Prestilol pills 5mg+5mg, 30pcs

Composition

1 film-coated tablet contains: Active ingredients: bisoprolol fumarate 5 mg (corresponding to 4.24 mg bisoprolol), perindopril arginine 5 mg (corresponding to 3.39 mg perindopril). Auxiliary substances: 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, colloidal anhydrous silicon 0.48 mg, magnesium stearate 0.90 mg. Film coating: 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 yellow dye 0.06048 mg, iron oxide red dye 0.020382 mg

Pharmacological action

Bisoprolol

Bisoprolol is a highly selective blocker of β_-1-adrenergic receptors, which does not have a stimulating and corresponding effect on the immune system. membrane-stabilizing effect. It shows only a slight affinity for β2-adrenoreceptors of the smooth muscles of the bronchi and blood vessels, as well as for β2-adrenoreceptors involved in metabolic regulation. Thus, bisoprolol generally has no effect on airway resistance and metabolic processes involving β2-adrenergic receptors. The selective effect of bisoprolol on β1-adrenergic receptors persists 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 converts angiotensin I to the vasoconstrictor angiotensin II, and breaks down bradykinin, which has a vasodilating effect, to an inactive heptapeptide. ACE inhibition leads to a decrease in the concentration of angiotensin II in blood plasma, which causes an increase in plasma renin activity (by the “negative feedback” mechanism) and a decrease in aldosterone secretion.

Since ACE inhibits bradykinin, ACE inhibition is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin systems, while the prostaglandin system is also activated. It is possible that this effect is part of the mechanism of the antihypertensive action of ACE inhibitors, as well as the mechanism of the development of some side effects (for example, 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 maximum effect is observed 3-4 hours after taking the drug. Since T_1/2is 10-12 hours, bisoprolol is effective for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved after 2 weeks.

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

Bisoprolol reduces the sympatho-adrenergic response by blocking the beta-adrenergic receptors of the heart. This leads to a decrease in heart rate and myocardial contractility, as a result of which the myocardial oxygen demand decreases, which is a required effect in angina associated with coronary heart 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 in the “lying” and “standing” positions.

Perindopril reduces OPSS, which leads to a decrease in blood pressure and an improvement in peripheral blood flow without changing the heart rate.

As a rule, taking perindopril increases renal blood flow, but GFR usually does not change.

Clinical efficacy and safety of

Bisoprolol

In a study involving patients with NYHA FC III and IV CHF with an ejection fraction There was a decrease 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 use and persists for at least 24 hours: residual effects are observed, which are approximately 87-100% of the maximum effects. Blood pressure decreases rapidly. In patients who respond to treatment, blood pressure normalization is achieved within a month and persists without the development of tachyphylaxis.

Discontinuation of 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.

Adjunctive 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 coronary artery disease

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

Treatment with perindopril tert-butylamine at a dose of 8 mg / day (equivalent to 10 mg of perindopril arginine) resulted in a significant reduction in the absolute risk of complications by 1.9% (reduction in relative risk-20%). In patients who had previously had a 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% (reduction in relative risk – 24%) compared to beta-blocker therapy without the addition of perindopril.

Double blockade of the RAAS

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

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

These studies did not show 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 to monotherapy.

Taking into account the similar intragroup pharmacodynamic properties of ACE inhibitors and ARA 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 ARA II inhibitors should not be used simultaneously in patients with diabetic nephropathy.

There is evidence from a clinical study investigating the effect of adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes mellitus and chronic kidney disease or cardiovascular disease, or who have a combination of these diseases. The study was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular death and stroke were reported more frequently in the aliskiren-treated group compared to the placebo group, and adverse events and serious adverse events of particular interest (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Children’s patients

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

Indications

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

Contraindications

— hypersensitivity to bisoprolol, the perindopril, other ACE inhibitors or auxiliary substances included in the composition of the drug (see section “Dosage form, composition and packaging”);

acute heart failure or episodes of decompensation of heart failure, when required in intravenous inotropic drugs;

— cardiogenic shock;

— AV-block II and III degree (without pacemaker);

— SSSU;

— sinoatrial block;

— severe bradycardia (heart rate less than 60 beats/min);

— severe arterial hypotension (systolic blood pressure less than 100 mm Hg. St. )

— severe asthma or severe COPD;

