Prestylol - instructions for use, dose, side effects, contraindications

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Dosage form: & nbspfilm coated tablets

Composition:

1 tablet, film-coated, contains:

Dosage length of 5 mg + 5 mg:

Core

Active substances: bisoprolol fumarate 5 mg (corresponding to 4.24 mg bisoprolol), perindopril arginine 5 mg (corresponding to 3.39 mg perindopril). Excipients: microcrystalline cellulose 40 mg, calcium carbonate 41.238 mg, pregelatinized starch 23.782 mg, sodium carboxymethyl starch 1,8 mg, sodium croscarmellose 1.8 mg, silicon colloidal anhydrous 0.48 mg, magnesium stearate 0.90 mg.

Film sheath

Glycerol 0.18144 mg, hypromellose 3.015936 mg, macrogol 6000 0.192576 mg, magnesium stearate 0.18144 mg, titanium dioxide 0.499746 mg, iron oxide dye yellow 0.06048 mg, iron oxide dye red 0.020382 mg .

Dosage duration of 5 mg + 10 mg:

Core

Active substances: bisoprolol fumarate 5 mg (corresponding to 4.24 mg bisoprolol), perindopril arginine 10 mg (corresponding to 6.79 mg perindopril). Excipients: microcrystalline cellulose 60 mg, calcium carbonate 61.857 mg, pregelatinized starch 35.673 mg, sodium carboxymethyl starch 1,8 mg, sodium croscarmellose 3.6 mg, silicon colloidal anhydrous 0.72 mg, magnesium stearate 1.35 mg.

Film sheath

Glycerol 0.2272 mg, hypromellose 4.523904 mg, macrogol 6000 0.288864 mg, magnesium stearate 0.27216 mg, titanium dioxide 0.749619 mg, iron oxide dye yellow 0.09072 mg, iron oxide dye red 0.030573 mg .

For the dosage of 10 mg + 5 mg:

Core

Active substances: bisoprolol fumarate 10 mg (corresponding to 8.49 mg bisoprolol), perindopril arginine 5 mg (corresponding to 3.39 mg perindopril). Excipients: microcrystalline cellulose 60 mg, calcium carbonate 61.857 mg, pregelatinized starch 35.673 mg, sodium carboxymethyl starch 1,8 mg, sodium croscarmellose 1.8 mg, silicon colloidal anhydrous 0.72 mg, magnesium stearate 1.35 mg.

Film sheath

For the dosage of 10 mg + 10 mg:

Core

Active substances: bisoprolol fumarate 10 mg (corresponding to 8.49 mg bisoprolol), perindopril arginine 10 mg (corresponding to 6.79 mg perindopril). Excipients: microcrystalline cellulose 80 mg, calcium carbonate 82.476 mg, pregelatinized starch 47.564 mg, sodium carboxymethyl starch 1,8 mg, sodium croscarmellose 3.6 mg, silicon colloidal anhydrous 0.96 mg, magnesium age 1.8 mg.

Film sheath

Glycerol 0.36288 mg, hypromellose 6.031872 mg, macrogol 6000 0.385152 mg, magnesium stearate 0.36288 mg, titanium dioxide 0.999492 mg, iron oxide dye yellow 0.12096 mg, iron oxide dye red 0.040764 mg .

Description:

Tablets of 5 mg + 5 mg:

oblong biconvex tablets, covered with a film shell of orange-pink color, with a dividing risk, engraved "5/5" on one side and engraved "" on the other side.

Tablets of 5 mg + 10 mg:

oblong biconvex tablets, covered with a film cover of orange-pink color, with a dividing risk, with an engraving "5/10" on one side and engraving "" on the other side.

Tablets of 10 mg + 5 mg:

round biconvex tablets, covered with a film coating of orange-pink color, with engraving "10/5" on one side and with engraving "" on the other side.

Tablets of 10 mg + 10 mg:

oblong biconvex tablets, film-coated orange-pink color, with engraving "10/10" on one side and with engraving "" on the other side.

Pharmacotherapeutic group:Antihypertensive drug combined (β1-adrenoblocker selective + ACE inhibitor)

ATX: & nbsp

ACE inhibitors, other combinations

Pharmacodynamics:

Mechanism of action

Bisoprolol

Bisoprolol is a highly selective blocker of beta1-adrenergic receptors, which does not have a stimulating and corresponding membrane-stabilizing action.He shows only a slight affinity for beta2-adrenoreceptors of smooth muscles of bronchi and vessels, as well as for beta2-adrenoreceptors involved in metabolic regulation. In this way, bisoprolol in general, does not affect the resistance of the respiratory tract and metabolic processes in which beta2-adrenoreceptors participate. The selective effect of bisoprolol on beta 1-adrenergic receptors persists beyond the range of therapeutic doses.

Perindopril

Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (an ACE inhibitor). Angiotensin-converting enzyme (ACE), or kinase II, is an exopeptidase that carries out both the conversion of angiotensin I into a vasoconstrictor substance, angiotensin II, and the disintegration of bradykinin. having a vasodilating action, to an inactive heptapeptide. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which causes an increase in renin activity of blood plasma (by the mechanism of "negative feedback") and a decrease in the secretion of aldosterone.

Since the ACE inactivates bradykinin,suppression of ACE is accompanied by an increase in the activity of both circulating and tissue kallikrein-kinin system, while the system of prostaglandins is also activated. It is possible that this effect is part of the mechanism of antihypertensive action of ACE inhibitors. and also the mechanism of development of some by-effects (for example, cough). Perindopril It has a therapeutic effect due to the active metabolite perindoprilat. Other metabolites have no inhibitory effect on ACE in vitro.

Pharmacodynamic effects

Bisoprolol

Bisoprolol does not have significant negative inotropic effects.

The maximum effect is noted 3-4 hours after taking the drug. Since the half-life is 10-12 hours, bisoprolol valid for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved in 2 weeks.

With a single admission of patients with ischemic heart disease (CHD) without chronic heart failure (CHF) bisoprolol reduces the heart rate (heart rate) and stroke volume, which leads to a decrease in cardiac output and oxygen consumption.With continued use, the initially increased peripheral vascular resistance is reduced. Reduction of renin activity in blood plasma is considered as one of the mechanisms of action underlying the antihypertensive effect of beta-blockers.

Bisoprolol reduces the sympathetic adrenergic response by blocking the beta-adrenergic receptors of the heart. This leads to a decrease in heart rate and contractility of the myocardium, as a result of which myocardial oxygen demand decreases, which is the desired effect in patients with coronary artery disease associated with ischemic heart disease.

Perindopril

Arterial hypertension

Perindopril is a treatment for arterial hypertension of any severity. Against the background of its use, there is a decrease in both systolic and diastolic arterial pressure (BP) in the "lying" and "standing" positions.

Perindopril reduces the overall peripheral vascular resistance, which leads to a decrease in blood pressure and an improvement in peripheral blood flow without a change in heart rate.

