Enalapril forte - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate (sugar milk) - 200.0 mg, microcrystalline cellulose 205.5 mg, calcium stearate 4.6 mg, talc 13.8 mg, silicon dioxide colloid (aerosil) 2.3 mg, crospovidone (kollidone CL-M, polyplasdone XL-10) -13.8 mg.

Description:

Tablets of white or almost white color, flat-cylindrical shape with a facet and a risk. Presence of marble is admissible.

Pharmacotherapeutic group:ACE inhibitor

ATX: & nbsp

C.09.A.A.02 Enalapril

Pharmacodynamics:

Enalapril, an antihypertensive agent, an angiotensin-converting enzyme (ACE) inhibitor, refers to drugs that affect the renin-angiotensin-aldosterone system (RAAS). It is used to treat essential hypertension (primary arterial hypertension (AH)) of any severity and reninvascular 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).

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

ACE (peptidyl-dipeptidase A) catalyzes the conversion of angiotensin I into the vasopressor peptide angiotensin II. After suction enalapril hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which leads to an increase in renin plasma activity (due to the elimination of negative feedback in response to the release of renin) and a decrease in aldosterone secretion. At the same time, systolic and diastolic blood pressure (AD), general peripheral vascular resistance (OPSS) decrease, post- and preload of the myocardium decreases.

Enalapril dilates arteries more than veins, and there is no reflex increase in heart rate (heart rate).

The ACE is identical to the kinase II enzyme, so enalapril can also block the destruction of bradykinin, a peptide that has a pronounced vasodilating effect. The significance of this effect in the therapeutic effect of enalapril needs clarification.The main mechanism of anti-hypertensive action of enalapril is the suppression of RAAS activity, which plays an important role in the regulation of blood pressure, but enalapril has an antihypertensive effect even in patients with hypertension and with reduced renin activity of blood plasma. The antihypertensive effect is more pronounced with a high concentration of renin than with a normal or low concentration of renin.

The use of enalapril in patients with AH leads to a decrease in blood pressure both in the "standing" and "lying" positions without a significant increase in heart rate. Symptomatic orthostatic (postural) hypotension in the treatment with enalapril develops rarely. Effective inhibition of ACE activity usually develops 2-4 hours after a single dose of enalapril ingested. Antihypertensive action 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. When the recommended doses are used, the antihypertensive effect and hemodynamic effects persist for 24 hours after taking the drug.

In some patients, achieving an optimal BP reduction may require several weeks of therapy. Interruption of enalapril therapy does not cause a sharp rise in blood pressure.

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

In patients with essential hypertension, a decrease in blood pressure is accompanied by a decrease in OPSS and an increase in cardiac output, but the heart rate does not change or changes insignificantly.

After taking enalapril, there is an increase in renal blood flow. At the same time the glomerular filtration rate (GFR) does not change, there are no signs of sodium or liquid retention. However, in patients with initially reduced glomerular filtration, its rate usually increases.

Enalapril reduces intra-cerebral hypertension, slowing the development of glomerulosclerosis and the risk of developing chronic renal failure (CRF).

Long-term use of enalapril in patients with essential hypertension and renal insufficiency can lead to an improvement in renal function, as evidenced by an increase in GFR.

In patients with renal insufficiency and with or without diabetes mellitus, there is a decrease in albuminuria, excretion of the immunoglobulin by the kidneys G (IgG), as well as a decrease in the total protein in the urine after enalapril intake.

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 the use of thiazide diuretics.

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

Therapy with enalapril is accompanied by a favorable effect on the ratio of lipoprotein fractions in blood plasma and the absence of influence or favorable effect on the concentration of total cholesterol.

In patients with chronic heart failure (CHF) on the background of therapy with cardiac glycosides and diuretics, enalapril treatment causes a decrease in the total peripheral resistance and blood pressure. Cardiac output is increased, while heart rate (usually elevated in patients with CHF) is reduced. Also, the pressure of wedging in the pulmonary capillaries decreases. Tolerance to physical activity and severity of heart failure, assessed by criteria of the New York Heart Association (NYHA), are improving. These effects are observed with prolonged therapy with enalapril.

In patients with mild and moderate severity of heart failure enalapril slows the progression of cardiac dilatation and heart failure, which is confirmed by a decrease in the endodastolic and systolic volumes of the left ventricle and an improvement in the left ventricular ejection fraction.

