Enalapril Reneval, tablets 5 mg 28 pcs

Enalapril refers to drugs affecting the renin-angiotensin-aldosterone system (RAAS), ACE inhibitors. Enalapril is used for treatment of essential hypertension (primary arterial hypertension (PH) of any severity and renovascular hypertension both in monotherapy and in combination with other hypotensive agents, in particular diuretics. Enalapril is also used to treat or prevent the development of heart failure (CHF).

Pharmacodynamics

Enalapril is a derivative of two amino acids, L-alanine and L-proline. After oral administration, enalapril is rapidly absorbed and hydrolyzed into enalaprilate, which is a highly specific and long-acting ACE inhibitor containing no sulfhydryl group.

The ACE (peptidyl dipeptidase A) catalyzes the conversion of angiotensin I into the pressor peptide angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilate, which inhibits ACE. ACE inhibition leads to a decrease in plasma concentration of angiotensin II, which entails an increase in plasma renin activity (due to the elimination of negative feedback in response to renin release) and a decrease in aldosterone secretion.

The ACE is identical to the enzyme kininase II, so enalapril can also block the degradation of bradykinin, a peptide with a marked vasodilatory effect. The significance of this effect in the therapeutic effect of enalapril needs to be clarified.

While the primary mechanism by which enalapril lowers blood pressure (BP) is considered to be inhibition of the RAAS activity, which plays an important role in BP regulation, enalapril shows antihypertensive effect even in patients with AH and with decreased plasma renin activity.

The use of enalapril in patients with AH leads to a decrease in BP in both standing and lying position without a significant increase in heart rate (HR).

Symptomatic postural hypotension develops infrequently. In some patients, it may take several weeks of therapy to achieve optimal BP reduction. Interruption of therapy with enalapril does not cause a sharp rise in BP.

Effective inhibition of ACE activity usually develops 2-4 hours after a single oral dose of enalapril. Antihypertensive effect develops within 1 hour, the maximum BP reduction is observed 4-6 hours after taking the drug. The duration of action depends on the dose. However, when using the recommended doses, the antihypertensive effect and hemodynamic effects are maintained for 24 hours.

Enalapril hypotensive therapy leads to significant regression of left ventricular hypertrophy and preservation of systolic function.

In clinical studies of hemodynamics in patients with essential hypertension, a decrease in BP was accompanied by a decrease in total peripheral vascular resistance, an increase in cardiac output, and no or little change in HR. An increase in renal blood flow was observed after enalapril administration.

There was no change in glomerular filtration rate (GFR) and no evidence of sodium or fluid retention. However, in patients with initially decreased glomerular filtration its rate usually increased.

Long-term use of enalapril in patients with essential hypertension and renal insufficiency may result in improvement of renal function as indicated by increased GFR.

In short clinical trials in patients with renal insufficiency and with or without diabetes mellitus, a decrease in albuminuria, renal IgG excretion, and total protein in the urine was observed after administration of enalapril.

When enalapril and thiazide diuretics are used concomitantly, a more pronounced antihypertensive effect is observed. Enalapril reduces or prevents the development of hypokalemia caused by taking thiazides.

Enalapril therapy is generally not associated with undesirable effects on plasma uric acid concentration.

Enalapril therapy is associated with favorable effects on plasma lipoprotein fraction ratios and no or favorable effects on total cholesterol concentrations.

In patients with CH patients on therapy with cardiac glycosides and diuretics, enalapril administration caused reduction of total peripheral resistance and BP. Cardiac output increased, while HR (usually elevated in patients with CH) decreased. Pulmonary capillary congestion pressure also decreased.

The exercise tolerance and severity of CH, as assessed by New York Heart Association (NYHA) criteria, improved. These effects were observed with long-term therapy.

In patients with mild to moderate CHF severity, enalapril delayed progression of cardiac dilatation and CHF, as indicated by decreased left ventricular end-diastolic and systolic volumes and improved left ventricular ejection fraction.

The clinical data showed that enalapril reduces the incidence of ventricular arrhythmias in patients with CHF, although the underlying mechanisms and clinical significance of this effect are not known.

Pharmacokinetics

Enalapril is rapidly absorbed in the gastrointestinal tract after oral administration. Maximum serum concentration of enalapril is reached within 1 hour after oral administration. The degree of absorption of enalapril when taken orally is approximately 60%. Food intake has no effect on the absorption of enalapril.

