Prestilol^® (Tablets) Instructions for Use

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Servier Laboratories Industrie (France)

Packaging and Quality Control Release

Servier (Ireland) Industries, Ltd. (Ireland)

ATC Code

C09BX02 (Bisoprolol and perindopril)

Active Substances

Bisoprolol (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Prestilol®	Film-coated tablets, 5 mg+5 mg: 30 or 90 pcs.
		Film-coated tablets, 5 mg+10 mg: 30 or 90 pcs.
		Film-coated tablets, 10 mg+5 mg: 30 or 90 pcs.
		Film-coated tablets, 10 mg+10 mg: 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets orange-pink in color, oblong, biconvex, with a score line, engraved with “5/5″ on one side and engraved with ” on the other side.

Excipients: microcrystalline cellulose, calcium carbonate, pregelatinized starch, sodium carboxymethyl starch, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.

Film coating composition: glycerol, hypromellose, macrogol 6000, magnesium stearate, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172).

30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a desiccant (silica gel) (1) – cardboard packs with first-opening control.

Packaging for hospitals:
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a desiccant (silica gel) (3) – cardboard packs with first-opening control.

Film-coated tablets orange-pink in color, oblong, biconvex, with a score line, engraved with “5/10″ on one side and engraved with ” on the other side.

Excipients: microcrystalline cellulose, calcium carbonate, pregelatinized starch, sodium carboxymethyl starch, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.

Film coating composition: glycerol, hypromellose, macrogol 6000, magnesium stearate, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172).

30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a desiccant (silica gel) (1) – cardboard packs with first-opening control.

Packaging for hospitals:
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a desiccant (silica gel) (3) – cardboard packs with first-opening control.

Film-coated tablets orange-pink in color, round, biconvex, engraved with “10/5″ on one side and engraved with ” on the other side.

Excipients: microcrystalline cellulose, calcium carbonate, pregelatinized starch, sodium carboxymethyl starch, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.

Film coating composition: glycerol, hypromellose, macrogol 6000, magnesium stearate, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172).

30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a desiccant (silica gel) (1) – cardboard packs with first-opening control.

Packaging for hospitals:
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a desiccant (silica gel) (3) – cardboard packs with first-opening control.

Film-coated tablets orange-pink in color, oblong, biconvex, engraved with “10/10″ on one side and engraved with ” on the other side.

Excipients: microcrystalline cellulose, calcium carbonate, pregelatinized starch, sodium carboxymethyl starch, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.

Film coating composition: glycerol, hypromellose, macrogol 6000, magnesium stearate, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172).

30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a desiccant (silica gel) (1) – cardboard packs with first-opening control.

Packaging for hospitals:
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a desiccant (silica gel) (3) – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Antihypertensive combination drug (selective beta₁-adrenergic blocker + ACE inhibitor)

Pharmacotherapeutic Group

Antihypertensive combination agent (selective beta1-adrenoblocker+ACE inhibitor)

Pharmacological Action

Pharmacodynamics

Mechanism of action

Bisoprolol

Bisoprolol is a highly selective beta₁-adrenergic receptor blocker that does not have intrinsic sympathomimetic activity or relevant membrane-stabilizing activity. It exhibits only slight affinity for the beta₂-adrenergic receptors of bronchial and vascular smooth muscles, as well as for the beta₂-adrenergic receptors involved in metabolic regulation. Thus, bisoprolol generally does not affect airway resistance and metabolic processes involving beta₂-adrenergic receptors. The selective action of bisoprolol on beta₁-adrenergic receptors is maintained even 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 carries out both the conversion of angiotensin I to the vasoconstrictor substance angiotensin II and the breakdown of bradykinin, which has a vasodilatory effect, into an inactive heptapeptide. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which causes an increase in plasma renin activity (via the “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 action of ACE inhibitors, as well as the mechanism of development of some side effects (for example, cough).

Perindopril exerts its therapeutic effect through 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 noted 3-4 hours after taking the drug. Since the T_1/2 is 10-12 hours, bisoprolol acts for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved after 2 weeks.

