Enalapril tablets 10 mg No. 20

Instructions for Enalapril tablets 10 mg No. 20

Warehouse

active ingredient: enalapril;

1 tablet contains enalapril maleate (calculated as 100% substance) – 10 mg;

Excipients: lactose monohydrate; potato starch; microcrystalline cellulose; povidone; colloidal anhydrous silica; talc; calcium stearate.

Dosage form

Pills.

Main physical and chemical properties: solid regular round cylinders, the upper and lower surfaces of which are flat, the edges of the surfaces are beveled, with a dividing line, white or almost white in color.

Pharmacotherapeutic group

Angiotensin-converting enzyme inhibitors, monocomponent.

ATX code C09A A02.

Pharmacological properties

Pharmacodynamics.

Enalapril maleate is the maleic acid salt of enalapril, a derivative of two amino acids, L-alanine and L-proline, which is hydrolyzed in the liver to form enalaprilat, which is an angiotensin-converting enzyme (ACE) inhibitor.

Inhibition of ACE leads to a decrease in the formation of angiotensin II in tissues and blood plasma, an additional decrease in aldosterone secretion and an increase in plasma renin activity. The consequence of ACE inhibition is an increase in the activity of kallikrein-kinin systems, the accumulation of bradykinin and, as a consequence, the activation of the prostaglandin system. The use of enalapril maleate in patients with arterial hypertension leads to a decrease in blood pressure without a compensatory increase in heart rate (HR), a decrease in peripheral vascular resistance. In patients with heart failure, the use of enalapril maleate causes a decrease in peripheral vascular resistance, which results in a decrease in cardiac afterload. When treated with enalapril maleate, an increase in cardiac output, an increase in stroke index and tolerance to exercise, a decrease in left ventricular hypertrophy, and an improvement in intraglomerular hemodynamics in the kidneys are observed. Enalapril maleate does not affect glucose and lipoprotein metabolism.

Pharmacokinetics.

After oral administration, enalapril maleate is rapidly absorbed, with 60% of the dose absorbed. Food intake does not affect its absorption. Peak plasma concentrations of enalaprilat are reached after approximately 4 hours. The effective half-life of enalaprilat after multiple oral administration is 11 hours. Effective inhibition of angiotensin-converting enzyme activity occurs 2-4 hours after a single dose of enalapril maleate. The onset of antihypertensive action is observed 1 hour after dosing, and the maximum effect is 4-6 hours after dosing. The duration of action depends on the dose, but at the recommended dosage, the antihypertensive and hemodynamic effects persist for at least 24 hours. In volunteers with normal renal function, the concentration of enalaprilat in the blood serum reaches its steady-state level approximately 4 days after the start of administration. In the range of therapeutically relevant concentrations in humans, plasma protein binding does not exceed 60%. Apart from conversion to enalaprilat, there is no evidence of further significant metabolism of enalapril maleate. Enalaprilat is excreted mainly by the kidneys. The main components in the urine are enalaprilat (40% of the dose) and unchanged enalapril maleate (about 20%).

Indication

– Treatment of arterial hypertension.

– Treatment of clinically significant heart failure.

– Prevention of clinically significant heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction ≤ 35%).

Contraindication

– Hypersensitivity to enalapril, to any of the excipients or to any other ACE inhibitor.

– History of angioedema associated with the use of ACE inhibitors.

– Hereditary or idiopathic angioedema.

– Use of enalapril with aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).

– Pregnancy or planning a pregnancy (see section “Use during pregnancy or breastfeeding”).

Enalapril should not be used in combination with neprilysin inhibitors (e.g. sacubitril). Enalapril should not be used within 36 hours of switching from/to sacubitril valsartan, a drug containing a neprilysin inhibitor (see sections 4.5 and 4.4).

Interaction with other medicinal products and other types of interactions

Hypotensive therapy

Concomitant use of antihypertensive drugs may enhance the hypotensive effect of enalapril. Concomitant use with nitroglycerin, other nitrates or other vasodilators may further reduce blood pressure.

