Bi-prestarium® 5 mg/5 mg

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Bi-PRESTARIUM® 5 mg/5 mg (Bi-PRESTARIUM® 5 mg/5 mg) Bi-PRESTARIUM® 5 mg/10 mg (Bi-PRESTARIUM® 5 mg/10 mg) Bi-PRESTARIUM® 10 mg/5 mg (Bi-PRESTARIUM® 10 mg/5 mg) Bi-PRESTARIUM® 10 mg/10 mg (Bi-PRESTARIUM® 10 mg/10 mg)

Composition:

Bi-PRESTARIUM® 5 mg/5 mg

Active substances: perindopril arginine/amlodipine;

One tablet contains perindopril arginine 5 mg (equivalent to 3.395 mg of perindopril) and amlodipine besylate 6.935 mg (equivalent to 5 mg of amlodipine);

Bi-PRESTARIUM® 5 mg/10 mg

Active substances: perindopril arginine/amlodipine;

One tablet contains perindopril arginine 5 mg (equivalent to 3.395 mg of perindopril) and amlodipine besylate 13.870 mg (equivalent to 10 mg of amlodipine);

Bi-PRESTARIUM® 10 mg/5 mg

Active substances: perindopril arginine/amlodipine;

One tablet contains perindopril arginine 10 mg (equivalent to 6.790 mg of perindopril) and amlodipine besylate 6.935 mg (equivalent to 5 mg of amlodipine);

Bi-PRESTARIUM® 10 mg/10 mg

Active substances: perindopril arginine/amlodipine;

One tablet contains perindopril arginine 10 mg (equivalent to 6.790 mg of perindopril) and amlodipine besylate 13.870 mg (equivalent to 10 mg of amlodipine);

Excipients: lactose monohydrate, magnesium stearate (E 470B), microcrystalline cellulose (E 460), colloidal anhydrous silicon dioxide (E 551).

Pharmaceutical form. Tablets.

Main physicochemical properties:

Bi-PRESTARIUM® 5 mg/5 mg: white, elongated tablet with the imprint "5/5" on one side and the other.

Bi-PRESTARIUM® 5 mg/10 mg: white, square-shaped tablet with the imprint "5/10" on one side and the other.

Bi-PRESTARIUM® 10 mg/5 mg: white, triangular-shaped tablet with the imprint "10/5" on one side and the other.

Bi-PRESTARIUM® 10 mg/10 mg: white, round tablet with the imprint "10/10" on one side and the other.

Pharmacotherapeutic group. ACE inhibitors, combinations. ACE inhibitors and calcium channel blockers. Perindopril and amlodipine. ATC code C09B B04.

Pharmacological Properties

Pharmacodynamics

Perindopril

Mechanism of Action

Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kininase, is an exopeptidase that catalyzes the conversion of angiotensin I into the vasoconstrictor angiotensin II, and also promotes the breakdown of the vasodilator bradykinin into inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II plasma concentration, resulting in increased plasma renin activity (due to suppression of the negative feedback on renin release) and decreased 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 the occurrence of certain adverse effects (e.g., cough).

Perindopril acts via its active metabolite—perindoprilat. Other metabolites do not demonstrate ACE-inhibiting activity under experimental conditions.

Clinical Efficacy and Safety

Arterial Hypertension

Perindopril effectively reduces arterial blood pressure in all stages of arterial hypertension: mild, moderate, and severe. Reduction in systolic and diastolic blood pressure is observed both in the supine and standing positions.

Perindopril reduces peripheral vascular resistance, leading to a decrease in arterial blood pressure. As a result, peripheral blood flow increases without affecting heart rate.

Renal blood flow usually increases, while glomerular filtration rate (GFR) typically remains unchanged.

The maximum antihypertensive effect develops 4–6 hours after a single dose and lasts at least 24 hours: the T/R ratio (efficacy just before the next dose / maximum efficacy) of perindopril ranges from 87 to 100%.

Blood pressure decreases rapidly. In patients responding to treatment, normalization of blood pressure occurs within one month and is maintained without the development of tachyphylaxis.

Upon discontinuation of perindopril, no rebound effect occurs.

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.

Prevention of Cardiovascular Complications in Patients with Documented Stable Coronary Heart Disease (CHD)

EUROPA is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial lasting 4 years. A total of 12,218 adult patients were randomized into treatment groups: 6,110 patients received 8 mg of perindopril tert-butylamine (equivalent to 10 mg of perindopril arginine), and 6,108 patients received placebo. The study included patients with confirmed ischemic heart disease and without clinically evident heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. The majority of patients in the study received perindopril in addition to standard therapy with antiplatelet agents, lipid-lowering drugs, and β-blockers.

The primary efficacy endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest followed by successful resuscitation. Treatment with 8 mg of perindopril tert-butylamine (equivalent to 10 mg of perindopril arginine) once daily resulted in a significant absolute reduction of the primary endpoint by 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6]; p<0.001).

Amlodipine

Mechanism of Action

Amlodipine is a calcium ion influx inhibitor belonging to the dihydropyridine class (a slow calcium channel blocker or calcium antagonist) that blocks the transmembrane influx of calcium ions into cardiac and vascular smooth muscle cells.

