Instructions for Eneas tablets No. 30
Composition
active ingredients: enalapril maleate; nitrendipine;
1 tablet contains 10 mg of enalapril maleate and 20 mg of nitrendipine;
excipients: sodium bicarbonate; lactose, monohydrate; povidone K 25; microcrystalline cellulose; corn starch; magnesium stearate; sodium lauryl sulfate.
Dosage form
Pills.
Main physicochemical properties: yellow, oblong biconvex tablets with “E/N” embossed on one side.
Pharmacotherapeutic group
Agents that affect the renin-angiotensin system. Angiotensin-converting enzyme inhibitors in combination with calcium antagonists. ATC code C09B B06.
Pharmacological properties
Pharmacodynamics.
The active compounds that make up the drug Eneas have a complementary effect.
After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits angiotensin-converting enzyme, which catalyzes the conversion of angiotensin I to angiotensin II. Inhibition of angiotensin-converting enzyme leads to a decrease in angiotensin II concentrations, an increase in plasma renin activity, and a decrease in aldosterone secretion.
The mechanism of action of enalapril is primarily associated with inhibition of the activity of the renin-angiotensin-aldosterone system, which plays an important role in the regulation of blood pressure, so enalapril can also have an antihypertensive effect in patients with low-renin hypertension. Long-term administration of enalapril in patients with primary arterial hypertension and renal failure can improve renal function by increasing the glomerular filtration rate.
Nitrendipine is a calcium antagonist, a derivative of 1,4-dihydropyridine. The mechanism of antihypertensive action is associated with the inhibition of the influx of calcium ions through the cell membranes of smooth muscle cells of the walls of blood vessels. By reducing the intracellular concentration of calcium in the cells, nitrendipine reduces the contractility of vascular muscles, dilating peripheral arteries reduces total peripheral resistance and pathologically elevated blood pressure. Nitrendipine has a moderate natriuretic effect, especially at the beginning of treatment.
Pharmacokinetics.
After oral administration, enalapril is rapidly absorbed, and the absorption of enalapril is not affected by the presence of food in the gastrointestinal tract. The maximum concentration in the serum is reached after 1 hour. Binding to plasma proteins is 50–60%. After absorption, enalapril is rapidly hydrolyzed to enalaprilat. The maximum concentration in the serum is reached after 3–4 hours after oral administration of the drug. Enalapril is excreted mainly by the kidneys (in unchanged form and 40% in the form of enalaprilat). With the exception of conversion to enalaprilat, there are no other signs of significant metabolic transformations of enalapril. The schedule of enalaprilat concentration in the serum is characterized by a prolonged terminal phase, which is associated with the binding of ACE. In patients with normal renal function, constant concentrations of enalaprilat were achieved on the fourth day of taking the drug. The effective half-life of enalaprilat accumulation after multiple oral doses of enalapril is 11 hours. The extent of absorption and hydrolysis of enalapril is similar within the recommended therapeutic range.
Nitrendipine is rapidly and almost completely (88%) absorbed. The maximum concentration in the blood serum is reached 1–3 hours after taking the drug. Bioavailability is 20–30%. Binding of nitrendipine to blood plasma proteins is 96–98%.
Nitrendipine is almost completely metabolized in the liver by oxidation.
The elimination half-life is 8–12 hours. No accumulation of the active compound or its metabolites was observed. In patients with chronic liver dysfunction, an increase in the concentration of nitrendipine in the blood plasma was observed.
Nitrendipine is excreted mainly by the kidneys in the form of inactive metabolites (approximately 77%) and through the bile ducts.
Concomitant administration of enalapril maleate and nitrendipine may slightly increase the bioavailability of these compounds, but is not clinically significant.
Indication
Treatment of essential hypertension in patients requiring combination therapy.
