Enalozid Forte tablets blister No. 20

Pharmacological properties

Pharmacodynamics. Enalozid forte is a combination of an ACE inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a decrease in plasma angiotensin II levels, which leads to an increase in plasma renin activity (due to inhibition of negative feedback on renin release) and a decrease in aldosterone secretion. Hydrochlorothiazide is a diuretic and antihypertensive agent that increases plasma renin activity. The mechanism of antihypertensive action of thiazides is unknown. Hydrochlorothiazide usually has no effect on normal blood pressure.

ACE is identical to kininase II. Enalapril can also block the breakdown of bradykinin, a potent vasodepressor peptide. However, the role of this fact in the therapeutic effects of enalapril remains unknown. While the mechanism by which enalapril lowers blood pressure is primarily associated with inhibition of the renin-angiotensin-aldosterone system (RAAS), which plays a major role in blood pressure regulation, enalapril can exert an antihypertensive effect even in patients with low-renin hypertension.

Hydrochlorothiazide is a diuretic and antihypertensive agent that increases plasma renin activity. The antihypertensive effects of the two components are additive and generally last for 24 hours. Although enalapril alone has a hypotensive effect even in patients with low-renin hypertension, concomitant use with hydrochlorothiazide in such patients results in a greater reduction in blood pressure. The enalapril component of the drug generally attenuates the potassium loss caused by hydrochlorothiazide.

Pharmacokinetics

Absorption. After oral administration, enalapril is rapidly absorbed, reaching C max in blood plasma within 1 hour. Taking into account the urinary excretion rate, the extent of absorption of enalapril after oral administration is approximately 60%.

After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. C max of enalaprilat in plasma is reached 3-4 hours after oral administration of enalapril maleate. Enalapril is excreted mainly by the kidneys. The main components in the urine are enalaprilat, which accounts for approximately 40% of the dose, and enalapril in unchanged form. With the exception of conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The plasma concentration profile of enalaprilat is characterized by a prolonged terminal phase, which is probably associated with binding to ACE. In individuals with normal renal function, steady-state plasma concentrations of enalaprilat are reached on the 4th day of oral administration of enalapril. The effective half-life of enalaprilat accumulation after multiple oral administration of enalapril is 11 hours. Food intake does not affect the absorption of enalapril from the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar when taking different doses within the recommended therapeutic range.

Distribution: Within the entire therapeutic concentration range, 60% of enalaprilat is bound to plasma proteins.

Biotransformation: Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys.

Excretion. Enalaprilat is excreted primarily by the kidneys. The main components of the drug in the urine are enalaprilat, which accounts for about 40% of the dose, and unchanged enalapril (about 20%). Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. When administered orally, at least 61% of the dose is excreted unchanged within 24 hours.

Renal impairment. Exposure to enalapril and enalaprilat is increased in patients with renal impairment. In patients with mild to moderate renal impairment (creatinine clearance 40-60 mL/min), steady-state AUC of enalaprilat was approximately 2-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤30 mL/min), AUC increased approximately 8-fold. With increasing renal impairment, the effective T½ of enalaprilat is increased and the time to steady state is delayed (see Dosage & Administration).

Enalaprilat can be removed from the general circulation by hemodialysis. The dialysis clearance of enalaprilat is 62 ml/min.

Indication

Treatment of ag in patients for whom combination therapy is indicated.

Application

Ag. usual dose - ½ tablet, if necessary can be increased to 1 tablet 1 time per day. maximum dose is 2 tablets per day.

Dosage in renal impairment: Thiazides may be insufficiently effective diuretics in patients with renal impairment and are ineffective in patients with creatinine clearance ≤30 mL/min (i.e., moderate to severe renal impairment).

Patients with creatinine clearance in the range of 30-80 ml/min can use Enalozid Forte only after preliminary dose selection of each component.

The recommended initial dose of enalapril maleate used alone in mild renal impairment is 5-10 mg, therefore Enalozide Forte is not recommended as initial therapy for such patients (see Precautions).

Children: The safety and efficacy of the drug in children have not been established.

Contraindication

Side effects

Enalozid forte is usually well tolerated. Side effects were mild, transient, and did not require discontinuation of therapy.

The most common adverse reactions observed during clinical trials of the combination of enalapril maleate and hydrochlorothiazide were headache and cough.

Cardiovascular: dizziness, hypotension, orthostatic hypotension, arrhythmias, angina pectoris, tachycardia, flushing, palpitations, myocardial infarction or stroke, possibly due to excessive hypotension in high-risk patients, Raynaud's syndrome.

