Prestilol® [Bisoprolol, Perindopril]

Pharmacological properties

Pharmacodynamics

Mechanism of action

Bisoprolol. Bisoprolol is a highly selective β blocker₁-adrenoreceptors, has no internal sympathomimetic and pronounced membrane-stabilizing activity. It has a low affinity for β₂receptors of smooth muscles of the bronchi and blood vessels, as well as to β₂-receptors responsible for the regulation of metabolism. Therefore, bisoprolol as a whole should not affect airway resistance and β₂-mediated metabolic effects. His β₁-selectivity extends beyond therapeutic dosing.

Perindopril. Perindopril is an enzyme inhibitor that converts angiotensin I to angiotensin II (ACE). A converting enzyme, or kinase, is an exopeptidase that makes it possible to convert angiotensin I into a vasoconstrictor angiotensin II, and also causes the breakdown of the bradykinin vasodilator to an inactive heptapeptide. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in blood plasma, which increases the activity of renin in blood plasma (by inhibiting the negative feedback of renin release) and reduces the secretion of aldosterone. Since ACE inactivates bradykinin, ACE inhibition also leads to increased activity of the circulating and local kallikrein-kinin system (and, thus, also leads to activation of the prostaglandin system). This mechanism of action leads to a decrease in blood pressure by ACE inhibitors and is partially responsible for the appearance of some side effects (for example, cough).

Perindopril acts through its active metabolite - perindoprilat. Other metabolites do not show activity in ACE inhibition in vitro.

Pharmacodynamic effects

Bisoprolol. Bisoprolol does not have a pronounced negative inotropic effect. The maximum effect of bisoprolol is achieved 3-4 hours after application. Thanks T_½, which is 10-12 hours, bisoprolol retains a therapeutic effect for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved after 2 weeks of use.

When used once in patients with coronary heart disease without chronic heart failure, bisoprolol reduces heart rate and stroke volume of blood and, thus, reduces cardiac output and oxygen consumption. With prolonged use, initially increased peripheral resistance decreases. A decrease in plasma renin activity is likely to cause the antihypertensive effect of β-adrenergic receptor blockers.

Bisoprolol reduces the sympathoadrenergic reaction by blocking the β-adrenergic receptors of the heart, which leads to a decrease in heart rate and contractility. This, in turn, leads to a decrease in oxygen consumption by the myocardium, which is necessary in the treatment of angina pectoris in coronary heart disease.

Perindopril. Perindopril effectively reduces blood pressure in all degrees of hypertension (mild, moderate and severe), a decrease in systolic and diastolic blood pressure is observed in the patient both in the supine position and in the standing position.

Perindopril reduces the resistance of peripheral vessels, which leads to a decrease in blood pressure. As a result, peripheral blood flow increases without affecting heart rate.

As a rule, renal blood flow also increases, while the glomerular filtration rate (GFR) usually does not change.

The maximum antihypertensive effect develops 4–6 hours after a single dose and lasts at least 24 hours: the residual effect is about 87–100% of the peak effect.

Blood pressure decreases rapidly. In patients who responded to treatment, normalization of blood pressure occurs within 1 month and persists without the occurrence of tachyphylaxis. Discontinuation of treatment is not accompanied by a withdrawal effect. Perindopril reduces left ventricular hypertrophy.

Clinical studies have shown that perindopril has vasodilating properties.It improves the elasticity of large arteries and reduces the ratio of wall thickness to the lumen of the vessel for small arteries.

Perindopril reduces the work of the heart by reducing pre- and afterload on the heart: it reduces the filling pressure of the left and right ventricles, reduces the heart rate, increases cardiac output and improves the cardiac index (according to research).

Pharmacokinetics The rate and degree of absorption of bisoprolol and perindopril in the composition of the drug Prestilol does not significantly differ from those of bisoprolol and perindopril when used separately in monotherapy.

