Enalapril Reneval, tablets 20 mg 28 pcs

Pharmacotherapeutic group: angiotensin-converting enzyme (ACE) inhibitor.

ATX code: C09AA02

Pharmacological properties

Enalapril refers to drugs affecting the renin-angiotensin-aldosterone system (RAAS) – ACE inhibitors. Enalapril Reneval 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 Reneval 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 that does not contain a 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. After enalapril administration, an increase in renal blood flow was observed. The glomerular filtration rate (GFR) did not change and there were no signs 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

Ensorption

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, equilibrium serum concentrations of enalapril are 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 through the kidneys. The major 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 (CKD 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 equilibrium state of enalaprilat concentration 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 mcg/L (0.54 to 5.9 mcg/L) 4 to 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, with maximum enalaprilate concentrations of 0.75 μg/L approximately 9 hours after administration. Mean concentrations in breast milk within 24 hours after enalapril administration were 1.44 μg/L and enalaprilat 0.63 μg/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

Essential hypertension of any severity;

in patients with clinical manifestations of CHF, Enalapril Reneval is also indicated to: improve patient survival, slow the progression of HF, and reduce the rate of hospitalizations for HF;

in patients without clinical symptoms of HF with left ventricular dysfunction, Enalapril Reneval is indicated to: slow the progression of clinical manifestations of HF, reduce the frequency of hospitalizations for HF;

Enalapril Reneval is indicated to: reduce the incidence of myocardial infarction, reduce the rate of hospitalizations for unstable angina.

Active ingredient

Composition

How to take, the dosage

Orally, regardless of meals.

In order to provide the dosing regimens listed below, if enalapril at a dose of 2.5 mg is necessary, preparations of enalapril from other manufacturers should be prescribed in the dosage form “2.5 mg tablets” or “5 mg tablets” with a slash.

Essential Hypertension

The initial dose is 10-20 mg depending on the severity of AH and is administered once daily. In mild degree of AH, the recommended starting dose is 10 mg once daily. In other degrees of AH the initial dose is 20 mg once daily. The maintenance dose is 1 tablet 20 mg once a day. The dosage is adjusted individually for each patient, but the maximum dose should not exceed 40 mg per day.

Renovascular Hypertension

Because patients in this group may have particularly sensitive BP and renal function to ACE inhibition, therapy is started with a low starting dose of 5 mg or less. The dose is then adjusted according to the patient’s needs and condition. Usually, an effective dose of 20 mg of Enalapril Reneval once daily with daily administration. Caution should be exercised when using Enalapril Reneval in patients who have recently taken diuretics (see concomitant treatment of AH with diuretics below).

Companion treatment of AH with diuretics

Symptomatic arterial hypotension may develop after the first administration of Enalapril Reneval. This effect is most likely in patients who take diuretics. It is recommended to use the drug with caution, since the water-electrolyte imbalance may be observed in these patients. Diuretics should be discontinued 2-3 days before starting therapy with Enalapril Reneval. If this is not possible, the initial dose of Enalapril Reneval should be reduced (to 5 mg or less) to determine the primary effect of the drug on BP. Thereafter, the dosage should be adjusted to the patient’s need and condition.

Dosage in renal failure

The interval between doses of Enalapril Reneval should be increased and/or the dose reduced*.

Creatinine clearance, mL/min

Initial dose, mg/day

< 80 > 30 ml/min

5-10 mg

≤ 30 > 10 ml/min

2.5 mg

≤ 10 ml/min

2.5 mg on dialysis days**

* See Caution; Special Instructions.

** Enalapril is subject to dialysis. Dose adjustments on days when dialysis is not being performed should be made depending on BP levels.