— expressed by human peripheral blood circulation or severe forms of Raynaud’s syndrome;

— untreated pheochromocytoma (see section “Special instructions”);

metabolic acidosis;

— angioedema (Quincke’s edema) in patients receiving other ACE inhibitors in history (see “Special instructions”);

— hereditary or idiopathic angioedema;

collapse;

— simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m 2 of the body surface area) (“Pharmacokinetics” and “Drug interactions”);

— simultaneous use of antagonists of receptors of angiotensin II (ARA II) in patients with diabetic nephropathy (see section “Special instructions”);

— simultaneous use of a combination of securitel+valsartan (see “Special instructions”, “Drug interactions”);

— extracorporeal therapy, leading to contact of blood with negatively charged surfaces (see section “Drug interactions”);

severe bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see “Special instructions”);

pregnancy (see section “Pregnancy and lactation” and “Special instructions”);

— the period of breast-feeding (see “Pregnancy and lactation” and “Special instructions”);

— age up to 18 years.

With caution

Patients with an increased risk of severe hypotension, hypovolemia, and hyponatremia (due to the salt-free diet and/or prior diuretic therapy, dialysis, vomiting, diarrhea), cerebrovascular disease (including cerebrovascular insufficiency), coronary insufficiency, a history of angioedema, patients of the Negroid race, risk factors of hyperkalemia, the combination with lithium preparations, concomitant use of potassium-sparing diuretics, medications containing potassium salts, blockers of receptors of angiotensin, the simultaneous use of iliskilendirmesi drugs, combination with blockers of slow calcium channels, antiarrhythmic means class I or antihypertensive medications Central action, abrupt cessation of therapy, bradycardia, AV-block I degree, mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy, Prinzmetal’s angina, impaired renal function (GFR<90 ml/min), renovascular hypertension, bilateral renal artery stenosis, stenosis of the artery to a solitary kidney (risk of severe hypotension and renal failure), patients after kidney transplantation, hemodialysis using a high-flow membranes (risk of anaphylactoid reactions) patients during the procedure LDL apheresis patients during desensitization treatment, neutropenia/agranulocytosis/thrombocytopenia/anaemia, bronchospasm (bronchial asthma, obstructive Airways disease), diabetes mellitus type 1 and diabetes mellitus type 2 with significant fluctuations in the concentration of glucose in the blood, a strict diet, occlusive peripheral arterial disease, surgery/General anesthesia (risk of excessive loss AD), psoriasis, pheochromocytoma, hyperthyroidism, severe liver dysfunction, restrictive cardiomyopathy, congenital heart disease, hemodynamically significant organic lesions of the heart valves, myocardial infarction, transferred in the last 3 months, congenital deficiency of glucose-6-phosphate dehydrogenase (isolated cases of hemolytic anemia), connective tissue diseases (including systemic lupus erythematosus, scleroderma), depression (including in history).

Side effects

Adverse reactions identified with bisoprolol monotherapy during clinical trials and / or in the post-marketing period: 

• infections and infestations: rare – rhinitis;
• mental disorders: infrequent – sleep disorders, depression;
• rarely – scary dreams, hallucinations;
• from the nervous system: often – headache, dizziness;
• rarely – a swoon;
• the part of the organ of vision: rarely – discounted tearing;
• rarely – conjunctivitis;
• on the part of the organ of hearing: rarely – hearing loss;
• heart: often – bradycardia;
• often worsen heart failure; 
• infrequently-violation of AV conduction; 
• from the side of the vessels: often, lower blood pressure (including accompanying effects), feeling numb or cold limbs;
• rarely – orthostatic hypotension;
• the gastro-intestinal tract: often – abdominal pain, nausea, vomiting, constipation, diarrhea, and
• hepatobiliary system: rarely – cytolytic or cholestatic hepatitis;
• the respiratory system, chest and mediastinum: rarely – bronchospasm;
• dermatological reactions: rarely – hypersensitivity reactions in the form of itching, redness, rash;
• very rarely – alopecia, the development of psoriasis or worsening of its course, the appearance of psoriasiform rash;
• on the part of the musculoskeletal system and connective tissue: infrequently – muscle spasms, muscle weakness;
• reproductive system and breast: rarely – violation of potency;
• General disorders: often – fatigue, asthenia;
• laboratory tests: rarely – increased activity of hepatic transaminases, increased levels of triglycerides.

