Amprilan NL tablets 2.5mg/12.5mg №10×3

Name:
Amprilan NL tab 2.5mg/12.5mg in a blister. in pack. No. 10х3
Description:
Tablets of white or almost white color, flat, capsule-shaped, with a risk on one side and marking “12.5” on the other side. The main active ingredient is hydrochlorothiazide (hydrochlorothiazide) Rec.INN registered by WHO ramipril (ramipril) Rec.INN registered by WHO Release form Tablets are white or almost white, flat, capsular, scored on one side and marked “12.5” on the other side. Dosage Take orally 1 time / day daily in the morning. This combination should be used only after individual selection of doses of each of the components. The dose can be increased at intervals of at least 3 weeks. The usual starting dose is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide. The usual maintenance dose is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide or 5 mg ramipril and 25 mg hydrochlorothiazide. The recommended maximum daily dose is 5 mg of ramipril and 25 mg of hydrochlorothiazide A transient hypotensive reaction is not a contraindication for subsequent administration of the drug. In some heart failure patients with normal or low blood pressure, ramipril may cause an additional decrease in systolic blood pressure. This effect can be predicted, so it is usually not a reason to stop treatment. If arterial hypotension is manifested by symptoms, it may be necessary to reduce the dose or stop treatment. As with other ACE inhibitors, ramipril should be used with caution in patients with aortic stenosis or left ventricular ejection obstruction (eg, aortic stenosis or hypertrophic cardiomyopathy). In some cases, the hemodynamic picture may make it unacceptable to take a fixed combination of ramipril and hydrochlorothiazide. Patients with a history of angioedema unrelated to an ACE inhibitor may be at an increased risk of developing angioedema in response to an ACE inhibitor. There are reports of anaphylactoid reactions in patients on hemodialysis using membranes with high hydraulic permeability (for example, AN69) while using ACE inhibitors. In such cases, consideration should be given to using a different type of membrane or another class of antihypertensive agents. In rare cases, patients taking an ACE inhibitor during LDL apheresis with dextran sulfate develop life-threatening anaphylactoid reactions. Such reactions can be avoided by temporarily refraining from taking an ACE inhibitor before each apheresis procedure. In patients taking ACE inhibitors, against the background of desensitizing therapy (for example, hymenoptera venom), prolonged anaphylactoid reactions develop. If such patients abstained from taking ACE inhibitors for the duration of desensitization, no reactions were observed, however, accidental administration of ACE provoked an anaphylactoid reaction. The development of a rare syndrome that begins with cholestatic jaundice or hepatitis and progresses to transient liver necrosis, sometimes with a fatal outcome, is associated with the use of ACE inhibitors. The mechanism of development of this syndrome is not clear. If patients taking ramipril develop jaundice or significantly increase liver enzymes, the drug should be discontinued, leaving the patient under medical supervision until the symptoms disappear. ACE inhibitors are more likely to cause the development of angioedema in patients of the black race compared to patients of other races. Like other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients compared to people of other races, possibly due to a higher incidence of people with low renin levels in the population of black patients suffering from arterial hypertension. It has been reported that the use of ACE inhibitors may be accompanied by cough. It is characteristic that the cough is dry and persistent, disappears after discontinuation of the drug. The fact that the cough is caused by taking an ACE inhibitor should be considered its differential diagnostic sign. In patients undergoing surgery or general anesthesia with blood pressure lowering drugs, ramipril may block the increase in angiotensin II formation under the influence of compensatory renin release. If it is assumed that arterial hypotension develops by this mechanism, it can be corrected by an increase in BCC. In diabetic patients taking oral hypoglycemic agents or insulin, blood glucose levels should be closely monitored during the first month of treatment with an ACE inhibitor. It is not indicated for patients whose condition requires dialysis, since the use of ACE inhibitors against the background of