Bis-aliter

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BIS-ALITER (BIS-ALITER)

Composition:

Active substances: bisoprolol, perindopril;

One 5 mg / 4 mg capsule contains:
5 mg bisoprolol fumarate equivalent to 4.24 mg bisoprolol, and 4 mg perindopril tert-butylamine equivalent to 3.34 mg perindopril;

One 5 mg / 8 mg capsule contains:
5 mg bisoprolol fumarate equivalent to 4.24 mg bisoprolol, and 8 mg perindopril tert-butylamine equivalent to 6.68 mg perindopril;

One 10 mg / 8 mg capsule contains:
10 mg bisoprolol fumarate equivalent to 8.49 mg bisoprolol, and 8 mg perindopril tert-butylamine equivalent to 6.68 mg perindopril;

Excipients:

for bisoprolol tablets: lactose monohydrate; microcrystalline cellulose; crospovidone; magnesium stearate; iron oxide (E 172);

for perindopril tablets: lactose monohydrate; microcrystalline cellulose; magnesium stearate; colloidal anhydrous silicon dioxide;

capsule (shell and cap): gelatin; water; titanium dioxide (E 171).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: opaque, hard gelatin capsules of white or almost white color, containing one white or almost white perindopril tablet and two yellow to yellow-brown bisoprolol tablets.

Pharmacotherapeutic group.
Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors, combinations. ACE inhibitors, other combinations. Perindopril and bisoprolol. ATC code C09BX02.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Bisoprolol

Bisoprolol is a highly selective β1-adrenoceptor blocker that has no intrinsic sympathomimetic activity and no pronounced membrane-stabilizing activity. It has low affinity for β2-receptors in the smooth muscle of bronchi and blood vessels, as well as for β2-receptors involved in metabolic regulation. Therefore, bisoprolol generally should not affect airway resistance or β2-mediated metabolic effects. Its β1-selectivity is maintained beyond the therapeutic dose range.

Perindopril

Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kinase, is an exopeptidase that enables the conversion of angiotensin I into the vasoconstrictive angiotensin II, and also causes degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II concentration in plasma, which increases plasma renin activity (due to inhibition of the negative feedback mechanism of renin release) and reduces aldosterone secretion. Since ACE inactivates bradykinin, ACE inhibition also increases the activity of circulating and local kinin-kallikrein systems (and thus activates prostaglandin systems). This mechanism of action underlies the antihypertensive effect of ACE inhibitors and partially accounts for the occurrence of certain adverse effects (e.g., cough). Perindopril acts via its active metabolite—perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE in vitro.

Pharmacodynamic effects

Bisoprolol

Bisoprolol does not exhibit a pronounced negative inotropic effect. The maximum effect of bisoprolol is achieved within 3–4 hours after administration. Due to its elimination half-life of 10–12 hours, bisoprolol maintains its therapeutic effect for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved within two weeks of treatment. After single-dose administration to patients with ischemic heart disease without chronic heart failure, bisoprolol reduces heart rate and stroke volume, thereby decreasing cardiac output and oxygen consumption. With prolonged use, initially elevated peripheral resistance is reduced. Reduction in plasma renin activity likely contributes to the antihypertensive effect of β-blockers. Bisoprolol reduces sympathoadrenergic response by blocking cardiac β-adrenoceptors, resulting in decreased heart rate and contractility. This, in turn, reduces myocardial oxygen consumption, which is essential in the treatment of angina in ischemic heart disease.

Perindopril

Perindopril effectively reduces arterial blood pressure in all stages of arterial hypertension (mild, moderate, and severe); reduction in systolic and diastolic blood pressure is observed in patients both in the supine and standing positions. Perindopril reduces peripheral vascular resistance, leading to a decrease in arterial blood pressure. As a result, peripheral blood flow increases without affecting heart rate. Renal blood flow usually increases, while glomerular filtration rate (GFR) typically remains unchanged. The maximum antihypertensive effect develops within 4–6 hours after a single dose and persists for at least 24 hours; the residual effect is approximately 87–100% of the peak effect. Blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure occurs within a month and is maintained without the development of tachyphylaxis. Discontinuation of treatment is not associated with a rebound effect. Perindopril reduces left ventricular hypertrophy. Clinical studies have demonstrated that perindopril has vasodilatory properties. It improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries. Perindopril reduces cardiac workload by decreasing both preload and afterload: it reduces filling pressure in the left and right ventricles, decreases total peripheral vascular resistance, increases cardiac output, and improves cardiac index (based on study data).

Pharmacokinetics.

The rate and extent of absorption of bisoprolol and perindopril in the medicinal product BIS-ALITER do not differ significantly from the rate and extent of absorption of bisoprolol and perindopril when administered separately as monotherapy.

Bisoprolol

Absorption

Bisoprolol is almost completely (>90%) absorbed from the gastrointestinal tract. The first-pass effect in the liver is minimal (approximately 10%), resulting in high bioavailability (approximately 90%) after oral administration.

Distribution

The volume of distribution is 3.5 L/kg. Plasma protein binding of bisoprolol is approximately 30%.

Biotransformation and elimination

Bisoprolol is eliminated from the body via two pathways. Fifty percent is metabolized in the liver into inactive metabolites, which are subsequently excreted by the kidneys, while the other 50% is excreted unchanged by the kidneys. Total clearance is approximately 15 L/h. The elimination half-life from plasma is 10–12 hours, which ensures a 24-hour effect after once-daily dosing.

Special patient groups

Bisoprolol kinetics are linear and independent of age. Since bisoprolol is eliminated equally by the kidneys and liver, dose adjustment is not required in patients with hepatic impairment or renal insufficiency. Pharmacokinetics in patients with chronic heart failure and impaired hepatic or renal function have not been studied. In patients with chronic heart failure (NYHA functional class III), plasma levels of bisoprolol are higher and the elimination half-life is longer compared to healthy volunteers. With a daily dose of 10 mg, the steady-state maximum plasma concentration is 64 ± 21 ng/mL, and the elimination half-life is 17 ± 5 hours.

Perindopril

Absorption

After oral administration, perindopril is rapidly absorbed, with maximum concentration reached within 1 hour. The elimination half-life of perindopril from plasma is 1 hour.

Distribution

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Plasma protein binding of perindoprilat is 20%, mainly to angiotensin-converting enzyme, and is dose-dependent.

Biotransformation

Perindopril is a prodrug. Twenty-seven percent of the administered dose of perindopril reaches the systemic circulation as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms five inactive metabolites. Maximum plasma concentration of perindoprilat is reached within 3–4 hours. Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril tert-butylamine is recommended to be administered orally as a single daily dose in the morning before food.

Elimination

Perindoprilat is excreted in urine; the terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady state is achieved within 4 days.

Linearity

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

Special patient groups

Elimination of perindoprilat is slowed in elderly patients and in patients with cardiac or renal insufficiency. Dose adjustment is recommended for patients with renal insufficiency based on the degree of renal impairment (creatinine clearance). Dialysis clearance of perindoprilat is 70 mL/min. Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of the parent compound is halved. However, the amount of formed perindoprilat does not decrease. Therefore, dose adjustment is not required in such patients (see sections "Special precautions" and "Dosage and administration").

Clinical characteristics.

Indications.

The medicinal product BIS-ALITER in dosage strengths of 5 mg/8 mg and 10 mg/8 mg is indicated for the treatment of arterial hypertension and/or stable ischemic heart disease (with history of myocardial infarction and/or revascularization) in adult patients who require therapy with bisoprolol and perindopril in doses available in fixed combination.

The medicinal product BIS-ALITER in dosage strength of 5 mg/4 mg is indicated for the treatment of arterial hypertension and/or stable ischemic heart disease (with history of myocardial infarction and/or revascularization) and/or stable chronic heart failure with reduced left ventricular systolic function in adult patients who require therapy with bisoprolol and perindopril in doses available in fixed combination.

Contraindications.

• Hypersensitivity to the active substances or to any of the excipients of the medicinal product, or to any other angiotensin-converting enzyme (ACE) inhibitors;
• Acute heart failure or decompensated heart failure requiring intravenous inotropic therapy;
• Cardiogenic shock;
• Second- or third-degree atrioventricular block (without a pacemaker);
• Sinus node dysfunction;
• Sinoatrial block;
• Symptomatic bradycardia;
• Symptomatic arterial hypotension;
• Severe form of bronchial asthma or severe course of chronic obstructive pulmonary disease;
• Severe form of peripheral arterial occlusive disease or severe form of Raynaud's syndrome;
• Untreated pheochromocytoma (see section "Special precautions");
• Metabolic acidosis;
• History of angioedema associated with previous ACE inhibitor therapy (see section "Special precautions");
• Hereditary or idiopathic angioedema;
• Pregnancy or planned pregnancy (see section "Use during pregnancy or breast-feeding");
• Concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions");
• Concomitant use with sacubitril/valsartan. BIS-ALITER must not be used earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions");
• Extracorporeal treatment methods leading to contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• Significant bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

In a drug interaction study conducted in healthy volunteers, no interaction between bisoprolol and perindopril was observed. Information on interactions with other medicinal products for each active ingredient is provided below.

Medicinal products that increase the risk of angioedema

Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as dual inhibition of neprilysin and ACE increases the risk of angioedema. Initiation of sacubitril/valsartan therapy should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions"). Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (see section "Special precautions").