The antihypertensive mechanism of amlodipine is due to its direct relaxing effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces angina symptoms is not fully elucidated, but amlodipine reduces total ischemic load through the following actions:

• Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Since heart rate remains unchanged, the reduced cardiac workload decreases myocardial energy consumption and oxygen demand.
• Amlodipine also promotes partial dilation of major coronary arteries and coronary arterioles in both normal and ischemic myocardial regions. This dilation increases oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal’s or variant angina).

Clinical Efficacy and Safety

In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant blood pressure reduction over 24 hours, both in supine and standing positions. Due to its slow onset of action, amlodipine does not cause acute hypotension.

In patients with angina, once-daily administration of amlodipine increases total exercise duration, time to onset of angina, and time to 1 mm ST-segment depression, reduces the frequency of angina attacks, and decreases the need for nitroglycerin use.

Amlodipine is not associated with any adverse metabolic effects or changes in plasma lipid levels, making it suitable for use in patients with asthma, diabetes, and gout.

Coronary Heart Disease (CHD)

The efficacy of amlodipine in preventing clinical events in patients with coronary heart disease (CHD) was evaluated in an independent, multicenter, randomized, double-blind, placebo-controlled trial involving 1,997 patients—the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study. Over 2 years, 663 patients received amlodipine 5–10 mg, 673 patients received enalapril 10–20 mg, and 655 patients received placebo, all in addition to standard therapy with statins, β-blockers, diuretics, and aspirin. The main efficacy outcomes are presented in the table below. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and fewer revascularization procedures in patients with CHD.

Number of Major Clinical Events in the CAMELOT Study

Frequency of cardiovascular events, number (%)				Amlodipine vs placebo
Outcome	Amlodipine	Placebo	Enalapril	Relative risk (95% Cl)	p value
Primary endpoint Unfavorable cardiovascular events	110 (16.6)	151 (23.1)	136 (20.0)	0.69 (0.54–0.88)	0.003
Individual components Coronary revascularization Hospitalizations due to angina Non-fatal myocardial infarction Stroke or transient ischemic attack Cardiovascular mortality Hospitalizations due to congestive heart failure Cardiac arrest with subsequent resuscitation Newly diagnosed peripheral vascular disease	78 (11.8) 51 (17.7) 14 (2.1) 6 (0.9) 5 (0.8) 3 (0.5) 0 5 (0.8)	103 (15.7) 84 (12.8) 19 (2.9) 12 (1.8) 2 (0.3) 5 (0.8) 4 (0.6) 2 (0.3)	95 (14.1) 86 (12.8) 11 (1.6) 8 (1.2) 5 (0.7) 4 (0.6) 1 (0.1) 8 (1.2)	0.73 (0.54–0.98) 0.58 (0.41–0.82) 0.73 (0.37–1.46) 0.50 (0.19–1.32) 2.46 (0.48–12.7) 0.59 (0.14–2.47) ̶ 2.6 (0.5–13.4)	0.03 0.002 0.37 0.15 0.27 0.46 0.04 0.24

Heart failure

Hemodynamic and clinical load-controlled studies involving patients with heart failure, NYHA functional class II – IV, showed that amlodipine did not cause clinical worsening based on exercise tolerance, left ventricular ejection fraction, or clinical symptoms.

The objective of the placebo-controlled PRAISE study was to evaluate the effect of amlodipine in patients with heart failure, NYHA functional class III – IV, who were receiving digoxin, diuretics, and ACE inhibitors. The study demonstrated that amlodipine did not increase the risk of mortality or the risk of morbidity/mortality related to heart failure.

PRAISE-2 was a long-term, placebo-controlled study. The objective was to evaluate the effect of amlodipine in patients with heart failure, NYHA functional class III – IV, without clinical symptoms or objective findings confirming or underlying ischemic heart disease. Patients enrolled in the study were receiving long-term treatment with ACE inhibitors, digitalis preparations, and diuretics. The study showed that amlodipine did not affect overall cardiovascular mortality. Within the study, amlodipine administration was associated with an increased number of reports of pulmonary edema.

ALLHAT – Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

The randomized, double-blind morbidity/mortality trial ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) was conducted in patients with mild to moderate arterial hypertension to compare modern therapeutic agents: amlodipine 2.5 – 10 mg/day (calcium channel blocker) or lisinopril 10 – 40 mg/day (ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone 12.5 – 25 mg/day.

A total of 33,357 hypertensive patients aged 55 years and older were enrolled and followed for a mean of 4.9 years. Patients had at least one additional cardiovascular risk factor, including: prior myocardial infarction or stroke > 6 months before enrollment, or documented other atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), LDL cholesterol (low-density lipoprotein) < 35 mg/dL (11.6%), left ventricular hypertrophy confirmed by electrocardiography or echocardiography (20.9%), smoking (21.9%).

The primary endpoint was a composite of fatal coronary heart disease or nonfatal myocardial infarction. There was no statistically significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: relative risk 0.98, 95% CI (0.90 – 1.07), p = 0.65. Regarding secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, relative risk 1.38, 95% CI [1.25 – 1.52], p < 0.001). However, there was no significant difference in all-cause mortality between amlodipine-based and chlorthalidone-based therapy (relative risk 0.96, 95% CI [0.89 – 1.02], p = 0.20).

