Prestirol® 5 mg/10 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRESTILOL® 5 mg/5 mg (PRESTILOL® 5 mg/5 mg) PRESTILOL® 5 mg/10 mg (PRESTILOL® 5 mg/10 mg) PRESTILOL® 10 mg/5 mg (PRESTILOL® 10 mg/5 mg) PRESTILOL® 10 mg/10 mg (PRESTILOL® 10 mg/10 mg)

Composition:

Active substances: bisoprolol fumarate/perindopril arginine;

PRESTILOL® 5 mg/5 mg: 1 tablet contains 5 mg of bisoprolol fumarate (equivalent to 4.24 mg of bisoprolol) and 5 mg of perindopril arginine (equivalent to 3.395 mg of perindopril);

PRESTILOL® 5 mg/10 mg: 1 tablet contains 5 mg of bisoprolol fumarate (equivalent to 4.24 mg of bisoprolol) and 10 mg of perindopril arginine (equivalent to 6.790 mg of perindopril);

PRESTILOL® 10 mg/5 mg: 1 tablet contains 10 mg of bisoprolol fumarate (equivalent to 8.49 mg of bisoprolol) and 5 mg of perindopril arginine (equivalent to 3.395 mg of perindopril);

PRESTILOL® 10 mg/10 mg: 1 tablet contains 10 mg of bisoprolol fumarate (equivalent to 8.49 mg of bisoprolol) and 10 mg of perindopril arginine (equivalent to 6.790 mg of perindopril);

Excipients: microcrystalline cellulose (type 102), calcium carbonate, pregelatinized starch (corn), sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate (E 470b), sodium croscarmellose;

Film coating: glycerol (E 422), hypromellose (E 464), macrogol 6000, magnesium stearate (E 470b), titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

PRESTILOL® 5 mg/5 mg: pinkish-beige, elongated film-coated tablet with a score line, embossed with « » on one side and «5/5» on the other. The tablet can be divided into two parts.

PRESTILOL® 5 mg/10 mg: pinkish-beige, elongated film-coated tablet with a score line, embossed with « » on one side and «5/10» on the other. The tablet can be divided into two parts.

PRESTILOL® 10 mg/5 mg: pinkish-beige, round film-coated tablet, embossed with « » on one side and «10/5» on the other.

PRESTILOL® 10 mg/10 mg: pinkish-beige, elongated film-coated tablet, embossed with « » on one side and «10/10» on the other.

Pharmacotherapeutic group. ACE inhibitors, other combinations. 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 does 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 that converts angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kinase, is an exopeptidase that catalyzes the conversion of angiotensin I into the vasoconstrictor angiotensin II, and also promotes the breakdown of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to reduced plasma concentrations of angiotensin II, increases plasma renin activity (due to inhibition of the negative feedback mechanism on renin release), and decreases aldosterone secretion. Since ACE inactivates bradykinin, ACE inhibition also increases the activity of circulating and local kinin-kallikrein systems (and thus also activates the prostaglandin system). This mechanism of action underlies 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 over 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved within two weeks of treatment. After single-dose administration in patients with ischemic heart disease without chronic heart failure, bisoprolol reduces heart rate and stroke volume, thereby decreasing cardiac output and oxygen consumption. With long-term 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 grades of hypertension (mild, moderate, and severe). Reduction in both systolic and diastolic blood pressure is observed in patients in both supine and standing positions. Perindopril reduces peripheral vascular resistance, leading to decreased arterial pressure. As a result, peripheral blood flow increases without affecting heart rate. Renal blood flow generally increases, while glomerular filtration rate (GFR) usually 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 reduction occurs rapidly. In patients who respond to treatment, normalization of blood pressure occurs within a month and is maintained without 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 preload and afterload: it lowers filling pressures 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 PRESTILOL® formulation do not differ significantly from those of bisoprolol and perindopril when administered separately as monotherapy.

Bisoprolol

Absorption. Bisoprolol is almost completely absorbed (>90%) from the gastrointestinal tract. First-pass metabolism 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 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 supports 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 to an equal extent 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. At 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 peak 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%, primarily to angiotensin-converting enzyme, and is dose-dependent.