Adverse reactions identified with perindopril monotherapy during clinical trials and / or in the post-marketing period: 

• infections and infestations: very rarely – rhinitis;
• the blood and lymphatic system: rarely – eosinophilia;
• very rarely – agranulocytosis, leukopenia, pancytopenia, thrombocytopenia, neutropenia, congenital deficiency of glucose-6-phosphate dehydrogenase – hemolytic anemia;
• on the part of metabolism and nutrition: infrequently – hypoglycemia, transient hyperkalemia, hyponatremia;
• mental disorders: infrequent – sleep disorders, disorders very rare – confusion;
• from the nervous system: often – headache, paresthesia, dizziness, dysgeusia, rare –
• on the part of the organ of vision: often – blurred vision;
• on the part of the organ of hearing: frequently – noise in ears;
• heart: rarely – palpitations, tachycardia; rarely – arrhythmia, angina, myocardial infarction;
• from the side of the vessels: often – decreased blood pressure (including accompanying effects); rarely, vasculitis; very rarely – stroke (most often in patients from high-risk groups, possibly due to a significant decrease in blood pressure);
• the respiratory system, chest and mediastinum: often – cough, shortness of breath; rarely – bronchospasm; very rarely – eosinophilic pneumonitis;
• from the gastrointestinal tract: often – abdominal pain, nausea, vomiting, dyspepsia, constipation, diarrhea; rarely, dryness of the mucous membrane of the mouth; very rarely – pancreatitis; hepatobiliary system: rarely – cytolytic or cholestatic hepatitis;
• dermatological reactions: often – itching, rash; rarely, angioneurotic edema (face, lips, mucous membranes, tongue, the glottis and/or larynx, extremities), rash, pemphigoid reaction of photosensitivity, rash; rarely – worsening of psoriasis; rarely – erythema multiforme;
• on the part of the musculoskeletal system and connective tissue: often – muscle spasms; infrequently – arthralgia, myalgia;
• from the urinary system: rarely – violation of kidney function; very rarely – acute renal failure;
• from the reproductive system and mammary glands: infrequent – erectile dysfunction; General disorders: often – asthenia; rarely, malaise, chest pain, peripheral edema, hyperthermia;
• laboratory findings: rarely is the high concentration of urea in the blood, the increase in the content of creatinine in the blood; rarely – increased activity of hepatic transaminases, increased bilirubin in the blood; very rarely – a decrease of hemoglobin and hematocrit;
• other: infrequently – fall.

Interaction

The interaction between bisoprolol and perindopril was not observed in studies involving healthy volunteers. Information on interactions with other drugs is provided below.

Medications that cause hyperkalemia. Certain medications and classes of medications may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor blockers, NSAIDs, heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. Combinations of these drugs increase the risk of hyperkalemia.

Simultaneous use is contraindicated (see the section “Contraindications”)

Aliskiren: concomitant use of Prestilol and aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function, as there is a risk of hyperkalemia, deterioration of renal function, and increased incidence of cardiovascular morbidity and mortality.

Extracorporeal methods of treatment: Extracorporeal treatments that cause blood to come into contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flow membranes (for example, polyacrylonitrile membranes) and LDL apheresis using dextran sulfate, are contraindicated due to the increased risk of severe anaphylactoid reactions (see section “Contraindications”). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or using a different class of antihypertensive medications.

Sacubitril+valsartan: concomitant use of perindopril with a combination of sacubitril+valsartan is contraindicated, since suppression of neprilysin simultaneously with the use of an ACE inhibitor may increase the risk of angioedema. The use of a combination of sacubitril+valsartan is possible no earlier than 36 hours after taking the last dose of perindopril. Use of perindopril is possible no earlier than 36 hours after taking the last dose of the combination sacubitril+valsartan (see sections “Contraindications” and “Special instructions”).

Simultaneous admission is not recommended

Related to bisoprolol

Antihypertensive agents of central action, such as clonidine and others (for example, methyldopa, moxonidine, rilmenidine): concomitant use of centrally acting antihypertensive agents may worsen the course of heart failure due to a decrease in central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Abrupt discontinuation of therapy, especially before a previous beta-blocker dose reduction, may increase the risk of rebound hypertension.

