Prestilol,10 mg+10 mg 30 pcs

Bisoprolol

Bisoprolol is a highly selective β1-adrenoreceptor blocker with no stimulating and corresponding membrane stabilizing effects. It has only a minor affinity for β2-adrenoceptors of bronchial and vascular smooth muscle as well as for β2-adrenoceptors involved in metabolic regulation. Thus, bisoprololol in general has no effect on airway resistance and metabolic processes in which β2-adrenoreceptors are involved. The selective effect of bisoprolol on β1-adrenoceptors is maintained beyond the therapeutic dose range.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE, or kinase II, is an exopeptidase that both converts angiotensin I into the vasoconstrictor angiotensin II and breaks down bradykinin, which has a vasodilator effect, into an inactive heptapeptide. ACE inhibition leads to a decrease in plasma angiotensin II concentration, which causes an increase in plasma renin activity (by a “negative feedback” mechanism) and a decrease in aldosterone secretion.

As ACE inactivates bradykinin, ACE suppression is accompanied by an increase in both circulating and tissue kallikrein-kinin system activity, while the prostaglandin system is also activated. It is possible that this effect is part of the mechanism of antihypertensive action of ACE inhibitors, as well as the mechanism of development of some side effects (e.g., cough).

Perindopril has a therapeutic effect due to the active metabolite perindoprilat. Other metabolites have no inhibitory effect on ACE in vitro.

Pharmacodynamic effects

Bisoprolol

Bisoprolol has no significant negative inotropic effects.

The maximal effect is noted 3-4 hours after taking the drug. Because T1/2 is 10-12 hours, bisoprololol has 24-hour action. The maximal antihypertensive effect of bisoprololol is usually reached after 2 weeks.

Bisoprolol decreases HR and stroke volume, which leads to a decrease in cardiac output and oxygen consumption when administered once in patients with CHF without chronic heart failure (CHF). With continuous use, initially increased peripheral vascular resistance decreases. Reduction of plasma renin activity is considered as one of the mechanisms of action underlying the antihypertensive effect of beta-adrenoblockers.

Bisoprolol reduces the sympathoadrenergic response by blocking the β-adrenoreceptors of the heart. This leads to a slower heart rate and myocardial contractility, resulting in reduced myocardial oxygen demand, which is a required effect in angina associated with CHD.

Perindopril

Arterial hypertension

Perindopril is a treatment for arterial hypertension of any severity. It has been shown to decrease both systolic and diastolic BP in the supine and standing position.

Perindopril decreases PPS, which leads to lower BP and improves peripheral blood flow without changing HR.

In general, perindopril administration increases renal blood flow, and FFR is usually unchanged.

Clinical efficacy and safety

Bisoprolol

In a study involving patients with NYHA class III and IV CHF with ejection fraction < 35% according to echocardiography, a decrease in overall mortality from 17.3% to 11.8% was shown. There was a decrease in cases 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 according to the NYHA classification was shown.

Perindopril

The arterial hypertension

The maximum antihypertensive effect develops 4-6 h after a single oral dose and persists for at least 24 h: residual effects are observed, which are approximately 87-100% of the maximum effects. Decrease in BP is rapid. In responsive patients, BP normalization is achieved within a month and persists without the development of tachyphylaxis.

The discontinuation of therapy does not cause a “ricochet” effect.

Perindopril reduces left ventricular hypertrophy.

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

The adjuvant 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 diuretic treatment.

Patients with stable CHD

The efficacy of perindopril in patients over 18 years of age with stable CHD without clinical symptoms of CHD was studied in a 4-year study. 90% of study participants had previously undergone myocardial infarction and/or revascularization procedure. Most patients received medications based on standard therapy, including platelet aggregation inhibitors, hypolipidemic agents, and beta-adrenoblockers. The primary efficacy criterion was a composite endpoint including cardiovascular mortality, nonfatal myocardial infarction and/or cardiac arrest with successful resuscitation.

Tert-butylamine perindopril therapy at a dose of 8 mg/day (equivalent to 10 mg perindopril arginine) resulted in a significant 1.9% reduction in absolute risk of complications (20% reduction in relative risk). In patients who had previously undergone a myocardial infarction or revascularization procedure, the absolute risk reduction was 2.2% (relative risk reduction – 22.4%) compared to the placebo group. When perindopril was added to patients receiving a beta-adrenoblocker, there was a significant reduction in absolute risk of cardiovascular mortality, nonfatal myocardial infarction and/or cardiac arrest with successful resuscitation of 2.2% (24% relative risk reduction) compared with beta-adrenoblocker therapy without perindopril addition.

Double RAAS blockade

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

There have been clinical studies involving patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes with confirmed target organ damage, as well as studies involving patients with type 2 diabetes and diabetic nephropathy.

These studies found no significant positive effect of combination therapy on the occurrence of renal and/or cardiovascular events and on mortality rates, while the risk of hyperkalemia, acute renal failure, and/or arterial hypotension increased compared to monotherapy.

With consideration of the similar within-group pharmacodynamic properties of ACE inhibitors and ARA II, these results would be expected for interactions between any other drugs in the ACE inhibitor and ARA II classes.

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

There are data from a clinical trial investigating the effect of adding 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 with a combination of these conditions. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the group of patients receiving aliskiren compared to the placebo group; also adverse events and serious adverse events of special interest (hyperkalemia, arterial hypotension and renal function disorders) were registered more frequently in the aliskiren group than in the placebo group.

Paediatric patients

There are no data on safety and efficacy of Prestilol® in children.

Indications

Treatment of arterial hypertension and/or stable coronary heart disease and/or stable chronic heart failure with reduced left ventricular systolic function in adult patients who are indicated for therapy with bisoprolol and perindopril in appropriate doses

Pharmacological effect

Pharmacotherapeutic group:

Combination antihypertensive drug (selective β1-blocker + ACE inhibitor).

ATX code: C09BX02

Mechanism of action

Bisoprolol Bisoprolol is a highly selective beta1-adrenergic receptor blocker that does not have a stimulating and corresponding membrane-stabilizing effect. It shows only slight affinity for beta2-adrenergic receptors of bronchial and vascular smooth muscle, as well as beta2-adrenergic receptors involved in metabolic regulation.

Thus, bisoprolol generally has no effect on airway resistance and metabolic processes in which beta2-adrenergic receptors are involved. The selective effect of bisoprolol on beta1-adrenergic receptors persists beyond the range of therapeutic doses. Perindopril Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor).

Angiotensin-converting enzyme (ACE), or kinase II, is an exopeptidase that carries out both the conversion of angiotensin I into the vasoconstrictor angiotensin II and the breakdown of bradykinin, which has a vasodilatory effect, into an inactive heptapeptide. ACE inhibition leads to a decrease in the concentration of angiotensin II in the blood plasma, which causes an increase in the activity of plasma renin (via a “negative feedback” mechanism) and a decrease in aldosterone secretion.