Medicinal products causing hyperkalemia

Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with BIS-ALITER. Some medicinal products (therapeutic classes) increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and cotrimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of BIS-ALITER with the above-mentioned agents is not recommended. If concomitant use is necessary, these agents should be used with caution and frequent monitoring of serum potassium levels should be performed.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren

Concomitant use of BIS-ALITER and aliskiren in patients with diabetes mellitus or renal impairment is contraindicated, as it increases the risk of hyperkalemia, worsening of renal function, and cardiovascular morbidity and mortality.

Extracorporeal treatments

Extracorporeal treatment methods leading to contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to an 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 another class of antihypertensive agents.

Concomitant use is not recommended

Interactions related to bisoprolol

Centrally acting antihypertensive agents, such as clonidine and others (e.g., methyldopa, moxonidine, rilmenidine)

Concomitant use with centrally acting antihypertensive agents may worsen heart failure due to reduced central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Sudden withdrawal of β-blocker therapy, especially without prior dose reduction, increases the risk of rebound hypertension.

Class I antiarrhythmic agents (e.g., quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone)

Possible potentiation of effects on atrioventricular conduction time and enhanced negative inotropic effect.

Calcium antagonists of the verapamil group and, to a lesser extent, diltiazem

Negative effects on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil to patients taking β-blockers may lead to marked arterial hypotension and atrioventricular block.

Interactions related to perindopril

Aliskiren

In all other patients, including those with diabetes mellitus or impaired renal function, there is an increased risk of hyperkalemia, worsening of renal function, and cardiovascular morbidity and mortality.

Concomitant use of ACE inhibitors and angiotensin receptor blockers

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of adverse reactions such as arterial hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), compared to use of a single agent affecting the RAAS (see sections "Contraindications" and "Special precautions"). Publications have reported that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker was associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to use of a single RAAS-affecting agent. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine

Risk of increased adverse reactions, particularly development of angioedema (angioedema).

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium salts

Risk of hyperkalemia (possibly fatal), especially in patients with renal impairment (additive hyperkalemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special precautions"). However, if concomitant use is necessary, they should be used with caution and frequent monitoring of serum potassium levels should be performed. For use of spironolactone in heart failure, see below.

Lithium

Reversible increases in serum lithium concentration and increased lithium toxicity have been reported with concomitant use of ACE inhibitors. Concomitant use of perindopril with lithium is not recommended. However, if such combination is justified, serum lithium levels should be monitored carefully (see section "Special precautions").

Concomitant use requiring special attention

Interactions related to bisoprolol and perindopril

Antidiabetic agents (insulin, oral hypoglycemic agents)

Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combination therapy and in patients with renal impairment. Concomitant use of bisoprolol with insulin and oral antidiabetic agents may enhance the hypoglycemic effect. β-Adrenoceptor blockade may mask symptoms of hypoglycemia.

NSAIDs, including acetylsalicylic acid at doses ≥ 3 g/day

Concomitant use of BIS-ALITER with NSAIDs (such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs) may reduce the antihypertensive effect of bisoprolol and perindopril. Additionally, concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening renal function, including possible acute renal failure, and elevated serum potassium levels, particularly in patients with pre-existing renal impairment. Such combinations should be used with caution, especially in elderly patients. Hydration should be restored, and renal function should be monitored after initiation of combination therapy and during ongoing treatment.

Antihypertensive medicinal products and vasodilators

Concomitant use with antihypertensive agents, vasodilators (e.g., nitroglycerin, other nitrates, or other vasodilators), or other agents that may lower blood pressure (e.g., tricyclic antidepressants, barbiturates, phenothiazines) increases the risk of hypotensive effects of perindopril and bisoprolol.

Tricyclic antidepressants/antipsychotics/anesthetics

Concomitant use of ACE inhibitors with certain anesthetics, tricyclic antidepressants, and antipsychotics may lead to further reduction in blood pressure. Concomitant use of bisoprolol with anesthetics may result in blunted reflex tachycardia and increased risk of arterial hypotension.

Sympathomimetics

β-Sympathomimetics (e.g., isoprenaline, dobutamine): concomitant use with bisoprolol may reduce the effects of both agents. Sympathomimetics activating both α- and β-adrenoceptors (e.g., noradrenaline, adrenaline): combination with bisoprolol may unmask α-adrenoceptor-mediated vasoconstrictive effects, leading to increased blood pressure and exacerbation of intermittent claudication. Such interactions are more likely with nonselective β-blockers. Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Interactions related to bisoprolol

Calcium antagonists of the dihydropyridine type, such as felodipine and amlodipine

Concomitant use increases the risk of arterial hypotension; increased risk of further deterioration of ventricular pump function in patients with heart failure.

Class III antiarrhythmic agents (e.g., amiodarone)

Possible enhancement of effects on atrioventricular conduction time.

Parasympathomimetic agents

Concomitant use may increase atrioventricular conduction time and risk of bradycardia.

Topically acting β-blockers (e.g., eye drops for glaucoma treatment)

Concomitant use may enhance systemic effects of bisoprolol.

Digitalis glycosides

Reduction in heart rate, increased atrioventricular conduction time.

Interactions related to perindopril

Baclofen

Enhances antihypertensive effect. Blood pressure should be monitored and dose adjusted if necessary.

Diuretics

In patients taking diuretics, particularly in case of fluid/electrolyte imbalance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effect is reduced by discontinuing the diuretic, increasing circulating blood volume, or increasing salt intake before starting therapy, which should begin with low doses and gradual dose escalation of perindopril. In arterial hypertension, when a previously prescribed diuretic may have caused fluid/electrolyte deficiency, the diuretic should be discontinued before starting ACE inhibitor therapy (in such cases, diuretic use may be resumed later), or ACE inhibitor therapy should be initiated with low doses and gradual dose escalation. In congestive heart failure on background of diuretic therapy, ACE inhibitor use should be initiated with a low dose, possibly after reducing the dose of the concomitant diuretic. In all cases, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone)

Concomitant use of eplerenone or spironolactone (12.5 to 50 mg daily) with low doses of ACE inhibitors: if recommendations for use of this combination are not followed, there is a risk of hyperkalemia (possibly fatal) during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and loop diuretic. Before initiating such combination, absence of hyperkalemia and renal impairment should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Concomitant use requiring attention

Interactions related to bisoprolol

Mefloquine

Increased risk of bradycardia.

Monoamine oxidase inhibitors (except MAO-B inhibitors)

Enhanced hypotensive effect of β-blockers and risk of hypertensive crisis.

Interactions related to perindopril

Gold

Rarely, concomitant use of ACE inhibitors, including perindopril, with injectable gold preparations (sodium aurothiomalate) may cause reactions similar to those seen with nitrates (symptoms: facial flushing, nausea, vomiting, and hypotension).

Special precautions for use.

All precautions related to the use of individual components of the medicinal product apply to the medicinal product BIS-ALITRE.

Arterial hypotension

ACE inhibitors may cause a marked decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and is more likely to occur in patients with hypovolemia, such as those receiving diuretics, on a low-salt diet, patients on dialysis, patients with diarrhea or vomiting, and patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). Symptomatic arterial hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic arterial hypotension is most likely in patients with more severe degrees of heart failure who are receiving high doses of loop diuretics, have hyponatremia, or have functional renal impairment. Patients at increased risk of developing symptomatic arterial hypotension require careful medical supervision at the beginning of therapy and during dose titration. These precautions also apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke. In case of arterial hypotension, the patient should be placed in a horizontal position and, if necessary, receive intravenous infusion of 9 mg/mL (0.9%) sodium chloride solution. Transient hypotension is not a contraindication for further use of the drug, which can usually be continued without difficulty after restoration of circulating blood volume and blood pressure elevation. In some patients with congestive heart failure and normal or low blood pressure, perindopril may cause additional reduction in systemic arterial pressure. This effect is expected and usually does not require discontinuation of treatment. If arterial hypotension becomes symptomatic, dose reduction or gradual discontinuation of treatment with individual components may be necessary.

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril (see section "Side effects"). This may occur at any time during treatment. In such cases, the use of the medicinal product BIS-ALITRE must be discontinued immediately. Therapy with a β-blocker should be continued. Appropriate monitoring of the patient's condition is required until complete resolution of symptoms. In cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment, although antihistamine drugs may be helpful in reducing symptoms. Angioedema associated with laryngeal edema may be fatal. If swelling spreads to the tongue, glottis, or larynx, potentially causing airway obstruction, emergency therapy must be initiated immediately, which may include administration of adrenaline and/or airway maintenance. The patient must remain under continuous medical supervision until complete and sustained resolution of symptoms. Patients with a history of angioedema not associated with ACE inhibitor therapy have an increased risk of developing angioedema (see section "Contraindications"). Rare cases of intestinal angioedema have been reported in patients during treatment with ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, there was no prior history of facial angioedema and serum C-1 esterase levels were normal. The diagnosis of intestinal angioedema was established by computed tomography, ultrasound, or during surgical intervention. After discontinuation of the ACE inhibitor, symptoms of angioedema resolved. When performing differential diagnosis of abdominal pain occurring in patients receiving ACE inhibitors, intestinal angioedema should be considered.