Bisoprolol

Absorption. Bisoprolol is almost completely (90%) absorbed in the digestive tract. The effect of the first passage through the liver is slightly expressed (about 10%), which leads to high bioavailability (about 90%) after oral administration.

Distribution. The volume of distribution is 3.5 l / kg body weight. The binding of bisoprolol to plasma proteins is about 30%.

Biotransformation and excretion. Bisoprolol is excreted from the body in two ways: 50% is metabolized in the liver to inactive metabolites, which are then excreted by the kidneys, and the remaining 50% are excreted by the kidneys in a non-metabolized form. The total clearance is about 15 l / h. T_½ from blood plasma is 10-12 hours, which leads to a 24-hour effect after taking 1 time per day.

The kinetics of bisoprolol is linear and does not depend on age.

Since the excretion of bisoprolol from the body is carried out equally by the kidneys and liver, patients with impaired liver function or renal insufficiency do not need dose adjustment. The pharmacokinetics in patients with chronic heart failure and impaired liver or kidney function has not been studied. In patients with chronic heart failure (NYHA functional class III), plasma bisoprolol levels are higher and T_½ longer compared to healthy volunteers. At a daily dose of 10 mg C_max in the blood plasma in equilibrium is 64 ± 21 ng / ml, and T_½ - 17 ± 5 hours

Perindopril

Absorption. After oral administration, perindopril is rapidly absorbed, C_max reached after 1 h. T_½ perindopril from blood plasma is 1 hour.

Distribution. The volume of distribution of unbound perindoprilat is about 0.2 l / kg. The binding of perindoprilat to plasma proteins is 20%, mainly with ACE, and is dose-dependent.

Biotransformation. Perindopril is a prodrug. 27% of the accepted dose of perindopril enters the bloodstream as an active metabolite of perindoprilat. In addition to active perindoprilat, perindopril forms another 5 inactive metabolites. C_max perindoprilat in plasma is reached after 3-4 hours

Since eating reduces the conversion of perindopril to perindoprilat, and therefore its bioavailability decreases, perindopril arginine is recommended to be taken orally in a single dose in the morning before meals.

Perindoprilat is excreted in the urine; the final half-life of the unbound fraction is about 17 hours. The equilibrium state is reached after 4 days.

Linearity. There is a linear relationship between the dose of perindopril and its concentration in blood plasma.

Excretion of perindoprilat slows down in elderly patients, as well as in patients with heart or kidney failure. It is recommended to select a dose for patients with renal failure, taking into account the degree of renal failure (creatinine clearance). The dialysis clearance of perindoprilat is 70 ml / min. The kinetics of perindopril changes in patients with cirrhosis, the hepatic clearance of the main molecule is halved. However, the amount of perindoprilat formed does not decrease. Therefore, such patients do not need to correct the dose (see APPLICATION and SPECIAL INSTRUCTIONS).

Indications

Prestilol 5 mg / 10 mg and prestilol 10 mg / 10 mg are indicated for the treatment of ag and / or stable coronary artery disease (with a history of myocardial infarction and / or revascularization) in adult patients who require therapy with bisoprolol and perindopril at doses available in fixed combinations.

Prestilol 5 mg / 5 mg and Prestilol 10 mg / 5 mg are indicated for the treatment of hypertension and / or stable coronary artery disease (with a history of myocardial infarction and / or revascularization) and / or stable chronic heart failure with decreased systolic function of the left ventricle in adults patients who need therapy with bisoprolol and perindopril in doses available in a fixed combination.

Application

Dosage usual dose - 1 tablet 1 time per day in the morning before meals. the health status of patients should be stable when using equivalent doses of bisoprolol and perindopril for at least 4 weeks. a fixed combination is not intended for initial therapy.

Patients stabilized with the use of 2.5 mg of bisoprolol and 2.5 mg of perindopril are recommended ½ tablets of 5 mg / 5 mg once a day.

