Enalapril Hexal, tablets 20 mg 50 pcs

ATC code: C09AA02

Pharmacological properties

Pharmacodynamics

. Enalapril is an angiotensin-converting enzyme (ACE) inhibitor used to treat arterial hypertension, heart failure, and diabetic nephropathy. The clinical effect of enalapril is due to inhibition of ACE activity and, as a consequence, reduction of angiotensin II formation from angiotensin I in tissues and circulating blood. Reducing the concentration of angiotensin II, in turn, leads to vasodilation, decreased secretion of aldosterone, increased potassium and plasma renin concentration.

Hemodynamic consequences of these changes are decreased total peripheral vascular resistance (TPR), systolic and diastolic blood pressure, increased cardiac output, and decreased post- and preload on the myocardium. Enalapril dilates arteries more than veins, and there is no reflex increase in heart rate (HR). It reduces bradykinin degradation and increases prostaglandin synthesis. Antihypertensive effect is more pronounced at high concentration of renin than at normal or reduced levels. Time of onset of antihypertensive effect when taken orally is 1 hour, which reaches a maximum after 4-6 hours and lasts up to 24 hours.

In some patients, therapy for several weeks is necessary to achieve optimal blood pressure (BP). In chronic heart failure noticeable clinical effect is observed with long-term treatment – 6 months or more. The duration of therapeutic effect is dose-dependent.

Vasodilating and some diuretic effect of enalapril are also provided by blockade of bradykinin destruction which in turn stimulates synthesis of vasodilatory and renal prostaglandins. Increased bradykinin both in blood plasma and locally in organs and tissues of the body blocks the pathological processes occurring in chronic heart failure in the myocardium, kidneys, vascular smooth muscle. At the same time there is an increase in coronary and renal blood flow, with prolonged use (3-4 weeks of treatment) left ventricular hypertrophy and myofibrils of arterial walls are reduced, left ventricular dilatation slows down and blood supply to ischemic myocardium is improved, metabolism improves and the frequency of arrhythmias after restoration of blood supply to the heart muscle decreases.
Due to moderate diuretic effect of the drug, intraclavian hypertension decreases, the development of glomerulosclerosis slows down and the risk of chronic renal failure decreases.

The decrease of BP within therapeutic limits (not lower than 110/60 mm Hg) does not affect the cerebral blood flow: the blood supply to the brain is maintained at the appropriate level even against the background of reduced BP.

The abrupt withdrawal of the treatment does not lead to the withdrawal syndrome (sharp rise in BP).

Enalapril does not cause metabolic disorders, does not affect glucose metabolism, does not increase the concentration of uric acid, does not change the profile of blood lipoproteins. Enalapril may decrease hypokalemic effect of thiazide diuretics.

Pharmacokinetics

Absorption
. When administered orally, enalapril is rapidly absorbed, the maximum concentration in blood plasma is reached within 1 hour.
Enalapril is well absorbed from the gastrointestinal tract (GIT), within 1 h (maximum 4-8 h) after oral administration the therapeutic effect is achieved. Food intake does not affect the absorption of the drug.

Distribution
In patients with normal renal function the equilibrium concentration of enalapril in plasma is reached on 2-3 days after the beginning of administration. It does not cumulate. Plasma protein binding is about 50%.

Elimination
Undergoes biotransformation in the liver to form the active metabolite – enalaprilat, the maximum concentration of which is determined 4 hours after intake. Excretion of enalapril is mainly through the kidneys – 60% (20% – as enalapril and 40% – as enalaprilat), through the intestine – 33% (6% – as enalapril and 27% – as enalaprilat). The elimination half-life (T1/2) is 11 hours.

In patients with a creatinine clearance (CK) less than 30 ml/min, the T1/2 of enalapril is increased. Reduced renal secretion of enalapril may increase hydrolysis to enalaprilate and increase extrarenal excretion of the drug.

The rate of hydrolysis of enalapril may be reduced in patients with impaired hepatic function without decreased therapeutic effect.
Passes through the placental barrier. It is excreted with breast milk. Virtually does not penetrate the blood-brain barrier. Does not accumulate in any tissues and organs.

Indications

Active ingredient

Composition

1 tablet contains:

the active ingredient:

enalapril malealate 5.0 mg/10.0 mg/20.0 mg;

excipients:

Sodium bicarbonate 2.6 mg/5.1 mg/10.2 mg;

lactose monohydrate 129.8 mg/124.6 mg/117.8 mg;

corn starch 22.4 mg/21.4 mg/13.9 mg;

Talc 6.0 mg/6.0 mg/6.0 mg;

Hyprolose 2.5 mg/-/-;

Magnesium stearate 1.7 mg/1.7 mg/1.7 mg;

Red iron oxide -/1.2 mg/0.1 mg;

Red iron oxide -/-/0.3 mg.

