Enalapril Renewal pills 10mg, 28pcs

Composition

Composition per tablet

Active ingredient: Enalapril maleate-0,01 Gspomogatelnye substances to obtain a tablet weighing 0,1 g: potato starch-0,0155 gcalcium stearate-0,0010 glactose (milk sugar) – 0,0700 gpovidone low molecular weight-0,0035 g

Pharmacological action

Enalapril is a drug that affects the renin-angiotensin-aldosterone system – RAAS) – ACE inhibitors. Enalapril is used for the treatment of essential hypertension (primary arterial hypertension (AH)) of any severity and renovascular hypertension both in monotherapy and in combination with other antihypertensive agents, in particular with diuretics. Enalapril is also used to treat or prevent the development of heart failure (HF).

Pharmacodynamics

Enalapril is a derivative of two amino acids, L-alanine and L-proline. After oral use, enalapril is rapidly absorbed and hydrolyzed to enalaprilate, which is a highly specific and long-acting ACE inhibitor that does not contain a sulfhydryl group.

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

ACE is identical to the kininase II enzyme, so enalapril can also block the degradation of bradykinin, a peptide that has a pronounced vasodilating effect. The significance of this effect in the therapeutic effect of enalapril requires clarification.

Despite the fact that the main mechanism by which enalapril reduces blood pressure (BP) is considered to be the suppression of RAAS activity, which plays an important role in regulating blood pressure, enalapril shows antihypertensive effects even in patients with hypertension and with reduced plasma renin activity.

The use of enalapril in patients with hypertension leads to a decrease in blood pressure both in the “standing” and “lying” positions without a significant increase in heart rate (HR).

Symptomatic postural hypotension develops infrequently. In some patients, achieving optimal BP reduction may require several weeks of therapy. Discontinuation of enalapril therapy does not cause a sharp rise in blood pressure.

Effective ACE inhibition usually develops 2-4 hours after a single oral dose of enalapril. The antihypertensive effect develops within 1 hour, the maximum decrease in blood pressure 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 persist for 24 hours.

Antihypertensive therapy with enalapril leads to significant regression of left ventricular hypertrophy and preservation of its systolic function.

In clinical hemodynamic studies in patients with essential hypertension, a decrease in blood pressure was accompanied by a decrease in total peripheral vascular resistance, an increase in cardiac output, and no changes or minor changes in heart rate. After taking enalapril, an increase in renal blood flow was observed.

At the same time, the glomerular filtration rate (GFR) did not change, and there were no signs of sodium or fluid retention. However, in patients with initially reduced glomerular filtration rate, its rate usually increased.

Long-term use of enalapril in patients with essential hypertension and renal insufficiency may lead to improved renal function, which is confirmed by an increase in GFR.

In short-term clinical studies, patients with renal insufficiency and with or without diabetes mellitus showed a decrease in albuminuria, renal excretion of IgG, and a decrease in total protein in the urine after taking enalapril.

With the simultaneous use of enalapril and thiazide diuretics, a more pronounced antihypertensive effect is observed. Enalapril reduces or prevents the development of hypokalemia caused by taking thiazides.

Enalapril therapy is usually not associated with an undesirable effect on the concentration of uric acid in blood plasma.

Enalapril therapy is accompanied by a favorable effect on the ratio of lipoprotein fractions in blood plasma and no effect or a favorable effect on the concentration of total cholesterol.

In patients with HF treated with cardiac glycosides and diuretics, enalapril use caused a decrease in total peripheral resistance and blood pressure. Cardiac output increased, while heart rate (usually elevated in patients with HF) decreased. The pressure of jamming in the pulmonary capillaries also decreased.

Exercise tolerance and heart failure severity, as assessed by the New York Heart Association (NYHA) criteria, improved. These effects were observed with long-term therapy.

In patients with mild to moderate HF, enalapril slowed the progression of cardiac dilatation and HF, which was confirmed by a decrease in the end-diastolic and systolic volumes of the left ventricle and an improvement in the left ventricular ejection fraction.

Clinical data have shown that enalapril reduces the incidence of ventricular arrhythmias in patients with HF, although the main mechanisms and clinical significance of this effect are not known.

