Am-aliter: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AM-ALITER (AM-ALITER)

Composition:

Active substances: perindopril, amlodipine;

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,

or perindopril tert-butylamine 4 mg, equivalent to 3.338 mg of perindopril, and amlodipine besylate 13.870 mg, equivalent to 10 mg of amlodipine,

or perindopril tert-butylamine 8 mg, equivalent to 6.676 mg of perindopril, and amlodipine besylate 6.935 mg, equivalent to 5 mg of amlodipine,

or 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; crospovidone; sodium hydrogen carbonate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white to almost white, round, biconvex tablets.

Pharmacotherapeutic group.

Agents acting on the renin-angiotensin system. ACE inhibitors, combinations. ACE inhibitors and calcium channel blockers. Perindopril and amlodipine.

ATC code C09B B04.

Pharmacological properties.

Pharmacodynamics.

Perindopril

Mechanism of action

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kinase, is an exopeptidase that enables the conversion of angiotensin I into the vasoconstrictive angiotensin II, as well as 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, resulting in increased plasma renin activity (due to suppression of the negative feedback mechanism of renin release) and reduced aldosterone secretion. Since ACE inactivates bradykinin, ACE inhibition also leads to increased activity of the circulating and local kallikrein-kinin system (and thus also contributes to activation of the prostaglandin system). This mechanism of action underlies the blood pressure-lowering 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 activity in inhibiting ACE 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 decreased arterial blood pressure. As a result, peripheral blood flow increases without affecting heart rate.

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

The maximum antihypertensive effect develops within 4–6 hours after a single dose and lasts at least 24 hours: the T/R ratio (effect just before the next dose / maximum effect) 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, 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 an international, multicenter, randomized, double-blind, placebo-controlled clinical trial lasting 4 years. A total of 12,218 adult patients were randomized into treatment groups: 6,110 patients received 8 mg of perindopril tert-butylamine (equivalent to 10 mg of perindopril arginine) and 6,108 patients received placebo. The study included patients with confirmed ischemic heart disease and without clinically evident heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. The majority of patients in the study received perindopril in addition to standard therapy: 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 once daily resulted in a significant absolute reduction in the primary endpoint by 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6] — p < 0.001).

Amlodipine

Mechanism of action

Amlodipine is a calcium ion influx inhibitor belonging to the dihydropyridine group (a slow calcium channel blocker or calcium ion antagonist) that blocks 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 total ischemic burden through the following actions:

Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Since heart rate remains unchanged, the reduced cardiac workload decreases myocardial energy consumption and oxygen demand;
Amlodipine also partially promotes dilation of major coronary arteries and coronary arterioles, both in normal and ischemic myocardial regions. This dilation increases oxygen delivery 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 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 mellitus, 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—CAMELOT (Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis). 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 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 significant clinical events in the CAMELOT study

Frequency of cardiovascular events, number (%)				Amlodipine vs placebo
Outcomes	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	78 (11.8)	103 (15.7)	95 (14.1)	0.73 (0.54–0.98)	0.03
Hospitalizations due to angina	51 (7.7)	84 (12.8)	86 (12.8)	0.58 (0.41–0.82)	0.002
Non-fatal myocardial infarction	14 (2.1)	19 (2.9)	11 (1.6)	0.73 (0.37–1.46)	0.37
Stroke or transient ischemic attack	6 (0.9)	12 (1.8)	8 (1.2)	0.50 (0.19–1.32)	0.15
Cardiovascular mortality	5 (0.8)	2 (0.3)	5 (0.7)	2.46 (0.48–12.7)	0.27
Hospitalizations due to congestive heart failure	3 (0.5)	5 (0.8)	4 (0.6)	0.59 (0.14–2.47)	0.46
Cardiac arrest with subsequent resuscitation	0	4 (0.6)	1 (0.1)	-	0.04
Newly diagnosed peripheral vascular disease	5 (0.8)	2 (0.3)	8 (1.2)	2.6 (0.5–13.4)	0.24

Heart Failure

Hemodynamic studies and clinical trials assessing load control in patients with heart failure classified as NYHA (New York Heart Association) functional class II–IV showed that amlodipine did not cause clinical worsening based on exercise tolerance, left ventricular ejection fraction, or clinical symptoms.

The objective of the placebo-controlled PRAISE study was to evaluate the effect of amlodipine in patients with heart failure classified as 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 study. Its objective was to evaluate the effect of amlodipine in patients with heart failure classified as NYHA functional class III–IV without clinical symptoms or objective evidence supporting or indicating underlying ischemic heart disease. Patients enrolled in the study were receiving long-term treatment with ACE inhibitors, digitalis preparations, and diuretics. The study showed that amlodipine did not affect overall cardiovascular mortality. However, within the study, amlodipine use 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 approaches: amlodipine at a dose of 2.5–10 mg/day (a calcium channel blocker) or lisinopril at 10–40 mg/day (an ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone at 12.5–25 mg/day.