How to take, the dosage

Enalapril Hexal is administered orally, regardless of meals, with plenty of fluids. Treatment with Enalapril Hexal is prolonged. The drug dose should be adjusted according to the patient’s condition.
Enalapril Hexal should be taken at the same time of day, usually in the morning, but Enalapril Hexal may be divided into two doses.

After the first dose, patient monitoring and regular BP measurement over the next few hours is recommended. If there is a high risk of arterial hypotension, such a patient should be given the first dose of Enalapril Hexal in a medical facility and the patient should be observed for at least 5 hours. The patient should be in the supine position during observation.

If the next dose of Enalapril Hexal is missed, the missed dose should be taken as soon as possible. If the next dose of Enalapril Hexal is approaching, you should skip the forgotten dose and take the next dose on time. The dose should never be doubled.
The dosing regimen is adjusted individually.

Interaction

The concomitant use of ACE inhibitors with other agents acting on the renin-angiotensin-aldosterone system (RAAS) increases the risk of arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure).

As with other ACE inhibitors and angiotensin II receptor antagonists, co-administration of enalapril and aliskiren in patients with diabetes mellitus or renal impairment (CK less than 60 ml/min) is contraindicated.

Mutual potentiation in concomitant use of enalapril with other hypotensive agents.
Simultaneous use with nitroglycerin or other nitrates or other vasodilators, tricyclic antidepressants, neuroleptics, general anesthetics, narcotic drugs leads to increased antihypertensive effect.

Concomitant use of enalapril with diuretics (thiazide or “loop” diuretics) may increase the antihypertensive effect. Concomitant use of enalapril and potassium-saving diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations or potassium-containing salt substitutes, as well as other drugs that increase plasma potassium content (e.g., heparin) is not recommended.
Simultaneous use of nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 (COX-2) inhibitors) may weaken the antihypertensive effect of antihypertensive drugs due to the increased plasma potassium content, which leads to reversible renal dysfunction, fluid retention. Thus, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be weakened by NSAIDs, including COX-2 inhibitors.

NSAIDs and ACE inhibitors have an additive effect with respect to an increase in serum potassium, which may lead to impaired renal function, especially in patients with impaired renal function. This effect is reversible. Concomitant use should be used with caution in patients with impaired renal function.

The concomitant use of enalapril and lithium preparations is not recommended because the concentration of lithium in blood plasma increases and, accordingly, its toxic effects are intensified. When concomitant use of enalapril and lithium preparations the lithium concentration in blood plasma should be monitored.

Concomitant use with thiazide diuretics leads to increased concentration of lithium salts in blood plasma.
Concomitant use of enalapril with gold drugs for parenteral administration (sodium aurothiomalate) may cause a symptom complex including facial hyperemia, nausea, vomiting, arterial hypotension.
Weakens the effect of drugs containing theophylline.

Concomitant use with insulin and hypoglycemic agents for oral administration increases the risk of hypoglycemia.
Immunosuppressants, allopurinol, cytostatics increase hematotoxicity.

Drugs that inhibit bone marrow function increase the risk of neutropenia and/or agranulocytosis.
Ethanol increases the antihypertensive effect of enalapril.

Enalapril may be used concomitantly with acetylsalicylic acid (as an antiplatelet agent), thrombolytics and β-adrenoblockers. Concomitant use with other ACE inhibitors may increase the risk of hyperkalemia. Antacids may decrease the bioavailability of ACE inhibitors. Sympathomimetics may decrease the antihypertensive effect of ACE inhibitors.

Special Instructions

During treatment it is necessary to conduct regular monitoring of BP, heart rate and electrocardiogram, clinical blood tests, potassium, creatinine, urea, activity of “liver” enzymes in blood plasma, protein content in urine.

Patients with decreased volume of circulating blood (as a result of diuretic therapy, restriction of table salt intake, hemodialysis, diarrhea and vomiting) should be treated with caution – the risk of sudden and marked BP decrease after even initial dose of Enalapril Hexal is increased. Transient arterial hypotension is not a contraindication for continuation of treatment with Enalapril Hexal after BP stabilization. In case of repeated pronounced BP decrease the dose should be reduced or the drug should be discontinued.

In case of excessive BP decrease, the patient should be transferred to the supine position with low headrest; if necessary, 0.9% sodium chloride solution and plasma substitute drugs should be administered.