Contraindication
Eneas should not be used:
patients with hypersensitivity to enalapril, nitrendipine or other components of the drug;
patients with a history of angioedema caused by any angiotensin-converting enzyme (ACE) inhibitor or hereditary/idiopathic angioedema;
in the 2nd–3rd trimester of pregnancy (see sections “Special precautions for use” and “Use during pregnancy or breastfeeding”);
patients with unstable hemodynamics, especially after cardiovascular shock, acute heart failure, acute coronary syndrome, acute stroke;
patients with bilateral renal artery stenosis or patients with unilateral renal artery stenosis of a single kidney;
patients with severe renal insufficiency (creatinine clearance less than 10 ml/min) and patients on hemodialysis;
patients with severe liver failure;
pregnant women or women planning to become pregnant (see section "Use during pregnancy or breastfeeding").
The simultaneous use of Eneas with allylskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Pharmacodynamics”).
Interaction with other medicinal products and other types of interactions
The hypotensive effect of Eneas is enhanced when used concomitantly with other antihypertensive agents, in particular diuretics, beta-blockers, alpha-adrenergic blockers, for example, prazoline.
Combinations of enalapril maleate with other agents that should be used with caution.
Antihypertensive therapy. Concomitant administration of these drugs may enhance the hypotensive effect of enalapril. Concomitant administration of nitroglycerin, other nitrates, or other vasodilators may further reduce blood pressure.
Potassium-sparing diuretics and potassium supplements. ACE inhibitors reduce potassium loss caused by diuretics. When taken simultaneously with potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, amiloride), potassium supplements and drugs that increase serum potassium levels (e.g. heparin), an increase in plasma potassium concentration is possible, especially in patients with impaired renal function. With the simultaneous use of such drugs, it is necessary to monitor the concentration of potassium in the blood plasma (see section "Special instructions").
Diuretics (thiazide or loop diuretics). Previous treatment with high doses of diuretics may result in volume depletion and an increased risk of hypotension at the start of enalapril therapy (see section 4.4). Hypotensive effects may be reduced by discontinuing the diuretic, increasing salt intake, or initiating therapy with a low dose of enalapril.
Antidiabetic agents: Epidemiological studies have shown that the concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may lead to a decrease in blood glucose levels with a risk of hypoglycaemia. This effect is most likely to occur during the first weeks of concomitant use in patients with renal impairment (see sections 4.4 and 4.8).
Lithium: Reversible increases in serum lithium levels and toxicity have been reported with concomitant use of ACE inhibitors and lithium. Concomitant use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and increase the risk of lithium toxicity. The use of enalapril with lithium is not recommended, but if the combination proves necessary for the patient, careful monitoring of serum lithium levels should be performed (see section 4.4).
Tricyclic antidepressants/neuroleptics/anesthetics/hypnotics: Concomitant administration of certain anesthetics, tricyclic antidepressants and neuroleptics with ACE inhibitors may lead to an additional decrease in blood pressure (see section "Special warnings and precautions for use").
Non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the hypotensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors.
Dual blockade of the renin-angiotensin-aldosterone system. Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to isolated cases with close monitoring of blood pressure, renal function, and electrolytes. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual blockade of the renin-angiotensin-aldosterone system is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a single agent that acts on the renin-angiotensin-aldosterone system.
Gold preparations: Nitritoid reactions (symptoms including flushing, nausea, vomiting, and hypotension) have been reported rarely in patients treated with injectable gold preparations (sodium aurothiomalate) and concomitant ACE inhibitors, including enalapril.
Sympathomimetics: Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Alcohol: Alcohol enhances the hypotensive effect of ACE inhibitors.
Acetylsalicylic acid, thrombolytics and beta-blockers. Enalapril can be safely used concomitantly with acetylsalicylic acid (in cardiological doses), thrombolytics and beta-blockers.
Baclofen. Baclofen may enhance the hypotensive effect of the drug. Blood pressure monitoring and dose adjustment are necessary.
Amifostine. Amifostine enhances the hypotensive effect of the drug.
When used with allopurinol, cytostatics, immunosuppressants, systemic corticosteroids, procainamide, leukopenia may develop.
Combinations of nitrendipine with other agents that should be used with caution.