With left ventricular dysfunction enalapril reduces the risk of developing major ischemic outcomes (including the incidence of myocardial infarction and the number of hospitalizations for unstable angina).

Enalapril reduces the incidence of ventricular arrhythmias in patients with heart failure, although the underlying mechanisms and the clinical significance of this effect are not known.

With CHF, a marked clinical effect is observed with long-term treatment for 6 months or more.

Pharmacokinetics:

Suction

After ingestion enalapril quickly absorbed in the gastrointestinal tract. The maximum concentration of enalapril in the blood serum is achieved within 1 h after ingestion. The degree of absorption of enalapril when ingested is approximately 60%. Simultaneous food intake does not affect the absorption of enalapril.

After suction enalapril quickly hydrolyzed with the formation of an active metabolite enalaprilata - a potent ACE inhibitor. The maximum concentration of enalaprilat in the blood serum is observed approximately 4 hours after taking enalapril dose inside. 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 enalaprilat in serum is achieved by day 4 from the beginning of reception of enalapril.

Distribution

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

Metabolism

There are no data on other significant ways of metabolism of enalapril, other than hydrolysis to enalaprilate. The rate of hydrolysis of enalapril may decrease in patients with impaired liver function without reducing the therapeutic effect.

Excretion

Enalapril is excreted mainly through the kidneys. The main metabolites, determined in urine, are enalaprilate (about 40% of the dose) and unchanged enalapril (approximately 20%).

The enalaprilate concentration curve in the blood plasma has a long final phase, apparently due to its binding to the ACE.The half-life of enalaprilat with the oral administration of the drug is 11 hours.

Pharmacokinetics in specific patient groups

Patients with impaired renal function

The area under the concentration-time curve (AUC) enalapril and enalaprilat increases in patients with renal insufficiency.

In patients with mild and moderate severity of renal insufficiency (creatinine clearance 40 to 60 ml / min) after enalapril administration at a dose of 5 mg once a day, the equilibrium value AUC Enalaprilat is approximately 2 times higher than in patients with unchanged renal function.

In patients with severe renal failure (QC not more than 30 ml / min) after repeated use of enalapril value AUC increases approximately 8-fold, the half-life of enalaprilate increases, reaching the equilibrium concentration of enalaprilat is delayed (see section "Method of administration and dose").

Enalaprilat can be withdrawn from the general blood flow by the hemodialysis procedure. The clearance for hemodialysis is 62 ml / min (1.03 ml / s).

Breastfeeding period

After a single administration of enalapril in a dose of 20 mg yof patients in the puerperium the mean maximum enalapril concentration in breast milk is 1.7 μg / L (0.54 to 5.9 μg / L) 4-6 hours after admission. The average maximum concentration of enalaprilate is 1.7 μg / l (1.2 to 2.3 μg / L) and is observed at different times within 24 hours after admission. Given the data on the maximum concentrations in breast milk, the estimated maximum intake of enalapril by a fully breastfed infant is 0.16% of the dose calculated with regard to the mother's body weight.

After taking enalapril orally 10 mg once a day for 11 months, the maximum concentration of enalapril in breast milk is 2 μg / l 4 hours after admission, the maximum concentration of enalaprilate is 0.75 μg / l approximately 9 hours after ingestion . The average concentration in breast milk within 24 hours after enalapril intake is 1.44 μg / l and enalaprilate is 0.63 μg / l.

Indications:

- Essential hypertension of any severity.

- Renovascular hypertension.

- Heart failure of any severity.

In patients with clinical manifestations of HF, the drug is also indicated for:

improved patient survival;
slowing the progression of heart failure;
decrease in the frequency of hospitalizations for HF.

- Prevention of the development of clinically significant heart failure.

- In patients without clinical symptoms of heart failure with left ventricular dysfunction, the drug is indicated for:

slowing the development of clinical manifestations of heart failure;
decrease in the frequency of hospitalizations for HF.

- Prevention of coronary ischemia in patients with left ventricular dysfunction.

The drug is indicated for:

decrease the incidence of myocardial infarction;
decrease in the frequency of hospitalizations for unstable angina.