When taken once by patients with coronary artery disease without chronic heart failure (CHF), bisoprolol reduces heart rate and stroke volume, leading to a decrease in cardiac output and oxygen consumption. With continuous use, the initially elevated peripheral vascular resistance decreases. The reduction in plasma renin activity is considered one of the mechanisms of action underlying the antihypertensive effect of beta-blockers.

Bisoprolol reduces the sympatho-adrenal response by blocking cardiac beta-adrenergic receptors. This leads to a decrease in heart rate and myocardial contractility, resulting in a reduction in myocardial oxygen demand, which is the desired effect in angina pectoris associated with coronary artery disease.

Perindopril

Arterial hypertension

Perindopril is a treatment for arterial hypertension of any severity. Its use leads to a decrease in both systolic and diastolic blood pressure in the “lying” and “standing” positions.

Perindopril reduces total peripheral 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, while the glomerular filtration rate usually does not change.

.

Pharmacokinetics

The rate and extent of absorption of bisoprolol and perindopril in the fixed combination do not differ significantly from the pharmacokinetics of bisoprolol and perindopril when taken separately as monotherapy.

Bisoprolol

Absorption

Bisoprolol is almost completely (>90%) absorbed from the gastrointestinal tract. Due to insignificant first-pass metabolism in the liver (approximately 10%), its bioavailability after oral administration is about 90%.

Distribution

The V_d is 3.5 L/kg. The binding of bisoprolol to plasma proteins is approximately 30%.

Metabolism and excretion

Bisoprolol is eliminated from the body by two routes. 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 unchanged. The total clearance is approximately 15 L/h. The T_1/2 from plasma is 10-12 hours, which ensures the effect is maintained for 24 hours after a single daily dose.

Special patient groups

The pharmacokinetics of bisoprolol are linear and independent of age.

Since elimination occurs equally through the kidneys and liver, dose adjustment for patients with impaired liver function or renal failure is not required. The pharmacokinetics in patients with CHF and impaired liver or kidney function have not been studied. In patients with NYHA functional class III CHF, the plasma concentration of bisoprolol is higher and the T_1/2 is longer compared to the same parameters in healthy volunteers. The C_max in plasma at steady state is 64±21 ng/ml when taking a daily dose of 10 mg, and the T_1/2 is 17±5 hours.

Perindopril

Absorption

When taken orally, perindopril is rapidly absorbed, with C_max in plasma reached within 1 hour. The T_1/2 from plasma is 1 hour.

Distribution

The V_d of free perindoprilat is approximately 0.2 L/kg. The binding of perindoprilat to plasma proteins, mainly to ACE, is 20% and is dose-dependent.

Metabolism

Perindopril is a prodrug. 27% of the total amount of perindopril taken orally enters the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril forms five inactive metabolites. The plasma concentration of perindoprilat reaches a maximum within 3-4 hours.

Food intake reduces the rate of conversion of perindopril to perindoprilat and, consequently, its bioavailability, therefore Perindopril arginine should be taken orally once a day in the morning before meals.

Excretion

Perindoprilat is eliminated from the body by the kidneys, and the terminal T_1/2 of the free fraction is approximately 17 hours, as a result, steady state is reached within 4 days.

Linearity

The relationship between the dose of perindopril and its plasma concentration has been shown to be linear.

Special patient groups

The elimination of perindoprilat is slowed in elderly patients, as well as in patients with heart or renal failure. In renal failure, it is advisable to adjust the dose depending on the degree of renal impairment (creatinine clearance).

The dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril in patients with liver cirrhosis are altered: the hepatic clearance of the parent molecule is reduced by 2 times. Nevertheless, the amount of perindoprilat formed does not decrease, and therefore, no dose adjustment is required.

Indications

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

ICD codes

Dosage Regimen

Orally in a single dose containing a fixed combination of active substances, once a day in the morning before meals.

Patients with impaired renal function require adjustment of the dosage regimen.

Patients with impaired liver function do not require dose adjustment.

In elderly patients, this combination should be used in accordance with the recommendations for patients with impaired renal function.