Concomitant use of mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus): in patients receiving mTOR inhibitors concomitantly, the risk of angioedema (including airway or tongue swelling, with or without respiratory impairment) is increased (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Sacubitril/valsartan therapy should not be initiated earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan therapy is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of other neutral endopeptidase (NEP) inhibitors (e.g., racecadotril) with ACE inhibitors also increases the risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, before initiating treatment with NEP inhibitors (e.g., racecadotril) in patients receiving perindopril, a careful benefit-risk assessment should be performed. Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Hepatic impairment

Rarely, use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly progressing liver necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. Patients who develop jaundice or a marked increase in liver enzymes while receiving ACE inhibitors should discontinue the ACE inhibitor and undergo appropriate medical evaluation and treatment (see section "Side effects").

Racial characteristics

ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. As with other ACE inhibitors, perindopril is less effective in reducing blood pressure in black patients with hypertension than in patients of other races, possibly due to lower plasma renin levels in these patients.

Cough

Cough has been reported during treatment with ACE inhibitors. This cough is non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Hyperkalemia

In some patients receiving ACE inhibitors, including perindopril, increased serum potassium concentration has been observed. ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. In patients with normal kidney function, this effect is usually mild. Risk factors for hyperkalemia include: renal impairment, worsening renal function, age > 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or use of other drugs that increase serum potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists and angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in serum potassium levels. Hyperkalemia may lead to serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously and undergo careful monitoring of serum potassium levels and renal function. If concomitant use of perindopril with any of the above-mentioned substances is considered necessary, such use requires caution and frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Combinations with lithium

Concomitant use of lithium and perindopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Combinations with potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes

Concomitant use of perindopril with potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the RAAS

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure). Therefore, dual blockade of the RAAS due to concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). However, if dual RAAS blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision with careful monitoring of renal function, electrolyte levels, and blood pressure. Patients with diabetic nephropathy should not receive concomitant ACE inhibitors and angiotensin II receptor blockers.

Combinations with calcium channel blockers, class I antiarrhythmic agents, and centrally-acting antihypertensive agents

Concomitant use of bisoprolol with verapamil-type or diltiazem-type calcium channel blockers, class I antiarrhythmic agents, and centrally-acting antihypertensive agents is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Discontinuation of treatment

Abrupt discontinuation of β-blocker therapy should be avoided, especially in patients with ischemic heart disease, as this may lead to transient worsening of cardiac function. Dose reduction should be gradual, using individual components, preferably over two weeks, and substitution therapy should be initiated if necessary.

Bradycardia

If during treatment the resting heart rate decreases to < 50–55 beats/min and the patient exhibits symptoms indicating bradycardia, the dose of the medicinal product BIS-ALITRE should be reduced using individual components of the drug. Bisoprolol should be administered at an appropriate dose.

First-degree atrioventricular block

Due to the negative dromotropic effect of β-blockers, they should be used with caution in patients with first-degree atrioventricular block.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy

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

Prinzmetal's angina

Use of β-blockers may increase the frequency and duration of attacks in patients with Prinzmetal's angina. Use of selective β1-adrenergic receptor blockers is possible in mild forms of the disease and only in combination with vasodilators.

Renal impairment

In case of renal impairment, the daily dose of the medicinal product BIS-ALITRE should be based on creatinine clearance (see section "Method of administration and dosage"). Routine monitoring of such patients should include monitoring of creatinine and potassium levels (see section "Side effects"). In patients with symptomatic heart failure, hypotension occurring at the beginning of ACE inhibitor therapy may lead to further worsening of renal function. Acute renal failure, usually reversible, has been reported. In some patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, increased blood urea nitrogen and serum creatinine concentrations have been observed during ACE inhibitor therapy, which usually returned to normal after discontinuation of treatment. This is more common in patients with renal impairment. The presence of renovascular hypertension increases the risk of severe hypotension and renal failure. Treatment of such patients should be initiated under careful medical supervision, starting with low doses and cautious dose titration. Due to the above, diuretics may contribute to the development of arterial hypotension; therefore, they should be discontinued and renal function should be monitored during the first weeks of BIS-ALITRE use. In some patients with hypertension, in whom no renovascular disease was detected before treatment initiation, slight transient increases in blood urea and serum creatinine levels have been observed, particularly when perindopril is used concomitantly with a diuretic. This condition is more likely in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril may be necessary.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure (see section "Contraindications"). Use of diuretics may be a contributing factor. Decreased renal function may be accompanied by only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Kidney transplantation

There is no experience with the use of perindopril tert-butylamine in patients who have recently undergone kidney transplantation.

Patients undergoing hemodialysis

In patients undergoing dialysis with high-flux membranes who were receiving ACE inhibitors, anaphylactoid reactions have been observed. A decision should be made regarding the use of a different type of dialysis membrane or a different class of antihypertensive agents for such patients.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

Rare cases of life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.

Anaphylactoid reactions during desensitization therapy

Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy (e.g., with bee venom preparations). These reactions can be avoided by temporarily discontinuing ACE inhibitors, but reactions may recur upon resumption of treatment. As with other β-blockers, bisoprolol may both increase sensitivity to allergens and exacerbate the severity of anaphylactoid reactions. In such cases, epinephrine treatment may not always produce the expected therapeutic effect.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other risk factors, neutropenia is rare. Perindopril should be used with extreme caution in patients with collagenoses, during immunosuppressive therapy, allopurinol, or procainamide therapy, or in combination with these risk factors, especially in the presence of renal impairment. In some of these patients, severe infections have been observed, in several cases resistant to intensive antibiotic therapy. In such patients, periodic monitoring of white blood cell count is recommended, and patients should be informed to report any signs of infection (e.g., sore throat, fever) to their physician.

Bronchospasm (bronchial asthma, obstructive respiratory diseases)

Concomitant therapy with bronchodilators is indicated in bronchial asthma or other chronic obstructive lung diseases that may cause bronchospasm symptoms. In some cases, due to increased airway tone during β-blocker use, patients with bronchial asthma may require higher doses of β2-sympathomimetics.

Patients with diabetes mellitus

The medicinal product BIS-ALITRE 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 β-blockers.

Strict diet

The medicinal product should be used with caution in patients on a strict diet.

Peripheral arterial occlusive disease

Symptom exacerbation is possible during β-blocker use, particularly at the beginning of treatment.

Anesthesia

In patients receiving general anesthesia, beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction, intubation, and the postoperative period. Maintenance of beta-blockade during the perioperative period is recommended. The anesthesiologist should be informed about beta-blockade due to potential interactions with other drugs that may lead to bradyarrhythmias, blunted reflex tachycardia, and reduced reflex capacity to compensate for blood loss. If discontinuation of β-blocker therapy before surgery is considered necessary, it should be done gradually and completed approximately 48 hours before anesthesia. If a patient is scheduled for surgery or requires anesthesia with agents causing hypotension, perindopril may block angiotensin II formation following compensatory renin release. Treatment with the drug should be discontinued one day before surgery. If hypotension has already occurred due to this mechanism, correction may be achieved by increasing circulating blood volume.

Psoriasis

β-blockers should be prescribed to patients with psoriasis or a history of psoriasis only after careful benefit-risk assessment.

Pheochromocytoma

In the presence of pheochromocytoma or suspicion thereof, bisoprolol should always be prescribed in combination with α-adrenergic blockers.

Thyrotoxicosis

Bisoprolol use may mask symptoms of thyrotoxicosis.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via inhibition of the renin-angiotensin system. Therefore, use of this medicinal product is not recommended in such patients.

Heart failure

There is no therapeutic experience with bisoprolol treatment of heart failure in patients with the following conditions: insulin-dependent diabetes mellitus (type 1), severe renal impairment, severe hepatic impairment, restrictive cardiomyopathy, congenital heart diseases, hemodynamically significant organic heart valve defects, or myocardial infarction within the last 3 months.

Use during pregnancy or breastfeeding.

Pregnancy. Use of the medicinal product BIS-ALITRE is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Breastfeeding. Use of the medicinal product BIS-ALITRE is not recommended during breastfeeding. If treatment is necessary, the decision to discontinue breastfeeding should be made.

Fertility. Clinical data on the effect of the bisoprolol/perindopril combination on fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product BIS-ALITRE has no direct effect on the ability to drive vehicles or operate machinery. However, in some patients, individual reactions related to decreased blood pressure, especially at the beginning of treatment or when changing therapy, and in combination with alcohol, may occur. As a result, the ability to drive vehicles or operate machinery may be impaired.

Method of Administration and Dosage

Dosage

The usual dose is 1 capsule once daily in the morning before food. Patients should have been stabilized on equivalent doses of bisoprolol and perindopril for at least 4 weeks prior to initiating therapy. The fixed combination is not intended for initial therapy.

Patients stabilized on 2.5 mg bisoprolol and 2.5 mg perindopril are recommended to use another medicinal product at the appropriate dosage.

Patients stabilized on 2.5 mg bisoprolol and 5 mg perindopril are recommended to use another medicinal product at the appropriate dosage.

If dosage adjustment is required, individual titration of each component of the medicinal product should be performed.

Special Patient Groups

Renal Impairment (see sections "Pharmacokinetics" and "Special Precautions")

The medicinal product BIS-ALITER at a dosage of 5 mg / 4 mg is not suitable for patients with severe renal impairment (creatinine clearance < 30 mL/min). For such patients, individual dose titration of each component is recommended. For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended daily dose of perindopril is 2.5 mg (use another medicinal product at the appropriate dosage). The medicinal product BIS-ALITER at a dosage of 5 mg / 4 mg may be used in patients with creatinine clearance ≥ 60 mL/min.