The study included 33,357 hypertensive patients aged 55 years or older, 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 II diabetes (36.1%), low HDL cholesterol (high-density lipoprotein) <35 mg/dL (11.6%), left ventricular hypertrophy confirmed by electrocardiography or echocardiography (20.9%), or smoking (21.9%).

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

Properties Common to Perindopril and Amlodipine

The morbidity and mortality trial ASCOT-BLPA (Anglo-Scandinavian Cardiac Outcomes Trial — Blood Pressure Lowering Arm) was conducted in 19,257 patients aged 40 to 79 years with hypertension and at least three of the following cardiovascular risk factors: left ventricular hypertrophy (confirmed by ECG or echocardiography), other ECG abnormalities, type II diabetes, peripheral arterial disease, history of 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 main objective of the study was to assess 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). Specifically, it compared amlodipine plus perindopril (added if necessary for blood pressure control) versus atenolol plus the diuretic bendroflumethiazide (added if necessary for blood pressure control).

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

The trial 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 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 components (except for fatal and nonfatal heart failure) in patients receiving amlodipine/perindopril.

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 individually and as part of the fixed combination AM-ALITER, do not differ significantly.

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 total 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 tert-butylamine should be taken once daily in the morning before a meal.

Distribution

A linear relationship exists between perindopril dose and its plasma concentration. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg.

Protein binding of perindoprilat is 20%, primarily to angiotensin-converting enzyme, but this value is dose-dependent.

Elimination

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

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

Hepatic impairment

The dialysis clearance of perindoprilat is 70 mL/min.

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

Amlodipine

Absorption, distribution, plasma protein binding

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

Food intake does not affect the bioavailability of amlodipine.

Biotransformation/elimination

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

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

Elderly patients

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

Hepatic impairment

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

Clinical characteristics.

Indications.

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

Contraindications.

Related to perindopril:

Hypersensitivity to perindopril 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 during pregnancy or breastfeeding");
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. AM-ALITER 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 contact of blood 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 amlodipine or to dihydropyridine derivatives;
Shock, including cardiogenic shock;
Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis);
Heart failure following acute myocardial infarction with unstable hemodynamics.

Related to the medicinal product AM-ALITER:

All the above-mentioned contraindications related to individual components of the fixed combination AM-ALITER;
- Hypersensitivity to any excipient.

Interaction with other medicinal products and other forms of interaction.

Interactions related to perindopril

Clinical 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 incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single medicinal product affecting 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 due to increased 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 racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (see section "Special precautions for use").

Medicinal products causing hyperkalemia. Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with AM-ALITER. Certain medicinal products or therapeutic classes of medicinal products may cause hyperkalemia, namely: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of AM-ALITER 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 hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality is increased.

Extracorporeal treatment methods. Extracorporeal treatment methods leading to contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

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

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

Published data show that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents affecting the renin-angiotensin-aldosterone system. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

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

Potassium-sparing diuretics (e.g., triamterene, amiloride, etc.), potassium salts. Hyperkalemia (possibly fatal) may occur, especially in patients with renal impairment (additive hyperkalemic 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 subsection "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 a combination is justified, serum lithium concentration should be monitored (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 hypoglycemic effect with a risk of hypoglycemia. 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 effect is reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake before 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 deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later) or the ACE inhibitor should be started 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 level) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). Particular attention is required when combining eplerenone or spironolactone (12.5–50 mg daily) with low doses of ACE inhibitors. If recommendations for prescribing this combination are not followed, there is a risk of hyperkalemia (possibly fatal) during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and a loop diuretic. Before prescribing this combination, absence of hyperkalemia and impaired renal function should be confirmed. Careful monitoring of potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g daily. The antihypertensive effect may be attenuated during concomitant use of ACE inhibitors with NSAIDs such as: acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including the possibility of acute renal failure, and increase plasma potassium levels, especially in patients with a history of renal impairment. This combination should be prescribed with caution, particularly in elderly patients. Patients should have their fluid balance restored and renal function monitored at the start of treatment with this combination and periodically during treatment.

Medicinal products requiring attention when co-administered

Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors.

Gold. Rarely, when ACE inhibitors, including perindopril, are used concomitantly with injectable gold medicinal products (sodium aurothiomalate), reactions similar to those occurring 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 combined with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the potential for hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients with malignant hyperthermia or in patients in whom malignant hyperthermia is suspected.

Medicinal products requiring special caution when co-administered

Inducers of CYP3A4. When used concomitantly with known CYP3A4 inducers, plasma concentrations of amlodipine may change. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, particularly when used with 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 concentration. 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 hypotension in patients taking clarithromycin in combination with amlodipine. These patients should be closely observed.