Since ACE inactivates bradykinin, suppression of ACE is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin system, while the prostaglandin system is also activated. It is possible that this effect is part of the mechanism of the antihypertensive effect of ACE inhibitors, as well as the mechanism of development of some side effects (for example, cough). Perindopril has a therapeutic effect due to the active metabolite perindoprilat. Other metabolites do not have an inhibitory effect on ACE in vitro.

Pharmacodynamic effects

Bisoprolol Bisoprolol does not have significant negative inotropic effects. The maximum effect is observed 3-4 hours after taking the drug. Since the half-life is 10-12 hours, bisoprolol is effective for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved after 2 weeks.

When taken once by patients with coronary heart disease (CHD) without chronic heart failure (CHF), bisoprolol reduces heart rate (HR) and stroke volume, which leads to a decrease in cardiac output and oxygen consumption. With continuous use, the initially increased peripheral vascular resistance decreases.

A decrease in renin activity in blood plasma is considered one of the mechanisms of action underlying the antihypertensive effect of beta-blockers. Bisoprolol reduces the sympathoadrenergic response by blocking beta-adrenergic receptors 25/30 of the heart. This leads to a decrease in heart rate and myocardial contractility, resulting in a decrease in myocardial oxygen demand, which is the desired effect for angina pectoris associated with coronary artery disease.

Perindopril Arterial hypertension Perindopril is a drug for the treatment of arterial hypertension of any severity. Against the background of its use, there is a decrease in both systolic and diastolic blood pressure (BP) in the “lying” and “standing” positions. Perindopril reduces total peripheral vascular resistance, which leads to a decrease in blood pressure and an improvement in peripheral blood flow without changing heart rate. As a rule, taking perindopril increases renal blood flow, but the glomerular filtration rate (GFR) usually does not change. Clinical efficacy and safety of Bisoprolol In a study involving patients with CHF III and IV functional class according to the NYHA classification, with an ejection fraction <35% according to echocardiography, a decrease in overall mortality was shown from 17.3% to 11.8%. There was a reduction in sudden deaths and a reduction in the number of heart failure-related episodes requiring hospitalization. As a result, a significant improvement in the functional status of CHF according to the NYHA classification was shown.Perindopril Arterial hypertension: The maximum antihypertensive effect develops 4-6 hours after a single oral dose and persists for at least 24 hours: residual effects are observed, which amount to approximately 87-100% of the maximum effects. The decrease in blood pressure occurs quickly. In patients who respond to treatment, normalization of blood pressure is achieved within a month and is maintained without the development of tachyphylaxis. Stopping therapy does not cause a rebound effect.Perindopril reduces left ventricular hypertrophy. Perindopril has a vasodilating effect. It helps restore the elasticity of large arteries and reduce the wall thickness:lumen ratio for small arteries. Adjuvant therapy with thiazide diuretics causes synergy in the form of summation of effects. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of hypokalemia associated with diuretic treatment. Patients with stable coronary heart disease: The effectiveness of perindopril in patients over 18 years of age with stable coronary artery disease without clinical symptoms of heart failure was studied during a 4-year study. 90% of study participants had previously suffered a myocardial infarction and/or a revascularization procedure.Most patients received medications based on standard therapy, including platelet aggregation inhibitors, lipid-lowering agents, and beta-blockers. The primary efficacy measure was a composite endpoint of cardiovascular mortality, nonfatal myocardial infarction, and/or cardiac arrest with successful resuscitation. Therapy with perindopril tert-butylamine at a dose of 8 mg/day (equivalent to 10 mg perindopril arginine) led to a significant reduction in the absolute risk of complications by 1.9% 26/30 (relative risk reduction – 20%). In patients with a previous myocardial infarction or revascularization procedure, the absolute risk reduction was 2.2% (relative risk reduction 22.4%) compared with the placebo group.When perindopril was added to patients receiving a beta-blocker, there was a significant reduction in the absolute risk of cardiovascular mortality, non-fatal myocardial infarction and/or cardiac arrest with successful resuscitation by 2.2% (relative risk reduction – 24%) compared with beta-blocker therapy without the addition of perindopril. Dual blockade of the renin-angiotensin-aldosterone system (RAAS):There are data from clinical studies of combination therapy using an ACE inhibitor and an angiotensin II receptor antagonist (ARA II). A clinical study was conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by confirmed target organ damage, as well as studies in patients with type 2 diabetes mellitus and diabetic nephropathy. Study data did not reveal a significant positive effect of combination therapy on the occurrence of renal and/or cardiovascular events and on mortality rates, while the risk of hyperkalemia, acute renal failure and/or arterial hypotension increased compared with monotherapy.Taking into account the similar intragroup pharmacodynamic properties of ACE inhibitors and ARB II, these results can be expected for the interaction of any other drugs, representatives of the classes of ACE inhibitors and ARA II. Therefore, ACE inhibitors and ARB II should not be used simultaneously in patients with diabetic nephropathy. There is data from a clinical study examining the effect of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin-converting enzyme inhibitor II in patients with type 2 diabetes mellitus and chronic kidney disease or cardiovascular disease, or a combination of these diseases. The study was stopped early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were observed more often in the group of patients receiving aliskiren compared with the placebo group; Also, adverse events and serious adverse events of special interest (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group. Children Data on the safety and effectiveness of the drugPrestilol is not available in children.Pharmacokinetic propertiesThe rate and extent of absorption of bisoprolol and perindopril as part of the drug Prestilol do not differ significantly from the pharmacokinetics of bisoprolol and perindopril when taken separately as monotherapy.BisoprololAbsorption Bisoprolol is almost completely (>90%) absorbed from the gastrointestinal tract. Due to its low first pass metabolism (approximately 10%), its bioavailability after oral administration is approximately 90%. Distribution 27/30 Volume of distribution is 3.5 l/kg. The binding of bisoprolol to plasma proteins is approximately 30%. Biotransformation Bisoprolol is excreted from the body in two ways. 50% is metabolized in the liver to form inactive metabolites, which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in unchanged form.

The total clearance is approximately 15 l/h.

Elimination

The half-life from blood plasma is 10-12 hours, which ensures that the effect is maintained for 24 hours after dosing once a day. Special groups of patients Impaired renal function In a study in patients with renal failure (average creatinine clearance [CC] 28 ml/min), it was shown that a decrease in creatinine clearance is accompanied by an increase in Cmax, AUC (area under the concentration-time curve) and T1/2 of bisoprolol. Since bisoprolol is cleared equally by the kidneys and liver, there is no significant accumulation of bisoprolol in patients with severe renal failure. Impaired liver function In patients with liver cirrhosis, there is high variability and a significant slowdown in elimination compared to healthy people (T1/2 of bisoprolol ranges from 8.3 to 21.7 hours). No clinically significant differences in pharmacokinetics were identified between patients with normal and impaired liver function.