Pharmacokinetics

Suction

After oral use, enalapril is rapidly absorbed in the gastrointestinal tract. The maximum concentration of enalapril in the blood serum is reached within 1 hour after oral use. The degree of absorption of enalapril when taken orally is approximately 60%. Food intake does not affect the absorption of enalapril.

After absorption, enalapril is rapidly hydrolyzed to form the active metabolite enalaprilate – a potent ACE inhibitor. The maximum concentration of enalaprilate in the blood serum is observed approximately 4 hours after taking a dose of enalapril orally.

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

Distribution

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

Metabolism

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

Deduction

Enalapril is excreted primarily through the kidneys. The main metabolites detected in the urine are enalaprilate, which accounts for approximately 40% of the dose, and unchanged enalapril (approximately 20%).

The enalaprilate concentration curve in blood plasma has a long final phase, apparently due to its binding to ACE. The half-life of enalaprilat with a course of oral use of the drug 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 increases in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml/min) after taking enalapril at a dose of 5 mg once a day, the steady-state AUC of enalaprilat was approximately 2 times higher than in patients with unchanged renal function.

In patients with severe renal insufficiency (creatinine clearance not exceeding 30 ml/min), the AUC value increased approximately 8-fold. The effective elimination half-life of enalaprilate after repeated use of enalapril in patients with severe renal insufficiency increased, and the onset of an equilibrium state of enalaprilate concentration was delayed (see the section “Dosage and use”).

Enalaprilate can be removed from the general bloodstream by a hemodialysis procedure. Hemodialysis clearance is 62 ml/min.

Breast-feeding

After a single oral use of enalapril at a dose of 20 mg in postpartum patients, the average maximum concentration of enalapril in breast milk was 1.7 mcg/l (from 0.54 to 5.9 mcg/l) 4-6 hours after use.

The average maximum concentration of enalaprilat was 1.7 mcg/l (from 1.2 to 2.3 mcg/L) and was observed at various times within 24 hours after use. Taking into account the data on maximum concentrations in breast milk, the estimated maximum intake of enalapril by a fully breastfed child is 0.16% of the dose calculated taking into account the mother’s body weight.

In a woman who took enalapril orally at a dose of 10 mg once a day for 11 months, the maximum concentrations of enalapril in breast milk were 2 mcg/l 4 hours after use, the maximum concentrations of enalaprilat were 0.75 mcg/l approximately 9 hours after use.

The average concentration in breast milk within 24 hours after taking enalapril was 1.44 mcg/l and enalaprilat-0.63 mcg/l. One woman who took enalapril 5 mg once and two women who took enalapril 10 mg once had breast milk concentrations of enalaprilate below the detectable level (less than 0.2 mcg/l) 4 hours after ingestion. The concentration of enalapril in them was not determined.

Indications

• Essential hypertension of any severity;
• renovascular hypertension;
• heart failure of any severity:
• in patients with the presence of clinical manifestations of HF, Enalapril is also indicated for: improving patient survival, slowing the progression of HF, reducing the frequency of hospitalizations for HF;
• preventing the development of clinically expressed heart failure:
• in patients without clinical symptoms of HF with left ventricular dysfunction, Enalapril is indicated for: slowing the development of clinical manifestations of HF, reducing the frequency of hospitalizations for HF;
• prevention of coronary ischemia in patients with left ventricular dysfunction:
• Enalapril is indicated for: reducing the incidence of myocardial infarction, reducing the frequency of hospitalizations for unstable angina.