For patients with creatinine clearance ≥ 60 mL/min, the recommended daily dose is 2.5 mg bisoprolol and 4 mg perindopril (use another medicinal product at the appropriate dosage). The medicinal product BIS-ALITER at a dosage of 5 mg / 8 mg is not suitable for patients with creatinine clearance < 60 mL/min (moderate and severe renal impairment). For such patients, individual dose titration of each component is recommended.

The medicinal product BIS-ALITER at a dosage of 10 mg / 8 mg is not suitable for patients with renal impairment. For such patients, individual dose titration of each component is recommended.

Hepatic Impairment (see sections "Pharmacokinetics" and "Special Precautions")

Patients with hepatic impairment do not require dose adjustment of the medicinal product BIS-ALITER.

Elderly Patients

The medicinal product BIS-ALITER may be used, taking renal function into account.

Children

The safety and efficacy of the medicinal product BIS-ALITER in children (under 18 years of age) have not been established. Data are lacking. Therefore, use of the medicinal product in children (under 18 years of age) is contraindicated.

Overdose

Data regarding overdose with the combination bisoprolol/perindopril are lacking.

Bisoprolol

Symptoms

Typical manifestations of β-blocker overdose include bradycardia, arterial hypotension, bronchospasm, acute heart failure, and hypoglycemia. Several cases of bisoprolol overdose (maximum dose 2000 mg) have been reported in patients with hypertension and/or ischemic heart disease, presenting with bradycardia and/or hypotension; all patients recovered. There is wide individual variability in sensitivity to a single high dose of bisoprolol; patients with heart failure are likely to be particularly sensitive.

Treatment

In case of overdose, bisoprolol therapy should be discontinued and supportive and symptomatic treatment initiated. Some data suggest that bisoprolol is poorly dialyzable. Based on expected pharmacological effects and recommendations for other β-blockers, the following clinically justified general measures should be considered:

Bradycardia: administer intravenous atropine. If response is inadequate, cautiously administer isoprenaline or another agent with positive chronotropic properties. In some cases, transvenous insertion of a pacemaker may be required.

Arterial hypotension: intravenous fluid administration and vasoconstrictor agents. Intravenous glucagon may be beneficial.

Atrioventricular block (Grade II or III): careful patient monitoring, infusion of isoprenaline, or transvenous insertion of a cardiac pacemaker.

Acute worsening of heart failure: intravenous diuretics, inotropic agents, or vasodilators.

Bronchospasm: bronchodilator therapy, e.g., administration of isoprenaline, β2-sympathomimetics, and/or aminophylline.

Hypoglycemia: intravenous glucose administration.

Perindopril

Symptoms

Information on perindopril overdose is limited. Symptoms of ACE inhibitor overdose include arterial hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Treatment

In case of overdose, intravenous administration of 9 mg/mL (0.9%) sodium chloride solution is recommended. If hypotension occurs, the patient should be placed in a supine position with legs elevated. If feasible, consider administration of angiotensin II and/or intravenous catecholamines. Perindopril may be removed from systemic circulation by hemodialysis (see section "Special Precautions"). In cases of treatment-resistant bradycardia, a cardiac pacemaker is indicated. Monitoring of vital signs, serum electrolytes, and serum creatinine is necessary.

Adverse Reactions

The most commonly observed adverse reactions during bisoprolol use are: headache, dizziness, worsening of heart failure, hypotension, cold sensation in the extremities, nausea, vomiting, abdominal pain, diarrhea, constipation, asthenia, and fatigue.

The most commonly observed adverse reactions during clinical trials with perindopril are: headache, dizziness, vertigo, paresthesia, visual disturbances, tinnitus, arterial hypotension, cough, dyspnea, nausea, vomiting, abdominal pain, diarrhea, constipation, taste disturbances (dysgeusia), dyspepsia, rash, pruritus, muscle cramps, and asthenia.

During clinical trials and/or post-marketing surveillance with bisoprolol or perindopril used separately, the following adverse reactions have been reported, classified by organ systems according to MedDRA [Medical Dictionary for Regulatory Activities] and by frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

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

Blood and lymphatic system disorders: eosinophilia (uncommon* — perindopril), agranulocytosis (very rare — perindopril), pancytopenia (very rare — perindopril), leukopenia (very rare — perindopril), neutropenia (very rare — perindopril), thrombocytopenia (very rare — perindopril), hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency (very rare — perindopril).

Metabolism and nutrition disorders: hypoglycemia (uncommon* — perindopril), hyperkalemia, reversible upon discontinuation of the active substance (uncommon* — perindopril), hyponatremia (uncommon* — perindopril).

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH) (rare — perindopril).

Psychiatric disorders: mood changes (uncommon — perindopril), sleep disturbances (uncommon — bisoprolol, perindopril), depression (uncommon — bisoprolol, uncommon* — perindopril), nightmares, hallucinations (rare — bisoprolol), confusion (very rare — perindopril).

Nervous system disorders: headache** (common — bisoprolol, perindopril), dizziness** (common — bisoprolol, perindopril), vertigo (common — perindopril), taste disturbances (dysgeusia) (common — perindopril), paresthesia (common — perindopril), somnolence (uncommon* — perindopril), syncope (rare — bisoprolol, uncommon* — perindopril).

Eye disorders: visual disturbances (common — perindopril), decreased lacrimation (should be considered in contact lens wearers) (rare — bisoprolol), conjunctivitis (very rare — bisoprolol).

Ear and labyrinth disorders: tinnitus (common — perindopril), hearing disturbances (rare — bisoprolol).

Cardiac disorders: palpitations (uncommon* — perindopril), tachycardia (uncommon* — perindopril), bradycardia (very common — bisoprolol), worsening of heart failure (common — bisoprolol), atrioventricular conduction disturbances (uncommon — bisoprolol), arrhythmia (very rare — perindopril), angina pectoris (very rare — perindopril), myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients (very rare — perindopril).

Vascular disorders: arterial hypotension and related symptoms (common — bisoprolol, perindopril), cold sensation or numbness in extremities (common — bisoprolol), orthostatic hypotension (uncommon — bisoprolol), vasculitis (uncommon* — perindopril), hot flushes (rare* — perindopril), stroke, possibly due to excessive reduction in blood pressure in high-risk patients (very rare — perindopril), Raynaud's syndrome (frequency not known — perindopril).

Respiratory, thoracic and mediastinal disorders: cough (common — perindopril), dyspnea (common — perindopril), bronchospasm (uncommon — bisoprolol, perindopril), eosinophilic pneumonia (very rare — perindopril).

Gastrointestinal disorders: abdominal pain (common — bisoprolol, perindopril), constipation (common — bisoprolol, perindopril), diarrhea (common — bisoprolol, perindopril), nausea (common — bisoprolol, perindopril), vomiting (common — bisoprolol, perindopril), dyspepsia (common — perindopril), dry mouth (uncommon — perindopril), pancreatitis (very rare — perindopril).

Hepatobiliary disorders: cytolytic or cholestatic hepatitis (rare — bisoprolol, very rare — perindopril).

Skin and subcutaneous tissue disorders: rash (common — perindopril), pruritus (common — perindopril), angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (uncommon — perindopril), urticaria (uncommon — perindopril), photosensitivity reactions (uncommon* — perindopril), pemphigoid (uncommon* — perindopril), hyperhidrosis (uncommon — perindopril), hypersensitivity reactions (pruritus, erythema, rash) (rare — bisoprolol), exacerbation of psoriasis symptoms (rare* — perindopril), erythema multiforme (very rare — bisoprolol), alopecia (very rare — bisoprolol), β-blockers may induce or exacerbate psoriasis and provoke psoriatic rashes (very rare — bisoprolol).

Musculoskeletal and connective tissue disorders: muscle cramps (uncommon — bisoprolol, common — perindopril), muscle weakness (uncommon — bisoprolol), arthralgia (uncommon* — bisoprolol), myalgia (uncommon* — perindopril).

Renal and urinary disorders: renal failure (uncommon — perindopril), acute renal failure (rare — perindopril), anuria/oliguria (rare* — perindopril).

Reproductive system and breast disorders: erectile dysfunction (uncommon — perindopril), potency disorders (rare — bisoprolol).

General disorders: asthenia (common — bisoprolol, perindopril), fatigue (common — bisoprolol), chest pain (uncommon* — perindopril), malaise (uncommon* — perindopril), peripheral edema (uncommon* — perindopril), hyperthermia (uncommon* — perindopril).

Investigations: increased blood urea levels (uncommon* — perindopril), increased blood creatinine levels (uncommon* — perindopril), increased liver enzymes (rare — bisoprolol, perindopril), increased blood bilirubin levels (rare — perindopril), increased triglyceride levels (rare — bisoprolol), decreased hemoglobin and decreased hematocrit (very rare — perindopril).

Injury, poisoning and procedural complications: falls (uncommon* — perindopril).

*Frequency of adverse reactions identified from spontaneous reports calculated from clinical trial data.

**These symptoms are particularly observed at the beginning of treatment. Generally, they are mild and often disappear within 1–2 weeks.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after the medicinal product has been authorized. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 capsules in a blister pack, 3 blisters per cardboard box.