Chronic heart failure

In patients with CHF III functional class according to the NYHA classification, higher levels of bisoprolol in the blood plasma and an increased half-life were noted compared to healthy volunteers. The maximum concentration of bisoprolol in blood plasma at steady state is 64±21 ng/ml at a daily dose of 10 mg; The half-life is 17±5 hours. The pharmacokinetics of bisoprolol in patients with CHF and concomitant liver or kidney dysfunction have not been studied. Elderly In elderly patients, there is a slight increase in some pharmacokinetic parameters (T1/2, AUC, Cmax) of bisoprolol compared to young patients, presumably due to an age-related decrease in renal clearance. However, these differences are not clinically significant and do not require dose adjustment of bisoprolol.

Perindopril

Absorption

When taken orally, perindopril is rapidly absorbed, with maximum plasma concentrations achieved within 1 hour. The half-life from blood plasma is 1 hour.

Distribution

The volume of distribution of free perindoprilate is approximately 0.2 l/kg. The association of perindoprilate with plasma proteins, mainly with ACE, is 20% and is dose-dependent. Biotransformation Perindopril is a prodrug. 27% of the total amount of perindopril taken orally enters the bloodstream in the form of the active metabolite perindoprilate. In addition to the active perindoprilate, perindopril forms five inactive metabolites.

The concentration of perindoprilate in the blood plasma reaches a maximum within 3-4 hours. 28/30 Eating reduces the rate of conversion of perindopril to perindoprilat and, therefore, its bioavailability, therefore perindopril arginine should be taken orally once a day in the morning before meals. Elimination Perindoprilat is excreted from the body by the kidneys, and the terminal half-life of the free fraction is approximately 17 hours, resulting in an equilibrium state achieved within 4 days. Linearity It has been shown that the relationship between the dose of perindopril and its concentration in the blood plasma is linear.

Special patient groups

The elimination of perindoprilate is slowed down in elderly patients, as well as in patients with cardiac or renal failure. In case of renal failure, it is advisable to adjust the dose depending on the degree of renal impairment (creatinine clearance). The dialysis clearance of perindoprilate is 70 ml/min. The pharmacokinetics of perindopril in patients with liver cirrhosis is altered: the hepatic clearance of the parent molecule is reduced by half. However, the amount of perindoprilate formed does not decrease and, therefore, no dose adjustment is required.

Special instructions

With caution

Patients with an increased risk of developing severe arterial hypotension, hypovolemia and hyponatremia (due to a salt-free diet and/or previous diuretic therapy, dialysis, vomiting, diarrhea), unstable angina, cerebrovascular diseases, renovascular hypertension, primary hyperaldosteronism, history of angioedema, patients of the Negroid race, risk factors for the development of hyperkalemia, simultaneous use with potassium-sparing diuretics, drugs containing potassium salts, with lithium preparations, simultaneous use of aliskiren and drugs containing aliskiren in patients without diabetes mellitus or impaired renal function, simultaneous use of angiotensin II receptor antagonists (ARA II) in patients without diabetic nephropathy, simultaneous use with blockers of “slow” calcium channels, class I antiarrhythmic drugs or centrally acting antihypertensive drugs, abrupt cessation of therapy, bradycardia, AV block of the first degree, mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy, Prinzmetal angina, impaired renal function, bilateral renal artery stenosis, neutropenia/agranulocytosis/thrombocytopenia/anemia, immunosuppressive therapy, allopurinol, procainamide (risk of developing neutropenia, agranulocytosis), patients after kidney transplantation, hemodialysis using high-flow membranes (risk of developing anaphylactoid reactions), patients undergoing low-density lipoprotein (LDL) apheresis, patients during desensitizing treatment, type 1 diabetes mellitus and type 2 diabetes mellitus with significant fluctuations in blood glucose concentrations, severe forms of chronic obstructive pulmonary disease, mild forms of bronchial asthma, bronchospasm (history), strict diet, mild to moderate peripheral arterial circulation disorders, extensive surgical interventions and general anesthesia (risk of developing an excessive decrease in blood pressure), psoriasis, pheochromocytoma, hyperthyroidism, severe liver dysfunction, restrictive cardiomyopathy, congenital heart defects or heart valve disease with severe hemodynamic disorders, myocardial infarction suffered in the last 3 months, allergic reactions (history), congenital deficiency of glucose-6-phosphate dehydrogenase
(isolated cases of hemolytic anemia), systemic connective tissue diseases (systemic lupus erythematosus, scleroderma, etc.).

All special instructions and precautions apply to the drug Prestilol
related to each component.

Bisoprolol

Termination of therapy and “withdrawal syndrome”. Do not abruptly interrupt treatment with bisoprolol or change the recommended dose without
prior consultation with a doctor, as this may lead to a temporary deterioration in heart function. Treatment should not be interrupted suddenly, especially in patients with coronary artery disease (worsening attacks of angina, development of myocardial infarction and the occurrence of
ventricular arrhythmias in patients with coronary artery disease with sudden cessation of beta-blockers). If discontinuation of treatment is necessary, the dose of bisoprolol should be reduced gradually.

In case of significant worsening of angina or development of acute coronary syndrome, bisoprolol should be temporarily resumed.

Diseases for which it is necessary to use the drug with caution

Bisoprolol should be used with caution in the following cases:

• severe forms of COPD and non-severe forms of bronchial asthma;
• diabetes mellitus with significant fluctuations in blood glucose concentration:
bisoprolol may mask the symptoms of hypoglycemia (marked decrease
blood glucose concentrations), such as tachycardia, palpitations or increased
sweating;
• strict diet;
• carrying out desensitizing therapy;
• atrioventricular block of the first degree;
• vasospastic angina (Prinzmetal’s angina). Cases of spasm have been observed
coronary vessels. Despite the high beta-1 selectivity of bisoprolol, when it
Prescription to patients with angina Prinzmetal cannot be completely excluded
development of angina attacks);
• mild to moderate peripheral arterial circulation disorder
(intensification of symptoms may occur at the beginning of therapy);
• psoriasis (including history).

Diseases of the cardiovascular system

Beta blockers should not be used in decompensated chronic heart failure until the patient’s condition has stabilized. At the initial stages of using bisoprolol, patients need constant monitoring. Beta blockers may cause bradycardia. If the resting heart rate decreases to less than 50-55 beats/min, the dose should be reduced or discontinued taking bisoprolol.
Like other beta blockers, bisoprolol may cause a prolongation of the PQ interval by
ECG.

