manifestations.

With regard to the urinary system: infrequently – impaired renal function, proteinuria, renal failure; rarely – oliguria.

From the sexual system: infrequent – decreased potency; rarely – gynecomastia.

Muscular system disorders: infrequent – muscle cramps.

Laboratory parameters:often – hyperkalemia, increased serum creatinine concentration; infrequently – hyponatremia, increased serum urea concentration; rarely – increased liver transaminase activity and bilirubin concentration.

Allergic reactions:often – hypersensitivity reactions/angioedema of the face, lips, tongue, pharynx and/or larynx; infrequently – skin itching, urticaria.

Others: frequency unknown – syndrome of inadequate ADH secretion.

An undesirable phenomena detected during the post-marketing use of Enap®, but no causal relationship to the drug administration has been established: Urinary tract infections, upper respiratory tract infections, bronchitis, cardiac arrest, atrial fibrillation, shingles, melena, ataxia, pulmonary branch thromboembolism and pulmonary infarction, hemolytic anemia, including cases of hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.

Overdose

Symptoms: approximately 6 hours after oral administration – marked BP decrease up to the development of collapse, water-electrolyte balance disorders, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough, seizures, stupor.

After oral administration of enalapril at doses of 300 and 440 mg, serum plasma concentrations of enalaprilat were 100 and 200 times higher than normal therapeutic concentrations, respectively.

Treatment: the patient should be transferred to a horizontal position with a low headboard. In mild cases gastric lavage and ingestion of activated charcoal are indicated; in more severe cases – intravenous infusion of 0.9% sodium chloride solution, plasma substitutes, if necessary – intravenous catecholamine administration.

Enalaprilat may be excreted by hemodialysis, excretion rate is 62 ml/min. In patients with bradycardia resistant to therapy, a pacemaker is indicated. Serum electrolyte and serum creatinine concentration should be monitored carefully.

Similarities