Properties common to perindopril and amlodipine

The morbidity and mortality trial ASCOT-BLPA (Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm) included 19,257 patients aged 40 to 79 years with hypertension and at least three of the following cardiovascular risk factors: left ventricular hypertrophy (detected by ECG or echocardiography), other ECG abnormalities, type 2 diabetes, peripheral arterial disease, history of stroke or transient ischemic attack, male sex, age ≥55 years, microalbuminuria or proteinuria, plasma total cholesterol to HDL cholesterol ratio ≥6, family history of premature ischemic heart disease.

The main objective of the study was to evaluate and compare the long-term effects of two antihypertensive treatment regimens on a composite primary endpoint of nonfatal myocardial infarction (including silent myocardial infarction) and fatal complications of ischemic heart disease (IHD). The regimens were amlodipine in combination with perindopril (added if necessary for blood pressure control) versus atenolol in combination with the diuretic bendroflumethiazide (added if necessary for blood pressure control).

At the end of the study, the majority of patients (78%, 14,974 out of 19,242) were receiving at least two antihypertensive agents, while only 15% (1,401 out of 9,634) and 9% (857 out of 9,608) were receiving monotherapy with amlodipine or atenolol, respectively.

The study was prematurely terminated after a mean of 5.5 years of follow-up by the Data Safety Monitoring Board (DSMB) due to significantly higher mortality observed in the atenolol-based treatment group compared to the amlodipine-based treatment group.

The study results showed a non-significant 10% reduction in the primary composite endpoint of nonfatal myocardial infarction (including silent myocardial infarction) and fatal complications of ischemic heart disease (IHD) in the amlodipine/perindopril group compared to the atenolol/bendroflumethiazide group. However, there was a significant reduction in all secondary endpoint measures (except for fatal and nonfatal heart failure) in the amlodipine/perindopril group.

Endpoints:

Secondary endpoints	Relative risk reduction	95 % CI	p
Non-fatal myocardial infarction (excluding asymptomatic) + fatal IHD	13 %	0.76 – 1.00	0.0458
Total coronary endpoint	13 %	0.79 – 0.96	0.007
Coronary events and interventions	16 %	0.78 – 0.90	<0.0001
All-cause mortality	11 %	0.81 – 0.99	0.0247
Cardiovascular mortality	24 %	0.65 – 0.90	0.0010
Fatal and non-fatal stroke	23 %	0.66 – 0.89	0.0003
Fatal and non-fatal heart failure	16 %	0.66 – 1.05	0.1257

Pharmacokinetics.

The rate and extent of absorption of perindopril and amlodipine, both as individual agents and in the fixed combination Bi-PRESTARIUM®, are not significantly different.

Perindopril

Absorption

After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.

Perindopril is a prodrug. Approximately 27% of the administered dose reaches the systemic circulation as the active metabolite, perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five inactive metabolites. Maximum plasma concentration of perindoprilat is achieved 3–4 hours after administration.

Food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability. Therefore, the daily dose of perindopril arginine should be taken once daily in the morning before a meal.

Distribution

A linear relationship between perindopril dose and its plasma concentration is observed. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Plasma protein binding of perindoprilat is about 20%, primarily to angiotensin-converting enzyme, although this value is dose-dependent.

Elimination

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

Elimination of perindoprilat is slowed in elderly patients and in patients with cardiac or renal impairment (see section "Special precautions for use"). Therefore, routine medical monitoring should include frequent assessment of creatinine and potassium levels.

Hepatic impairment

The dialysis clearance of perindoprilat is 70 mL/min.

Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of perindopril is reduced by half. However, the amount of formed perindoprilat is not decreased. Therefore, dose adjustment is not required in such patients (see section "Special precautions for use").

Amlodipine

Absorption, distribution, plasma protein binding

After oral administration of therapeutic doses, amlodipine is well absorbed and reaches peak blood concentrations 6–12 hours after administration. Absolute bioavailability ranges from 64% to 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine in blood is bound to plasma proteins.

Food intake does not affect the bioavailability of amlodipine.

Biotransformation/Elimination

The elimination half-life from plasma is approximately 35–50 hours, allowing for once-daily dosing.

Amlodipine is primarily metabolized in the liver to inactive metabolites. About 60% of metabolites are excreted in urine, and 10% are excreted unchanged.

Elderly patients. The time to reach peak plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced clearance of amlodipine, resulting in increased AUC and prolonged elimination half-life. The increase in AUC and elimination half-life observed in patients with congestive heart failure corresponded to the age-related characteristics of the studied patient population.

Hepatic impairment

There is very limited clinical data on the use of amlodipine in patients with impaired liver function. In patients with hepatic impairment, clearance of amlodipine is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.

Clinical characteristics.

Indications.

Arterial hypertension and/or ischemic heart disease (when treatment with perindopril and amlodipine is required).

Contraindications.

Related to perindopril:

• Hypersensitivity to the active substance or to any other angiotensin-converting enzyme (ACE) inhibitors;
• History of angioedema associated with previous treatment with ACE inhibitors;
• Hereditary or idiopathic angioedema;
• Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation");
• Concomitant use with medicinal products containing the active substance aliskiren in patients with diabetes or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction");
• Concomitant use with sacubitril/valsartan. Bi-PRESTARIUM® must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
• Extracorporeal treatments 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 solitary functioning kidney (see section "Special precautions for use").

