Perindopress® a

INSTRUCTIONS for medical use of the medicinal product PERINDOPRES® A (PERINDOPRES A)

Composition:

Active substances: perindopril / amlodipine

PERINDOPRES® A 4 mg/5 mg

1 tablet contains: perindopril tert-butylamine 4 mg (equivalent to 3.338 mg of perindopril) and amlodipine besylate 6.935 mg (equivalent to 5 mg of amlodipine);

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide (hydrophobic), magnesium stearate.

PERINDOPRES® A 8 mg/10 mg

1 tablet contains: perindopril tert-butylamine 8 mg (equivalent to 6.676 mg of perindopril) and amlodipine besylate 13.870 mg (equivalent to 10 mg of amlodipine);

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide (hydrophobic), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

PERINDOPRES® A 4 mg/5 mg: tablets of white or almost white color, flat cylindrical shape with bevel.

PERINDOPRES® A 8 mg/10 mg: tablets of white or almost white color, flat cylindrical shape with bevel.

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

Pharmacological properties.

Pharmacodynamics.

Perindopril

Perindopril is an inhibitor of the angiotensin-converting enzyme (ACE), which converts angiotensin I into angiotensin II. Converting enzyme, or kinase, is an exopeptidase that enables the transformation of angiotensin I into the vasoconstrictive angiotensin II, and also promotes the breakdown of the vasodilator bradykinin into inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II concentration in blood plasma, increases plasma renin activity (due to suppression of negative feedback on renin release), and reduces aldosterone secretion. Since ACE inactivates bradykinin, inhibition of ACE also increases the activity of circulating and local kallikrein-kinin system (and thus also leads to activation of 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 exerts its action 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 supine and standing positions.

Perindopril reduces peripheral vascular resistance, leading to decreased arterial blood pressure. As a result, peripheral blood flow increases without affecting heart rate. Renal blood flow usually increases, while glomerular filtration rate remains unchanged. The maximum antihypertensive effect develops within 4–6 hours after a single dose and persists for at least 24 hours: the T/R ratio (maximum effect/minimum effect over 24 hours) of perindopril ranges from 87% to 100%. Blood pressure reduction occurs rapidly. In patients responding to treatment, normalization of blood pressure occurs within one month and is maintained without development of tachyphylaxis. Upon discontinuation of perindopril, there is no rebound effect. Perindopril reduces left ventricular hypertrophy. Clinical studies have demonstrated that perindopril possesses 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 established stable ischemic heart disease (IHD)

The EUROPA study was 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. Patients enrolled in the study had confirmed IHD and no clinically evident heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients in the study received perindopril in addition to standard therapy: antiplatelet agents, lipid-lowering drugs, and β-blockers. The primary efficacy endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and/or resuscitated cardiac arrest. 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

Amlodipine is a calcium ion influx inhibitor belonging to the dihydropyridine group (a slow calcium channel blocker or calcium antagonist) that blocks transmembrane calcium ion influx into vascular and cardiac 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 overall ischemic burden through the following actions:

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

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 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. 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 mellitus, and gout.

Patients with IHD

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

Table 1.

Number of major clinical events in the CAMELOT study

Use in Patients with Heart Failure

Hemodynamic and clinical exercise tolerance studies in patients with heart failure (NYHA functional class II–IV) have shown that amlodipine does not lead to clinical deterioration based on exercise tolerance, left ventricular ejection fraction, or clinical symptoms.

The PRAISE placebo-controlled trial evaluated 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 combined risk of morbidity/mortality related to heart failure. PRAISE-2 was a long-term, placebo-controlled trial designed to assess the effect of amlodipine in patients with heart failure (NYHA functional class III–IV) without clinical signs or objective evidence confirming or suggesting ischemic heart disease. Patients enrolled in the study were on long-term treatment with ACE inhibitors, digitalis preparations, and diuretics. The study showed that amlodipine did not affect overall cardiovascular mortality. However, during the trial, amlodipine treatment 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 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 (a calcium channel blocker) or lisinopril 10–40 mg/day (an 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 or 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 (overall 51.5%), type 2 diabetes (36.1%), low HDL cholesterol (high-density lipoprotein) <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 between amlodipine-based therapy and chlorthalidone-based therapy for the primary endpoint: 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 ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial – Antihypertensive Arm), a morbidity and mortality trial, included 19,257 patients aged 40 to 79 years with arterial 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, total plasma cholesterol to HDL cholesterol ratio ≥6, or family history of premature coronary heart disease. The primary objective was to evaluate and compare the long-term effects of two antihypertensive treatment regimens on a composite endpoint of nonfatal myocardial infarction (including silent myocardial infarction) and fatal coronary heart disease complications: amlodipine plus perindopril (added as needed for blood pressure control) versus atenolol plus the diuretic bendroflumethiazide (added as needed for blood pressure control). At the end of the trial, the majority of patients (78%, 14,974 out of 19,242) received at least two antihypertensive agents, while only 15% (1,401 out of 9,634) and 9% (857 out of 9,608) received monotherapy with amlodipine or atenolol, respectively. The trial was prematurely terminated after a median 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 group.