Antiarrhythmic drugs Class I (for example, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): combined use may affect AV 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 AV conduction. Intravenous use of verapamil to patients receiving beta-blockers may result in severe hypotension and AV block.

In connection with perindopril

Aliskiren: patients who do not have diabetes mellitus or impaired renal function also have an increased risk of hyperkalemia, deterioration of renal function, increased incidence of adverse events from the cardiovascular system, and mortality from cardiovascular diseases.

Concomitant treatment with ACE inhibitors and angiotensin receptor blockers: data from clinical studies have shown that double blockade of the RAAS by the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure), compared with the use of only one drug that affects the RAAS (see sections “Contraindications”, “Special Instructions” and “Pharmacological action”).

In the literature, cases have been described where in patients with confirmed atherosclerosis, heart failure, or diabetes mellitus with target organ damage, the simultaneous 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 that affects the RAAS. Dual blockade (for example, using 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.

Estramustin: there is a risk of increasing the frequency of adverse events such as angioedema.

Concomitant use with co-trimoxazole (trimethoprim+sulfamethoxazole)there may be an increased risk of hyperkalemia (see section “Special Warnings and Precautions for use”).

Potassium-sparing diuretics (for example, triamterene, amiloride), potassium salts: hyperkalemia may develop (with a possible fatal outcome), especially when combined with renal failure (additional effects associated with hyperkalemia). Concomitant use of perindopril and the above medications is not recommended (see the section “Special instructions”). If concomitant use is necessary, they should be used with the observance of precautions and regular monitoring of the potassium content in the blood serum. Information on the use of spironolactone in heart failure is described later in the text.

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

Simultaneous reception requires special care

In connection with bisoprolol and perindopril

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

NSAIDs (including acetylsalicylic acid in doses ≥3 g / day): taking Prestilol concomitantly with NSAIDs (i. e., acetylsalicylic acid in doses that have anti-inflammatory effects, COX-2 inhibitors, and non-selective NSAIDs) may weaken the antihypertensive effects of bisoprolol and perindopril.

In addition, concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of deterioration of renal function, including the possibility of acute renal failure, as well as an increase in serum potassium, especially in patients with initially reduced renal function. This combination should be used 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.

Antihypertensive and vasodilating agents: concomitant use of antihypertensive and vasodilating agents (such as nitroglycerin, other nitrates or other vasodilators) or other medications that have the ability to reduce blood pressure (for example, tricyclic antidepressants, barbiturates, phenothiazines) may increase the antihypertensive effects of perindopril and bisoprolol.

Tricyclic Antidepressants/Antipsychotics/General Anaesthetics: Concomitant use of ACE inhibitors with certain anaesthetics, tricyclic antidepressants, and antipsychotics may result in an additional reduction in blood pressure.

Concomitant use of bisoprolol and anaesthetics may reduce reflex tachycardia and increase the risk of hypotension.

Sympathomimetics: concomitant use of bisoprolol and beta-sympathomimetics (such as isoprenaline, dobutamine) may reduce the effect of both drugs.

Sympathomimetics that activate both beta-and alpha-adrenergic receptors (e. g., norepinephrine, epinephrine): combination with bisoprolol may reveal alpha-adrenergic-mediated vasoconstrictive effects of these drugs, which may lead to increased blood pressure and increased intermittent claudication. Such interactions are more typical for non-selective beta-blockers.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Related to bisoprolol

Dihydropyridine slow calcium channel blockers, such as felodipine and amlodipine: concomitant 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 not excluded.

Class III antiarrhythmic drugs (for example, amiodarone): it is possible to increase the effect on AV conductivity.

Parasympathomimetics: concomitant use may reduce AV conduction and increase the risk of developing bradycardia.

Topical beta-blockers (for example, eye drops prescribed for the treatment of glaucoma): when used concomitantly, the systemic effects of bisoprolol may increase.

Digitalis preparations: lower heart rate, slower AV conduction.

In connection with perindopril

Baclofen: increased antihypertensive effect. Blood pressure should be carefully monitored and, if necessary, the dose of the antihypertensive drug should be adjusted.