Bisoprolol should be used with caution in patients with first degree atrioventricular block. Non-selective beta-blockers may increase the frequency and duration of angina attacks in patients with vasospastic angina (Prinzmetal’s angina) due to alpha-receptor-mediated coronary vasoconstriction
arteries. Cardioselective beta1-blockers (including bisoprolol) should be used with caution in vasospastic angina.

To date, there is insufficient data regarding the use of bisoprolol in patients with CHF in combination with type 1 diabetes mellitus, severe renal and/or liver dysfunction, restrictive cardiomyopathy, congenital heart defects or heart valve disease with severe hemodynamic disturbances. Also, sufficient data have not yet been obtained regarding patients with CHF with myocardial infarction within the last 3 months.

Respiratory system

Despite the fact that selective beta1-blockers have a lesser effect on the function of the respiratory system than non-selective beta-blockers, patients with chronic obstructive pulmonary disease COPD and mild forms of bronchial asthma should be prescribed bisoprolol with extreme caution and only if possible
the benefits of its use outweigh the potential risks.

For bronchial asthma or COPD, simultaneous use of bronchodilators is indicated. In patients with bronchial asthma, there may be an increase in airway resistance, which requires a higher dose of beta2-agonists.

In patients with COPD, bisoprolol prescribed in combination therapy to treat heart failure should be started at the lowest dose possible and patients should be closely monitored for new symptoms (eg, shortness of breath, exercise intolerance, cough).

Major surgery and general anesthesia

If surgical interventions are necessary, the anesthesiologist should be warned that the patient is taking beta-blockers (risk of drug interactions with the development of severe bradyarrhythmias, reduction of reflex tachycardia and arterial hypotension). It is recommended not to stop taking bisoprolol in the perioperative period unless clearly necessary (since blockade of beta-adrenergic receptors reduces the risk of arrhythmias and myocardial ischemia during induction of anesthesia and tracheal intubation). If it is necessary to interrupt treatment with bisoprolol before surgery, the drug should be discontinued at least 48 hours before surgery.

Pheochromocytoma

In patients with pheochromocytoma, bisoprolol can only be prescribed while using alpha-blockers.

Thyrotoxicosis

With hyperthyroidism, beta-blockers (including bisoprolol) can mask tachycardia and reduce the severity of symptoms of thyrotoxicosis. Abrupt withdrawal of the drug may cause an exacerbation of the symptoms of the disease and the development of a thyrotoxic crisis.

Hypersensitivity reactions

Beta blockers, including bisoprolol, may increase sensitivity to allergens and the severity of anaphylactic/hypersensitivity reactions due to decreased adrenergic compensatory regulation by beta blockers. The use of conventional therapeutic doses of epinephrine (adrenaline) while taking beta-blockers does not always lead to the achievement of the desired clinical effect. Caution should be exercised when prescribing bisoprolol to patients with a history of severe hypersensitivity reactions or undergoing desensitization.

Psoriasis

When deciding on the use of bisoprolol in patients with psoriasis, one should carefully weigh the expected benefits of using the drug and the possible risk of exacerbation of psoriasis.

Contact lenses

Patients who use contact lenses should take into account that the use of beta-blockers may reduce the production of tear fluid.

Perindopril

Severe arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Severe arterial hypotension rarely develops in patients with uncomplicated arterial hypertension. The risk of excessive reduction in blood pressure is increased in patients with reduced blood volume, for example, during diuretic therapy, while following a strict salt-free diet, hemodialysis, diarrhea or vomiting, as well as in patients with severe arterial hypertension with high renin activity (see sections 4.5. and 4.8.). Severe arterial hypotension can be observed in patients with clinical manifestations of heart failure, both with and without renal failure. This risk is more likely in patients with 7/30 severe heart failure as a reaction to loop diuretics, hyponatremia or functional renal failure. Patients at increased risk of developing symptomatic hypotension should be under close medical supervision during initiation of therapy and dose adjustment. A similar approach is applied to patients with coronary artery disease or cerebrovascular disease in whom
An excessive decrease in blood pressure can lead to the development of myocardial infarction or acute cerebrovascular accident.

If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of 9 mg/ml (0.9%) sodium chloride solution. Transient arterial hypotension is not a contraindication for further use of the drug. As a rule, the drug can be continued after replenishment of blood volume and increase in blood pressure.

In some patients with CHF who have normal or low blood pressure, an additional decrease in blood pressure may occur as a result of the action of perindopril. This effect is predictable and does not usually require discontinuation of therapy. If symptoms of arterial hypotension develop
It may be necessary to reduce the dose or gradually discontinue the drug, or use its individual components as monotherapy.

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported in patients treated with ACE inhibitors, including perindopril (see section 4.8.). These phenomena can develop in any
moment of treatment. In such cases, treatment with Prestilol should be stopped immediately. Therapy with beta-blockers should be continued. The patient should be observed until signs of swelling completely disappear. In cases where the swelling affects only the face and lips, the condition usually resolves without treatment, although antihistamines may be used to relieve symptoms.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If these symptoms occur, emergency treatment is required, including subcutaneous injection of epinephrine (adrenaline) and/or airway management. The patient must be under medical supervision until complete and persistent
disappearance of symptoms. If the patient has a history of angioedema not associated with treatment with an ACE inhibitor, then the risk of developing angioedema while taking an ACE inhibitor may be increased.

In rare cases, the development of intestinal angioedema has been described in patients treated with ACE inhibitors. At the same time, patients experienced abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without
previous angioedema of the face and with normal levels of C-1 esterase. Diagnosis is made using abdominal computed tomography, ultrasound, or surgery. Symptoms disappeared after stopping the ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis it is necessary
take into account the possibility of developing angioedema of the intestine.

Combination valsartan+sacubitril

Due to the increased risk of developing angioedema, it is contraindicated
simultaneous use of perindopril with the combination of valsartan + sacubitril. The use of the combination of valsartan + sacubitril is possible no earlier than 36 hours after taking the last dose of perindopril. The use of perindopril is possible no earlier than
than 36 hours after the last dose of the valsartan + sacubitril combination. When ACE inhibitors are co-administered with NEP inhibitors (eg, racecadotril), mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus), and gliptins (eg, linagliptin, saxagliptin, sitagliptin, vildagliptin), the risk of developing angioedema (eg, edema
respiratory tract or tongue, accompanied or not accompanied by respiratory dysfunction). Caution should be exercised when prescribing racecadotril, mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus), and gliptins (eg, linagliptin, saxagliptin, sitagliptin, vildagliptin) to patients already taking an ACE inhibitor.