Contraindications:

- Hypersensitivity to enalapril, other components of the drug, or other ACE inhibitors;

- angioedema in history, associated with previous use of ACE inhibitors, as well as hereditary or idiopathic angioedema;

- simultaneous use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and / or renal dysfunction (GFR less than 60 ml / min / 1.73 m²) (see the section "Interaction with other medicinal products");

- age under 18 years of age (safety and efficacy not studied);

- pregnancy and the period of breastfeeding;

- hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Carefully:

- Bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney;

- condition after kidney transplantation;

- aortic or mitral stenosis (with disturbances in hemodynamics);

- hypertrophic obstructive cardiomyopathy (GOKMP);

- ischemic heart disease (IHD);

- cerebrovascular diseases (including cerebral circulatory insufficiency);

- renal failure (CC less than 80 ml / min);

- Renovascular hypertension;

- oppression of bone marrow hematopoiesis;

- systemic connective tissue diseases (including scleroderma, systemic lupus erythematosus), immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors;

- liver failure;

- diabetes;

- hyperkalemia;

- when used simultaneously with potassium-sparing diuretics, potassium preparations, potassium-containing substitutes for table salt and lithium preparations;

- when performing the procedure of apheresis of low-density lipoproteins (LDL-apheresis) using dextran sulfate;

- aggravated allergic anamnesis or angioedema in the anamnesis;

- conditions accompanied by a decrease in the volume of circulating blood (including with diuretic therapy, diet with restriction of table salt, dialysis, diarrhea, or vomiting);

- during desensitization with the allergen from the Hymenoptera venom;

- in patients on dialysis using high-flux membranes (such as AN 69®);

- in patients after major surgical interventions or in general anesthesia;

- in patients of the Negroid race.

Pregnancy and lactation:

The use of the drug in pregnancy is not recommended. At the onset of pregnancy, taking the drug should be stopped immediately, unless taking the drug is not considered vital for the mother.

Epidemiological data indicate a possible teratogenic effect on the fetus of ACE inhibitors in the first trimester of pregnancy. If therapy with an ACE inhibitor is not vital, then women planning a pregnancy,It is necessary to use other, hypotensive drugs approved in pregnancy, which have proven safety.

ACE inhibitors can cause disease or death of the fetus or newborn when used in the II and III trimesters of pregnancy. The use of ACE inhibitors during this period was accompanied by a negative impact on the fetus and newborn, including the development of arterial hypotension, renal failure, hyperkalemia and / or hypoplasia of the skull bones in a newborn. Preterm birth, intrauterine growth retardation, and non-spreading of the arterial (Botallova) duct were also reported, but it is unclear whether these cases were associated with the action of ACE inhibitors. In those 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. If an oligohydramnion is detected during an ultrasound examination, it is necessary to stop taking the drug, unless its reception is considered vital for the mother.Nevertheless, both the patient and the doctor should know that the oligohydramnion develops with irreversible damage to the fetus. If ACE inhibitors are used during pregnancy and the development of oligohydramnion is observed, depending on the week of pregnancy, it may be necessary to perform a stress test, a stress test, or a biophysical profile of the fetus to assess the functional state of the fetus.

Perhaps the development of oligohydramnion, is due to a decrease in the function of the kidneys of the fetus. This complication can lead to limb contracture, deformation of the skull bones, including its facial part, and lung hypoplasia. When using the drug, the patient should be informed of the potential risk to the fetus. Newborns whose mothers took the drug should be carefully monitored for the detection of arterial hypotension, oliguria, and hyperkalemia.

Enalapril, which penetrates the placenta, can be partially removed from the bloodstream of the newborn by peritoneal dialysis; in theory, it can be removed by means of an exchange blood transfusion.

Enalapril and enalaprilate in trace concentrations are excreted in breast milk. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, squeezed a small amount of liquid. Tablets can be taken regardless of the time of eating, regularly and at the same time of day. To ensure the following dosing regimen, enalapril can be used in doses of 2.5 mg, 5 mg from other manufacturers.

If the drug is missed, you should take the missed dose. In the event that several hours are left until the next dose is applied, the dose of the drug should not be taken. The dose should never be doubled.

Essential hypertension

The initial dose is 10-20 mg, depending on the severity of hypertension and is applied 1 time per day. With a mild degree of hypertension, the recommended initial dose is 10 mg (1/2 tablets of 20 mg) once a day. At other degrees of AH the initial dose is 20 mg once a day. The maintenance dose is usually 20 mg once daily. Dosage is selected individually for each patient, but the maximum dose should not exceed 40 mg per day (in 1 or 2 administration).