Or 30 capsules in a bottle, 1 bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

MICROCHEM LLC (responsible for batch release, excluding batch control/testing).

JSC "Farmak" (all manufacturing stages except batch release).

Manufacturer's address and place of business

Ukraine, 01013, Kyiv, 5 Budynstroi Street.

Ukraine, 04080, Kyiv, 74 Kyrylivska Street.

INSTRUCTION

for medical use of the medicinal product

BIS-ALITER

(BIS-ALITER)

Composition:

Active substances: bisoprolol, perindopril;

1 capsule of 5 mg / 4 mg contains:
5 mg bisoprolol fumarate, equivalent to 4.24 mg bisoprolol, and 4 mg perindopril tert-butylamine, equivalent to 3.34 mg perindopril;

1 capsule of 5 mg / 8 mg contains:
5 mg bisoprolol fumarate, equivalent to 4.24 mg bisoprolol, and 8 mg perindopril tert-butylamine, equivalent to 6.68 mg perindopril;

1 capsule of 10 mg / 8 mg contains:
10 mg bisoprolol fumarate, equivalent to 8.49 mg bisoprolol, and 8 mg perindopril tert-butylamine, equivalent to 6.68 mg perindopril;

Excipients:

for bisoprolol tablets: lactose monohydrate; microcrystalline cellulose; crospovidone; magnesium stearate; iron oxide (E 172);

for perindopril tablets: lactose monohydrate; microcrystalline cellulose; magnesium stearate; colloidal anhydrous silicon dioxide;

capsule (shell and cap): gelatin; water; titanium dioxide (E 171).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: opaque, hard gelatin capsules of white or almost white color, containing one white or almost white perindopril tablet and two yellow to yellowish-brown bisoprolol tablets.

Pharmacotherapeutic group.
Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors, combinations. ACE inhibitors, other combinations. Perindopril and bisoprolol. ATC code C09BX02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Bisoprolol

Bisoprolol is a highly selective β1-adrenoceptor blocker that has no intrinsic sympathomimetic activity and no pronounced membrane-stabilizing activity. It has low affinity for β2-receptors in bronchial and vascular smooth muscle, as well as for β2-receptors involved in metabolic regulation. Therefore, bisoprolol generally should not affect airway resistance or β2-mediated metabolic effects. Its β1-selectivity extends beyond the therapeutic dose range.

Perindopril

Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kininase, is an exopeptidase that enables the transformation of angiotensin I into the vasoconstrictive angiotensin II, and also causes degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a decrease in angiotensin II concentration in plasma, increases plasma renin activity (due to inhibition of the negative feedback on renin release), and reduces aldosterone secretion. Since ACE inactivates bradykinin, ACE inhibition also increases the activity of circulating and local kallikrein-kinin systems (and thus activates prostaglandin systems). This mechanism of action causes the antihypertensive effect of ACE inhibitors and partially accounts for certain adverse effects (e.g., cough). Perindopril acts via its active metabolite—perindoprilat. Other metabolites do not demonstrate ACE-inhibiting activity in vitro.

Pharmacodynamic effects

Bisoprolol

Bisoprolol does not exhibit a pronounced negative inotropic effect. The maximum effect of bisoprolol is achieved within 3–4 hours after administration. Due to its elimination half-life of 10–12 hours, bisoprolol maintains a therapeutic effect for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved within two weeks of treatment. After single-dose administration to patients with ischemic heart disease without chronic heart failure, bisoprolol reduces heart rate and stroke volume, thereby decreasing cardiac output and oxygen consumption. With prolonged use, initially elevated peripheral resistance decreases. Reduction in plasma renin activity likely contributes to the antihypertensive effect of β-blockers. Bisoprolol reduces sympathoadrenergic response by blocking cardiac β-adrenoceptors, resulting in decreased heart rate and contractility. This, in turn, reduces myocardial oxygen consumption, which is essential in the treatment of angina in ischemic heart disease.

Perindopril

Perindopril effectively reduces arterial pressure in all grades of arterial hypertension (mild, moderate, and severe); reduction in systolic and diastolic arterial pressure is observed in patients both in supine and standing positions. Perindopril reduces peripheral vascular resistance, leading to a decrease in arterial pressure. As a result, peripheral blood flow increases without affecting heart rate. Renal blood flow usually increases, while glomerular filtration rate (GFR) generally remains unchanged. The maximum antihypertensive effect develops within 4–6 hours after a single dose and persists for at least 24 hours: the residual effect is approximately 87–100% of the peak effect. Arterial pressure decreases rapidly. In patients who respond to treatment, normalization of arterial pressure occurs within a month and is maintained without tachyphylaxis. Discontinuation of treatment is not associated with a rebound effect. Perindopril reduces left ventricular hypertrophy. Clinical studies have demonstrated that perindopril has vasodilatory properties. It improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries. Perindopril reduces cardiac workload by decreasing preload and afterload: it lowers filling pressure in the left and right ventricles, reduces total peripheral vascular resistance, increases cardiac output, and improves cardiac index (based on study data).

Pharmacokinetics.

The rate and extent of absorption of bisoprolol and perindopril in the medicinal product BIS-ALITER are not significantly different from the rate and extent of absorption of bisoprolol and perindopril when administered separately as monotherapy.

Bisoprolol

Absorption

Bisoprolol is almost completely (>90%) absorbed from the gastrointestinal tract. The first-pass effect in the liver is minimal (approximately 10%), resulting in high bioavailability (approximately 90%) after oral administration.

Distribution

The volume of distribution is 3.5 L/kg. Plasma protein binding of bisoprolol is approximately 30%.

Biotransformation and elimination

Bisoprolol is eliminated from the body via two pathways. Fifty percent is metabolized in the liver into inactive metabolites, which are then excreted by the kidneys, while the remaining 50% is excreted unchanged by the kidneys. Total clearance is approximately 15 L/h. The elimination half-life from plasma is 10–12 hours, which ensures a 24-hour effect after once-daily dosing.

Special patient groups

The kinetics of bisoprolol are linear and independent of age. Since bisoprolol is eliminated equally by the kidneys and liver, dose adjustment is not required in patients with hepatic impairment or renal insufficiency. Pharmacokinetics in patients with chronic heart failure and impaired liver or kidney function has not been studied. In patients with chronic heart failure (NYHA functional class III), plasma levels of bisoprolol are higher and the elimination half-life is longer compared to healthy volunteers. At a daily dose of 10 mg, the steady-state maximum plasma concentration is 64 ± 21 ng/mL, and the half-life is 17 ± 5 hours.

Perindopril

Absorption

After oral administration, perindopril is rapidly absorbed, with maximum concentration reached within 1 hour. The elimination half-life of perindopril from plasma is 1 hour.

Distribution

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Plasma protein binding of perindoprilat is 20%, mainly to angiotensin-converting enzyme, and is dose-dependent.

Biotransformation

Perindopril is a prodrug. Twenty-seven percent of the administered dose of perindopril reaches systemic circulation as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms five other inactive metabolites. Maximum plasma concentration of perindoprilat is reached within 3–4 hours. Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril tert-butylamine is recommended to be taken orally as a single daily dose in the morning before meals.

Elimination

Perindoprilat is excreted in urine; the terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady state is achieved within 4 days.

Linearity

There is a linear relationship between perindopril dose and its plasma concentration.

Special patient groups

Elimination of perindoprilat is slowed in elderly patients, as well as in patients with cardiac or renal insufficiency. Dose adjustment is recommended for patients with renal insufficiency based on the degree of renal impairment (creatinine clearance). Dialysis clearance of perindoprilat is 70 mL/min. Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of the parent compound is halved. However, the amount of formed perindoprilat does not decrease. Therefore, dose adjustment is not required in such patients (see sections "Special precautions" and "Dosage and administration").

Clinical characteristics.

Indications.

The medicinal product BIS-ALITER in dosage strengths of 5 mg/8 mg and 10 mg/8 mg is indicated for the treatment of arterial hypertension and/or stable ischemic heart disease (with history of myocardial infarction and/or revascularization) in adult patients who require therapy with bisoprolol and perindopril in doses available in fixed combination.

The medicinal product BIS-ALITER in dosage strength of 5 mg/4 mg is indicated for the treatment of arterial hypertension and/or stable ischemic heart disease (with history of myocardial infarction and/or revascularization) and/or stable chronic heart failure with reduced left ventricular systolic function in adult patients who require therapy with bisoprolol and perindopril in doses available in fixed combination.

Contraindications.

• Hypersensitivity to the active substances or to any of the excipients of the medicinal product, or to any other ACE inhibitors;
• acute heart failure or heart failure in decompensation stage requiring intravenous inotropic therapy;
• cardiogenic shock;
• second- or third-degree atrioventricular block (without pacemaker);
• sinoatrial node dysfunction syndrome;
• sinoatrial block;
• symptomatic bradycardia;
• symptomatic arterial hypotension;
• severe form of bronchial asthma or severe course of chronic obstructive pulmonary disease;
• severe form of peripheral arterial occlusive disease or severe form of Raynaud's syndrome;
• untreated phaeochromocytoma (see section "Special precautions for use");
• history of angioedema associated with previous therapy with ACE inhibitors (see section "Special precautions for use");
• hereditary or idiopathic angioedema;
• pregnancy or planned pregnancy (see section "Use during pregnancy or lactation");
• concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use");
• concomitant use with sacubitril/valsartan. BIS-ALITER should not be administered earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use");
• extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

In a drug interaction study conducted in healthy volunteers, no interaction between bisoprolol and perindopril was observed. Information on interactions with other medicinal products for each active substance is provided below.