Enalapril is rapidly hydrolyzed after absorption to form the active metabolite enalaprilate, a potent ACE inhibitor. Maximum serum concentration of enalaprilat is observed approximately 4 hours after an oral dose of enalapril.

The duration of absorption and hydrolysis of enalapril is similar for various recommended therapeutic doses. In healthy volunteers with normal renal function, the equilibrium serum concentration of enalaprilat is reached by day 4 from the start of enalapril administration.

Distribution

In therapeutic dose range, binding of enalaprilat to plasma proteins does not exceed 60%.

Metabolism

There are no data on other significant pathways of metabolism of enalapril other than hydrolysis to enalaprilat.

Elevation

Elevation of enalapril is primarily via the kidneys. The main metabolites detected in the urine are enalaprilate, accounting for approximately 40% of the dose, and unchanged enalapril (approximately 20%).

The plasma concentration curve of enalaprilat has a prolonged terminal phase apparently due to its binding to ACE. The elimination half-life of enalaprilat with oral administration is 11 hours.

Pharmacokinetics in special patient groups

Patients with impaired renal function

The area under the concentration-time curve (AUC) of enalapril and enalaprilat is increased in patients with renal impairment. In patients with mild to moderate renal impairment (creatinine clearance (CK) 40-60 mL/min), the equilibrium AUC of enalaprilat was approximately 2-fold higher after administration of enalapril at a dose of 5 mg once daily than in patients with unchanged renal function.

In patients with severe renal impairment (CK of 30 ml/min or less), the AUC increased approximately 8-fold. The effective elimination half-life of enalaprilat after repeated administration of enalapril in patients with severe renal impairment was prolonged and the onset of equilibrium concentration of enalaprilat was delayed (see section “Dosage and administration”).

Enalaprilat may be eliminated from the general bloodstream by hemodialysis procedures. Clearance in hemodialysis is 62 ml/min.

Breastfeeding

After a single oral administration of enalapril at a dose of 20 mg in postpartum patients, the mean maximum concentration of enalapril in breast milk was 1.7 µg/L (0.54 to 5.9 µg/L) 4-6 hours after administration.

The mean maximum concentration of enalaprilat was 1.7 µg/L (1.2 to 2.3 µg/L) and was observed at various times within 24 hours of administration. Taking into account data on maximum concentrations in breast milk, the estimated maximum intake of enalapril for a fully breastfed infant is 0.16% of the dose based on maternal body weight.

In a woman who took enalapril orally at a dose of 10 mg once daily for 11 months, maximum concentrations of enalapril in breast milk were 2 μg/L 4 hours after administration, and maximum enalaprilate concentrations were 0.75 μg/L approximately 9 hours after administration.

The mean concentrations in breast milk at 24 hours after enalapril administration were 1.44 mcg/L and enalaprilat was 0.63 mcg/L. One woman who took enalapril at a dose of 5 mg once and two women who took enalapril at a dose of 10 mg once had breast milk concentrations below the detectable level (less than 0.2 µg/L) 4 hours after ingestion. Their enalapril concentrations were not detectable.

Indications

Active ingredient

Composition

One tablet:
Active ingredient
Enalapril maleate – 0.005 g
Excipients – to obtain a tablet weight of 0.1 g

How to take, the dosage

In monotherapy of arterial hypertension, the initial dose is 5 mg once daily.
If there is no clinical effect, the dose is increased by 5 mg after 1-2 weeks. After the initial dose, patients should be under medical supervision for 2 hours and an additional 1 hour until BP stabilizes. If necessary and tolerated well enough, the dose can be increased to 40 mg/day in 2 doses. After 2-3 weeks, switch to a maintenance dose of 10-40 mg/day divided into 1-2 doses. With moderate arterial hypertension, the average daily dose is about 10 mg.

Interaction

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

. Dual RAAS blockade with APA II, ACE inhibitors, or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia, and renal function impairment (including acute renal failure) compared to monotherapy.

The BP, renal function, and blood electrolyte levels should be monitored regularly in patients taking enalapril and other drugs that affect the RAAS simultaneously.

The concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

The concomitant use of ACE inhibitors with angiotensin II receptor antagonists (APA II) is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Kalium-saving diuretics, potassium preparations, potassium-containing salt substitutes, and other drugs that can increase serum potassium levels

. Concomitant use of enalapril with potassium-saving diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing food salt substitutes and other medications that can increase serum potassium (including angiotensin II receptor antagonists, heparin, tacrolimus, cyclosporine; drugs containing co-trimoxazole [trimethoprim + sulfamethoxazole]) may lead to a significant increase in plasma potassium. Plasma potassium should be monitored regularly if enalapril should be used with the above drugs.

Potassium preserving (thiazide and “loop”) diuretics

High-dose diuretics may lead to hypovolemia (due to decreased blood circulation), and addition of enalapril to therapy may cause significant BP decrease. Excessive antihypertensive effect of enalapril can be reduced either by diuretic withdrawal or by increasing RBC or table salt intake and by reducing enalapril dose.

When enalapril is used concomitantly with potassium-saving (thiazide or “loop”) diuretics, hypokalemia caused by diuretics is usually attenuated by the effect of enalapril.

Other hypotensive drugs

Additive effect may be observed with concomitant use of enalapril and other hypotensive therapy.

When using enalapril concomitantly with other hypotensive drugs, especially diuretics, an increase in antihypertensive effect may be observed.

The concomitant use of enalapril with beta-adrenal blockers, methyldopa or slow calcium channel blockers increased the severity of antihypertensive effect.

The concomitant use of enalapril with alpha-adrenoblockers, beta-adrenoblockers and ganglionic blockers should be under close medical supervision.

The concomitant use of enalapril with nitroglycerin, other nitro-containing agents or other vasodilators increases the antihypertensive effect.

Lithium drugs

Like other drugs that affect sodium excretion, ACE inhibitors may decrease renal excretion of lithium and lead to increased cardiotoxic and neurotoxic effects of lithium. If concomitant use of drugs containing lithium and ACE inhibitors is necessary, the lithium concentration in blood serum should be monitored regularly.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors and high doses of acetylsalicylic acid (≥3 g/day)

NSAIDs, including selective cyclooxygenase-2 inhibitors (COX-2) and acetylsalicylic acid at doses of 3 g/day or higher, may reduce the antihypertensive effect of diuretics and other hypotensive agents. Consequently, the antihypertensive effect of angiotensin II receptor antagonists (APA II) or ACE inhibitors may be weakened with concomitant use of NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those taking diuretics) receiving NSAID therapy (including selective COX-2 inhibitors), concomitant use of ACE inhibitors or APA II may cause further impairment of renal function, including development of acute renal failure and hyperkalemia.

These effects are usually reversible. Concomitant use of ACE inhibitors and NSAIDs should be used with caution (especially in elderly patients and in patients with impaired renal function). Patients should receive adequate amounts of fluid. Careful monitoring of renal function is recommended, both at the beginning and during treatment.

The use of enalapril in combination with acetylsalicylic acid as an antiplatelet agent is not contraindicated.

Hypoglycemic drugs

Epidemiologic studies have shown that concomitant use of ACE inhibitors and hypoglycemic drugs (insulin, oral hypoglycemic drugs) can increase the hypoglycemic effect of the latter with a risk of hypoglycemia. This phenomenon was usually most frequently observed during the first weeks of combined therapy, as well as in patients with impaired renal function.

In diabetic patients taking oral hypoglycemic drugs or insulin, blood glucose concentrations should be monitored regularly, especially during the first month of concomitant use with ACE inhibitors.

Tricyclic antidepressants/neuroleptics/general anesthetics/drugs

Augmentation of the antihypertensive effect of ACE inhibitors (further decrease in BP with concomitant use) and increased risk of orthostatic hypotension.

Alpha- and beta-adrenomimetics

Alpha- and beta-adrenomimetics (sympathomimetics) such as epinephrine (adrenaline), isoproterenol, dobutamine, dopamine may decrease the antihypertensive effect of ACE inhibitors.

Baclofen

It enhances the antihypertensive effect of ACE inhibitors. Blood pressure should be monitored carefully and, if necessary, the dosage of hypotensive drugs should be adjusted.

Ethanol

Ethanol increases the antihypertensive effect of ACE inhibitors.

Theophylline

Enalapril weakens the effect of drugs containing theophylline.