Potassium-sparing diuretics: patients receiving diuretics, and especially those with reduced BCC and/or salts, may experience an excessive decrease in blood pressure at the beginning of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by stopping diuretic therapy, replenishing BCC or increasing salt intake before starting perindopril therapy, as well as by prescribing perindopril in a low dose with a gradual increase.

In patients with arterial hypertension, when previous diuretic therapy may have caused a decrease in BCC/salts, it is necessary either to cancel the diuretic before starting treatment with an ACE inhibitor (in this case, a potassium-sparing diuretic can be prescribed again later), or to start therapy with an ACE inhibitor at a low dose, followed by a gradual increase.

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

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 – in the treatment of patients with NYHA FC II-IV heart failure with ejection fraction

Before starting combination therapy, you should make sure that there is no hyperkalemia and impaired renal function. 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.

Racecadotril: Angioedema has been reported with ACE inhibitors (such as perindopril). The risk of developing angioedema may increase with concomitant use of racecadotril (an antidiarrheal agent).

mTOR inhibitors (mammalian rapamycin targets) (e. g. sirolimus, everolimus, temsirolimus): patients receiving concomitant therapy with mTOR inhibitors may have an increased risk of developing angioedema (see section “Special instructions”).

Drug combinations that require attention

In connection with bisoprolol

Mefloquine: increased risk of developing bradycardia.

MAO inhibitors (excluding type B MAO inhibitors): increased antihypertensive effect of beta-blockers, but there is also a risk of hypertensive crisis.

In connection with perindopril

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): increased risk of angioedema due to decreased dipeptidyl peptidase IV (DPP-IV) activity under the action of gliptin in patients treated with an ACE inhibitor.

Gold preparations: patients receiving injectable gold preparations (sodium aurothiomalate) concomitantly with an ACE inhibitor, including perindopril, have been reported to develop rare cases of nitritoid reactions (flushing of blood to the face, nausea, vomiting, and hypotension).

How to take, course of use and dosage

Prestilol tablets are taken orally, in the morning before meals,1 time a day.

The dose of the drug is determined by the doctor on the basis of clinical indications, including taking into account the doses of bisoprolol and perindopril of previous monotherapy.

If 2.5 mg of bisoprolol and 2.5 mg of perindopril are indicated, take 1/2 tablet of Prestilol 5 mg + 5 mg 1 time a day.

When prescribing the drug at a dose of 2.5 mg bisoprolol and 5 mg perindopril, take 1/2 tablet with a dosage of 5 mg + 10 mg 1 time a day.

In case of impaired renal function, a single dose of Prestilol is prescribed taking into account individual creatinine clearance in the blood and can be the following amount of active components (bisoprolol + perindopril):

• Creatinine clearance 60 ml / min and above: the initial dose is 2.5 mg + 5 mg. In the absence of the desired therapeutic effect and good tolerability, the dose of bisoprolol can be increased and Prestilol 5 mg + 5 mg or 10 mg + 5 mg tablets can be used;
• creatinine clearance 30-60 ml / min: 2.5 mg + 2.5 mg (1/2 tablet at a dose of 5 mg + 5 mg);
• Creatinine clearance less than 30 ml / min: the drug should not be taken. It is recommended to select the doses of each component separately.

For the treatment of elderly patients, doses should be prescribed in accordance with the recommendations for patients with impaired renal function, and titration of doses should be carried out under the close supervision of a doctor.

Overdose

There are no data on overdose of Prestilol® in humans.

Bisoprolol

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

Treatment: in case of overdose, treatment should be discontinued and supportive symptomatic therapy should be provided. There is limited evidence that bisoprolol is poorly excreted during dialysis. Based on the expected pharmacological effects and recommendations for other beta-blockers, the following measures should be considered::

– Bradycardia – intravenous use of atropine. If the effect is insufficient, isoprenaline or another agent with a positive chronotropic effect can be administered with caution. Sometimes a transvenous installation of an artificial pacemaker may be required.

– Severe arterial hypotension – intravenous fluids and vasoconstrictors should be administered. Intravenous use of glucagon may be effective.

– AV block (II or III degree) – requires careful monitoring of the patient’s condition and infusion of isoprenaline or transvenous installation of an artificial pacemaker.

– Acute worsening of the course of heart failure – intravenous use of diuretics, inotropic agents, vasodilators.

– Bronchospasm – use of bronchodilators, such as isoprenaline, beta_-2-sympathomimetics and / or aminophylline.