Renovascular hypertension

Because in patients in this group, blood pressure and renal function may be particularly sensitive to ACE inhibition, therapy is initiated with a low initial dose of 5 mg or less. Then the dose is selected in accordance with the needs and condition of the patient. In the absence of a therapeutic effect, the dose is increased after 1 to 2 weeks by 5 mg. Usually the effective dose is 20 mg of the drug once a day with daily intake. Caution should be exercised when using the drug in patients who had recently taken diuretics (see "Adjuvant treatment with AH diuretics" below).

Concomitant treatment with AH diuretics

After the first administration of the drug, symptomatic arterial hypotension may develop. This effect is most likely in patients who take diuretics. The drug should be used with caution, as these patients may have a disturbance of the water-electrolyte balance. Admission diuretikov should be stopped 2-3 days before the start of therapy with the drug. If this is not possible, the initial dose of the drug should be reduced (to 5 mg or less) to determine the primary effect of the drug on blood pressure.Further dosage should be selected taking into account the needs and conditions of the patient.

Dosage for renal failure

The interval between drug intake and / or dose reduction should be increased.

Creatinine clearance, ml / min	Initial dose, mg / day
30-80 ml / min	5-10 mg
10-30 ml / min	2.5-5 mg
<10 ml / min	2.5 mg on dialysis days **

*Cm. sections "With caution"; "Special instructions".

** Enalapril undergoes dialysis. Correction of the dose on days when dialysis is not performed, should be carried out depending on the level of blood pressure.

Heart failure and prevention of the development of clinically significant heart failure

The initial dose of the drug in patients with clinically severe heart failure or with asymptomatic left ventricular dysfunction is 2.5 mg. In this case, the drug should be administered under close medical supervision to determine the primary effect of the drug on blood pressure.

The drug can be used to treat HF with severe clinical manifestations, usually in conjunction with diuretics and, when necessary, with cardiac glycosides. In the absence of symptomatic arterial hypotension (resulting from treatmentdrug) or after its correction, the dose should be increased gradually (by 2.5-5 mg every 3-4 days) to the usual maintenance dose of 20 mg, which is applied either singly or divided into 2 receptions depending on the patient's tolerance of the drug. Selection of the dose is carried out within 2-4 weeks or can be carried out in a shorter time, if there are residual signs and symptoms of heart failure. This therapeutic regimen effectively reduces the mortality rates of patients with clinically significant heart failure.

Both before and after the beginning of treatment with the drug, regular monitoring of blood pressure and kidney function should be performed (see section "Special instructions"), as it was reported that the development of arterial hypotension following administration of the drug, followed by (more rarely) acute renal failure. In patients taking diuretics, the dose of diuretics should be reduced as far as possible before starting treatment with the drug. The development of arterial hypotension after taking the first dose of the drug does not mean that arterial hypotension will re-develop with long-term treatment, and does not indicate the need to stop taking the drug.

When treating the drug should also monitor the potassium content in the blood serum (see section "Interaction with other drugs").

Side effects:

In general, the drug is well tolerated. In most cases, adverse events are mild, transient and do not require withdrawal of therapy.

The incidence of adverse reactions is given in accordance with the World Health Organization (WHO) classification: very often more than 1/10, often more than 1/100 and less than 1/10, infrequently more than 1/1000 and less than 1/100, rarely - more than 1/10000 and less than 1/1000, very rarely - less than 1/10000, including individual messages, the frequency is unknown (it is impossible to determine the frequency of occurrence according to available data).

From the side of the blood and lymphatic system: infrequently, anemia (including aplastic and hemolytic); rarely - neutropenia, a decrease in hemoglobin and hematocrit, thrombocytopenia, agranulocytosis, oppression of bone marrow hematopoiesis, pancytopenia, lymphadenopathy, autoimmune diseases.

From the side of metabolism and nutrition: infrequently - hypoglycemia (see section "Special instructions").

From the side of the psyche and the nervous system: very often - dizziness; often - headache, depression; infrequently - confusion, drowsiness, insomnia, increased excitability, paresthesia, vertigo; rarely - unusual dreams, sleep disturbances.

From the side of the hearing organ and labyrinthine disorders: infrequently, noise in the ears.

From the side of the organ of vision: rarely - odd sight.

From the side of the heart and blood vessels: often - marked decrease in blood pressure, fainting, chest pain, heart rhythm disorder, angina, tachycardia; infrequently, orthostatic hypotension, palpitations, myocardial infarction, or stroke (possibly due to a sharp decrease in blood pressure in patients at high risk) (see section "Special instructions"); rarely - Raynaud's syndrome.