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

Clinical efficacy and safety

Bisoprolol

In a study involving patients with CHF III and IV functional class by classification NYHA, with an ejection fraction <35% according to echocardiography, a reduction in total mortality was shown from 17.3% to 11.8%. There was a decrease in the incidence of sudden death and a reduction in the number of episodes associated with heart failure requiring hospitalization. As a result, a significant improvement in the functional status of CHF on classification NYHA.

Perindopril

Arterial hypertension:

The maximum antihypertensive effect develops 4-6 hours after a single oral intake and lasts for at least 24 hours: residual effects are observed, which are approximately 87-100% of the maximal effects. Reduction of blood pressure occurs quickly. In patients responding to treatment, the normalization of BP is achieved within a month and persists without the development of tachyphylaxis.

Termination of therapy does not cause a ricochet effect.

Perindopril reduces hypertrophy of the left ventricle.

Perindopril has a vasodilating effect. It helps restore the elasticity of large arteries and reduce the ratio of wall thickness: lumen for small arteries.

Auxiliary therapy with thiazide diuretics causes synergy by the type of summation of effects. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of hypokalemia. associated with treatment with a diuretic.

Patients with stable ischemic heart disease:

The efficacy of perindopril in patients older than 18 years with stable coronary artery disease without clinical symptoms of CHF was studied in a 4-year study. 90% of study participants had previously suffered myocardial infarction and / or revascularization procedure. Most patients received medications on the basis of standard therapy, including platelet aggregation inhibitors, lipid-lowering agents and beta-blockers. The main efficacy criterion was a composite endpoint, including cardiovascular mortality, non-fatal myocardial infarction and / or cardiac arrest with successful resuscitation.

Therapy with perindopril tetrabutylamine at a dose of 8 mg / day (equivalent to 10 mg perindopril arginine) resulted in a significant reduction in the absolute risk of complications by 1.9% (a relative risk reduction of 20%).In patients who had previous myocardial infarction or revascularization procedure, absolute risk reduction was 2.2% (a relative risk reduction of 22.4%) compared with the placebo group. When adding perindopril to patients who received a beta-blocker. There was a significant decrease in the absolute risk of cardiovascular mortality, nonfatal myocardial infarction and / or cardiac arrest with successful resuscitation by 2.2% (a relative risk reduction of 24%) compared with beta-blockers without the addition of perindopril.

Double blockade of the renin-angiotensin-aldosterone system (RAAS):

There are data from clinical trials of combined therapy with ACE inhibitor and angiotensin II receptor antagonist (ARA II).

A clinical study was conducted involving patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus, accompanied by confirmed lesion of the target organ, as well as studies involving patients with type 2 diabetes and diabetic nephropathy.

These studies did not reveal a significant positive effect of combination therapy on the occurrence of renal and / or cardiovascular events and mortality,while the risk of developing hyperkalemia, acute renal failure and / or arterial hypotension increased compared with monotherapy.

Taking into account the similar intra-group pharmacodynamic properties of ACE inhibitors and APA II, these results can be expected for the interaction of any other drugs, representatives of ACE inhibitors and APA II classes.

Therefore, ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy.

There is evidence from a clinical trial to study the effect of the addition of aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease or a combination of these diseases. The study was terminated early due to the increased risk of adverse outcomes. Cardiovascular death and stroke were more common in the group of patients receiving aliskiren, compared with the placebo group; and adverse events and serious adverse events of special interest (hyperkalemia, arterial hypotension, and renal dysfunction) were more frequent in the aliskiren group than in the placebo group.

Patients of childhood:

Data on the safety and efficacy of using Prestilol® in children are not available.

Pharmacokinetics:

The speed and degree of absorption of bisoprolol and perindopril in the preparation of Prestilol® does not differ significantly from the pharmacokinetics of bisoprolol and perindopril when taken separately as monotherapy.

Bisoprolol

Suction

Bisoprolol is almost completely (> 90%) absorbed from the gastrointestinal tract. In view of the insignificant metabolism at the first passage through the liver (approximately 10%), its bioavailability after ingestion is approximately 90%.

Distribution

The volume of distribution is 3.5 l / kg. Bisoprolol binding to plasma proteins is approximately 30%.

Metabolism and excretion

Bisoprolol is excreted from the body in two ways. 50% is metabolized in the liver with the formation of inactive metabolites, which are then excreted by the kidneys. The remaining 50% are excreted by the kidneys in unchanged form. The total ground clearance is approximately 15 l / h. The half-life period from plasma is 10-12 hours, which ensures the preservation of the effect within 24 hours after administration once a day.

Special patient groups

The pharmacokinetics of bisoprolol is linear and does not depend on age. Since excretion occurs through the kidneys and liver in equal measure, dose adjustment for patients with impaired liver function or renal failure is not required. Pharmacokinetics in patients with chronic heart failure and impaired liver or kidney function has not been studied. In patients with CHF III functional class by classification NYHA the concentration of bisoprolol in the blood plasma is higher, and the half-life period has a longer duration, compared to similar values in healthy volunteers. The maximum concentration in Plasma in the equilibrium phase is 64 ± 21 ng / ml with a daily dose of 10 mg, and the half-life is 17 ± 5 hours.

Perindopril

Suction

Ingestion perindopril quickly absorbed, the maximum concentration in the blood plasma is reached within 1 hour. The half-life of plasma is 1 hour.

Distribution

The volume of distribution of free perindoprilata is approximately 0.2 l / kg.The association of perindoprilat with plasma proteins, mainly with ACE, is 20% and is dose-dependent.

Metabolism

Perindopril is a prodrug. 27% of the total amount taken internally perindoprila enters the bloodstream as an active metabolite of perindoprilat. In addition to active perindoprilata, perindopril forms five inactive metabolites. The concentration of perindoprilata in the blood plasma reaches a maximum within 3-4 hours. Eating food reduces the rate of perindopril conversion to perindoprilat and, consequently, its bioavailability, therefore perindopril arginine should be taken orally once a day in the morning before meals.

Excretion

Perindoprilat is excreted from the body by the kidneys, and the final half-life of the free fraction is approximately 17 hours, as a result, the equilibrium state is reached within 4 days.

Linearity

It was shown that the relationship between the dose of perindopril and its concentration in the blood plasma is linear.

Special patient groups

The excretion of perindoprilate is slow in elderly patients, as well as in patients with cardiac or renal insufficiency.With renal failure, it is desirable to adjust the dose depending on the degree of impaired renal function (creatinine clearance).

The dialytic clearance of perindoprilat is 70 ml / min.

The pharmacokinetics of perindopril in patients with cirrhosis of the liver is changed: the hepatic clearance of the original molecule is reduced by half. Nevertheless, the amount of perindoprilat formed does not decrease, and therefore no dose adjustment is required (see the sections "Dosage and Administration" and "Special Instructions").

Indications:

Treatment of arterial hypertension and / or stable ischemic heart disease and / or stable chronic heart failure with reduced left ventricular systolic function in adult patients who are treated with bisoprolol and perindopril at appropriate doses.