Patients stabilized with the use of 2.5 mg bisoprolol 5 mg perindopril are recommended ½ tablets 5 mg / 10 mg once a day.

If necessary, change the dose should be an individual selection of doses of each of the components of the drug.

Prestilol 5 mg / 5 mg and Prestilol 5 mg / 10 mg tablets have a notch for separation into two parts.

Special patient groups

Impaired renal function (see SPECIAL INSTRUCTIONS and Pharmacokinetics). Prestilol 5 mg / 5 mg is unacceptable for use in patients with severe renal failure (creatinine clearance 30 ml / min). For such patients, an individual dose selection of each of the components is recommended. For patients with moderate renal failure (creatinine clearance - 30-60 ml / min), the recommended dose of perindopril is 2.5 mg / day. Therefore, ½ tablets of the drug Prestilol 5 mg / 5 mg are used once a day. Prestilol 5 mg / 5 mg can be used in patients with creatinine clearance ≥60 ml / min.

Prestilol 5 mg / 10 mg and Prestilol 10 mg / 5 mg: for patients with creatinine clearance ≥60 ml / min, the recommended daily dose of Prestilol 5 mg / 10 mg is ½ tablet, and Prestilol 10 mg / 5 mg - 1 tablet. Prestilol 5 mg / 10 mg and Prestilol 10 mg / 5 mg are not suitable for use in patients with creatinine clearance of 60 ml / min (moderate and severe renal failure). For such patients, an individual dose selection of each of the components is recommended.

Prestilol 10 mg / 10 mg is unacceptable for use in patients with renal failure. For such patients, an individual dose selection of each of the components is recommended.

Impaired liver function (see SPECIAL INSTRUCTIONS and Pharmacokinetics). Patients with impaired liver function do not require dose selection.

Elderly patients. The use of the drug Prestilol is possible taking into account the function of the kidneys.

Children. The safety and effectiveness of the use of the drug Prestilol in children (under the age of 18 years) have not been established. No data available. Therefore, it is contraindicated to use the drug in children (under the age of 18 years).

Contraindications

• Hypersensitivity to the active substances or any of the excipients or any other inhibitors of APF; acute heart failure or heart failure in the stage of decompensation, which requires iv inotropic therapy; cardiogenic shock; av- block II or III degree (without artificial pacemaker); sick sinus syndrome; sinoatrial block; symptomatic bradycardia; symptomatic arterial hypotension; severe ba or severe hobl; a severe form of obliterating disease of the peripheral arteries or a severe form of Raynauds syndrome; untreated pheochromocytoma (see special instructions); metabolic acidosis; a history of angioedema associated with prior therapy with APF inhibitors; hereditary or idiopathic angioedema; pregnancy or pregnancy planning (see use during pregnancy and lactation); concomitant use with drugs containing aliskiren in patients with diabetes mellitus or renal failure (SCF 60 ml / min / 1.73 m2) (see special instructions, interactions).

Side effects

The most common adverse reactions observed with bisoprolol are headache, dizziness, worsening heart failure, hypotension, a feeling of coldness in the extremities, nausea, vomiting, abdominal pain, diarrhea, constipation, asthenia, and fatigue.

The most common adverse reactions noted during clinical trials using perindopril are headache, dizziness, vertigo, paresthesia, visual impairment, tinnitus, hypotension, cough, dyspnea, nausea, vomiting, abdominal pain, diarrhea, constipation, taste disturbance (dysgeusia), dyspepsia, rash, itching, muscle cramps and asthenia.

During clinical trials and / or post-marketing observations with bisoprolol or perindopril, which were used separately, the following adverse reactions were reported, which are classified by MedDRA organ system classes and frequency: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000, 1/1000); very rarely (1/10 000); frequency is unknown (cannot be determined from the available information).

Infections and infestations: rhinitis (bisoprolol - rarely, perindopril - very rare).