On the part of the respiratory system, the organs of the thorax and the mediastinum: very often - cough; often shortness of breath; infrequently - rhinorrhea, sore throat, hoarseness of the voice, bronchospasm / bronchial asthma; rarely - pulmonary infiltrates, rhinitis, allergic alveolitis / eosinophilic pneumonia.

From the digestive system: very often - nausea; often - diarrhea, pain in the abdomen, a violation of taste; infrequently - intestinal obstruction, pancreatitis,vomiting, indigestion, constipation, anorexia, stomach irritation, dryness of the oral mucosa, stomach and duodenal ulcer; rarely - stomatitis / aphthous ulcers, glossitis; very rarely - intestinal edema.

From the liver and biliary tract: rarely - hepatic insufficiency, hepatitis (hepatocellular or cholestatic), including hepatic necrosis, cholestasis (including jaundice).

From the skin and subcutaneous tissues: often - hypersensitivity reactions / angioedema, edema of the face, extremities, lips, tongue, vocal folds and / or larynx, skin rash; infrequently - increased sweating, itching, hives, alopecia; rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, pemphigus, erythroderma.

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

From the side of the kidneys and urinary tract: infrequently - renal dysfunction, renal failure, proteinuria; rarely - oliguria.

From the endocrine system: frequency is unknown - syndrome of inadequate secretion of antidiuretic hormone.

From the genitals and breast: infrequently - erectile dysfunction; rarely - gynecomastia.

Laboratory and instrumental data: often - hyperkalemia, an increase in the concentration of creatinine in the blood serum; infrequently - hyponatremia, increased urea concentration in the blood; rarely - increased activity of "liver" transaminases, an increase in the concentration of bilirubin in the blood serum.

General disorders: very often - asthenia; often - increased fatigue; infrequently - muscle cramps, "hot flashes" of blood to the skin of the face, a feeling of discomfort, fever.

In rare cases with simultaneous use of ACE inhibitors (including enalapril) and intravenous administration of gold preparations (sodium aurotomy malate) describes a symptom complex that includes reddening of the facial skin, nausea, vomiting and arterial hypotension.

Undesirable phenomena that were observed in the period of post-marketing application enalapril (causal relationship not established): urinary tract infection, upper respiratory tract infection, bronchitis, cardiac arrest, atrial fibrillation, herpes zoster, melena, ataxia, pulmonary artery thromboembolism and pulmonary infarction, hemolytic anemia, including hemolysis cases in patients with deficiency of glucose-6-phosphate dehydrogenase.

Overdose:

Symptoms: a marked decrease in blood pressure (starts approximately 6 hours after taking the drug), up to the development of collapse, myocardial infarction, acute cerebrovascular accident or thromboembolic complications, disturbance of water electrolyte balance, renal failure, rapid breathing, tachycardia, palpitations, bradycardia, dizziness, anxiety , a sense of fear, cramps, coughing, stupor. The concentration of enalaprilate in the blood plasma is 100-200 times higher than after the application of therapeutic doses, was observed after ingestion of 300 mg and 440 mg of enalapril, respectively.

Treatment: the patient is transferred to a horizontal position with a low headboard.

In light cases, gastric lavage and ingestion of activated carbon are shown, in more serious cases,directed to the normalization of blood pressure: intravenous injection of 0.9% sodium chloride solution, plasma substitutes, if necessary - intravenous catecholamines, hemodialysis (the rate of excretion of enalaprilate - 62 ml / min). Patients with a bradycardia that is resistant to therapy are shown staging the pacemaker.

Interaction:

Other antihypertensives

Additive effect can be observed with the simultaneous use of the drug and other antihypertensive therapy.

When applying the drug simultaneously with other antihypertensive drugs, especially with diuretics, an increase in the antihypertensive effect may be observed. Simultaneous use of the drug with beta-blockers, methyldopa or blockers of "slow" calcium channels increases the severity of the antihypertensive effect.

Simultaneous use of the drug with alpha, beta-adrenoblockers and ganglion blockers should be carried out under close medical supervision.

Simultaneous use of the drug with nitroglycerin, other nitro drugs or other vasodilators increases the antihypertensive effect.

