Amlodipine + Perindopril-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

C09BB04 (Perindopril and Amlodipine)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Amlodipine + Perindopril-SZ	Tablets 5 mg+4 mg: 30 or 60 pcs.
		Tablets 5 mg+8 mg: 30 or 60 pcs.
		Tablets 10 mg+4 mg: 30 or 60 pcs.
		Tablets 10 mg+8 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat-cylindrical with a bevel.

Excipients: microcrystalline cellulose 102, sodium carboxymethyl starch, pregelatinized starch (starch 1500), sodium bicarbonate, magnesium stearate, colloidal anhydrous silicon dioxide (anhydrous aerosil).

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical with a bevel and a score on one side; the break line (score) is intended only for breaking to facilitate swallowing and not for dividing into equal doses.

Excipients: microcrystalline cellulose 102, sodium carboxymethyl starch, pregelatinized starch (starch 1500), sodium bicarbonate, magnesium stearate, colloidal anhydrous silicon dioxide (anhydrous aerosil).

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical with a bevel.

Excipients: microcrystalline cellulose 102, sodium carboxymethyl starch, pregelatinized starch (starch 1500), sodium bicarbonate, magnesium stearate, colloidal anhydrous silicon dioxide (anhydrous aerosil).

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical with a bevel and a score on one side; the break line (score) is intended only for breaking to facilitate swallowing and not for dividing into equal doses.

Excipients: microcrystalline cellulose 102, sodium carboxymethyl starch, pregelatinized starch (starch 1500), sodium bicarbonate, magnesium stearate, colloidal anhydrous silicon dioxide (anhydrous aerosil).

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Combined antihypertensive and antianginal drug

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; ACE inhibitors in combination with other agents; ACE inhibitors in combination with calcium channel blockers

Pharmacological Action

Amlodipine

Amlodipine is a BMCC, a dihydropyridine derivative. Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and vascular smooth muscle cells.

The antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells. The detailed mechanism by which Amlodipine exerts its antianginal action is not fully established, but it is known that Amlodipine reduces the total ischemic load through two mechanisms.

• Causes dilation of peripheral arterioles, reducing TPR (afterload). Since heart rate does not change, myocardial oxygen demand decreases;
• Causes dilation of coronary arteries and arterioles in both ischemic and intact areas. Their 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, taking amlodipine once daily provides a clinically significant reduction in blood pressure in the standing and lying positions over 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is uncharacteristic.

In patients with angina, taking amlodipine once daily increases total exercise time, increases time to onset of angina attack and time to 1 mm ST segment depression, and reduces the frequency of angina attacks and sublingual nitroglycerin consumption.

Amlodipine has no adverse metabolic effects and does not affect plasma lipid concentrations. The drug can be used in patients with concomitant bronchial asthma, diabetes mellitus and gout.

Coronary artery disease

Efficacy assessment results indicate that amlodipine use was associated with fewer cases of hospitalization for angina and revascularization procedures in patients with coronary artery disease.

Heart failure

Results of hemodynamic studies, as well as results of clinical studies involving patients with chronic heart failure of NYHA functional class II-IV, demonstrated that Amlodipine does not lead to clinical deterioration, based on data on exercise tolerance, left ventricular ejection fraction and clinical symptoms.

In patients with chronic heart failure of NYHA functional class III-IV, taking digoxin, diuretics and ACE inhibitors, it was shown that taking amlodipine does not lead to an increased risk of mortality or mortality and morbidity associated with heart failure.

Results of long-term studies in patients with chronic heart failure of NYHA functional class III and IV without clinical symptoms of coronary artery disease or objective data indicating the presence of coronary artery disease, while taking stable doses of ACE inhibitors, cardiac glycosides and diuretics, showed that taking amlodipine has no effect on the rate of cardiovascular mortality. In this patient population, the use of amlodipine was accompanied by an increased number of reports of pulmonary edema.

Myocardial infarction prevention

The efficacy and safety of amlodipine at a dose of 2.5-10 mg/day, the ACE inhibitor lisinopril at a dose of 10-40 mg/day and the thiazide diuretic chlorthalidone at a dose of 12.5-25 mg/day as first-line drugs were studied in patients with mild or moderate hypertension and at least one additional risk factor for coronary artery disease.

No significant differences were found in the primary efficacy criterion (combined rate of fatal coronary heart disease outcomes and non-fatal myocardial infarction rate) between the amlodipine and chlorthalidone groups. The incidence of heart failure in the amlodipine group was significantly higher than in the chlorthalidone group – 10.2% and 7.7%, respectively. No significant differences in overall mortality rates were found between the amlodipine and chlorthalidone groups.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE or kininase II is an exopeptidase that both converts angiotensin I to the vasoconstrictor substance angiotensin II and breaks down bradykinin, which has a vasodilating effect, into an inactive heptapeptide.

Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which causes an increase in plasma renin activity (via a negative feedback mechanism) and a decrease in aldosterone secretion.

Since ACE inactivates bradykinin, suppression of ACE is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin system, while the prostaglandin system is also activated. It is possible that this effect is part of the mechanism of the antihypertensive action of ACE inhibitors, as well as the mechanism of development of some side effects of drugs in this class (for example, cough).

Perindopril exerts its therapeutic effect through an active metabolite, perindoprilat. Other metabolites do not have an inhibitory effect on ACE in vitro.

Clinical efficacy and safety

Arterial hypertension

Perindopril is a drug for the treatment of arterial hypertension of any severity. Its use is accompanied by a decrease in both systolic and diastolic blood pressure in the lying and standing positions. Perindopril reduces TPR, which leads to a decrease in elevated blood pressure and improved peripheral blood flow without changing heart rate.