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

Endpoints:

Table 2.

Pharmacokinetics.

The rate and extent of absorption of perindopril and amlodipine, both as individual agents and in the fixed combination PERINDOPRES® A, do not differ significantly.

Perindopril

After oral administration, perindopril is rapidly absorbed. Maximum plasma concentration is reached within 1 hour. The conversion period of perindopril in plasma is 1 hour. Perindopril is a prodrug. 27% of the total administered perindopril reaches the systemic circulation as the active metabolite—perindoprilat. Besides the active metabolite perindoprilat, the drug forms five metabolites which are inactive. 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 is recommended to be taken once daily in the morning before a meal. 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 20%, mainly to ACE, although this parameter is dose-dependent. Perindoprilat is excreted in urine. The terminal 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, as well as in patients with cardiac or renal insufficiency (see section "Special precautions"). Therefore, routine medical monitoring should include frequent monitoring of creatinine and potassium levels. Dialysis clearance of perindoprilat is 70 mL/min. Perindopril kinetics are altered in patients with hepatic 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

After oral administration of therapeutic doses, amlodipine is well absorbed and reaches maximum blood concentration 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. The elimination half-life from plasma is approximately 35−50 hours, allowing 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.

Use in elderly patients: The time to reach maximum amlodipine concentration is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, resulting in increased area under the concentration-time curve (AUC) and prolonged elimination half-life. Increased AUC and elimination half-life observed in patients with congestive heart failure corresponded to the age-related characteristics of the studied patients.

Use in patients with hepatic impairment: Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic insufficiency, amlodipine clearance is reduced, leading to 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 lactation");
• 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. PERINDOPRES® A must not be administered 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");
• 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 haemodynamics.

Related to the medicinal product PERINDOPRES® A:

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

• Hypersensitivity to any excipient.

Interaction with other medicinal products and other forms of interaction.

Interactions related to perindopril

Clinical study 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 arterial hypotension, hyperkalaemia, and impaired renal function (including acute renal failure), compared to treatment with a single agent acting on the RAAS (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. Initiation of perindopril therapy should not occur 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 PERINDOPRES® A. Some medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, namely: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and fixed-dose combination with sulfamethoxazole (co-trimoxazole). Concomitant use of these medicinal products increases the risk of hyperkalaemia. Therefore, concomitant use of PERINDOPRES® A with the above-mentioned agents is not recommended. If concomitant use of these substances is necessary, they should be used with caution and frequent monitoring of serum potassium levels should be performed.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren. In patients with diabetes mellitus or renal impairment, the risk of hyperkalaemia, 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 haemofiltration using certain high-flux membranes (e.g. polyacrylonitrile) and low-density lipoprotein (LDL) apheresis using dextran sulfate, due to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive medicinal products.

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

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

Published data indicate that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers was associated with an increased incidence of arterial hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents acting on the renin-angiotensin-aldosterone system (RAAS).

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 incidence of adverse reactions such as angioedema.

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

Risk of hyperkalaemia (possibly fatal), especially in patients with renal impairment (additive hyperkalaemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use of these substances is necessary, they should be used with caution and frequent monitoring of plasma potassium levels should be performed. 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

Epidemiological studies suggest that concomitant use of ACE inhibitors with antidiabetic agents (insulin, oral antidiabetic agents) may enhance the hypoglycaemic effect with a 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, 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 is 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, when a previously prescribed diuretic may have caused water/electrolyte depletion, the diuretic 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 a background of 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 an ACE inhibitor. Failure to follow recommendations for prescribing such a combination carries a risk of hyperkalaemia (possibly fatal) in 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 hyperkalaemia and renal dysfunction should be confirmed. Careful monitoring of kaliemia and creatininemia 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 be adequately hydrated and renal function should be monitored at the start of treatment with such a combination 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 flushes, nausea, vomiting, and arterial 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 combined with hyperkalaemia were observed after intravenous administration of verapamil and dantrolene. Given the potential for hyperkalaemia, it is recommended to avoid concomitant administration of calcium channel blockers such as amlodipine to patients with malignant hyperthermia or suspected malignant hyperthermia.