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. When used concomitantly with amlodipine, there is a risk of increased blood levels of tacrolimus. To avoid toxic effects of tacrolimus, its blood levels should be monitored and its dose adjusted as needed 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. Studies on the interaction between cyclosporine and amlodipine in healthy volunteers or other individuals have not been conducted, except in kidney transplant patients, in whom fluctuations in cyclosporine concentration were observed with an average increase from 0% to 40%. In kidney transplant patients receiving amlodipine and cyclosporine, cyclosporine blood levels should be monitored and the cyclosporine dose reduced if necessary.

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

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

Grapefruit or grapefruit juice should not be used concomitantly with amlodipine, as in some patients bioavailability may increase, leading to enhanced hypotensive effect.

Interactions related to the fixed combination AM-ALITER

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 therefore should be used with caution.

Corticosteroids, tetracosactide attenuate the antihypertensive effect (due to water and salt retention).

Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin) enhance the antihypertensive effect and increase the risk of orthostatic hypotension.

Amifostine may enhance the antihypertensive effect of amlodipine.

Tricyclic antidepressants / antipsychotropic agents / anesthetics enhance the antihypertensive effect and increase the risk of orthostatic hypotension.

Special precautions for use.

All warnings regarding the use of individual components of the medicinal product apply to the fixed combination AM-ALITER as well.

Special precautions for the use of 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 "Adverse reactions"). Angioedema may occur at any time during treatment. In such cases, AM-ALITER must be discontinued immediately and appropriate monitoring of the patient's condition should be instituted until complete resolution of symptoms. When swelling is limited to the face and lips, the condition usually resolves without treatment; antihistamine therapy may be helpful in relieving symptoms.

Angioedema associated with laryngeal edema may be fatal. In cases where swelling involves the tongue, glottis or larynx, with potential airway obstruction, emergency therapy must be initiated immediately, 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 persistently resolved.

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

Rare cases of intestinal angioedema have been reported during treatment with ACE inhibitors. These patients presented with abdominal pain (with or without nausea and vomiting); in some cases, there was no prior history of facial angioedema and serum C-1 esterase levels were normal. The diagnosis of intestinal angioedema was established by computed tomography, ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain occurring in patients receiving ACE inhibitors (see section "Adverse reactions").

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan 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 therapy 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 receiving ACE inhibitors undergoing LDL apheresis with dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy prior to each apheresis session.

Anaphylactoid reactions during desensitization therapy. Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors undergoing desensitization therapy with bee venom-containing products. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy, but may recur upon inadvertent re-exposure.

Neutropenia/agranulocytosis/thrombocytopenia/anemia. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, immunosuppressive therapy, allopurinol, or procainamide, or in combination with these risk factors, especially if renal function is impaired. Some of these patients have 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 advised 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 to a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal impairment (see section "Contraindications"). Concomitant diuretic therapy may be a contributing factor. Renal function deterioration may be accompanied by only minor changes in serum creatinine levels, 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 impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual blockade therapy is considered absolutely necessary, it should be performed only under specialist supervision with frequent 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 drugs acting via inhibition of the renin-angiotensin system. Therefore, this medicinal product is not recommended for such patients.

Precautions for the use of perindopril

Hypotension. ACE inhibitors may cause a rapid decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension but occurs more frequently in patients with hypovolemia, e.g. those receiving diuretic therapy, on a salt-free diet, undergoing hemodialysis, or with 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 "Adverse reactions"). Patients at high risk of symptomatic hypotension, as well as those with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke, should be closely monitored for blood pressure, renal function, and serum potassium concentration during treatment with AM-ALITER. 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 administered with caution to patients with mitral valve stenosis and 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 of the medicinal product is recommended (see section "Dosage and administration"). Routine monitoring of serum potassium and creatinine levels is part of standard medical practice in patients with impaired renal function (see section "Adverse reactions"). Reversible increases in blood urea nitrogen and serum creatinine may occur in some patients with bilateral renal artery stenosis or stenosis of the artery to 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. Some patients with arterial hypertension, in whom no renovascular disease was previously detected, developed increases in blood urea nitrogen and serum creatinine, 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 are more likely to cause angioedema in black patients than in patients of other races. As with other ACE inhibitors, perindopril is less effective in lowering blood pressure in black patients with hypertension compared to patients of other races, possibly due to lower plasma renin levels in these patients.

Cough. Cough has been reported during ACE inhibitor therapy. This cough is non-productive, persistent, and resolves after discontinuation of the medicinal product. ACE inhibitor-induced cough should be considered in the differential diagnosis of chronic cough.

Surgery / anesthesia. During surgery or anesthesia, particularly with anesthetics that lower blood pressure, AM-ALITER may block the formation of angiotensin II following compensatory renin release. The medicinal product 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 increasing circulating blood volume.