ACE inhibitors increase the potassium loss caused by diuretics. The use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), as well as the use of dietary supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium levels (e.g. drugs containing trimethoprim), especially in patients with impaired renal function, may lead to a significant increase in serum potassium levels. If the above agents are indicated in connection with hypokalemia, they should be used with caution, with regular determination of serum potassium levels (see section "Special instructions").

Diuretics (thiazide or loop diuretics)

Previous treatment with high doses of diuretics may lead to 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 drugs

Epidemiological studies have shown that the concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may lead to a decrease in blood glucose levels with a risk of hypoglycemia. This phenomenon is most likely during the first weeks of concomitant administration and in patients with renal insufficiency (see sections "Special warnings and precautions for use", "Adverse reactions").

Serum 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").

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors

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 NSAIDs, including selective COX-2 inhibitors.

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors has an additive effect on serum potassium and may lead to deterioration of renal function. These effects are usually reversible.

Acute renal failure may occur rarely, especially in some patients with impaired renal function (e.g. elderly patients or patients with reduced circulating blood volume, including those receiving diuretics). Therefore, this combination should be administered with caution to patients with impaired renal function. Patients should be adequately hydrated and renal function should be closely monitored at the beginning of concomitant therapy and periodically during such treatment.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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. In patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual blockade of the RAAS has been reported in several studies 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 single RAAS-acting agent. Enalapril should not be used with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.3 and 4.4).

Gold preparations

Nitritoid reactions (symptoms including facial swelling, nausea, vomiting and hypotension) have been reported rarely in patients treated with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitors, including enalapril.

mTOR inhibitors

Concomitant use with mTOR inhibitors (such as temsirolimus, sirolimus, everolimus) may increase the risk of angioedema (see section "Special warnings and precautions for use").

Neprilysin inhibitors

Concomitant use with neprilysin inhibitors (e.g. sacubitril) may increase the risk of angioedema (see sections 4.4 and 4.5).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol

Acetylsalicylic acid, thrombolytics and β-blockers

Enalapril can be safely used concomitantly with acetylsalicylic acid (in cardiological doses), thrombolytics, and β-blockers.

Application features

Symptomatic hypotension

Symptomatic hypotension has been observed rarely in patients with uncomplicated hypertension. In hypertensive patients receiving enalapril, symptomatic hypotension is more likely to occur in patients with hypovolemia, such as those who are volume-depleted by diuretic therapy, salt restriction, hemodialysis, or in patients with diarrhea or vomiting (see Interactions and Adverse Reactions). Symptomatic hypotension has also been observed in patients with heart failure, with or without renal insufficiency. Symptomatic hypotension has been observed more frequently in patients with more severe heart failure, who are receiving higher doses of loop diuretics, who have hyponatremia, or who have impaired renal function. In such patients, treatment with enalapril should be initiated under medical supervision. When changing the dose of Enalapril and/or diuretic, special care should be taken. Similarly, patients with ischemic heart disease and cerebrovascular disease should be monitored, in whom an excessive decrease in blood pressure could lead to myocardial infarction or stroke.

If hypotension develops, the patient should be placed in a horizontal position and, if necessary, intravenous saline should be administered. Transient hypotension while taking Enalapril is not a contraindication for further administration, which can usually be continued without complications after normalization of blood pressure by restoring fluid volume.

In some patients with heart failure with normal or low blood pressure, enalapril may further reduce blood pressure. This reaction to the drug is expected and is usually not a reason to stop treatment. If hypotension becomes resistant to treatment, the dose should be reduced and/or the diuretic and/or enalapril should be discontinued.

Aortic or mitral stenosis/hypertrophic cardiomyopathy

As with all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and outflow tract obstruction; they should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Kidney dysfunction

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, predominantly in patients with severe heart failure or renal disease, including renal artery stenosis. Renal impairment associated with enalapril therapy is usually reversible with prompt recognition and appropriate treatment.

In some hypertensive patients with no known pre-existing renal disease, enalapril in combination with diuretics has caused, usually minor and transient, increases in blood urea and serum 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 section 4.4 Renovascular hypertension).