As a rule, taking perindopril increases renal blood flow, while GFR does not change.

The antihypertensive effect of the drug reaches its maximum 4-6 hours after a single oral dose and lasts for 24 hours.

The antihypertensive effect 24 hours after a single oral dose is about 87-100% of the maximum antihypertensive effect. The decrease in blood pressure is achieved quite quickly.

The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of treatment does not cause a “rebound” effect.

Perindopril has a vasodilating effect, helps restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

Stable coronary artery disease

The efficacy of perindopril in patients (12,218 patients over 18 years of age) with stable coronary artery disease without clinical symptoms of chronic heart failure was studied in a 4-year study. 90% of the study participants had previously suffered an acute myocardial infarction and/or a revascularization procedure.

Most patients received, in addition to the study drug, standard therapy, including antiplatelet agents, lipid-lowering agents and beta-blockers. The primary efficacy criterion was a combined endpoint, including cardiovascular mortality, non-fatal myocardial infarction and/or cardiac arrest with successful resuscitation.

Treatment with perindopril tert-butylamine at a dose of 8 mg/day, once/day (equivalent to 10 mg perindopril arginine) led to a significant reduction in the absolute risk for the combined endpoint of 1.9%; in patients who had previously suffered a myocardial infarction and/or a revascularization procedure, the reduction in absolute risk was 2.2% compared with the placebo group.

Dual blockade of the renin-angiotensin-aldosterone system

There is data from clinical studies of combination therapy using an ACE inhibitor and an angiotensin II receptor blocker.

A clinical study was conducted involving patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by confirmed target organ damage, as well as studies involving patients with type 2 diabetes and diabetic nephropathy.

Data from the studies did not reveal a significant positive effect of combination therapy on the occurrence of renal and/or cardiovascular events and on mortality rates, while the risk of hyperkalemia, acute renal failure and/or hypotension increased compared with monotherapy.

Given the similar intragroup pharmacodynamic properties of ACE inhibitors and ARBs, these results can be expected for the interaction of any other drugs, representatives of the classes of ACE inhibitors and ARBs.

Therefore, the use of ACE inhibitors in combination with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy.

There is data from a clinical study on the positive effect of adding aliskiren to standard therapy with an ACE inhibitor or ARB in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or a combination of these diseases. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were observed more often in the group of patients receiving aliskiren compared with the placebo group; also, adverse events and serious adverse events of special interest (hyperkalemia, hypotension and renal impairment) were recorded more often in the aliskiren group than in the placebo group.

Amlodipine, Perindopril

The efficacy of long-term use of amlodipine in combination with perindopril and atenolol in combination with bendroflumethiazide in patients aged 40 to 79 years with hypertension and at least three additional risk factors was studied.

The primary efficacy criterion was the combined rate of non-fatal myocardial infarction (including silent) and fatal coronary heart disease outcomes.

The incidence of complications provided for by the primary efficacy criterion in the amlodipine/perindopril group was 10% lower than in the atenolol/bendroflumethiazide group, but this difference was not statistically significant. A significant reduction in the incidence of complications provided for by additional efficacy criteria (except for fatal and non-fatal heart failure) was noted in the amlodipine/perindopril group.

Pharmacokinetics

The extent of absorption of amlodipine and perindopril when using the drug Amlodipine + Perindopril-SZ does not differ significantly from that when using the monodrugs.

Amlodipine

Absorption, distribution

After oral administration, Amlodipine is slowly absorbed from the gastrointestinal tract. Food intake does not affect the bioavailability of amlodipine.

C_max of amlodipine in plasma is reached 6-12 hours after oral administration of the drug. Absolute bioavailability is 64-80%, V_d is approximately 21 L/kg.

In vitro studies have shown that about 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism, excretion

The terminal T_1/2 from plasma is 35-50 hours, which allows the drug to be taken once daily. Amlodipine is metabolized in the liver to form inactive metabolites, with 10% of the taken dose of amlodipine excreted unchanged and 60% by the kidneys as metabolites. Amlodipine is not removed from the body by dialysis.

Pharmacokinetics in special patient groups

Elderly patients. The time from drug administration to reaching C_max of amlodipine does not differ between elderly and younger patients. Elderly patients show a slowdown in amlodipine clearance, leading to an increase in AUC. The increase in AUC and T_1/2 in patients with chronic heart failure corresponds to the expected value for this age group.

Patients with impaired renal function. In patients with impaired renal function, changes in amlodipine plasma concentrations do not correlate with the degree of renal failure. A slight increase in T_1/2 is possible.

Patients with impaired liver function. Data on the use of amlodipine by patients with hepatic insufficiency are limited. In patients with hepatic insufficiency, a decrease in amlodipine clearance is observed, leading to an increase in T_1/2 and AUC by approximately 40-60%.

Perindopril

Absorption

After oral administration, Perindopril is rapidly absorbed, C_max in plasma is reached within 1 hour. T_1/2 from plasma is 1 hour. Food intake slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, the drug should be taken once a day, in the morning, before meals.

Distribution

V_d of free perindoprilat is approximately 0.2 L/kg. The binding of perindoprilat to plasma proteins, mainly to ACE, is about 20%, and is dose-dependent.

Metabolism

Perindopril has no pharmacological activity. Approximately 27% of the total amount of Perindopril taken orally enters the bloodstream in the form of the active metabolite perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity. C_max of perindoprilat in plasma is reached 3-4 hours after oral administration.

Excretion

Perindoprilat is excreted from the body by the kidneys. The terminal T_1/2 of the free fraction is about 17 hours, so equilibrium is reached within 4 days.

