Instructions Enalapril-HL-Health tablets 10 mg + 12.5 mg No. 20
Composition
active ingredients: enalapril, hydrochlorothiazide;
1 tablet contains enalapril maleate 10 mg, hydrochlorothiazide 12.5 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch, potato starch, magnesium stearate, colloidal anhydrous silicon dioxide, povidone.
Dosage form
Pills.
Main physicochemical properties: tablets of white or white with a creamy tint, flat-cylindrical shape with a score and a bevel.
Pharmacotherapeutic group
Agents acting on the renin-angiotensin system. Combined preparations of ACE inhibitors. Enalapril and diuretics. ATC code C09B A02.
Pharmacological properties
The drug contains a combination of two antihypertensive agents. The hypotensive effects of the two components complement each other and persist for 24 hours. The presence of enalapril allows to reduce the loss of potassium associated with the use of hydrochlorothiazide.
Pharmacodynamics. Enalapril is a highly specific competitive ACE antagonist, a prodrug that is converted in the body to the active metabolite enalaprilat.
Enalaprilat inhibits the activity of ACE, as a result of which angiotensin I is not converted to angiotensin II - a substance with a significant vasoconstrictor effect, and also reduces the secretion of aldosterone, due to which the concentration of angiotensin II and aldosterone in the blood decreases. It inhibits the breakdown of bradykinin, which is a potent vasopressor peptide. The mechanism by which enalapril lowers blood pressure is primarily associated with inhibition of the activity of the renin-angiotensin-aldosterone system, which regulates blood pressure; enalapril can have an antihypertensive effect even in patients with low-renin hypertension.
Pressor (sympathoadrenal) and depressor (kallikrein-kinin and prostaglandin) systems of the body are suppressed and the formation of vascular endothelial factor increases. As a result of these effects, total peripheral vascular resistance, arterial pressure, pressure in the small circle of blood circulation decrease, and cardiac output increases. Enalapril causes a gradual decrease in systolic and diastolic pressure.
Enalapril administration to hypertensive patients results in a reduction in supine and standing blood pressure without a significant increase in heart rate. Symptomatic postural hypotension is uncommon. In some patients, achieving optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of enalapril has not resulted in a rapid increase in blood pressure. Effective inhibition of ACE activity is usually achieved 2-4 hours after oral administration of an individual dose of enalapril. The onset of antihypertensive activity is usually recorded 1 hour later, and the peak reduction in blood pressure is achieved 4-6 hours after administration of the drug. The duration of the effect is dose-dependent. However, at recommended doses, the antihypertensive and hemodynamic effects were maintained for at least 24 hours after a single oral dose.
In patients with essential hypertension, the reduction in blood pressure was usually accompanied by a decrease in peripheral arterial resistance with some increase in cardiac output and little or no change in heart rate. Renal blood flow increased after enalapril administration; glomerular filtration rate did not change. However, in patients with low glomerular filtration rate before treatment, it usually increased. Antihypertensive therapy with enalapril leads to significant regression of left ventricular hypertrophy with preservation of left ventricular systolic function. Treatment with enalapril was associated with beneficial effects on plasma lipoprotein fractions and with or without beneficial effects on total cholesterol.
The degree of blood pressure reduction observed with the combination of enalapril and hydrochlorothiazide exceeded that with the separate use of the individual components.
Hydrochlorothiazide is an active diuretic, the action of which is due to a decrease in the reabsorption of sodium and chlorine ions in the proximal part of the convoluted tubules. There is also an inhibition of the reabsorption of potassium and bicarbonates. The diuretic effect develops after 2 hours, the maximum effect - after 4 hours and lasts up to 12 hours. The diuretic effect is manifested in alkalosis and acidosis, does not decrease with prolonged use.
Hydrochlorothiazide increases plasma renin activity. Although enalapril has antihypertensive effects even in patients with low-renin hypertension, concomitant administration of hydrochlorothiazide results in a greater reduction in blood pressure in these patients.