Liver failure

In rare cases, while taking ACE inhibitors, a syndrome of development of cholestatic jaundice with transition to fulminant liver necrosis, sometimes with death, is observed. The mechanism of development of this syndrome is unclear. Patients taking ACE inhibitors who develop jaundice or significant elevations in liver enzymes should stop taking the ACE inhibitor and receive appropriate medical treatment
observation.

Ethnic differences

In black patients, ACE inhibitors cause angioedema more often than in patients of other races.
Like other ACE inhibitors, perindopril may be less effective in lowering blood pressure in blacks than in other races, which may be due to a higher prevalence of low-renin conditions in blacks with hypertension.

Cough

Cough may occur when using ACE inhibitors. It is typical that the cough is dry, persistent and resolves after cessation of therapy. This should be taken into account when carrying out the differential diagnosis of cough.

Hyperkalemia

Increases in serum potassium concentrations have been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia because they inhibit the release of aldosterone. In patients with normal renal function, this effect is usually clinically insignificant. Risk factors for the development of hyperkalemia include renal failure, deterioration of renal function, age over 70 years, diabetes mellitus, certain concomitant conditions (dehydration, acute cardiac decompensation, metabolic acidosis) and concomitant use of potassium-sparing diuretics (for example, such as spironolactone, eplerenone, triamterene or
amiloride), potassium supplements or potassium-containing salt substitutes/food additives. Patients taking other drugs that increase serum potassium levels (eg, heparin, cotrimoxazole (fixed combination of trimethoprim and sulfamethoxazole) and especially aldosterone antagonists or ARB II are also at risk. The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes/dietary supplements, especially in patients with impaired renal function, may lead to significant increases Serum potassium concentrations. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. Potassium-sparing diuretics and ARBs should be used with caution and monitoring in patients receiving ACE inhibitors.
serum potassium levels and renal function. If the simultaneous use of the specified
above means are necessary, they should be used with caution against the background of regular monitoring of potassium levels in the blood serum.

Lithium preparations

The simultaneous use of perindopril and lithium preparations is not recommended. Potassium-sparing diuretics, potassium preparations, potassium-containing table salt substitutes and food additives The simultaneous use of perindopril and potassium-sparing diuretics is not recommended
as well as potassium preparations, potassium-containing substitutes for table salt and food additives. Dual blockade of the renin-angiotensin-aldosterone system
There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and renal dysfunction (including acute renal
failure). Thus, dual blockade of the RAAS by simultaneous use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended. If dual block therapy is considered absolutely necessary, it should only be carried out under strict medical supervision and with regular monitoring of renal function, blood electrolytes and blood pressure.
ACE inhibitors should not be used in combination with angiotensin II receptor blockers in patients with diabetic nephropathy. Mitral stenosis/aortic stenosis/hypertrophic cardiomyopathy As with other ACE inhibitors, perindopril should be used with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction, such as aortic valve stenosis or hypertrophic cardiomyopathy.

Renal dysfunction

In case of renal dysfunction, the daily dose of Prestilol is selected depending on creatinine clearance. For these patients, routine monitoring of blood potassium and creatinine concentrations is part of routine therapeutic practice. In patients with clinically significant symptoms of heart failure, hypotension resulting from initiation of treatment with ACE inhibitors may lead to further deterioration of renal function. Acute renal failure has been reported, which is usually reversible. In some patients with bilateral renal artery stenosis or solitary renal artery stenosis who were treated with ACE inhibitors, increases in serum urea and creatinine levels were observed, usually resolving when therapy was discontinued. This effect was observed more often in patients with renal failure. The additional presence of renovascular hypertension causes an increased risk of severe hypotension and renal failure in such patients. Treatment in such patients should be initiated at low doses under close medical supervision and with careful dose titration. Since treatment with diuretics may contribute to the development of the phenomena described above, diuretics should be temporarily discontinued and renal function monitored during the first weeks of therapy. In some patients with arterial hypertension without signs of renal vascular damage, an increase in serum urea and creatinine concentrations was observed, usually slight and transient, especially when perindopril and a diuretic were prescribed simultaneously. The development of such phenomena is more likely in patients with a history of impaired renal function. Dose reduction and/or discontinuation of the diuretic and/or perindopril may be required.

Renovascular hypertension

In patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney, the risk of arterial hypotension and renal failure increases during therapy with ACE inhibitors (see section 4.3.). The use of diuretics may be an additional risk factor. Deterioration of renal function can be observed with even a slight change in serum creatinine concentration, even in
patients with unilateral renal artery stenosis.

Kidney transplantation

There is no experience in treating patients with a previously transplanted kidney with perindopril arginine.

Patients on hemodialysis

Cases of anaphylactoid reactions have been reported in patients undergoing hemodialysis using high-flux membranes who received an ACE inhibitor. These patients should be treated with a different class of antihypertensive drug or use a different type of dialysis membrane.

Anaphylactoid reactions during low-density lipoprotein apheresis

Life-threatening anaphylactoid reactions have rarely been observed in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions were prevented by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.

Anaphylactoid reactions during desensitization

Anaphylactoid reactions have been observed in patients receiving ACE inhibitors during desensitization therapy (eg, hymenoptera venom). Such reactions were prevented by temporary discontinuation of the ACE inhibitor, but if treatment was accidentally restarted, the reactions could develop again. As with other beta-blockers, bisoprolol may increase both sensitivity to allergens and the severity of anaphylactic reactions. Treatment with epinephrine (adrenaline) does not always give the expected therapeutic effect.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Cases of neutropenia/agranulocytosis, thrombocytopenia and anemia have been described in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases, those receiving immunosuppressants, allopurinol or procainamide, or a combination of these risk factors, especially if there is a history of renal impairment. Some of these patients developed severe infections, in some cases refractory to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the white blood cell count and instruct patients to report any signs of infectious diseases (for example, sore throat, fever) to the doctor.

Anesthesia

In patients undergoing major surgery or the use of anesthetic agents that cause hypotension, the use of perindopril may block the formation of angiotensin II against the background of compensatory renin release.

Treatment should be stopped one day before surgery. If arterial hypotension develops according to the specified mechanism, blood pressure should be maintained by replenishing blood volume.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually not responsive to antihypertensive drugs that act by inhibiting the RAAS. Therefore, the use of this drug in these patients is not recommended.

Active ingredient

Bisoprolol, Perindopril

Composition

Active ingredients: 10 mg bisoprolol fumarate (corresponds to 8.49 mg bisoprolol and 10 mg perindopril arginine (corresponds to 6.790 mg perindopril).

Pregnancy

Pregnancy

Considering the influence of individual components of this combination, Prestilol is contraindicated during pregnancy.