– Hypoglycemia – intravenous use of glucose.

Perindopril

Symptoms: data on overdose in humans are limited. Symptoms associated with an ACE inhibitor overdose may include hypotension, circulatory shock, impaired water-electrolyte balance, renal failure, hyperventilation, tachycardia, palpitation, bradycardia, dizziness, restlessness, and coughing.

Treatment: for the treatment of overdose, an intravenous infusion of sodium chloride solution at a concentration of 9 mg/ml (0.9%) is recommended. With severe hypotension, the patient should be placed in a supine position with raised legs. If necessary, angiotensin II and/or a catecholamine solution may be administered intravenously. Perindopril can be removed from the systemic circulation by hemodialysis (see section “Special instructions”). If therapy-resistant bradycardia develops, it may be necessary to install an artificial pacemaker. It is necessary to constantly monitor the indicators of the main vital functions of the body, the concentration of electrolytes and creatinine in the blood serum.

Special instructions

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

Severe arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Severe arterial hypotension rarely develops in patients with an uncomplicated course of arterial hypertension. The risk of excessive blood pressure reduction is increased in patients with reduced BCC, for example, during diuretic therapy, with a strict salt-free diet, with hemodialysis, diarrhea or vomiting, as well as in patients with severe arterial hypertension with high renin activity (see sections “Drug interaction” and “Side effects”). Severe arterial hypotension may occur in patients with clinical manifestations of heart failure, both with and without renal insufficiency. This risk is more likely in patients with severe heart failure as a reaction to loop diuretics, hyponatremia, or functional renal failure. Patients with an increased risk of developing symptomatic hypotension should be closely monitored during the initiation of therapy and dose adjustment. A similar approach is also applied to patients with CHD or cerebrovascular disease, in which 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 “lying” position and, if necessary, an intravenous infusion of 9 mg/ml (0.9%) sodium chloride solution should be performed. Transient arterial hypotension is not a contraindication for further use of the drug. As a rule, the drug can be continued after filling the BCC and increasing 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 usually does not require discontinuation of therapy. If symptoms of arterial hypotension develop, it may be necessary to reduce the dose or gradually cancel 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 “Side effects”). These symptoms may occur at any time during treatment. In such cases, treatment with Prestilol should be discontinued immediately. Beta-blocker therapy should be continued. The patient should be monitored until the signs of edema disappear completely. In cases where the swelling only affects the face and lips, the condition usually resolves without treatment, although antihistamines can be used to relieve symptoms.

Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms occur, emergency therapy is required, including subcutaneous use of epinephrine (epinephrine) and / or ensuring airway patency. The patient should be under medical supervision until complete and persistent disappearance of symptoms. If the patient has a history of angioedema that is not associated with treatment with an ACE inhibitor, then the risk of developing angioedema against the background of taking an ACE inhibitor may be increased (see the section “Contraindications”).

In rare cases, patients treated with ACE inhibitors have been described to develop angioedema of the intestine. 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. The diagnosis is established by computed tomography of the abdominal cavity, ultrasound, or surgical intervention. Symptoms disappeared after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain treated with ACE inhibitors, the possibility of developing angioedema of the intestine should be taken into account during differential diagnosis.

mTOR inhibitors (e. g. sirolimus, everolimus, thermolimus)

Patients receiving concomitant therapy with mTOR inhibitors (for example, sirolimus, everolimus, temsirolimus) may have an increased risk of developing angioedema (including edema of the respiratory tract or tongue with/without respiratory disorders) (see the section “Drug interaction”).

Sacubitril+Valsartan combination

Due to the increased risk of angioedema, concomitant use of perindopril with a combination of sacubitril+valsartan is contraindicated (see the section “Contraindications”). The use of a combination of sacubitril+valsartan is possible no earlier than 36 hours after taking the last dose of perindopril. The use of perindopril is possible no earlier than 36 hours after taking the combination of sacubitril+valsartan (see the sections “Contraindications” and “Drug interaction”). Concomitant use of ACE inhibitors with other enkephalinase inhibitors (for example, racecadotril) may increase the risk of angioedema (see section “Drug interactions”). In patients receiving perindopril, the risk-benefit ratio should be carefully evaluated before prescribing enkephalinase inhibitors (for example, racecadotril).