The safety and efficacy of using this combination in children and adolescents have not been established. Relevant data are not available. Therefore, use in this category of patients is contraindicated.

Adverse Reactions

The most common adverse reactions when taking bisoprolol include headache, dizziness, worsening of heart failure, arterial hypotension, feeling of cold extremities, nausea, vomiting, abdominal pain, diarrhea, constipation, asthenia and increased fatigue.

The most common adverse reactions when taking perindopril, reported in clinical studies, include headache, dizziness, vertigo, paresthesia, visual disturbances, tinnitus, arterial hypotension, cough, dyspnea, nausea, vomiting, abdominal pain, diarrhea, constipation, dysgeusia, dyspepsia, pruritus, skin rash, muscle cramps and asthenia.

The following classification is used to denote the frequency of adverse events reported during clinical studies and/or in the post-registration period with separate administration of bisoprolol or perindopril: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (frequency cannot be established from the available data).

*The frequency assessment of adverse reactions identified from spontaneous reports is based on data from clinical study results.

**Symptoms were usually observed at the start of therapy. They were usually mild and often resolved within 1-2 weeks.

Cases of syndrome of inappropriate antidiuretic hormone secretion have been noted with the use of other ACE inhibitors. The syndrome of inappropriate antidiuretic hormone secretion is a very rare but possible complication of therapy with ACE inhibitors, including perindopril.

Contraindications

• Hypersensitivity to bisoprolol, perindopril, other ACE inhibitors;
• Acute heart failure or episodes of decompensated heart failure requiring intravenous administration of inotropic drugs;
• cardiogenic shock;
• second- or third-degree atrioventricular (AV) block (without a pacemaker);
• sick sinus syndrome (SSS);
• sinoatrial block;
• severe bradycardia (heart rate less than 60 beats per minute);
• severe arterial hypotension (systolic blood pressure less than 100 mm Hg);
• severe bronchial asthma or severe chronic obstructive pulmonary disease (COPD);
• severe peripheral arterial circulatory disorders or severe forms of Raynaud’s syndrome;
• untreated pheochromocytoma (see the “Special Precautions” section);
• metabolic acidosis;
• history of angioedema (Quincke’s edema) associated with previous use of other ACE inhibitors;
• hereditary or idiopathic angioedema;
• collapse;
• concomitant use with drugs containing aliskiren in patients with diabetes mellitus or impaired renal function (GFR <60 ml/min/1.73 m² body surface area);
• concomitant use with angiotensin II receptor antagonists (ARBs) in patients with diabetic nephropathy;
• concomitant use with the combination of sacubitril + valsartan;
• extracorporeal therapies leading to blood contact with negatively charged surfaces;
• severe bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney;
• pregnancy;
• breastfeeding period;
• age under 18 years.

Use in Pregnancy and Lactation

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

Pregnancy

Considering the effects of the individual components of this combination, its use during pregnancy is contraindicated.

Bisoprolol

Bisoprolol has pharmacological effects that may have a negative impact on the course of pregnancy and/or the condition of the fetus/newborn (reduced placental blood flow accompanied by fetal growth retardation, intrauterine fetal death, abortion or premature birth, as well as adverse events (e.g., hypoglycemia and bradycardia) in the fetus or newborn). If beta-blocker therapy is necessary, beta₁-blockers should be preferred in this situation. Bisoprolol should not be used during pregnancy unless absolutely necessary. If treatment with bisoprolol is deemed necessary, monitoring of uteroplacental blood flow and fetal growth should be performed. If an adverse effect on the course of pregnancy or fetal development occurs, alternative treatment options should be considered. The newborn should be closely monitored.

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

Perindopril

There is currently no conclusive epidemiological data on the teratogenic risk of ACE inhibitor use in the first trimester of pregnancy. However, a slight increase in the risk of fetal developmental disorders cannot be ruled out. Patients planning a pregnancy should be switched to an alternative antihypertensive agent with an established safety profile for use during pregnancy. Once pregnancy is confirmed, treatment with ACE inhibitors should be discontinued immediately and, if necessary, alternative antihypertensive therapy should be initiated.