Contraindications:

- Hypersensitivity to bisoprolol, perindopril, other ACE inhibitors or excipients included in the preparation (see section "Composition")

- Acute congestive heart failure or episodes of cardiac decompensation deficiency when intravenous administration of inotropic drugs is required

- Cardiogenic shock

- Atrioventricular (AV) blockade of 2 or 3 degrees (without pacemaker)

- Sinus node weakness syndrome

- Sinoatrial blockade

- Pronounced bradycardia (heart rate less than 60 beats per minute)

- Severe arterial hypotension (systolic blood pressure less than 100 mm Hg)

- Severe bronchial asthma or severe chronic obstructive pulmonary disease

- Severe disorders of peripheral arterial blood circulation or severe forms of Raynaud's syndrome

- Untreated pheochromocytoma (see section "Special instructions")

- Metabolic acidosis

- Angioedema (angioedema) on the background of taking other ACE inhibitors in history

- Hereditary or idiopathic angioedema

- Pregnancy and the period of breastfeeding (see sections "Special instructions" and "Use during pregnancy and during breastfeeding"

- Collapse

- Age under 18 years old

- Simultaneous reception with drugs containing aliskiren, in patients with diabetes mellitus or renal dysfunction (GFR <60ml / min / 1.73m² surface area of the body) (see sections "Pharmacodynamics" and "Interaction with other medicinal products").

Carefully:

Patients with an increased risk of developing severe arterial hypotension, hypovolemia and hyponatremia (due to a salt-free diet and / or previous therapy with diuretics, dialysis, vomiting, diarrhea), cerebrovascular diseases (including cerebral circulatory insufficiency), coronary insufficiency, angioedema, Negroid race, risk factors for hyperkalemia. combination with lithium preparations, simultaneous administration with potassium-sparing diuretics, preparations containing potassium salts, angiotensin receptor blockers, simultaneous use with aliskiren-containing drugs, combination with slow calcium channel blockers, class 1 antiarrhythmic drugs or central antihypertensive drugs, abrupt cessation therapy, bradycardia, AV blockade of 1 degree, mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy, prinzmetal angina, renal dysfunction (GFR <90 ml / min), renovascular hypertension, bilateral stenosis of the renal arteries,stenosis of the artery of a single kidney (risk of developing severe arterial hypotension and renal insufficiency), patients after kidney transplantation, hemodialysis using high-flow membranes (risk of anaphylactoid reactions), patients during low density lipoprotein (LDL) apheresis procedure, patients during desensitizing treatment, neutropenia / agranulocytosis / thrombocytopenia / anemia, bronchospasm (bronchial asthma, obstructive airways diseases), type 1 diabetes mellitus and type 2 diabetes mellitus with significant fluctuations in blood glucose concentration, a strict diet, peripheral arterial occlusive diseases, surgical intervention / general anesthesia (risk of excessive blood pressure lowering), psoriasis, pheochromocytoma, hyperthyroidism, severe violations of the liver function, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant organic damage to the heart valves, myocardial infarction, pere Yesenia in the last 3 months, congenital deficiency of glucose-6-phosphate dehydrogenase (single cases the development of hemolytic anemia), connective tissue disease (including systemic lupus erythematosus, scleroderma), depression (including history).

Pregnancy and lactation:

Reproductive function:

There are no clinical data on the effect of the drug Prestylol® on reproductive function.

Pregnancy:

Given the influence of the individual components of this combination, the drug Prestylol® is contraindicated in pregnancy.

Bisoprolol

Bisoprolol has pharmacological effects that can adversely affect the course of pregnancy and / or fetal / newborn (reduced placental blood flow, accompanied by delayed growth of the fetus, intra-uterine fetal death, abortion or premature labor, as well as adverse effects (e.g., hypoglycemia and bradycardia ) in a fetus or newborn). If you need a beta-blocker therapy in this situation should be preferred beta1-blocker. Bisoprolol Do not use during pregnancy if there is no absolute indication for this. If treatment with bisoprolol is considered necessary, monitoring of uteroplacental blood flow and fetal growth should be carried out.If there is an adverse effect on the course of pregnancy or fetal development, alternative treatment options should be considered. The newborn should be carefully monitored.

The appearance of symptoms of hypoglycemia and bradycardia can usually be expected during the first 3 days of life.

Perindopril

At the moment, there is no conclusive epidemiological evidence of teratogenic risk when taking ACE inhibitors in the first trimester of pregnancy. However, a small increase in the risk of fetal development disorders can not be ruled out. Patients planning pregnancy should appoint an alternative antihypertensive agent with the established safety profile for use in pregnancy. When establishing pregnancy, treatment with ACE inhibitors should be stopped immediately and. if necessary, prescribe an alternative antihypertensive therapy.

It is known that ACE inhibitor in the second and third trimesters of pregnancy may cause foetotoxic effect on the fetus in man (decrease in renal function, oligohydramnios, delayed ossification of bones of the skull) and lead to the development of complications in the newborn (renal failure, hypotension, hyperkalaemia).In the case of ACE inhibitors in the second and third trimester of pregnancy, an ultrasound is recommended to evaluate the function of the kidneys and the condition of the bones of the fetal skull. Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision because of the risk of developing arterial hypotension (see the sections "Contraindications" and "Special instructions").

Breastfeeding period:

The drug Prestylol® is contraindicated in the period of breastfeeding. It is not known whether bisoprolol with human breast milk. Due to the lack of information on the use of perindopril during breastfeeding, it is contraindicated. During breastfeeding it is recommended to use other drugs with a more studied safety profile, especially when feeding newborns or premature babies.

Dosing and Administration:

Inside, 1 tablet 1 time per day in the morning before eating.

Patients who are receiving 2.5 mg of bisoprolol and 2.5 mg of perindopril should be taken ½ Prelistol® tablets 5 mg + 5 mg once a day.

Patients who are receiving a 2.5 mg bisoprolol and 5 mg perindopril should take ½ Prelistol® tablets 5 mg + 10 mg once a day.

Special patient groups

Patients with impaired renal function (see sections "Special instructions" and "Pharmacokinetics").

In patients with impaired renal function, Prestilol® is given in accordance with the values of creatinine clearance as indicated in the table.

Creatinine clearance (ml / min)	The recommended dose
Creatinine clearance (ml / min)	Tablet 5 mg + 5 mg	Tablet 5 mg + 10 mg	Tablet 10 mg + 5 mg	Tablet 10 mg + 10 mg
Cl_CR ≥ 60	One tablet of Prestylol® 5 mg+5 mg	½ tablets Prestylol® 5 mg + 10 mg	One tablet of Prestylol® 10 mg + 5 mg	It should not be taken. Individual dosing of individual components is recommended.
30 < Cl_CR < 60	½ tablets Prestylol® 5 mg + 5 mg	It should not be taken. Individual dosing of individual components is recommended.	It should not be taken. Individual dosing of individual components is recommended.	It should not be taken. Individual dosing of individual components is recommended.
Cl_CR < 30	It should not be taken. Individual dosing of individual components is recommended.	It should not be taken. Individual dosing of individual components is recommended.	It should not be taken. Individual dosing of individual components is recommended.	It should not be taken. Individual dosing of individual components is recommended.