Related to amlodipine:

• Severe arterial hypotension;
• Hypersensitivity to the active substance or to dihydropyridine derivatives;
• Shock, including cardiogenic shock;
• Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis);
• Heart failure after acute myocardial infarction with unstable hemodynamics.

Related to the medicinal product Bi-PRESTARIUM®:

All the above-mentioned contraindications related to each component of the medicinal product apply to the fixed combination Bi-PRESTARIUM®.

• Hypersensitivity to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Interactions related to perindopril

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single RAAS-acting agent (see sections "Contraindications" and "Special precautions for use").

Medicinal products increasing the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Therapy with perindopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (see section "Special precautions for use").

Medicinal products causing hyperkalemia. Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Bi-PRESTARIUM®. Some medicinal products or therapeutic classes of medicinal products may cause 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), as trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant administration of these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of Bi-PRESTARIUM® with the above-mentioned agents is not recommended. If concomitant use of these agents 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. In patients with diabetes or renal impairment, the risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality is increased.

Extracorporeal treatments. Extracorporeal treatments 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, increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

Concomitant use is not recommended (see section "Special precautions for use").

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

Published data show that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with an increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents 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 with careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine. There is a risk of increased frequency of adverse reactions, such as angioedema.

Potassium-sparing diuretics (e.g., triamterene, amiloride, etc.), potassium salts. 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 for use"). However, if concomitant administration of these agents is necessary, they should be used with caution and frequent monitoring of plasma potassium levels is required. For use of spironolactone in heart failure, see section "Medicinal products requiring special attention when co-administered".

Lithium. Concomitant use of lithium and ACE inhibitors is not recommended due to the possibility of reversible increase in serum lithium concentration and, consequently, increased toxicity (severe neurotoxicity). However, if such combination is justified, monitoring of serum lithium concentration is recommended (see section "Special precautions for use").

Medicinal products requiring special attention when co-administered

Antidiabetic agents (insulin, oral antidiabetic agents). Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral antidiabetic agents) may enhance the blood glucose-lowering effect, increasing the risk of hypoglycemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment.

Diuretics. In patients receiving diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake prior to starting perindopril therapy, which should be initiated at low doses with gradual dose escalation. In arterial hypertension, if a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation. In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In any case, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). Particular attention is required when co-administering eplerenone or spironolactone at doses from 12.5 mg to 50 mg daily with low doses of ACE inhibitors. Failure to follow recommendations for prescribing such combinations increases the 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 such a combination, absence of hyperkalemia and renal dysfunction should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g daily. The antihypertensive effect may be reduced during concomitant use of ACE inhibitors with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including the possibility of acute renal failure, and elevated plasma potassium levels, especially in patients with a history of renal dysfunction. Such combinations should be prescribed with caution, particularly in elderly patients. Patients should be adequately hydrated, and renal function should be monitored at the beginning of treatment with such combinations and periodically during therapy.

Medicinal products requiring attention when co-administered

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold. Rarely, reactions similar to those observed with nitrates (facial flushing, hot flashes, nausea, vomiting, and hypotension) may occur when ACE inhibitors, including perindopril, are used concomitantly with injectable gold preparations (sodium aurothiomalate).

Interactions related to amlodipine

Concomitant use is not recommended

Dantrolene (infusion). In experimental studies, ventricular fibrillation with fatal outcome and cardiovascular collapse combined with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the potential risk of hyperkalemia, it is recommended to avoid concomitant administration of calcium channel blockers such as amlodipine in patients with malignant hyperthermia or suspected malignant hyperthermia.

Medicinal products requiring special caution when co-administered

Inducers of CYP3A4. Plasma concentrations of amlodipine may vary during concomitant use with known inducers of CYP3A4. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, especially strong inducers (e.g., rifampicin, St. John’s wort (Hypericum perforatum)).

Inhibitors of CYP3A4. Concomitant use of amlodipine with potent or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may increase amlodipine concentrations. The clinical manifestation of these pharmacokinetic changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment are required in such cases. There is an increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Close monitoring is recommended for such patients.

Medicinal products requiring attention when co-administered

Concomitant use of amlodipine with other medicinal products with antihypertensive properties may result in an additive antihypertensive effect.

Tacrolimus. There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine. To avoid toxic effects of tacrolimus, blood levels should be monitored and the dose adjusted as necessary in patients receiving amlodipine.

Inhibitors of mechanistic target of rapamycin (mTOR). mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. When used concomitantly with mTOR inhibitors, amlodipine may increase the concentration of mTOR inhibitors.

Cyclosporine. Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in kidney transplant patients, where fluctuations in cyclosporine concentration were observed, with an average increase from 0% to 40%. Kidney transplant patients receiving both amlodipine and cyclosporine should have cyclosporine blood levels monitored and cyclosporine dose reduced if necessary.

Simvastatin. Administration of amlodipine at doses ≥10 mg in combination with 80 mg simvastatin resulted in a 77% increase in simvastatin concentration compared to monotherapy. Patients should limit simvastatin dose to 20 mg daily.