Pharmacokinetics. Enalapril is well absorbed. After oral administration, approximately 60% of enalapril is absorbed in the digestive system. Simultaneous food intake does not affect absorption. It is hydrolyzed in the liver to form enalaprilat. Bioavailability is almost 40%. When enalapril is taken orally, Cmax in blood plasma is observed for enalapril after 1 hour, for enalaprilat - after 3-4 hours. Enalaprilat easily penetrates histohematological barriers, except for the blood-brain barrier, penetrates the placenta, and is excreted in small amounts in breast milk. Enalaprilat is not biotransformed. Enalaprilat binds to plasma proteins by less than 50%. After taking enalapril, 33% of the dose is excreted in the feces (6% in the form of enalapril, 27% in the form of enalaprilat), with urine about 60% (20% in an unchanged form, 40% in the form of enalaprilat). Renal clearance is 150 ± 44 ml / min. T½ of enalaprilat is 11 hours. In renal failure, T½ increases. Enalaprilat is removed from the body during hemodialysis.
Hydrochlorothiazide is rapidly absorbed after oral administration (60-80%). The diuretic effect develops within 1-2 hours or more. Hydrochlorothiazide accumulates in erythrocytes 3-9 times more than in blood plasma. Binding to plasma proteins is 40-70%. The volume of distribution in the terminal elimination phase is 3-6 l/kg (equivalent to 210-420 l with a body weight of 70 kg). Hydrochlorothiazide is poorly metabolized. When plasma levels were assessed for at least 24 hours, the plasma half-life ranged from 5.6 to 14.8 hours. Hydrochlorothiazide is rapidly eliminated by the kidneys, T½ is 10 hours, almost 95% of the substance is excreted in the urine. Hydrochlorothiazide crosses the placenta and into breast milk, but does not cross the blood-brain barrier.
In patients with severe renal insufficiency, T½ of enalaprilat and hydrochlorothiazide increases.
Co-administration of multiple doses of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of these drugs. The combination tablet is bioequivalent to the separate administration of its components.
Indication
Arterial hypertension in patients for whom combination therapy is indicated.
Contraindication
Hypersensitivity to ACE inhibitors, thiazide diuretics, other sulfonamide derivatives, other components of the drug; history of angioedema caused by the use of an ACE inhibitor, hereditary or idiopathic angioedema, severe renal failure (creatinine clearance <30 ml/min) and treatment by hemodialysis, clinical condition after kidney transplantation, anuria, primary hyperaldosteronism, bilateral renal artery stenosis, hepatic failure, treatment-resistant hypokalemia or hypercalcemia, refractory hyponatremia, symptomatic hyperuricemia (gout), simultaneous use of enalapril with aliskiren in diabetic patients, pregnant women or women planning to become pregnant (see section "Use during pregnancy and breastfeeding").
Interaction with other medicinal products and other types of interactions
Potassium-sparing diuretics or potassium supplements. ACE inhibitors reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, amiloride), potassium supplements or salt substitutes containing potassium may lead to significant increases in serum potassium. If concomitant use of these drugs is indicated due to hypokalaemia, they should be used with caution and serum potassium should be monitored regularly.
Diuretics (thiazide and loop diuretics). Previous treatment with high doses of diuretics may lead to dehydration and the risk of hypotension in the early stages of enalapril therapy. Hypotensive effects can be reduced by discontinuation of diuretics, increasing salt and fluid intake, and by using enalapril in low initial doses.
Tricyclic antidepressants, neuroleptics, anesthetics, narcotics. A significant decrease in blood pressure is possible with the simultaneous use of the above drugs with ACE inhibitors.
Angiotensin receptor antagonists. In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been reported to be associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a renin-angiotensin-aldosterone system agent alone. Dual blockade (e.g., by combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function, potassium levels, and blood pressure.
Gold preparations: Rare nitroid reactions have been reported with concomitant use of ACE inhibitors, including enalapril, with injectable gold preparations (sodium aurothiomalate), accompanied by symptoms such as flushing, nausea, vomiting, and hypotension.
Sympathomimetics: Possible weakening of the effect of ACE inhibitors.
Pressor amines (e.g. adrenaline): The effect of pressor amines may be reduced, but not to the extent that would preclude their use.
Ethanol. The effect of ACE inhibitors is enhanced.
Acetylsalicylic acid, thrombolytic agents. The simultaneous use of enalapril with acetylsalicylic acid (in cardiological doses) and thrombolytic agents does not pose a risk.
NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid >3 g/day and non-selective NSAIDs. When taken simultaneously, NSAIDs may weaken the antihypertensive effect of hydrochlorothiazide and increase its effect on serum potassium levels.
Beta-blockers and diazoxide. Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
Amantadine: Thiazides, including hydrochlorothiazide, may increase the risk of side effects caused by amantadine.