Medicinal products increasing the risk of angioedema

Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as dual inhibition of neprilysin and ACE increases the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use"). Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (see section "Special precautions for use").

Medicinal products causing hyperkalemia

Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with BIS-ALITER. Some medicinal products (therapeutic classes) increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and cotrimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of BIS-ALITER with the above-mentioned agents is not recommended. If concomitant use is necessary, they should be used with caution and frequent monitoring of serum potassium levels should be performed.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren

Concomitant use of BIS-ALITER and aliskiren in patients with diabetes mellitus or renal impairment is contraindicated, as it increases the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality.

Extracorporeal treatment methods

Extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or switching to another class of antihypertensive agents.

Concomitant use not recommended

Interactions related to bisoprolol

Centrally-acting antihypertensive agents such as clonidine and others (e.g., methyldopa, moxonidine, rilmenidine)

Concomitant use with centrally-acting antihypertensive agents may worsen heart failure due to reduced central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Sudden withdrawal of β-blocker therapy, particularly without prior dose reduction, increases the risk of rebound hypertension.

Class I antiarrhythmic agents (e.g., quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone)

Possible potentiation of effects on atrioventricular conduction time and enhanced negative inotropic effect.

Calcium antagonists of the verapamil group and to a lesser extent diltiazem

Negative effects on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil to patients receiving β-blockers may lead to marked arterial hypotension and atrioventricular block.

Interactions related to perindopril

Aliskiren

In any other patients, as in those with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality is increased.

Concomitant use of ACE inhibitors and angiotensin receptor blockers

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of adverse reactions such as arterial hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to use of a single agent affecting RAAS (see sections "Contraindications" and "Special precautions for use"). Publications have reported that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker was associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to use of a single RAAS-acting agent. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine

Risk of increased adverse reactions, particularly development of angioedema (angioedema).

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium salts

Development of hyperkalemia (possibly fatal), especially in patients with renal impairment (additive hyperkalemic effect). The above-mentioned agents are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use of these substances is necessary, they should be used with caution and frequent monitoring of serum potassium levels should be performed. For use of spironolactone in heart failure, see below.

Lithium

Reversible increases in serum lithium concentration and increased lithium toxicity have been reported with concomitant use of ACE inhibitors. Concomitant use of perindopril with lithium is not recommended. However, if such combination is justified, serum lithium levels should be closely monitored (see section "Special precautions for use").

Concomitant use requiring special attention

Interactions related to bisoprolol and perindopril

Antidiabetic agents (insulin, oral hypoglycemic agents)

Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect with risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combination therapy and in the presence of renal impairment. Concomitant use of bisoprolol with insulin and oral antidiabetic agents may enhance the hypoglycemic effect. β-Blockade may mask symptoms of hypoglycemia.

NSAIDs, including acetylsalicylic acid at doses ≥ 3 g/day

Concomitant use of BIS-ALITER with NSAIDs (such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs) may reduce the antihypertensive effect of bisoprolol and perindopril. Additionally, concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening renal function, including possible acute renal failure, and elevated blood potassium levels, particularly in patients with pre-existing renal impairment. Such combinations should be prescribed with caution, especially in elderly patients. It is necessary to restore the patient's fluid balance and consider monitoring renal function after initiation of combination therapy and during ongoing treatment.

Antihypertensive medicinal products and vasodilators

Concomitant use with antihypertensive medicinal products, vasodilators (e.g., nitroglycerin, other nitrates or other vasodilators), or other agents that may lower blood pressure (e.g., tricyclic antidepressants, barbiturates, phenothiazines) increases the risk of hypotensive effect of perindopril and bisoprolol.

Tricyclic antidepressants/antipsychotics/anesthetics

Concomitant use of ACE inhibitors and certain anesthetics, tricyclic antidepressants, and antipsychotics may lead to further reduction in blood pressure. Concomitant use of bisoprolol with anesthetics may result in attenuated reflex tachycardia and increased risk of arterial hypotension.

Sympathomimetics

β-Sympathomimetics (e.g., isoprenaline, dobutamine): concomitant use with bisoprolol may reduce the effects of both agents. Sympathomimetics activating α- and β-adrenergic receptors (e.g., noradrenaline, adrenaline): combination with bisoprolol may unmask α-adrenergic-mediated vasoconstrictive effects of these agents, leading to increased blood pressure and exacerbation of intermittent claudication. Such interactions are more likely with nonselective β-blockers. Sympathomimetics may reduce antihypertensive effects of ACE inhibitors.

Interactions related to bisoprolol

Calcium antagonists of the dihydropyridine type, such as felodipine and amlodipine

Concomitant use increases the risk of arterial hypotension; increased risk of further worsening of ventricular pump function in patients with heart failure.

Class III antiarrhythmic agents (e.g., amiodarone)

Possible enhancement of effects on atrioventricular conduction time.

Parasympathomimetic agents

Concomitant use may increase atrioventricular conduction time and risk of bradycardia.

Topically-acting β-blockers (e.g., eye drops for glaucoma treatment)

Concomitant use may enhance systemic effects of bisoprolol.

Cardiac glycosides (digoxin)

Reduced heart rate, increased atrioventricular conduction time.

Interactions related to perindopril

Baclofen

Enhances antihypertensive effect. Blood pressure should be monitored and dose adjustment performed if necessary.

Diuretics

In patients taking diuretics, particularly in case of water/electrolyte imbalance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effect is reduced by discontinuation of the diuretic, increasing circulating blood volume, or salt intake prior to initiation of therapy, which should begin with low doses and gradual dose escalation of perindopril. In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued prior to initiation of ACE inhibitor therapy (in such cases diuretic use may be resumed later) or ACE inhibitor therapy should be initiated with low doses and gradual dose escalation. In congestive heart failure, when diuretic therapy is ongoing, ACE inhibitor therapy should be initiated with a low dose, possibly after reduction of the concomitant diuretic dose. In all cases, renal function (creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone)

Concomitant use of eplerenone or spironolactone at doses of 12.5 to 50 mg daily with low doses of ACE inhibitors: if recommendations for use of this combination are not followed, there is a risk of hyperkalemia (possibly fatal) during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and loop diuretic. Before prescribing such combination, absence of hyperkalemia and renal impairment should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.

Concomitant use requiring attention

Interactions related to bisoprolol

Mefloquine

Increased risk of bradycardia.

Monoamine oxidase inhibitors (except MAO-B inhibitors)

Enhanced hypotensive effect of β-blockers and risk of hypertensive crisis.

Interactions related to perindopril

Gold

Rarely, concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate) may cause reactions similar to those seen with nitrates (symptoms: facial flushing, nausea, vomiting, and hypotension).

Special precautions for use.

All precautions related to the use of individual components of the medicinal product apply to the medicinal product BIS-ALITRE.

Arterial hypotension

ACE inhibitors may cause a marked decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and is more likely to occur in patients with hypovolemia, such as those receiving diuretics, those on a low-salt diet, patients on dialysis, patients with diarrhea or vomiting, and patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects"). Symptomatic arterial hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic arterial hypotension is most likely in patients with more severe degrees of heart failure who are receiving high doses of loop diuretics, have hyponatremia, or have functional renal impairment. Patients at increased risk of developing symptomatic arterial hypotension require careful medical supervision at the beginning of therapy and during dose titration. These precautions also apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke. In case of development of arterial hypotension, the patient should be placed in a supine position and, if necessary, administered 9 mg/mL (0.9%) sodium chloride solution intravenously. Transient hypotension is not a contraindication for further use of the medicinal product, which can usually be continued without difficulty after restoration of circulating blood volume and increase in blood pressure. In some patients with congestive heart failure and normal or low blood pressure, perindopril may cause additional reduction in systemic arterial pressure. This effect is expected and usually does not require discontinuation of treatment. If arterial hypotension becomes symptomatic, dose reduction or gradual discontinuation of treatment with individual components may be necessary.

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril (see section "Undesirable effects"). This may occur at any time during treatment. In such cases, the use of the medicinal product BIS-ALITRE must be discontinued immediately. Therapy with a β-blocker should be continued. Appropriate monitoring of the patient's condition is required until complete resolution of symptoms. In cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment, although antihistamine drugs may be helpful in reducing symptoms. Angioedema associated with laryngeal swelling may be fatal. If swelling extends to the tongue, glottis, or larynx, potentially leading to airway obstruction, emergency therapy must be initiated immediately, which may include administration of adrenaline and/or airway support. The patient must remain under continuous medical supervision until complete and sustained resolution of symptoms. Patients with a history of angioedema not related to ACE inhibitor therapy have an increased risk of developing angioedema (see section "Contraindications"). Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, there was no prior history of facial angioedema and C-1 esterase levels were normal. The diagnosis of intestinal angioedema was established by computed tomography, ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain occurring in patients receiving ACE inhibitors.