Use during pregnancy and lactation

Pregnancy The use of Enalapril during pregnancy is not recommended. When pregnancy is diagnosed, Enalapril should be discontinued immediately, unless the drug is considered vital for the mother. In the published results of a retrospective epidemiological study of newborns whose mothers took ACE inhibitors during the first trimester of pregnancy, there was an increased risk of developing serious congenital malformations compared to newborns whose mothers did not take ACE inhibitors during the first trimester of pregnancy. The number of cases of birth defects was low, and the results of this study were not re-confirmed. ACE inhibitors can cause disease or death of 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 was accompanied by negative effects on the fetus and newborn, which manifested itself in the form of arterial hypotension, renal failure, hyperkalemia and/or hypoplasia of the skull bones in the newborn. Preterm birth, delayed fetal development, and non-closure of the ductus arteriosus have also been reported, but it is unclear whether these cases were related to the action of ACE inhibitors. Perhaps the development of oligohydramnion occurs due to a decrease in fetal kidney function. This complication can lead to contracture of the extremities, deformity of the skull bones, including its facial part, and hypoplasia of the fetal lungs. When prescribing Enalapril during pregnancy, the patient should be informed about the potential risk to the fetus. These undesirable effects on the embryo and fetus do not appear to be the result of intrauterine action of ACE inhibitors during the first trimester of pregnancy. In rare cases where the use of an ACE inhibitor during pregnancy is considered necessary, periodic ultrasound examinations should be performed to assess the amniotic fluid index. In case of detection of oligohydramnion during ultrasound examination, it is necessary to stop taking Enalapril, unless taking the drug is considered vital for the mother. However, both the patient and the doctor should be aware that oligohydramnion develops when the fetus is permanently damaged. If ACE inhibitors are used during pregnancy and oligohydramnion develops, then depending on the week of pregnancy, a stress test, a non-stress test, or a biophysical profile of the fetus may be necessary to assess the functional state of the fetus. Newborns whose mothers have taken Enalapril during pregnancy should be carefully evaluated for hypotension, oliguria, and hyperkalemia. When developing oliguria, special attention should be paid to maintaining blood pressure and renal perfusion. Enalapril penetrates the placental barrier. It can be partially removed from the newborn’s circulation by peritoneal dialysis. In theory, it can also be removed through an exchange blood transfusion. Breast-feeding enalapril and enalaprilat are excreted in the mother’s breast milk in trace amounts. If it is necessary to use the drug during breastfeeding, the patient should stop breastfeeding.

Contraindications

Hypersensitivity to enalapril and other ACE inhibitors; a history of angioedema associated with treatment with ACE inhibitors; concomitant use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m2 of body surface area); concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic angiotensin II receptor antagonists (ARA II). nephropathy; porphyria; pregnancy; breast-feeding period; age up to 18 years (efficacy and safety have not been established); hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome. With caution Arterial hypotension, bilateral renal artery stenosis or stenosis of the artery of a single kidney; renovascular hypertension; renal failure; condition after kidney transplantation; aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; chronic heart failure; ischemic heart disease or cerebrovascular diseases; systemic connective tissue diseases (systemic lupus erythematosus, scleroderma, etc. ), depression bone marrow hematopoiesis, immunosuppressive therapy, concomitant use of allopurinol or procainamide, or a combination of these complicating factors (risk of neutropenia and agranulocytosis); liver failure; diabetes mellitus; hyperkalemia; concomitant use with potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes; concomitant use with lithium preparations; burdened allergic history or angioedema history of hymenopteran venom desensitization; concomitant use of low-density lipoprotein apheresis (LDL apheresis) using dextran sulfate; hemodialysis using high-flow membranes (such as AN69®); conditions associated with reduced circulating blood volume (including diuretic therapy, dietary restriction of table salt, dialysis, diarrhea or vomiting) and hyponatremia use during major surgical procedures or during general anesthesia; use in patients of the black race; use in elderly patients (over 65 years of age).

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, AES were mild, transient, and did not require discontinuation of therapy.

The following criteria were used to assess the frequency of AE: “very often” (≥ 1/10); “often” (≥ 1/100, < 1/10); “infrequently” (≥ 1/1000, < 1/100); “rarely” (≥ 1/10000, < 1/1000); “very rare” ( 

AES are grouped according to the system-organ classes of the MedDRA medical dictionary for regulatory activities. Within each class, AES are listed in descending order of frequency of occurrence, and within each group allocated by frequency of occurrence, AES are distributed in decreasing order of their importance.

Disorders of the blood and lymphatic system

Infrequently: anemia (including aplastic and hemolytic).

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

Endocrine disorders

Frequency unknown: syndrome of inadequate secretion of antidiuretic hormone.

Metabolic and nutritional disorders

Infrequently: hypoglycemia (see section “Special instructions”).

Nervous system disorders and mental disorders

are common: headache, depression.

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

Rare: unusual dreams, sleep disturbances.

Visual disturbances

Very common: blurred vision.