Patients with impaired hepatic function (see the sections "Special instructions" and "Pharmacokinetics").

Patients with violations of the function of the liver dose adjustment is not required.

Elderly patients

The drug should be prescribed in accordance with the recommendations for patients with impaired renal function.

Children and teens

The safety and effectiveness of the use of the drug Prestylol® in children and adolescents is not established. No relevant data are available. Therefore, the appointment of the drug to children and adolescents is not recommended.

Side effects:

The most frequent adverse reactions associated with bisoprolol include headache, dizziness, worsening of heart failure, arterial hypotension, chills, nausea, vomiting, abdominal pain, diarrhea, constipation, asthenia, and fatigue.

The most frequent adverse reactions with perindopril, reported in clinical trials, include headache, dizziness, vertigo, paresthesia, visual impairment, tinnitus, arterial hypotension, cough, shortness of breath, nausea, vomiting, abdominal pain, diarrhea, constipation, dyspepsia, dyspepsia, itching, skin rash, muscle spasms and asthenia.

To indicate the incidence of adverse events reported during clinical trials and / or post-marketing periods with separate administration of bisoprolol or perindopril, the following classification is used:

Very often (≥ 1/10 cases)

Often (≥ 1/100, <1/10)

Infrequently (≥ 1/1000, <1/100)

Rarely (≥ 1/10000, <1/1000)

Very rarely (<1/10000)

The frequency is unknown (the frequency can not be set based on the available data)

Classes and systems of organs MedDRA	Adverse events	Frequency
Classes and systems of organs MedDRA	Adverse events	Bisoprolol	Parindopril
Infections and invasions	Rhinitis	Rarely	Rarely
Violations of the blood and lymphatic system	Eosinophilia	-	Infrequently*
	Agranulocytosis (see section "Special instructions")	-	Rarely
	Pancytopenia	-	Rarely
	Leukopenia	-	Rarely
	Neutropenia (see section "Special instructions")	-	Rarely
	Thrombocytopenia (see section "Special instructions")	-	Rarely
	Hemolytic anemia in patients with congenital insufficiency of glucose-6-phosphate dehydrogenase (G-6-FDH)	-	Rarely
Disorders from the metabolism and nutrition	Hypoglycemia (see sections "Special instructions" and "Interaction with other medicinal products")	-	Infrequently*
	Hyperkalemia reversible after drug withdrawal	-	Infrequently*
	Hyponatremia	-	Infrequently*
Mental disorders	Mood disorders	-	Infrequently
	Sleep Disorders	Infrequently	Infrequently
	Depression	Infrequently	-
	Nightmares, hallucinations	Rarely	-
	Confusion of consciousness	-	Rarely
Disturbances from the nervous system	Headache**	Often	Often
	Dizziness**	Often	Often
	Vertigo	-	Often
	Dysgeusia	-	Often
	Paresthesia	-	Often
	Drowsiness	-	Infrequently*
	Fainting	Rarely	Infrequently*
Disturbances on the part of the organ of sight	Visual disturbances	-	Often
	Reduced lacrimation (to be taken into account in patients using contact lenses)	Rarely	-
	Conjunctivitis	Highly rarely	-
Hearing disorders	Noise in ears	-	Often
Hearing disorders	Hearing Impairment	Rarely	-
Heart Disease	Heart palpitations	-	Infrequently*
	Tachycardia	-	Infrequently*
	Bradycardia	Highly often	-
	Deterioration of the course of heart failure	Often	-
	Violation AV conductivity	Infrequently	-
	Arrhythmia	-	Rarely
	Angina pectoris	-	Rarely
	Myocardial infarction, possibly due to excessive blood pressure lowering in patients at high risk (see section "Special instructions")	-	Rarely
Vascular disorders	Reduction of blood pressure and the effects associated with this	Often	Often
	Feeling cold or numbness of limbs	Often	-
	Orthostatic hypotension	Infrequently	-
	Vasculitis	-	Infrequently*
	Stroke, possibly due to excessive blood pressure lowering in patients at high risk (see section "Special instructions")	-	Rarely
Disturbances from the respiratory system, chest and mediastinal organs	Cough	-	Often
	Dyspnea	-	Often
	Bronchospasm	Infrequently	Infrequently
	Eosinophilic pneumonia	-	Rarely
Disorders from the gastrointestinal tract	Abdominal pain	Often	Often
	Constipation	Often	Often
	Diarrhea	Often	Often
	Nausea	Often	Often
	Vomiting	Often	Often
	Dyspepsia	-	Often
	Dryness of the oral mucosa	-	Infrequently
	Pancreatitis	-	Rarely
Disturbances from the liver and bile ducts	Cytolytic or cholestatic hepatitis (see section "Special instructions")	Rarely	Rarely
Disturbances from the skin and subcutaneous tissue	Skin rash	-	Often
	Itchy skin	-	Often
	Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and / or larynx (see section "Special instructions")	-	Infrequently
	Hives	-	Infrequently
	Photosensitivity reactions	-	Infrequently*
	Pemphigoid	-	Infrequently*
	Hyperhidrosis	-	Infrequently
	Hypersensitivity reactions (itching, redness, skin rash)	Rarely	-
	Exacerbation of psoriasis	-	Rarely
	Erythema multiforme	-	Rarely
	Alopecia	Highly rarely	-
	Beta-blockers can cause or aggravate the course of psoriasis or can cause the appearance of psoriasis-like rash	Highly rarely	-
Disturbances from the musculoskeletal system and connective tissue	Muscle spasms	Infrequently	Often
	Muscle weakness	Infrequently	-
	Arthralgia	-	Infrequently*
	Myalgia	-	Infrequently*
Disorders from the kidneys and urinary tract	Impaired renal function	-	Infrequently
Disorders from the kidneys and urinary tract	Acute kidney failure	-	Rarely
Disorders from the reproductive system and mammary glands	Violation of potency	Rarely	-
Disorders from the reproductive system and mammary glands	erectile disfunction	-	Infrequently
General disorders and complications at the site of administration	Asthenia	Often	Often
	Increased fatigue	Often	-
	Chest pain	-	Infrequently*
	Malaise	-	Infrequently*
	Peripheral edema	-	Infrequently*
	Hyperthermia	-	Infrequently*
Laboratory indicators and results of other surveys	Increase in the concentration of urea in the blood	-	Infrequently*
	Increase in the concentration of creatinine in the blood	-	Infrequently
	Increased activity of "liver" transaminases	Rarely	Rarely
	Increase in the concentration of bilirubin in the blood	-	Rarely
	Increase in the concentration of triglycerides	Rarely	-
	Reduction of hemoglobin and hematocrit (see section "Special instructions")	-	Rarely*
Trauma, intoxication and complications of manipulation	Falls	-	Infrequently*

* An estimate of the incidence of adverse reactions identified by spontaneous reports was made on the basis of clinical trial results.