Concomitant use of mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus): the risk of angioedema (including airway or tongue swelling, with or without respiratory compromise) is increased in patients receiving mTOR inhibitors concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan should not begin earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of other neutral endopeptidase (NEP) inhibitors (e.g., racecadotril) and ACE inhibitors also increases the risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, a careful benefit-risk assessment should be performed before initiating NEP inhibitors (e.g., racecadotril) in patients receiving perindopril. Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Hepatic impairment

Rarely, use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly progressing liver necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. Patients who develop jaundice or a marked increase in liver enzymes while receiving ACE inhibitors should discontinue the ACE inhibitor and undergo appropriate medical evaluation and treatment (see section "Undesirable effects").

Racial characteristics

ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. As with other ACE inhibitors, perindopril is less effective in lowering blood pressure in black patients with hypertension than in patients of other races, possibly due to lower plasma renin levels in these patients.

Cough

Cough has been reported during treatment with ACE inhibitors. This cough is non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Hyperkalemia

Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia by suppressing aldosterone release. In patients with normal renal function, this effect is usually mild. Risk factors for hyperkalemia include: renal impairment, worsening renal function, age > 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists and angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to a significant increase in serum potassium levels. Hyperkalemia may lead to serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously and require careful monitoring of serum potassium levels and renal function. If concomitant use of perindopril and any of the above-mentioned substances is considered appropriate, such use requires caution and frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Combinations with lithium

Concomitant use of lithium and perindopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Combinations with potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes

Concomitant use of perindopril with potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the RAAS

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal function impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). However, if dual RAAS blockade is considered absolutely necessary, it should be performed only under specialist supervision with careful monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy.

Combinations with calcium channel blockers, class I antiarrhythmic drugs, and centrally acting antihypertensive agents

Concomitant use of bisoprolol with calcium channel blockers of the verapamil or diltiazem type, class I antiarrhythmic drugs, and centrally acting antihypertensive agents is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Discontinuation of treatment

Abrupt discontinuation of β-blocker therapy should be avoided, especially in patients with ischemic heart disease, as this may lead to transient worsening of cardiac function. Dose reduction should be gradual, using individual components, preferably over two weeks, and substitution therapy should be initiated if necessary.

Bradycardia

If, during treatment, the resting heart rate decreases to < 50–55 beats/min and the patient exhibits symptoms indicating bradycardia, the dose of the medicinal product BIS-ALITRE should be reduced using individual components of the drug. Bisoprolol should be administered at the appropriate dose.

First-degree atrioventricular block

Due to the negative dromotropic effect of β-blockers, they should be used with caution in patients with first-degree atrioventricular block.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy

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

Prinzmetal's angina

Use of β-blockers may increase the frequency and duration of attacks in patients with Prinzmetal's angina. Use of selective β1-adrenergic receptor blockers is possible in mild forms of the disease and only in combination with vasodilators.

Renal impairment

In case of renal impairment, the daily dose of the medicinal product BIS-ALITRE should be based on creatinine clearance (see section "Method of administration and dosage"). Routine monitoring of such patients should include monitoring of creatinine and potassium levels (see section "Undesirable effects"). In patients with symptomatic heart failure, hypotension occurring at the beginning of ACE inhibitor therapy may lead to further worsening of renal function. Acute renal failure, usually reversible, has been reported. In some patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, increased blood urea nitrogen and serum creatinine levels have been observed during ACE inhibitor therapy, which usually returned to normal after discontinuation of treatment. This is more common in patients with renal impairment. The presence of renovascular hypertension increases the risk of severe hypotension and renal failure. Treatment of such patients should be initiated under careful medical supervision with low doses and cautious titration. Due to the above, diuretics may contribute to the development of arterial hypotension; therefore, they should be discontinued and renal function should be monitored during the first weeks of treatment with the medicinal product BIS-ALITRE. In some patients with hypertension, in whom no renovascular disease was detected before the start of treatment, a slight transient increase in blood urea and serum creatinine levels has been observed, especially when perindopril is used concomitantly with a diuretic. This condition is more likely to occur in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril may be necessary.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure (see section "Contraindications"). Use of diuretics may be a contributing factor. Decreased renal function may be accompanied by only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Kidney transplantation

There is no experience with the use of perindopril tert-butylamine in patients who have recently undergone kidney transplantation.

Patients undergoing hemodialysis

Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux membranes while receiving ACE inhibitors concomitantly. A decision should be made regarding the use of a different type of dialysis membrane or a different class of antihypertensive agents for such patients.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

Rare cases of life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.

Anaphylactoid reactions during desensitization therapy

Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy (e.g., with bee venom preparations). These reactions can be avoided by temporarily discontinuing ACE inhibitors, but may recur upon inadvertent resumption of therapy. As with other β-blockers, bisoprolol may both increase sensitivity to allergens and exacerbate the severity of anaphylactoid reactions. In such cases, epinephrine treatment may not always produce the expected therapeutic effect.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Cases of 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 risk factors. Perindopril should be used with great caution in patients with collagenoses, during immunosuppressive therapy, allopurinol, or procainamide therapy, or in combination with these risk factors, especially in the presence of renal impairment. In some of these patients, severe infectious diseases have been observed, in several cases resistant to intensive antibiotic therapy. In such patients, periodic monitoring of white blood cell count is recommended, and patients should be informed to report any signs of infection (e.g., sore throat, fever) to their physician.

Bronchospasm (bronchial asthma, obstructive respiratory diseases)

Concomitant therapy with bronchodilators is indicated in bronchial asthma or other chronic obstructive lung diseases that may cause bronchospasm symptoms. In some cases, patients with bronchial asthma may require higher doses of β2-sympathomimetics due to increased airway tone during β-blocker therapy.

Patients with diabetes mellitus

The medicinal product BIS-ALITRE should be used with caution in patients with diabetes mellitus and significant fluctuations in blood glucose levels. Symptoms of hypoglycemia may be masked during β-blocker therapy.

Strict diet

The medicinal product should be used with caution in patients on a strict diet.

Peripheral arterial occlusive disease

Symptoms may worsen during β-blocker therapy, especially at the beginning of treatment.

Anesthesia

In patients receiving general anesthesia, beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction, intubation, and the postoperative period. Maintenance of beta-blockade during the perioperative period is recommended. The anesthesiologist should be informed about beta-blockade due to potential interactions with other drugs that may lead to bradyarrhythmias, blunted reflex tachycardia, and reduced reflex capacity to compensate for blood loss. If discontinuation of beta-blocker therapy before surgery is considered necessary, it should be done gradually and completed approximately 48 hours before anesthesia. If a patient is scheduled for surgery or requires anesthesia with agents that cause hypotension, perindopril may block angiotensin II formation after compensatory renin release. Treatment with the drug should be discontinued one day before surgery. If hypotension has already occurred due to this mechanism, correction can be achieved by increasing circulating blood volume.

Psoriasis

β-blockers should be prescribed to patients with psoriasis or a history of psoriasis only after careful benefit-risk assessment.

Pheochromocytoma

In the presence of pheochromocytoma or suspicion thereof, bisoprolol should always be prescribed in combination with α-adrenergic blockers.

Thyrotoxicosis

Bisoprolol use may mask symptoms of thyrotoxicosis.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via inhibition of the renin-angiotensin system. Therefore, use of this medicinal product is not recommended in such patients.

Heart failure

There is no therapeutic experience with bisoprolol treatment of heart failure in patients with the following conditions: insulin-dependent diabetes mellitus (type 1), severe renal impairment, severe hepatic impairment, restrictive cardiomyopathy, congenital heart diseases, hemodynamically significant organic heart valve defects, or myocardial infarction within the last 3 months.

Use during pregnancy or breastfeeding.

Pregnancy. Use of the medicinal product BIS-ALITRE is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Breastfeeding. Use of the medicinal product BIS-ALITRE is not recommended during breastfeeding. If treatment is necessary, the decision to discontinue breastfeeding should be made.

Fertility. Clinical data on the effect of the bisoprolol/perindopril combination on fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product BIS-ALITRE has no direct effect on the ability to drive vehicles or operate machinery. However, in some patients, individual reactions related to decreased blood pressure may occur, particularly at the beginning of treatment or when changing therapy, as well as in combination with alcohol. As a result, the ability to drive vehicles or operate machinery may be impaired.

Method of Administration and Dosage

Dosage

The usual dose is 1 capsule once daily in the morning before food. Patients should have been stabilized on equivalent doses of bisoprolol and perindopril for at least 4 weeks. This fixed combination is not intended for initial therapy.

Patients stabilized on 2.5 mg of bisoprolol and 2.5 mg of perindopril are recommended to use another medicinal product at the appropriate dosage.

Patients stabilized on 2.5 mg of bisoprolol and 5 mg of perindopril are recommended to use another medicinal product at the appropriate dosage.

If dosage adjustment is required, individual titration of the dose of each component of the medicinal product should be performed.

Special Patient Groups

Renal Impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")

The medicinal product BIS-ALITER at a dosage of 5 mg / 4 mg is not suitable for use in patients with severe renal impairment (creatinine clearance < 30 mL/min). For such patients, individual dose titration of each component is recommended. For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended daily dose of perindopril is 2.5 mg (use another medicinal product at the appropriate dosage). The medicinal product BIS-ALITER at a dosage of 5 mg / 4 mg may be used in patients with creatinine clearance ≥ 60 mL/min.