Linearity (non-linearity)

There is a linear relationship between the plasma concentration of perindopril and its dose.

Pharmacokinetics in special patient groups

Elderly patients, patients with heart and renal failure. The excretion of perindoprilat is slowed in the elderly, as well as in patients with heart and renal failure (see section “Dosage regimen”). Therefore, in these groups of patients, it is necessary to regularly monitor plasma creatinine and potassium concentrations.

Patients with impaired liver function. The dialysis clearance of perindoprilat is 70 ml/min. The pharmacokinetics of perindopril are impaired in patients with liver cirrhosis: its hepatic clearance is reduced by 2 times. Nevertheless, the amount of perindoprilat formed does not decrease, which does not require dose adjustment (see sections “Dosage regimen” and “Special instructions”).

Preclinical safety data

Amlodipine

Reproductive toxicity

Reproductive toxicity studies in rats and mice showed an increase in the gestation period, an increase in the duration of delivery and a decrease in offspring survival when the drug was used at doses exceeding the maximum recommended for humans by approximately 50 times (when calculated in mg/kg).

Impairment of Fertility

When amlodipine was administered at doses up to 10 mg/kg/day (which is 8 times* the maximum recommended human dose of 10 mg on a mg/m² basis), no effects on fertility were found in rats treated with Amlodipine (males for 64 days and females for 14 days prior to mating). In another rat study in which males received amlodipine besylate for 30 days at a dose comparable to the human dose (on a mg/kg basis), a decrease in plasma follicle-stimulating hormone and testosterone concentrations, as well as a reduction in sperm density and the number of mature spermatids and Sertoli cells, were found.

Carcinogenesis, Mutagenesis

In rats and mice receiving Amlodipine with feed for 2 years at concentrations calculated to provide daily doses of 0.5, 1.25, and 2.5 mg/kg/day, no signs of carcinogenicity were found. The highest dose (for mice – similar to the maximum recommended clinical dose of 10 mg on a mg/m² basis, and for rats – 2 times* higher) was close to the maximum tolerated dose for mice but not for rats.

In mutagenicity studies, no effects associated with the drug were found at either the gene or chromosomal level.

* Based on a patient weight of 50 kg.

Perindopril

In chronic toxicity studies (in rats and monkeys) with oral administration, the target organ is the kidneys, and the impairments are reversible.

No mutagenicity was noted in in vitro and in vivo studies.

Reproductive toxicity studies (in rats, mice, rabbits, and monkeys) did not reveal signs of embryotoxicity or teratogenicity. However, it has been shown that ACE inhibitors, as a class, have an undesirable effect on late fetal development, leading to fetal death and congenital abnormalities in rodents and rabbits: kidney lesions and increased perinatal and postnatal mortality were observed. No impairment of fertility was noted in either males or females.

No carcinogenicity was noted in long-term drug use studies in rats and mice.

Indications

Adults

• Arterial hypertension and/or ischemic heart disease: stable exertional angina in patients requiring therapy with amlodipine and perindopril.

ICD codes

Dosage Regimen

Orally, preferably in the morning before meals. The tablet should be swallowed whole without chewing, with water.

The recommended dose is 1 tablet once daily.

The drug Amlodipine + Perindopril-SZ is not intended for initial therapy.

The dose of the drug Amlodipine + Perindopril-SZ is selected after prior titration of the doses of the individual components of the drug: perindopril and amlodipine in patients with arterial hypertension and/or ischemic heart disease.

If therapeutically necessary, the dose of the drug Amlodipine + Perindopril-SZ may be changed or an individual selection of doses of the individual components may be performed beforehand. If necessary, the dose of the drug Amlodipine + Perindopril-SZ may be changed based on an individual selection of doses of the individual components: (Amlodipine 5 mg + Perindopril 4 mg) or (Amlodipine 10 mg + Perindopril 4 mg) or (Amlodipine 5 mg + Perindopril 8 mg) or (Amlodipine 10 mg + Perindopril 8 mg).

Maximum daily dose: Amlodipine 10 mg + Perindopril 8 mg.

Special Patient Groups

Elderly patients and patients with renal impairment(see sections “Pharmacokinetics” and “Special Precautions”)

The elimination of perindoprilat is slowed in elderly patients and patients with renal impairment. Therefore, in such patients, plasma creatinine and potassium concentrations should be regularly monitored.

The drug Amlodipine + Perindopril-SZ can be prescribed to patients with CrCl≥60 mL/min.

The drug Amlodipine + Perindopril-SZ is contraindicated in patients with CrCl<60 mL/min(see section “Contraindications”). Patients with impaired renal function are recommended to have an individual selection of doses of amlodipine and perindopril.

Amlodipine, used in equivalent doses, is equally well tolerated by both elderly and younger patients. No dose adjustment is required in elderly patients; however, dose increases should be performed with caution due to age-related changes and an increase in T_1/2. Changes in plasma amlodipine concentration do not correlate with the severity of renal impairment. Amlodipine is not removed from the body by dialysis.

Patients with hepatic impairment(see sections “Dosage Regimen” and “Special Precautions”)

For patients with mild or moderate hepatic impairment, dose selection must be performed with caution. It is recommended to start taking the drug at low doses (see sections “Dosage Regimen” and “Special Precautions”). The choice of the optimal initial and maintenance dose for patients with hepatic impairment should be made individually, using amlodipine and perindopril drugs in monotherapy. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. For such patients, amlodipine should be started at the lowest dose and increased gradually.