** Usually symptoms were observed at the beginning of therapy. They were usually mild and often lasted for 1-2 weeks.

Overdose:

Data on overdose in humans with the drug Prestylol® are absent.

Bisoprolol

Symptoms: the most frequent signs, the development of which can be expected with an overdose of beta-adrenoblockers, are bradycardia, arterial hypotension, bronchospasm, acute heart failure and hypoglycemia.So far, only a few cases of bisoprolol overdose (maximum dose: 2000 mg) that have occurred in patients with hypertension and / or IHD have been described, with bradycardia and / or arterial hypotension. All the patients described recovered. The degree of individual sensitivity to bisoprolol in a single dose of a high dose varies widely, and it is likely that patients with heart failure are more sensitive.

Treatment: In case of an overdose, treatment should be discontinued and supporting symptomatic therapy. There is limited evidence that bisoprolol poorly excreted in dialysis. Based on the expected pharmacological effects and recommendations for other beta-blockers, the following measures should be considered: Bradycardia: intravenous administration of atropine. If the effect is insufficient, with caution, you can enter isoprenaline or another agent that has a positive chronotropic effect. Sometimes it may be necessary to transvenous install an artificial pacemaker.

Pronounced arterial hypotension: intravenous fluids and vasoconstrictors should be administered. Can be effective intravenous administration of glucagon.

AV blockade (2 or 3 degrees): requires careful monitoring of the patient's condition and infusion of isoprenaline or transvenous installation of an artificial pacemaker. Acute deterioration of the course of heart failure: intravenous injection of diuretics, inotropes, vasodilators.

Bronchospasm: the administration of bronchodilators, such as isoprenaline, beta2-sympathomimetics and / or aminophylline.

Hypoglycemia: intravenous glucose administration.

Perindopril

Symptoms:

Data on overdose in humans are limited. Symptoms associated with an overdose of ACE inhibitors may include arterial hypotension, circulatory shock, water-electrolyte balance disorders, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Treatment: To treat an overdose, an intravenous infusion of sodium chloride solution at a concentration of 9 mg / ml (0.9%) is recommended.With severe arterial hypotension, the patient should be placed in the "lying" position on the back with raised legs. If necessary, angiotensin II and / or a solution of catecholamines may be administered intravenously. Perindopril can be removed from the systemic blood flow by hemodialysis (see section "Special instructions"). When developing a bradycardia-resistant therapy, it may be necessary to install an artificial pacemaker. It is necessary to constantly monitor the indices of the basic vital functions of the body, the concentration of electrolytes and creatinine in the blood serum.

Interaction:

The interaction between bisoprolol and perindopril was not observed in studies involving healthy volunteers. Below you will find information on interactions with other drugs.

Medications that cause hyperkalemia: Some drugs and classes of drugs may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors. angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as ciclosporin or tacrolimus, trimethoprim.Combinations of these drugs increase the risk of hyperkalemia.

Simultaneous reception is contraindicated (see section "Contraindications"):

Aliskiren: The simultaneous administration of Prestilol® and aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction, as there is a risk of hyperkalemia, impaired renal function, and an increased incidence of cardiovascular morbidity and mortality.

Simultaneous reception is not recommended:

In connection with bisoprolol:

Hypotensive agents of central action, such as clonidine and others (for example, methyldopa, moxonidine, rilmenidine): simultaneous administration of antihypertensive agents of central action can lead to a worsening of the course of heart failure due to a decrease in the central sympathetic tone (decrease in heart rate and cardiac output, vasodilation). A sharp cessation of therapy, especially prior to a previous reduction in the dose of the beta-blocker, may increase the risk of developing "ricochetial" hypertension.

Antiarrhythmics / class (for example, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): joint application may affect atrioventricular conduction, and also to enhance the negative inotropic effect.

Blocks of "slow" calcium channels (verapamil and, to a lesser extent, diltiazem): Negative effect on contractility and atrioventricular conductivity. Intravenous administration of verapamil to patients receiving beta-blockers can lead to severe arterial hypotension and atrioventricular blockade.

In connection with perindopril:

Aliskiren: In patients who do not have diabetes mellitus or a disturbance of the function of the nights, the risk of hyperkalemia also increases. impairment of kidney function, increased incidence of adverse cardiovascular events and mortality from cardiovascular disease.

Simultaneous treatment with ACE inhibitors and angiotensin receptor blockers: Clinical studies have shown that the double blockade of the renin-angiotensin-aldosterone system through the combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse events such as hypotension,hyperkalaemia and decreased renal function (including acute renal failure), compared with the use of only one drug that affects RAAS (see "Contraindications", "Special instructions" and "Pharmacodynamics").

In the literature, cases have been described where patients with confirmed atherosclerosis, heart failure or diabetes with target organ damage, simultaneous use of an ACE inhibitor and an angiotensin receptor blocker were associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and impaired renal function including acute renal failure), compared with the use of only one drug that affects RAAS. Double blockade (eg, with the combination of an ACE inhibitor and an angiotensin II receptor antagonist) should be limited to single cases with careful monitoring of kidney function, potassium levels, and blood pressure.

Estramustine: There is a risk of an increase in the incidence of such adverse events as angioedema.

Potassium-sparing diuretics (for example. triamterene, amiloride), potassium salts: Hyperkalemia may develop (with a possible fatal outcome), especially when combined with renal insufficiency (additional effects associated with hyperkalemia). Simultaneous use of perindopril and the above medicines is not recommended (see section "Special instructions"). In case if simultaneous application is necessary, they should be applied with precaution and regular monitoring of potassium content in blood serum. Information on the use of spironolactone in heart failure is described further in the text.

Lithium preparations: With simultaneous use of lithium drugs and ACE inhibitors, a reversible increase in the concentration of lithium in the blood and associated toxic effects were described. The use of perindopril concomitantly with lithium preparations is not recommended, but if the use of such a combination is deemed necessary, careful monitoring of lithium serum concentration is required.

Simultaneous reception requires special care:

In connection with bisoprolol and perindopril:

Hypoglycemic agents (insulins, hypoglycemic agents for oral administration): On the basis of epidemiological studies, it can be assumed that the use of ACE inhibitors simultaneously with hypoglycemic agents (insulin, hypoglycemic agents for oral administration) may increase the hypoglycemic effect with the risk of hypoglycemia. The development of this phenomenon appears to be more likely in the first weeks of combined therapy, as well as in patients with impaired renal function. Simultaneous reception of bisoprolol with insulin and oral hypoglycemic agents can cause an increase in hypoglycemic effect. Blockade of beta-adrenoceptors can mask symptoms of hypoglycemia.

Non-steroidal anti-inflammatory drugs (including acetylsalicylic acid in doses ≥ 3 g / day): Prestilol®concomitantly with NSAIDs (ie, acetylsalicylic acid in anti-inflammatory doses, cyclooxygenase-2 inhibitors and nonselective NSAIDs) may lead to a weakening of the hypotensive effect of bisoprolol and perindopril.