Potassium of blood serum

In patients with hypertension who took the drug in monotherapy for more than 48 weeks, there was an increase in potassium in the blood serum by an average of 0.2 mmol / l.

With the simultaneous use of the drug with diuretics that cause the loss of potassium ions (thiazides or loop diuretics), hypokalemia caused by the action of diuretics is usually weakened by the effect of enalapril.

Risk factors for the development of hyperkalemia are renal failure, diabetes mellitus, concomitant use of potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene or amiloride), as well as potassium-containing supplements and salts. The use of potassium supplements, potassium-sparing diuretics or potassium-containing salts, especially in patients with impaired renal function, can lead to a significant increase in potassium in the serum. If you need to simultaneously use the potassium-containing or potassium-raising drugs listed above, you should be careful and regularly monitor the potassium content in the blood serum.

Hypoglycemic agents

Simultaneous use of ACE inhibitors and hypoglycemic agents (insulin, hypoglycemic agents for ingestion) can enhance the hypoglycemic effect of the latter with the risk of developing hypoglycemia. This phenomenon, as a rule, is most often observed during the first weeks of combined therapy, as well as in patients with impaired renal function. In patients with diabetes mellitus taking hypoglycemic agents for ingestion or insulin, the blood glucose concentration should be monitored regularly, especially during the first month of simultaneous use with ACE inhibitors.

Lithium preparations

Like other drugs that affect the excretion of sodium, ACE inhibitors can reduce the excretion of lithium by the kidneys, so when lithium drugs and ACE inhibitors are used simultaneously, the concentration of lithium in serum should be monitored regularly.

Tricyclic antidepressants / antipsychotics / general anesthetics / drugs

The simultaneous use of certain anesthetic drugs, tricyclic antidepressants and neuroleptics with ACE inhibitors may lead to a further reduction in blood pressure (see section "Special instructions").

Ethanol

Ethanol enhances the antihypertensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and beta-blockers

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

Sympathomimetics

Sympathomimetics can reduce the antihypertensive effect of ACE inhibitors.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs, including selective inhibitors of cyclooxygenase-2 (COX-2), can reduce the effect of diuretics and other antihypertensive agents. As a result, the antihypertensive effect of angiotensin II receptor antagonists (APA II) or ACE inhibitors can be weakened when used simultaneously with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (eg, in 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 function kidney, including the development of acute renal failure.These effects are usually reversible, so the simultaneous use of these medicines should be carried out with caution in patients with impaired renal function.

Double blockade of the renin-angiotensin-aldosterone system

Double blockade of RAAS with the use of ARA II, ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, kidney function and electrolyte content in the blood in patients taking both the drug and other drugs that affect RAAS are necessary. Enalapril should not be used concurrently with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and / or with impaired renal function (GFR less than 60 mL / min / 1.73 m²).

The simultaneous use of ACE inhibitors with receptor antagonists for angiotensin II in patients with diabetic nephropathy is contraindicated.

Preparations of gold

Symptomocomplex (nitrate-like reactions), including a "tide" of blood to the skin of the face, nausea,vomiting and arterial hypotension, is observed in rare cases with simultaneous use of gold preparations for parenteral administration (sodium aurotomy malate) and ACE inhibitors, including enalapril.

Inhibitors mTOR

In patients using simultaneously an ACE inhibitor and an enzyme inhibitor mTOR (mammalion Terget of Rapamycin - a target of rapamycin in mammalian cells) (for example, tessirolimus, sirolimus, everolimus), therapy may be accompanied by an increased risk of angioedema.

Other medicines

There is no clinically significant pharmacokinetic drug interaction between the drug and the following drugs: hydrochlorohyazide, furosemide, digoxin, timolol, methyldopa, warfarin, indomethacin, sulindac and cimetidine.

With the simultaneous use of the drug and propranolol, enalaprilat concentration in serum is reduced, but this effect is not clinically significant.

Special instructions:

Symptomatic arterial hypotension

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated hypertension.In patients with hypertension taking Enalapril Forte, arterial hypotension develops more often on the background of dehydration, which occurs, for example, as a result of diuretic therapy, restriction of consumption of table salt, in patients on dialysis, as well as in patients with diarrhea or vomiting (see Sections "Side effect," "Interaction with other drugs"). Symptomatic arterial hypotension is also observed in patients with heart failure with or without renal failure.