It is known that ACE inhibitor therapy during the second and third trimesters of pregnancy can have fetotoxic effects on the human fetus (impaired renal function, oligohydramnios, delayed skull ossification) and lead to complications in the newborn (renal failure, arterial hypotension, hyperkalemia). If exposure to ACE inhibitors occurred during the second and third trimesters of pregnancy, an ultrasound examination is recommended to assess fetal kidney function and skull status.

Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision due to the risk of arterial hypotension (see “Contraindications” and “Special Precautions” sections).

Breastfeeding period

This combination is contraindicated during breastfeeding. It is not known whether bisoprolol is excreted in human breast milk. Due to the lack of information regarding the use of perindopril during breastfeeding, its use is contraindicated. During breastfeeding, it is recommended to use other drugs with a better-studied safety profile, especially when feeding newborns or premature infants.

Use in Hepatic Impairment

For patients with hepatic impairment, no dose adjustment is required.

Use in Renal Impairment

For patients with renal impairment, the drug Prestilol^® is prescribed taking into account CrCl values.

Geriatric Use

For elderly patients, the drug should be prescribed in accordance with the recommendations for patients with renal impairment.

Special Precautions

All special warnings and precautions relating to each component apply to this combination.

Severe arterial hypotension

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

If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, intravenous infusion of 9 mg/ml (0.9%) sodium chloride solution should be administered. Transient arterial hypotension is not a contraindication for further use of the drug. As a rule, administration of the drug can be continued after restoration 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 usually does not require discontinuation of therapy. If symptoms of arterial hypotension develop, a dose reduction or gradual withdrawal of the drug, or the use of its individual components as monotherapy, may be required.

Hypersensitivity/Angioedema

Rare cases of angioedema affecting the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx have been reported in patients treated with ACE inhibitors, including perindopril. These phenomena can occur at any time during treatment. In such cases, treatment with this combination should be discontinued immediately. Beta-blocker therapy should be continued. The patient should be observed until the signs of edema have completely resolved. In cases where the edema affects only the face and lips, the condition usually resolves without treatment, although antihistamines may be used to relieve symptoms.

Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction. If such symptoms appear, emergency therapy is required, including subcutaneous administration of epinephrine (adrenaline) and/or ensuring airway patency. The patient should be under medical supervision until the symptoms have completely and permanently resolved. If the patient has a history of angioedema not associated with ACE inhibitor therapy, the risk of developing angioedema while taking an ACE inhibitor may be increased.

In rare cases, intestinal angioedema has been described in patients treated with ACE inhibitors. In these cases, patients experienced abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C-1 esterase levels. The diagnosis is made using computed tomography of the abdomen, ultrasound, or during surgery. Symptoms resolved after discontinuation of the ACE inhibitor. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

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

When used concomitantly with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), the risk of developing angioedema (including edema of the airways or tongue, with or without respiratory impairment) may be increased.

Sacubitril + Valsartan combination

Due to the increased risk of angioedema, concomitant use of perindopril with the sacubitril + valsartan combination is contraindicated. Use of the sacubitril + valsartan combination 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 sacubitril + valsartan combination. When ACE inhibitors are used concomitantly with other enkephalinase inhibitors (e.g., racecadotril), the risk of angioedema may be increased. In patients receiving perindopril, a careful risk/benefit assessment should be performed before prescribing enkephalinase inhibitors (e.g., racecadotril).

Hepatic impairment

In rare cases, a syndrome of cholestatic jaundice progressing to fulminant hepatic necrosis, sometimes fatal, has been observed during treatment with ACE inhibitors. The mechanism of development of this syndrome is unclear. Patients taking ACE inhibitors who develop jaundice or a significant increase in liver enzymes should discontinue the ACE inhibitor and receive appropriate medical supervision.

Ethnic differences

ACE inhibitors cause angioedema more frequently in Black patients than in patients of other races.

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

Cough

A cough may occur during the use of ACE inhibitors. Characteristically, the cough is dry, persistent, and resolves after discontinuation of therapy. This should be considered in the differential diagnosis of cough.