In addition, simultaneous administration of ACE inhibitors and NSAIDs may lead to an increased risk of impaired renal function,including the possibility of developing acute renal failure, as well as an increase in potassium in the blood serum, especially in patients with initially reduced renal function. This combination should be administered with caution, especially elderly patients. Patients should receive an adequate amount of fluid, it is recommended to monitor kidney function both at the beginning of the combination therapy and periodically during the treatment.

Hypotensive and vasodilator funds: Simultaneous reception of antihypertensive and vasodilating agents (such as nitroglycerine, other nitrates or other vasodilators) or other drugs that have the ability to lower blood pressure (eg, tricyclic antidepressants, barbiturates, phenothiazines), can enhance the antihypertensive effects of perindopril and bisoprolol.

Tricyclic antidepressants / antipsychotics / agents for general anesthesia: Simultaneous administration of ACE inhibitors with certain anesthetics, tricyclic antidepressants and antipsychotic drugs can lead to an additional reduction in blood pressure.

Simultaneous administration of bisoprolol and anesthetics can lead to a decrease in reflex tachycardia and an increased risk of hypotension.

Sympathomimetics: Simultaneous reception of bisoprolol and beta-sympathomimetics (such as isoprenaline. dobutamine) can lead to a decrease in the effect of both drugs.

Sympathomimetics, which activate both beta and alpha-adrenoreceptors (for example, noradrenaline, adrenaline): a combination with bisoprolol may reveal alpha-adrenergic receptor mediated vasoconstrictor effects of these drugs, which can lead to increased blood pressure and increased intermittent claudication. Such interactions are more typical for non-selective beta-blockers.

Sympathomimetics can reduce the antihypertensive effect of ACE inhibitors.

In connection with bisoprolol:

The blockers of the "slow" calcium channels of the dihydropyridine series, such as felodipine and amlodipine: Simultaneous reception may increase the risk of hypotension, and further deterioration of the pumping function of the ventricles of the heart in patients with heart failure is not ruled out.

Antiarrhythmic drugs of the III class (for example, amiodarone): It is possible to increase the effect on atrioventricular conductivity.

Parasympathomimetics: Simultaneous reception can reduce atrioventricular conduction and increase the risk of developing bradycardia.

Beta-blockers local action (for example, eye drops, prescribed for the treatment of glaucoma): With simultaneous use, it is possible to enhance the systemic effects of bisoprolol.

Drugs of digitalis: Reduction in heart rate, slowing of atrioventricular conduction.

In connection with perindopril:

Baclofen: Increased antihypertensive effect. You should carefully monitor the blood pressure level and, if necessary, adjust the dose of the antihypertensive drug.

Potassium-sparing diuretics: In patients receiving diuretics, and especially in individuals with reduced circulating blood and / or salts, there may be an excessive decrease in blood pressure at the beginning of therapy with an ACE inhibitor. The likelihood of hypotensive effects may be reduced by stopping diuretic therapy, replenishing circulating blood volume (BCC) or increasing salt intake prior to initiation of perindopril therapy, and by prescribing perindopril at a low dose with gradual increase.

With arterial hypertension, when the previous diuretic therapy could cause a decrease in the volume of circulating blood / salts, it is necessary either to cancel the diuretic before starting treatment with an AIF inhibitor (in which case a potassium-sparing diuretic can later be prescribed again), or initiate therapy with an ACE inhibitor at a low dose followed by a gradual its increase.

In patients with CHF treated with diuretics, treatment with an ACE inhibitor should begin with very low doses and. if possible, after a reduction in the dose of the simultaneously used potassium-sparing diuretic.

In all cases, during the first few weeks of therapy with an ACE inhibitor, monitoring of renal function (creatinine level) is required.

Potassium-sparing diuretics (eplerenone, spironolactone): When receiving eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day and ACE inhibitors in low doses: in the treatment of patients with heart failure II-IV functional class by classification NYHA with an ejection fraction <40%, and previous therapy with ACE inhibitors and loop diuretics, there is a risk of developing hyperkalemia (possibly fatal), especially if the prescribed recommendations for this combination of drugs are not followed.

Before starting the combination therapy, you should be convinced of the absence of hyperkalemia and renal dysfunction. It is recommended to regularly monitor the concentration of creatinine and potassium in the blood: weekly in the first month of treatment and every month during treatment.

Racecadotril: An angioneurotic edema was reported on the background of the administration of ACE inhibitors (such as perindopril). The risk of developing angioedema may increase with the simultaneous use of racecadotril (antidiarrhoea).

Inhibitors mTOR (mammalian rapamycin targets) (for example, sirolimus, everolimus, tessirolimus): In patients who are simultaneously receiving therapy with inhibitors mTOR, the risk of developing angioedema may increase (see section "Special instructions").

Combinations of medicines requiring attention:

In connection with bisoprolol

Mefloquine: Increased risk of bradycardia.

Inhibitors of monoamine oxidase (MAO) (with the exception of MAO inhibitors type B): Increased antihypertensive effect of beta-blockers. but there is also a risk of hypertensive crisis.

In connection with perindopril

Glyptins (linaglyptin. saxagliptin. sitagliptin, vildagliptin): Increased risk of angioedema development due to decreased activity of dipeptidyl-peptidase IV (DPP-IV) by the action of glyptin in patients receiving treatment with an ACE inhibitor.

Preparations of gold: In patients receiving gold injections (sodium aurotomy malate) simultaneously with an ACE inhibitor, including perindopril, the development in rare cases of nitrite reactions (blood flow to the face, nausea, vomiting and arterial hypotension) has been described.

Special instructions:

All special instructions and precautions relating to each component are applicable to Prestilol®.

Severe arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Severe arterial hypotension rarely develops in patients with uncomplicated course of arterial hypertension. The risk of excessive reduction in blood pressure is increased in patients with reduced bcc, for example, with diuretic therapy, with a strict salt-free diet, with hemodialysis, diarrhea or vomiting, as well as in patients with severe hypertension with high renin activity (see.sections "Interaction with other medicinal products" and "Side effect"). The expressed arterial hypotension can be observed at patients with clinical displays of intimate insufficiency both with presence, and without renal insufficiency. This risk is more likely in patients with severe heart failure, as a response to the use of "loop" diuretics, hyponatremia or functional renal failure. Patients with an increased risk of developing symptomatic arterial hypotension during the initiation of therapy and dose adjustment should be under close medical supervision. This approach is also applied to patients with IHD or cerebrovascular disease, in whom excessive reduction of blood pressure can lead to the development of myocardial infarction or acute impairment of cerebral circulation.

With the development of arterial hypotension, the patient should be placed in the "lying down" position and, if necessary, an intravenous infusion of 9 mg / ml (0.9%) sodium chloride solution. Transient arterial hypotension is not a contraindication for further administration of the drug.As a rule, taking the drug can be continued after replenishment of bcc and increased blood pressure.