Biotransformation. Perindopril is a prodrug. Twenty-seven percent of the administered dose of perindopril reaches the 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 arginine is recommended to be taken orally as a single daily dose in the morning before meals.

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

Linearity. A linear relationship exists between perindopril dose and its plasma concentration.

Special patient groups. Elimination of perindoprilat is delayed in elderly patients, as well as in patients with cardiac or renal insufficiency. Dose adjustment is recommended for patients with renal impairment based on the degree of renal dysfunction (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 "Dosage and administration" and "Special precautions").

Clinical characteristics.

Indications.

Prestilol® 5 mg/10 mg and Prestilol® 10 mg/10 mg are 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.

Prestilol® 5 mg/5 mg and Prestilol® 10 mg/5 mg are 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 or to any other ACE inhibitors;
• acute heart failure or heart failure in decompensated stage requiring intravenous inotropic therapy;
• cardiogenic shock;
• second- or third-degree atrioventricular block (without a pacemaker);
• sinoatrial node dysfunction;
• sinoatrial block;
• symptomatic bradycardia;
• symptomatic arterial hypotension;
• severe bronchial asthma or severe chronic obstructive pulmonary disease (COPD);
• severe peripheral arterial occlusive disease or severe 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 in pregnancy or breastfeeding");
• concomitant use with aliskiren-containing products in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction");
• concomitant use with sacubitril/valsartan. Prestilol® should not be administered earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction");
• 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").

Interaction with other medicinal products and other forms of interaction.

In an 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 ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Therapy with perindopril 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 racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase 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 Prestilol®. Some medicinal products (therapeutic classes) may increase the risk of hyperkalemia, namely: 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 co-trimoxazole (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 Prestilol® with the above-mentioned agents is not recommended. If concomitant use of these substances 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 Prestilol® and aliskiren in patients with diabetes or renal impairment is contraindicated, as it increases the risk of hyperkalemia, worsening renal function, cardiovascular disease, and death.

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 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

Central-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). Abrupt withdrawal of β-blocker therapy, particularly without prior dose reduction, may increase 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 or renal impairment, the risk of hyperkalemia, worsening renal function, cardiovascular disease, and death 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 RAAS-acting agent (see sections "Contraindications" and "Special precautions"). 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 agent affecting the renin-angiotensin-aldosterone system. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases under strict 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). The above-mentioned agents are not recommended for concomitant use with perindopril (see section "Special precautions"). 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 concentration should be closely monitored (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 with a 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.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses ≥ 3 g/day. Concomitant use of Prestilol® 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 may increase the risk of worsening renal function, including probable acute renal failure, and elevate serum potassium levels, particularly in patients with pre-existing renal impairment. This combination should be prescribed with caution, especially in elderly patients. Patients should have their fluid balance restored and renal function monitored after initiation of combination therapy and during ongoing treatment.

Antihypertensive agents 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) may increase the hypotensive effect 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-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 worsening 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 may increase the risk of arterial hypotension; increased risk of further deterioration of ventricular pump function in patients with heart failure cannot be excluded.

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 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 fluid/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later) or ACE inhibitor therapy should be initiated with low doses and gradual dose escalation. In congestive heart failure, 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 mg 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 a loop diuretic. Before prescribing this 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, 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 warnings associated with each component of the medicinal product apply to the medicinal product PRESTILOL®.

Arterial hypotension. ACE inhibitors may cause a sudden drop in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and more likely in patients with hypovolemia, such as those taking diuretics, on a low-salt diet, patients on dialysis, patients with diarrhea or vomiting, or 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 heart failure who are taking high doses of loop diuretics, have hyponatremia, or 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 warnings 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 arterial hypotension, the patient should be placed in a horizontal position and, if necessary, receive an intravenous infusion of sodium chloride 9 mg/mL (0.9%). 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 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 taking ACE inhibitors, including perindopril (see section "Side effects"). This may occur at any time during treatment. In such cases, PRESTILOL® should 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 antihistamines may be helpful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. If swelling involves the tongue, glottis, or larynx, potentially leading to airway obstruction, emergency treatment is required, which may include administration of adrenaline and/or airway support. The patient must remain under continuous medical supervision until symptoms have completely and stably resolved. 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 confirmed 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 taking ACE inhibitors. Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications"). Sacubitril/valsartan should not be initiated 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 ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without impaired respiratory function) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating therapy with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already taking ACE inhibitors.