dialysis using membranes that provide high current intensity is often accompanied by anaphylactoid reactions. This combination is not allowed. Hydrochlorothiazide In patients with kidney disease, thiazides can cause azotemia. Taking medications against the background of impaired renal function can lead to cumulative effects. If renal failure progresses, characterized by an increase in non-protein nitrogen, the need for therapy should be carefully evaluated and the possibility of discontinuing diuretics should be considered. In patients with impaired or progressive hepatic impairment, thiazides should be administered with caution, since even slight fluctuations in the water and electrolyte balance can cause hepatic coma. Thiazide therapy may decrease glucose tolerance. In diabetes mellitus, it may be necessary to adjust the dose of insulin or oral hypoglycemic agents. Therapy with thiazides can cause the manifestation of latent diabetes mellitus. An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy. Some patients receiving thiazide diuretics may experience an increase in uric acid levels or manifestations of gout. In some patients, thiazide therapy may increase uric acid levels and/or cause gout. However, ramipril may increase the excretion of uric acid, thus attenuating the degree of increase in uric acid levels caused by hydrochlorothiazide. Thiazides, incl. hydrochlorothiazide, can cause a violation of the water and electrolyte balance (hypokalemia, hyponatremia and hypochloremic alkalosis). Symptoms of fluid and electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, myalgia or muscle spasms, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea and vomiting. Although the use of thiazide diuretics can lead to the development of hypokalemia, while taking ramipril, it is possible to reduce the severity of hypokalemia caused by diuretics. The likelihood of developing hypokalemia is highest in cirrhosis of the liver, in patients with increased diuresis, with inadequate oral intake of electrolytes, as well as during treatment with corticosteroids and ACTH. Thiazides can reduce the excretion of calcium ions in the urine, leading to a slight periodic increase in the level of calcium in the blood, even in the absence of obvious disorders of calcium metabolism. Overt hypercalcemia may indicate latent hyperparathyroidism. Thiazides should be discontinued until the results of the study of the function of the parathyroid glands. Thiazides have been shown to increase renal excretion of magnesium, which can lead to a decrease in blood magnesium levels. The combination of fixed doses of ramipril and hydrochlorothiazide should be discontinued if neutropenia (neutrophil count less than 1000/µl) occurs or is suspected. Hydrochlorothiazide may give a positive reaction in anti-doping controls. Influence on the ability to drive vehicles and mechanisms Possibly a slight or moderate effect on the ability to drive a car and work with mechanisms. Due to differences in individual reactions, some patients may be impaired in the ability to drive a car, operate machinery, and perform other types of work that require increased attention. This is especially pronounced at the beginning of treatment and / or after increasing the dosage. Pharmacological action Combined antihypertensive drug, which includes the ACE inhibitor ramipril and the thiazide diuretic hydrochlorothiazide. It has antihypertensive and diuretic effects. It has antihypertensive and diuretic effects. The hypotensive effect of both components is almost additive. Ramipril is an ACE inhibitor. It is a prodrug, in the body it turns into the active metabolite ramiprilat, which has an inhibitory effect on ACE. ACE catalyzes the conversion of angiotensin I in tissues into the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. A decrease in the amount of angiotensin II and suppression of the breakdown of bradykinin leads to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in the release of aldosterone. Ramipril reduces OPSS. Reception of ramipril by patients with arterial hypertension reduces blood pressure in the standing and lying position without a compensatory increase in heart rate. In most patients, the antihypertensive effect appears 1-2 hours after taking a single dose. The severity of the effect reaches a maximum after 3-6 hours after administration. As a rule, the antihypertensive effect after a single dose persists for 24 hours. With prolonged treatment with ramipril, the maximum antihypertensive effect is usually achieved after 2-4 weeks. It has been shown that with long-term therapy, the antihypertensive effect can be maintained for 2 years. Abrupt discontinuation of ramipril does not lead to a rapid and excessive increase in blood pressure. As a rule, there are no significant changes in the rate of renal blood flow and glomerular filtration. Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chlorine, potassium, magnesium, and water ions in the distal nephron; delays the excretion of calcium ions, uric acid. Has antihypertensive properties; hypotensive effect develops due to the expansion of arterioles. Virtually no effect on the normal level of blood pressure. The excretion of electrolytes and water begins approximately 2 hours after administration, the maximum effect is achieved in 3-6 hours and lasts for 6-12 hours. The antihypertensive effect is achieved in 3-4 days of treatment and lasts for 1 week after the completion of the drug. With long-term treatment, a decrease in blood pressure is achieved using smaller doses than those necessary for a diuretic effect. The decrease in blood pressure is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance and renin activity in blood plasma. Hydrochlorothiazide at a single dose in high doses leads to a decrease in plasma volume, GFR, renal blood flow and mean blood pressure. With long-term use in small doses, the volume of blood plasma remains reduced, while the minute volume and glomerular filtration rate return to the initial level preceding the start of treatment. Mean blood pressure and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with breast milk production. Pharmacokinetics Ramipril After oral administration, ramipril is rapidly absorbed. Judging by the radioactivity determined in the urine after ingestion of labeled ramipril (renal excretion is only one of several routes), at least 56% of the drug is absorbed. Simultaneous ingestion of food does not affect absorption. Ramipril is a prodrug that undergoes first-pass metabolism through the liver, resulting in the formation (due to hydrolysis, mainly in the liver) of the only active metabolite ramiprilat. In addition to being converted to the active metabolite ramiprilat, ramipril is conjugated with glucuronic acid and converted to the diketopiperazine ester of ramipril. Ramiprilat also undergoes conjugation with glucuronic acid and is converted into diketopiperazine-ramiprilat (acid). Due to the activation/metabolism of ramipril, the bioavailability after oral administration is approximately 20%. Cmax of ramipril in plasma is achieved within 1 hour after ingestion. Cmax of ramiprilat in plasma is achieved within 2-4 hours after oral administration of ramipril. Plasma protein binding for ramipril and ramiprilat is approximately 73% and 56%, respectively. In experimental studies, it was found that ramipril is excreted in breast milk. T1 / 2 of ramipril is 5.1 hours. The decrease in the concentration of ramiprilat in the blood plasma has a multiphase character. The initial distribution and elimination phase is characterized by a T1 / 2 of about 3 hours. This is followed by an intermediate phase (T1 / 2 of about 15 hours) and a final phase during which plasma concentrations of ramiprilat are very low (T1 / 2 – 4-5 days ). This final phase is due to the slow dissociation of ramiprilat from strong but saturated complexes with ACE. Despite the length of the elimination phase, Css of ramipril is achieved in about 4 days with a daily intake of 2.5 mg or more of ramipril. The effective T1 / 2 (a parameter related to the choice of dose) is 13-17 hours after taking several doses. After ingestion of 10 mg of labeled ramipril, about 40% of the radioactivity is excreted through the intestines and 60% by the kidneys. Within 24 hours after ingestion of 5 mg of ramipril by patients with a catheter that removes the formed bile, equal amounts of excretion of ramipril and its metabolites by the kidneys and bile were found. Approximately 80-90% of the metabolites excreted by the kidneys and bile were represented by ramiprilat and drugs for its further metabolism. The share of glucuronide and diketopiperazine derivative of ramipril accounted for approximately 10-20%, and unmetabolized ramipril accounted for approximately 2% of the total amount of ramipril. Hydrochlorothiazide After oral administration, Cmax of hydrochlorothiazide is achieved within 1-3 hours. Absolute bioavailability is estimated from the cumulative renal excretion of hydrochlorothiazide and is about 60%. Plasma protein binding is 40-70%. Vd – 0.8±0.3 l/kg. It is not metabolized in the human body and is excreted in the