Amphotericin B (for parenteral administration), carbenoxolone, corticosteroids, corticotropin (ACTH), stimulant laxatives. Hydrochlorothiazide increases electrolyte imbalance, mainly hypokalemia.
Ethanol, barbiturates, narcotic analgesics. Possible increase in orthostatic hypotension.
Antidiabetic agents (oral antidiabetic agents, insulin). Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin or oral agents) may be associated with a significant decrease in blood glucose levels and an increased risk of hypoglycaemia. This is most likely to occur during the first weeks of treatment and in patients with impaired renal function. In diabetic patients receiving oral antidiabetic agents or insulin, blood glucose levels should be monitored closely for hypoglycaemia, especially during the first month of treatment with an ACE inhibitor.
Possible weakening of the hypoglycemic effect under the influence of hydrochlorothiazide (with thiazide therapy, glucose tolerance may decrease). Dosage adjustment may be required. Metformin should be used with caution due to the risk of lactic acidosis due to possible functional renal failure caused by hydrochlorothiazide.
Calcium salts. Thiazide diuretics increase serum calcium levels by decreasing its excretion. If calcium supplements are required, serum calcium levels should be monitored and the calcium dose adjusted accordingly.
Medicinal products whose effects are affected by changes in serum potassium levels: Periodic monitoring of serum potassium levels and ECG is recommended if hydrochlorothiazide is taken concomitantly with medicinal products whose effects are affected by changes in serum potassium levels (e.g. digitalis glycosides and antiarrhythmic medicinal products).
Cardiac glycosides. Against the background of possible hypoglycemia caused by hydrochlorothiazide, the risk of developing intoxication with digitalis preparations increases.
Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may contribute to the development of arrhythmias caused by digitalis drugs.
Cholestyramine and colestipol. These agents may reduce the absorption of hydrochlorothiazide. Sulfonamide diuretics should be administered at least 1 hour before or 4-6 hours after cholestyramine or colestipol.
Drugs that cause torsades de pointes (ventricular tachycardia) (including some antiarrhythmics). Due to the increased risk of hypokalemia, hydrochlorothiazide should be used with caution simultaneously with drugs that can cause polymorphic torsades de pointes, since hypokalemia is a factor contributing to the development of torsades de pointes: class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide), class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide), some neuroleptics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpiride, tiapride, pimozide, haloperidol, droperidol), other drugs (e.g. bepridil, cisapride, diphemanil, erythromycin for intravenous administration, halofantrine, mizolastine, pentamidine, terfenadine, vincamine for intravenous administration).
Carbamazepine: Clinical and biological monitoring is necessary due to the risk of symptomatic hyponatremia.
Iodinated contrast media: In the case of diuretic-induced dehydration, the risk of acute renal failure is increased, especially with high doses of iodinated contrast media. Patients should be rehydrated before administration of iodinated contrast media.
Immunosuppressants, systemic corticosteroids, procainamide. Possible decrease in leukocyte count, leukopenia.
Cytostatics (e.g. cyclophosphamide, fluorouracil, methotrexate). Increased bone marrow toxicity, including granulocytopenia, may occur due to impaired renal excretion of these agents caused by hydrochlorothiazide.
Medicines for the treatment of gout (e.g. allopurinol, benzbromarone, probenecid, sulfinpyrazone). The dose of these medicines may need to be increased as hydrochlorothiazide increases the level of uric acid in the blood. The frequency of hypersensitivity reactions to allopurinol may be increased with concomitant use of thiazides.
Anticholinergics (e.g. atropine, biperiden): Due to decreased gastrointestinal motility and decreased gastric emptying rate, the bioavailability of thiazide-type diuretics increases.
Salicylates: When using high doses of salicylates, hydrochlorothiazide may enhance their toxic effects on the central nervous system.
Methyldopa: Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.
Cyclosporine: Concomitant use of cyclosporine may increase hyperuricemia and increase the risk of complications such as gout.
Clinical Laboratory Tests: Hydrochlorothiazide may interfere with the results of the benthiromide test. Thiazide diuretics may decrease serum protein-bound iodine in the absence of other signs of thyroid disease.
Other antihypertensive agents. With simultaneous use, the hypotensive effects of enalapril and hydrochlorothiazide may be enhanced. When combined with nitroglycerin, other nitro drugs or vasodilators, a further significant decrease in blood pressure is possible.