Estrogens

Estrogens weaken the antihypertensive effect of enalapril due to fluid retention.

Allopurinol, procainamide, cytostatics, immunosuppressants, glucocorticosteroids (when used systemically)

Concomitant use with ACE inhibitors may increase the risk of neutropenia/agranulocytosis.

Gold preparations

In concomitant use of parenteral gold preparations (sodium aurothiomalate) and ACE inhibitors, including enalapril, a symptom complex (nitrate-like reactions) has been described, including blood “flush” to the face, nausea, vomiting and hypotension.

Inhibitors of mTOR (mammalion Target of Rapamycin in mammalian cells) (e.g., temsirolimus, sirolimus, everolimus)

. In patients taking ACE inhibitors and mTOR inhibitors (temsirolimus, sirolimus, everolimus) simultaneously, an increased incidence of angioedema was observed.

Dipeptidyl peptidase type IV (DPP-IV) inhibitors (glyptins) such as sitagliptin, saxagliptin, vildagliptin, linagliptin

. In patients taking ACE inhibitors and type IV dipeptidyl peptidase inhibitors (glyptins) simultaneously, an increased incidence of angioedema has been observed.

Estramustine

An increased incidence of angioedema when used concomitantly with ACE inhibitors.

Neutral endopeptidase inhibitors (NEIs)

An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and racecadotril (an encephalinase inhibitor).

Acetylsalicylic acid, thrombolytics and beta-adrenoblockers

Enalapril can be used simultaneously with acetylsalicylic acid (as an antiplatelet agent), thrombolytics and beta-adrenoblockers.

Pharmacokinetic interactions

Antacids

The bioavailability of ACE inhibitors may be reduced.

Other drugs

There have been no clinically significant pharmacokinetic drug interactions between enalapril and the following drugs: hydrochlorothiazide, furosemide, digoxin, timolol, methyldopa, warfarin, indomethacin, sulindac and cimetidine.

Concomitant use of enalapril and propranololol decreases the serum concentration of enalaprilat, but this effect is not clinically significant.

Special Instructions

Symptomatic arterial hypotension

Symptomatic arterial hypotension is rarely seen in patients with uncomplicated AH. In AH patients taking enalapril, arterial hypotension develops more frequently with dehydration resulting from, for example, diuretic therapy, restriction of table salt intake, dialysis patients, and patients with diarrhea or vomiting.

Symptomatic arterial hypotension has been observed in patients with CHF in combination with or without chronic renal failure.

Arterial hypotension is more likely to develop in patients with more severe CHF with hyponatremia or impaired renal function in whom higher doses of “loop” diuretics are used. In such patients, treatment with enalapril should be initiated under physician supervision, which should be particularly careful when changing the dose of enalapril and/or diuretic.

In a similar manner, patients with coronary heart disease or cerebrovascular disease in whom excessive BP reduction may lead to myocardial infarction or stroke should be monitored.

In case of arterial hypotension, the patient should be transferred to a horizontal position and, if necessary, 0.9% sodium chloride solution should be administered. Transient arterial hypotension during enalapril administration is not a contraindication for further use and increase of enalapril dose, which can be continued after fluid replacement and normalization of BP.

In some patients with CHF and with normal or reduced BP, enalapril may cause an additional decrease in BP. This response to enalapril is expected and is not a reason to discontinue treatment. In cases where arterial hypotension is stable, the dose should be reduced and/or the diuretic and/or enalapril should be discontinued.

Aortic stenosis/ mitral stenosis/hypertrophic obstructive cardiomyopathy

As with all medications with vasodilator effects, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

In patients with impaired renal function (creatinine clearance < 80 ml/min) the initial dose and/or the frequency of enalapril administration should be reduced depending on the creatinine clearance value. In such cases, renal function (creatinine and potassium in blood) should be regularly monitored during the first few weeks of treatment.

In some patients, arterial hypotension developing after initiation of treatment with ACE inhibitors may lead to worsening of renal function. Cases of oliguria, progressive azotemia and acute renal failure (including fatal) with ACE inhibitors have been described, mainly in patients with chronic heart failure or concomitant renal disease (including renal artery stenosis).

With timely detection and appropriate treatment, ACE inhibitor-induced acute renal failure is usually reversible.