urine almost unchanged. About 60% of the dose taken orally is excreted within 48 hours. Renal clearance is about 250-300 ml / min. T1 / 2 – 10-15 hours. There is a difference in plasma concentrations in men and women. Women tend to have a clinically significant increase in plasma concentrations of hydrochlorothiazide. In patients with impaired renal function, the rate of elimination of hydrochlorothiazide is reduced. Studies conducted with the participation of patients with CC 90 ml / min showed that T1 / 2 of hydrochlorothiazide increases. In patients with reduced renal function, T1 / 2 is about 34 hours. Ramipril and hydrochlorothiazide Simultaneous administration of ramipril and hydrochlorothiazide does not affect the bioavailability of each of the components. Indications for use Arterial hypertension. Chronic heart failure (as part of combination therapy), incl. developed on days 2–9 after myocardial infarction. Diabetic nephropathy and nephropathy against the background of chronic diffuse kidney diseases (preclinical and clinical stages), incl. chronic glomerulonephritis with severe proteinuria. Reducing the risk of myocardial infarction, stroke and cardiovascular mortality in patients with high cardiovascular risk, including patients with confirmed coronary heart disease (with or without a history of myocardial infarction), patients undergoing percutaneous transluminal coronary angioplasty, coronary bypass grafting, with a history of stroke and patients with occlusive lesions of peripheral arteries. Use during pregnancy and lactation The drug Amprilan® is contraindicated for use during pregnancy, because. it can have adverse effects on the fetus (including impaired renal function, hyperkalemia, hypoplasia of the skull bones, hypoplasia of the lungs). Therefore, before starting the use of the drug Amprilan® in women of childbearing age, pregnancy should be excluded. When diagnosing pregnancy, Amprilan® should be discontinued as soon as possible. If necessary, the use of the drug Amprilan® during lactation, breastfeeding should be discontinued. Dosage and administration Inside, whole, without chewing, regardless of the meal, drinking plenty of fluids. The dose is selected depending on the therapeutic effect and tolerability of the drug by the patient. Treatment with Amprilan® is long-term, its duration in each case is determined by the doctor. Arterial hypertension: the recommended initial dose of Amprilan® is 2.5 mg once a day. Depending on the response of the patient, the dose may be doubled at 1-2 week intervals. The usual maintenance dose is 2.5–5 mg/day, with a maximum daily dose of 10 mg. Patients taking diuretics should cancel or reduce their dose at least 3 days before starting Amprilan®. CHF: the recommended initial dose of Amprilan® is 1.25 mg 1 time per day. Depending on the therapeutic effect, the dose may be doubled with an interval of 1-2 weeks. The maximum daily dose is 10 mg. In patients receiving large doses of diuretics, before starting therapy with Amprilan®, the dose of diuretics should be reduced. Heart failure that developed within a few days (from 2 to 9 days) after acute myocardial infarction: the recommended initial dose is 5 mg / day, divided into 2 single doses of 2.5 mg (Table 1), one of which is taken in the morning, and the second – in the evening. If the patient does not tolerate the initial dose (an excessive decrease in blood pressure is observed), it should be reduced to 1.25 mg 2 times a day. Then, depending on the response of the patient, the dose may be doubled again (2.5 mg) at intervals of 1-3 days. Later, the daily dose, which was initially divided by two, can be given once. The maximum daily dose is 10 mg. If the patient does not tolerate a dose increase to 2.5 mg 2 times a day, then treatment with the drug should be discontinued. Diabetic nephropathy and nephropathy on the background of chronic diffuse kidney diseases: the recommended initial dose of Amprilan® is 1.25 mg 1 time per day. Depending on the patient’s tolerance to ramipril, the dose of the drug may further increase: it is recommended to double the dose every 2 weeks to a maintenance dose of 5 mg 1 time per day. Reducing the risk of myocardial infarction, stroke and cardiovascular mortality: the recommended initial dose of Amprilan® is 2.5 mg 1 time per day, which subsequently gradually increases depending on the tolerability of the drug: it is recommended to double the dose after 1 week of therapy, and then again after 2-3 weeks – until the target maintenance dose of 10 mg 1 time per day is reached. Special groups