Liver failure

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

Ethnic differences

In black patients, ACE inhibitors cause angioedema more often than in patients who are representatives of other races.

Like other ACE inhibitors, perindopril may be less effective in lowering blood pressure in black people than in other races, which may be associated with a higher prevalence of low-renin conditions in black people with arterial hypertension.

Cough

When using ACE inhibitors, coughing may occur. It is characteristic that the cough is dry, persistent and resolves after discontinuation of therapy. This should be taken into account when conducting a differential diagnosis of cough.

Hyperkalemia

Some patients receiving ACE inhibitors, including perindopril, have experienced increased serum potassium concentrations. 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 (such as spironolactone, eplerenone, triamterene or amiloride), potassium preparations or potassium-containing salt substitutes/supplements. Patients who take other medications that increase serum potassium levels (such as heparin) are also at risk. The use of potassium preparations, potassium-sparing diuretics or potassium-containing salt substitutes/dietary supplements, especially in patients with impaired renal function, can lead to a significant increase in serum potassium concentrations. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If concomitant use of the above drugs is necessary, they should be used with caution against the background of regular monitoring of the potassium content in the blood serum (see the section “Drug interaction”).

Lithium preparations

Concomitant use of perindopril and lithium preparations is not recommended (see section “Drug interactions”).

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

Simultaneous use of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing salt substitutes and food additives is not recommended (see the section “Drug interaction”).

Double blockade of the RAAS

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Thus, dual blockade of the RAAS by co-use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections “Drug interaction” and “Pharmacological action”). If dual blockade therapy is considered absolutely necessary, it should only be performed under strict medical supervision and with regular monitoring of kidney function, blood electrolyte levels, and blood pressure.

ACE inhibitors in combination with angiotensin II receptor blockers should not be used in patients with diabetic nephropathy.

Slow calcium channel blockers, Class I antiarrhythmics, and central-acting antihypertensives

Concomitant use of bisoprolol and calcium channel blockers such as verapamil or diltiazem, Class I antiarrhythmics and centrally acting antihypertensive agents is not recommended (see section “Drug interactions”).

Drug withdrawal

Abrupt discontinuation of beta-blocker therapy should be avoided, especially in patients with coronary artery disease, as this may lead to a temporary deterioration of cardiac activity. The dose should be reduced gradually, using individual components, preferably within 2 weeks and in parallel with the start of replacement treatment (if necessary).

Bradycardia

If during treatment the resting heart rate is reduced to 50-55 beats / min or less and the patient develops symptoms associated with bradycardia, you should start reducing the dose of Prestilol®, using individual components with an acceptable dose of bisoprolol.

AV blockage of the first degree

Given the negative dromotropic effect, beta-blockers should be prescribed with caution to patients with grade I AV blockade.

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 exit tract obstruction, such as aortic valve stenosis or hypertrophic cardiomyopathy.

Prinzmetal

angina Beta-blockers may increase the frequency and duration of angina episodes in patients with Prinzmetal angina. The use of selective beta_-1-blockers is possible with a mild degree of the disease and only in combination with vasodilators.

Kidney failure

In the case of renal insufficiency, the daily dose of Prestilol® is selected depending on the creatinine clearance (see the section “Dosage regimen”). For these patients, standard monitoring of blood potassium and creatinine concentrations is part of the usual therapeutic practice (see section “Side effects”). In patients with clinically significant symptoms of heart failure, hypotension as a result of starting treatment with ACE inhibitors may lead to further deterioration of renal function. Acute renal failure, which was usually reversible, has been reported.

Some patients with bilateral renal artery stenosis or single kidney artery stenosis who were treated with ACE inhibitors experienced elevated serum urea and creatinine levels, which usually disappear when therapy is discontinued. This effect was more often observed in patients with renal insufficiency. The additional presence of renovascular hypertension leads to an increased risk of severe hypotension and renal failure in these patients. Treatment in such patients should be initiated at low doses under close medical supervision and with careful titration of the dose. Since diuretic treatment may contribute to the development of the events 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 insignificant and transient, especially with simultaneous use of perindopril and a diuretic. Such events are more likely to occur in patients with a history of renal impairment. It may be necessary to reduce the dose and/or discontinue the diuretic and / or perindopril.