The use of dialysis membranes with high throughput (including AN69®) increases the risk of anaphylactic reaction. Adjustment of the dosing regimen on days free of dialysis should be made depending on BP.
Patients taking ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate have rarely developed anaphylactoid reactions. Therefore, this method should not be used in patients receiving ACE inhibitors.

Patients with decompensated chronic heart failure, coronary heart disease, cerebrovascular disease in whom a sharp decrease in BP may lead to myocardial infarction, stroke, or impaired renal function should be closely monitored.

The abrupt withdrawal of treatment does not lead to “withdrawal” syndrome (a sharp rise in BP).

In patients with ischemic heart disease or cerebral circulatory insufficiency treatment should be started with low doses of the drug.

Patients with diabetes mellitus with normoalbuminuria should note that Enalapril Hexal is only prescribed after determination of functional renal reserve, with micro- and macroalbuminuria – without prior determination. In patients with reduced renal function, the single dose should be reduced or the intervals between doses should be increased. In patients with diabetes mellitus the blood glucose concentration should be monitored regularly, especially against the background of hypokalemia.

During treatment with Enalapril Hexal, there may be increase of potassium in serum, especially in patients with chronic renal insufficiency, diabetes mellitus, in simultaneous prescription of potassium-saving diuretics (spironolactone, eplerenone, triamterene, amiloride are not recommended) or potassium preparations. These patients should be informed about the need to consult a physician in case of muscle weakness and arrhythmia.

The use of ACE inhibitors may result in dry cough. Cough episodes are persistent, but quickly disappear after discontinuation of the drug. This peculiarity should be taken into account in differential diagnosis of cough. If necessary, treatment may be continued.

During desensitization to wasp or bee venom, patients receiving Enalapril Hexal may develop hypersensitivity reactions. To avoid such reactions, temporary discontinuation of ACE inhibitor treatment before each desensitization procedure is recommended.

Before surgical procedures (including dentistry), the surgeon/anesthesiologist should be warned about the use of Enalapril Hexal.

In rare cases cholestatic jaundice occurs with the use of ACE inhibitors, with progression of which fulminant necrosis of the liver develops, sometimes with fatal outcome. If jaundice occurs and “liver” transaminases activity increases during the use of Enalapril Hexal, treatment should be discontinued. There have been cases of neutropenia/agranulocytosis, thrombocytopenia and anemia in patients taking ACE inhibitors.

In patients with normal renal function in the absence of other complications, neutropenia is rare. Enalapril Hexal should be used with great caution in patients with connective tissue diseases (including systemic lupus erythematosus, scleroderma) concomitantly receiving immunosuppressive therapy, allopurinol or procainamide, or with a combination of these factors, especially with existing renal dysfunction. These patients may develop severe infections that are not amenable to intensive antibiotic therapy.

If patients do take Enalapril Hexal, periodic monitoring of blood leukocytes is recommended. The patient should be warned to consult a physician if there are any signs of infection. If angioedema of the face occurs, withdrawal of therapy and administration of antihistamines to the patient is usually sufficient.

The angioedema of the tongue, pharynx or larynx can be fatal. If angioedema of the tongue, pharynx, or larynx can lead to airway obstruction, epinephrine (0.3-0.5 ml of epinephrine (adrenaline) solution subcutaneously at a ratio of 1:1000) should be given immediately and airway patency maintained (intubation or tracheostomy).

The incidence of angioedema is higher among patients of the Negro race receiving ACE inhibitor therapy than among patients of other racial backgrounds. Patients with a history of angioedema not associated with ACE inhibitor use have an increased risk of developing angioedema when taking any ACE inhibitor.
There is no experience of using the drug in patients after kidney transplantation, therefore treatment with Enalapril Hexal is not recommended in patients after kidney transplantation.

Influence on driving, operating machinery

When taking Enalapril Hexal, caution should be exercised while driving vehicles and engaging in potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.

Contraindications

– hypersensitivity to enalapril and to other ACE inhibitors, as well as to any other component of the drug;
– lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
– history of angioedema associated with previous use of ACE inhibitors, hereditary angioedema or idiopathic angioedema;
– concomitant use of enalapril and aliskiren in patients with diabetes mellitus or renal insufficiency (CK less than 60 ml/min);
– age less than 18 years (effectiveness and safety are not established);
– pregnancy.
– period of breastfeeding.

