Instructions Enalozid 25 tablets blister No. 30
Composition
active ingredients: enalapril maleate, hydrochlorothiazide;
1 tablet contains, calculated as 100%, the following substances: enalapril maleate 10 mg, hydrochlorothiazide 25 mg;
excipients: lactose monohydrate, potato starch, povidone, calcium stearate.
Dosage form
Pills.
Main physicochemical properties: tablets from white to yellow-white color with a flat surface, a bevel and a score.
Pharmacotherapeutic group
Combinations of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors and diuretics. ATC code C09B A02.
Pharmacological properties
Pharmacodynamics
Enalozid 25 is a combination of an angiotensin-converting enzyme inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).
Angiotensin-converting enzyme (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 the negative feedback loop on renin release) and a decrease in aldosterone secretion.
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, which plays a major role in blood pressure regulation, enalapril may 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
Enalapril maleate. After oral administration, enalapril is rapidly absorbed, reaching peak serum concentrations within 1 hour. Based on urinary excretion, the extent of absorption of enalapril after oral administration is approximately 60%.
After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin-converting enzyme inhibitor. Peak serum concentrations of enalaprilat are reached 3-4 hours after oral administration of enalapril maleate. Enalapril is excreted primarily by the kidneys. The major components in the urine are enalaprilat, which accounts for approximately 40% of the dose, and unchanged enalapril. Apart from conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The serum concentration profile of enalaprilat is characterized by a prolonged terminal phase, which is probably due to binding to ACE. In subjects with normal renal function, steady-state serum concentrations of enalaprilat are reached by 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.
Hydrochlorothiazide. When plasma levels were monitored for at least 24 hours, the plasma half-life was 5.6-14.8 hours. Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. At least 61% of the oral dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier and does not cross the blood-brain barrier.
Enalapril/hydrochlorothiazide: Multiple simultaneous administration of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of these drugs. The combination tablet is bioequivalent to its individual components when administered simultaneously.
Kidney failure
In patients with renal impairment, exposure to enalapril and enalaprilat is increased. 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. At this level of renal impairment, the effective half-life of enalaprilat is prolonged and the time to steady-state is delayed.
Enalaprilat can be removed from the general circulation by hemodialysis. The dialysis clearance of enalaprilat is 62 ml/min.
Indication
Treatment of arterial hypertension in patients for whom combination therapy is indicated.
Contraindication
Hypersensitivity to the active substance or any other component of the drug.
Severe renal impairment (creatinine clearance ≤ 30 ml/min).
Treatment-resistant hypokalemia.
Symptomatic hyperuricemia (gout).
Anury.
History of angioedema associated with previous use of ACE inhibitors.
Hereditary or idiopathic angioedema.
Hypersensitivity to drugs that are sulfonamide derivatives.
Pregnant women or women planning to become pregnant (see “Use during pregnancy or breastfeeding”).
Severe liver dysfunction.
Concomitant use of Enalozid 25 with aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73m2) (see section “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Dual blockade of the renin-angiotensin-aldosterone system (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 RAAS agent (see sections "Contraindications", "Special instructions for use").
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 serum 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 25 with lithium preparations is not recommended, but if such a combination proves necessary, serum lithium levels should be carefully monitored (see section 4.4).
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the antihypertensive effects of ACE inhibitors, diuretics and/or other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors or diuretics may be attenuated by NSAIDs, including selective COX-2 inhibitors.
Concomitant use of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors has been shown to have an additive effect on serum potassium and may lead to deterioration of renal function. These effects are usually reversible. Rarely, renal failure may occur, particularly in patients with compromised 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 compromised renal function.
Enalapril maleate
Potassium-sparing diuretics or potassium supplements. ACE inhibitors reduce diuretic-induced potassium loss. Potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene or amiloride), potassium supplements or salt substitutes containing potassium may lead to significant increases in serum potassium. If concomitant use of such agents is indicated due to hypokalaemia, treatment should be carried out with caution and serum potassium should be monitored frequently (see section 4.4).
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 may be attenuated by discontinuation of the diuretic, volume expansion, or increased salt intake.
Tricyclic antidepressants/neuroleptics/anesthetics: Concomitant administration of certain anesthetics, tricyclic antidepressants and neuroleptics with ACE inhibitors may lead to an additional decrease in blood pressure (see section 4.4).