Heart failure/asymptomatic left ventricular dysfunction

The starting dose of Enalapril in patients with clinically significant CHF or asymptomatic left ventricular dysfunction is 2.5 mg. At the same time, the drug should be used under close medical supervision to determine the primary effect of the drug on BP. Enalapril Reneval
may be used for treatment of CH with marked clinical manifestations usually in combination with diuretics and, when necessary, with cardiac glycosides. In case of absence of symptomatic arterial hypotension (resulting from Enalapril Reneval treatment) or after its correction, the drug dose should be gradually increased to the usual maintenance dose of 20 mg, which is used either once or divided into 2 doses depending on patient’s tolerability. The dose may be adjusted over 2-4 weeks or at shorter intervals if there are residual signs and symptoms of CH. This therapeutic regimen effectively reduces mortality rates in patients with clinically significant HF.

At both before and after treatment with Enalapril Reneval, BP and renal function should be monitored regularly (see section “Cautions”), since there have been reports of arterial hypotension with subsequent (more rare) occurrence of acute renal failure due to drug administration. In patients taking diuretics, the dose of diuretics should be decreased, if possible, before starting treatment with Enalapril Reneval. Development of arterial hypotension after the first dose of Enalapril Reneval does not mean that arterial hypotension will develop again during long-term treatment, and does not indicate the need to discontinue the drug. Serum potassium levels should also be monitored during treatment with Enalapril Reneval (see section “Interaction with other medicinal products”).

Interaction

Other hypotensive agents

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

When enalapril is used concomitantly with other hypotensive agents, especially diuretics, an increase in antihypertensive effect may be observed.

The concomitant use of enalapril with beta-adrenoblockers, methyldopa or slow calcium channel blockers increased the severity of antihypertensive effect. Concomitant use of enalapril with alpha-, beta-adrenoblockers and ganglionic blockers should be performed under close medical supervision.

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

Kalium-saving diuretics, potassium-containing supplements, or other drugs that can increase serum potassium

The ACE inhibitors attenuate diuretic-induced loss of potassium. The use of potassium-saving diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), as well as potassium-containing supplements, potassium-containing salt substitutes, or other drugs that can increase serum potassium content (e.g., drugs containing trimethoprim) may lead to a significant increase in serum potassium. If concomitant use of enalapril and the potassium-containing or potassium-enhancing drugs listed above is necessary, caution should be exercised and serum potassium levels should be monitored regularly (see section “Special Precautions”).

Kalinergic (thiazide and “loop”) diuretics

Treatment with high doses of diuretics prior to initiating therapy with enalapril may decrease circulating blood volume and risk of arterial hypotension. Hypotensive effects may be reduced by discontinuing the diuretic, replenishing fluid volume or increasing salt intake, or by initiating low-dose enalapril therapy.

Hypoglycemic agents

Epidemiologic studies have shown that concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may increase the hypoglycemic effect of the latter with risk of hypoglycemia. This phenomenon is usually the most frequently observed during the first weeks of combined therapy, as well as in patients with impaired renal function. In patients with diabetes mellitus taking oral hypoglycemic agents or insulin, blood glucose concentration should be monitored regularly
especially during the first month of concomitant use with ACE inhibitors.

Lithium preparations

Like other drugs that affect sodium excretion, ACE inhibitors may decrease renal excretion of lithium, so serum lithium concentration should be monitored regularly if lithium preparations and ACE inhibitors are used concomitantly.

Tricyclic antidepressants/neuroleptics/general anesthetics/drugs

. Concomitant use of certain anesthetic drugs, tricyclic antidepressants, and neuroleptics with ACE inhibitors may cause a further decrease in BP (see “Special Precautions”).

Ethanol

Ethanol increases the antihypertensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and beta-adrenoblockers

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

Sympathomimetics

Sympathomimetics may decrease the antihypertensive effect of ACE inhibitors.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the effect of diuretics and other hypotensive agents. Consequently, the antihypertensive effect of angiotensin II receptor antagonists (ARA II) or ACE inhibitors may be weakened when used concomitantly with 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 ARA II or ACE inhibitors may cause further impairment of renal function, including development of acute renal failure. These effects are usually reversible, so concomitant use of these drugs should be conducted with caution in patients with impaired renal function.