On the part of the digestive system: nausea, diarrhea, abdominal pain, ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers, flatulence, stomatitis/aphthous ulcers, glossitis, intestinal angioedema.

Nervous system/psychiatric disorders: headache, syncope, altered taste, insomnia, nervousness, restlessness, drowsiness, paresthesia, vertigo, confusion, sleep disorders, abnormal dreams, paresis (due to hypokalemia), decreased libido, depression.

Musculoskeletal and connective tissue disorders: muscle cramps, muscle spasms, joint pain.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, rhinorrhea, sore throat and hoarseness, bronchospasm, asthma, pulmonary infiltrates, respiratory distress (including pneumonitis and pulmonary edema), rhinitis, allergic alveolitis/eosinophilic pneumonia.

Hepatobiliary system: hepatic failure, liver necrosis (may be fatal), hepatitis (hepatocellular or cholestatic), jaundice, cholecystitis (especially in patients with pre-existing cholelithiasis).

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolic disorders: hypokalemia, disturbances of water and electrolyte balance (including hyponatremia), increased blood cholesterol and triglyceride levels, hypoglycemia, hyperuricemia, gout, hypomagnesemia, hyperglycemia, hypercalcemia.

Renal and urinary disorders: renal dysfunction, renal failure, proteinuria, oliguria, interstitial nephritis, glucosuria.

Hearing and balance disorders: tinnitus.

On the part of the organ of vision: loss of visual acuity, transient loss of visual acuity, xanthopsia.

From the reproductive system and mammary glands: gynecomastia, impotence.

Skin and subcutaneous tissue disorders: rash (rash), hypersensitivity, angioedema: angioedema of the face, extremities, lips, tongue, glottis and/or larynx, diaphoresis, pruritus, urticaria, alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, pemphigus, erythroderma have been reported.

A symptom complex has been reported that may include some or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis and arthralgia/arthritis, positive antinuclear factor test, increased ESR, eosinophilia, leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur.

Blood and lymphatic system disorders: decreased hemoglobin and hematocrit, thrombocytopenia, neutropenia, leukopenia, pancytopenia, agranulocytosis, anemia (including aplastic and hemolytic anemia), lymphadenopathy, bone marrow depression, autoimmune diseases.

Immune system disorders: anaphylactic reactions.

Laboratory data: hyperkalemia, increased plasma creatinine levels, increased blood urea nitrogen levels, hyponatremia, increased liver enzymes, increased plasma bilirubin levels.

General disorders and administration site conditions: asthenia, chest pain, fever, fatigue, discomfort.

Special instructions

Enalapril maleate and hydrochlorothiazide

Hypotension and electrolyte imbalance. Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. Among patients taking Enalozid Forte, symptomatic hypotension occurs more often in patients with fluid imbalance, for example, as a result of diuretic therapy, a diet with limited salt intake, diarrhea or vomiting. In such patients, plasma electrolyte levels should be determined regularly, at established intervals. Particular care should be taken in the treatment of patients with ischemic heart disease or cerebrovascular disease, since an excessive decrease in blood pressure can lead to myocardial infarction or stroke. Symptomatic hypotension has been observed in patients with hypertension and heart failure with and without renal impairment.

If hypotension develops, the patient should be placed in bed and, if necessary, intravenous saline should be administered. Transient hypotension during drug administration is not a contraindication to its continued use. If, after normalization of the BCC, an increase in blood pressure occurs, therapy can be resumed at the usual doses.

Renal impairment. Enalozide Forte should not be administered to patients with renal impairment (creatinine clearance 80 ml/min and 30 ml/min) until titration of the individual components of the drug reaches the doses of the drug in this dosage form (see Method of administration).

When treated with enalapril in combination with a diuretic, some patients with hypertension without any signs of renal disease before the start of treatment have developed increases in blood urea and creatinine. In such cases, treatment with Enalapril should be discontinued. This situation may indicate the possibility of renal artery stenosis.

Dual blockade of the RAAS. There is evidence that in patients receiving concomitant treatment with ACE inhibitors, angiotensin II receptor antagonists or aliskiren, the risk of hypotension, hyperkalaemia and renal impairment (including acute renal failure) is increased. Therefore, dual blockade of the RAAS (concurrent use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren) is not recommended (see Interactions with other medicinal products and other forms of interaction). If dual blockade is considered absolutely necessary, it should be carried out under medical supervision with close regular monitoring of renal function, fluid and electrolyte balance, and blood pressure. ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Hyperkalemia. With the combined use of enalapril and a low-dose diuretic, the possibility of developing hyperkalemia cannot be excluded.

