Prestance^® (Tablets) Instructions for Use

ATC Code

C09BB04 (Perindopril and amlodipine)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combined antihypertensive drug (ACE inhibitor + slow calcium channel blocker)

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + ACE inhibitor)

Pharmacological Action

Combined medicinal product.

Pharmacodynamics

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 carries out both the conversion of angiotensin I to the vasoconstrictor substance angiotensin II and the breakdown of bradykinin, which has a vasodilatory 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 the activity of plasma renin (via a “negative feedback” mechanism) and a decrease in the secretion of aldosterone.

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.

Arterial hypertension

Perindopril is a drug for the treatment of arterial hypertension of any severity. Against the background of its use, a decrease in both systolic and diastolic blood pressure in the “lying” and “standing” positions is noted.

Perindopril reduces total peripheral vascular resistance, which leads to a decrease in blood pressure and an improvement in peripheral blood flow without changing heart rate.

As a rule, taking perindopril increases renal blood flow, while the glomerular filtration rate does not change.

The antihypertensive effect of the drug reaches its maximum 4-6 hours after a single oral dose and persists 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 to 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 had 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 combined endpoint, including cardiovascular mortality, non-fatal myocardial infarction and/or cardiac arrest with successful resuscitation, was chosen as the primary efficacy criterion.

Treatment with perindopril tert-butylamine at a dose of 8 mg once/day (equivalent to 10 mg perindopril arginine) led to a significant reduction in the absolute risk for the combined endpoint by 1.9%; in patients who had previously had 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 RAAS

There is evidence from clinical studies of combination therapy using an ACE inhibitor and an angiotensin II receptor antagonist (ARA II).

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 mellitus and diabetic nephropathy.

Data from 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 arterial hypotension increased compared with monotherapy.

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

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 ARA II in patients with type 2 diabetes mellitus 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 more frequent in the group of patients receiving aliskiren compared with the placebo group; also, adverse events and serious adverse events of special interest (hyperkalemia, arterial hypotension and renal dysfunction) were recorded more frequently in the aliskiren group than in the placebo group.

Amlodipine

Mechanism of action

Amlodipine is a slow calcium channel blocker (CCB), 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 effects

• Causes dilation of peripheral arterioles, reducing total peripheral vascular resistance (afterload). Since the heart rate does not change, the myocardial oxygen demand decreases;
• Causes dilation of the 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 a day provides a clinically significant reduction in blood pressure in the “standing” and “lying” positions for 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is not typical.

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

Amlodipine does not have 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 taking amlodipine is characterized by 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, while 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 does not affect the rate of mortality from cardiovascular diseases. In this patient population, the use of amlodipine was accompanied by an increase in reports of pulmonary edema.

Myocardial infarction prevention

The efficacy and safety of using 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 was 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 evaluation criterion (combined rate of fatal outcomes from coronary artery disease and the frequency of non-fatal myocardial infarctions) 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 the overall mortality rate were found in the amlodipine and chlorthalidone groups.

Perindopril, amlodipine

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 3 additional risk factors was studied.

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

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

Pharmacokinetics

The extent of absorption of perindopril and amlodipine when using this combination does not differ significantly from that when using the active substances separately.

Perindopril

Absorption

When taken orally, perindopril is rapidly absorbed, C_max in blood plasma is reached within 1 hour. T_1/2 of perindopril from blood plasma is 1 hour.

Perindopril does not have 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 blood plasma is reached 3-4 hours after oral administration. 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

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

Elimination

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

Special patient groups

The elimination of perindoprilat is slowed down in the elderly, as well as in patients with heart and renal failure. Therefore, in these groups of patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood plasma.

The dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril is 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.

Amlodipine

Absorption

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 blood plasma is reached 6-12 hours after oral administration of the drug. The absolute bioavailability is about 64-80%.

Distribution

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 and excretion

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

Special patient groups

The time from drug administration to reaching C_max of amlodipine does not differ between elderly and younger patients. In elderly patients, there is a slowdown in the clearance of amlodipine, which leads to an increase in AUC.

The increase in AUC and T_1/2 in patients with CHF corresponds to the expected value for this age group.

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

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

Indications

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

ICD codes

Dosage Regimen

Tablets

Orally in a single dose once a day, preferably in the morning before meals.

The dose of this combination is selected after previously conducted titration of the doses of the individual components – perindopril and amlodipine in patients with arterial hypertension and/or coronary artery disease.

If therapeutically necessary, the dose of this combination can be changed or an individual selection of doses of the individual components can be carried out beforehand.

Special patient groups

The elimination of perindoprilat in elderly patients and patients with renal failure is slowed down. Therefore, in such patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood plasma. This combination can be used in patients with CrCl ≥ 60 ml/min.

Contraindicated for use in patients with CrCl < 60 ml/min. Such patients are recommended to individually select the doses of perindopril and amlodipine. Amlodipine, used in equivalent doses, is equally well tolerated by both elderly and younger patients. No change in the dosing regimen is required in elderly patients, but the dose increase should be carried out with caution, which is associated with age-related changes and an increase in T_1/2. Changes in plasma amlodipine concentration do not correlate with the severity of renal failure. Amlodipine is not removed from the body by dialysis.

For patients with mild or moderate hepatic impairment, dose selection should be carried out with caution. It is recommended to start taking the drug at low doses. The search for the optimal initial and maintenance dose for patients with hepatic impairment should be carried out individually, using amlodipine and perindopril preparations 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.

This combination 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 the use of perindopril and amlodipine in these groups of patients, both as monotherapy and as combination therapy.