Hyperkalemia

An increase in serum potassium concentration has been observed in some patients receiving ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal failure, worsening hepatic function, age over 70 years, diabetes mellitus, certain concomitant conditions (dehydration, acute decompensated heart failure, metabolic acidosis) and concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, or amiloride), potassium preparations, or potassium-containing salt substitutes/dietary supplements. Patients taking other drugs that contribute to increased serum potassium levels (e.g., heparin) are also at risk. The use of potassium preparations, potassium-sparing diuretics, or potassium-containing salt substitutes/dietary supplements, especially in patients with renal impairment, can lead to a significant increase in serum potassium concentration. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If concomitant use of the above agents is necessary, they should be used with caution and with regular monitoring of serum potassium levels.

Lithium preparations

Concomitant use of perindopril and lithium preparations is not recommended.

Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and dietary supplements

Concomitant use of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing salt substitutes and dietary supplements, is not recommended.

Dual 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 concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. If dual blockade therapy is considered absolutely necessary, it should be carried out only under strict medical supervision and with regular monitoring of renal function, blood electrolyte levels, and blood pressure.

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

Slow calcium channel blockers, Class I antiarrhythmic drugs and centrally acting antihypertensive agents

Concomitant use of bisoprolol and calcium channel blockers such as verapamil or diltiazem, Class I antiarrhythmic drugs and centrally acting antihypertensive agents is not recommended.

Drug withdrawal

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

Bradycardia

If during treatment the resting heart rate decreases to 50-55 beats per minute or less and the patient develops symptoms associated with bradycardia, the dose of this combination should be reduced, using individual components with an acceptable dose of bisoprolol.

First-degree AV block

Given the negative dromotropic effect, beta-blockers should be prescribed with caution to patients with first-degree AV block.

Mitral stenosis/Aortic stenosis/Hypertrophic cardiomyopathy

As with other ACE inhibitors, perindopril should be used with caution in patients with mitral valve stenosis and obstruction of the left ventricular outflow tract, for example, with aortic valve stenosis or hypertrophic cardiomyopathy.

Prinzmetal’s angina

Beta-blockers may increase the frequency and duration of angina episodes in patients with Prinzmetal’s angina. The use of selective beta₁-blockers is possible in mild forms of the disease and only in combination with vasodilators.

Renal impairment

In case of renal failure, the daily dose of the combination is selected depending on the CrCl. For these patients, standard monitoring of blood potassium and creatinine levels is part of routine therapeutic practice. In patients with clinically significant symptoms of heart failure, arterial hypotension resulting from the initiation of ACE inhibitor treatment may lead to further deterioration of renal function. Acute renal failure has been reported, which was usually reversible.

In some patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney who received therapy with ACE inhibitors, an increase in serum urea and creatinine levels was observed, which usually resolved upon discontinuation of therapy. This effect was more often observed in patients with renal failure. The additional presence of renovascular hypertension increases the risk of developing severe arterial hypotension and renal failure in such patients. Treatment in such patients should be started with low doses under close medical supervision and with careful dose titration. Since diuretic treatment may contribute to the development of the phenomena described above, diuretics should be temporarily withdrawn and renal function monitored during the first weeks of therapy. In some patients with hypertension without signs of renal vascular disease, an increase in serum urea and creatinine levels was noted, usually minor and transient, especially when perindopril and a diuretic were prescribed simultaneously. Such phenomena are more likely to develop in patients with a history of renal impairment. A reduction in dose and/or discontinuation of the diuretic and/or perindopril may be required.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, the risk of developing arterial hypotension and renal failure increases during therapy with ACE inhibitors. The use of diuretics may be an additional risk factor. Deterioration of renal function may 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 with the use of perindopril arginine in patients with a previously transplanted kidney.

Patients on hemodialysis

Cases of anaphylactoid reactions have been noted in patients undergoing hemodialysis using high-flux membranes who were receiving an ACE inhibitor. Such patients should be prescribed an antihypertensive drug of another class or a different type of dialysis membrane should be used.