From the blood system and lymphatic system: eosinophilia (perindopril - infrequently *); agranulocytosis (perindopril - very rare); pancytopenia (perindopril - very rare); leukopenia (perindopril - very rare); neutropenia (perindopril - very rare); thrombocytopenia (perindopril - very rare); hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency (perindopril is very rare).

From the side of metabolism and metabolism: hypoglycemia (perindopril - infrequently *); hyperkalemia, reversible when the active substance is canceled (perindopril - infrequently *); hyponatremia (perindopril - infrequently *).

From the psyche: mood changes (perindopril - infrequently); sleep disturbances (bisoprolol - infrequently, perindopril - infrequently); depression (bisoprolol - infrequently); nightmares, hallucinations (bisoprolol - rarely); confusion (perindopril - very rare).

From the nervous system: headache ** (bisoprolol - often, perindopril - often); dizziness ** (bisoprolol - often, perindopril - often); vertigo (perindopril - often); taste disturbance (dysgeusia) (perindopril - often); paresthesia (perindopril - often); drowsiness (perindopril - infrequently *); fainting (bisoprolol - rarely, perindopril - infrequently *).

From the side of the organ of vision: visual impairment (perindopril - often); decreased lacrimation (should be taken into account when wearing contact lenses) (bisoprolol is rare); conjunctivitis (bisoprolol is very rare).

From the side of the organ of hearing and balance: ringing in the ears (perindopril - often); hearing impairment (bisoprolol - rarely).

From the side of the heart: palpitation (perindopril - infrequently *); tachycardia (perindopril - infrequently *); bradycardia (bisoprolol - very often); worsening heart failure (bisoprolol - often); violation of AV conduction (bisoprolol - infrequently); arrhythmia (perindopril - very rare); angina pectoris (perindopril - very rare); myocardial infarction can occur due to an excessive decrease in blood pressure in patients at high risk (perindopril is very rare).

From the vascular system: hypotension and related symptoms (bisoprolol - often, perindopril - often); feeling of cold or numbness of the extremities (bisoprolol - often); orthostatic hypotension (bisoprolol - infrequently); vasculitis (perindopril - infrequently *); a stroke, possibly due to an excessive decrease in blood pressure in patients at high risk (perindopril is very rare).

From the respiratory system, chest and mediastinal organs: cough (perindopril - often); dyspnea (perindopril - often); bronchospasm (bisoprolol - infrequently, perindopril - infrequently); eosinophilic pneumonia (perindopril - very rare).

From the digestive system: abdominal pain (bisoprolol - often, perindopril - often); constipation (bisoprolol - often, perindopril - often); diarrhea (bisoprolol - often, perindopril - often); nausea (bisoprolol - often, perindopril - often); vomiting (bisoprolol - often, perindopril - often); dyspepsia (perindopril - often); dry mouth (perindopril - infrequently); pancreatitis (perindopril - very rare).

From the hepatobiliary system: cytolytic or cholestatic hepatitis (bisoprolol - rarely, perindopril - very rare).

On the part of the skin and subcutaneous tissue: rash (perindopril - often); itching (perindopril - often); angioedema of the face, limbs, lips, mucous membrane, tongue, glottis and / or larynx (perindopril - infrequently); urticaria (perindopril - infrequently); photosensitivity reactions (perindopril - infrequently *); pemphigoid (perindopril - infrequently *); hyperhidrosis (perindopril - infrequently); hypersensitivity reactions - itching, redness, rash (bisoprolol - rarely); erythema multiforme (perindopril - very rare); alopecia (bisoprolol - very rare); β-adrenoreceptor blockers can cause or exacerbate psoriasis, provoke psoriatic rashes (bisoprolol is very rare).

From the musculoskeletal system and connective tissue: muscle cramps (bisoprolol - infrequently, perindopril - often); muscle weakness (bisoprolol - infrequently); arthralgia (perindopril - infrequently *); myalgia (perindopril - infrequently *).

