Prestilol® 5 mg/5 mg

Ukraine
Brand name Prestilol® 5 mg/5 mg
Form tablets, film-coated
Active substance / Dosage
bisoprolol · 5 mg
perindopril · 5 mg
Prescription type prescription only
ATC code
C09BX02
Registration number UA/15827/01/01
Manufacturer Laboratoires Servier Industry (manufacturing, analysis, primary and secondary packaging, batch release)

Table of Contents

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 bisoprolol fumarate (equivalent to 4.24 mg bisoprolol) and 5 mg perindopril arginine (equivalent to 3.395 mg perindopril);

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

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

PRESTILOL® 10 mg/10 mg: 1 tablet contains 10 mg bisoprolol fumarate (equivalent to 8.49 mg bisoprolol) and 10 mg perindopril arginine (equivalent to 6.790 mg 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: glycerin (E 422), hypromellose (E 464), macrogol 6000, magnesium stearate (E 470b), titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

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

PRESTILOL® 10 mg/10 mg: pink-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 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 promotes the breakdown of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II concentration in blood plasma, 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 kallikrein-kinin 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 its therapeutic effect for 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 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 blood pressure in all degrees of arterial hypertension (mild, moderate, and severe); reduction in both systolic and diastolic blood pressure is observed in patients both in the 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 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 blood pressure occurs within one 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 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 PRESTILOL® are not significantly different 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 hepatic metabolism 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 enables a 24-hour effect after once-daily dosing.

Special patient groups. Bisoprolol pharmacokinetics 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 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%, 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 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 achieved 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 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. A linear relationship exists 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 reduced by half. 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.

PRESILOL® 5 mg/10 mg and PRESILOL® 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.

PRESILOL® 5 mg/5 mg and PRESILOL® 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, to any of the excipients, or to any other 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 syndrome;
  • sinoatrial block;
  • symptomatic bradycardia;
  • symptomatic arterial hypotension;
  • severe form of bronchial asthma or severe chronic obstructive pulmonary disease;
  • severe form of peripheral arterial occlusive disease or severe Raynaud's syndrome;
  • untreated phaeochromocytoma (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 medicinal products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction");
  • concomitant use with sacubitril/valsartan. PRESILOL® must 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 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 involving healthy volunteers, no interaction between bisoprolol and perindopril was observed. Information on interactions with other medicinal products for each of the active substances 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. Initiation of perindopril therapy should not occur 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 PRESILOL®. Certain medicinal products (therapeutic classes) may 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 co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these agents increases the risk of hyperkalemia. Therefore, concomitant use of PRESILOL® 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 is required.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren. Concomitant use of PRESILOL® and aliskiren in patients with diabetes mellitus or renal impairment is contraindicated due to increased risk of hyperkalemia, worsening renal function, cardiovascular events, and death.

Extracorporeal treatment methods. 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 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 central-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, 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 all other patients, including those with diabetes mellitus or impaired renal function, there is an increased risk of hyperkalemia, worsening renal function, cardiovascular events, and death.

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 the RAAS (see sections "Contraindications" and "Special precautions"). Published reports indicate 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 careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine. Risk of increased adverse reactions, particularly development of 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 is required. 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 antidiabetic agents). Epidemiological study results suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral antidiabetic agents) may enhance the blood glucose-lowering effect with risk of hypoglycemia. This phenomenon is most likely 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 blood glucose-lowering effect. β-Adrenoceptor blockade may mask symptoms of hypoglycemia.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses ≥ 3 g/day. Concomitant use of PRESILOL® 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 possible acute renal failure, and elevate blood potassium levels, particularly in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored after initiation and during continued combination therapy.

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-adrenoceptors (e.g., noradrenaline, adrenaline): combination with bisoprolol may unmask α-adrenoceptor-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.

Locally acting β-blockers (e.g., ophthalmic solutions 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 adjustment performed if necessary.

Diuretics. In patients receiving 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 discontinuation of diuretic, increase in circulating blood volume, or salt intake prior to initiation of therapy, which should begin with low doses and gradual increase in perindopril dose. In arterial hypertension, when a previously prescribed diuretic may have caused fluid/electrolyte deficiency, it should be discontinued before initiation of ACE inhibitor therapy (in such cases, diuretic therapy 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 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 from 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. Concomitant use of ACE inhibitors, including perindopril, with injectable gold preparations (sodium aurothiomalate) may rarely 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 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, or 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 heart failure who are receiving high doses of loop diuretics, have hyponatremia, or have functional renal impairment. Patients at increased risk of 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 disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke. In the event of hypotension, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of sodium chloride 9 mg/ml (0.9%). Transient hypotension is not a contraindication to 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 hypotension becomes symptomatic, dose reduction or gradual discontinuation of therapy using 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, PRESTILOL® must be discontinued immediately. Therapy with a β-blocker should be continued. Appropriate monitoring of the patient is required until complete resolution of symptoms. In cases where swelling is limited to the face and lips, the condition usually improves without treatment, although antihistamines may be helpful in reducing symptoms. Angioedema involving 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 unrelated to ACE inhibitor therapy are at 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 serum C-1 esterase levels were normal. 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 receiving ACE inhibitors. Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to 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 respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Liver function impairment. Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly developing hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevation of liver enzymes while receiving ACE inhibitors should discontinue the ACE inhibitor and receive 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 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. Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia by inhibiting 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, and 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 (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and particularly aldosterone antagonists or angiotensin receptor blockers. Concomitant use of potassium-containing supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalemia may result in serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution and require close monitoring of serum potassium and renal function. If concomitant use of perindopril with any of the above-mentioned agents 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 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 renal 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"). If dual RAAS blockade is considered absolutely necessary, it should be performed only under specialist supervision with frequent and 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 this may lead to transient worsening of cardiac function. Dose reduction should be gradual, 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 develops symptoms suggestive of 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 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 ruled out when bisoprolol is administered to patients with Prinzmetal's angina.