Lithium: The combination of lithium with enalapril and diuretics is generally not recommended (see Interactions with other drugs).

Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist. The combination of an ACE inhibitor with an angiotensin II receptor antagonist should be limited to individual cases, accompanied by careful monitoring of renal function, potassium levels and blood pressure (see Interactions with other drugs).

enalapril maleate

Aortic stenosis/hypertrophic cardiomyopathy: As with all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction. They should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Renal failure: Renal failure has been reported with enalapril, predominantly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. With prompt diagnosis and appropriate treatment, renal failure associated with enalapril is usually reversible (see Dosage & Administration).

Renovascular hypertension. There is an increased risk of hypotension and renal dysfunction when patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ACE inhibitors. Decreased renal function may occur even with minor changes in serum creatinine. In such patients, treatment should be initiated at low doses and under medical supervision, with caution when increasing the dose and monitoring renal function.

Patients on hemodialysis. Enalapril is contraindicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been reported in patients on dialysis using high-flux membranes (AN 69 ®) and receiving concomitant ACE inhibitor therapy. In such patients, a different type of dialysis membrane or a different class of antihypertensive drug should be used.

Hepatic failure. Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant necrotizing hepatitis, sometimes fatal. The mechanism of this syndrome is unknown. Patients treated with ACE inhibitors who develop jaundice or significant elevations of liver enzymes should discontinue the ACE inhibitor and receive appropriate medical attention.

Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia has been reported rarely in patients with normal renal function and in the absence of other complicating factors. Enalapril should be used with caution in patients with collagen vascular disease who are receiving immunosuppressive therapy, allopurinol, or procainamide, or a combination of these complicating factors, especially if renal function is already impaired. Some patients have developed serious infections, some of which have not responded to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended when enalapril is prescribed to such patients, and patients should report any signs of infection.

Hyperkalemia: Elevations in plasma potassium have been observed in some patients treated with ACE inhibitors, including enalapril. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, patients over 70 years of age, intercurrent conditions such as dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or salt substitutes containing potassium, and other medicinal products associated with increases in plasma potassium (e.g. heparin). The use of potassium supplements, potassium-sparing diuretics, and potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to significant increases in plasma potassium.

Hyperkalemia can cause serious and even fatal arrhythmias. If concomitant administration of Enalozid Forte and any of the above drugs is necessary, these drugs should be used with caution and plasma potassium levels should be monitored frequently (see Interactions with other drugs).

Hypoglycemia: Diabetic patients taking oral antidiabetic agents or insulin and starting an ACE inhibitor should be advised to monitor their blood glucose levels closely, especially during the first month of combination therapy (see Interactions with other medicinal products).

Hypersensitivity/angioedema. Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported with ACE inhibitors, including enalapril maleate. These reactions may occur at any time during treatment. In such cases, treatment with Enalapril should be discontinued immediately and the patient should be closely monitored for clinical symptoms. Even in cases where only tongue swelling is observed without respiratory distress, prolonged monitoring of the patient is necessary, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal cases have been reported as a result of angioedema, which was accompanied by swelling of the larynx or tongue. In patients with swelling of the tongue, glottis or larynx, airway obstruction may occur, especially in patients with a history of airway surgery. In cases where the swelling is localized in the tongue, glottis or larynx, which may lead to airway obstruction, an adrenaline solution 1: 1000 (0.3-0.5 ml) should be administered immediately subcutaneously and/or other appropriate therapeutic measures should be taken.

Angioedema has been reported more frequently in black patients treated with ACE inhibitors than in white patients. However, it is generally accepted that black patients are at increased risk of angioedema.

Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema while receiving ACE inhibitors (see Adverse Reactions).

Anaphylactoid reactions during low-density lipoprotein apheresis. Life-threatening anaphylactoid reactions have rarely occurred in patients receiving ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis session.

Cough: Cough has been reported with ACE inhibitors. The cough is usually non-productive, persistent, and resolves after discontinuation of the drug. Cough resulting from ACE inhibitors should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: During major surgery or during anesthesia with agents that produce hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If hypotension develops due to a similar mechanism, it can be corrected by volume expansion (see Interactions with other drugs).

Pregnancy. ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ACE inhibitor treatment should be stopped immediately, and, if possible, alternative therapy should be started.