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 more likely to occur during the first weeks of concomitant treatment and in patients with renal impairment (see section 4.4).
Acetylsalicylic acid, thrombolytics and β-blockers. Enalapril can be used with caution with acetylsalicylic acid (in cardiological doses), thrombolytics and β-blockers.
Gold preparations: Nitroid reactions (facial flushing, nausea, vomiting, and hypotension) have been reported in patients treated with injectable gold preparations (sodium aurothiomalate) concomitantly with an ACE inhibitor, including enalapril.
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 is 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 determined cases and accompanied by careful monitoring of renal function, potassium levels, 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 necessary (see Precautions).
Cholestyramine and colestipol resins. The absorption of hydrochlorothiazide is reduced in the presence of anion exchange resins. A single dose of a cholestyramine or colestipol resin preparation 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).
Corticosteroids, ACTH: Electrolyte imbalance, particularly hypokalemia, is exacerbated.
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 section 4.5).
Cytotoxic drugs (e.g. cyclophosphamide, methotrexate): Thiazides may reduce the renal excretion of cytotoxic drugs and enhance their myelosuppressive effects.
Application features
Enalapril maleate and hydrochlorothiazide
Hypotension and electrolyte/water imbalance. Symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. Symptomatic hypotension occurs more often in patients with water balance disorders who use Enalozid 25, for example, due to diuretic therapy, a diet with a limited salt intake, diarrhea or vomiting. In such patients, serum electrolyte levels should be determined regularly at regular intervals. Particular attention should be paid to the treatment of patients with ischemic heart disease or cerebrovascular disease, since a significant decrease in blood pressure can lead to myocardial infarction or stroke.
Symptomatic hypotension has been observed in patients with hypertension and heart failure, with or without renal insufficiency.
If hypotension develops, the patient should be placed on his back and, if necessary, intravenously administered saline solution. Transient hypotension is not a contraindication to further use of the drug. If after normalization of the circulating blood volume an increase in blood pressure occurs, therapy can be resumed in the usual doses.
Renal impairment. Enalozid 25 should not be administered to patients with renal impairment (creatinine clearance <80 mL/min >30 mL/min) until titration of the individual components of the drug reaches the doses of the drug in this dosage form.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS). In patients receiving concomitant treatment with ACE inhibitors, angiotensin II receptor antagonists or aliskiren, there is an increased risk of hypotension, hyperkalaemia and renal impairment (including acute renal failure). 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: The combination of enalapril and a diuretic at low doses may cause hyperkalemia.
Lithium: Concomitant use of enalapril and lithium is generally not recommended.
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 individually defined cases and accompanied by careful monitoring of renal function, potassium levels and blood pressure (see section 4.5).
Enalapril maleate
Aortic stenosis/hypertrophic cardiomyopathy. ACE inhibitors (as with all other vasodilators) should be used with caution in patients with left ventricular outflow obstruction. ACE inhibitors should be avoided in cardiogenic shock and in cases of haemodynamically 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 and Administration).
Renovascular hypertension. When treating patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney with ACE inhibitors, there is an increased risk of hypotension and renal dysfunction. Renal dysfunction 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 and renal function monitored.
Patients undergoing hemodialysis. Enalapril is contraindicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been observed in patients undergoing dialysis using high-flux membranes (such as AN 69) and receiving concomitant ACE inhibitor therapy. In these patients, a different type of dialysis membrane or a different class of antihypertensive drug should be used.
Kidney transplantation: There is no experience with the use of the drug in patients who have recently undergone kidney transplantation. Therefore, treatment with the drug is not recommended in these patients.
Hepatic failure. Rarely, the use of ACE inhibitors has been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant necrotizing hepatitis, sometimes with a fatal outcome. 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 supervision.
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 great caution in patients with collagen vascular disease who are receiving immunosuppressive therapy, allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing renal impairment. 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: Increases in serum potassium have been observed in some patients treated with ACE inhibitors, including enalapril.
The use of potassium supplements, potassium-sparing diuretics, and salt substitutes containing potassium, particularly in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalemia may cause serious and even fatal arrhythmias.