Cimetidine and ranitidine: Cimetidine (to a lesser extent ranitidine) increases the plasma concentration of nitrendipine, but the clinical significance of this effect is unknown.
Digoxin. Nitrendipine may increase the plasma concentration of digoxin when used concomitantly. The patient should be observed for symptoms of digoxin overdose. Plasma digoxin levels should be monitored.
Muscle relaxants: Nitrendipine may enhance the effect and duration of muscle relaxants such as pancuronium.
Grapefruit juice inhibits the oxidative metabolism of nitrendipine, increasing its concentration in blood plasma, which enhances the hypotensive effect of Eneas.
Nitrendipine is metabolized in the intestinal mucosa and liver with the participation of the cytochrome P450 3A4 system. Agents that stimulate this system, for example, anticonvulsants (phenytoin, phenobarbital, carbamazepine) and rifampicin, can cause a strong decrease in the bioavailability of nitrendipine. Agents that inhibit this enzymatic system, for example, antifungal agents (intraconazole, etc.), contribute to an increase in the concentration of nitrendipine in the blood plasma.
Beta-blockers. Nitrendipine and beta-blockers have synergistic effects. This may be of particular importance in patients whose sympathetic vascular responses are not regulated by additional beta-blockers.
Application features
Symptomatic hypotension. Symptomatic hypotension has been observed in patients with heart failure, with or without renal insufficiency. Symptomatic hypotension has been reported more frequently in patients with more severe heart failure, who have been treated with higher doses of loop diuretics, who have hyponatremia, or who have impaired renal function. Treatment should be initiated under medical supervision in such patients. Monitoring should be particularly close when changing the dose of enalapril and/or diuretic.
Hypersensitivity/angioedema. Swelling of the face, extremities, eyes, lips, mucous membranes, tongue, glottis or larynx may occur during treatment with ACE inhibitors, especially during the first weeks of treatment. However, in rare cases, severe angioedema may develop after long-term treatment with ACE inhibitors. In such cases, treatment should be discontinued completely. Even when swelling of the tongue alone is noted without respiratory distress, patients require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient. Angioedema of the tongue, glottis or larynx may be fatal. Emergency treatment should be initiated immediately. The patient should be hospitalized and observed for at least 12-24 hours until the symptoms have completely disappeared.
Angioedema was more common in black patients treated with ACE inhibitors than in patients of other races.
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 complications. The drug should be used with caution in patients with collagen vascular diseases (e.g. systemic lupus erythematosus, scleroderma), with concomitant therapy with antidepressants, allopurinol or procainamide, or with a combination of these factors, especially if there is already impaired renal function. Some of these patients have developed serious infections, sometimes not responding to intensive antibiotic therapy. If Eneas is to be used in such patients, it is recommended to perform a blood leukocyte count analysis. Patients should be instructed to report any signs of infection immediately. The drug should be discontinued if neutropenia (neutrophils less than 1000/mm3) is detected or suspected.
Renal impairment: In patients with renal impairment (creatinine clearance < 80 ml/min), the initial dose of enalapril should be titrated according to creatinine clearance (see section 4.2) and then adjusted according to response to treatment. Regular monitoring of potassium and creatinine levels is standard medical practice in such patients.
Renal impairment has been reported in association with enalapril, primarily in patients with severe heart failure or renal disease, including renal artery stenosis. With timely recognition and appropriate treatment, renal impairment associated with enalapril therapy is usually reversible.
In some hypertensive patients with no known renal disease prior to treatment, concomitant use of enalapril with diuretics has been associated with, usually minor and transient, increases in serum urea and creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation increases the likelihood of pre-existing renal artery stenosis (see Renovascular hypertension/renal artery stenosis).
Patients with moderate renal impairment (creatinine clearance > 30 ml/min; serum creatinine < 3 mg/ml) do not require dose adjustment. There are no data on the use of Eneas in patients with a recent kidney transplant.
Proteinuria: In patients with renal insufficiency, proteinuria may occur in isolated cases. Patients with proteinuria (more than 1 g/day) should use the drug after a careful assessment of the benefit/risk ratio and under the control of clinical laboratory parameters.