Medicinal products requiring special caution when co-administered

Inducers of CYP3A4. Plasma concentrations of amlodipine may change when used concomitantly with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, particularly strong CYP3A4 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. In such cases, clinical monitoring and dose adjustment are necessary. There is an increased risk of arterial 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 used concomitantly 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). Such mTOR inhibitors 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 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 simvastatin 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 effect.

Interactions related to the fixed combination PERINDOPRES® A

Medicinal products requiring special caution when co-administered

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

Medicinal products requiring attention when co-administered

• Antihypertensive agents (such as ß-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: attenuation of antihypertensive effect (due to water and salt retention by corticosteroids).
• Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): enhance antihypertensive effect and increase the risk of orthostatic hypotension.
• Amifostine: may enhance the antihypertensive effect of amlodipine.
• Tricyclic antidepressants/antipsychotropic agents/anesthetics: enhance 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 PERINDOPRES**®** A.

Special precautions related to perindopril

Hypersensitivity/angioedema. Rare cases of angioedema of 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 "Undesirable effects"). This may occur at any time during therapy. In such cases, immediate discontinuation of PERINDOPRES**®** A is required, and appropriate monitoring of the patient should be maintained until complete and sustained disappearance of symptoms. When swelling is limited to the face and lips, the condition usually resolves without treatment; administration of antihistamines may be helpful in relieving symptoms.

Angioedema associated with laryngeal edema may be fatal. In cases where swelling involves the tongue, glottis or larynx, potentially causing airway obstruction, emergency therapy is required, which may include administration of adrenaline and/or measures to maintain airway patency. The patient must remain under close medical supervision until symptoms have completely and stably resolved.

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 surgical exploration. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain in patients receiving ACE inhibitors (see section "Undesirable effects").

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications").

Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Anaphylactoid reactions during LDL apheresis. Rare, life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors undergoing LDL apheresis with dextran sulfate. Anaphylactoid reactions may 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 receiving ACE inhibitors undergoing desensitization treatment with bee venom-containing products. These reactions may be avoided by temporarily discontinuing ACE inhibitors, but may recur upon inadvertent 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, procainamide, or combinations of these risk factors, especially if renal impairment is present. Some patients developed severe infections, sometimes resistant to intensive antibiotic therapy. If perindopril must be used in such patients, periodic monitoring of white blood cell counts is recommended. Patients should be informed to report any signs of infection (e.g., sore throat, fever).

Renovascular hypertension. Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney have an increased risk of hypotension and renal impairment during ACE inhibitor therapy (see section "Contraindications"). Concomitant diuretic use may be a contributing factor. Renal function deterioration may occur with only minor changes in serum creatinine, even in patients with unilateral renal artery stenosis.

Dual blockade of the 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 is considered absolutely necessary, it should be performed only under specialist supervision with frequent 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 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 rapid drop in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension but occurs more frequently in patients with hypovolemia, such as those receiving diuretic therapy, on a salt-free diet, undergoing hemodialysis, or experiencing diarrhea or vomiting, as well as in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects"). In patients at high risk of symptomatic hypotension, and in patients with ischemic heart disease or cerebrovascular disease, where excessive blood pressure reduction may lead to myocardial infarction or stroke, careful monitoring of blood pressure, renal function, and serum potassium concentration is required during treatment with PERINDOPRES**®** A.

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 beginning of treatment is not a contraindication for continued use of the medicinal product, which can usually be resumed after restoration of circulating 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 or left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Renal impairment. In patients with renal impairment (creatinine clearance <60 mL/min), individual dose adjustment of each component is recommended (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 "Undesirable effects"). During ACE inhibitor therapy, reversible increases in blood urea nitrogen and serum creatinine may occur in some patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney. 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, without prior evidence of renovascular disease, increases in blood urea nitrogen and serum creatinine have been observed, usually mild and transient, particularly when perindopril is administered concomitantly with a diuretic. This is more common in patients with pre-existing renal dysfunction.

Hepatic impairment. Rarely, ACE inhibitors have 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 during ACE inhibitor therapy should discontinue the ACE inhibitor and receive appropriate medical evaluation and treatment (see section "Undesirable effects").

