Bi-prestarium® 10 mg/10 mg

for medical use of the medicinal product Bi-PRESTARIUM® 5 mg/5 mg, Bi-PRESTARIUM® 5 mg/10 mg, Bi-PRESTARIUM® 10 mg/5 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 on the other.

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

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

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

Pharmacotherapeutic group. ACE inhibitors, combinations. ACE inhibitors and calcium channel blockers. Perindopril and amlodipine. ATC code: C09BB04.

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 an inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II concentration in blood plasma, which increases plasma renin activity (due to suppression of the negative feedback mechanism regulating 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 prostaglandin systems). This mechanism of action underlies the antihypertensive effect of ACE inhibitors and partially accounts for the occurrence of certain adverse effects (e.g., cough).

Perindopril acts via its active metabolite—perindoprilat. Other metabolites do not demonstrate 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 within 4–6 hours after a single dose and lasts for at least 24 hours; the T/R ratio (effect just before the next dose / maximum effect) for 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 ischemic heart disease (IHD).

EUROPA is a 4-year, international, multicenter, randomized, double-blind, placebo-controlled clinical trial. 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. Patients included in the study had confirmed ischemic heart disease but no 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 outcome: 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 statistically 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 channel blocker belonging to the dihydropyridine group (a slow calcium channel blocker or calcium ion antagonist) that inhibits transmembrane calcium ion influx into vascular smooth muscle and cardiac muscle cells.

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

• Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Since heart rate remains unchanged, reduced cardiac workload decreases myocardial energy consumption and oxygen demand.
• Amlodipine also partially promotes dilation of major coronary arteries and coronary arterioles, both in unaffected and ischemic myocardial regions. This dilation increases oxygen supply to the myocardium in patients with vasospastic angina (Prinzmetal’s angina 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 the supine and standing positions. Due to its gradual 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 negative metabolic effects or changes in plasma lipid levels, making it suitable for use in patients with asthma, diabetes, and gout.

Ischemic heart disease (IHD)

The efficacy of amlodipine in preventing clinical events in patients with ischemic heart disease (IHD) 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. Results indicate that amlodipine treatment was associated with fewer hospitalizations due to angina and fewer revascularization procedures in patients with IHD.

Number of major clinical events in the CAMELOT study

Cardiovascular event rates, number (%)				Amlodipine vs placebo
Outcome	Amlodipine	Placebo	Enalapril	Relative risk (95% CI)	p value
Primary endpoint Adverse cardiovascular events	110 (16.6)	151 (23.1)	136 (20.0)	0.69 (0.54–0.88)	0.003
Individual components Coronary revascularization Hospitalizations for angina Non-fatal myocardial infarction Stroke or transient ischemic attack Cardiovascular mortality Hospitalizations for congestive heart failure Cardiac arrest with subsequent resuscitation Newly diagnosed peripheral vascular disease	78 (11.8) 51 (7.7) 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, demonstrated that amlodipine did not lead to 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 showed 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 evidence confirming or underlying ischemic heart disease. Patients enrolled in the study were on long-term treatment with ACE inhibitors, digitalis preparations, and diuretics. The study demonstrated that amlodipine did not affect overall cardiovascular mortality. However, during 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 duration 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 (51.5% overall), type 2 diabetes (36.1%), LDL dyslipidemia (HDL <35 mg/dL) (11.6%), left ventricular hypertrophy confirmed by ECG or echocardiography (20.9%), or 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 ASCOT-BLPA (Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm) study 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, prior stroke or transient ischemic attack, male sex, age ≥55 years, microalbuminuria or proteinuria, smoking, plasma total cholesterol to HDL cholesterol ratio ≥6, or family history of premature ischemic heart disease (IHD).

The primary 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 compared 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 of 19,242) were receiving at least two antihypertensive agents, while only 15% (1,401 of 9,634) and 9% (857 of 9,608) were receiving monotherapy with amlodipine or atenolol, respectively.

The study was prematurely terminated after a mean follow-up of 5.5 years 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 silent) + 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 of 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 perindopril 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 plasma concentration is observed. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding of perindoprilat to plasma proteins is 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 delayed in elderly patients and in patients with cardiac or renal impairment (see section "Special precautions"). 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 does not decrease. Therefore, dose adjustment is not required in these patients (see section "Special precautions").

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 intake. 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 plasma protein-bound.

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, forming inactive metabolites. About 60% of metabolites are excreted in urine, and 10% are excreted unchanged.

Elderly patients. Time to reach maximum 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. Increased AUC and half-life in patients with congestive heart failure corresponded to the age-related characteristics of the studied 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, amlodipine clearance is reduced, leading to a prolonged elimination half-life and an increase in AUC by approximately 40–60%.

Clinical characteristics.

Indications.

Arterial hypertension and/or ischaemic 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 breast-feeding");
• Concomitant use with medicinal products containing the active substance aliskiren in patients with diabetes mellitus 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 used 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 treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• Severe bilateral renal artery stenosis or stenosis of the artery of a single 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 haemodynamics.

Related to 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 excipient.