Patients with hepatic impairment. The drug should be used with caution in patients with mild to moderate hepatic impairment, as there is insufficient experience with combination therapy. The drug is contraindicated in patients with severe hepatic impairment. In elderly patients with impaired liver function, the elimination of nitrendipine may be delayed, which may lead to hypotension. In the event of adverse events (cholestatic jaundice, increased liver enzymes), which may lead to liver necrosis and sometimes death, the drug should be discontinued and a doctor should be consulted.
Renovascular hypertension/renal artery stenosis: When treated with ACE inhibitors, patients with renovascular hypertension and renal artery stenosis (bilateral or unilateral) are at significantly increased risk of hypotension and renal failure, which may lead to loss of renal function even with very small changes in serum creatinine (see section 4.3).
Lithium: The combination of lithium and enalapril is generally not recommended (see section 4.5).
Arterial hypotension. In some cases, Eneas may cause orthostatic hypotension. Patients should be examined to identify and eliminate clinical signs of water-salt balance disorders due to the use of diuretics, a low-salt diet, hemodialysis, diarrhea or vomiting. As with other antihypertensive drugs, some patients may develop symptomatic hypotension, which disappears after the patient is placed in a supine position and correction of blood pressure and circulating blood volume. The approach to the treatment of patients with ischemic heart disease or cerebrovascular diseases should be especially careful, since an excessive decrease in blood pressure can lead to myocardial infarction or stroke. If arterial hypotension occurs, the patient should be placed in a supine position. If necessary, administer 0.9% sodium chloride solution intravenously. Transient hypotension with restored blood pressure and circulating fluid volume is not a contraindication for treatment with Eneas.
Aortic or aortic valve stenosis. ACE inhibitors should be used with caution in patients with aortic or aortic valve stenosis. The drug should not be used in patients with severe hemodynamic compromise (see Contraindications).
Cough: Cough has been reported with ACE inhibitors. The cough is usually non-productive and persistent and resolves after discontinuation of the drug. Cough occurring during treatment with ACE inhibitors should be considered in the differential diagnosis of cough.
Primary hyperaldosteronism. Patients with primary aldosteronism are usually resistant to therapy with antihypertensive agents that act on the renin-angiotensin-aldosterone system, and therefore the use of the drug is not recommended.
Patients undergoing hemodialysis. Due to the increased risk of anaphylactic reactions such as facial edema, flushing, hypotension, and dyspnea, the drug should not be administered to patients undergoing hemodialysis using high-flux polyacrylonitrile membranes (such as AN 69®). The use of Eneas is contraindicated in patients undergoing hemodialysis.
Hypoglycemia: Diabetic patients receiving oral antidiabetic agents or insulin and initiating therapy with an ACE inhibitor should be advised to monitor their blood sugar levels closely, especially during the first few months of concomitant use (see Interactions with other medicinal products and other forms of interaction).
Anaphylactoid reactions during low-density lipoprotein apheresis/desensitization to insect venom. In some cases, patients taking ACE inhibitors have developed life-threatening anaphylactoid reactions during low-density lipoprotein apheresis using dextran sulfate. In patients taking ACE inhibitors during specific immunotherapy (desensitization) to insect venom (e.g. bees or wasps), anaphylactoid reactions (e.g. hypotension, dyspnea, vomiting, skin allergy), which in some cases can be life-threatening, may occur. If apheresis or specific immunotherapy (desensitization) to insect venom is necessary, such reactions can be avoided by temporarily replacing ACE inhibitors with other drugs for the treatment of arterial hypertension or heart failure.
Surgery/Anesthesia: During major surgery or anesthesia with drugs that increase blood pressure, the drug blocks the formation of angiotensin II secondary to compensatory renin release. If hypotension develops, it is corrected by increasing plasma volume.
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, accompanied by careful monitoring of renal function, potassium levels and blood pressure (see section 4.5).