In some patients with no evidence of renal disease prior to treatment, use of enalapril in combination with diuretics has caused increased serum urea and creatinine concentrations. In such cases, dose reduction and/or discontinuation of the diuretic and/or enalapril may be required.

An appropriate evaluation is recommended because these abnormalities may be an indication of previously unrecognized renal artery stenosis.

Renovascular hypertension

Patients with bilateral renal artery stenosis or renal artery stenosis of the sole kidney have an increased risk of arterial hypotension and renal failure when using ACE inhibitors. Renal failure may initially manifest itself only by small changes in plasma creatinine. Enalapril therapy in such patients should be started with low doses under close medical supervision and monitoring of renal function.

Kidney transplantation

There is no experience with enalapril in patients who have recently undergone a kidney transplantation. Therefore, the use of enalapril in these patients is not recommended.

Hepatic dysfunction

The use of ACE inhibitors has rarely been associated with the development of a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant liver necrosis, sometimes with a fatal outcome. The mechanism of development of this syndrome is unknown.

If jaundice or significant increase in “hepatic” transaminase activity occurs with the use of the drug, enalapril should be discontinued and appropriate adjuvant therapy should be administered. The patient should be appropriately monitored.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

In patients taking ACE inhibitors, cases of neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported. Neutropenia is rare in patients with normal renal function and without other complicating factors.

Enalapril should be used with particular caution in patients with systemic connective tissue diseases (systemic lupus erythematosus, scleroderma and others), those taking immunosuppressive therapy, allopurinol or procainamide, or with a combination of these complicating factors, especially if renal function is impaired.

Some patients have developed serious infectious diseases, which in some cases did not respond to intensive antibiotic therapy.

When using enalapril in patients at high risk of neutropenia/agranulocytosis, regular monitoring of blood leukocyte count is recommended. Patients should be warned to seek immediate medical attention if there are any signs of infectious disease (e.g., fever, sore throat).

Hypersensitivity reactions / angioedema

In the use of ACE inhibitors, including enalapril, rare cases of angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx have been observed. Angioneurotic edema may develop at any time during treatment.

In such cases, enalapril should be discontinued immediately and the patient should be closely monitored for control and correction of clinical symptoms. Even in cases where only tongue swelling without respiratory distress syndrome is present, patients may require prolonged monitoring, as therapy with antihistamines and corticosteroids may not be sufficient.

The angioedema associated with swelling of the larynx and tongue may very rarely be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction, especially in patients who have had surgery on the respiratory system.

If airway obstruction develops, appropriate treatment should be administered immediately, including subcutaneous injection of 0.3-0.5 ml of 0.1% epinephrine (adrenaline) solution and/or ensuring airway patency (intubation or tracheostomy).

In rare cases, intestinal edema (angioedema of the intestine) develops during therapy with ACE inhibitors. Patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without prior angioedema of the face and with normal C1-esterase levels.

The diagnosis is established by abdominal computed tomography, ultrasound, or surgery. Symptoms disappeared after discontinuation of ACE inhibitors. The possibility of intestinal edema should be considered in the differential diagnosis of abdominal pain in patients taking ACE inhibitors.

Patients with a history of angioedema not associated with ACE inhibitor therapy may be at greater risk for angioedema with ACE inhibitor therapy.

Patients of the Negro race taking ACE inhibitors were more likely to have angioedema than patients of other races.

An increased risk of angioedema was seen in patients taking ACE inhibitors and drugs such as mTOR inhibitors (temsirolimus, sirolimus, everolimus), inhibitors

dipeptidyl peptidase type IV inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin), estramustine, neutral endopeptidase inhibitors (racecadotril).

Anaphylactoid reactions during desensitization with Hymenoptera venom allergen

In rare cases, patients taking ACE inhibitors have developed life-threatening anaphylactoid reactions during desensitization with Hymenoptera venom allergen.

The adverse reactions can be avoided by temporarily discontinuing the ACE inhibitor prior to desensitization. Enalapril should be avoided in patients receiving bee venom immunotherapy.

Anaphylactoid reactions during low-density lipoprotein apheresis (LDL apheresis)

In patients taking ACE inhibitors during LDL apheresis with dextran sulfate, life-threatening anaphylactoid reactions have rarely been observed. These reactions can be prevented by temporarily withdrawing the ACE inhibitor prior to each LDL-apheresis procedure.