Children and adolescents

The drug Amlodipine + Perindopril-SZ should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the efficacy and safety of amlodipine and perindopril use in these patient groups as combination therapy.

Adverse Reactions

Summary of the safety profile

The most frequent adverse reactions when taking amlodipine and perindopril as monotherapy are edema, drowsiness, dizziness, headache (especially at the start of treatment), dysgeusia (taste disturbance), paresthesia, visual disturbances (including diplopia), tinnitus, vertigo, palpitations, flushing, arterial hypotension (and symptoms related to this), dyspnea, cough, abdominal pain, nausea, vomiting, dyspepsia, change in frequency and character of stool, diarrhea, constipation, pruritus, skin rash, exanthema, joint swelling (ankle swelling), muscle cramps, increased fatigue, asthenia.

Tabulated summary of adverse reactions

Adverse reactions, classified as possibly related to therapy with the components amlodipine and perindopril, based on clinical study data and post-registration experience, are listed in Table 1 by system-organ class and absolute frequency. Frequency is defined as follows: very common (≥1/10); common (≥1/100 but <1/10), uncommon ( ≥1/1000 but <1/100), rare ( ≥1/10000 but <1/1000), very rare (<1/10000); frequency not known (cannot be estimated from the available data).

Table 1. Summary table of adverse reactions associated with the use of the combination of amlodipine and perindopril

* The assessment of the frequency of adverse reactions identified from spontaneous reports is based on data from clinical study results.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to the active substances, to other ACE inhibitors or dihydropyridine derivatives, or to any of the excipients of the drug;
• History of angioedema (including when taking other ACE inhibitors);
• Hereditary/idiopathic angioedema;
• Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR <60 mL/min/1.73 m² body surface area) (see sections “Pharmacological Action” and “Drug Interactions”);
• Concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy (see section “Special Precautions”);
• Concomitant use with combined drugs containing sacubitril/valsartan (see sections “Special Precautions” and “Drug Interactions”);
• Extracorporeal therapy leading to contact of blood with negatively charged surfaces (see section “Drug Interactions”);
• Severe bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section “Special Precautions”);
• Severe arterial hypotension (systolic BP <90 mm Hg);
• Shock (including cardiogenic);
• Left ventricular outflow tract obstruction (e.g., significant aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Renal failure (CrCl less than 60 mL/min);
• Pregnancy;
• Breastfeeding period.

With caution

Renal artery stenosis (including bilateral), single functioning kidney, hepatic impairment, renal impairment, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis), reduced blood volume (diuretic use, salt-free diet, vomiting, diarrhea), burdened allergy history or history of angioedema, atherosclerosis, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, primary hyperaldosteronism, chronic heart failure, concomitant use of dantrolene, estramustine, potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and lithium preparations, clarithromycin, tacrolimus, cyclosporine, inhibitors or inducers of the CYP3A4 isoenzyme, hyperkalemia, surgery/general anesthesia, old age, desensitizing therapy, LDL apheresis, aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy, use in patients of Black race, CHF of non-ischemic etiology NYHA functional class III-IV.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and breastfeeding.

The significance of therapy for the mother should be assessed to make a decision to discontinue breastfeeding or to withdraw the drug.

Pregnancy

Amlodipine

The safety of amlodipine use during pregnancy has not been established.

In experimental animal studies, fetotoxic and embryotoxic effects of the drug were established when used in high doses. Use during pregnancy is possible only in the absence of a safer alternative and when the disease poses a greater risk to the mother and fetus.

Perindopril

The use of ACE inhibitors is not recommended in the first trimester of pregnancy (see section “Special Precautions”). The use of ACE inhibitors is contraindicated in the second and third trimesters of pregnancy (see sections “Contraindications” and “Special Precautions”).

Currently, there is no conclusive epidemiological data on the teratogenic risk of taking ACE inhibitors in the first trimester of pregnancy. However, a small increase in the risk of fetal development disorders cannot be ruled out. When planning pregnancy, the drug should be discontinued and other antihypertensive agents approved for use during pregnancy should be prescribed. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if necessary, other therapy should be prescribed.

It is known that exposure to ACE inhibitors on the fetus during the second and third trimesters of pregnancy can lead to impaired development (decreased renal function, oligohydramnios, delayed skull ossification) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

If the patient received ACE inhibitors during the second and third trimester of pregnancy, an ultrasound is recommended to assess the condition of the skull and renal function of the fetus/child.

Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision due to the risk of arterial hypotension (see sections “Contraindications” and “Special Precautions”).

Breastfeeding period

Amlodipine

Amlodipine is excreted in breast milk. The proportion of the maternal dose received by the infant was estimated with an interquartile range from 3% to 7%, with a maximum of up to 15%. The effect of amlodipine on infants is unknown. The decision to continue/discontinue therapy or breastfeeding should be made taking into account the benefit of breastfeeding for the child and the benefit of amlodipine for the mother.

Perindopril

Due to the lack of information regarding the use of perindopril during breastfeeding, perindopril is not recommended; it is preferable to adhere to alternative treatment with a more established safety profile during breastfeeding, especially when feeding newborns or premature infants.

There are no data regarding the excretion of perindopril in breast milk.

Effect on Fertility

Amlodipine

In some patients receiving slow calcium channel blockers, biochemical changes in the sperm head were found. However, there is currently insufficient clinical data regarding the potential effect of amlodipine on fertility. A study in rats revealed adverse effects on fertility in males.

Perindopril

No effect of perindopril on reproductive function or fertility was identified.

Use in Hepatic Impairment

With caution: hepatic impairment.

Use in Renal Impairment

Contraindications: severe bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney; renal failure (CrCl less than 60 mL/min).