of patients. Renal dysfunction: in patients with Cl creatinine more than 30 ml / min, dose adjustment is not required. For patients with Cl creatinine less than 30 ml / min, the initial daily dose is 1.25 mg, and the maximum daily dose is 5 mg. Liver dysfunction. The initial dose is 1.25 mg once a day. The maximum dose is 2.5 mg once a day. Elderly patients: Careful monitoring of elderly patients (over 65 years of age) taking diuretics is necessary. The dose of Amprilan® should be selected depending on the level of blood pressure. Application during pregnancy and lactation Use during pregnancy and lactation (breastfeeding) is contraindicated. Precautions Interaction with other drugs Vasopressor sympathomimetics (epinephrine, norepinephrine) may reduce the hypotensive effect of ramipril. With the simultaneous use of these drugs, blood pressure levels should be carefully monitored. ACE inhibitors enhance the inhibitory effect of ethanol on the central nervous system. Lithium preparations: with the simultaneous use of lithium preparations and ACE inhibitors, cases of a reversible increase in the concentration of lithium in the blood serum have been reported. Simultaneous use with thiazide diuretics may increase the concentration of lithium and the risk of its toxic effect while taking an ACE inhibitor. NSAIDs: a combination of ACE inhibitors with NSAIDs (non-selective COX-1 and COX-2 inhibitors from the NSAID group, for example, acetylsalicylic acid in doses that have an anti-inflammatory effect): the hypotensive effect of ACE inhibitors decreases; increases the risk of impaired renal function, up to the development of acute renal failure; increases the content of potassium in the blood serum in patients with pre-existing impaired renal function. Tricyclic antidepressants, antipsychotics (neuroleptics): increase the hypotensive effect and increase the risk of orthostatic hypotension (additive effect). GCS, tetracosactide: decrease in the hypotensive effect (fluid retention). Potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone) and potassium preparations: The combined use of ramipril and potassium-sparing diuretics, as well as potassium preparations and potassium-containing table salt substitutes, is not recommended. Caution should be exercised and regular monitoring of the content of potassium in the blood plasma and ECG parameters should be carried out. Oral hypoglycemic agents (sulfonylurea derivatives) and insulin: The use of ACE inhibitors may increase the hypoglycemic effect of oral hypoglycemic agents and insulin in patients with diabetes mellitus; with their combined use, an increase in glucose tolerance is possible, which may require dose adjustment of hypoglycemic agents for oral administration and insulin. Allopurinol, cytostatic drugs, immunosuppressants, corticosteroids (with systemic use) and procainamide: the simultaneous use of these drugs with ACE inhibitors may increase the risk of developing leukopenia. General anesthetics: ACE inhibitors may increase the hypotensive effect of some general anesthetics. Gold preparations: when prescribing ACE inhibitors, incl. ramipril, patients receiving a gold preparation (sodium aurothiomalate) intravenously experienced nitrate-like reactions (nausea, vomiting, a pronounced decrease in blood pressure, flushing of the skin of the face). Contraindications Hypersensitivity to ramipril and any other component of the drug or other ACE inhibitors. Angioedema in history (hereditary, idiopathic or angioedema due to the use of ACE inhibitors). Hemodynamically significant bilateral stenosis of the renal arteries. Stenosis of the artery of a single kidney. Condition after kidney transplantation. Hemodialysis. Renal failure (Cl creatinine Hemodynamically significant aortic and / or mitral stenosis (risk of excessive decrease in blood pressure with subsequent impaired renal function). Hypertrophic obstructive cardiomyopathy (GOKMP). Chronic heart failure in the stage of decompensation. Severe arterial hypotension (BP less than 90 mm Hg. Art. .) or unstable hemodynamics Primary hyperaldosteronism Galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome Nephropathy treated with corticosteroids, NSAIDs, immunomodulators and / or cytostatics Pregnancy Lactation period Age up to 18 years (efficacy and safety not with caution: severe lesions of the coronary and cerebral arteries (danger of reducing blood flow with an excessive decrease in blood pressure); malignant arterial hypertension; unstable angina pectoris; aortic and / or mitral stenosis; severe ventricular