Fertility: In rare cases, nitrendipine may cause reversible biochemical changes in the head of spermatozoa during artificial insemination, which may affect the functional state of sperm. In case of repeated failure of in vitro fertilization and in the absence of other causes, the use of calcium antagonists may be considered as a possible cause of this phenomenon.
Ethnic differences: As with other ACE inhibitors, the antihypertensive effect of Eneas is less pronounced in black patients than in non-blacks, probably because of the higher prevalence of low-renin hypertension in the black population.
Patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy. Epidemiological data on the teratogenic risk after exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increase in risk cannot be excluded. If pregnancy is confirmed during treatment with this medicinal product, its use should be stopped immediately and an alternative medicinal product which has an established safety profile for use in pregnancy should be used instead. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started. The use of ACE inhibitors during the second and third trimesters of pregnancy is known to induce fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Oligohydramnios resulting from renal impairment may lead to fetal limb contractures, craniofacial deformities and hypoplastic lung development. If exposure to ACE inhibitors has occurred from the second trimester of pregnancy, ultrasound examination of the kidneys and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).
Breastfeeding. Limited pharmacokinetic data have shown that enalapril is excreted in breast milk in small quantities (see section "Pharmacokinetics"). The drug should not be used during breast-feeding of premature infants and in the first few weeks after birth, since due to insufficient clinical experience there is a hypothetical risk of effects on the cardiovascular system and kidneys. The use of Eneas during breast-feeding of an infant may be considered if treatment is necessary for the mother, and the child will be observed for any side effects.
The ability to influence the reaction speed when driving or working with other mechanisms
Some patients may experience changes in reaction time during the use of the drug, which may interfere with driving or operating machinery. This is especially important at the beginning of treatment and when changing the drug, as well as in interaction with alcohol.
Method of administration and doses
Swallow the tablets whole, without breaking or chewing, with sufficient water.
Individual dose selection is recommended for combination therapy.
According to indications and under the supervision of a physician, a direct transition from monotherapy to a fixed combination is possible.
Adults, including elderly patients. The recommended dose is 1 tablet per day.
Patients with hepatic impairment. The drug is contraindicated in patients with severe hepatic impairment (see section "Contraindications"). Monotherapy with enalapril and nitrendipine is not contraindicated in patients with mild to moderate hepatic impairment. The drug should be used with caution in patients with mild to moderate hepatic impairment due to the lack of data on the use of the drug in this group of patients (see section "Special warnings and precautions for use").
Patients with renal impairment. The drug is contraindicated in patients with severe renal impairment (creatinine clearance less than 10 ml/min) or in patients undergoing hemodialysis (see sections "Contraindications" and "Special warnings and precautions for use").
Children
There are no clinical data on the efficacy and safety of the drug for the treatment of children and adolescents, therefore it should not be used in children.
Overdose
To date, no cases of overdose have been reported with Eneas. The most likely symptom of overdose is hypotension.
Treatment. Primary detoxification - gastric lavage, administration of absorbents and/or sodium sulfate (if possible within the first 30 minutes). Close monitoring of vital signs is necessary. In case of arterial hypotension, the patient should be placed in a supine position and ensure restoration of water and electrolyte balance. In severe overdose, intravenous administration of catecholamine, angiotensin II and hemodialysis (rate 62 ml/min; polyacrylonitrile membranes with high permeability should be avoided). In case of bradycardia, atropine should be administered. An artificial pacemaker may be used. Serum creatinine and electrolyte concentrations should be carefully monitored (see section "Special instructions").
Side effects
The most common adverse reactions (1–10%): flushing, edema, headache, cough. Uncommon adverse reactions (0.1–1%): dizziness, tachycardia, erythematous rash, nausea, dyspepsia, hypotension. Very rare adverse reactions (<0.01%), including isolated cases: asthenia, hypothermia, palpitations, peripheral ischemia, hematuria, pharyngitis, tracheitis, dyspnea, abdominal distension, increased liver enzymes, hypokalemia, drowsiness, paresthesia, tremor, and convulsions. The information on adverse reactions is based on spontaneous post-marketing reports of adverse reactions during the use of Eneas.