Anaphylactoid reactions during LDL 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 desensitizing therapy (e.g., with hymenoptera venom). Such reactions were prevented by temporarily discontinuing the ACE inhibitor, but if treatment was accidentally resumed, 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 produce 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 complicating factors, neutropenia rarely develops. Perindopril should be used with particular caution in patients with systemic connective tissue diseases receiving immunosuppressants, allopurinol or procainamide, or with 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 not responding to intensive antibiotic therapy. When prescribing perindopril to such patients, periodic monitoring of white blood cell counts is recommended and patients should be instructed to report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Bronchospasm (bronchial asthma, obstructive airway disease)

In bronchial asthma and other chronic obstructive pulmonary diseases, concomitant treatment with bronchodilators should be administered. Sometimes, when beta-blockers are used in patients with bronchial asthma, airway resistance may increase, thus it may be necessary to increase the dose of beta₂-adrenergic agonists.

Patients with diabetes mellitus

This combination should be used with caution in 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 on a strict diet/fasting.

Peripheral arterial occlusive disease

Deterioration of symptoms may be observed when taking beta-blockers, especially during the initial stages of treatment.

Anesthesia

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

In patients scheduled for extensive surgery or the use of anesthetic agents causing arterial hypotension, the use of perindopril may block the formation of angiotensin II against the background of compensatory renin release. Treatment should be discontinued one day before surgery. If arterial hypotension develops due to this mechanism, blood pressure should be maintained by replenishing the circulating blood volume.

Psoriasis

Beta-blockers can be prescribed to patients with psoriasis or a history of psoriasis only after a careful assessment of the benefit-risk ratio.

Pheochromocytoma

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

Hyperthyroidism

Symptoms of hyperthyroidism may be masked during treatment with bisoprolol.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are generally not responsive to antihypertensive drugs whose action is based on inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of this medicinal product in such patients is not recommended.

Pregnancy

An alternative antihypertensive agent with an established safety profile for use during pregnancy should be prescribed to those planning pregnancy, except in cases where ACE inhibitor therapy is deemed necessary. If pregnancy is detected, ACE inhibitor treatment should be discontinued immediately and, if necessary, alternative antihypertensive therapy should be prescribed (see sections “Contraindications” and “Pregnancy and Lactation”).

Heart failure

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

• Type 1 diabetes mellitus;
• Severe renal impairment;
• Severe hepatic impairment;
• Restrictive cardiomyopathy;
• Congenital heart defects;
• Hemodynamically significant organic heart valve lesions;
• Myocardial infarction within the last 3 months.

Depression

It is recommended to discontinue therapy with Prestilol^® if depression develops.

Sodium content

The sodium content in the medicinal product Prestilol^® is negligible, as it contains less than 1 mmol sodium (23 mg) per one tablet.

With caution

Patients with an increased risk of developing marked arterial hypotension, hypovolemia and hyponatremia (due to a salt-free diet and/or prior diuretic therapy, dialysis, vomiting, diarrhea), cerebrovascular diseases (including cerebral circulatory insufficiency), coronary insufficiency, history of angioedema, patients of Black race, risk factors for hyperkalemia, combination with lithium preparations, concomitant use with potassium-sparing diuretics, preparations containing potassium salts, angiotensin receptor blockers, simultaneous use with aliskiren-containing preparations, combination with slow calcium channel blockers, class I antiarrhythmic agents or centrally acting antihypertensive agents, abrupt discontinuation of therapy, bradycardia, first-degree AV block, mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy, Prinzmetal’s angina, renal impairment (GFR<90 ml/min), renovascular hypertension, bilateral renal artery stenosis, stenosis of the artery of a solitary kidney (risk of developing severe arterial hypotension and renal failure), patients after kidney transplantation, hemodialysis using high-flux membranes (risk of anaphylactoid reactions), patients undergoing LDL apheresis procedure, patients during desensitizing therapy, neutropenia/agranulocytosis/thrombocytopenia/anemia, bronchospasm (bronchial asthma, obstructive airway diseases), type 1 diabetes mellitus and type 2 diabetes mellitus with significant fluctuations in blood glucose concentration, strict diet, peripheral arterial occlusive diseases, surgery/general anesthesia (risk of excessive BP reduction), psoriasis, pheochromocytoma, hyperthyroidism, severe hepatic impairment, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant organic heart valve lesions, myocardial infarction within the last 3 months, congenital glucose-6-phosphate dehydrogenase deficiency (isolated cases of hemolytic anemia), connective tissue diseases (including systemic lupus erythematosus, scleroderma), depression (including history).