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. This effect is usually mild in patients with normal renal function. Risk factors for hyperkalemia include: renal impairment or reduced renal function, age over 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other medicinal products that increase serum potassium (heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and particularly aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in serum potassium levels. Hyperkalemia may result in serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution and undergo careful monitoring of serum potassium and renal function. If concomitant use of perindopril and any of the above-mentioned agents is considered necessary, 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 for the use of 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 antagonists, 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 increased; dosage recommendations have not been established. Therefore, amlodipine therapy should be initiated at the lowest doses and with caution both at the start of treatment 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 with caution (see sections "Pharmacodynamics" and "Dosage and administration").

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

Warnings for the use of the medicinal product AM-ALITER

Excipients. The medicinal product contains lactose; therefore, it is not recommended for patients with hereditary galactose intolerance, glucose-galactose malabsorption syndrome, or severe lactase deficiency.

Interactions. Concomitant use of lithium, potassium-sparing medicinal products, potassium-containing dietary supplements, or dantrolene with AM-ALITER 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 AM-ALITER is contraindicated during pregnancy.

Use of the medicinal product AM-ALITER 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 convincing epidemiological evidence of teratogenic risk with ACE inhibitor use during the first trimester of pregnancy; however, a small increased risk cannot be excluded. If continuation of ACE inhibitor therapy is considered essential, pregnant women or 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 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 (impaired renal function, oligohydramnios, delayed ossification of the skull) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors have been used from the second trimester of pregnancy, ultrasound assessment 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-dose administration. Use of the medicinal product during pregnancy is recommended only if no safer alternative therapy 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-studied safety profile should be considered, especially when breastfeeding a newborn or preterm infant.

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

Fertility

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

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

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

Studies on the effect of the medicinal product AM-ALITER on the ability to drive vehicles or operate machinery have not been conducted. Amlodipine may have a negligible or moderate effect on the ability to drive vehicles or operate machinery. Impaired driver reaction 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 a meal. The tablet must not be divided.

Dosage should be individually adjusted for each patient depending on the indication, course of the disease, and blood pressure levels. The maximum daily dose is 1 tablet of AM-ALITER 8 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 perindoprilat is reduced in patients with renal insufficiency and in elderly patients; therefore, frequent monitoring of creatinine and potassium levels is required during treatment.

AM-ALITER 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 is recommended.

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

Plasma concentrations of amlodipine are independent of the degree of renal impairment.

Amlodipine is not removed by 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 initial and maintenance dosing in patients with hepatic impairment, separate dose titration of amlodipine and perindopril is required. Pharmacokinetic studies of amlodipine in patients with severe hepatic impairment have not been conducted. In patients with severe hepatic impairment, treatment with amlodipine should be initiated at the lowest doses, which should be gradually increased.

Children

AM-ALITER is not recommended for use in children due to lack of studies in this patient group.

Overdose

Cases of overdose with AM-ALITER have not been reported. Data on intentional overdose of amlodipine are limited.

Symptoms: Available data suggest that ingestion of very high doses may lead to excessive peripheral vasodilation and a moderate reflex tachycardia. Profound, possibly prolonged systemic hypotension and shock with fatal outcome have been reported. Rarely, non-cardiogenic pulmonary edema has been reported as a consequence of amlodipine overdose, which may develop with delay (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

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 elevation of the lower limbs, and careful monitoring of circulating blood volume and diuresis.

Administration of vasopressors may be beneficial to restore vascular tone and arterial 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 indicated. 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. Infusion of angiotensin II and/or intravenous catecholamines should be considered. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special Warnings and Precautions for Use"). In case of persistent bradycardia unresponsive to treatment, temporary 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 and amlodipine separately, the following adverse reactions have been observed, classified by MedDRA system organ classes according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); 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); hypoaesthesia (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 (mainly cholestasis-related) (very rare — amlodipine).

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

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

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

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

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

Investigations: weight gain, weight loss (uncommon — amlodipine); increased blood urea (uncommon* — perindopril); increased 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 of suspected adverse reactions after marketing authorisation is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

30 tablets (10×3) in a blister pack in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

NVF "MIKROKHIM" LLC (responsible for batch release, excluding batch control/testing).

JSC "Farmak" (full-cycle manufacturing).

You can report adverse events associated with the use of this medicinal product to the pharmacovigilance system of NVF "MIKROKHIM" LLC at the following phone number: +38(050) 309-83-54 (24/7) or via the link: https://microkhim.com.ua/farmakonaglyad/

Manufacturer's location and address of business activity.

Ukraine, 01013, Kyiv, Budynstustrii St., 5.

Ukraine, 04080, Kyiv, Kyrylivska St., 74.

INSTRUCTION

for medical use of the medicinal product

AM-ALITER

(AM-ALITER)

Composition:

Active substances: perindopril, amlodipine;

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,

or perindopril tert-butylamine 4 mg, equivalent to 3.338 mg of perindopril, and amlodipine besylate 13.870 mg, equivalent to 10 mg of amlodipine,

or perindopril tert-butylamine 8 mg, equivalent to 6.676 mg of perindopril, and amlodipine besylate 6.935 mg, equivalent to 5 mg of amlodipine,

or 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; crospovidone; sodium hydrogencarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white to almost white, round biconvex tablets.