Renovascular hypertension

There is an increased risk of hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with minimal changes in serum creatinine. In such patients, treatment should be initiated at low doses under close medical supervision with careful titration and monitoring of renal function.

Kidney transplantation

There is no experience with the use of enalapril in patients who have recently undergone kidney transplantation. Therefore, treatment with enalapril is not recommended in these patients.

Liver failure

Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome remains unclear. Patients taking ACE inhibitors who develop jaundice or marked elevations of liver enzymes should discontinue the ACE inhibitor and receive appropriate medical attention.

Neutropenia/agranulocytosis, thrombocytopenia and anaemia 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 receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if renal function is already impaired. Some of these patients have developed serious infections, sometimes unresponsive to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended when enalapril is prescribed to such patients, and patients should be advised to report any signs of infection.

Hypersensitivity/angioedema

Isolated cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported with ACE inhibitors, including enalapril, occurring at different times during treatment. In such cases, enalapril should be discontinued immediately and the patient should be monitored closely to ensure complete resolution of symptoms. Only then should monitoring be discontinued. Even when only the tongue is involved and there is no respiratory distress, patients may require prolonged monitoring, as treatment with antihistamines and corticosteroids may be inadequate.

Very rarely, fatal cases of angioedema of the larynx or tongue have been reported. If the swelling is localized to the tongue, glottis or larynx, especially in patients with a history of airway surgery, airway obstruction may occur. When there is involvement of the tongue, pharynx or larynx and this may cause airway obstruction, appropriate therapy should be initiated immediately, which may include subcutaneous administration of epinephrine 1:1000 (0.3-0.5 ml) and/or measures to maintain a patent airway.

Angioedema was more common in black patients treated with ACE inhibitors than in patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of developing angioedema while receiving an ACE inhibitor (see also section 4.3).

Concomitant use of ACE inhibitors with mTOR inhibitors (such as temsirolimus, sirolimus, everolimus) may increase the risk of angioedema.

Concomitant use of ACE inhibitors and neprilysin inhibitors may increase the risk of angioedema (see sections 4.3 and 4.5).

Anaphylactoid reactions during hyposensitization with a hymenoptera venom allergen

Rarely, patients receiving ACE inhibitors during hymenoptera venom allergen desensitization have developed anaphylactoid reactions, which may be life-threatening. Such reactions can be avoided by temporarily stopping the ACE inhibitor before the desensitization begins.

Anaphylactoid reactions during low-density lipoprotein apheresis

Rarely, patients receiving ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily stopping ACE inhibitors before each apheresis.

Patients on hemodialysis

Anaphylactoid reactions have occasionally been reported in patients dialysed with high-flux membranes (e.g. AN 69®) and concomitantly treated with an ACE inhibitor. Therefore, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent in such patients.

Hypoglycemia

Diabetic patients taking oral antidiabetic agents or insulin and initiating therapy with an ACE inhibitor should be advised to monitor blood sugar levels closely, especially during the first few months of concomitant use (see section 4.5).

Cough

Cough has been reported with ACE inhibitors. The cough is usually non-productive and persistent and resolves after discontinuation of the drug. Cough due to ACE inhibitor therapy should be considered in the differential diagnosis of cough.

Surgical operations/anesthesia

During major surgery or anesthesia with drugs that cause hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If hypotension develops, which can be explained by these mechanisms of interaction, it is corrected by increasing the volume of fluid.

During treatment with ACE inhibitors, including enalapril, some patients have experienced increases in blood potassium levels. The risk of hyperkalemia is increased in patients with renal insufficiency, with impaired renal function, age > 70 years, with diabetes mellitus, with transient conditions, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride); with the use of potassium-containing food supplements or salt substitutes; and in patients taking other drugs that may increase blood potassium (e.g. heparin, drugs containing trimethoprim). In particular, the use of potassium-sparing diuretics, food supplements or salt substitutes containing potassium in patients with impaired renal function may lead to a significant increase in blood potassium levels. Hyperkalemia may cause serious, sometimes fatal arrhythmias. If concomitant use of enalapril and any of the above-mentioned drugs is considered necessary, they should be used with caution and with regular monitoring of serum potassium (see section 4.5).