Other combinations

Clinical interaction studies have demonstrated that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Amlodipine should not be used together with grapefruit or grapefruit juice, as in some patients bioavailability may increase, leading to an enhanced hypotensive effect.

Interactions related to the fixed combination Bi-PRESTARIUM®

Medicinal products requiring special caution when co-administered

Baclofen enhances the antihypertensive effect. Blood pressure should be monitored and dose adjustment performed if necessary.

Medicinal products requiring attention when co-administered

• Antihypertensive agents (such as beta-blockers) and vasodilators:

Concomitant use of these agents may enhance the hypotensive effect of perindopril and amlodipine.

Concomitant use with nitroglycerin and other nitrates or with other vasodilators may cause further reduction in blood pressure and should therefore be used with caution.

• Corticosteroids, tetracosactide reduce the antihypertensive effect (due to water and salt retention by corticosteroids).
• Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin) enhance the antihypertensive effect and increase the risk of orthostatic hypotension.
• Amifostine may enhance the antihypertensive effect of amlodipine.
• Tricyclic antidepressants/antipsychotropic agents/anesthetics enhance the antihypertensive effect and increase the risk of orthostatic hypotension.

Special precautions for use.

All warnings associated with each component of the medicinal product apply to the fixed combination BID PRESTARILUM®.

Special precautions related to perindopril

Hypersensitivity/Angioedema. Rare cases of angioedema affecting the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx have been reported during treatment with angiotensin-converting enzyme (ACE) inhibitors, including perindopril (see section "Adverse reactions"). This may occur at any time during treatment. In such cases, immediate discontinuation of BID PRESTARILUM® is required, and appropriate monitoring of the patient must be instituted until complete and sustained disappearance of signs and symptoms. When angioedema is limited to the face and lips, the condition usually resolves without treatment; antihistamines may be helpful in relieving symptoms.

Angioedema involving swelling of the larynx may be fatal. If swelling involves the tongue, glottis, or larynx, possibly causing airway obstruction, emergency therapy must be instituted immediately, which may include administration of adrenaline and/or measures to ensure airway patency. The patient must remain under close medical supervision until complete and sustained resolution of symptoms.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema during ACE inhibitor treatment (see section "Contraindications").

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, prior angioedema of the face was not observed, and C-1 esterase levels were normal. The diagnosis of intestinal angioedema was confirmed by computed tomography, ultrasound, or during surgery. 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 (see section "Adverse reactions").

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan therapy should not occur 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 inhibitors (NEP) (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., swelling of the airways or tongue, with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised 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.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rare, life-threatening anaphylactoid reactions have been reported in patients taking ACE inhibitors during LDL apheresis with dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy prior to each apheresis session.

Anaphylactoid reactions during desensitization therapy. Anaphylactoid reactions have been reported in patients taking ACE inhibitors undergoing desensitization therapy with bee venom allergens. These reactions can be avoided by temporarily discontinuing ACE inhibitors, but may recur upon reinitiation of therapy.

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 vascular diseases, immunosuppressive therapy, allopurinol, or procainamide, or in combination of these risk factors, especially if renal impairment is present. Some of these patients developed severe infections, sometimes resistant to intensive antibiotic therapy. If perindopril is prescribed to such patients, periodic monitoring of white blood cell count is recommended. Patients should also be informed to report any signs of infection (e.g., sore throat, fever).

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 hypotension and renal impairment (see section "Contraindications"). Concomitant use of diuretics may be a contributing factor. Renal function deterioration may be associated with only minor changes in serum creatinine, even in patients with unilateral renal artery stenosis.

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 hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, dual blockade of 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 blockade therapy is considered absolutely necessary, it should be performed only under specialist supervision with frequent and careful monitoring of renal function, electrolytes, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

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

Precautions related to perindopril

Hypotension. ACE inhibitors may cause a marked fall in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension but occurs more frequently in patients with hypovolemia, e.g., those on diuretic therapy, on a salt-free diet, undergoing hemodialysis, or with diarrhea or vomiting, or in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Careful monitoring of blood pressure, renal function, and serum potassium concentration is essential in patients at high risk of symptomatic hypotension, as well as in 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 hypotension, the patient should be placed in a supine position and, if necessary, infused intravenously with 0.9% sodium chloride solution. Transient hypotension at the start of treatment is not a contraindication to continuing the drug, which can usually be resumed after restoration of blood volume and normalization of blood pressure.

Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy. ACE inhibitors should be administered with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Renal impairment. Individual dose adjustment of each component of the medicinal product is recommended in patients with renal impairment (creatinine clearance < 60 ml/min) (see section "Dosage and administration"). Routine monitoring of serum potassium and creatinine levels is part of standard medical practice in patients with renal impairment (see section "Adverse reactions"). Reversible increases in blood urea nitrogen and serum creatinine may occur in some patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney during ACE inhibitor therapy. This is more common in patients with pre-existing renal impairment. The presence of renovascular hypertension increases the risk of severe hypotension and renal failure. In some patients with arterial hypertension and no prior evidence of renovascular disease, increases in blood urea nitrogen and serum creatinine, usually mild and transient, have been observed, particularly when perindopril was administered concomitantly with a diuretic. This is more common in patients with pre-existing renal impairment.