With caution: renal artery stenosis (including bilateral), single functioning kidney, renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age (efficacy and safety have not been established).

Geriatric Use

No dose adjustment is required in elderly patients; however, dose increases should be performed with caution due to age-related changes and an increase in T_1/2.

Special Precautions

Amlodipine + Perindopril-SZ

Special precautions concerning amlodipine and perindopril also apply to the drug Amlodipine + Perindopril-SZ.

Amlodipine

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

Heart failure

Treatment of patients with heart failure should be carried out with caution.

When using amlodipine in patients with chronic heart failure NYHA functional class III and IV, pulmonary edema may develop. Slow calcium channel blockers, including Amlodipine, must be used with caution in patients with congestive heart failure, due to a possible increase in the risk of adverse cardiovascular reactions and an increased risk of death.

Hepatic impairment

In patients with impaired liver function, the T_1/2 and AUC of amlodipine increase. Dosing recommendations for the drug have not been established. Amlodipine should be started at the lowest doses and precautions should be taken, both at the start of treatment and when increasing the dose. In patients with severe hepatic impairment, the dose should be increased gradually, ensuring careful monitoring of the clinical condition.

Elderly patients

In elderly patients, dose increases should be performed with caution (see sections “Dosage Regimen” and “Pharmacokinetics”).

Renal impairment

Patients with renal impairment can take Amlodipine at standard doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not removed from the body by dialysis.

Perindopril

Hypersensitivity/Angioneurotic Edema

During the use of ACE inhibitors, including perindopril, the development of angioneurotic edema of the face, extremities, lips, mucous membranes, tongue, vocal folds and/or larynx may be observed in rare cases (see the “Adverse Reactions” section). This can occur at any time during therapy. If these symptoms appear, the administration of the drug Amlodipine + Perindopril-SZ should be stopped immediately and the patient should be monitored until the signs of edema completely disappear. If the edema affects only the face and lips, its manifestations usually resolve on their own or antihistamines may be used to treat its symptoms.

Angioneurotic edema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms occur, epinephrine (adrenaline) should be administered subcutaneously immediately and/or airway patency should be ensured. The patient should be under medical supervision until the symptoms have completely and permanently resolved.

Patients with a history of angioedema not associated with the use of ACE inhibitors may have an increased risk of its development while using drugs of this group (see the “Contraindications” section).

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis is established using computed tomography of the abdominal area, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered during differential diagnosis (see the “Adverse Reactions” section).

Concomitant use with combined medicinal products containing sacubitril + valsartan

Concomitant use of perindopril with combined medicinal products containing valsartan + sacubitril is contraindicated, as the risk of developing angioedema is increased (see the “Contraindications” section). The use of a combined medicinal product containing valsartan + sacubitril is possible no earlier than 36 hours after the last dose of perindopril. The use of perindopril is possible no earlier than 36 hours after discontinuation of the combined medicinal product containing valsartan + sacubitril (see sections “Contraindications” and “Drug Interactions”). When ACE inhibitors are used concomitantly with other neprilysin inhibitors (e.g., racecadotril), the risk of developing angioedema may also be increased (see the “Drug Interactions” section). In patients receiving Perindopril, a thorough risk/benefit assessment should be performed before starting treatment with enkephalinase inhibitors (e.g., racecadotril).

Concomitant use with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)

Patients receiving therapy with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) may have an increased risk of developing angioedema (e.g., swelling of the airways or tongue with or without impaired breathing function) (see the “Drug Interactions” section).

Anaphylactoid reactions during LDL apheresis

In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each apheresis procedure.

Anaphylactoid reactions during desensitization procedures

There are isolated reports of the development of anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy (e.g., with hymenoptera venom). In these same patients, the anaphylactoid reaction was avoided by temporarily discontinuing ACE inhibitors, and when the drug was accidentally taken, the anaphylactoid reaction recurred.

Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia

There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia during the use of ACE inhibitors. In patients with normal renal function and in the absence of other concomitant factors, neutropenia rarely develops. Perindopril should be used with extreme caution in the presence of systemic connective tissue diseases, as well as during the use of immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.

Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When using perindopril, it is recommended to periodically monitor white blood cells in such patients. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, the risk of arterial hypotension and renal failure increases during therapy with ACE inhibitors. The use of diuretics may be an additional risk factor (see the “Contraindications” section). Deterioration of renal function may be observed even with a slight change in serum creatinine concentration, even in patients with unilateral renal artery stenosis.

Dual blockade of the RAAS

There is evidence of an increased risk of arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure) when ACE inhibitors are used concomitantly with ARBs or aliskiren. Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors with angiotensin II receptor antagonists or aliskiren is not recommended (see sections “Pharmacological Action” and “Drug Interactions”). If dual blockade is absolutely necessary, this should be done under strict specialist supervision with regular monitoring of renal function, blood electrolyte concentrations and blood pressure.

The use of ACE inhibitors in combination with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see sections “Contraindications” and “Drug Interactions”).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are generally not susceptible to antihypertensive drugs whose action is based on inhibition of the RAAS. Therefore, the use of the drug in such patients is not recommended.

Arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic arterial hypotension rarely develops in patients without concomitant diseases. The risk of excessive blood pressure reduction is increased in patients with reduced circulating blood volume, which may occur during diuretic therapy, while following a strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe arterial hypertension with high renin activity (see sections “Drug Interactions” and “Adverse Reactions”). In patients with an increased risk of developing symptomatic arterial hypotension, blood pressure, renal function and serum potassium levels should be carefully monitored during therapy with the drug Amlodipine + Perindopril-SZ.