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 use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher frequency of adverse reactions, such as hypotension, hyperkalaemia, and decreased renal function (including acute renal failure), compared to use of 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, as it increases the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Therapy with perindopril should 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 hyperkalaemia. Serum potassium levels usually remain within normal limits, but hyperkalaemia may occur in some patients treated with Bi-PRESTARIUM®. Some medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, namely: aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these medicinal products increases the risk of hyperkalaemia. Therefore, concomitant use of Bi-PRESTARIUM® with the above-mentioned medicinal products is not recommended. If concomitant use of these substances 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 mellitus or renal impairment, the risk of hyperkalaemia, worsening renal function, cardiovascular morbidity, and mortality is increased.

Extracorporeal treatment methods. Extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as dialysis or haemofiltration using certain high-flux membranes (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulphate, 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 all other patients, including those with diabetes mellitus or renal impairment, the risk of hyperkalaemia, worsening renal function, cardiovascular morbidity, and mortality is increased.

Published data show that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) compared to monotherapy with RAAS-acting agents. 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. Hyperkalaemia (possibly fatal), especially in patients with renal impairment (additive hyperkalaemic effect). These medicinal products are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use of these substances is necessary, they should be used with caution and frequent monitoring of 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 lithium 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 hypoglycaemic effect, increasing the risk of hypoglycaemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment.

Diuretics. In patients taking diuretics, particularly those with impaired 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 (in such cases, diuretic therapy 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 caution 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 may result in hyperkalaemia (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 combinations, absence of hyperkalaemia and renal dysfunction should be confirmed. Careful monitoring of potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g daily. The antihypertensive effect may be attenuated during concomitant use of ACE inhibitors with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective 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 impairment. Such combinations should be prescribed with caution, particularly in elderly patients. Patients should maintain adequate hydration, and renal function should be monitored at the start 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, when ACE inhibitors, including perindopril, are used concomitantly with injectable gold preparations (sodium aurothiomalate), reactions similar to those seen with nitrates (facial flushing, hot flashes, nausea, vomiting, and hypotension) may occur.

Interactions related to amlodipine

Concomitant use is not recommended

Dantrolene (infusion). In experimental studies, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalaemia were observed after intravenous administration of verapamil and dantrolene. Due to the potential for hyperkalaemia, concomitant use of calcium channel blockers such as amlodipine should be avoided 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 CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, particularly strong inducers (e.g. rifampicin, St John’s wort (Hypericum perforatum)).

Inhibitors of CYP3A4. Concomitant use of amlodipine with strong 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 additive antihypertensive effects.

Tacrolimus. There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine. To avoid toxic effects of tacrolimus, its blood levels should be monitored and its dose adjusted if 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 inhibitor of CYP3A. 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 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 enhanced hypotensive effects.

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, if necessary, dose adjustments made.

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 prescribed 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/antipsychotics/anaesthetics 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 Bi-PRESTARIUM®.

Special precautions related to perindopril

Hypersensitivity/Angioedema. Rare cases of angioedema involving 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 therapy. In such cases, Bi-PRESTARIUM® must be discontinued immediately and appropriate monitoring of the patient must be instituted until symptoms completely resolve. When swelling is limited to the face and lips, the condition usually resolves without treatment; antihistamines may be helpful in relieving symptoms.

Angioedema associated with laryngeal swelling may be fatal. In cases where swelling involves the tongue, glottis, or larynx, potentially causing airway obstruction, emergency therapy must be initiated immediately, which may include administration of adrenaline and/or measures to ensure airway patency. The patient must remain under continuous medical supervision until complete and sustained resolution of symptoms occurs.

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 and vomiting); in some cases, prior angioedema of the face was not observed and C-1 esterase levels were normal. Diagnosis of intestinal angioedema was confirmed by computed tomography, ultrasound, or during surgery. Symptoms 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 (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 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. These 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-containing products. 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, those receiving immunosuppressants, allopurinol, or procainamide, or in patients with a 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 counts 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 diuretic use 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 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 blockade therapy is considered absolutely necessary, it should only be performed under specialist supervision with frequent and careful monitoring of renal function, electrolyte levels, 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 agents acting via 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 drop in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and 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"). Patients at high risk of symptomatic hypotension, as well as patients with ischemic heart disease or cerebrovascular disease in whom excessive blood pressure reduction may precipitate myocardial infarction or stroke, should be carefully monitored for blood pressure, renal function, and serum potassium concentration during treatment with Bi-PRESTARIUM®. If hypotension occurs, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of 0.9% sodium chloride solution. Transient hypotension at the start of treatment is not a contraindication to continuing therapy, 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 used with caution in patients with mitral valve stenosis and left ventricular outflow obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Renal impairment. In patients with renal impairment (creatinine clearance < 60 mL/min), individual dose adjustment of each component of the medicinal product is recommended (see section "Method of administration and dosage"). 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 and serum creatinine concentrations 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 who had no evidence of renovascular disease prior to treatment, increases in blood urea and serum creatinine occurred, usually mild and transient, particularly when perindopril was administered concomitantly with a diuretic. This is more common in patients with pre-existing renal impairment.