Racial factors. 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 reducing blood pressure in black hypertensive patients 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, especially when using anesthetics that lower blood pressure, PERINDOPRES**®** A may block angiotensin II formation following compensatory renin release. The medicinal product should be discontinued one day before surgery. If hypotension occurs and is considered to be due to this mechanism, the patient's condition can be corrected by increasing circulating blood volume.

Hyperkalemia. Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia by inhibiting aldosterone release. In patients with normal renal function, this effect is usually mild. Risk factors for hyperkalemia include renal impairment or reduced renal function, age (>70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use with 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 II 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 II receptor blockers with caution, and serum potassium and renal function should be closely monitored. 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 frequently monitored (see section "Interaction with other medicinal products and other forms of interaction").

In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, blood glucose levels should be 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 doses, with caution both at initiation and during dose escalation. Patients with severe hepatic impairment may require gradual dose titration and close monitoring.

Elderly patients. Dose escalation in elderly patients should be performed with caution (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 medicinal product PERINDOPRES® A

Important information on excipients. The medicinal product contains lactose; therefore, if the patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

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

Use during pregnancy or breastfeeding.

Use of the medicinal product PERINDOPRES**®** A is contraindicated during pregnancy.

Use of the medicinal product 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 is no conclusive epidemiological evidence of teratogenic risk with ACE inhibitors during the first trimester of pregnancy, but a small increased risk cannot be excluded. In cases where continuation of ACE inhibitor therapy 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 immediately discontinued and, if necessary, replaced with a 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 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. Data on the safety of amlodipine use in pregnant women are still insufficient.

Animal studies have shown toxic effects on reproduction at high doses. Use of the medicinal product during pregnancy is recommended only if no safer alternative treatment is available and if the disease poses a greater risk to the mother and fetus.

Breastfeeding period

Perindopril. Use of perindopril 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 between 3–7%, with a maximum of 15% of the maternal dose. The effect of amlodipine on infants is unknown. The decision to continue/discontinue breastfeeding or to continue/discontinue amlodipine therapy should be based on 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.

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 influence reaction speed when driving or operating machinery.

No studies on the effect of the medicinal product PERINDOPRES**®** A on the ability to drive or operate machinery have been conducted. Amlodipine may have a slight or moderate effect on the ability to drive and operate machinery. Impaired reaction time may occur if dizziness, headache, weakness, fatigue, or nausea develop. 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 food. 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.

Maximum daily dose – 1 tablet of PERINDOPRES**®** A 8 mg/10 mg once daily.

Patients at risk – 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 perindoprilat is reduced in patients with renal insufficiency and in elderly patients; therefore, frequent monitoring of creatinine and potassium levels is required during treatment.

PERINDOPRES**®** A 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 medicinal product should be considered separately.

With good tolerability, amlodipine dosing is the same for both 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 function impairment.

Amlodipine is not removed by dialysis.

Patients with 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, starting with 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, amlodipine therapy should be initiated at the lowest doses with gradual dose escalation.

Children

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

Overdose

There have been no reports of overdose with PERINDOPRES**®** A. 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. Profound, 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 administration) and may require mechanical ventilation. Early resuscitative measures (including fluid loading) to support perfusion and cardiac output may be provocative.

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 a vasopressor may be beneficial in restoring vascular tone and blood pressure, provided there are no contraindications. Intravenous calcium gluconate may help counteract the effects of calcium channel blockade.

In some cases, gastric lavage may be appropriate. Studies in healthy 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 not effective.

Information on perindopril overdose 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. 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 case 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 the individual use of perindopril and amlodipine include: edema, somnolence, dizziness, headache (particularly at the beginning of treatment), taste disturbances (dysgeusia), paresthesia, visual disturbances (including diplopia), tinnitus, vertigo, palpitations, flushing, hypotension (and associated symptoms), dyspnea, cough, abdominal pain, nausea, vomiting, dyspepsia, altered defecation rhythm, diarrhea, constipation, pruritus, rash, exanthema, joint swelling (ankle edema), muscle cramps, increased fatigue, asthenia.

Adverse reactions observed during treatment with perindopril or amlodipine are listed separately and classified according to the MedDRA system organ classification and by frequency as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from the available data).

Table 3.

*Frequency was calculated based on spontaneous reports of adverse reactions identified during clinical trials.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and/or lack of drug efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 3 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of its business activities.

13, Boryspylska Street, Kyiv, 02093, Ukraine.