A similar approach is used in patients with angina and cerebrovascular diseases, in whom severe arterial hypotension can lead to myocardial infarction or cerebrovascular accident.

If arterial hypotension develops, the patient should be placed in the “supine” position with legs elevated. If necessary, the circulating blood volume should be replenished by intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further use of the drug. After restoration of circulating blood volume and blood pressure, treatment can be continued.

Mitral stenosis/Aortic stenosis/Hypertrophic cardiomyopathy

Perindopril, like other ACE inhibitors, should be prescribed with caution to patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as to patients with mitral stenosis.

Impaired renal function

In patients with renal failure (creatinine clearance <60 ml/min), individual dose selection of perindopril and amlodipine is recommended (see the "Dosage Regimen" section). Such patients require regular monitoring of serum potassium and creatinine levels (see the "Adverse Reactions" section).

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, an increase in serum urea and creatinine concentrations may occur during therapy with ACE inhibitors, which usually resolves upon discontinuation of therapy. This effect is more often observed in patients with renal failure. The additional presence of renovascular hypertension causes an increased risk of severe arterial hypotension and renal failure in such patients.

In some patients with arterial hypertension without signs of renal vascular disease, an increase in serum urea and creatinine concentrations may occur, especially when perindopril is prescribed simultaneously with a diuretic, usually minor and transient. This effect is more often observed in patients with pre-existing renal impairment.

Hepatic insufficiency

In rare cases, cholestatic jaundice occurs during the use of ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in liver enzyme activity occurs during the use of ACE inhibitors, the drug should be discontinued (see the “Adverse Reactions” section) and a doctor should be consulted.

Ethnic differences

Patients of the Black race develop angioedema more often than representatives of other races during the use of ACE inhibitors. Perindopril, like other ACE inhibitors, may have a less pronounced antihypertensive effect in patients of the Black race compared to representatives of other races. This difference may be due to the fact that Black patients with arterial hypertension more often have low renin activity.

Cough

A dry cough may occur during therapy with an ACE inhibitor. The cough persists for a long time during the use of drugs of this group and disappears after their discontinuation. This should be taken into account when conducting a differential diagnosis of cough.

Surgery/General anesthesia

In patients scheduled for major surgery or the use of agents for anesthesia that cause arterial hypotension, the use of perindopril may block the formation of angiotensin II against the background of compensatory renin release. Treatment should be discontinued one day before surgery. If arterial hypotension develops due to this mechanism, blood pressure should be supported by replenishing the circulating blood volume.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing salt substitutes, and the use of other drugs that contribute to an increase in plasma potassium levels (for example, heparin, co-trimoxazole, also known as a combination of sulfamethoxazole + trimethoprim). The use of potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in blood potassium levels, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If concomitant use of perindopril and the above drugs is necessary, treatment should be carried out with caution while regularly monitoring serum potassium levels (see the “Drug Interactions” section).

Patients with diabetes mellitus

When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be carefully monitored during the first month of therapy (see the “Drug Interactions” section).

Excipients

Due to the presence of lactose in the drug composition, the drug should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Drug interactions

Concomitant use of the drug Amlodipine + Perindopril-SZ with lithium preparations, potassium-sparing diuretics, potassium-containing substitutes or dantrolene is not recommended (see the “Drug Interactions” section).

Effect on the ability to drive vehicles and mechanisms

Although no negative effect on the ability to drive vehicles or other complex mechanisms was observed during the use of the drug Amlodipine + Perindopril-SZ, due to the possible excessive decrease in blood pressure, development of dizziness, drowsiness and other adverse reactions, caution should be exercised in the listed situations, especially at the beginning of treatment and when increasing the dose.

Overdose

There is no information on drug overdose in humans.

Amlodipine

Information on amlodipine overdose is limited.

Symptoms: excessive peripheral vasodilation leading to reflex tachycardia, and pronounced and persistent decrease in blood pressure, including with the development of shock and fatal outcome.

Rare cases of non-cardiogenic pulmonary edema as a result of amlodipine overdose have been reported, which may manifest with a delay (24-48 hours after oral administration of the drug) and require artificial ventilation. Early resuscitation measures (including hypervolemia) to maintain perfusion and cardiac output may be aggravating factors.

Treatment: pronounced decrease in blood pressure caused by amlodipine overdose requires active measures aimed at maintaining the function of the cardiovascular system, including monitoring of heart and lung performance indicators, elevated position of the extremities and control of circulating blood volume and diuresis. The use of a vasoconstrictor drug may be useful to restore vascular tone and blood pressure, if there are no contraindications to its use; to eliminate the consequences of calcium channel blockade – intravenous administration of calcium gluconate. In some cases, gastric lavage may be effective. Administration of activated charcoal within the first 2 hours after taking amlodipine at a dose of 10 mg delays the absorption of the drug. Since Amlodipine is actively bound to plasma proteins, hemodialysis is ineffective.

Perindopril

Data on perindopril overdose in humans are limited.

Symptoms: in case of overdose of ACE inhibitors, a pronounced decrease in blood pressure, shock, disturbances in water-electrolyte balance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough may be noted.

Treatment: intravenous infusion of 0.9% sodium chloride solution. If blood pressure decreases significantly, the patient should be placed in the “supine” position with legs elevated. If necessary, a solution of catecholamines may be administered intravenously. Perindopril can be removed from the systemic bloodstream by dialysis (see the “Special Instructions” section). If bradycardia resistant to therapy develops, the installation of a pacemaker may be required. Basic vital signs, serum creatinine and electrolyte concentrations should be constantly monitored.