Lithium. Reversible increases in serum lithium levels and toxicity have been reported with concomitant use of ACE inhibitors. Thiazide diuretics may further increase the risk of lithium toxicity, which already occurs with ACE inhibitors. Therefore, concomitant use of lithium is not recommended, and serum lithium levels should be closely monitored if such therapy is necessary.
Application features
Symptomatic hypotension. Symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. When using enalapril, the risk of its development increases with impaired water and electrolyte metabolism, a diet with salt restriction, dialysis, diarrhea or vomiting. Arterial hypotension has been observed in patients with heart failure with or without concomitant renal failure. Its risk is higher in patients with more severe heart failure, which is associated with the use of high doses of loop diuretics, hyponatremia or impaired renal function. In such patients, treatment should be initiated under strict medical supervision and their condition should be regularly monitored during treatment. These recommendations also apply to patients with ischemic heart disease or with cerebrovascular disease, in whom an excessive decrease in blood pressure can lead to myocardial infarction or acute cerebrovascular accident. If hypotension occurs, the patient should be placed in a horizontal position and, if necessary, an infusion of 0.9% sodium chloride solution should be administered. Transient hypotension is not a contraindication for further treatment, which may be continued after normalization of blood pressure on the background of infusion therapy.
Renal impairment. In renal impairment, the initial dose of enalapril should be determined based on creatinine clearance and then adjusted according to the body's response to treatment. In such patients, serum potassium and creatinine levels should be monitored regularly. There have been reports of renal failure during treatment with enalapril, mainly in patients with severe heart failure or renal disease, including renal artery stenosis. With timely diagnosis and adequate treatment, this renal failure is reversible. In some patients without obvious renal pathology, an increase in the concentration of urea and creatinine in the blood has been observed, especially with the simultaneous use of enalapril and diuretics. In this case, a reduction in the dose of enalapril and/or discontinuation of the diuretic may be required. In this case, the possibility of renal artery stenosis should be considered first.
Thiazide diuretics are not always appropriate in the treatment of patients with impaired renal function. They are ineffective at creatinine clearance values of 30 ml/min and below (e.g., in patients with moderate or severe renal insufficiency). In patients with renal disease, the use of thiazide diuretics may exacerbate azotemia. Cumulative effects of the drug may be observed in impaired renal function. If progressive renal insufficiency becomes evident (increased non-protein nitrogen fraction), the prescribed treatment should be carefully reviewed and, if necessary, hydrochlorothiazide should be discontinued.
Vasorenal arterial hypertension. The use of ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney increases the risk of arterial hypotension and renal failure. In this case, impaired renal function may be accompanied by only minor changes in serum creatinine. In such patients, the drug should be used under constant medical supervision in a low dose, which should be gradually and carefully increased, under the control of renal function.
Kidney transplantation. There is no clinical experience with the use of the drug in patients who have recently undergone kidney transplantation, therefore the drug is not recommended for this category of patients.
Hepatic failure. Rarely, the use of ACE inhibitors has been associated with a syndrome that began with cholestatic jaundice or hepatitis and ended with fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is not known. Patients who develop jaundice or significantly elevated liver enzymes while receiving ACE inhibitors should discontinue the ACE inhibitor and initiate appropriate treatment.
Thiazide drugs should be used with caution in patients with impaired liver function or progressive liver disease, as minor changes in fluid and water-salt balance in the body can cause hepatic coma.
Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other predisposing factors. Enalapril should be used with caution in patients with vascular disease associated with collagen vascular disease, immunosuppressive therapy, allopurinol, procainamide or a combination of these factors, especially in patients with pre-existing renal impairment. Some patients have developed severe infections that have not responded to antibiotic therapy. During treatment with enalapril, the complete blood count should be monitored periodically in such patients, and all patients are advised to report any signs of infection to their physician.
Anaphylactic reactions during insect venom desensitization: Rarely, life-threatening anaphylactic reactions have been observed in patients receiving ACE inhibitors during insect venom desensitization. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before each desensitization procedure.
Anaphylactic reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactic reactions have been observed in patients receiving ACE inhibitors during LDL apheresis with dextrin sulfate. Such reactions can be avoided by temporarily stopping the ACE inhibitor before each apheresis procedure.
Hemodialysis: Anaphylactic reactions have been reported during hemodialysis with high-flux membranes (e.g. AN 69) in patients receiving ACE inhibitors. If such a procedure is necessary, it is recommended to use a different type of dialysis membrane or use a different antihypertensive drug class.