From the kidneys and urinary tract: renal failure (perindopril - infrequently); ARF (perindopril - very rare).

From the reproductive system and mammary glands: erectile dysfunction (perindopril - infrequently); violation of potency (bisoprolol - rarely).

General disorders: asthenia (bisoprolol - often, perindopril - often); fatigue (bisoprolol - often); chest pain (perindopril - infrequently *); malaise (perindopril - infrequently *); peripheral edema (perindopril - infrequently *); hyperthermia (perindopril - infrequently *).

Research: increased blood urea (perindopril - infrequently *); increased blood creatinine (perindopril - infrequently *); increased levels of hepatic enzymes (bisoprolol - rarely, perindopril - rarely); increased levels of bilirubin in the blood (perindopril - rarely); increased levels of TG (bisoprolol - rarely); a decrease in hemoglobin and a decrease in hematocrit (perindopril is very rare).

Damage, poisoning and complications of administration: drop (perindopril - infrequently *).

* The frequency of manifestations of adverse reactions identified using spontaneous messages, calculated according to clinical studies.

** These symptoms are observed especially at the beginning of treatment. In general, they are weakly expressed and often disappear within 1–2 weeks.

Reported suspected adverse reactions. Reporting suspected adverse reactions after drug registration is important. This will allow continued monitoring of the benefit / risk ratio of the drug. Health professionals are required to report any suspected adverse reactions through the national reporting system.

special instructions

All warnings associated with each of the components of the drug relate to the drug pretilol.

Arterial hypotension. ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and is more likely in patients with hypovolemia, for example, those who take diuretics, follow a diet with a limited amount of sodium chloride, in patients on dialysis, in patients with diarrhea or vomiting, or in patients with severe renin-dependent hypertension (see INTERACTIONS and ADVERSE EFFECTS). Symptomatic arterial hypotension is more likely in patients with symptomatic heart failure with or without concomitant renal failure.The occurrence of symptomatic arterial hypotension is most likely in patients with a more severe degree of heart failure, taking high-dose loop diuretics, with hyponatremia or functional renal failure. Patients with an increased risk of developing symptomatic arterial hypotension at the beginning of therapy and at the stage of dose selection need careful medical supervision. These warnings also apply to patients with coronary artery disease or cerebrovascular disease, in whom an excessive decrease in blood pressure can lead to myocardial infarction or stroke. In the event of the development of arterial hypotension, the patient must be given a horizontal position and, if necessary, inject 9 mg / ml (0.9%) iv into the sodium chloride solution. Transient hypotension is not a contraindication for the further use of the drug, which can usually be used without any obstacles after the restoration of BCC and increased blood pressure. In some patients with congestive heart failure with normal or low blood pressure, perindopril may cause an additional decrease in systemic blood pressure. This effect is expected and usually does not require discontinuation of treatment. If arterial hypotension is symptomatic, it may be necessary to reduce the dose or phase out treatment using individual components.

Hypersensitivity / angioedema. In patients taking ACE inhibitors, including perindopril, rare cases of the development of angioedema of the face, limbs, lips, mucous membrane, tongue, glottis and / or larynx have been reported (see ADVERSE EFFECTS). This can occur at any time during treatment. In such cases, you must immediately stop using the drug Prestilol. Therapy with β-adrenoreceptor blockers should be continued. Adequate monitoring of the patients health should be established until the symptoms disappear completely. In cases where the swelling spread only to the face and lips, the patients condition usually improved without treatment, however, the use of antihistamines may be useful to reduce the severity of symptoms. Angioneurotic edema associated with laryngeal edema can be fatal. If the swelling extends to the tongue, glottis or larynx, which can lead to airway obstruction, urgent therapy is urgently needed, which may include administering adrenaline and / or maintaining airway patency. The patient should be under constant medical supervision until the symptoms disappear completely and permanently. In patients with a history of angioedema, which was not associated with ACE inhibitor therapy, an increased risk of developing angioedema is noted (see CONTRAINDICATIONS). In patients with treatment with ACE inhibitors, rare cases of the occurrence of intestinal angioedema have been reported. In such patients, abdominal pain was observed (with or without nausea and vomiting); in some cases, no previous angioedema of the face was noted and the level of C-1 esterase was normal. The diagnosis of intestinal angioedema is made during computed tomography or ultrasound or surgery. After the withdrawal of the ACE inhibitor, the symptoms of angioedema disappeared. When conducting a differential diagnosis of abdominal pain that occurs in patients with ACE inhibitors, it is necessary to consider the possibility of intestinal angioedema.