Drug Interactions

Amlodipine

Combinations not recommended for use

Dantrolene (intravenous administration)

In laboratory animals, cases of fatal ventricular fibrillation and collapse were noted during the use of verapamil and intravenous administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, concomitant use of slow calcium channel blockers, including amlodipine, should be avoided in patients susceptible to malignant hyperthermia, as well as during the treatment of malignant hyperthermia.

Combinations requiring special attention

Inducers of the CYP3A4 isoenzyme

When used concomitantly with studied inducers of the CYP3A4 isoenzyme, the plasma concentration of amlodipine may vary. Therefore, it is necessary to monitor blood pressure and adjust the drug dose both during treatment and after concomitant use (in particular, when used concomitantly with strong inducers of the CYP3A4 isoenzyme (such as rifampicin, St. John’s wort).

Inhibitors of the CYP3A4 isoenzyme

Concomitant use of amlodipine and strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungals, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in the concentration of amlodipine. The clinical manifestations of these pharmacokinetic deviations may be more pronounced in elderly patients. In this regard, monitoring of clinical condition and dose adjustment may be required. In patients taking Amlodipine simultaneously with clarithromycin, the risk of arterial hypotension is increased. Careful monitoring of patients taking Perindopril simultaneously with clarithromycin should be carried out.

Combinations requiring attention

Amlodipine enhances the hypotensive effect of drugs with antihypertensive action.

Tacrolimus

There is a risk of increased plasma concentration of tacrolimus when used concomitantly with amlodipine. To avoid toxic effects of tacrolimus when these drugs are used concomitantly, monitoring of plasma tacrolimus concentration and adjustment of its dose is required if necessary.

mTOR inhibitors

MTOR inhibitors, such as sirolimus, temsirolimus and everolimus, are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly, Amlodipine may increase the exposure of mTOR inhibitors.

Cyclosporine

Interaction studies of amlodipine and cyclosporine have not been conducted in healthy volunteers or in other populations, except for patients who have undergone kidney transplantation, in whom variability in the increase in the minimum plasma concentrations of cyclosporine was noted (on average from 0 to 40%). The possibility of monitoring plasma cyclosporine concentration in patients after kidney transplantation when used concomitantly with amlodipine should be considered. If necessary, the dose of cyclosporine should be reduced.

Simvastatin

When several doses of amlodipine 10 mg and simvastatin 80 mg were taken concomitantly, a 77% increase in simvastatin exposure was noted compared to simvastatin taken alone. In patients taking Amlodipine, the dose of simvastatin should be limited to 20 mg/day.

Other drug combinations

In clinical drug interaction studies, Amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.

Concomitant use of amlodipine and consumption of grapefruit or grapefruit juice is not recommended due to a possible increase in the bioavailability of amlodipine in some patients, which, in turn, may lead to increased blood pressure-lowering effects.

Perindopril

Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) due to the simultaneous use of ACE inhibitors, ARBs, or aliskiren leads to an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) compared to situations where only one drug affecting the RAAS is used (see sections “Pharmacological action”, “Contraindications”, “Special instructions”).

Drugs causing hyperkalemia

Some drugs may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs, heparins, immunosuppressants (such as cyclosporine or tacrolimus), trimethoprim, and medicinal products containing co-trimoxazole (sulfamethoxazole + trimethoprim). The combination of these drugs increases the risk of hyperkalemia.

Concomitant use is contraindicated

Aliskiren and medicinal products containing aliskiren

Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR <60 ml/min/1.73 m² body surface area) (see section "Contraindications"). The risk of hyperkalemia, worsening renal function, cardiovascular morbidity and mortality is increased.

Extracorporeal therapy

Extracorporeal treatments leading to contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile), or LDL apheresis using dextran sulfate, are contraindicated due to an increased risk of severe anaphylactoid reactions (see section “Contraindications”). If a patient requires extracorporeal therapy, the possibility of using a different type of dialysis membrane or another class of antihypertensive drugs should be considered.

Concomitant use with combined medicinal products containing sacubitril + valsartan

Concomitant use of perindopril with the combination of valsartan + sacubitril is contraindicated, as suppression of neprilysin during concomitant use of an ACE inhibitor may increase the risk of angioedema. Use of the combination valsartan + sacubitril is possible no earlier than 36 hours after taking the last dose of perindopril. Use of perindopril is possible no earlier than 36 hours after taking the last dose of the combination valsartan + sacubitril (see sections “Contraindications” and “Special instructions”).

Combinations not recommended for use

Aliskiren and medicinal products containing aliskiren

In patients without diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m² body surface area), there is an increased risk of hyperkalemia, worsening renal function, and increased frequency of cardiovascular morbidity and mortality (see section "Special instructions").

Combination therapy with ACE inhibitors and ARBs

According to available literature, in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, the concomitant use of ACE inhibitors and ARBs leads to an increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to situations where only one drug affecting the RAAS is used. The use of dual RAAS blockade (e.g., simultaneous use of ACE inhibitors and ARBs) should be limited to isolated cases with strict monitoring of renal function, plasma potassium levels, and blood pressure (see section “Special instructions”).

Estramustine

Concomitant use may lead to an increased risk of side effects, such as angioedema.

Co-trimoxazole (sulfamethoxazole + trimethoprim)

When used concomitantly with co-trimoxazole (sulfamethoxazole + trimethoprim), the risk of hyperkalemia may increase (see section “Special instructions”).