Pharmacotherapeutic group.

Agents acting on the renin-angiotensin system. ACE inhibitors, combinations. ACE inhibitors and calcium channel blockers. Perindopril and amlodipine.

ATC code C09B B04.

Pharmacological properties.

Pharmacodynamics.

Perindopril

Mechanism of action

Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kininase, is an exopeptidase that catalyzes the conversion of angiotensin I into the vasoconstrictive angiotensin II, and also promotes the breakdown of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II concentration in plasma, resulting in increased plasma renin activity (due to suppression of the negative feedback mechanism regulating renin release) and decreased aldosterone secretion. Since ACE inactivates bradykinin, ACE inhibition also increases the activity of circulating and local kallikrein-kinin systems (and thus also activates the prostaglandin system). This mechanism of action underlies the antihypertensive effect of ACE inhibitors and partially accounts for the occurrence of certain adverse effects (e.g., cough).

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

Clinical efficacy and safety

Arterial hypertension

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

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

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

Blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure occurs within one month and is maintained without 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 was a 4-year international, multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 12,218 adult patients were randomized: 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 without 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 outcome: cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest followed by successful resuscitation. Treatment with 8 mg of perindopril tert-butylamine once daily resulted in a significant absolute reduction of the primary endpoint by 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6] — p < 0.001).

Amlodipine

Mechanism of action

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

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

Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). As heart rate remains unchanged, the 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 delivery to the myocardium in patients with vasospastic angina (Prinzmetal’s angina or variant angina).

Clinical efficacy and safety

In patients with angina, once-daily 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 mellitus, 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 1997 patients—CAMELOT (Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis). 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 aspirin. The main efficacy outcomes are presented in the table below. The 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

Frequency of cardiovascular events, number (%)				Amlodipine vs placebo
Outcomes	Amlodipine	Placebo	Enalapril	Relative risk (95% CI)	p-value
Primary endpoint Unfavorable cardiovascular events	110 (16.6)	151 (23.1)	136 (20.0)	0.69 (0.54–0.88)	0.003
Individual components
Coronary revascularization	78 (11.8)	103 (15.7)	95 (14.1)	0.73 (0.54–0.98)	0.03
Hospitalizations due to angina	51 (7.7)	84 (12.8)	86 (12.8)	0.58 (0.41–0.82)	0.002
Non-fatal myocardial infarction	14 (2.1)	19 (2.9)	11 (1.6)	0.73 (0.37–1.46)	0.37
Stroke or transient ischemic attack	6 (0.9)	12 (1.8)	8 (1.2)	0.50 (0.19–1.32)	0.15
Cardiovascular mortality	5 (0.8)	2 (0.3)	5 (0.7)	2.46 (0.48–12.7)	0.27
Hospitalizations due to congestive heart failure	3 (0.5)	5 (0.8)	4 (0.6)	0.59 (0.14–2.47)	0.46
Cardiac arrest with subsequent resuscitation	0	4 (0.6)	1 (0.1)	-	0.04
Newly diagnosed peripheral vascular disease	5 (0.8)	2 (0.3)	8 (1.2)	2.6 (0.5–13.4)	0.24

Heart Failure

Hemodynamic studies and clinical trials assessing load control in patients with heart failure of NYHA (New York Heart Association) functional class II–IV have shown that amlodipine did not cause clinical worsening based on exercise tolerance, left ventricular ejection fraction, or clinical symptoms.

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

PRAISE-2 was a long-term, placebo-controlled study. The objective of the study was to evaluate the effect of amlodipine in patients with heart failure of NYHA functional class III–IV without clinical symptoms or objective evidence supporting or indicating underlying ischemic heart disease. Patients enrolled in the study were receiving long-term treatment with ACE inhibitors, digitalis agents, and diuretics. The study showed that amlodipine did not affect overall cardiovascular mortality. Within the study, amlodipine use 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 at a dose of 2.5–10 mg/day (a calcium channel blocker) or lisinopril at a dose of 10–40 mg/day (an ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone at a dose of 12.5–25 mg/day.

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

Properties common to perindopril and amlodipine

The morbidity and mortality trial ASCOT-BLPA (Anglo-Scandinavian Cardiac Outcomes Trial — Blood Pressure Lowering Arm) was conducted in 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 II 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 (CHD).

The main objective of the study was to evaluate and compare the long-term effects of two antihypertensive treatment regimens on a composite primary endpoint of nonfatal myocardial infarction (including silent myocardial infarction) and fatal complications of ischemic heart disease (IHD). Specifically, the regimen of amlodipine combined with perindopril (added if additional blood pressure reduction was needed) was compared to atenolol combined with the diuretic bendroflumethiazide (added if additional blood pressure reduction was needed).