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney during ACE inhibitor therapy have an increased risk of hypotension and renal failure (see section “Contraindications”). The use of diuretics may be an additional risk factor. Deterioration of renal function can be observed even with 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 previously transplanted kidney with perindopril arginine.

Patients undergoing hemodialysis

Anaphylactoid reactions have been reported in patients undergoing hemodialysis using high-flow membranes who received an ACE inhibitor. These patients should be given a different class of antihypertensive medication or use a different type of dialysis membrane.

Anaphylactoid reactions during LDL apheresis

Patients receiving ACE inhibitors have rarely experienced life-threatening anaphylactoid reactions during the LDL apheresis procedure with dextran sulfate. These reactions were prevented by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.

Anaphylactoid reactions during desensitization

Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitizing therapy (e. g., hymenopteran venom). Such reactions were prevented by temporarily stopping the ACE inhibitor, but if the treatment was accidentally resumed, the reactions could develop again. As with other beta-blockers, bisoprolol can increase both sensitivity to allergens and the severity of anaphylactic reactions. Treatment with epinephrine (epinephrine) does not always give the expected therapeutic effect.

Neutropenia/agranulocytosis / thrombocytopenia/anemia

Neutropenia / agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other aggravating factors. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases treated with immunosuppressants, allopurinol or procainamide, or with a combination of these risk factors, especially if there is a history of impaired renal function. Some of these patients developed severe infections, which in some cases did not respond to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to conduct periodic monitoring of the content of white blood cells in the blood and instruct patients to inform the doctor about any signs of infectious diseases (for example, sore throat, fever).

Bronchospasm (bronchial asthma, obstructive airway disease)

For bronchial asthma and other chronic obstructive pulmonary diseases, concomitant treatment with bronchodilators should be carried out. Sometimes, when using beta-blockers in patients with bronchial asthma, airway resistance may increase, so an increase in the dose of beta_-2-adrenomimetics may be required.

Patients with diabetes mellitus

Caution is recommended when prescribing Prestilol® to patients with diabetes mellitus who have significant fluctuations in blood glucose levels. Symptoms of hypoglycemia may be masked by the effects of beta-blockers.

Strict diet

Caution is recommended when treating patients who follow a strict diet / fast.

Occlusive diseases of the peripheral arteries

When taking beta-blockers, symptoms may worsen, especially in the initial stages of treatment.

Anesthesia

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

In patients who are planning to undergo extensive operations or use anaesthetic 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. With the development of arterial hypotension by this mechanism, blood pressure should be maintained by filling the BCC.

Psoriasis

Patients with psoriasis or a history of psoriasis should be given beta-blockers only after careful assessment of the benefit-risk ratio.

Pheochromocytoma

In patients with confirmed or suspected pheochromocytoma, bisoprolol should always be given only in combination with an alpha-adrenergic blocker.

Hyperthyroidism

Symptoms of hyperthyroidism may be masked by treatment with bisoprolol.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism, as a rule, are not susceptible to antihypertensive drugs, the action of which is based on the inhibition of RAAS. Therefore, the use of this drug in such patients is not recommended

Pregnancy

Those planning pregnancy should be prescribed an alternative antihypertensive agent with an established safety profile for use during pregnancy, except in cases where ACE inhibitor therapy is considered necessary. If pregnancy is detected, treatment with ACE inhibitors should be stopped immediately and, if necessary, alternative antihypertensive therapy should be prescribed (see sections “Contraindications” and “Pregnancy and lactation”).

Heart failure

There is no experience of using bisoprolol for the treatment of heart failure in patients with the following diseases and conditions:

– type 1 diabetes mellitus;

– severe renal dysfunction;

– severe liver function disorders;

– restrictive cardiomyopathy;

– congenital heart defects;

– hemodynamically significant organic lesions of the heart valves;

– myocardial infarction suffered in the last 3 months.

Depression

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

Influence on the ability to drive vehicles and other mechanisms

The drug Prestilol® It does not directly affect the ability to drive a vehicle or work with mechanisms, 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 taken with alcohol.

As a result, the ability to drive a vehicle and work with mechanisms may be impaired.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C.

Shelf

life is 2 years.

Do not use after the expiration date indicated on the package.

Active ingredient

Bisoprolol, Perindopril

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Heart Failure, Hypertension, Arrhythmia