Bisoprolol

Bisoprolol has pharmacological effects that may have a negative impact on the course of pregnancy and/or the condition of the fetus/newborn (decreased placental blood flow, accompanied by fetal growth restriction, intrauterine fetal death, termination of pregnancy or premature birth, as well as adverse events (for example, hypoglycemia and bradycardia) in the fetus or newborn). If therapy with beta-blockers is necessary, then in this situation preference should be given to beta1-blockers. Bisoprolol should not be used during pregnancy unless absolutely indicated. If treatment with bisoprolol is considered necessary, monitoring of uteroplacental blood flow and fetal growth should be carried out. If adverse effects on pregnancy or fetal development occur, alternative treatment options should be considered. The newborn should be closely monitored. Symptoms of hypoglycemia and bradycardia can usually be expected within the first 3 days of life.

Perindopril

At the moment, there is no conclusive epidemiological data on the teratogenic risk when taking ACE inhibitors in the first trimester of pregnancy. However, a slight increase in the risk of fetal developmental disorders cannot be excluded. Patients planning pregnancy should be prescribed an alternative antihypertensive agent with an established safety profile for use during pregnancy. If pregnancy is established, treatment with ACE inhibitors should be stopped immediately and, if necessary, alternative antihypertensive therapy should be prescribed.

It is known that therapy with an ACE inhibitor in the second and third trimesters of pregnancy can have a fetotoxic effect on the human fetus (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and lead to the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia). In case of exposure to ACE inhibitors in the second and third trimester of pregnancy, it is recommended to perform an ultrasound examination to assess the renal function and condition of the fetal skull bones.

Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision due to the risk of developing arterial hypotension.

Lactation

The drug Prestilol is contraindicated during breastfeeding. It is not known whether bisoprolol is excreted into breast milk in humans. Due to the lack of information regarding the use of perindopril during breastfeeding, its use
contraindicated. During breastfeeding, it is recommended to use other drugs with a more studied safety profile, especially when feeding newborns or premature infants.

Fertility

There are no clinical data on the effect of Prestilol on reproductive function.

Contraindications

Hypersensitivity to the active substances, other ACE inhibitors or to any of the excipients listed in this section.

• Acute heart failure or episodes of decompensated heart failure requiring intravenous inotropic drugs
• Cardiogenic shock
• Atrioventricular (AV) block 2 or 3 degrees (without pacemaker)
• Sick sinus syndrome
• Sinoatrial block
• Severe bradycardia (heart rate less than 60 beats/min) before starting therapy
• Severe hypotension (systolic blood pressure less than 100 mmHg)
• Severe forms of bronchial asthma
• Severe peripheral arterial circulation disorders or severe forms of Raynaud’s syndrome
• Untreated pheochromocytoma
• Metabolic acidosis
• History of angioedema (Quincke’s edema) while taking other ACE inhibitors
• Hereditary or idiopathic angioedema
• Pregnancy and breastfeeding
• Collapse
• Combined use with drugs containing aliskiren in patients with diabetes mellitus or impaired renal function (GFR < 60 ml/min/1.73 m² body surface area)
• Combined use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy
• Combined use with the combination of valsartan + sacubitril. Prestilol should not be taken earlier than 36 hours after the last dose of the valsartan + sacubitril combination
• Extracorporeal therapy resulting in contact of blood with negatively charged surfaces 4/30
• Severe bilateral renal artery stenosis or single artery stenosis
functioning kidney

Side Effects

Infections infestations

Rhinitis:
Bisoprolol – Rarely
Perindopril – Very rare
Disorders of the blood side of the lymphatic system

Perindopril
Very rare: Agranulocytosis, Pancytopenia, Leukopenia, Neutropenia, Thrombocytopenia, Hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase (G-6-FDG) deficiency.
Uncommon: Eosinophilia.
Metabolic and nutritional disorders

Perindopril

Uncommon: Hypoglycemia, Hyperkalemia, reversible after discontinuation of the drug, Hyponatremia.
Mental disorders

Bisoprolol

Uncommon: Sleep disturbances, Depression.
Rare: Nightmares, hallucinations
Perindopril
Uncommon: Mood disturbances, Sleep disturbances
Very rare: Confusion
Nervous system disorders

Bisoprolol
Common: Headache**, Dizziness** Rare: Fainting
Perindopril
Common: Vertigo, Dysgeusia, Paresthesia
Uncommon* : Drowsiness, Fainting
Visual disorders

Bisoprolol
Rare: Reduced tear production (consider in patients using contact lenses).
Very rare: Conjunctivitis.
Perindopril
Common: Visual impairment.
Hearing disorders

Bisoprolol
Rare: Hearing impairment
Perindopril
Common: Tinnitus
Cardiac disorders

Bisoprolol
Very common: Bradycardia
Common: Worsening of heart failure
Perindopril
Uncommon: Palpitations, Tachycardia
MedDRA Classes and Organ Systems

Bisoprolol
Uncommon: AV conduction disturbance.
Perindopril

Very rare: Arrhythmia, Angina pectoris, Myocardial infarction, possibly due to excessive reduction in blood pressure in high-risk patients

Vascular disorders

Bisoprolol
Common: Decreased blood pressure and related effects, Feeling of coldness or numbness in the extremities
Uncommon: Orthostatic hypotension
Perindopril
Common: Decreased blood pressure and related effects
Uncommon*: Vasculitis
Very rare: Stroke, possibly due to excessive reduction in blood pressure in high-risk patients (see section “Special instructions”) Respiratory, thoracic and mediastinal disorders
Bisoprolol
Uncommon: Bronchospasm
Perindopril
Common: Cough, Shortness of breath
Uncommon: Bronchospasm
Very rare: Eosinophilic pneumonia
Gastrointestinal disorders

Bisoprolol
Common: Abdominal pain, Constipation, Diarrhea, Nausea.
Perindopril
Common: Abdominal pain, Constipation, Diarrhea, Nausea.
Bisoprolol
Common: Vomiting – Perindopril
Common: Dyspepsia, Vomiting
Uncommon: Dry oral mucosa
Very rare: Pancreatitis
Disorders of the liver and biliary tract

Bisoprolol
Rare: Cytolytic or cholestatic hepatitis
Perindopril
Very rare: Cytolytic or cholestatic hepatitis
Disorders of the skin and subcutaneous tissue

Bisoprolol

Rare: Hypersensitivity reactions (itching, redness, skin rash).