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

The study was prematurely terminated after a mean 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 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, either individually or as part of the fixed combination AM-ALITER, are not significantly different.

Perindopril

Absorption

After oral administration, perindopril is rapidly absorbed, with peak plasma concentration reached within 1 hour. The half-life 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. In addition to the active metabolite perindoprilat, the drug forms five inactive metabolites. Peak plasma concentration of perindoprilat is achieved 3–4 hours after administration.

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, but this value is dose-dependent.

Elimination

Perindoprilat is excreted in the 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 Considerations"). Therefore, routine medical monitoring should include frequent monitoring of creatinine and potassium levels.

Hepatic insufficiency

The dialysis clearance of perindoprilat is 70 mL/min.

The pharmacokinetics of perindopril are altered in patients with liver cirrhosis: hepatic clearance of perindopril is reduced by half. However, the amount of perindoprilat formed is not decreased. Therefore, dose adjustment is not required in these patients (see section "Special Considerations").

Amlodipine

Absorption, distribution, plasma protein binding

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

Food intake does not affect the bioavailability of amlodipine.

Biotransformation/Elimination

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

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

Elderly patients

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

Hepatic insufficiency

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

Clinical characteristics.

Indications.

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

Contraindications.

Related to perindopril:

Hypersensitivity to perindopril or to any other angiotensin-converting enzyme (ACE) inhibitors;
History of angioedema associated with previous ACE inhibitor therapy;
Hereditary or idiopathic angioedema;
Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding");
Concomitant use with medicinal products containing 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. AM-ALITER 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 treatments leading to contact of blood 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 amlodipine or to dihydropyridine derivatives;
Shock, including cardiogenic shock;
Obstruction of left ventricular outflow (e.g., severe aortic stenosis);
Heart failure after acute myocardial infarction with unstable hemodynamics.

Related to the medicinal product AM-ALITER:

All the above-mentioned contraindications related to individual components of the fixed combination AM-ALITER;
- Hypersensitivity to any excipient.

Interaction with other medicinal products and other forms of interaction.

Interactions related to perindopril

Clinical data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to using a single medicinal product affecting 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 due to increased risk of angioedema. Initiation of sacubitril/valsartan therapy should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

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

Medicinal products causing hyperkalemia. Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients receiving AM-ALITER. Certain medicinal products or therapeutic classes may cause hyperkalemia, namely: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of AM-ALITER with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium levels.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren. In patients with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality is increased.

Extracorporeal treatments. Extracorporeal treatments leading to contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

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

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

Published data show that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents affecting the renin-angiotensin-aldosterone system. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

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

Potassium-sparing diuretics (e.g., triamterene, amiloride, etc.), potassium salts. Risk of hyperkalemia (possibly fatal), especially in patients with renal impairment (additive hyperkalemic effect). These medicinal products are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use is necessary, they should be used with caution and frequent monitoring of plasma potassium levels. For use of spironolactone in heart failure, see subsection "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, serum lithium concentration should be monitored (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 hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment.

Diuretics. In patients 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 can be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake before starting perindopril therapy, which should begin with low doses and gradually increase. In arterial hypertension, if a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation. In congestive heart failure on background diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In any case, renal function (creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). Particular attention is required when combining eplerenone or spironolactone (doses from 12.5 mg to 50 mg daily) with low doses of ACE inhibitors. Failure to follow recommendations for prescribing such combinations carries a risk of hyperkalemia (possibly fatal) during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and loop diuretic. Before prescribing such combinations, absence of hyperkalemia and renal dysfunction should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.

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

Medicinal products requiring attention when co-administered

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold. Rarely, 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 combined with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the potential risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients with malignant hyperthermia or in whom malignant hyperthermia is suspected.

Medicinal products requiring special caution when co-administered

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

Inhibitors of CYP3A4. Concomitant use of amlodipine with potent or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may increase amlodipine concentrations. The clinical manifestation of these pharmacokinetic changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment are required. 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 having antihypertensive properties may result in additive antihypertensive effects.

Tacrolimus. Concomitant use with amlodipine may increase blood levels of tacrolimus. To avoid toxic effects of tacrolimus, blood levels should be monitored and dosage adjusted as needed in patients receiving amlodipine.

Cyclosporine. Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in kidney transplant recipients, where fluctuations in cyclosporine concentration were observed, with an average increase of 0% to 40%. In kidney transplant recipients receiving both amlodipine and cyclosporine, cyclosporine blood levels should be monitored and the 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 their 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.

Grapefruit or grapefruit juice should not be used concomitantly with amlodipine, as bioavailability may be increased in some patients, leading to enhanced hypotensive effects.