Disorders of the heart and blood vessels

Very common: dizziness.

Often: marked decrease in blood pressure, fainting, chest pain, arrhythmia, angina pectoris, tachycardia.

Infrequently: orthostatic hypotension, palpitation, myocardial infarction or stroke*, possibly secondary to severe hypotension in high-risk patients (see section “Special instructions”).

Rare: Raynaud’s syndrome.

Respiratory, thoracic and mediastinal disorders

Very common: cough.

Often: shortness of breath.

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

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

Disorders of the digestive system

Very common: nausea.

Common: diarrhea, abdominal pain, taste problems.

Infrequently: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, stomach irritation, dry oral mucosa, stomach and duodenal ulcers.

Rare: stomatitis/aphthous ulcers, glossitis.

Very rare: intestinal edema.

Liver and biliary tract disorders

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

Skin and subcutaneous tissue disorders

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

Infrequently: increased sweating, pruritus, urticaria, alopecia.

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

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.

Kidney and urinary tract disorders

Infrequently: impaired renal function, renal failure, proteinuria.

Rare: oliguria.

Genital and breast disorders

Infrequently: erectile dysfunction.

Rare: gynecomastia.

Common disorders

Very common: asthenia.

Often: increased fatigue.

Infrequently: muscle cramps, “flushes” of blood to the skin of the face, tinnitus, discomfort, fever.

Laboratory and instrumental data

Often: hyperkalemia, increased serum creatinine concentration.

Infrequently: increased blood urea concentration, hyponatremia.

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

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

The following adverse events were identified during post-marketing surveillance, but no causal relationship was established with Enalapril: urinary tract infections, upper respiratory tract infections, bronchitis, cardiac arrest, atrial fibrillation, herpes zoster, melena, ataxia, pulmonary embolism and pulmonary infarction, hemolytic anemia, including cases of hemolysis in patients with glucose-6 deficiency-phosphate dehydrogenase.

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

Health professionals report any adverse drug reactions through national adverse reaction reporting systems.

Interaction

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

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

Regular monitoring of blood pressure, renal function, and blood electrolyte levels is necessary in patients taking enalapril and other medications that affect the RAAS at the same time.

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

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.

Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes, and other medications that can increase the potassium content in the blood serum

Concomitant use of enalapril with potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes, and other drugs that can increase the content of potassium in the blood serum (including angiotensin II receptor antagonists, heparin, tacrolimus, cyclosporine; drugs containing co-trimoxazole [trimethoprim + sulfamethoxazole]) can lead to a significant increase in the potassium content in blood plasma. If it is necessary to use enalapril with the drugs listed above, regular monitoring of the potassium content in the blood plasma should be carried out.

Potassium-sparing (thiazide and loop) diuretics

The use of diuretics in high doses can lead to hypovolemia (due to a decrease in BCC), and the addition of enalapril to therapy can lead to a pronounced decrease in blood pressure. The excessive antihypertensive effect of enalapril can be reduced either by discontinuing the diuretic, or by increasing the BCC or using table salt, as well as by reducing the dose of enalapril.

When enalapril is co-administered with potassium-sparing (thiazide or “loop”) diuretics, hypokalemia caused by diuretics is usually reduced due to the effect of enalapril.

Other antihypertensive medications

An additive effect can be observed with the simultaneous use of enalapril and other antihypertensive therapy.

When enalapril is used simultaneously with other antihypertensive agents, especially with diuretics, an increase in the antihypertensive effect may occur.

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

Concomitant use of enalapril with alpha-blockers, beta-blockers and ganglioblockers should be carried out under close medical supervision.

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

Lithium preparations

Like other drugs that affect sodium excretion, ACE inhibitors can reduce the excretion of lithium by the kidneys and lead to an increase in the cardiotoxic and neurotoxic effects of lithium. If the concomitant use of drugs containing lithium and ACE inhibitors is necessary, the concentration of lithium in the blood serum should be regularly monitored.