Very rare: Alopecia, Beta blockers may cause or worsen psoriasis or may cause a psoriasis-like rash

Perindopril
Common: Skin rash, pruritus
Uncommon: Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria, hyperhidrosis.
Uncommon: Photosensitivity reactions, Pemphigoid
Rare*: Worsening of psoriasis
Very rare: Erythema multiforme
Musculoskeletal and connective tissue disorders

Bisoprolol
Uncommon: Muscle spasms, Muscle weakness.
Perindopril
Common: Muscle spasms.
Uncommon*: Arthralgia, Myalgia.
Renal and urinary tract disorders

Perindopril
Uncommon: Renal impairment
Very rare: Acute renal failure
Disorders of the reproductive system and mammary glands

Bisoprolol
Rare: Impaired potency
Perindopril
Uncommon: Erectile dysfunction
General disorders and complications at the injection site

Bisoprolol
Common: Asthenia, Fatigue
Perindopril
Common: Asthenia
Uncommon*: Chest pain, Malaise, Peripheral edema, Hyperthermia
Laboratory values ​​and results of other examinations

Bisoprolol
Rarely: Increased activity of liver transaminases, Increased triglyceride concentrations
Perindopril
Uncommon*: Increased blood urea concentration, Increased blood creatinine concentration
Rarely: Increased activity of “liver” transaminases, Increased concentration of bilirubin in the blood

Interaction

An interaction between bisoprolol and perindopril was not observed in studies involving healthy volunteers. Below is information about interactions with other drugs.

Drugs that increase the risk of developing angioedema:

The combined use of ACE inhibitors with the combination of valsartan + sacubitril is contraindicated, as this increases the risk of developing angioedema. The combination of valsartan + sacubitril can be taken no earlier than 36 hours after taking the last dose of perindopril.

Perindopril can be taken no earlier than 36 hours after taking the last dose of the valsartan + sacubitril combination
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus) and gliptins (eg, linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of developing angioedema.

Drugs that cause hyperkalemia: Although serum potassium levels usually remain within the normal range, some patients taking Prestilol may develop hyperkalemia. Certain drugs and classes of drugs may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), ACE inhibitors, ARB II, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants (such as cyclosporine or tacrolimus), trimethoprim and co-trimoxazole (sulfamethoxazole + trimethoprim), since trimethoprim is known to act like a potassium-sparing diuretic like amiloride. The combination of these drugs increases the risk of developing hyperkalemia. Therefore, the combined use of Prestilol with the above medications is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium levels.

Concomitant use is contraindicated:

Aliskiren: Concomitant use of Prestilol and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment due to the risk of hyperkalemia, deterioration of renal function and increased incidence of cardiovascular morbidity and mortality. Extracorporeal treatments: Extracorporeal treatments that expose blood to negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (eg, polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to the increased risk of severe anaphylactoid reactions (see section 4.3.). If such treatment is necessary, use of a different type of dialysis membrane or use of a different class of antihypertensive drugs should be considered.

Concomitant use is not recommended:

In connection with bisoprolol:

Centrally acting antihypertensives, such as clonidine and others (for example, methyldopa, moxonidine, rilmenidine): Concomitant use of centrally acting antihypertensives may worsen heart failure by reducing central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Abrupt cessation of therapy, especially before a previous beta-blocker dose reduction, may increase the risk of developing rebound hypertension.

Class I antiarrhythmic drugs (for example, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): simultaneous use may affect atrioventricular conduction, as well as enhance the negative inotropic effect.

Slow calcium channel blockers (verapamil and, to a lesser extent, diltiazem):

Negative effect on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients receiving beta-blockers can lead to severe arterial hypotension and atrioventricular block. Fingolimod: Fingolimod may enhance the negative chronotropic effect of beta-blockers and lead to significant bradycardia. Concomitant use of fingolimod and bisoprolol is not recommended. If simultaneous use of fingolimod and Prestilol is necessary, careful monitoring of the patient’s condition is required. It is recommended that combination therapy be initiated in a hospital setting and appropriate monitoring be carried out (long-term monitoring of heart rate is indicated, at least until the morning of the next day after the first simultaneous use of fingolimod and Prestilol).

In connection with perindopril:

Aliskiren: In patients without diabetes mellitus or renal impairment, the risk of hyperkalemia, deterioration of renal function, increased incidence of adverse cardiovascular events and cardiovascular mortality is also increased. Combination therapy with ACE inhibitors and AR II:

Data from clinical studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, ARB II or aliskiren is associated with a higher incidence of such adverse events.
phenomena such as arterial hypotension, hyperkalemia and decreased renal function (including acute renal failure), compared with the use of only one drug affecting the RAAS

Cases have been described in the literature in which, in patients with documented atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of an ACE inhibitor and an angiotensin receptor blocker was associated with a higher incidence of hypotension, syncope, hyperkalemia, and deterioration of renal function (including acute renal failure), compared with the use of only one drug affecting the RAAS. Dual blockade (eg, with a combination of an ACE inhibitor and an angiotensin II receptor antagonist) should be limited to isolated cases with careful monitoring of renal function, potassium levels and blood pressure.
Estramustine: there is a risk of increased incidence of adverse events such as angioedema.

Potassium-sparing diuretics (eg, triamterene, amiloride), potassium salts: Hyperkalemia may occur (possibly fatal), especially when combined with renal failure (additional effects associated with hyperkalemia). The combined use of perindopril and the above medications is not recommended. If simultaneous use is necessary, they should be used with
taking precautions and regularly monitoring serum potassium levels
blood.

Information on the use of spironolactone in heart failure is described

further in the text. Lithium preparations: with the combined use of lithium preparations and ACE inhibitors, a reversible increase in the concentration of lithium in the blood and associated toxic effects have been described. The use of perindopril in combination with lithium preparations is not recommended, but if
The use of such a combination is considered necessary; careful monitoring of lithium concentrations in the blood serum is required.

Concomitant use requiring special caution:

In connection with bisoprolol and perindopril:

Hypoglycemic agents (insulins, oral hypoglycemic agents): Based on epidemiological studies, it can be assumed that the use of ACE inhibitors simultaneously with hypoglycemic agents (insulins, oral hypoglycemic agents) may enhance the hypoglycemic effect with the risk of developing hypoglycemia. The development of this phenomenon appears to be more likely in the first weeks of combination therapy, as well as in patients with impaired renal function. The combined use of bisoprolol with insulin and oral hypoglycemic agents may increase the hypoglycemic effect. Beta-adrenergic receptor blockade may mask symptoms of hypoglycemia.

Non-steroidal anti-inflammatory drugs (including acetylsalicylic acid in doses ≥ 3 g/day): when ACE inhibitors and NSAIDs are used together (acetylsalicylic acid in a dose that has an anti-inflammatory effect, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs), a weakening of the antihypertensive effect of bisoprolol and perindopril.

In addition, the combined use of ACE inhibitors and NSAIDs may lead to an increased risk of deterioration of renal function, including the possibility of developing acute renal failure, as well as an increase in serum potassium, especially in patients with initially reduced renal function. This combination should be prescribed with caution, especially in elderly patients. Patients should receive an adequate amount of fluid, and it is recommended to monitor renal function both at the beginning of combination therapy and periodically during treatment. Antihypertensives and vasodilators: Concomitant use of antihypertensives and vasodilators (such as nitroglycerin, other nitrates or other vasodilators) or other drugs that have the ability to lower blood pressure (for example, tricyclic antidepressants, barbiturates, phenothiazines) may enhance the antihypertensive effects of perindopril and bisoprolol.