Liver function impairment. Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapid hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked increases in liver enzymes while taking ACE inhibitors should discontinue the ACE inhibitor and receive 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 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 ACE inhibitor therapy. 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 because they suppress 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, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium salt substitutes, or other drugs that increase serum potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium salt substitutes, particularly in patients with impaired renal function, may lead to significant increases in serum potassium levels. Hyperkalemia may cause 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 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 salt substitutes. Concomitant use of perindopril with potassium-sparing agents, potassium-containing dietary supplements, or potassium salt substitutes is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (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"). If dual RAAS blockade therapy is considered absolutely necessary, it should be conducted only under specialist supervision with frequent 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 calcium channel blockers of the verapamil or diltiazem type, 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 it may lead to transient worsening of cardiac function. Dosage should be gradually reduced using individual components, preferably over two weeks, and replacement therapy should be initiated if necessary.

Bradycardia. If heart rate at rest decreases to < 50–55 beats/min during treatment and the patient exhibits symptoms indicating bradycardia, the dose of PRESTILOL® 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. Cases of coronary vasospasm have been observed. Despite high β1-selectivity, angina attacks cannot be completely excluded when bisoprolol is administered to patients with Prinzmetal's angina.

Renal function impairment. In case of renal function impairment, the daily dose of PRESTILOL® should be based on creatinine clearance (see section "Dosage and administration"). 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 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 begin under careful medical supervision with low doses and cautious dose titration. Due to the above, diuretics may contribute to arterial hypotension and should be discontinued, and renal function should be monitored during the first weeks of treatment with PRESTILOL®. 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 were observed, especially when perindopril was 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 favorable factor. Impaired 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 arginine in patients who have recently undergone kidney transplantation.

Patients undergoing hemodialysis. Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux membranes who were concurrently taking ACE inhibitors. For such patients, a decision should be made regarding the use of another type of dialysis membrane or another class of antihypertensive agents.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rare cases of life-threatening anaphylactoid reactions have been reported in patients taking ACE inhibitors during low-density lipoprotein (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 taking 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 careless resumption of therapy. As with other β-blockers, bisoprolol may enhance sensitivity to allergens and increase 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 taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagenoses, during immunosuppressive therapy, with allopurinol or procainamide, or in combination with these risk factors, especially in the presence of renal impairment. Some of these patients developed severe infections, in several cases resistant to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended when prescribing perindopril to such patients, 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. PRESTILOL® 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 drug 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 is recommended throughout the perioperative period. The anesthesiologist should be informed of 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 surgical procedure or anesthesia with hypotensive agents is planned, perindopril may block angiotensin II formation after compensatory renin release. Treatment 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 assessment of the benefit-risk ratio.

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

Thyrotoxicosis. Bisoprolol may mask symptoms of thyrotoxicosis.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting by inhibition of the renin-angiotensin system. Therefore, this drug is not recommended for such patients.

Heart failure. There is no therapeutic experience with bisoprolol treatment of heart failure in patients with the following conditions: insulin-dependent diabetes (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.

Excipients.

Sodium content: PRESTILOL® contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is almost sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Use of PRESTILOL® is contraindicated during pregnancy.

Breastfeeding. Use of PRESTILOL® is not recommended during breastfeeding. If treatment is necessary, the decision to discontinue breastfeeding should be considered.

Fertility. Clinical data on the effect on fertility with the use of PRESTILOL® are lacking.

Ability to affect reaction speed when driving or operating machinery.

PRESTILOL® has no direct effect on the ability to drive or operate machinery. However, in some patients, individual reactions related to decreased blood pressure may occur, especially at the beginning of treatment or when changing therapy, as well as in combination with alcohol. As a result, the ability to drive or operate machinery may be impaired.