In some patients with CHF, who have normal or low blood pressure, there may be an additional reduction in blood pressure as a result of perindopril. This effect is predictable and usually does not require discontinuation of therapy. With the development of symptoms of arterial hypotension, a dose reduction or gradual withdrawal of the drug, or the use of its individual components in the form of monotherapy, may be required.

Hypersensitivity / angioedema

There have been reports of rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and / or larynx in patients treated with ACE inhibitors, including perindopril (see section "Side effect"). These phenomena can develop at any time of treatment. In such cases, stop treatment with Prestilol® immediately. Therapy with beta-blockers should be continued. The patient should be observed until the signs of edema disappear completely. In cases where the edema affects only the face and lips, the condition is usually resolved without treatment, although antihistamines may be used to alleviate the symptoms.

Angioedema, accompanied by swelling of the larynx, can lead to death. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction. When these symptoms appear, emergency therapy is required, including subcutaneous injection of epinephrine (adrenaline) and / or ensuring airway patency. The patient should be under medical supervision until the symptoms disappear completely and persistently. If a patient has a history of angioedema, an unrelated ACE inhibitor. the risk of developing angioedema may be elevated when taking an ACE inhibitor (see "Contraindications").

In rare cases, patients treated with ACE inhibitors. the development of angioedema of the intestine was described. In this case, patients had abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without a previous angioedema and at a normal level of C-1 esterase. The diagnosis is established by means of computed tomography of the abdominal cavity, ultrasound examination or surgical intervention. Symptoms disappeared after discontinuation of ACE inhibitors.Therefore, patients with abdominal pain receiving ACE inhibitors should take into account the possibility of developing angioedema of the intestine during differential diagnosis.

Inhibitors mTOR (eg, sirolimus, everolimus, tessirolimus):

In patients who are simultaneously receiving therapy with inhibitors mTOR (eg, sirolimus, everolimus, tessirolimus), the risk of developing angioedema (including edema of the respiratory tract or tongue with / without respiratory function impairment) may increase (see "Interaction with Other Drugs").

Liver failure

In rare cases, against the background of the administration of ACE inhibitors, there is a syndrome of development of cholestatic jaundice with the transition to fulminant liver necrosis, sometimes with a lethal outcome. The mechanism of development of this syndrome is unclear. Patients taking ACE inhibitors who develop jaundice or a significant increase in liver enzyme activity should stop taking an ACE inhibitor and receive appropriate medical supervision (see "Side effect" section).

Ethnic differences

In patients of the Negroid race, ACE inhibitors cause angioedema more often than patients who are representatives of other races.

Like other ACE inhibitors, in representatives of the Negroid race perindopril may be less effective in lowering blood pressure than in representatives of other races, which may be due to the higher prevalence of low-grade conditions in patients of the Negroid race with hypertension.

Cough

With the use of ACE inhibitors, cough may occur. It is characteristic that cough is dry, persistent and is resolved after discontinuation of therapy. This should be taken into account in the differential diagnosis of cough.

Hyperkalemia

In some patients receiving ACE inhibitors, including perindopril, an increase in the serum potassium concentration was observed. Risk factors for hyperkalemia include renal failure, impaired liver function, age over 70 years, diabetes mellitus, certain concomitant conditions (dehydration, acute cardiac decompensation, metabolic acidosis) and concomitant use of potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene or amiloride), preparations of potassium or potassium-containing substitutes for edible salt / food additives. Patients taking other drugs that promote serum potassium levels (eg, heparin) are also at risk. The use of potassium, potassium-sparing diuretics or potassium-containing salt substitutes / nutritional supplements, especially in patients with impaired renal function, can lead to a significant increase in serum potassium concentration. Hyperkalemia can lead to serious, sometimes fatal, heart rhythm disturbances. If simultaneous reception of the above mentioned means is necessary, they should be applied with caution against the background of regular monitoring of potassium content in the blood serum (see section "Interaction with other medicinal products").

Lithium preparations

Simultaneous use of perindopril and lithium preparations is not recommended (see the section "Interaction with Other Drugs").

Potassium-sparing diuretics, potassium preparations, potassium-containing substitutes for edible salt and food additives

The simultaneous use of perindopril andpotassium-sparing diuretics, and also preparations of potassium, potassium-containing substitutes for edible salt and food additives (see the section "Interaction with other medicinal products").

Double blockade of the renin-angiotensin-aldosterone system

There is evidence that joint use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Thus, a double blockade of RAAS by the combined use of ACE inhibitors. blockers of angiotensin II receptors or aliskiren is not recommended (see the sections "Interaction with other medicinal products" and "Pharmacodynamics"). If double blockade therapy is considered absolutely necessary, it should be performed only under strict medical supervision and with regular monitoring of kidney function, electrolyte content in blood and blood pressure.

Do not use ACE inhibitors in combination with angiotensin II receptor blockers in patients with diabetic nephropathy.

Blockers of "slow" calcium channels, antiarrhythmics of the first class and antihypertensive agents of central action

Simultaneous use of bisoprolol and calcium channel blockers, such as verapamil or diltiazem, anti-arrhythmic drugs of the first class and antihypertensive agents of central action are not recommended (see the section "Interaction with other medicinal products").

Abolition of the drug

It should avoid abrupt cessation of treatment with beta-blockers. especially in patients with ischemic heart disease, as this can lead to a temporary deterioration in cardiac activity. The dose should be reduced gradually, using individual components., Preferably for 2 weeks and in parallel with the onset of replacement therapy (if necessary).

Bradycardia

If, during treatment, the heart rate at rest is reduced to 50-55 beats per minute or less, and the patient has symptoms associated with bradycardia, a reduction in the dose of Prestilol® should be started using individual components with an acceptable dose of bisoprolol.

AV blockade of 1 degree

Given the negative dromotropic effect, prescribe beta-blockers to patients with AV blockade 1 degree should be done with caution.

Mitral stenosis / aortic stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, perindopril caution should be given to patients with stenosis of the mitral valve and obstruction of the exit tract left ventricle, for example, with stenosis of the aortic valve or mri hypertrophic cardiomyopathy.

Prinzmetal's angina pectoris:

Beta-blockers may increase the incidence and duration of angina episodes in patients with Prinzmetal angina pectoris. The use of selective beta 1-adrenoblockers is possible with mild disease and only in combination with vasodilators.

Renal insufficiency:

In the case of kidney failure, the daily dose of the drug Prestylol® is selected depending on the creatinine clearance (see section "Method of administration and dose"). For these patients, part of the usual therapeutic practice is the standard control of the potassium and creatinine concentrations in the blood (see the "Side effect" section).

In patients with clinically significant symptoms of heart failure, arterial hypotension as a result of the initiation of treatment with ACE inhibitors may lead to further deterioration in kidney function.There was reported acute renal failure, which was usually reversible.