Nonsteroidal 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 (COX-2) inhibitors and acetylsalicylic acid at doses of 3 g / day or higher, may reduce the antihypertensive effect of diuretics and other antihypertensive agents. As a result, the antihypertensive effect of angiotensin II receptor antagonists (APA II) or ACE inhibitors may be weakened when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

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

These effects are usually reversible. Concomitant use of ACE inhibitors and NSAIDs should be carried out with caution (especially in elderly patients and in patients with impaired renal function). Patients should receive an adequate amount of fluid. It is recommended to carefully monitor kidney function, both at the beginning and during treatment.

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

Hypoglycemic medications

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

In patients with diabetes mellitus who are taking hypoglycemic medications for oral use or insulin, blood glucose concentrations should be monitored regularly, especially during the first month of concomitant use with ACE inhibitors.

Tricyclic Antidepressants / Antipsychotics / General anaesthetics / Narcotic drugs

Increased antihypertensive effect of ACE inhibitors (further reduction of blood pressure with simultaneous use) and increased risk of orthostatic hypotension.

Alpha-and beta-adrenomimetics

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

Baclofen

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

Ethanol

Ethanol enhances 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 (for systemic use)

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

Gold preparations

When gold preparations for parenteral use (sodium aurothiomalate) and ACE inhibitors, including enalapril, are used simultaneously, a symptom complex (nitrate-like reactions) is described, including a “rush” of blood to the skin of the face, nausea, vomiting, and arterial hypotension.

mTOR inhibitors (mammalion Target of Rapamycin-target of rapamycin in mammalian cells) (for example, temsirolimus, sirolimus, everolimus)

Patients taking concomitant ACE inhibitors and mTOR inhibitors (temsirolimus, sirolimus, everolimus) showed an increased incidence of angioedema.

Dipeptidyl peptidase type IV (DPP-IV) inhibitors (gliptins), e. g. sitagliptin, saxagliptin, vildagliptin, linagliptin

Angioedema increased in patients taking concomitant ACE inhibitors and dipeptidyl peptidase type IV inhibitors (gliptins).

Estramustin

Increased incidence of angioedema when used concomitantly with ACE inhibitors.

Neutral endopeptidase (NEP)inhibitors

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

Acetylsalicylic acid, thrombolytics and beta-blockers

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

Pharmacokinetic interactions

Antacids

It is possible to reduce the bioavailability of ACE inhibitors.

Other medicinal products

There was no clinically significant pharmacokinetic interaction between enalapril and the following drugs: hydrochlorothiazide, furosemide, digoxin, timolol, methyldopa, warfarin, Indometacin, sulindac and cimetidine.

Concomitant use of enalapril and propranolol reduces the concentration of enalaprilate in the blood serum, but this effect is not clinically significant.

How to take, course of use and dosage

For monotherapy of arterial hypertension, the initial dose is 5 mg once a day. In the absence of a clinical effect, the dose is increased by 5 mg after 1-2 weeks. After taking the initial dose, patients should be under medical supervision for 2 hours and an additional 1 hour until blood pressure stabilizes. If necessary and sufficiently well tolerated, the dose can be increased to 40 mg / day in 2 divided doses. After 2-3 weeks, they 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. The maximum daily dose of the drug is 40 mg / day.

Overdose

Information about overdose is limited. The most characteristic symptoms of overdose: a marked decrease in blood pressure, starting approximately 6 hours after taking the drug simultaneously with RAAS blockade, and stupor. Serum concentrations of enalaprilate exceeding 100 and 200 times the concentrations observed at therapeutic doses occurred after taking 300 mg and 440 mg of enalapril, respectively.

Recommended treatment for overdose: intravenous infusion of 0.9% sodium chloride solution. If the drug was taken recently, provoke vomiting. Enalaprilate can be removed from the systemic circulation by hemodialysis (see section “Special instructions” for patients on hemodialysis).

Special instructions

Symptomatic arterial hypotension

Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. In patients with hypertension taking enalapril, hypotension develops more often against the background of dehydration, which occurs, for example, as a result of diuretic therapy, restriction of table salt intake, in patients on dialysis, as well as in patients with diarrhea or vomiting.

Symptomatic hypotension was observed in patients with CHF with or without chronic renal failure.

Hypotension is more likely to occur in patients with more severe HF 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 especially careful when changing the dose of enalapril and / or a diuretic.

Similarly, patients with ischaemic heart disease or cerebrovascular diseases should be monitored for excessive lowering of blood pressure, which can lead to the development of myocardial infarction or stroke.