Hepatic impairment. Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes while receiving an ACE inhibitor should discontinue the ACE inhibitor and receive appropriate medical evaluation and treatment (see section "Adverse reactions").

Racial characteristics. ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. Like 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.

Surgery/Anesthesia. During surgery or anesthesia, particularly with anesthetics that lower blood pressure, Bi-PRESTARIUM® may block angiotensin II formation 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 patient's condition can be corrected by volume expansion.

Hyperkalemia. Increased serum potassium concentrations have been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. In patients with normal renal function, this effect is usually mild. Risk factors for hyperkalemia include renal impairment or reduced renal function, age (over 70 years), diabetes mellitus, intercurrent illness (e.g., 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 (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), 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 cause 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 and any of the above-mentioned agents 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 functional 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 in elderly patients should be performed cautiously (see sections "Pharmacodynamics" and "Method of administration and dosage").

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 Bi-PRESTARIUM®

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 Bi-PRESTARIUM® is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Use of Bi-PRESTARIUM® is contraindicated during pregnancy.

Use of Bi-PRESTARIUM® is not recommended during breastfeeding. If use of the medicinal product is necessary, breastfeeding should be discontinued.

Pregnancy

Perindopril. The 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 continued treatment with ACE inhibitors is considered essential, 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 pregnancy. It is known that ACE inhibitor use during the second and third trimesters of pregnancy causes fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors were used from the second trimester of pregnancy, ultrasound evaluation 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 is not recommended during breastfeeding due to lack of data. An alternative treatment with a better-established safety profile should be considered during breastfeeding, 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/stop breastfeeding or to continue/stop amlodipine therapy should be made taking into account 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 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. Adverse effects on male fertility have been observed in rat studies.

Ability to affect reaction speed when driving vehicles or operating machinery.

No studies on the effect of Bi-PRESTARIUM® on the ability to drive vehicles or operate machinery have been conducted. Amlodipine may have a slight or moderate effect on the ability to drive vehicles or operate machinery. Impaired driver reaction may occur due to dizziness, headache, weakness, fatigue, or nausea. Caution is advised, 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, disease course, and blood pressure levels. The maximum daily dose is 1 tablet of BIDIPRESTAR® 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.

BIDIPRESTAR® can be prescribed to patients with creatinine clearance ≥ 60 mL/min and should not be prescribed to patients with creatinine clearance < 60 mL/min. In 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 done 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 initial and maintenance doses in patients with hepatic impairment, separate dose titration of amlodipine and perindopril is required. 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

BIDIPRESTAR® is not recommended for use in children due to lack of clinical data in this patient group.

Overdose

There have been no reported cases of overdose with BIDIPRESTAR®. Data regarding intentional overdose of amlodipine are limited. Symptoms: available data suggest that ingestion of very high doses may lead to excessive peripheral vasodilation and possible reflex tachycardia. Marked, possibly prolonged systemic hypotension and shock with fatal outcome have been reported.

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

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 amlodipine reduces the rate of amlodipine absorption. Amlodipine is highly protein-bound in systemic circulation; therefore, hemodialysis is ineffective.

Information on perindopril overdose is limited. In cases of ACE inhibitor overdose, the following may occur: hypotension, circulatory shock, electrolyte disturbances, 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. Consideration should be given to infusion of angiotensin II and/or intravenous administration of catecholamines. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special Warnings and Precautions for Use"). In cases of persistent bradycardia unresponsive to treatment, temporary cardiac pacing may be considered. Continuous monitoring of vital signs, serum electrolyte levels, and serum creatinine is required.

Adverse reactions

The most commonly reported adverse reactions with perindopril and amlodipine used separately are: oedema, somnolence, dizziness, headache (especially 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 administered separately, the following adverse reactions have been observed. These are classified according to the MedDRA standardized medical terminology system organ classes and listed by frequency as follows: 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 the 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, which resolves after 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 (especially at the beginning of treatment) (common − amlodipine; uncommon* − perindopril); dizziness (especially at the beginning of treatment) (common − amlodipine and perindopril); headache (especially 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: angioneurotic oedema Quincke (very rare − amlodipine); angioneurotic oedema 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: increased body weight, decreased body weight (uncommon − amlodipine); increased blood urea (uncommon* − perindopril); increased blood 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 suspected adverse reactions

Reporting suspected adverse reactions after marketing authorisation 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 temperature requirements for storage.

Packaging.

30 tablets in a tablet container; 1 tablet container in a cardboard box.

Prescription status. Prescription only.

Marketing Authorisation Holder.

Les Laboratoires Servier.

Address of the Marketing Authorisation Holder.

50 rue Carnot, 92284 Suresnes cedex, France.

Manufacturer.

Les Laboratoires Servier Industrie.

Address of the Manufacturer and site of manufacturing activity.

905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd.

Address of the Manufacturer and site of manufacturing activity.

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

Manufacturer.

ANPHARM Przedsiębiorstwo Farmaceutyczne S.A.

Address of the 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.