Hemodialysis using high-flow membranes

Anaphylactoid reactions have been observed in patients on dialysis using high-flow polyacrylonitrile membranes (such as AN69®) and receiving ACE inhibitor therapy simultaneously. In such cases, a different type of dialysis membrane should be used or other classes of hypotensive agents should be used.

Diabetes mellitus

When using enalapril in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be monitored regularly. Patients receiving oral hypoglycemic agents or insulin should be informed about the necessity of regular monitoring of blood glucose concentration (hypoglycemia) before starting ACE inhibitors, especially during the first month of concomitant use of the mentioned drugs.

Cough

There have been cases of cough on therapy with ACE inhibitors. As a rule, the cough is non-productive and persistent and stops after discontinuation of the drug. Cough associated with the use of ACE inhibitors should be considered in the differential diagnosis of dry cough.

Surgical interventions/general anesthesia

In major surgical interventions or general anesthesia with antihypertensive agents, enalaprilat blocks angiotensin II formation caused by compensatory renin release. If a pronounced decrease in BP develops due to this mechanism, it may be corrected by increasing circulating blood volume.

Hyperkalemia

Hyperkalemia may develop with ACE inhibitor therapy, including enalapril. Risk factors of hyperkalemia development are renal insufficiency, elderly age (>65 years), diabetes mellitus, some concomitant conditions (decreased BOD, decompensated acute heart failure, metabolic acidosis), concomitant use of potassium-saving diuretics (such as spironolactone, eplerenone, triamterene, or amiloride), as well as potassium preparations, potassium-containing salt substitutes, and other medications that contribute to increased plasma potassium levels (such as heparin, tacrolimus, cyclosporine; drugs containing co-trimoxazole [trimethoprim + sulfamethoxazole]).

The use of potassium supplements, potassium-saving diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to a significant increase in serum potassium. Hyperkalemia can lead to serious cardiac rhythm disturbances, sometimes with fatal outcome.

When concomitant use of enalapril and the above potassium-containing or potassium-boosting medications is necessary, caution should be exercised and serum potassium levels should be monitored regularly.

Hypokalemia

When ACE inhibitors are used concomitantly with thiazide diuretics, there is a risk of hypokalemia; therefore, regular monitoring of blood potassium levels during therapy should be performed.

Double blockade of renin-angiotensin-aldosterone system (RAAS)

. The development of arterial hypotension, syncope, stroke, hyperkalemia, and renal dysfunction (including acute renal failure) has been reported in susceptible patients, especially if combined therapy with drugs affecting the RAAS is used.

The concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

The concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

In cases where simultaneous administration of two drugs acting on the RAAS is necessary, their use should be performed under medical supervision with extreme caution and with regular monitoring of renal function, BP and plasma electrolyte content.

Lithium preparations

The concomitant use of enalapril and lithium-containing medications is not recommended.

Alcohol

Any alcoholic beverages are not recommended during treatment, because ethanol increases the antihypertensive effect of ACE inhibitors.

The use in elderly patients

The clinical studies of efficacy and safety of enalapril have been similar in elderly and younger patients with AH.

Ethnic differences

Enalapril, like other ACE inhibitors, has less pronounced antihypertensive effects in non-Hispanic patients compared to other races, which may be due to the higher prevalence of conditions with low plasma renin activity in non-Hispanic patients with arterial hypertension.

Cessation of therapy

An abrupt discontinuation of enalapril generally does not lead to development of withdrawal syndrome.

The effect of Enalapril on driving and operating machinery

The effect of Enalapril on driving and operating machinery has not been studied. However, some adverse events (e.g., dizziness) which have been observed while taking Enalapril may affect the ability to drive and operate machinery (see section “Adverse effects”).

Contraindications

Side effects

In general, Enalapril is well tolerated. In clinical trials, the cumulative incidence of adverse events (AEs) with Enalapril did not exceed that with placebo. In most cases, NTIs were mild, transient and did not require therapy withdrawal.

The following criteria were used to assess the incidence of NIH: “very common” (≥1/10); “common” (≥1/100, < 1/10); “infrequent” (≥1/1000, < 1/100); “rare” (≥1/10000, < 1/1000); “very rare” (< 1/10000); “frequency unknown” (no frequency estimate based on available data).