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

Hyperkalemia (possibly fatal), especially in case of impaired renal function (additive effects related to hyperkalemia). The combination of perindopril with the aforementioned drugs is not recommended (see section “Special instructions”). If, nevertheless, concomitant use is indicated, they should be used with precautions and regular monitoring of serum potassium levels.
The specifics of using spironolactone in chronic heart failure are described further in the text (see subsection “Combinations requiring special attention”).

Lithium preparations

Reversible increases in plasma lithium levels and related toxic effects (severe neurotoxic effects) have been reported with the concomitant use of lithium preparations and ACE inhibitors. Concomitant use of perindopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of plasma lithium levels is required (see section “Special instructions”).

Combinations requiring special attention

Hypoglycemic agents (insulin, sulfonylurea derivatives)

Epidemiological studies have shown that the concomitant use of ACE inhibitors and hypoglycemic agents (insulins, oral hypoglycemic drugs) may enhance the hypoglycemic effect of insulin and oral hypoglycemic agents up to the development of hypoglycemia. This effect is most likely to be observed in the first weeks of concomitant use and in patients with impaired renal function.

Non-potassium-sparing diuretics

In patients receiving diuretics, especially in patients with hypovolemia and/or reduced salt concentration, an excessive decrease in blood pressure may be observed at the beginning of perindopril therapy, the risk of which can be reduced by discontinuing the diuretic, replenishing fluid or salt loss before starting perindopril therapy, and by prescribing perindopril at a low dose with its subsequent gradual increase.

In arterial hypertension in patients with hypovolemia or reduced salt concentration during diuretic therapy, diuretics should either be discontinued before starting the ACE inhibitor (in which case the non-potassium-sparing diuretic may be re-prescribed later), or the ACE inhibitor should be prescribed at a low dose with its subsequent gradual increase.

In the use of diuretics in chronic heart failure the ACE inhibitor should be prescribed at a very low dose, possibly after reducing the dose of the concomitantly used non-potassium-sparing diuretic.

In all cases, renal function (creatinine concentration) should be monitored during the first weeks of ACE inhibitor use.

Potassium-sparing diuretics (eplerenone, spironolactone)

Use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg/day and low doses of ACE inhibitors: in the treatment of chronic heart failure of NYHA functional class II-IV with left ventricular ejection fraction <40% in patients previously receiving ACE inhibitors and "loop" diuretics, there is a risk of hyperkalemia (possibly fatal), especially in case of non-compliance with recommendations regarding this drug combination.

Before using this drug combination, it is necessary to ensure the absence of hyperkalemia and impaired renal function. It is recommended to regularly monitor blood creatinine and potassium concentrations: weekly during the first month of treatment and monthly thereafter.

Racecadotril

During the use of ACE inhibitors (including perindopril), the development of angioedema may be observed. This risk may increase with concomitant use of racecadotril (a drug used to treat acute diarrhea).

mTOR (mammalian target of rapamycin) inhibitors (e.g., sirolimus, everolimus, temsirolimus)

When used concomitantly with mTOR inhibitors, the risk of angioedema increases (see section “Special instructions”).

NSAIDs, including high doses of acetylsalicylic acid (≥ 3 g/day)

When ACE inhibitors are used concomitantly with NSAIDs (acetylsalicylic acid at a dose exerting an anti-inflammatory effect, COX-2 inhibitors, and non-selective NSAIDs), a weakening of the antihypertensive effect may be observed. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening renal function, including the development of acute renal failure, and an increase in serum potassium levels, especially in patients with reduced renal function. Caution should be exercised when using the combination of the drug and NSAIDs, especially in elderly patients. Patients should compensate for fluid loss and carefully monitor renal function, both at the beginning of treatment and periodically during treatment.

Recombinant tissue plasminogen activators (rtPA, alteplase)

Patients receiving ACE inhibitors and receiving alteplase for thrombolytic therapy in acute ischemic stroke may have an increased risk of developing angioedema.

Combinations requiring attention

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

When used concomitantly with ACE inhibitors, the risk of angioedema increases due to decreased dipeptidyl peptidase IV (DPP-IV) activity under the influence of the gliptin.

Sympathomimetics

May weaken the antihypertensive effect of ACE inhibitors.

Gold preparations

Rare cases of nitritoid reactions (with symptoms such as facial flushing, nausea, vomiting, hypotension) have been reported in patients during concomitant use of ACE inhibitors, including perindopril, and injectable gold preparation (sodium aurothiomalate).

Allopurinol, immunosuppressive agents, corticosteroids (for systemic use) and procainamide

Concomitant use with ACE inhibitors may be associated with an increased risk of leukopenia, especially in patients with pre-existing renal impairment.

General anesthetics

Concomitant use of ACE inhibitors and general anesthetics may lead to a hypotensive effect.

Amlodipine+ Perindopril-SZ

Combinations requiring special attention

Baclofen

Enhancement of the antihypertensive effect is possible. Blood pressure should be monitored; if necessary, dose adjustment of amlodipine is required.

Combinations requiring attention

Antihypertensive agents (e.g., beta-blockers) and vasodilators

Enhancement of the antihypertensive effect of amlodipine and perindopril is possible. Caution should be exercised when used concomitantly with nitroglycerin, other nitrates, or other vasodilators, as this may lead to an additional decrease in blood pressure.

Corticosteroids (mineralo- and glucocorticoids), tetracosactide

Reduction of the antihypertensive effect (fluid and sodium ion retention due to the action of corticosteroids).

Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin)

Enhancement of the antihypertensive effect and increased risk of orthostatic hypotension.

Amifostine

Enhancement of the antihypertensive effect of amlodipine is possible.

Tricyclic antidepressants/neuroleptics/general anesthetics

Enhancement of the antihypertensive effect and increased risk of orthostatic hypotension.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.