If concomitant administration of Enalozid 25 and the above-mentioned agents is deemed necessary, they should be used with caution and with frequent monitoring of serum potassium levels.
Hypoglycemia: Diabetic patients receiving oral antidiabetic agents or insulin and starting an ACE inhibitor should be advised to closely monitor their blood sugar levels, especially during the first month of combination therapy (see section 4.5).
Hypersensitivity/angioedema. Isolated cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported with ACE inhibitors, including enalapril maleate. In such cases, treatment with the drug should be discontinued immediately and the patient should be closely monitored for clinical symptoms. Even in cases where only tongue swelling occurs without respiratory distress, prolonged monitoring of the patient is necessary, as treatment with antihistamines and corticosteroids may be inadequate.
Very rare cases of fatal angioedema associated with laryngeal or tongue oedema have been reported. Patients with tongue, glottis or larynx oedema may develop airway obstruction, particularly in patients with a history of airway surgery.
In cases where the swelling is localized in the area of the tongue, glottis, or larynx, which may lead to airway obstruction, a 1:1000 adrenaline solution (0.3-0.5 ml) should be immediately administered subcutaneously and other appropriate treatment measures should be taken.
Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema while receiving ACE inhibitors.
Angioedema has been reported more frequently in black patients taking ACE inhibitors than in white patients. However, it is generally accepted that black patients are at increased risk of angioedema.
Anaphylactoid reactions during desensitization with hymenoptera venom.
Rarely, patients receiving ACE inhibitors have developed severe anaphylactoid reactions during desensitization with hymenoptera venom. Such reactions can be avoided by temporarily stopping the ACE inhibitor before the desensitization.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Life-threatening anaphylactoid reactions have rarely occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor prior to 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 secondary to ACE inhibitors should be considered in the differential diagnosis of cough.
Surgery/Anesthesia: During major surgery or during anesthesia with agents that produce hypotension, enalaprilat 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.
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered 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 not be effective diuretics in patients with renal impairment or when creatinine clearance is 30 mL/min or less (i.e., moderate to severe renal impairment).
Hepatic impairment: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since even minor disturbances of fluid and electrolyte balance may precipitate hepatic coma.
Elevations in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy, however, minimal or no effect has been reported with low doses of hydrochlorothiazide (12.5 mg).
Thiazides may reduce urinary calcium excretion and cause occasional slight increases in serum calcium.
Marked hypercalcemia may be a manifestation of latent hyperparathyroidism. Thiazides should be discontinued before performing tests for parathyroid function.
Thiazide diuretic 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, serum electrolyte levels should be measured regularly at appropriate intervals.
Thiazides (including hydrochlorothiazide) may cause fluid and electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Dangerous signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargic sleep, drowsiness, fatigue, muscle pain or cramps, muscle weakness, hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting).
Although hypokalemia may occur during thiazide diuretic therapy, 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, in patients with inadequate oral electrolyte intake, and in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).
In hot weather, hyponatremia may occur in patients prone to edema. Chloride deficiency is usually mild and does not require treatment.
Thiazides increase urinary magnesium excretion, which may lead to hypomagnesemia.
Increased sensitivity
Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma while taking thiazides. Cases of exacerbation or reactivation of systemic lupus erythematosus have been reported.
Special precautions regarding inactive ingredients of the drug.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ability to influence reaction speed when driving vehicles or other mechanisms
Some of the undesirable effects listed in the "Adverse reactions" section may affect the ability to drive and/or use machines.
Use during pregnancy or breastfeeding
Enalozid 25 should not be used by pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicine, its use should be stopped immediately and replaced with another medicine approved for use in pregnant women.
Breast-feeding.
Enalapril and thiazide diuretics pass into breast milk. The use of Enalozid 25 during breastfeeding is not recommended.
Method of administration and doses
With arterial hypertension.
The initial dose of the drug is 1 tablet once a day. If the desired effect is not achieved, the daily dose should be increased to 2 tablets once a day. The maximum dose is 2 tablets per day.
In renal failure.
For patients with impaired renal function, moderate or severe renal failure (with a creatinine clearance of 30 ml/min or less), thiazides may not be sufficiently effective.
If the creatinine level is in the range of >30 to <80 ml/min, Enalozid 25 should be used only after prior determination of the dose of each component.