Effect on ability to drive vehicles and operate machinery

The use of this combination does not have a direct effect on the ability to drive vehicles and operate machinery, but some patients may develop individual reactions associated with low BP, especially at the beginning of treatment or when switching the drug, as well as when taken with alcohol.

As a result, the ability to drive vehicles and operate machinery may be impaired.

Drug Interactions

No interaction between bisoprolol and perindopril was observed in studies involving healthy volunteers. Information on interactions with other drugs is presented below.

Drugs causing hyperkalemia. Some drugs and drug classes 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.

Concomitant use is contraindicated

Aliskiren: concomitant use of this combination and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment, due to the risk of hyperkalemia, worsening of renal function, and increased cardiovascular morbidity and mortality.

Extracorporeal treatments: extracorporeal treatments leading to contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and LDL apheresis using dextran sulfate, are contraindicated due to an increased risk of severe anaphylactoid reactions. If such treatment is necessary, the possibility of using a different type of dialysis membrane or a different class of antihypertensive drugs should be considered.

Sacubitril/valsartan: concomitant use of perindopril with the sacubitril/valsartan combination is contraindicated, as suppression of neprilysin concurrently with ACE inhibitor use may increase the risk of angioedema. Use of the sacubitril/valsartan combination 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 sacubitril/valsartan combination.

Concomitant use is not recommended

Related to bisoprolol

Centrally acting antihypertensive agents such as clonidine and others (e.g., methyldopa, moxonidine, rilmenidine): concomitant use of centrally acting antihypertensive agents may lead to worsening of heart failure due to a reduction in central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Abrupt discontinuation of therapy, especially prior to a preceding reduction in the beta-blocker dose, may increase the risk of rebound arterial hypertension.

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): concomitant 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 influence on contractility and AV conduction. Intravenous administration of verapamil to patients receiving beta-blockers may lead to marked arterial hypotension and AV block.

Related to perindopril

Aliskiren: in patients without diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening of renal function, increased frequency of adverse cardiovascular events and cardiovascular mortality also increases.

Concomitant treatment with ACE inhibitors and ARBs: clinical trial data have shown that dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as arterial hypotension, hyperkalemia and reduced renal function (including acute renal failure), compared to the use of only one drug affecting the RAAS.

Cases have been described in the literature where, in patients with confirmed atherosclerosis, heart failure or diabetes with target organ damage, the simultaneous use of an ACE inhibitor and an angiotensin receptor blocker was associated with a higher frequency of arterial hypotension, syncope, hyperkalemia and worsening of renal function (including acute renal failure), compared to the use of only one drug affecting the RAAS. Dual blockade (e.g., 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 frequency of adverse events such as angioedema.

When used concomitantly with co-trimoxazole (trimethoprim+sulfamethoxazole), the risk of hyperkalemia may increase.

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium salts hyperkalemia may develop (possibly fatal), especially in combination with renal failure (additional effects associated with hyperkalemia). Concomitant use of perindopril and the aforementioned drugs is not recommended. If concomitant use is necessary, they should be used with precautions and regular monitoring of serum potassium levels. Information on the use of spironolactone in heart failure is described further in the text.

Lithium preparations: reversible increases in blood lithium concentrations and associated toxic effects have been described with the concomitant 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 deemed necessary, careful monitoring of serum lithium concentration is required.