Ethnic differences: As with other ACE inhibitors, enalapril is less effective in lowering blood pressure in black patients than in non-black patients. This may be due to a higher prevalence of low-renin systems in black hypertensive patients.

Hydrochlorothiazide

Renal impairment: Thiazides may be insufficiently effective diuretics in patients with renal impairment and are ineffective in patients with creatinine clearance ≤30 mL/min (i.e., moderate or severe renal impairment) (see Dosage and Administration).

Liver disease: Thiazides should be administered with caution to patients with impaired or progressive liver function, since even minor disturbances of fluid and electrolyte balance may result in hepatic coma.

Metabolic and endocrine effects: Thiazide therapy may alter glucose tolerance. In some cases, dose adjustment of antidiabetic drugs, including insulin, may be necessary.

Elevations in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, minimal or no effects have been reported with hydrochlorothiazide 12.5 mg.

Thiazide therapy may cause hyperuricemia and/or exacerbation of gout in some patients. However, enalapril may increase urinary uric acid levels and thus may attenuate the hyperuricemic effect of hydrochlorothiazide.

For patients receiving diuretic therapy, plasma electrolyte levels should be measured regularly at appropriate intervals.

Thiazides (including hydrochlorothiazide) can cause disturbances of water and electrolyte balance (hypokalemia, hyponatremia and hypochloremic alkalosis). Dangerous signs of disturbances of water and electrolyte balance are xerostomia, thirst, weakness, lethargic sleep, drowsiness, increased fatigue, muscle pain or cramps, muscular weakness, arterial hypotension, oliguria, tachycardia, disturbances from the digestive system (nausea, vomiting).

Although hypokalemia may occur during the use of thiazide diuretics, concomitant therapy with enalapril may reduce diuretic-induced hypokalemia. The risk of hypokalemia may be increased in patients with cirrhosis of the liver, in patients with increased diuresis, with insufficient oral electrolyte intake, and in patients receiving concomitant therapy with corticosteroids or ACTH (see Interactions with other drugs).

In hot weather, hyponatremia may occur in patients prone to edema. Chloride deficiency is usually mild and does not require treatment.

Thiazides may reduce urinary calcium excretion and may cause periodic and minor increases in plasma calcium levels in the absence of calcium metabolism disorders. Marked hypercalcemia may be a manifestation of latent hyperparathyroidism. Thiazides should be discontinued before parathyroid function tests are performed.

Thiazides increase urinary magnesium excretion, which may lead to hypomagnesemia.

Hypersensitivity: Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma while taking thiazides. Exacerbation or reactivation of systemic lupus erythematosus has been reported.

Use during pregnancy and breastfeeding. Enalozid Forte should not be used by pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with the drug, its use should be immediately discontinued and replaced with another drug approved for use in pregnant women.

Ability to influence the reaction speed when driving vehicles or working with other mechanisms. Some of the undesirable effects mentioned in the Side Effects section may affect the ability to drive vehicles and/or mechanisms.

Children: Drug interaction studies have only been conducted in adult patients.

Interactions

Dual blockade of the RAAS. Clinical studies have shown that dual blockade of the RAAS with the simultaneous use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased risk of adverse events (hypotension, hyperkalemia and deterioration of renal function, including acute renal failure) compared with the use of a single AAS drug (see contraindications, special instructions).

Other antihypertensive agents. Concomitant use of these agents may potentiate the hypotensive effect of enalapril and hydrochlorothiazide. Concomitant use with nitroglycerin, other nitrates or other vasodilators may further reduce blood pressure.

Lithium: Reversible increases in plasma lithium concentrations and toxicity have been reported during concomitant use of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may further increase lithium levels and increase the risk of lithium toxicity when an ACE inhibitor is used.

The use of Enalozid Forte simultaneously with lithium preparations is not recommended, but if such a combination is necessary, the level of lithium in the blood plasma should be carefully monitored (see Features of use).

NSAIDs, including selective COX-2 inhibitors. NSAIDs, including selective COX-2 inhibitors, may attenuate the antihypertensive effects of ACE inhibitors, diuretics and/or other antihypertensive drugs. For this reason, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors or diuretics may be attenuated by the use of NSAIDs, including selective COX-2 inhibitors.