Double blockade of the renin-angiotensin-aldosterone system

Dual RAAS blockade with APA II, ACE inhibitors, or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure) compared with monotherapy. Regular monitoring of BP, renal function and blood electrolytes in patients taking enalapril and other drugs affecting the RAAS simultaneously is necessary. Concomitant use of ACE inhibitors with aliskiren or aliskiren-containing drugs is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal dysfunction (GFR less than 60 ml/min/1.73 m2 of body surface area) and is not recommended in other patients (see sections “Contraindications”, “Special Indications”). Concomitant use of ACE inhibitors with ARA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see sections “Contraindications”, “Special Considerations”).

Gold preparations

. A symptomcomplex (nitrate-like reactions) including blood “rush” to the face, nausea, vomiting, and arterial hypotension has rarely been observed when parenteral gold drugs (sodium aurothiomalate) and ACE inhibitors, including enalapril are used concurrently.

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

. In patients taking ACE inhibitors and mTOR inhibitors concomitantly, an increased risk of angioedema has been observed (see section “Special Precautions”).

Neutral endopeptidase inhibitors (NEIs)

An increased risk of angioedema has been reported with concomitant use of ACE inhibitors with racecadotril (an enkephalinase inhibitor used to treat acute diarrhea).

The simultaneous use of ACE inhibitors with drugs containing sacubitril (neprilysin inhibitor) increases the risk of angioedema, therefore simultaneous use of these drugs is contraindicated. ACE inhibitors should be administered not earlier than 36 hours after withdrawal of drugs containing Sacubitril. Administration of drugs containing Sacubitril is contraindicated in patients receiving ACE inhibitors and also within 36 hours after cancellation of ACE inhibitors.

Tissue plasminogen activators

The observational studies found an increased incidence of angioedema in patients taking ACE inhibitors after using alteplase for thrombolytic therapy of ischemic stroke.

Other Drugs

No clinically significant pharmacokinetic drug interactions have been observed between enalapril and the following drugs: hydrochlorothiazide, furosemide, digoxin, timolol, methyldopa, warfarin, indomethacin, sulindac, and cimetidine. Concomitant use of enalapril and propranolol 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 against a background of dehydration resulting from, for example, diuretic therapy, restriction of table salt intake, in patients on dialysis, and in 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 common in patients with more severe CHF with hyponatremia or impaired renal function who use higher doses of “loop”
diuretics. In such patients, treatment with enalapril should be initiated under medical supervision, which should be particularly careful when changing the dose of enalapril and/or diuretic. Similarly, 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 drugs with vasodilatory effects, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

Renal dysfunction

In patients with impaired renal function (creatinine clearance < 80 ml/min), the initial dose and/or frequency of enalapril 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 without signs of renal disease prior to treatment, the use of enalapril in combination with diuretics has caused increased serum urea and creatinine concentrations. In such cases, a dose reduction and/or withdrawal of the diuretic and/or enalapril may be required. 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 artery stenosis of the single kidney have an increased risk of arterial hypotension and renal failure when using ACE inhibitors. Renal insufficiency 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 transplant. Therefore, the use of enalapril in these patients is not recommended.

Hepatic dysfunction

The use of ACE inhibitors has rarely been accompanied by 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 this syndrome is unknown. If jaundice or significant increase in liver transaminase activity occurs during drug administration, 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 with high risk of neutropenia/agranulocytosis, regular monitoring of blood leukocyte count is recommended. Patients should be warned to consult a physician immediately in case of 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 preceding angioedema of the face and with normal C1-esterase levels. The diagnosis was 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 observed in patients taking ACE inhibitors and medications such as mTOR inhibitors (temsirolimus, sirolimus, everolimus), type IV dipeptidyl peptidase inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin), estramustine, neutral endopeptidase inhibitors (ratsecadotril) concurrently.