Concomitant use requires special caution

Related to bisoprolol and perindopril

Hypoglycemic agents (insulins, oral hypoglycemic agents): based on epidemiological studies, it can be assumed that the use of ACE inhibitors concomitantly with hypoglycemic agents (insulins, oral hypoglycemic agents) may enhance the hypoglycemic effect with a risk of 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. Concomitant use of bisoprolol with insulin and oral hypoglycemic agents may cause an enhancement of the hypoglycemic effect. Blockade of beta-adrenergic receptors may mask the symptoms of hypoglycemia.

NSAIDs (including acetylsalicylic acid in doses ≥3 g/day): use of this combination concomitantly with NSAIDs (i.e., acetylsalicylic acid in doses exerting an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may lead to a weakening of the antihypertensive effect of bisoprolol and perindopril.

Furthermore, concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening renal function, including the possibility of acute renal failure, as well as an increase in serum potassium levels, especially in patients with pre-existing reduced renal function. Such a combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate amounts of fluid, and it is recommended to monitor renal function both at the start 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 drugs that have the ability to lower BP (e.g., tricyclic antidepressants, barbiturates, phenothiazines), may enhance the antihypertensive effects of perindopril and bisoprolol.

Tricyclic antidepressants/antipsychotic agents/general anesthetics: concomitant use of ACE inhibitors with some anesthetics, tricyclic antidepressants and antipsychotic agents may lead to an additional decrease in BP.

Concomitant use of bisoprolol and anesthetics may lead to a reduction in reflex tachycardia and an increased risk of arterial hypotension.

Sympathomimetics: concomitant use of bisoprolol and beta-sympathomimetics (such as isoprenaline, dobutamine) may lead to a reduction in the effect of both drugs.

Sympathomimetics that activate both beta- and alpha-adrenergic receptors (e.g., norepinephrine, epinephrine) combination with bisoprolol may reveal the alpha-adrenergic receptor-mediated vasoconstrictive effects of these drugs, which may lead to an increase in BP and worsening of intermittent claudication. Such interactions are more characteristic of 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 worsening of ventricular pump function in patients with heart failure cannot be excluded.

Class III antiarrhythmic agents (e.g., amiodarone): possible enhancement of the effect on AV conduction.

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

Topical beta-blockers (e.g., eye drops prescribed for glaucoma treatment): concomitant use may enhance the systemic effects of bisoprolol.

Digitalis preparations: decrease in heart rate, slowing of AV conduction.

Related to perindopril

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

Non-potassium-sparing diuretics: in patients receiving diuretics, and especially in individuals with reduced circulating blood volume and/or salts, an excessive decrease in BP may be observed at the start of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing diuretic therapy, replenishing circulating blood volume or increasing salt intake prior to initiating perindopril therapy, as well as by prescribing perindopril at a low dose with its gradual increase.

In arterial hypertension, where prior diuretic therapy may have caused a reduction in circulating blood volume/salts, it is necessary to either discontinue the diuretic before starting ACE inhibitor treatment (in which case the non-potassium-sparing diuretic can be reintroduced later), or to initiate ACE inhibitor therapy at a low dose with its subsequent gradual increase.

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

In all cases, monitoring of renal function (creatinine level) 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 NYHA functional class II-IV with ejection fraction <40% and previously conducted therapy with ACE inhibitors and “loop” diuretics, there is a risk of hyperkalemia (possibly fatal) especially if the prescribed recommendations regarding this drug combination are not followed.

Before starting combination therapy, it should be ensured that there is no hyperkalemia or renal function impairment. Regular monitoring of blood creatinine and potassium concentrations is recommended: weekly during the first month of treatment and monthly during the course of treatment.

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

mTOR (mammalian target of rapamycin) inhibitors (e.g., sirolimus, everolimus, temsirolimus): when used concomitantly with mTOR inhibitors, the risk of developing angioedema may increase (see section “Special Instructions”).

Drug combinations requiring attention

Related to bisoprolol

Mefloquine: increased risk of bradycardia.

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

In relation to perindopril

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

Gold preparations: in patients receiving injectable gold preparations (sodium aurothiomalate) concurrently with an ACE inhibitor, including perindopril, nitritoid reactions (facial flushing, nausea, vomiting, and arterial hypotension) have been rarely described.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.