Metabolic and endocrine effects: Diabetic patients taking oral antidiabetic agents or insulin should be advised to monitor blood sugar levels carefully before starting ACE inhibitors to avoid hypoglycemia, especially during the first month of concomitant use.
Thiazide diuretics may impair glucose tolerance. Patients with diabetes mellitus may require a change in the dosage of oral antidiabetic agents. Latent diabetes mellitus may be manifested during the use of thiazide diuretics. The use of thiazide diuretics may lead to an increase in serum cholesterol and triglycerides, and some patients may develop hyperuricemia or gout.
Cough: Non-productive cough has been reported with ACE inhibitors and has resolved after discontinuation, which should be considered in the differential diagnosis of the cause of cough.
Surgery/Anesthesia: During surgery or anesthesia with antihypertensive drugs, enalapril blocks the formation of angiotensin II through compensatory renin release. In the event of hypotension caused by this mechanism, it is eliminated by infusion therapy.
Electrolyte disturbances. Some patients taking ACE inhibitors, including enalapril, have experienced increases in serum potassium. Risk factors for the development of hyperkalemia include renal insufficiency, decreased renal function, advanced age (over 70 years), diabetes mellitus, intercurrent diseases and conditions, including dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium-containing salt substitutes, or other agents that increase serum potassium (e.g. heparin). When using potassium preparations, potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, significant increases in serum potassium may occur in patients with impaired renal function. Hyperkalemia can cause the development of severe arrhythmias, including fatal ones. If the use of the above-mentioned drugs with enalapril is advisable, treatment should be carried out with caution, regularly monitoring the level of potassium in the blood.
Anti-doping test. Hydrochlorothiazide contained in the drug may cause a false-positive result in an anti-doping test.
Lithium. The drug is not recommended for simultaneous use with lithium preparations due to increased toxicity of the latter.
Ethnic differences: As with other ACE inhibitors, the antihypertensive effect of enalapril may be less pronounced in black patients than in non-black patients, possibly because of a higher prevalence of low-renin states in this race.
Laboratory studies. The drug may reduce the level of protein-bound iodine in the blood plasma, treatment with the drug should be discontinued before conducting laboratory tests to assess the function of the parathyroid glands, the drug is able to increase the concentration of free bilirubin in the blood serum.
Other: Hypersensitivity reactions may occur in patients with or without a history of bronchial asthma. There have also been reports of an increased risk of exacerbation or activation of systemic lupus erythematosus.
The drug contains lactose, which should be taken into account in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.
Use during pregnancy or breastfeeding
The drug is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be discontinued immediately and, if necessary, replaced with another drug approved for use in pregnant women.
ACE inhibitors when used by women during the second and third trimesters of pregnancy may cause fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull bones) or neonatal toxicity (renal failure, hypotension, hyperkalemia).
If ACE inhibitors were taken during the second trimester of pregnancy, an ultrasound examination of the kidneys and skull is recommended.
Daily use of diuretics during pregnancy places the mother and fetus at an unnecessary risk of complications, including fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions seen in adult patients.
Newborns whose mothers have taken the drug should be carefully observed for hypotension, oliguria, and hyperkalemia. Enalapril, which has the ability to cross the placenta, can be partially removed from the newborn by peritoneal dialysis; theoretically, it can be removed by exchange transfusion.
Enalapril and hydrochlorothiazide pass into breast milk. If the use of the drug is considered necessary, breastfeeding should be discontinued.
Ability to influence reaction speed when driving vehicles or other mechanisms
At the beginning of the use of the drug (the period is determined individually by the doctor) it is forbidden to drive a car and work with other mechanisms. Later, the degree of prohibition is determined individually by the doctor.
Method of administration and doses
The drug is prescribed to patients whose blood pressure is not adequately controlled with enalapril alone. The use of a fixed combination of enalapril and hydrochlorothiazide is not suitable for initial therapy and is usually recommended after adjusting the doses of the individual components, however, if clinically appropriate, it is possible to switch directly from monotherapy to treatment with this combination drug.
The dosage regimen should be set individually depending on the patient's condition and the severity of arterial hypertension. Treatment should be started with low doses of the drug with a gradual increase in dosage. The established daily dose should be taken in the morning with plenty of fluid.
The drug is administered orally, regardless of meals. Adults should be prescribed the drug in an initial dose of 1 tablet per day, if necessary, the dose can be increased.