arrhythmias; chronic heart failure st (IV functional class according to NYHA classification); decompensated cor pulmonale; renal and / or liver failure; hyperkalemia; hyponatremia (including against the background of diuretics and a diet with limited salt intake); conditions accompanied by a decrease in BCC, incl. diarrhea, vomiting; systemic connective tissue diseases; diabetes; oppression of bone marrow hematopoiesis; elderly age; hemodialysis using high-flow polyacrylonitrile membranes – the risk of developing anaphylactoid reactions; before the LDL apheresis procedure; simultaneous desensitizing therapy with allergens (for example, hymenoptera venom). Composition Active ingredient: ramipril – 2.5 mg, hydrochlorothiazide 12.5. Excipients: sodium bicarbonate – 2.5 mg; lactose monohydrate – 155 mg; croscarmellose sodium – 4 mg; pregelatinized starch – 30 mg; sodium stearyl fumarate – 2 mg, a mixture of dyes “PB 22886 yellow” (lactose monohydrate, iron dye yellow oxide (E172) – 4 mg. Overdose Symptoms: pronounced decrease in blood pressure, bradycardia, shock, impaired water and electrolyte balance, acute renal failure, stupor. Treatment: in mild cases of overdose – gastric lavage, the appointment of adsorbents and sodium picosulfate (preferably within 30 minutes after ingestion).In case of a pronounced decrease in blood pressure – intravenous administration of catecholamines, alpha1-adrenergic agonists (norepinephrine, dopamine), angiotensin II ( angiotensinamide), the patient should be laid supine on a surface with a low headboard, if necessary, the BCC can be replenished by infusion of 0.9% sodium chloride solution; in case of bradycardia, a temporary artificial pacemaker can be placed. Blood pressure, kidney function and potassium levels should be carefully monitored in blood serum.The effectiveness of hemodialysis has not been established.Side effectsClassification of the frequency of development side effects (WHO): Very often -? 1/10. Often – from? 1/100 to Infrequently – from? 1/1000 to <1/100. Rarely - from? 1/10000 to <1/1000. Very rarely - from < 1/10000, including individual messages. From the side of the cardiovascular system: often - a pronounced decrease in blood pressure (at the beginning of therapy, with an increase in the dose or addition of a diuretic to therapy), orthostatic hypotension, syncope; rarely - peripheral edema, palpitations, angina pectoris, arrhythmia; very rarely - myocardial ischemia, myocardial infarction, increased circulatory disorders against the background of stenosing vascular lesions, Raynaud's syndrome, vasculitis, tachycardia, flushing of the skin of the face. From the nervous system: often - headache, weakness; rarely - increased fatigue, nervousness, depression, tremor, imbalance, confusion, anxiety, dizziness, restlessness, sleep disorder; very rarely - paresthesia, impaired odor perception (parosmia), transient ischemic attacks, ischemic stroke, cerebral ischemia, impaired concentration. From the genitourinary system: rarely - transient impotence, decreased libido, impaired renal function, up to acute renal failure, increased urine output, increased pre-existing proteinuria, increased urea and creatinine concentrations; very rarely - gynecomastia. On the part of the respiratory system: often - dry non-productive cough, aggravated at night and in the supine position, more common in women and non-smokers, sinusitis, bronchitis, shortness of breath; rarely - nasal congestion, pharyngitis, bronchospasm, including aggravation of the course of bronchial asthma. From the side of the skin: often - maculopapular skin rash; rarely - pruritus, excessive sweating (against the background of a decrease in blood pressure); very rarely - maculopapular exanthema and erythema, pemphigus, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, worsening of psoriasis, psoriasis, pemphigoid and lichenoid lesions of the skin and mucous membranes, alopecia; very rarely - urticaria, onycholysis, exfoliative dermatitis, photosensitivity. From the digestive system: often - inflammation of the gastrointestinal mucosa, indigestion, discomfort in the abdomen, dyspepsia, nausea, diarrhea, vomiting; rarely - increased activity of liver enzymes, increased bilirubin concentration, cholestatic jaundice, acute liver failure, cholestatic hepatitis, hepatocellular lesions, dryness of the oral mucosa, abdominal pain, gastritis, constipation, pancreatitis, incl. and fatal (cases of fatal pancreatitis when taking ACE inhibitors were extremely rare), intestinal angioedema, loss of appetite, anorexia; very rarely - glossitis; aphthous