Anaphylactoid reactions during desensitization with a Hymenoptera venom allergen

. In rare cases, patients taking ACE inhibitors have developed life-threatening anaphylactoid reactions during desensitization with hymenopteran 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)

. Life-threatening anaphylactoid reactions have rarely been observed in patients taking ACE inhibitors during LDL apheresis with dextran sulfate. 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 simultaneously receiving ACE inhibitor therapy. 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 administration, especially during the first month of concomitant use of the mentioned drugs.

Cough

Cases of cough have been observed with ACE inhibitor therapy. As a rule, the cough is non-productive and persistent and stops after discontinuation of the drug. Cough associated with use of ACE inhibitors should be considered in 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 significant decrease in BP develops due to this mechanism, it may be corrected by increasing circulating blood volume.

Hyperkalemia

Hyperkalemia may develop on therapy with ACE inhibitors, 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, the risk of hypokalemia cannot be excluded; therefore, in such cases, regular monitoring of blood potassium levels should be performed during therapy.

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 (FFR 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 monitored by a physician 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

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

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

Synopsis

Contraindications

Hypersensitivity to any of the components of the drug;

sup>2 body surface area) (see “Interaction with other medicinal products”, “Cautions”); concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy; concomitant use with neprilysin inhibitors (e.g., sacubitril). When changing to neprilysin inhibitors and sacubitril/valvsartan preparations, Enalapril Reneval should be discontinued at least 36 hours before the first dose of these drugs (see sections “Interaction with other medicinal products”, “Cautions”); Age under 18 years of age (efficacy and safety not established) pregnancy and breastfeeding Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

With caution

Arterial hypotension, bilateral renal artery stenosis or artery stenosis of the sole renal artery; renovascular hypertension; renal failure; post renal transplant condition; aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; chronic heart failure; coronary heart disease or cerebrovascular disease; systemic connective tissue diseases (systemic lupus erythematosus, scleroderma, etc.), inhibition of bone marrow function.), bone marrow inhibition, immunosuppressive therapy, concomitant use of allopurinol or procainamide, or a combination of these complicating factors (risk of neutropenia and agranulocytosis); liver failure; diabetes; hyperkalemia; concomitant use with potassium-saving diuretics, potassium preparations, potassium-containing salt substitutes; concomitant use with lithium preparations; history of severe allergic reactions or angioedema; simultaneous desensitization with Hymenoptera venom allergen; concomitant low-density lipoprotein apheresis (LDL-apheresis) with dextran sulfate; hemodialysis with high-flow membranes (such as AN69®); conditions associated with decreased circulating blood volume (including diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting) and hyponatremia; use during major surgical procedures or general anesthesia; use in patients of non-human race; use in elderly patients (over 65 years).

Side effects

In general, Enalapril Reneval is well tolerated. In clinical trials, the cumulative incidence of adverse events (AEs) when using Enalapril Reneval was not higher than that when taking placebo. In most cases, NIs were mild, transient and did not require therapy withdrawal. The following criteria were used to assess the frequency 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). The NUIs are grouped according to the system-organ classes of the MedDRA Medical Regulatory Dictionary, within each class the NUIs are listed in decreasing order of frequency, within each group allocated by frequency of occurrence the NUIs 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

Frequency unknown: syndrome of inadequate secretion of antidiuretic hormone.

Disorders of metabolism and nutrition

Infrequent: hypoglycemia (see “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 often: blurred vision.

Disorders of the heart and blood vessels

very often:dizziness.

Frequently:Evident decrease in BP, fainting, chest pain, rhythm disturbances, angina pectoris, tachycardia.

Infrequent: Orthostatic hypotension, palpitations, myocardial infarction or stroke*, possibly secondary to marked arterial hypotension in high-risk patients (see Special Instructions).

Rarely: Rainault syndrome.