NJs are grouped according to the system-organ classes of the MedDRA Medical Regulatory Dictionary, within each class the NJs are listed in decreasing order of frequency, within each group allocated by frequency of occurrence the NJs are categorized in decreasing order of importance.

Disorders of the blood and lymphatic system

Infrequent: anemia (including aplastic and hemolytic).

Rarely: neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, suppression of bone marrow function, pancytopenia, lymphadenopathy, autoimmune diseases.

Endocrine system disorders

Prevalence unknown: syndrome of inadequate secretion of antidiuretic hormone.

Metabolic and nutritional disorders

Infrequent: hypoglycemia (see section “Special Precautions”).

Nervous system disorders and mental disorders

Often: headache, depression.

Infrequent: confusion, drowsiness, insomnia, increased nervousness, paresthesia, systemic dizziness.

Rarely: unusual dreams, sleep disturbances.

Visual disturbances

Very common: blurred vision.

Heart and vascular disorders

Very common: dizziness.

Often: marked decrease in BP, fainting, chest pain, impaired rhythm, angina pectoris, tachycardia.

Infrequent: orthostatic hypotension, palpitations, myocardial infarction or stroke*, possibly secondary to severe arterial hypotension in high-risk patients (see “Special Precautions”).

Rarely: Raynaud’s syndrome.

Respiratory system, thorax and mediastinum disorders

Very common: cough.

Often: shortness of breath.

Infrequent: rhinorrhea, sore throat, hoarseness of voice, bronchospasm/bronchial asthma.

Rarely: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Disorders of the digestive system

very often: nausea.

Often: diarrhea, abdominal pain, impaired taste.

Infrequent: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, stomach irritation, dry oral mucosa, gastric and duodenal ulcer.

Rarely: stomatitis/aphthous ulcers, glossitis.

Very rare: intestinal edema.

Liver and biliary tract disorders

Rarely: liver failure, hepatitis (hepatocellular or cholestatic), hepatitis (including necrosis), cholestasis (including jaundice).

Skin and subcutaneous tissue disorders

Often: skin rash, hypersensitivity reactions/angioedema: angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx (see section “Special indications”).

Infrequent: increased sweating, skin itching, urticaria, alopecia.

Rarely: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

The development of a symptom complex has been reported that may include all or some of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis. Skin rash, photosensitization, and other skin reactions may also occur.

Repnal and urinary tract disorders

Infrequent: renal function disorders, renal failure, proteinuria.

Rarely: oliguria.

Genital and breast disorders

Infrequent: erectile dysfunction.

Rarely: gynecomastia.

General disorders

Very common: asthenia.

Often: increased fatigue.

Infrequent: muscle cramps, “rushes” of blood to the skin of the face, tinnitus, feeling of discomfort, fever.

Laboratory and instrumental data

Often: hyperkalemia, increased serum creatinine concentration.

Infrequent: increase in blood urea concentration, hyponatremia.

Rarely: increased activity of “hepatic” transaminases, increased concentration of bilirubin in blood serum.

* The incidence of cases was comparable to the incidence observed in clinical studies with placebo or other comparison drugs.

The adverse events listed below have been identified during post-registration follow-up, but a causal relationship to Enalapril administration has not been established: Urinary tract infections, upper respiratory tract infections, bronchitis, cardiac arrest, atrial fibrillation, herpes zoster, melena, ataxia, pulmonary branch thromboembolism and pulmonary infarction, hemolytic anemia, including cases of hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.

It is important to report the development of adverse reactions to ensure continuous monitoring of the benefit-risk ratio of the drug. If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Medical professionals report any adverse reactions to the drug through the national adverse reaction reporting systems.

Overdose

The information on overdose is limited. The most characteristic symptoms of overdose: marked BP decrease, beginning approximately 6 hours after drug administration simultaneously with RAAS blockade, and stupor. Serum concentrations of enalaprilat exceeding 100 and 200 times the concentrations observed with therapeutic doses occurred after administration of 300 mg and 440 mg of enalapril, respectively.

The recommended treatment of overdose is intravenous infusion of 0.9% sodium chloride solution. If the drug has been taken recently, induce vomiting. Enalaprilat may be removed from the systemic circulation by hemodialysis (see section “Special Precautions” Patients on hemodialysis).

Pregnancy use

Similarities