Renal function impairment. In cases of renal 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 "Undesirable effects"). In patients with symptomatic heart failure, hypotension occurring at the beginning of ACE inhibitor therapy may lead to further deterioration of renal function. Acute renal failure, usually reversible, has been reported. In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, ACE inhibitors may cause increases in blood urea and serum creatinine, which usually return 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 the development of arterial hypotension; therefore, they should be discontinued and renal function should be monitored during the first weeks of treatment with PRESTILOL®. In some patients with hypertension who had no evidence of renovascular disease before treatment, slight transient increases in blood urea and serum creatinine were observed, particularly when perindopril was used concomitantly with a diuretic. This 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. Renal function impairment may be accompanied by only minor changes in serum creatinine, 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 on hemodialysis. Anaphylactoid reactions have been observed in patients on dialysis using high-flux membranes who were concurrently receiving ACE inhibitors. For such patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rare cases of life-threatening anaphylactoid reactions have been reported in patients receiving 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 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 if therapy is resumed carelessly. 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 receiving 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 collagen diseases, immunosuppressive therapy, allopurinol, or procainamide, or in combination with these risk factors, especially in the presence of renal impairment. In some of these patients, severe infections have developed, 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 while receiving β-blockers.

Patients with diabetes mellitus. PRESTILOL® 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 drug should be used with caution in patients on a strict diet.

Peripheral arterial occlusive disease. Worsening of symptoms may occur with β-blockers, especially at the beginning of treatment.

Anesthesia. In patients undergoing 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 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 patient is scheduled for surgery or requires anesthesia with hypotensive agents, perindopril may block the formation of angiotensin II 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 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 patients with pheochromocytoma or suspected pheochromocytoma, bisoprolol should always be administered 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 via inhibition of the renin-angiotensin system. Therefore, this drug is not recommended for such patients.

Heart failure. There is no therapeutic experience with bisoprolol in the 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.

Excipients.

Sodium content: PRESTILOL® contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "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 made.

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, particularly at the beginning of treatment or when changing therapy, and especially 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 a meal. Patients should have been stabilized on equivalent doses of bisoprolol and perindopril for at least 4 weeks prior to initiating therapy. Fixed-dose 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 of the drug should be performed.

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

Special Patient Groups

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

PRESILOL® 5 mg/5 mg is not suitable for use in 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 PRESILOL® 5 mg/5 mg once daily should be used. PRESILOL® 5 mg/5 mg may be used in patients with creatinine clearance ≥ 60 ml/min.

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

PRESILOL® 10 mg/10 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 "Special Warnings" and "Pharmacokinetics").

Patients with hepatic impairment do not require dose adjustment.

Elderly Patients

PRESILOL® may be used, taking renal function into account.

Children

The safety and efficacy of PRESILOL® in children (under 18 years of age) have not been established. Data are lacking. Therefore, the use of the drug in children (under 18 years of age) is contraindicated.

Overdose

Data regarding overdose with PRESILOL® are lacking.

Bisoprolol

Symptoms. The most common manifestations of β-blocker overdose are bradycardia, arterial hypotension, bronchospasm, acute heart failure, and hypoglycemia. Several cases of bisoprolol overdose (maximum dose – 2000 mg) have been reported in patients with arterial hypertension and/or ischemic heart disease, presenting with bradycardia and/or hypotension; all patients recovered. There is wide variability in individual 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. Limited data suggest that bisoprolol is poorly dialyzable. Given the 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.

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

Atrioventricular block (Grade II or III). Close monitoring is required, with infusion of isoprenaline or transvenous insertion of a temporary pacemaker.

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 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 feasible, 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"). In case of persistent bradycardia unresponsive to treatment, a temporary pacemaker should be used. Continuous monitoring of vital signs, serum electrolytes, and serum creatinine is required.

Adverse Reactions

The most commonly observed adverse reactions during bisoprolol administration 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 of bisoprolol or perindopril used separately, the following adverse reactions have been reported. These are 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 glucose-6-phosphate dehydrogenase (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 disturbances: 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*; syncope: 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, extremities, 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 serum creatinine levels: perindopril – uncommon*; increased liver enzymes: bisoprolol – rare, perindopril – rare; increased bilirubin levels: perindopril – rare; increased triglyceride levels: bisoprolol – rare; decreased hemoglobin and decreased hematocrit: perindopril – very rare.

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

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

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

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via 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.

Laboratoires Servier Industrie / 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.

Gorey Road, Arklow, Co. Wicklow, Y14 E284, Ireland.

Marketing Authorization Holder.

Les Laboratoires Servier.

Marketing Authorization Holder's location.

50, rue Carnot, 92284 Suresnes Cedex, France.

For any questions, please contact LLC "Servier Ukraine" at tel. (044) 490 3441.