Method of Administration and Dosage

Dosage

The usual dosage is one tablet 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 initiation of this fixed combination. This fixed combination is not intended for initial therapy.

For patients stabilized on 2.5 mg bisoprolol and 2.5 mg perindopril, half a tablet of 5 mg/5 mg once daily is recommended.

For patients stabilized on 2.5 mg bisoprolol and 5 mg perindopril, half a tablet of 5 mg/10 mg once daily is recommended.

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

Prestilol® 5 mg/5 mg and Prestilol® 5 mg/10 mg tablets are scored to allow division into two equal parts.

Special Patient Groups

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

Prestilol® 5 mg/5 mg is not suitable for patients with severe renal impairment (creatinine clearance below 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. Therefore, half a tablet of Prestilol® 5 mg/5 mg once daily should be administered. Prestilol® 5 mg/5 mg may be used in patients with creatinine clearance ≥ 60 mL/min.

Prestilol® 5 mg/10 mg and Prestilol® 10 mg/5 mg: in patients with creatinine clearance ≥ 60 mL/min, the recommended daily dose is half a tablet of Prestilol® 5 mg/10 mg or one tablet of Prestilol® 10 mg/5 mg. Prestilol® 5 mg/10 mg and Prestilol® 10 mg/5 mg are not suitable for patients with creatinine clearance below 60 mL/min (moderate to severe renal impairment). For such patients, individual dose titration of each component is recommended.

Prestilol® 10 mg/10 mg is not suitable for patients with renal impairment. For such patients, individual dose titration of each component is recommended.

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

Patients with hepatic impairment do not require dose adjustment.

Elderly Patients

Prestilol® may be used in elderly patients, taking into account renal function.

Children

Safety and efficacy of Prestilol® in children (under 18 years of age) have not been established. Data are lacking. Therefore, use of this medicinal product in children (under 18 years of age) is contraindicated.

Overdose

Data regarding overdose with Prestilol® are lacking.

Bisoprolol

Symptoms. The most common manifestations of β-blocker overdose are bradycardia, hypotension, bronchospasm, acute heart failure, and hypoglycemia. Several cases of bisoprolol overdose (maximum dose reported: 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 should be discontinued and supportive and symptomatic therapy initiated. Limited 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 temporary pacemaker may be required.

Hypotension. Intravenous fluid administration and vasopressors. Intravenous glucagon may be beneficial.

Atrioventricular block (Grade II or III). Close monitoring 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 ACE inhibitors overdose include 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, infusion of angiotensin II and/or intravenous administration of catecholamines should be considered. 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, temporary pacing is indicated. Continuous monitoring of vital signs, serum electrolytes, and serum creatinine is necessary.

Adverse Reactions.

The most common adverse reactions observed during the use of bisoprolol are: headache, dizziness, worsening of heart failure, hypotension, cold sensation in the 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 MedDRA organ system classes and 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: bisoprolol – rare, perindopril – very rare.

Endocrine system disorders. Syndrome of inappropriate antidiuretic hormone secretion (SIADH): perindopril – rare.

Blood and lymphatic system disorders. Eosinophilia: perindopril – uncommon*; agranulocytosis: perindopril – very rare; pancytopenia: perindopril – very rare; leukopenia: perindopril – very rare; neutropenia: perindopril – very rare; thrombocytopenia: perindopril – very rare; hemolytic anemia in patients with congenital G-6-PD deficiency: perindopril – very rare.

Metabolism and nutrition disorders. Hypoglycemia: perindopril – uncommon*; hyperkalemia, reversible upon discontinuation of the active substance: perindopril – uncommon*; hyponatremia: perindopril – uncommon*.

Psychiatric disorders. Mood changes: perindopril – uncommon; sleep disorders: bisoprolol – uncommon, perindopril – uncommon; depression: perindopril – uncommon*, bisoprolol – uncommon; nightmares, hallucinations: bisoprolol – rare; confusion: perindopril – very rare.