Concomitant use of non-steroidal anti-inflammatory drugs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors has shown an additive effect on increasing plasma potassium levels and may lead to renal dysfunction. These effects are usually reversible. Rarely, renal failure may develop, particularly in patients with impaired renal function (e.g. elderly patients or patients with dehydration, including patients receiving diuretic therapy). Therefore, this combination should be used with caution in patients with impaired renal function.

enalapril maleate

Potassium-sparing diuretics or potassium supplements. ACE inhibitors reduce the potassium loss induced by diuretics. Potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene or amiloride), potassium supplements or salt substitutes containing potassium may lead to significant increases in plasma potassium. If concomitant use of such drugs is indicated because of hypokalaemia, treatment should be carried out with caution and frequent monitoring of plasma potassium should be performed (see Precautions).

Diuretics (thiazide or loop diuretics). Previous treatment with high doses of diuretics may lead to dehydration and a risk of hypotension at the beginning of treatment with enalapril. The hypotensive effect can be reduced by discontinuing the diuretic, increasing body volume, or increasing salt intake.

Tricyclic antidepressants/neuroleptics/anesthetics: Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may lead to an additional decrease in blood pressure (see Precautions).

Sympathomimetics: Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Antidiabetic agents: Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulins, oral hypoglycaemic agents) may lead to a decrease in blood glucose levels with a risk of hypoglycaemia. This effect is likely to be more pronounced during the first weeks of concomitant treatment and in patients with renal impairment (see Precautions).

Alcohol: Alcohol potentiates the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and β-adrenergic blockers. Enalapril can be used with caution with acetylsalicylic acid (in cardiological doses), thrombolytics and β-adrenergic blockers.

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist. In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target 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 either RAAS agent alone. Dual blockade (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) should be limited to individual cases and should be accompanied by close monitoring of renal function, potassium, and blood pressure.

Hydrochlorothiazide

Non-depolarizing muscle relaxants: Thiazides may increase susceptibility to tubocurarine.

Alcohol, barbiturates, or narcotic analgesics. May potentiate the development of orthostatic hypotension.

Antidiabetic agents (oral agents and insulin): Dose adjustment of the antidiabetic agent may be required (see Precautions).

Cholestyramine and colestipol resins. Absorption of hydrochlorothiazide is reduced in the presence of anion exchange resins. A single dose of cholestyramine or colestipol resin binds to hydrochlorothiazide and reduces its absorption from the gastrointestinal tract by 85 and 43%, respectively.

QT prolongation (quinidine, procainamide, amiodarone, sotalol). Increased risk of ventricular fibrillation.

Digitalis glycosides: Hypokalemia may potentiate or exacerbate the cardiac response to the toxic effects of digitalis (e.g., increased ventricular excitability).

GCS, ACTH. Electrolyte imbalance, in particular hypokalemia, is aggravated.

Kaliuretic diuretics (e.g. furosemide), carbenoxolone or laxative abuse. Hydrochlorothiazide may increase potassium and/or magnesium losses.

Pressor amines (e.g. adrenaline). The effect of pressor amines may be reduced (see Interactions with other drugs).

Cytotoxic drugs (e.g. cyclophosphamide, methotrexate). Thiazides may reduce the renal excretion of cytotoxic drugs and enhance their bone marrow suppressive effects.

Overdose

Enalapril maleate. The main manifestation of overdose is pronounced arterial hypotension, occurring within 6 hours after taking the drug and is accompanied by blockade of the RAAS system and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. It was reported that after taking enalapril maleate in doses of 300 mg and 440 mg, the levels of enalaprilat in the blood plasma were 100 and 200 times higher than the levels when using therapeutic doses of the drug, respectively.

The recommended treatment for overdose is intravenous administration of 0.9% sodium chloride solution.

If hypotension occurs, the patient should be placed in the supine position with the legs elevated. If necessary, consider intravenous administration of angiotensin II and/or intravenous administration of catecholamines. If the drug has been taken recently, measures should be taken to eliminate enalapril maleate from the body (induction of vomiting, gastric lavage, administration of absorbents and sodium sulfate). Enalapril can be removed from the systemic circulation by hemodialysis (see Precautions).

In case of bradycardia resistant to current therapy, the use of a pacemaker is indicated. It is necessary to constantly monitor the main vital signs of the body, the levels of electrolytes and creatinine in the blood plasma.

Hydrochlorothiazide. The most common signs and symptoms are hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis. Hypokalemia may increase the course of arrhythmias when administered concomitantly with digitalis preparations.

Treatment: symptomatic and supportive. The drug should be discontinued and the patient carefully examined. Suggested measures include: inducing vomiting, administration of active