Hepatic 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 elevations in liver enzymes while on ACE inhibitor therapy should discontinue the ACE inhibitor and receive appropriate medical evaluation and treatment (see section "Adverse reactions").

Racial characteristics. ACE inhibitors are more likely to cause angioedema 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 compared to 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.

Surgery/Anesthesia. During surgery or anesthesia, especially when using anesthetics that lower blood pressure, BID PRESTARILUM® may block the formation of angiotensin II following compensatory renin release. The drug should be discontinued one day prior to surgery. If hypotension develops and is considered to be due to this mechanism, the condition can be corrected by volume expansion.

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

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Precautions related to amlodipine

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Heart failure. Amlodipine should be used with caution in these patients. In a long-term, placebo-controlled study in patients with severe heart failure (NYHA classes III–IV), the incidence of pulmonary edema was higher with amlodipine than with placebo (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality.

Hepatic impairment. In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC values are high; dosage recommendations are not established. Therefore, amlodipine therapy should be initiated at the lowest dose, with caution both at initiation and during dose escalation. Patients with severe hepatic impairment may require gradual dose titration and careful monitoring.

Elderly patients. Dose escalation should be performed cautiously in elderly patients (see sections "Pharmacodynamics" and "Dosage and administration").

Renal impairment. Amlodipine can be used at standard doses in these patients. Plasma concentration fluctuations of amlodipine are independent of the degree of renal impairment. Amlodipine is not removed by dialysis.

Precautions related to the fixed combination BID PRESTARILUM®

Excipients. The medicinal product contains lactose; therefore, it is not recommended for patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

Interactions. Concomitant use of lithium, potassium-sparing agents, potassium-containing dietary supplements, or dantrolene with BID PRESTARILUM® is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Use of BID PRESTARILUM® is contraindicated during pregnancy.

Use of BID PRESTARILUM® is not recommended during breastfeeding. If use of the medicinal product is necessary, breastfeeding should be discontinued.

Pregnancy

Perindopril. Use of ACE inhibitors is contraindicated during pregnancy. There are no conclusive epidemiological data on teratogenic risk with ACE inhibitor use during the first trimester of pregnancy; however, a small increased risk cannot be excluded. If continuation of ACE inhibitor therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with established safety during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use in pregnant women. It is known that ACE inhibitor use during the second and third trimesters of pregnancy causes fetotoxicity (renal dysfunction, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors were used from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull development is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be monitored for timely detection and correction of arterial hypotension.

Amlodipine. The safety of amlodipine use in pregnant women has not been established. In animal studies, toxic effects on reproduction were observed with high doses. Use of the medicinal product during pregnancy is recommended only if no safer alternative treatment is available and the disease poses a greater risk to the mother and fetus.

Breastfeeding

Perindopril. Perindopril use during breastfeeding is not recommended due to lack of data. During breastfeeding, it is preferable to prescribe an alternative treatment with a better-studied safety profile, especially when nursing a newborn or premature infant.

Amlodipine. Amlodipine passes into breast milk. The dose received by the infant has been estimated on an interquartile basis and ranges from 3–7%, with a maximum of 15%, of the maternal dose. The effect of amlodipine on infants is unknown. The decision to continue or discontinue breastfeeding or to continue or discontinue amlodipine therapy should be made considering the benefits of breastfeeding for the child and the benefits of amlodipine therapy for the mother.

Fertility

Perindopril. No effect on reproductive function or fertility has been observed.

Amlodipine. Reversible biochemical changes in the sperm head have been reported in some patients treated with calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. In rat studies, adverse effects on male fertility have been observed.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of BID PRESTARILUM® on the ability to drive or operate machinery have been conducted. Amlodipine may have a slight or moderate effect on the ability to drive or operate machinery. Impaired reaction may occur if dizziness, headache, weakness, fatigue, or nausea develop. Caution is recommended, especially at the beginning of treatment.

Method of Administration and Dosage

For oral use.

The recommended dose for adults is 1 tablet once daily, preferably in the morning before a meal. The tablet must not be divided.

Dosage should be individually adjusted for each patient depending on the indication, course of the disease, and blood pressure levels. The maximum daily dose is 1 tablet of BID-PRESTAR*IUM® 10 mg/10 mg per day.

For patients in risk groups, see section "Special Warnings and Precautions for Use".

Patients with renal impairment and elderly patients (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). Elimination of perindopril is reduced in patients with renal insufficiency and in elderly patients; therefore, frequent monitoring of creatinine and potassium levels is required during treatment.

BID-PRESTAR*IUM® can be prescribed to patients with creatinine clearance ≥ 60 mL/min and should not be prescribed to patients with creatinine clearance < 60 mL/min. For such patients, individual dose titration of each component of the drug should be performed separately.

With good tolerability, the dosing of amlodipine is the same for younger and elderly patients. The usual dosing regimen is recommended for elderly patients; however, dose escalation should be performed cautiously.

Plasma concentrations of amlodipine do not depend on the degree of renal impairment.

Amlodipine is not removed during dialysis.