If hypotension develops, the patient should be moved to a horizontal position and, if necessary, a 0.9% sodium chloride solution should be administered. Transient arterial hypotension when taking enalapril is not a contraindication to further use and an increase in the dose of enalapril, which can be continued after filling the fluid volume and normalizing blood pressure.

In some patients with CHF and with normal or reduced blood pressure, enalapril may cause an additional decrease in blood pressure. This reaction to enalapril is expected and does not warrant discontinuation of treatment. In cases where hypotension is stable, the dose should be reduced and/or the use of diuretics and / or enalapril should be discontinued.

Aortic stenosis / mitral stenosis / hypertrophic obstructive cardiomyopathy

Like all drugs with vasodilating effects, ACE inhibitors should be used with caution in patients with obstruction of the blood outflow pathways from the left ventricle.

Impaired renal function

In patients with impaired renal function (creatinine clearance In such cases, renal function (creatinine and potassium levels in the blood) should be monitored regularly during the first few weeks of treatment.

In some patients, hypotension that develops after starting treatment with ACE inhibitors can lead to deterioration of renal function. Cases of oliguria, progressive azotemia, and acute renal failure (including fatal ones) have been reported with ACE inhibitors, mainly in patients with chronic heart failure or concomitant kidney disease (including renal artery stenosis).

With timely detection and appropriate treatment, acute renal failure caused by the use of ACE inhibitors is usually reversible.

In some patients without signs of kidney disease prior to treatment, the use of enalapril in combination with diuretics caused an increase in the concentration of urea and creatinine in the blood serum. In such cases, it may be necessary to reduce the dose and/or discontinue the diuretic and / or enalapril.

It is recommended to conduct an appropriate examination, as these deviations may be a sign of the patient’s previously unrecognized renal artery stenosis.

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney have an increased risk of hypotension and renal failure when using ACE inhibitors. Renal failure may initially be manifested only by small changes in the level of creatinine in blood plasma. The use of enalapril in such patients should be initiated at low doses, under close medical supervision and monitoring of renal function.

Kidney transplantation

There is no experience of using enalapril in patients who have recently undergone a kidney transplant. Therefore, the use of enalapril in such patients is not recommended.

Impaired liver function

The use of ACE inhibitors in rare cases was accompanied by the development of a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant liver necrosis, sometimes with a fatal outcome. The mechanism of development of this syndrome is unknown.

If jaundice occurs or there is a significant increase in the activity of” hepatic ” transaminases against the background of the drug, enalapril should be discontinued and appropriate auxiliary therapy should be prescribed. The patient should be under appropriate supervision.

Neutropenia / agranulocytosis / thrombocytopenia / anemia

Neutropenia / agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other complicating factors.

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

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

When using enalapril in patients with a high risk of neutropenia/agranulocytosis, regular monitoring of the number of white blood cells in the blood is recommended. Patients should be warned to seek immediate medical attention if any signs of an infectious disease (such as fever, sore throat) appear.

Hypersensitivity reactions / angioedema

Rare cases of angioedema of the face, extremities, lips, tongue, vocal folds, and/or larynx have been reported with ACE inhibitors, including enalapril. Angioedema may develop at any time during treatment.

In such cases, you should immediately stop taking enalapril and carefully monitor the patient’s condition in order to control and correct clinical symptoms. Even in cases where only tongue edema is observed without the development of respiratory distress syndrome, patients may need long-term follow-up, since antihistamines and corticosteroids may not be sufficient.

Angioedema associated with laryngeal and tongue edema can be fatal in very rare cases. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction, especially in patients who have undergone respiratory surgery.

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

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

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

Patients with a history of angioedema that is not associated with ACE inhibitors may be more at risk of developing angioedema with ACE inhibitor therapy.

Angioedema was observed more frequently in black patients taking ACE inhibitors than in non-black patients.

An increased risk of angioedema has been observed in patients taking concomitant ACE inhibitors and medications such as mTOR inhibitors (temsirolimus, sirolimus, everolimus), dipeptidyl

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

Anaphylactoid reactions during desensitization with an allergen from hymenopteran venom

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

Adverse reactions can be avoided if the ACE inhibitor is temporarily discontinued prior to desensitization. Enalapril should be avoided in patients receiving bee venom immunotherapy.