Interactions related to the fixed combination AM-ALITER

Medicinal products requiring special caution when co-administered

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

Medicinal products requiring attention when co-administered

Antihypertensive agents (such as beta-blockers) and vasodilators. Concomitant use of these agents may enhance the hypotensive effect of perindopril and amlodipine; concomitant use with nitroglycerin and other nitrates or 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).

Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin) enhance the antihypertensive effect and increase the risk of orthostatic hypotension.

Amifostine may enhance the antihypertensive effect of amlodipine.

Tricyclic antidepressants / antipsychotropic agents / anesthetics enhance the antihypertensive effect and increase the risk of orthostatic hypotension.

Special precautions for use.

All warnings regarding the use of individual components of the medicinal product apply to the fixed combination AM-ALITER as well.

Special precautions for use of 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 "Adverse reactions"). Angioedema may occur at any time during treatment. In such cases, AM-ALITER must be discontinued immediately and appropriate medical monitoring should be initiated until complete and sustained resolution of symptoms occurs. When swelling is limited to the face and lips, symptoms usually resolve without treatment; antihistamines may be helpful in relieving symptoms.

Angioedema involving swelling of the larynx may be fatal. If swelling involves the tongue, glottis or larynx, 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 close medical supervision until symptoms have completely and stably resolved.

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

Rare cases of intestinal angioedema have been reported during treatment with ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, there was no prior history of facial angioedema and C-1 esterase levels were normal. The diagnosis of intestinal angioedema was confirmed by computed tomography, ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain 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 begin earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan therapy 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. of the airways or tongue, with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating therapy 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 receiving ACE inhibitors undergoing LDL apheresis with dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Anaphylactoid reactions during desensitization therapy. Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors undergoing desensitization therapy with bee venom-containing agents. These reactions can be avoided by temporarily discontinuing ACE inhibitors, but may recur upon re-exposure.

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 combination with these risk factors, especially if renal function is impaired. Some of these patients have 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 advised 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 to a single functioning kidney, treatment with ACE inhibitors increases the risk of hypotension and renal impairment (see section "Contraindications"). Concomitant use of diuretics may increase this risk. 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 impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual 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.

Precautions for use of perindopril

Hypotension. ACE inhibitors may cause a rapid decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension but occurs more frequently in patients with hypovolemia, e.g. those receiving diuretic therapy, on a salt-free diet, undergoing hemodialysis, or with 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 "Adverse reactions"). Patients at high risk of symptomatic hypotension, and those with ischemic heart disease or cerebrovascular disease in whom excessive blood pressure reduction could precipitate myocardial infarction or stroke, should be closely monitored for blood pressure, renal function, and serum potassium concentration during treatment with AM-ALITER. In case of hypotension, the patient should be placed in a supine position and, if necessary, given 0.9% sodium chloride solution intravenously. Transient hypotension at the beginning of treatment is not a contraindication to 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 administered 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 impaired renal function (see section "Adverse reactions"). Reversible increases in blood urea and serum creatinine may occur in some patients with bilateral renal artery stenosis or stenosis of the artery to 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. Some patients with arterial hypertension, in whom no renovascular disease was detected prior to treatment, developed increases in blood urea and serum creatinine, usually mild and transient, particularly when perindopril was 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 increases 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 differences. ACE inhibitors are more likely to cause angioedema in black patients than in other racial groups. As with other ACE inhibitors, perindopril is less effective in lowering blood pressure in black hypertensive patients than in other racial groups, 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 when using anesthetics that lower blood pressure, AM-ALITER may block angiotensin II formation following compensatory renin release. The medicinal product should be discontinued one day before surgery. If hypotension develops and is thought to be due to this mechanism, the patient's condition can be corrected by volume expansion.

Hyperkalemia. Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia by suppressing 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 conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium (heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and particularly aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, 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 serum potassium and renal function should be closely monitored. If concomitant use of perindopril with any of the above agents is considered necessary, 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").

Precautions for use of 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 trial in patients with severe heart failure (NYHA classes III–IV), the incidence of pulmonary edema was higher with amlodipine than with placebo (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality.

Hepatic impairment. In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC is increased; dosage recommendations have not been established. Therefore, amlodipine therapy should be initiated at the lowest dose with caution both at the start of treatment 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 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.

Warnings for use of the medicinal product AM-ALITER

Use during pregnancy or breastfeeding.

Use of AM-ALITER is contraindicated during pregnancy.

Use of AM-ALITER is not recommended during breastfeeding. If use of the medicinal product is necessary, breastfeeding should be discontinued.

Pregnancy

Perindopril. Use of ACE inhibitors is contraindicated during pregnancy. There are no convincing epidemiological data on teratogenic risk with ACE inhibitor use during the first trimester of pregnancy; however, a small increased risk cannot be excluded. If continuation of ACE inhibitor therapy is considered essential, pregnant women or 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 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 (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 assessment of fetal kidney 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. Toxic effects on reproduction were observed in animal studies 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. During breastfeeding, it is preferable to use alternative therapy with a better-studied safety profile, especially when nursing a newborn or premature infant.