Hepatic impairment (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). There are no specific dosage recommendations for patients with mild to moderate hepatic impairment; therefore, dose selection should be cautious, and therapy should be initiated at the lowest doses (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). For optimal selection of the initial and maintenance dose in patients with hepatic impairment, amlodipine and perindopril should be individually titrated. Pharmacokinetic studies of amlodipine have not been conducted in patients with severe hepatic impairment. In patients with severe hepatic impairment, treatment with amlodipine should be initiated at the lowest doses, which may be gradually increased.

Children

BID-PRESTAR*IUM® is not recommended for use in children due to lack of data from clinical studies in this patient group.

Overdose

There have been no reported cases of overdose with BID-PRESTAR*IUM®. Data on intentional overdose of amlodipine are limited. Symptoms: available data suggest that ingestion of very large doses may lead to excessive peripheral vasodilation and possible reflex tachycardia. Profound, possibly prolonged systemic hypotension and shock with fatal outcome have been reported.

Rare cases of non-cardiogenic pulmonary edema have been reported as a consequence of amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may be precipitating factors.

Treatment: clinically significant hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with legs elevated, and careful monitoring of circulating blood volume and urine output.

Administration of vasopressors may be beneficial to restore vascular tone and blood pressure, provided there are no contraindications. Intravenous calcium gluconate may help reverse the effects of calcium channel blockade.

In some cases, gastric lavage may be appropriate. Studies in volunteers have shown that administration of activated charcoal 2 hours after ingestion of 10 mg of amlodipine reduces the rate of amlodipine absorption. Amlodipine is highly protein-bound in systemic circulation; therefore, hemodialysis is ineffective.

Information on overdose with perindopril is limited. In cases of ACE inhibitor overdose, the following may occur: hypotension, circulatory shock, electrolyte imbalances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

In case of overdose, intravenous administration of 0.9% sodium chloride solution is recommended. If hypotension occurs, the patient should be placed in a supine position. 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 cases of treatment-resistant bradycardia, temporary cardiac pacing may be necessary. Continuous monitoring of vital signs, serum electrolyte levels, and serum creatinine is required.

Adverse Reactions

The most commonly reported adverse reactions associated with the individual use of perindopril and amlodipine are: oedema, somnolence, dizziness, headache (particularly at the beginning of treatment), taste disturbances (dysgeusia), paraesthesia, visual disturbances (including diplopia), tinnitus, vertigo, palpitations, flushing, hypotension (and associated symptoms), dyspnoea, cough, abdominal pain, nausea, vomiting, dyspepsia, altered defecation rhythm, diarrhoea, constipation, pruritus, rash, exanthema, joint swelling (ankle oedema), muscle cramps, increased fatigue, asthenia.

During clinical trials and/or post-marketing use of perindopril or amlodipine alone, the following adverse reactions have been observed. These are classified according to the MedDRA standardized medical terminology system organ class, with the following frequency categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations: rhinitis (uncommon − amlodipine; very rare − perindopril).

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

Blood and lymphatic system disorders: eosinophilia (uncommon* − perindopril); leucopenia/neutropenia (very rare − amlodipine and perindopril) (see section "Special warnings and precautions for use"); agranulocytosis or pancytopenia (very rare − perindopril) (see section "Special warnings and precautions for use"); thrombocytopenia (very rare − amlodipine and perindopril) (see section "Special warnings and precautions for use"); enzyme-specific haemolytic anaemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency (very rare − perindopril) (see section "Special warnings and precautions for use").

Immune system disorders: hypersensitivity (very rare − amlodipine; uncommon − perindopril).

Metabolism and nutrition disorders: hypoglycaemia (uncommon* − perindopril) (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction"); hyperkalaemia, reversible upon discontinuation of the drug (uncommon* − perindopril) (see section "Special warnings and precautions for use"); hyponatraemia (uncommon* − perindopril); hyperglycaemia (very rare − amlodipine).

Psychiatric disorders: insomnia (uncommon − amlodipine); mood disturbances (including anxiety) (uncommon − amlodipine and perindopril); depression (uncommon − amlodipine, uncommon* − perindopril); sleep disorders (uncommon − perindopril).

Nervous system disorders: somnolence (particularly at the beginning of treatment) (common − amlodipine; uncommon* − perindopril); dizziness (particularly at the beginning of treatment) (common − amlodipine and perindopril); headache (particularly at the beginning of treatment) (common − amlodipine and perindopril); taste disturbances (dysgeusia) (uncommon − amlodipine; common − perindopril); tremor (uncommon − amlodipine); hypoesthesia (uncommon − amlodipine); paraesthesia (uncommon − amlodipine; common − perindopril); syncope (uncommon − amlodipine; uncommon* − perindopril); confusion (rare − amlodipine; very rare − perindopril); hypertonia (very rare − amlodipine); peripheral neuropathy (very rare − amlodipine); cerebrovascular events may occur due to excessive reduction in blood pressure in high-risk patients (very rare − perindopril) (see section "Special warnings and precautions for use"); extrapyramidal disorders (extrapyramidal syndrome) (frequency not known − amlodipine).

Eye disorders: visual disturbances (common − amlodipine and perindopril); diplopia (common − amlodipine).