stomatitis. From the musculoskeletal system: often - myalgia, muscle cramps; rarely - arthralgia. From the sensory organs: rarely - visual disorders, including blurred vision, conjunctivitis, hearing impairment, olfactory and taste disorders (for example, a metallic taste, partial or temporary loss of taste sensations). Allergic reactions: very rarely - angioedema involving the mucous membrane of the lips, eyes, tongue, larynx and pharynx, anaphylactic or anaphylactoid reactions (insect poisons), increased concentration of antinuclear bodies. Laboratory indicators: rarely - hyperkalemia, moderate (sometimes severe) hypohemoglobinemia or neutropenia, erythropenia and thrombocytopenia, increased activity of pancreatic enzymes; very rarely - hyponatremia, proteinuria (although usually ACE inhibitors reduce previous proteinuria) or increased diuresis (in combination with worsening heart function), agranulocytosis, pancytopenia, bone marrow depression, hemolytic anemia. Others: rarely - hyperthermia; very rarely - fever. Special instructions At the beginning of treatment, it is necessary to evaluate the function of the kidneys. It is necessary to carefully monitor renal function in patients with impaired renal function, heart failure, bilateral renal artery stenosis or stenosis of the artery of a single kidney, as well as in patients after kidney transplantation. Liver failure In rare cases, cholestatic jaundice occurs during the use of ACE inhibitors, with the progression of which develops fulminant liver necrosis, sometimes with a fatal outcome. With the appearance of jaundice or a significant increase in the activity of hepatic transaminases while taking ACE inhibitors, the use of the drug Amprilan® should be discontinued. In patients with uncomplicated arterial hypertension after taking the first dose of the drug, symptomatic arterial hypotension rarely develops. The risk of arterial hypotension is increased in the following patients: With severe CHF: treatment begins with the lowest possible dose of Amprilan® (1.25 mg). Taking diuretics: if possible, it is necessary to cancel the diuretic in advance or reduce its dose; treatment begins with the minimum dose of the drug Amprilan® (1.25 mg). With the risk of developing hypovolemia due to insufficient fluid intake, diarrhea, vomiting or excessive sweating in conditions of insufficient compensation for the loss of salt and fluid. It is usually recommended to adjust the BCC before starting treatment, but if these conditions become clinically significant, treatment with Amprilan® can be started and / or continued with a minimum dose (1.25 mg) and under medical supervision. Aortic stenosis/mitral stenosis/HOCM ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and aortic and/or mitral stenosis. Neutropenia/agranulocytosis Patients taking ACE inhibitors may experience neutropenia/agranulocytosis, thrombocytopenia, and anemia. In patients with normal renal function in the absence of other complications, neutropenia rarely develops and resolves spontaneously after discontinuation of ACE inhibitors. Ramipril should be used with great caution in patients with connective tissue disease and concomitantly receiving immunosuppressive therapy, allopurinol or procainamide, especially in existing renal dysfunction. These patients may develop severe infections that are not amenable to intensive antibiotic therapy. In the case of the use of ramipril, it is recommended to periodically monitor the number of leukocytes in the blood. The patient should be warned that in case of any signs of an infectious disease (sore throat, fever), you should immediately consult a doctor. Hyperkalemia May develop during treatment with ACE inhibitors, incl. and ramipril. Risk factors for hyperkalemia are renal failure, advanced age, diabetes mellitus, some concomitant conditions (decrease in BCC, acute heart failure in the stage of decompensation, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as drugs potassium or potassium-containing table salt substitutes and the use of other drugs that increase the content of potassium in the blood plasma (for example, heparin). Hyperkalemia can lead to serious heart rhythm disturbances, sometimes fatal. Potassium-sparing diuretics and potassium preparations The combined use of the drug Amprilan® and potassium-sparing diuretics, as well as potassium preparations and potassium-containing table salt substitutes is not recommended. Surgery/General Anesthesia The use of ACE inhibitors in patients undergoing surgery under general anesthesia can lead to a pronou