The following adverse reactions have been associated with the use of either drug in monotherapy:
Enalapril
From the cardiovascular system.
Uncommon: arterial and/or orthostatic hypotension with the following symptoms: dizziness, weakness, visual disturbances, rarely - syncope (especially at the beginning of treatment; when increasing the dose of enalapril maleate and/or diuretics in patients with impaired water and electrolyte balance, heart failure, severe or renal arterial hypertension).
Very rare: due to a sudden decrease in blood pressure - tachycardia, palpitations, arrhythmia, bradycardia, atrial fibrillation, chest pain, angina pectoris, myocardial infarction, transient ischemic attack, cerebrovascular accident, stroke, pulmonary embolism, pulmonary infarction, pulmonary edema.
From the kidneys and urinary tract.
Uncommon: onset or worsening of renal dysfunction, renal failure.
Rare: oliguria, proteinuria, patients with impaired renal function may experience back pain.
Very rare: acute renal failure.
On the part of the respiratory system.
Common: shortness of breath.
Uncommon: dry cough, sore throat, wheezing, bronchitis, rhinorrhea.
Rare: dyspnea, sinusitis, rhinitis, allergic alveolitis/eosinophilic pneumonia.
Very rare: bronchospasm/asthma, pulmonary infiltrates, stomatitis, glossitis, dry mouth, pneumonia, angioedema involving the larynx, pharynx and/or tongue, which in some cases may cause airway obstruction (risk group – patients of the Negroid race).
From the gastrointestinal tract and liver.
Uncommon: nausea, upper abdominal pain, indigestion, stomach irritation, peptic ulcers.
Rare: vomiting, diarrhea, constipation, loss of appetite.
Very rare: intestinal angioedema, liver function abnormalities, hepatocellular or cholestatic hepatitis, hepatitis including necrosis, cholestasis (including jaundice), hepatic failure, pancreatitis, intestinal obstruction, stomatitis, glossitis.
From the endocrine system.
Very rare: gynecomastia.
Not known: syndrome of inappropriate antidiuretic hormone secretion.
From the nervous system.
Uncommon: headache, fatigue, drowsiness, insomnia.
Rare: dizziness, sleep disturbances, depression, impotence, peripheral neuropathy with paraesthesia, balance disorders, muscle cramps, nervousness, confusion, abnormal dreams.
On the part of blood vessels and skin.
Common: rash.
Uncommon: allergic skin reactions (exanthema).
Rare: erythroderma, pruritus, urticaria, angioedema of the face, extremities, lips, tongue, glottis and/or larynx.
Very rare: severe skin reactions (pemphigus, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome or toxic epidermal necrosis), photosensitivity, increased sweating, alopecia, onycholysis and exacerbation of Raynaud's phenomenon. Skin disorders may be accompanied by fever, myalgia/myositis, arthralgia/arthritis, vasculitis, serositis, eosinophilia, leukocytosis, increased erythrocyte sedimentation rate, positive antinuclear antibody test.
On the part of metabolism.
Uncommon: hypoglycaemia.
From the sensory organs.
Rare: ringing in the ears, blurred vision, change in taste or short-term loss of taste, loss of smell, dry eyes, tearing.
General disorders and administration site reactions.
Very common: asthenia.
Uncommon: hot flashes.
Changes in laboratory parameters.
Uncommon: decrease in hemoglobin, hematocrit, leukocyte count and platelet count.
Rarely: in patients with impaired renal function, collagen disease or patients taking allopurinol, procainamide or immunosuppressants: aplastic anemia, thrombocytopenia, neutropenia, eosinophilia (in isolated cases - agranulocytosis, pancytopenia), bone marrow suppression, lymphadenopathy, autoimmune diseases; in patients with impaired renal function, severe heart failure, renovascular hypertension: increased concentration of urea, creatinine, potassium in serum, decreased sodium concentration, hyperkalemia (in patients with diabetes mellitus), increased excretion of albumin from the blood.