In some patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney that received therapy with ACE inhibitors, there was an increase in the level of urea and creatinine in the blood serum, which usually occurs when therapy is withdrawn. This effect was more often observed in patients with renal insufficiency. The additional presence of reninvascular hypertension causes an increased risk of severe arterial hypotension and renal insufficiency in such patients. Treatment in such patients should start with low doses under close medical supervision and with careful titration of the dose. Since diuretic therapy can contribute to the development of the phenomena described above, diuretics should be temporarily discontinued and monitoring of renal function should be performed during the first weeks of therapy. In some patients with arterial hypertension without signs of renal vascular disease, there was an increase in the concentration of urea and creatinine in the serum, usually minor and transient,especially with the simultaneous administration of perindopril and a diuretic. More likely the development of such phenomena in patients with a history of renal dysfunction. Dose reduction and / or cancellation of the diuretic and / or perindopril may be required.

Kidney Transplantation

The experience of treatment with perindopril arginine patients with a previously transplanted kidney is absent.

Patients on hemodialysis

In patients undergoing hemodialysis using high-flux membranes that received an ACE inhibitor, cases of anaphylactoid reactions were noted. Such patients should prescribe a hypotensive drug of another class or use a dialysis membrane of a different type.

Anaphylactoid reactions during apheresis of low density lipoproteins

In patients receiving ACE inhibitors, during the procedure of apheresis of LDL with the use of dextran sulfate, the development of life threatening anaphylactoid reactions was rarely observed. These reactions could be prevented by temporarily discontinuing therapy with an ACE inhibitor before each apheresis procedure.

Anaphylactoid reactions during desensitization

Anaphylactoid reactions were observed in patients receiving ACE inhibitors during desensitizing therapy (for example, by venom of Hymenoptera insects). Such reactions could be prevented by the temporary withdrawal of the ACE inhibitor, but with occasional resumption of treatment the reactions could develop again. As in the case of other beta-blockers, bisoprolol can increase both the sensitivity to allergens, and the severity of anaphylactic reactions. Treatment with epinephrine (adrenaline) does not always produce the expected therapeutic effect.

Neutropenia / agranulocytosis / thrombocytopenia / anemia

In patients receiving ACE inhibitors, cases of neutropenia / agranulocytosis, thrombocytopenia and anemia have been described. In patients with normal renal function and in the absence of other aggravating factors, neutropenia develops rarely. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases receiving immunosuppressants, allopurinol or procainamide, or a combination of these risk factors, especially if there is a history of renal dysfunction.Some of these patients developed severe infections, in some cases not responding to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically check the white blood cell count and instruct patients to tell the doctor about any signs of infectious diseases (eg, sore throat, fever).

Bronchospasm (bronchial asthma, obstructive airway disease)

With bronchial asthma and other chronic obstructive pulmonary diseases, concomitant treatment with bronchodilators should be performed. Sometimes, when using beta-blockers in patients with bronchial asthma, respiratory tract resistance may increase, so an increase in the dose of beta2-adrenomimetics may be required.

Patients with diabetes mellitus

It is recommended that Prestilol® be given with caution in patients with diabetes mellitus who have significant fluctuations in blood glucose levels. Symptoms of hypoglycemia can be masked by the effects of beta-adrenoblockers.

Strict diet

It is advisable to use caution when treating patients who follow a strict diet / fast.

Occlusion diseases of peripheral arteries

When taking beta-blockers, there may be a worsening of symptoms, especially at the initial stages of treatment.

Anesthesia

In patients undergoing general anesthesia, beta-blockers reduce the incidence of arrhythmias and myocardial ischemia during the initial phase of anesthesia and intubation, and also in the postoperative period. Currently, it is recommended to continue therapy with beta-blockers in the perioperative period. An anesthesiologist should be informed of the use of beta-blockers by the patient due to possible drug interactions leading to bradyarrhythmias, weakening of the reflex tachycardia and reduce the reflex ability to compensate for the effects associated with blood loss. If before surgery it is necessary to cancel beta-blocker therapy, this should be done gradually and the cancellation is completed approximately 48 hours before anesthesia.

In patients who are scheduled to undergo extensive surgery or use of anesthesia medications that cause arterial hypotension,The use of perindopril can block the formation of angiotensin II against the background of compensatory release of renin. Treatment should be discontinued one day before surgery. With the development of arterial hypotension by this mechanism, BP should be maintained by replenishing the BCC.

Psoriasis

Patients with psoriasis or having a history of psoriasis may be prescribed beta-blockers only after a thorough assessment of the benefit / risk ratio.

Pheochromocytoma

Patients with a confirmed or suspected pheochromocytoma, bisoprolol should always be prescribed only in combination with an alpha-adrenergic blocker.

Hyperthyroidism

Symptoms of hyperthyroidism may be masked against the background of bisoprolol treatment.

Pregnancy

An alternative hypotensive drug with an established safety profile for use during pregnancy should be scheduled for pregnancy planning, except when ACE inhibitor therapy is considered necessary. When pregnancy is detected, treatment with ACE inhibitors should be stopped immediately and, if necessary, an alternative antihypertensive therapy (seesections "Contraindications" and "Use during pregnancy and during breast-feeding").

Heart failure

Experience with bisoprolol in the treatment of heart failure in patients with the following diseases and conditions is absent:

- type 1 diabetes mellitus,

- severe renal dysfunction,

- severe violations of the liver.

- restrictive cardiomyopathy.

- congenital heart diseases,

- hemodynamically significant organic lesions of the heart valves.

- myocardial infarction, transferred in the last 3 months.

Depression

It is recommended to stop therapy with Prestilol® in the development of depression.

Effect on the ability to drive transp. cf. and fur:

The drug Prestylol® does not directly affect the ability to drive and operate machinery, but some patients may develop individual reactions associated with low blood pressure, especially at the beginning of treatment or when replacing the drug, as well as when taking with alcohol.

As a result, the ability to drive and operate machinery can be compromised.

Form release / dosage:

Tablets, film-coated, 5 mg + 5 mg, 5 mg + 10 mg, 10 mg + 5 mg, 10 mg + 10 mg.

Packaging:

For 29 or 30 tablets, film-coated, in a bottle of polypropylene, equipped with a dispenser made of polyethylene and a lid containing a desiccant (silica gel). For 1 bottle together with instructions for use in a pack of cardboard with the control of the first autopsy.

Packaging for hospitals: 30 tablets per bottle of polypropylene, equipped with a dispenser made of polyethylene and a lid containing a desiccant (silica gel).

For 3 bottles of 30 tablets with instructions for use in an amount corresponding to the number of bottles, in a pack of cardboard with the control of the first opening.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004521

Date of registration:31.10.2017

Expiration Date:31.10.2022

The owner of the registration certificate:Servier LaboratoriesServier Laboratories France

Manufacturer: & nbsp

Les Laboratoires Servier Industrie France

Representation: & nbspServier Laboratories Servier Laboratories France

Information update date: & nbsp23.11.2017

Illustrated instructions

Instructions

Prestylol® (Prestilol®)