Tricyclic antidepressants/antipsychotics/general anesthetics: Concomitant use of ACE inhibitors with certain anesthetics, tricyclic antidepressants and antipsychotics may result in an additional reduction in blood pressure.

The simultaneous use of bisoprolol and anesthetics can lead to a decrease in reflex tachycardia and an increase in the risk of arterial hypotension.

Sympathomimetics: Concomitant use of bisoprolol and beta-sympathomimetics (such as dobutamine) may result in a decreased effect of both drugs.
Sympathomimetics that activate both beta- and alpha-adrenergic receptors (eg, norepinephrine, epinephrine): combination with bisoprolol may elicit the alpha-adrenergic receptor-mediated vasoconstrictor effects of these drugs, which may lead to increased blood pressure and worsening intermittent claudication. Such interactions are more common with non-selective beta-blockers.
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

In connection with bisoprolol:

Slow calcium channel blockers of the dihydropyridine series, such as felodipine and amlodipine: simultaneous use 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 possible.

Class III antiarrhythmic drugs (for example, amiodarone): may increase the effect on atrioventricular conduction.
Parasympathomimetics: Concomitant use may reduce atrioventricular conduction and increase the risk of bradycardia.

Local beta-blockers (for example, eye drops prescribed for the treatment of glaucoma): when used together, the systemic effects of bisoprolol may be enhanced. Digitalis preparations: decreased heart rate, slowed atrioventricular conduction. In connection with perindopril: Baclofen: increased antihypertensive effect. Blood pressure levels should be carefully monitored and the dose of the antihypertensive drug adjusted if necessary. Non-potassium-sparing diuretics: Patients receiving diuretics, and especially those with reduced circulating blood volume and/or salts, may experience an excessive decrease in blood pressure when initiating ACE inhibitor therapy.

The likelihood of hypotensive effects can be reduced by stopping diuretic therapy, replenishing circulating blood volume (CBV) or increasing salt intake before starting perindopril therapy, as well as prescribing perindopril at a low dose with a gradual increase in it.

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

In patients with CHF treated with diuretics, treatment with an ACE inhibitor should be started with very low doses and, if possible, after reducing the dose of the concomitantly used potassium-sparing diuretic.

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

Potassium-sparing diuretics (eplerenone, spironolactone): when taking eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day and ACE inhibitors in low doses: when treating patients with heart failure of functional class II – IV according to the NYHA classification with an ejection fraction <40%, and previously treated with ACE inhibitors and loop diuretics, there is risk of developing hyperkalemia (with possible death), especially if prescribed recommendations regarding
this combination of drugs. Before starting combination therapy, you should ensure that there is no 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 monthly during treatment.

Combinations of drugs requiring attention:

In connection with bisoprolol:

Mefloquine: increased risk of bradycardia. Monoamine oxidase (MAO) inhibitors (except MAO type B inhibitors): enhancement
antihypertensive effect of beta-blockers, but there is also a risk of hypertensive crisis. Ergot alkaloids: Non-hydrogenated ergot alkaloids increase the risk of developing peripheral circulatory disorders. Ergotamine increases the risk of developing the disorder
peripheral circulation. Pharmacokinetic interactions: Rifampin increases the metabolic clearance and shortens the half-life of bisoprolol. Usually no dose adjustment is required. Caution should be exercised when using bisoprolol simultaneously with inducers of liver microsomal oxidation isoenzymes.

It is possible to increase the concentration of bisoprolol in the blood plasma when used simultaneously with inhibitors of the CYP3A4 isoenzyme and reduce it when used simultaneously with CYP3A4 inducers. Bisoprolol may increase the plasma concentration of drugs metabolized by the isoenzyme CYP3A4 and possibly CYP2D6.

Pharmacokinetic studies did not reveal interactions of bisoprolol with thiazide diuretics, digoxin and cimetidine. Bisoprolol does not affect prothrombin time in patients receiving a stable dose of warfarin.

In connection with perindopril:

Gold preparations: In patients receiving injectable gold preparations (sodium aurothiomalate) concomitantly with an ACE inhibitor, including perindopril, the development of rare cases of nitritoid reactions (flushing, nausea, vomiting and hypotension) has been described.

Overdose

There are no data on overdose in humans with Prestilol.

Bisoprolol Symptoms The most common signs that can be expected to develop with an overdose of beta-blockers are bradycardia, arterial hypotension, bronchospasm, acute heart failure and hypoglycemia. To date, only a few cases of bisoprolol overdose (maximum dose: 2000 mg) have been described, which occurred in patients with arterial hypertension and/or coronary artery disease, with the development of bradycardia and/or arterial hypotension. All described patients recovered. The degree of individual sensitivity to bisoprolol following a single high dose varies widely, and patients with heart failure are likely to be more sensitive.

Treatment

In case of overdose, treatment should be stopped and supportive symptomatic therapy should be carried out. There is limited data suggesting that bisoprolol is poorly eliminated by dialysis.

Based on the expected pharmacological effects and recommendations for other beta-blockers, the following measures should be considered: Bradycardia: Intravenous atropine.

If the effect is insufficient, a drug with a positive chronotropic effect can be administered with caution. Sometimes a transvenous pacemaker may be required.

Severe arterial hypotension: intravenous fluids and vasoconstrictors should be administered. Intravenous glucagon may be effective. AV block (2nd or 3rd degree): careful monitoring of the patient’s condition and transvenous installation of a pacemaker are required.

Acute worsening of heart failure: intravenous administration of diuretics, inotropes, vasodilators.

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

Hypoglycemia: intravenous administration of glucose.

Perindopril Symptoms Data on overdose in humans are limited.

Symptoms associated with overdose of ACE inhibitors may include hypotension, circulatory shock, fluid and electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, restlessness and cough.

Treatment

For the treatment of overdose, intravenous infusion of sodium chloride solution at a concentration of 9 mg/ml (0.9%) is recommended. In case of severe arterial hypotension, the patient should be placed in a supine position with legs elevated. If necessary, angiotensin II and/or a catecholamine solution can be administered intravenously.

Perindopril can be removed from the systemic circulation using hemodialysis. If treatment-resistant bradycardia develops, a pacemaker may be required. It is necessary to constantly monitor indicators of basic vital functions of the body, the concentration of electrolytes and creatinine in the blood serum.

Storage conditions

Store at a temperature not exceeding 30 °C

Shelf life

30 months

Manufacturer

Servier Industry Laboratories, France