Ear and labyrinth disorders: tinnitus (uncommon − amlodipine; common − perindopril); vertigo (common − perindopril).

Cardiac disorders: palpitations (common − amlodipine; uncommon* − perindopril); tachycardia (uncommon* − perindopril); angina pectoris (very rare − perindopril) (see section "Special warnings and precautions for use"); myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients (very rare − amlodipine and perindopril) (see section "Special warnings and precautions for use"); arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation) (uncommon − amlodipine; very rare − perindopril).

Vascular disorders: flushing (common − amlodipine); hypotension (and associated symptoms) (uncommon − amlodipine; common − perindopril); hot flushes (rare* – perindopril); vasculitis (very rare − amlodipine; uncommon* − perindopril); Raynaud's phenomenon (frequency not known − perindopril).

Respiratory, thoracic and mediastinal disorders: dyspnoea (common − amlodipine and perindopril); cough (uncommon − amlodipine; common − perindopril); bronchospasm (uncommon − perindopril); eosinophilic pneumonia (very rare − perindopril).

Gastrointestinal disorders: gingival hyperplasia (very rare − amlodipine); abdominal pain (common − amlodipine and perindopril); nausea (common − amlodipine and perindopril); vomiting (uncommon − amlodipine; common − perindopril); dyspepsia (common − amlodipine and perindopril); altered defecation rhythm (common − amlodipine); dry mouth (uncommon − amlodipine and perindopril); diarrhoea (common − amlodipine and perindopril); constipation (common − amlodipine and perindopril); pancreatitis (very rare − amlodipine and perindopril); gastritis (very rare − amlodipine).

Hepatobiliary disorders: hepatitis, jaundice (very rare − amlodipine); cytolytic or cholestatic hepatitis (very rare − perindopril) (see section "Special warnings and precautions for use"); increased liver enzymes (predominantly cholestasis-related) (very rare − amlodipine).

Skin and subcutaneous tissue disorders: Quincke's angioedema (very rare − amlodipine); angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (very rare − amlodipine; uncommon − perindopril) (see section "Special warnings and precautions for use"); erythema multiforme (very rare − amlodipine and perindopril); alopecia (uncommon − amlodipine); purpura (uncommon − amlodipine); skin discoloration (uncommon − amlodipine); hyperhidrosis (uncommon − amlodipine and perindopril); pruritus (uncommon − amlodipine; common − perindopril); rash, exanthema (uncommon − amlodipine; common − perindopril); urticaria (uncommon − amlodipine and perindopril) (see section "Special warnings and precautions for use"); photosensitivity reactions (very rare − amlodipine; uncommon* − perindopril); pemphigoid (uncommon* − perindopril); worsening of psoriasis symptoms (rare − perindopril); Stevens-Johnson syndrome (very rare − amlodipine); exfoliative dermatitis (very rare − amlodipine); toxic epidermal necrolysis (frequency not known − amlodipine).

Musculoskeletal and connective tissue disorders: joint swelling (ankle oedema) (common − amlodipine); arthralgia (uncommon − amlodipine; uncommon* − perindopril); myalgia (uncommon − amlodipine; uncommon* − perindopril); muscle cramps (common − amlodipine and perindopril); back pain (uncommon − amlodipine).

Renal and urinary disorders: micturition disorders, nocturia, pollakiuria (frequent urination) (uncommon − amlodipine); renal failure (uncommon − perindopril); acute renal failure (rare − perindopril); anuria/oliguria (rare* – perindopril).

Reproductive system and breast disorders: erectile dysfunction (uncommon − amlodipine and perindopril); gynaecomastia (uncommon − amlodipine).

General disorders and administration site conditions: oedema (very common − amlodipine); peripheral oedema (uncommon* − perindopril); increased fatigue (common − amlodipine); chest pain (uncommon − amlodipine; uncommon* − perindopril); asthenia (common − amlodipine and perindopril); pain (uncommon − amlodipine); malaise (uncommon − amlodipine; uncommon* − perindopril); hyperthermia (uncommon* − perindopril).

Investigations: weight gain, weight loss (uncommon − amlodipine); increased blood urea (uncommon* − perindopril); increased serum creatinine (uncommon* − perindopril); increased blood bilirubin (rare − perindopril); increased liver enzymes (rare − perindopril); decreased haemoglobin and haematocrit (very rare − perindopril).

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

*Frequency calculated from spontaneous adverse reaction reports identified during clinical trials.

Reporting of 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 are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store tablets in a tightly closed container. No special storage temperature requirements.

Packaging.

30 tablets per tablet container; 1 tablet container per cardboard box.

Prescription status. Prescription only.

Marketing Authorization Holder.

Les Laboratoires Servier.

Address of Marketing Authorization Holder.

50 rue Carnot, 92284 Suresnes cedex, France.

Manufacturer.

Les Laboratoires Servier Industrie.

Address of Manufacturer and site of manufacturing activity.

905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd.

Address of Manufacturer and site of manufacturing activity.

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

Manufacturer.

ANPHARM Przedsiębiorstwo Farmaceutyczne S.A.

Address of Manufacturer and site of manufacturing activity.

ul. Annopol 6B, Warszawa, 03-236, Poland.

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