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

Patients taking ACE inhibitors during LDL apheresis using dextran sulfate have rarely experienced life-threatening anaphylactoid reactions. These reactions can be prevented if the ACE inhibitor is temporarily discontinued prior to each LDL apheresis procedure.

Hemodialysis using high-flow membranes

Anaphylactoid reactions have been observed in patients undergoing dialysis using high-flow polyacrylonitrile membranes (such as AN69®) and simultaneously receiving ACE inhibitor therapy. In such cases, it is necessary to use dialysis membranes of a different type or use antihypertensive agents of other classes.

Diabetes mellitus

When using enalapril preparations in patients with diabetes mellitus receiving hypoglycemic agents for oral use or insulin, it is necessary to regularly monitor the concentration of glucose in the blood. Patients taking oral hypoglycemic agents or insulin should be informed before starting the use of ACE inhibitors about the need for regular monitoring of blood glucose concentrations (hypoglycemia), especially during the first month of simultaneous use of these drugs.

Cough

There have been cases of cough during therapy with ACE inhibitors. As a rule, the cough is unproductive, permanent and stops after the drug is discontinued. Cough associated with the use of ACE inhibitors should be considered in the differential diagnosis of dry cough.

Surgical procedures / General anesthesia

During major surgical procedures or during general anesthesia with antihypertensive agents, enalaprilat blocks the formation of angiotensin II caused by the compensatory release of renin. If a marked decrease in blood pressure occurs due to such a mechanism, it can be corrected by increasing the volume of circulating blood.

Hyperkalemia

Hyperkalaemia may develop during therapy with ACE inhibitors, including enalapril. Risk factors for hyperkalemia include renal failure, advanced age (over 65 years), diabetes mellitus, certain concomitant conditions (decreased BCC, acute heart failure in the decompensation stage, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene or amiloride), as well as potassium preparations, potassium-containing salt substitutes and other drugs that contribute to an increase in the content of potassium in blood plasma (such as spironolactone, eplerenone, triamterene or amiloride). such as heparin, tacrolimus, cyclosporin; preparations containing co-trimoxazole [trimethoprim + sulfamethoxazole]).

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

If the concomitant use of enalapril and the drugs listed above containing potassium or increasing the potassium content in blood plasma is necessary, caution should be exercised and the serum potassium content should be regularly monitored.

Hypokalemia

When using ACE inhibitors simultaneously with thiazide diuretics, the risk of hypokalemia is not excluded, so in such cases, regular monitoring of blood potassium levels should be carried out during therapy.

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

Hypotension, syncope, stroke, hyperkalemia, and impaired renal function (including acute renal failure) have been reported in susceptible patients, especially if combination therapy with drugs that affect the RAAS is used.

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

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 use of two drugs that affect the RAAS is necessary, their use should be carried out under the supervision of a doctor with extreme caution and with regular monitoring of renal function, blood pressure and blood plasma electrolytes.

Lithium preparations

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

Alcohol

During the treatment period, it is not recommended to consume alcoholic beverages, as ethanol increases the antihypertensive effect of ACE inhibitors.

Use in elderly patients

Clinical studies on the efficacy and safety of enalapril were similar in older and younger patients with hypertension.

Ethnic differences

Enalapril, like other ACE inhibitors, has a less pronounced antihypertensive effect in patients of the black race, compared with representatives of other races, which may be explained by the higher prevalence of conditions with low plasma renin activity in patients of the black race with arterial hypertension.

Discontinuation of therapy

Sudden discontinuation of enalapril usually does not lead to the development of “withdrawal”syndrome.

Influence on the ability to drive vehicles and mechanisms

The effect of Enalapril on the ability to drive vehicles and work with mechanisms has not been studied. However, some adverse events (such as dizziness) that have been observed while taking Enalapril may affect the ability to drive vehicles and work with mechanisms (see the section “Side effects”).

Composition

Tablet Form of production

Storage conditions

Store in a dry place protected from light at a temperature not exceeding 30 ° C. Keep out of reach of children.

Shelf

life is 3 years.

Active ingredient

Enalapril

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Heart Failure, Hypertension