For patients with creatinine clearance ≥ 60 mL/min, the recommended daily dose is 2.5 mg of bisoprolol and 4 mg of perindopril (use another medicinal product at the appropriate dosage). The medicinal product BIS-ALITER at a dosage of 5 mg / 8 mg is not suitable for use in patients with creatinine clearance < 60 mL/min (moderate to severe renal impairment). For such patients, individual dose titration of each component is recommended.

The medicinal product BIS-ALITER at a dosage of 10 mg / 8 mg is not suitable for use in patients with renal impairment. For such patients, individual dose titration of each component is recommended.

Hepatic Impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")

Patients with hepatic impairment do not require dose adjustment of the medicinal product BIS-ALITER.

Elderly Patients

The medicinal product BIS-ALITER may be used, taking renal function into account.

Children

The safety and efficacy of the medicinal product BIS-ALITER in children (under 18 years of age) have not been established. Data are lacking. Therefore, the use of this medicinal product in children (under 18 years of age) is contraindicated.

Overdose

Data regarding overdose of the combination bisoprolol/perindopril are lacking.

Bisoprolol

Symptoms

Typically, the most common manifestations of β-blocker overdose include bradycardia, arterial hypotension, bronchospasm, acute heart failure, and hypoglycemia. Several cases of bisoprolol overdose (maximum dose 2000 mg) have been reported in patients with hypertension and/or ischemic heart disease, presenting with bradycardia and/or hypotension; all patients recovered. There is wide individual variability in sensitivity to a single high dose of bisoprolol; patients with heart failure are likely to be particularly sensitive.

Treatment

In case of overdose, bisoprolol treatment should be discontinued and supportive and symptomatic therapy initiated. Some data suggest that bisoprolol is poorly dialyzable. Based on expected pharmacological effects and recommendations for other β-blockers, the following general measures, which are clinically justified, should be considered:

Bradycardia: administer intravenous atropine. If the response is inadequate, cautiously administer isoprenaline or another agent with positive chronotropic properties. In some cases, transvenous insertion of a pacemaker may be required.

Arterial hypotension: intravenous administration of fluids and vasoconstrictor agents. Intravenous glucagon may be beneficial.

Atrioventricular block (Grade II or III): close monitoring of the patient is required; infuse isoprenaline or apply transvenous pacemaker insertion.

Acute worsening of heart failure: administer intravenous diuretics, inotropic agents, or vasodilators.

Bronchospasm: perform bronchodilator therapy, e.g., administer isoprenaline, β2-sympathomimetics, and/or aminophylline.

Hypoglycemia: administer intravenous glucose.

Perindopril

Symptoms

Information on perindopril overdose is limited. Symptoms of angiotensin-converting enzyme (ACE) inhibitor overdose include arterial hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Treatment

In case of overdose, intravenous administration of 9 mg/mL (0.9%) sodium chloride solution is recommended. If hypotension occurs, the patient should be placed in a supine position with elevated legs. If possible, consider the feasibility of infusion with angiotensin II and/or intravenous administration of catecholamines. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special Warnings and Precautions for Use"). In case of persistent bradycardia unresponsive to treatment, a pacemaker should be indicated. Monitoring of vital signs, serum electrolyte concentrations, and serum creatinine levels is necessary.

Adverse reactions.

The most common adverse reactions observed during the use of bisoprolol are: headache, dizziness, worsening of heart failure, hypotension, cold extremities, nausea, vomiting, abdominal pain, diarrhea, constipation, asthenia, and fatigue.

The most common adverse reactions observed during clinical trials with perindopril are: headache, dizziness, vertigo, paresthesia, visual disturbances, tinnitus, arterial hypotension, cough, dyspnea, nausea, vomiting, abdominal pain, diarrhea, constipation, taste disturbances (dysgeusia), dyspepsia, rash, pruritus, muscle cramps, and asthenia.

During clinical trials and/or post-marketing surveillance with bisoprolol or perindopril used separately, the following adverse reactions have been reported, classified by system organ classes according to MedDRA [Medical Dictionary for Regulatory Activities] and by frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

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

Blood and lymphatic system disorders: eosinophilia (uncommon* — perindopril), agranulocytosis (very rare — perindopril), pancytopenia (very rare — perindopril), leukopenia (very rare — perindopril), neutropenia (very rare — perindopril), thrombocytopenia (very rare — perindopril), hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency (very rare — perindopril).

Metabolism and nutrition disorders: hypoglycemia (uncommon* — perindopril), hyperkalemia, reversible upon discontinuation of the active substance (uncommon* — perindopril), hyponatremia (uncommon* — perindopril).

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH) (rare — perindopril).

Psychiatric disorders: mood changes (uncommon — perindopril), sleep disturbances (uncommon — bisoprolol, perindopril), depression (uncommon — bisoprolol, uncommon* — perindopril), nightmares, hallucinations (rare — bisoprolol), confusion (very rare — perindopril).

Nervous system disorders: headache** (common — bisoprolol, perindopril), dizziness** (common — bisoprolol, perindopril), vertigo (common — perindopril), taste disturbances (dysgeusia) (common — perindopril), paresthesia (common — perindopril), somnolence (uncommon* — perindopril), syncope (rare — bisoprolol, uncommon* — perindopril).

Eye disorders: visual disturbances (common — perindopril), decreased lacrimation (should be considered in contact lens wearers) (rare — bisoprolol), conjunctivitis (very rare — bisoprolol).

Ear and labyrinth disorders: tinnitus (common — perindopril), hearing disturbances (rare — bisoprolol).

Cardiac disorders: palpitations (uncommon* — perindopril), tachycardia (uncommon* — perindopril), bradycardia (very common — bisoprolol), worsening of heart failure (common — bisoprolol), atrioventricular conduction disturbances (uncommon — bisoprolol), arrhythmia (very rare — perindopril), angina pectoris (very rare — perindopril), myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients (very rare — perindopril).

Vascular disorders: arterial hypotension and related symptoms (common — bisoprolol, perindopril), cold sensation or numbness in extremities (common — bisoprolol), orthostatic hypotension (uncommon — bisoprolol), vasculitis (uncommon* — perindopril), hot flushes (rare* — perindopril), stroke, possibly due to excessive reduction in blood pressure in high-risk patients (very rare — perindopril), Raynaud's syndrome (frequency not known — perindopril).

Respiratory, thoracic and mediastinal disorders: cough (common — perindopril), dyspnea (common — perindopril), bronchospasm (uncommon — bisoprolol, perindopril), eosinophilic pneumonia (very rare — perindopril).

Gastrointestinal disorders: abdominal pain (common — bisoprolol, perindopril), constipation (common — bisoprolol, perindopril), diarrhea (common — bisoprolol, perindopril), nausea (common — bisoprolol, perindopril), vomiting (common — bisoprolol, perindopril), dyspepsia (common — perindopril), dry mouth (uncommon — perindopril), pancreatitis (very rare — perindopril).

Hepatobiliary disorders: cytolytic or cholestatic hepatitis (rare — bisoprolol, very rare — perindopril).

Skin and subcutaneous tissue disorders: rash (common — perindopril), pruritus (common — perindopril), angioedema of the face, limbs, lips, mucous membranes, tongue, glottis and/or larynx (uncommon — perindopril), urticaria (uncommon — perindopril), photosensitivity reactions (uncommon* — perindopril), pemphigoid (uncommon* — perindopril), hyperhidrosis (uncommon — perindopril), hypersensitivity reactions (pruritus, erythema, rash) (rare — bisoprolol), exacerbation of psoriasis symptoms (rare* — perindopril), erythema multiforme (very rare — bisoprolol), alopecia (very rare — bisoprolol), beta-blockers may cause or exacerbate psoriasis, provoke psoriatic rashes (very rare — bisoprolol).

Musculoskeletal and connective tissue disorders: muscle cramps (uncommon — bisoprolol, common — perindopril), muscle weakness (uncommon — bisoprolol), arthralgia (uncommon* — bisoprolol), myalgia (uncommon* — perindopril).

Renal and urinary disorders: renal failure (uncommon — perindopril), acute renal failure (rare — perindopril), anuria/oliguria (rare* — perindopril).

Reproductive system and breast disorders: erectile dysfunction (uncommon — perindopril), potency disorders (rare — bisoprolol).

General disorders: asthenia (common — bisoprolol, perindopril), fatigue (common — bisoprolol), chest pain (uncommon* — perindopril), malaise (uncommon* — perindopril), peripheral edema (uncommon* — perindopril), hyperthermia (uncommon* — perindopril).

Investigations: increased blood urea nitrogen (uncommon* — perindopril), increased serum creatinine (uncommon* — perindopril), increased liver enzymes (rare — bisoprolol, perindopril), increased blood bilirubin (rare — perindopril), increased triglycerides (rare — bisoprolol), decreased hemoglobin and decreased hematocrit (very rare — perindopril).

Injury, poisoning and procedural complications: falls (uncommon* — perindopril).

*Frequency of adverse reactions identified from spontaneous reports, calculated from clinical trial data.

**These symptoms are particularly observed at the beginning of treatment. Generally, they are mild and often disappear within 1–2 weeks.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 capsules in a blister, 3 blisters in a cardboard pack.

Or 30 capsules in a bottle, 1 bottle in a cardboard pack.

Prescription category.

Prescription only.

Manufacturer.

LLC NPF "MIKROKHEM" (production unit).

Manufacturer's address and location of business operations.

24-v Promyslova St., Severodonetsk, Luhansk region, 93400, Ukraine.