Impaired liver function. Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and passes into transient liver necrosis, sometimes with a fatal outcome. The mechanism of this syndrome is unknown.Patients who develop jaundice while taking ACE inhibitors or significantly increase the level of liver enzymes should stop taking the ACE inhibitor and undergo appropriate medical examination and treatment (see ADVERSE EFFECTS).

Racial features. ACE inhibitors often cause angioedema in patients of the Negroid race than in representatives of other races. Like other ACE inhibitors, perindopril is less effective in lowering blood pressure in patients of the Negroid race with hypertension than in other races, which may be explained by the low level of renin in the blood of these patients.

Cough. Coughing has been reported while taking ACE inhibitors. This cough is unproductive, persistent and stops after drug withdrawal. A cough provoked by an ACE inhibitor should be part of a differential diagnosis of cough.

Hyperkalemia In some patients, while taking ACE inhibitors, including perindopril, an increase in the concentration of potassium in the blood plasma was noted. Risk factors for hyperkalemia include renal failure, impaired renal function, age 70, diabetes mellitus, intercurrent conditions such as dehydration, acute cardiac decompensation, metabolic acidosis and the simultaneous use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium salt substitutes; or taking other drugs that increase the concentration of potassium in the blood plasma (in particular heparin). The use of potassium supplements, potassium-sparing diuretics or potassium salt substitutes, especially in patients with impaired renal function, can lead to a significant increase in plasma potassium levels. Hyperkalemia can cause severe, sometimes fatal, arrhythmia. If the simultaneous use of perindopril and any of the above substances is considered appropriate, such use requires caution and frequent monitoring of the level of potassium in the blood plasma (see INTERACTIONS).

Combinations with lithium. The simultaneous use of lithium and perindopril is usually not recommended (see INTERACTIONS).

Combinations with potassium-sparing drugs, potassium-containing food additives, or potassium salt substitutes. The simultaneous use of perindopril with potassium-sparing drugs or food additives containing potassium, or salt substitutes with potassium is usually not recommended (see INTERACTIONS).

Combinations with calcium antagonists, class I antiarrhythmic drugs and centrally acting antihypertensive drugs. The simultaneous use of bisoprolol with calcium antagonists such as verapamil or diltiazem, with class I antiarrhythmic drugs and central antihypertensive drugs is usually not recommended (see INTERACTIONS).

Discontinuation of treatment. Avoid abrupt cancellation of treatment with β-adrenergic receptor blockers, especially for patients with coronary artery disease, as this can lead to a transient deterioration of heart function. The dose should be reduced gradually, with the use of individual components, preferably within 2 weeks, and if necessary, start replacement therapy.

Bradycardia If during treatment, heart rate at rest decreases to 50–55 beats / min and the patient has symptoms indicating the presence of bradycardia, the dose of Prestilol should be reduced with the use of individual components of the drug. Bisoprolol must be used in an appropriate dose.

AV block I degree. Given the negative dromotropic effect of β-adrenoreceptor blockers, they should be prescribed with caution to patients with degree I AV block.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy.Like other ACE inhibitors, perindopril should be prescribed with caution to patients with mitral valve stenosis and obstruction of the exit from the left ventricle (aortic stenosis or hypertrophic cardiomyopathy).