Arterial hypotension develops more often in patients with a more severe degree of HF with hyponatremia or impaired renal function, which have higher doses of "loop" diuretics. In these patients, treatment with the drug should begin under medical supervision, which should be particularly careful when changing the dose of the drug and / or diuretic. Similarly, patients with ischemic heart disease or cerebrovascular disease should be monitored, in whom excessive BP reduction can lead to myocardial infarction or stroke.

With the development of arterial hypotension, the patient should be laid and, if necessary, to enter a 0.9% solution of sodium chloride.Transient arterial hypotension when taking the drug is not a contraindication to further use and increase in the dose of the drug, which can be continued after replenishing the volume of fluid and normalizing blood pressure.

In some patients with HF and with normal or reduced blood pressure, the drug may cause an additional decrease in blood pressure. This response to taking the drug is expected and is not a basis for discontinuing treatment. In those cases when arterial hypotension assumes a stable character, the dose should be reduced and / or discontinued with a diuretic and / or drug.

Aortic or mitral stenosis / hypertrophic obstructive cardiomyopathy

Like all drugs that have a vasodilating effect, ACE inhibitors should be administered with caution to patients with obstruction of the outflow path from the left ventricle.

Impaired renal function

In some patients, arterial hypotension, which develops after the initiation of treatment with ACE inhibitors, may lead to further deterioration in kidney function. In some cases, the development of acute renal failure, usually reversible, has been reported.

Patients with renal insufficiency may need to reduce the dose and / or frequency of taking the drug (see section "Method of administration and dose"). In some patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, there was an increase in the concentration of urea in the blood and creatinine in the serum. The changes were usually reversible, and the indicators returned to their initial values after the cessation of treatment. This pattern of changes is most likely in patients with renal insufficiency.

In some patients who did not have renal disease prior to treatment, the drug in combination with diuretics caused a usually minor and transient increase in urea concentration in the blood and serum creatinine. In such cases, a dose reduction and / or cancellation of the diuretic and / or Enalapril Forte may be required.

Kidney Transplantation

There is no experience of use in patients after kidney transplantation, so treatment with Enalapril Forte is not recommended in patients after kidney transplantation.

Liver failure

ACE inhibitors are rarely associated with the development syndrome beginning with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis, sometimes with fatal consequences. The mechanism of this syndrome has not been studied. When jaundice or a significant increase in activity of "hepatic" transaminases on treatment with ACE inhibitors should be discontinued taking the drug and assign appropriate supportive therapy, the patient must be under appropriate supervision.

Neutropenia / agranulocytosis

Neutropenia / agranulocytosis, thrombocytopenia and anemia are observed in patients taking ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and without other complicating factors.

FORTE Enalapril should be used with extreme caution in patients with connective tissue diseases (systemic lupus erythematosus, scleroderma, etc.), Receiving immunosuppressive therapy, allopurinol or procainamide, or a combination of these complicating factors, especially if there are already existing impairments of kidney function.Some of these patients develop serious infectious diseases, which in some cases do not respond to intensive antibiotic therapy. If such patients are used enalapril, it is recommended that the number of leukocytes and lymphocytes in the blood be monitored regularly and patients should be warned about the need to report any signs of an infectious disease.

Hypersensitivity reactions / angioedema

With the use of ACE inhibitors, including Enalapril Forte, rare cases of angioedema, facial, extremities, lips, tongue, vocal folds and / or larynx occur in different periods of treatment. In very rare cases, the development of intestinal edema is possible. In such cases, immediately stop taking the drug and carefully monitor the patient's condition in order to monitor 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 antihistamine and corticosteroid therapy may not be sufficient.

Very rarely reported a lethal outcome due to angioedema, associated with laryngeal edema or edema of the tongue. Swelling of the tongue, vocal folds or larynx can lead to airway obstruction, especially in patients who underwent surgery on the respiratory organs. In cases where the edema is localized in the area of the tongue, vocal folds or larynx and can cause airway obstruction, immediate treatment should be prescribed, which may include subcutaneous administration of 0.1% epinephrine (adrenaline) solution (0.3-0.5 ml) and / or provide airway patency.

In patients of the Negroid race, taking ACE inhibitors, angioedema is observed more often than in patients of other races.

Patients with a history of angioedema, not associated with the administration of ACE inhibitors, may be more at risk of developing angioedema due to therapy with ACE inhibitors (see "Contraindications"),

Anaphylactoid reactions during desensitization with an allergen from Hymenoptera venom

In rare cases, patients taking ACE inhibitors develop life-threatening anaphylactoid reactions during desensitization with an allergen from Hymenoptera venom. Undesirable reactions can be avoided if prior to the initiation of desensitization temporarily stop the intake of an ACE inhibitor.