Disorders of the respiratory system, thorax and mediastinum

very often: cough.

Frequently:dyspnea.

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

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

Disorders of the digestive system

very often: nausea.

Frequently: diarrhea, abdominal pain, taste disorder.

Infrequent: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric 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

Frequently: skin rash, hypersensitivity reactions/angioneurotic edema: Angioneurotic edema of the face, extremities, lips, tongue, vocal folds and/or larynx (see “Special Indications”).

Infrequent:high 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.

Renal and urinary tract disorders

Infrequent: disorders of renal function, renal failure, proteinuria.

Rarely: oliguria.

Disorders of the genitals and mammary gland

Infrequent: erectile dysfunction.

Rarely: gynecomastia.

General disorders

very often: asthenia.

Frequently:increased fatigue.

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

Laboratory and instrumental findings

Often: hyperkalemia, increased serum creatinine concentration.

Infrequent: increased blood urea concentration, hyponatremia.

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

* The frequency of cases was comparable to the frequency observed in clinical studies when taking placebo or another comparison drug.

The adverse events listed below have been identified during post-registration follow-up, but a causal relationship with Enalapril reneval 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. Healthcare professionals report any adverse reactions to the medicine through the national adverse reaction reporting systems.

Overdose

Pregnancy use

Pregnancy

The use of Enalapril Reneval during pregnancy is not recommended. If pregnancy is diagnosed, Enalapril Reneval should be discontinued immediately, unless administration of the drug is considered vital for the mother.

In published results of a retrospective epidemiologic study of newborns whose mothers took ACE inhibitors during the first trimester of pregnancy, there was an increased risk of serious birth defects compared to newborns whose mothers did not take ACE inhibitors during the first trimester of pregnancy. The incidence of birth defects was low, and the results of this study have not been re-confirmed.

ACE inhibitors can cause illness or death to the fetus or newborn when used by pregnant women during the second and third trimesters of pregnancy. The use of ACE inhibitors during these periods has been accompanied by adverse effects on the fetus and the newborn in the form of arterial hypotension, renal failure, hyperkalemia and/or skull bone hypoplasia in the newborn. Prematurity, fetal intrauterine developmental delay, and nondelivery of the arterial (Botall’s) duct have also been reported, but it is unclear whether these cases were related to the effects of ACE inhibitors.

It is possible that the development of oligohydramnios is due to reduced fetal renal function. This complication may lead to limb contractures, bone deformities of the skull, including its facial part, fetal lung hypoplasia. When prescribing Enalapril Reneval during pregnancy, the patient should be informed about the potential risk to the fetus.

These adverse effects on the fetus and embryo do not appear to be the result of intrauterine effects of ACE inhibitors during the first trimester of pregnancy.

In the rare cases in which ACE inhibitor use during pregnancy is deemed necessary, periodic ultrasound examinations should be performed to evaluate the amniotic fluid index. If oligohydramnios are detected on ultrasound examination, Enalapril Reneval should be discontinued unless administration of the drug is considered vital for the mother. However, both patient and physician should be aware that oligohydramnios develops when there is irreversible damage to the fetus.

If ACE inhibitors are used during pregnancy and oligohydramnios develops, a stress test, non-stress test, or fetal biophysical profile determination may be necessary depending on the week of pregnancy to assess fetal functional status.

Newborns whose mothers have taken Enalapril Reneval during pregnancy should be carefully screened for arterial hypotension, oliguria, and hyperkalemia. If oliguria develops, special attention should be paid to maintaining BP and renal perfusion. Enalapril penetrates the placental barrier. It can be partially removed from the neonatal circulation by peritoneal dialysis. Theoretically, it can also be removed by exchange blood transfusion.

Period of breastfeeding

Enalapril and enalaprilat are excreted with the mother’s breast milk in trace amounts. If it is necessary to use the drug while breastfeeding, the patient should stop breastfeeding.

Similarities