Lithium

The combination of lithium and enalapril is generally not recommended (see section “Interaction with other medicinal products and other types of interactions”).

Concomitant therapy with an ACE inhibitor and angiotensin receptor antagonist

There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended.

If dual blockade is necessary, therapy should be under specialist supervision and with regular monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Children

There is limited experience of its efficacy and safety in children with hypertension aged 6 years and older, but no experience in other indications. There are also limited pharmacokinetic data in children aged 2 months and older (see sections 5.1 and 5.2). Enalapril is not recommended for use in children with conditions other than hypertension.

Enalapril is not recommended for use in neonates and children with a glomerular filtration rate <30 ml/min/1.73 m2 due to lack of data (see section 4.2).

Pregnancy

The medicine should not be used by pregnant women or women planning to become pregnant.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if possible, alternative therapy should be started (see sections 4.3 and 4.4).

Ethnic features

Like other ACE inhibitors, enalapril is less effective in lowering blood pressure in black patients than in non-blacks, possibly because low-renin states are more common in this population of hypertensive patients.

Lactose

The drug contains lactose, so it should not be prescribed to patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Pregnancy

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

ACE inhibitors when used in the 2nd and 3rd 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.

Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections "Contraindications", "Special warnings and precautions for use").

Breast-feeding

Limited pharmacokinetic data indicate very low concentrations in breast milk (see section 5.2). Although these concentrations are considered to be of no clinical significance, the use of enalapril is not recommended during breast-feeding of premature infants and infants in the first few weeks after birth because of the hypothetical risk of cardiovascular and renal effects and because of the lack of experience. In older infants, the use of enalapril during breast-feeding may be considered if treatment is necessary for the mother and the infant is observed for any adverse effects.

The ability to influence the reaction speed when driving vehicles and other mechanisms

When driving or operating other machinery, the possible development of dizziness or increased fatigue should be taken into account.

Method of administration and doses

Food intake does not affect the absorption of Enalapril tablets.

Dosage should be selected individually according to each patient's condition.

(see section "Special warnings and precautions for use") and blood pressure responses.

If enalapril is prescribed in a dosage of less than 5 mg, an enalapril preparation with the possibility of such a dosage should be used.

Arterial hypertension

The dose of the drug ranges from an initial 5 mg to a maximum of 20 mg depending on the degree of arterial hypertension and the patient's condition (see below). Enalapril should be taken once a day. In mild arterial hypertension, the recommended initial dose is 5-10 mg.

In patients with a highly activated RAAS (e.g. renovascular hypertension, salt and/or fluid imbalance, cardiac decompensation or severe hypertension), an excessive decrease in blood pressure after the initial dose may occur. In such patients, a starting dose of 5 mg or lower is recommended, and initiation of treatment should be under medical supervision.

Previous treatment with high doses of diuretics may lead to fluid depletion and a risk of hypotension at the start of enalapril therapy. In such patients, a starting dose of 5 mg or less is recommended. If possible, diuretic treatment should be discontinued 2-3 days before starting treatment with Enalapril. Renal function and serum potassium should be monitored.

The usual maintenance dose is 20 mg once daily. The maximum maintenance dose is 40 mg daily.

Heart failure/asymptomatic left ventricular dysfunction

For the treatment of clinically significant heart failure, enalapril should be used together with diuretics and, if necessary, digitalis or β-blockers. The initial dose of Enalapril for patients with clinically significant heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, while the use of the drug should be carried out under careful medical supervision in order to establish the initial effect of the drug on blood pressure. In the absence of effect or after appropriate correction of symptomatic hypotension that occurred at the beginning of treatment with enalapril for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, which is administered once or divided into 2 doses, depending on what is better tolerated by the patient. Dose selection is recommended to be carried out within 2-4 weeks. Such a therapeutic regimen effectively reduces mortality rates in patients with clinically significant heart failure. The maximum dose is 40 mg per day in 2 doses.