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

Fertility

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

Amlodipine. Reversible biochemical changes in 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 or operating machinery.

Studies on the effect of AM-ALITER on the ability to drive or operate machinery have not been conducted. Amlodipine may have a slight or moderate effect on the ability to drive and operate machinery. Impaired reaction 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.

Adults should be given 1 tablet once daily, preferably in the morning before a meal. The tablet must not be divided.

The dose should be individually adjusted for each patient depending on the indication, course of the disease, and blood pressure levels. The maximum daily dose is 1 tablet of AM-ALITER 8 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 perindoprilat is reduced in patients with renal insufficiency and in elderly patients; therefore, frequent monitoring of creatinine and potassium levels is required during treatment.

AM-ALITER may be prescribed to patients with creatinine clearance ≥ 60 mL/min and should not be prescribed to patients with creatinine clearance < 60 mL/min. For such patients, individual dose titration of each component of the medicinal product should be considered separately.

Plasma concentration of amlodipine does 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 dosing 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 in patients with severe hepatic impairment have not been conducted. In patients with severe hepatic impairment, treatment with amlodipine should be initiated at the lowest doses, which should be gradually increased.

Children

AM-ALITER is not recommended for use in children due to lack of studies in this patient group.

Overdose

There have been no reported cases of overdose with the medicinal product AM-ALITER. Data on intentional overdose of amlodipine are limited.

Symptoms: available data suggest that ingestion of very high doses may lead to excessive peripheral vasodilation and moderate reflex tachycardia. Severe, possibly prolonged systemic hypotension and shock with fatal outcome have been reported. Rarely, non-cardiogenic pulmonary edema has been reported as a consequence of amlodipine overdose, which may develop with delay (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors may include early resuscitation measures (including fluid overload) aimed at supporting perfusion and cardiac output.

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

Administration of a vasoconstrictor 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 imbalance, 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 concentrations, and serum creatinine levels is required.

Adverse reactions.

The most commonly reported adverse reactions during individual use of perindopril and amlodipine are: edema, somnolence, dizziness, headache (especially at the beginning of treatment), taste disturbance (dysgeusia), paraesthesia, 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.

During clinical trials and/or post-marketing use of perindopril and amlodipine 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 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); leukopenia/neutropenia (very rare — amlodipine and perindopril) (see section "Special precautions for use"); agranulocytosis or pancytopenia (very rare — perindopril) (see section "Special precautions for use"); thrombocytopenia (very rare — amlodipine and perindopril) (see section "Special precautions for use"); enzyme-specific hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency (very rare — perindopril) (see section "Special precautions for use").

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

Metabolism and nutrition disorders: hypoglycemia (uncommon* — perindopril) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction"); hyperkalemia, which resolves after discontinuation of the drug (uncommon* — perindopril) (see section "Special precautions for use"); hyponatremia (uncommon* — perindopril); hyperglycemia (very rare — amlodipine).

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 disturbance (dysgeusia) (uncommon — amlodipine; common — perindopril); tremor (uncommon — amlodipine); hypesthesia (uncommon — amlodipine); paraesthesia (uncommon — amlodipine; common — perindopril); loss of consciousness (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 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 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 precautions for use"); arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation) (uncommon — amlodipine; very rare — perindopril).

Respiratory, thoracic and mediastinal disorders: dyspnea (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); diarrhea (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 precautions for use"); elevated liver enzymes (predominantly cholestasis-related) (very rare — amlodipine).

Skin and subcutaneous tissue disorders: angioneurotic edema Quincke (very rare — amlodipine); angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (very rare — amlodipine; uncommon — perindopril) (see section "Special 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 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 edema) (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 disorder, 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); gynecomastia (uncommon — amlodipine).

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

Investigations: weight gain, weight loss (uncommon — amlodipine); increased blood urea (uncommon* — perindopril); increased blood creatinine (uncommon* — perindopril); increased blood bilirubin (rare — perindopril); increased liver enzymes (rare — perindopril); decreased hemoglobin and hematocrit (very rare — perindopril).

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

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

Reporting of suspected adverse reactions after drug authorization is highly important. It allows continuous monitoring of the benefit-risk profile of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

30 tablets (10×3) in a blister pack within a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC NPF "MIKROKHIM".

You can report any adverse events associated with the use of this medicinal product to the pharmacovigilance system of LLC NPF "MIKROKHIM" at the phone number: +38(050) 309-83-54 (24/7) or via the link: https://microkhim.com.ua/farmakonaglyad/

Manufacturer's address and location of business activity.

Ukraine, 93400, Luhansk region, Severodonetsk, Promyslova St., 24v.