With caution Enalapril Hexal should be used in patients with bilateral renal artery stenosis or artery stenosis of the sole kidney, primary hyperaldosteronism, hyperkalemia, condition after kidney transplantation; cerebrovascular diseases (incl.ч. cerebrovascular insufficiency); coronary heart disease (CHD), recent myocardial infarction (up to 3 months); chronic heart failure, aortic and/or mitral stenosis (with hemodynamic disorders), hypertrophic obstructive cardiomyopathy; hypovolemic state (associated with long-term use of diuretics, salt-restricted diet, diarrhea or vomiting, hemodialysis, after surgical intervention); severe autoimmune systemic connective tissue diseases (includingч. scleroderma, systemic lupus erythematosus); inhibition of medullary hematopoiesis; in hepatic insufficiency; in old age (over 65 years); in diabetes mellitus; in renal insufficiency (proteinuria – more than 1 g/day); concomitant use with immunosuppressants and diuretics; in patients undergoing dialysis with high flow membranes (such as AN69®); during desensitization; in patients of non-human race; during low density lipoprotein apheresis.

Side effects

According to the World Health Organization (WHO), adverse effects are classified according to their frequency of development as follows: Very common (≥1/10), common (≥1/100 to < 1/10), infrequent (≥1/1,000 to < 1/100), rare (≥1/10,000 to < 1/1,000), very rare (< 1/10,000); frequency unknown – the incidence could not be determined from available data.

Cardiovascular system side
very common: dizziness;
frequent: pronounced BP decrease (including orthostatic), syncopal states, chest pain, arrhythmia, tachycardia, angina pectoris;
infrequently: palpitations, myocardial infarction, stroke, including.secondary after development of severe hypotension;
rarely: pulmonary artery branch thromboembolism, Raynaud’s syndrome.

As for central nervous system
often: headache, depression;
infrequently: dizziness, somnolence, insomnia, hyperexcitability, mental confusion, paresthesia, vertigo;
rarely: unusual dreams, sleep disturbance.

Respiratory system
very common: cough;
frequent: shortness of breath;
infrequent: rhinorrhea, sore throat, hoarseness of voice, bronchospasm (bronchial asthma);
rarely: pulmonary infiltrate, rhinitis, allergic alveolitis, (eosinophilic pneumonia).

Digestive system disorders
very common: nausea;
frequent: diarrhea, abdominal pain, taste disorder;
infrequent: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, peptic ulcer, dry oral mucosa, irritable bowel syndrome;
rare: stomatitis/aphthous ulcers, glossitis, liver failure, hepatitis (including liver necrosis), cholestasis, jaundice, increased activity of “hepatic” transaminases and bilirubin in blood plasma;
very rare: intestinal angioedema.

Urogenital system disorders
infrequent: renal dysfunction, renal failure, proteinuria, impotence, increased concentration of urea in plasma;
rare: oliguria, gynecomastia.

Visually impaired
very common: visual impairment.

On the blood and lymphatic system
infrequent: anemia (including aplastic, hemolytic);
rare: neutropenia, thrombocytopenia, agranulocytosis, suppression of medullary hematopoiesis, pancytopenia, decreased hemoglobin, reduced hematocrit, lymphoadenopathy, autoimmune diseases.

Endocrine system
frequency unknown: syndrome of inadequate secretion of antidiuretic hormone.

Allergic reactions
often: urticaria, skin rash, exanthema, hypersensitivity reactions/angioedema (angioedema of the face, extremities, lips, tongue, pharynx and/or larynx is described);
infrequent: increased sweating, skin itching, urticaria, alopecia;
rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome), exfoliative dermatitis, vesicles, erythroderma.

A symptom complex has been described that may include fever, myalgia and arthralgia, serositis, vasculitis, increased erythrocyte sedimentation rate, leukocytosis and eosinophilia, skin rash, positive antinuclear antibody test. A symptom complex has also been described that includes facial hyperemia, nausea, vomiting, and arterial hypotension and may develop with concomitant use of ACE inhibitors and intravenous gold drugs (sodium aurothiomalate).

Other
very common: asthenia;
common: increased fatigue, hyperkalemia, increased blood creatinine concentration;
infrequent: muscle twitching, tinnitus (tinnitus), hyperemia (redness of the skin), malaise, fever, dysphonia, hypoglycemia, hyponatremia, increased blood urea concentration.

Overdose

Symptoms: headache, marked BP decrease, up to the development of collapse, myocardial infarction, acute stroke or thromboembolic complications, seizures, stupor, tachycardia, palpitations, dizziness, bradycardia, palpitations, renal failure, cough, anxiety.

Treatment: symptomatic. The patient is transferred to the supine position with a low headboard. In mild cases gastric lavage and intake of activated charcoal are indicated, in more severe cases – measures aimed at BP stabilization: intravenous infusion of 0.9% sodium chloride solution, plasma substitutes, connection of artificial pacemaker with bradycardia resistant to drug therapy, hemodialysis (elimination rate of enalapril is 62 ml/min on average).

Similarities