Nervous system disorders. Headache**: bisoprolol – common, perindopril – common; dizziness**: bisoprolol – common, perindopril – common; vertigo: perindopril – common; taste disturbances (dysgeusia): perindopril – common; paresthesia: perindopril – common; somnolence: perindopril – uncommon*; loss of consciousness: bisoprolol – rare, perindopril – uncommon*.

Eye disorders. Visual disturbances: perindopril – common; decreased lacrimation (should be considered in contact lens wearers): bisoprolol – rare; conjunctivitis: bisoprolol – very rare.

Ear and labyrinth disorders. Tinnitus: perindopril – common; hearing disorders: bisoprolol – rare.

Cardiac disorders. Palpitations: perindopril – uncommon*; tachycardia: perindopril – uncommon*; bradycardia: bisoprolol – very common; worsening of heart failure: bisoprolol – common; atrioventricular conduction disturbances: bisoprolol – uncommon; arrhythmia: perindopril – very rare; angina pectoris: perindopril – very rare; myocardial infarction may occur due to excessive reduction in arterial pressure in high-risk patients: perindopril – very rare.

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

Respiratory, thoracic and mediastinal disorders. Cough: perindopril – common; dyspnea: perindopril – common; bronchospasm: bisoprolol – uncommon, perindopril – uncommon; eosinophilic pneumonia: perindopril – very rare.

Gastrointestinal disorders. Abdominal pain: bisoprolol – common, perindopril – common; constipation: bisoprolol – common, perindopril – common; diarrhea: bisoprolol – common, perindopril – common; nausea: bisoprolol – common, perindopril – common; vomiting: bisoprolol – common, perindopril – common; dyspepsia: perindopril – common; dry mouth: perindopril – uncommon; pancreatitis: perindopril – very rare.

Hepatobiliary disorders. Cytolytic or cholestatic hepatitis: bisoprolol – rare, perindopril – very rare.

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

Musculoskeletal and connective tissue disorders. Muscle cramps: bisoprolol – uncommon, perindopril – common; muscle weakness: bisoprolol – uncommon; arthralgia: perindopril – uncommon*; myalgia: perindopril – uncommon*.

Renal and urinary disorders. Renal failure: perindopril – uncommon; acute renal failure: perindopril – rare; anuria/oliguria: perindopril – rare*.

Reproductive system and breast disorders. Erectile dysfunction: bisoprolol – rare, perindopril – uncommon.

General disorders and administration site conditions. Asthenia: bisoprolol – common, perindopril – common; fatigue: bisoprolol – common; chest pain: perindopril – uncommon*; malaise: perindopril – uncommon*; peripheral edema: perindopril – uncommon*; hyperthermia: perindopril – uncommon*.

Investigations. Increased blood urea levels: perindopril – uncommon*; increased blood creatinine levels: perindopril – uncommon*; increased liver enzymes: bisoprolol – rare, perindopril – rare; increased blood bilirubin levels: perindopril – rare; increased triglyceride levels: bisoprolol – rare; decreased hemoglobin and hematocrit: perindopril – very rare.

Injury, poisoning and procedural complications. Falls: perindopril – uncommon*.

* 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. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

30 months.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

PRESTILOL® 5 mg/5 mg: 10, 30 or 100 tablets in a tablet container; 1 tablet container per cardboard packaging box.

PRESTILOL® 5 mg/10 mg, PRESTILOL® 10 mg/5 mg, PRESTILOL® 10 mg/10 mg: 30 or 100 tablets in a tablet container; 1 tablet container per cardboard packaging box.

Prescription status.

Prescription only.

Manufacturer.

Les Laboratoires Servier Industrie.

Manufacturer's location and address of place of business.

905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd.

Manufacturer's location and address of place of business.

Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland.

Marketing Authorization Holder.

Les Laboratoires Servier.

Marketing Authorization Holder's location.

50, rue Carnot, 92284 Suresnes Cedex, France.

For any information regarding this medicinal product, please contact LLC "Servier Ukraine" at tel. (044) 490 3441, fax: (044) 490 3440.