Anaphylactoid reactions during LDL-apheresis

In patients taking ACE inhibitors during LDL-apheresis using dextran sulfate, anaphylactoid reactions that are life-threatening are rare. The development of these reactions can be avoided if the ACE inhibitor is temporarily discontinued before the beginning of each LDL-apheresis procedure.

Patients on hemodialysis

Anaphylactoid reactions are observed in patients on dialysis using high-flux membranes (such as AN 69®) and concomitantly receiving therapy with ACE inhibitors. These patients need to use dialysis membranes of a different type or antihypertensive drugs of other classes.

Cough

There are cases of cough on the background of therapy with ACE inhibitors.As a rule, cough is unproductive, permanent and stops after the abolition of therapy. Cough associated with the use of ACE inhibitors should be taken into account in the differential diagnosis of cough.

Surgical interventions / general anesthesia

During large surgical interventions or general anesthesia with the use of agents that cause an antihypertensive effect, enalaprilate blocks the formation of angiotensin II, caused by compensatory release of renin. If there is a pronounced decrease in blood pressure, explained by a similar mechanism, it can be corrected by increasing the volume of circulating blood.

Hyperkalemia (see the section "Interaction with other medicinal products")

The risk of hyperkalemia is observed in renal failure, diabetes, as well as with the simultaneous use of potassium-sparing diuretics (eg spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium salts.

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

If it is necessary to simultaneously use the drug and the medicines listed above, you should be careful and regularly monitor the potassium content in the blood serum.

Hypoglycaemia

Patients with diabetes who take hypoglycemic agents for ingestion 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 medicines (see "Interaction with other medicinal products ").

Lithium preparations

It is not recommended simultaneous use of lithium drugs and enalapril forte (see section "Interaction with other drugs").

Double blockade of the renin-angiotensin-aldosterone system

It was reported on the development of arterial hypotension, syncope, stroke, hyperkalemia and renal dysfunction (including acute renal failure) in susceptible patients,especially if combined therapy is used with drugs that affect RAAS (see section "Interaction with other drugs"). It is not recommended to perform a double blockade of RAAS by the combined use of ACE inhibitors with ARA II or aliskiren.

Contraindicated simultaneous use of the drug with aliskiren or aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or with impaired renal function (GFR less than 60 ml / min / 1.73 m²) (see the section "Contraindications").

Application in elderly patients

The efficacy and safety of Enalapril Forte are similar in elderly and younger patients with AH.

Race

As with the use of other ACE inhibitors, Enalapril Forte appears to be less effective in reducing AD in patients of the Negroid race than in patients of other races, which may be explained by the higher prevalence of conditions with low renin activity of blood plasma in the Negroid race AG.

Effect on the ability to drive transp. cf. and fur:

When using the drug, care must be taken when driving vehicles and taking other potentially dangerous speciesactivities that require an increased concentration of attention and speed of psychomotor reactions, in connection with the possibility of developing dizziness and drowsiness.

Form release / dosage:Tablets, 20 mg.

Packaging:

For 10 or 20 tablets in contour mesh packaging made of polyvinylchloride film and aluminum foil printed lacquered.

20, 30, 40, 50, 60, 100 tablets in cans of polymer made of polypropylene, low-density polyethylene with a lid of a pull-up with the first opening for vitamins and drugs, polypropylene, low pressure polyethylene with a screw neck and screw cap for vitamins and medicines or plastic jars of polypropylene, low pressure polyethylene screw cap for vitamins and drugs.

Each jar, 2, 3 or 5 contour squares with instructions for use is placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003589

Date of registration:26.04.2016

Expiration Date:26.04.2021

The owner of the registration certificate:SYNTHESIS, OJSC SYNTHESIS, OJSC Russia

Manufacturer: & nbsp

SYNTHESIS, OJSC Russia

Representation: & nbspSYNTHESIS JSC Joint-Stock Kurgan Society of Medical Preparations and Products SYNTHESIS JSC Joint-Stock Kurgan Society of Medical Preparations and Products Russia

Information update date: & nbsp08.07.2016

Illustrated instructions

Instructions

Enalapril Fort (Enalapril forte)