Suggested Enalapril Dose Titration for Patients with Heart Failure/Asymptomatic Left Ventricular Dysfunction

Table 1

* The drug should be used with caution in patients with impaired renal function or those taking diuretics (see section "Special warnings and precautions for use").

Both before and after initiation of treatment with enalapril, blood pressure and renal function should be closely monitored (see section 4.4), as hypotension and (rarely) subsequent renal failure have been reported. Patients taking diuretics should have their dose reduced if possible before initiating treatment with enalapril. The development of hypotension after the initial dose of enalapril does not mean that hypotension will persist with continued treatment and does not indicate the need to discontinue the drug. Serum potassium and renal function should also be monitored.

Dosage in renal failure

In general, the interval between enalapril doses should be increased and/or the dosage of the drug should be reduced (see Table 2).

Table 2

* See section "Special warnings and precautions for use": Patients on hemodialysis.

Enalapril is removed by hemodialysis. Dosage adjustment on days when hemodialysis is not performed should be made depending on the level of blood pressure.

Elderly patients

The dose should be adjusted depending on the status of renal function (see section "Special warnings and precautions for use").

Clinical experience with enalapril in children with hypertension is limited (see sections 5.1, 5.2, 5.3, 5.4).

For children who can swallow tablets, the dose should be individualized according to the patient's condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg for patients weighing 20 to 50 kg and 5 mg for patients weighing ≥ 50 kg. Enalapril should be taken once daily. The dosage should be adjusted as needed to a maximum of 20 mg per day for patients weighing 20 to 50 kg and 40 mg for patients weighing ≥ 50 kg (see sections 4.4 and 4.4).

Children

Use for children aged 6 and over.

Enalapril is not recommended for neonates and children with glomerular filtration rate < 30 mL/min/1.73 m2 due to lack of data.

Overdose

There are limited data on overdose. The main signs of overdose, according to available data, are pronounced arterial hypotension, which begins approximately 6 hours after taking the drug and coincides with the blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose with ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. Plasma levels of enalaprilat, which exceed 100 and 200 times the maximum levels achieved with therapeutic doses, have been reported after taking 300 mg and 440 mg of enalapril, respectively.

For the treatment of overdose, intravenous infusions of isotonic solution are recommended. If hypotension occurs, the patient should be placed in a horizontal position. The need for infusions of angiotensin II and/or intravenous administration of catecholamines may be considered. If the drug has been taken recently, measures to eliminate enalapril maleate (such as induction of vomiting, gastric lavage, administration of absorbents and sodium sulfate) are recommended. Enalaprilat can be removed from the systemic circulation by hemodialysis (see section "Special instructions": patients undergoing hemodialysis). Pacemaker therapy is indicated for bradycardia resistant to therapeutic agents. Vital signs, electrolyte concentrations and serum creatinine levels should be monitored continuously.

Adverse reactions

From the blood system: anemia (including aplastic and hemolytic), neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune diseases, leukopenia.

On the part of the endocrine system: syndrome of inappropriate antidiuretic hormone secretion.

Metabolic disorders: hypoglycemia (see section "Special warnings and precautions for use").

From the nervous system and psyche: depression, headache, confusion, drowsiness, insomnia, nervousness, paresthesia, vertigo, sleep disorders, abnormal dreams, dizziness.

On the part of the organs of vision: blurred vision, visual impairment.

Cardiovascular system: arterial hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia, orthostatic hypotension, palpitations, myocardial infarction or stroke, possibly due to excessive blood pressure reduction in high-risk patients (see section "Special warnings and precautions for use"), Raynaud's phenomenon.

Respiratory system: cough, shortness of breath, rhinorrhea, sore throat and hoarseness, bronchospasm/asthma, pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia,

pharyngitis, bronchitis, interstitial pneumonitis.

Gastrointestinal: nausea, diarrhea, abdominal pain, taste perversion, intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers, stomatitis/aphthous ulcers, glossitis, intestinal angioedema.

Hepatobiliary system: hepatic failure