Prinzmetals angina pectoris. The use of β-adrenergic receptor blockers can increase the number and duration of seizures in patients with Prinzmetal angina. The use of selective β blockers¹-adrenoreceptors is possible with mild forms of the disease and only in combination with vasodilators.

Impaired renal function. In case of impaired renal function, the daily dose of Prestilol should be based on creatinine clearance (see APPLICATION). Routine medical supervision of such patients should include monitoring of creatinine and potassium levels (see ADVERSE EFFECTS). In patients with symptomatic heart failure, hypotension occurring at the beginning of treatment with ACE inhibitors can lead to further deterioration of renal function. An arrester has been reported, which is usually reversible. In some patients with bilateral renal artery stenosis or stenosis of a single kidney artery, when using ACE inhibitors, an increase in the level of blood urea and creatinine in the blood plasma was noted, which usually returned to normal after discontinuation of treatment. This is more common in patients with renal failure. The presence of renovascular hypertension increases the risk of severe hypotension and renal failure. Treatment of these patients should begin under close medical supervision, with low doses and with careful titration. In view of the above, diuretics can lead to arterial hypotension, therefore, they should be canceled and kidney function should be monitored in the first weeks of treatment with Prestilol. In some patients with hypertension, in whom prior to the start of treatment no renovascular diseases were detected, a slight temporary increase in the level of urea in the blood and creatinine in the blood plasma was noted, especially with the simultaneous use of perindopril with a diuretic. The occurrence of this condition is more likely in patients with existing renal failure. You may need a dose reduction and / or withdrawal of a diuretic and / or perindopril.

Kidney transplantation. There is no experience with perindopril arginine in patients with recent kidney transplantation.

Patients on hemodialysis. Anaphylactoid reactions were noted in patients undergoing dialysis using high-flow membranes and taking ACE inhibitors at the same time. For these patients, it is necessary to decide on the use of another type of dialysis membranes or another class of antihypertensive drugs.

Anaphylactoid reactions during apheresis of LDL. Rare cases of life-threatening anaphylactoid reactions have been reported in patients taking ACE inhibitors during LDL apheresis using dextransulfate. The development of anaphylactoid reactions can be avoided if treatment with ACE inhibitors is temporarily discontinued before each apheresis.

Anaphylactoid reactions during desensitizing therapy. In patients taking ACE inhibitors during desensitization (for example, preparations containing bee venom), anaphylactoid reactions may occur. These reactions can be avoided by temporarily discontinuing the use of ACE inhibitors, but reactions can occur again with careless resumption of treatment.

Like other β-adrenoreceptor blockers, bisoprolol can increase both sensitivity to allergens and increase the severity of anaphylactoid reactions. In such cases, treatment with epinephrine does not always give the expected therapeutic effect.

Neutropenia / agranulocytosis / thrombocytopenia / anemia.Among patients taking ACE inhibitors, cases of neutropenia / agranulocytosis, thrombocytopenia, and anemia have been reported. In patients with normal renal function and in the absence of other risk factors, neutropenia is rare. Perindopril should be prescribed very carefully to patients with collagenoses, during therapy with immunosuppressants, allopurinol or procainamide, or with a combination of these aggravating factors, especially in the presence of impaired renal function. Some of these patients have noted the development of serious infectious diseases, in several cases resistant to intensive antibiotic therapy. When prescribing perindopril, it is recommended that these patients periodically monitor the number of leukocytes in the blood, and patients should be aware that any manifestation of an infectious disease (in particular, sore throat, fever) should be reported to the doctor.

Bronchospasm (AD, obstructive airway disease). In AD or other COPD, which can cause symptoms of bronchospasm, concomitant therapy with bronchodilators is indicated. In some cases, while taking β-adrenoreceptor blockers in patients with AD due to increased tone