The recommended starting dose of enalapril maleate used alone in mild renal impairment is 5 to 10 mg.
Previous treatment with diuretics.
If the patient is already receiving diuretics, it is recommended to discontinue treatment or reduce the dose of the diuretic at least 2-3 days before starting therapy with Enalozid 25 to avoid a sharp decrease in blood pressure. Symptomatic arterial hypotension may occur at the beginning of therapy with Enalozid 25, it is more often observed in patients in whom previous therapy with diuretics has caused a violation of water and electrolyte balance.
Children
The safety and effectiveness of the drug in children have not been established.
Overdose
Treatment is symptomatic and supportive. The drug should be discontinued and the patient carefully examined.
In case of accidental overdose, if the drug was taken recently, it is necessary to: wash the stomach, induce vomiting, take activated charcoal and laxatives, and correct water and electrolyte imbalance and arterial hypotension using standard measures.
Symptoms associated with ACE inhibitor overdose may include circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
Plasma levels of enalaprilat exceeding 100 and 200 times the maximum levels were recorded after administration of 300 mg and 440 mg of enalapril maleate, respectively.
Intravenous saline is recommended for the treatment of overdose.
If hypotension occurs, the patient should be placed in the supine position with the legs elevated. If necessary, consider administering angiotensin II infusion and/or intravenous catecholamines. If the drug has been taken recently, measures should be taken to eliminate enalapril maleate from the body (induction of vomiting, gastric lavage, use of absorbents and sodium sulfate). Enalapril can be removed from the systemic circulation by hemodialysis. In case of bradycardia resistant to therapy, the use of a pacemaker is indicated. Vital signs, electrolytes and serum creatinine levels should be monitored continuously.
Hydrochlorothiazide. The most common symptoms are those caused by electrolyte loss (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis.
With simultaneous use of digitalis drugs, hypokalemia may aggravate the course of arrhythmias.
Adverse reactions
Infections and infestations: sialoadenitis.
Blood and lymphatic system disorders: decreased hemoglobin and hematocrit, thrombocytopenia, neutropenia, leukopenia, pancytopenia, agranulocytosis, anemia (including aplastic and hemolytic anemia), lymphadenopathy, bone marrow suppression, autoimmune diseases.
Immune system disorders: anaphylactic reactions.
On the part of the endocrine system: syndrome of inappropriate secretion of antidiuretic hormone.
Metabolic disorders: hypokalemia, gout, water and electrolyte imbalance (including hyponatremia), increased blood cholesterol and triglyceride levels, hypoglycemia, hyperuricemia, hypomagnesemia, hyperglycemia, hypercalcemia.
Nervous system/psychiatric disorders: headache, depression, syncope, altered taste, insomnia, nervousness, restlessness, drowsiness, paresthesia, vertigo, confusion, abnormal dreams, sleep disorders, paresis (due to hypokalemia), decreased libido.
On the part of the organs of vision: loss of visual acuity, transient loss of visual acuity, xanthopsia.
On the part of the organs of hearing: tinnitus.
Cardiovascular system: dizziness, hypotension, orthostatic hypotension, tachycardia, palpitations, arrhythmia, angina pectoris, Raynaud's syndrome, hot flashes, myocardial infarction/stroke (possibly due to excessive hypotension in high-risk patients).
Respiratory, thoracic and mediastinal disorders: sore throat and hoarseness, rhinitis, rhinorrhea, cough, shortness of breath, pulmonary infiltrates, allergic alveolitis/eosinophilic pneumonia, bronchospasm, asthma, respiratory distress (including pneumonitis and pulmonary edema).
Gastrointestinal: anorexia, dry mouth, stomatitis/aphthous ulcers, glossitis, nausea, vomiting, pancreatitis, diarrhea, dyspepsia, abdominal pain, flatulence, constipation, angioedema of the intestine, ileus, gastric irritation, peptic ulcers.
Hepatobiliary system: hepatic failure, liver necrosis (may be fatal), hepatitis (hepatocellular or cholestatic), jaundice, cholecystitis (especially in patients with pre-existing cholelithiasis).
Skin and subcutaneous tissue disorders: rash (exanthema), hypersensitivity, angioedema, including angioedema of the face, extremities, lips, tongue, glottis and/or larynx, purpura, dyspnea