Adverse Reactions

a. Summary of the safety profile

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

b. List of adverse reactions

The adverse reactions listed below, noted during clinical trials and/or post-registration use in monotherapy with perindopril and amlodipine, are presented in the following gradation: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), including isolated reports; frequency not known (frequency cannot be calculated from the available data).

*The frequency assessment of adverse reactions identified from spontaneous reports was based on data from clinical trial results.

Cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported with concomitant use of other ACE inhibitors. SIADH can be considered a very rare possible complication associated with treatment with ACE inhibitors, including perindopril.

Contraindications

• Hypersensitivity to the active substances, to other ACE inhibitors or dihydropyridine derivatives;
• Hypersensitivity to the excipients included in the drug;
• History of angioedema (including when taking other ACE inhibitors);
• Hereditary/idiopathic angioedema;
• Severe bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney;
• Severe arterial hypotension (systolic BP less than 90 mm Hg);
• Shock (including cardiogenic);
• Left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Renal failure (CrCl less than 60 ml/min);
• 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);
• Concomitant use with angiotensin II receptor antagonists (ARAs) in patients with diabetic nephropathy;
• Concomitant use with combined drugs containing sacubitril/valsartan;
• Extracorporeal therapy leading to blood contact with negatively charged surfaces;
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (efficacy and safety not established);
• Hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding. The significance of therapy for the mother should be assessed to make a decision to discontinue breastfeeding or to discontinue this combination.

Pregnancy

Perindopril

The use of ACE inhibitors is not recommended in the first trimester of pregnancy. The use of ACE inhibitors is contraindicated in the second and third trimesters of pregnancy.

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

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

If the patient received ACE inhibitors in the second and third trimesters of pregnancy, an ultrasound examination 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.

Amlodipine

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

In experimental animal studies, fetotoxic and embryotoxic effects of amlodipine 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.

Breastfeeding period

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 studied safety profile during breastfeeding, especially when feeding newborns or premature infants. There are no data regarding the excretion of perindopril in breast milk.

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 taking amlodipine for the mother.

Effect on fertility

Perindopril

No effect of perindopril on reproductive function or fertility has been identified.

Amlodipine

Biochemical changes in the sperm head have been detected in some patients receiving slow calcium channel blockers. 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.

Use in Hepatic Impairment

Caution should be exercised when prescribing Prestance^® to patients with hepatic impairment due to the lack of dosing recommendations for such patients.

Use in Renal Impairment

The elimination of perindoprilat is slowed in patients with renal impairment. Therefore, in such patients, plasma creatinine and potassium concentrations should be regularly monitored. Prestance^® can be prescribed to patients with CrCl ≥ 60 ml/min. Prestance^® is contraindicated in patients with CrCl < 60 ml/min. Individual dose selection of perindopril and amlodipine is recommended for such patients. Changes in amlodipine plasma concentration do not correlate with the severity of renal impairment.

Pediatric Use

Prestance^® 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 perindopril and amlodipine use in these patient groups, both as monotherapy and as combination therapy.

Geriatric Use

The elimination of perindoprilat is slowed in elderly patients. Therefore, in such patients, plasma creatinine and potassium concentrations should be regularly monitored. Prestance^® can be prescribed to patients with CrCl ≥ 60 ml/min. Prestance^® is contraindicated in patients with CrCl < 60 ml/min.

Special Precautions

Special precautions relating to perindopril and amlodipine apply to this combination.

Perindopril

Hypersensitivity/Angioedema

When taking ACE inhibitors, including perindopril, in rare cases, angioedema of the face, extremities, lips, mucous membranes, tongue, vocal folds and/or larynx may develop. This can occur at any time during therapy. If symptoms appear, the drug should be discontinued immediately and the patient should be observed until the signs of edema completely disappear. If the edema affects only the face and lips, its manifestations usually resolve on their own, although antihistamines may be used to treat the symptoms.

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

Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of developing it when taking drugs of this group.

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 or 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 in the differential diagnosis.

Concomitant use with combined drugs containing valsartan + sacubitril

Concomitant use of perindopril with combined drugs containing valsartan + sacubitril is contraindicated, as the risk of developing angioedema is increased. Use of the combined drug containing valsartan + sacubitril is possible no earlier than 36 hours after the last dose of perindopril. Use of perindopril is possible no earlier than 36 hours after discontinuation of the combined drug containing valsartan + sacubitril. When ACE inhibitors are used concomitantly with other neprilysin inhibitors (e.g., racecadotril), the risk of developing angioedema may be increased. 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)

When used concomitantly with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), the risk of developing angioedema (e.g., swelling of the airways or tongue with or without impaired breathing) may be increased.

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 temporarily discontinued before each apheresis procedure.

Anaphylactoid reactions during desensitization

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, anaphylactoid reactions were avoided by temporarily discontinuing ACE inhibitors, and when perindopril was accidentally taken, anaphylactoid reactions occurred again.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia while taking ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Perindopril should be used with particular caution in patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.

Some patients have experienced severe infections, in some cases resistant to intensive antibiotic therapy. When using perindopril, such patients are recommended to periodically monitor the white blood cell count. 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 solitary functioning kidney, therapy with ACE inhibitors increases the risk of arterial hypotension and renal failure. Diuretic use may be an additional risk factor. Worsening of renal function may occur 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) with the concomitant use of ACE inhibitors 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. If dual blockade is absolutely necessary, it should be carried out under the strict supervision of a specialist with medical monitoring and regular monitoring of renal function, blood electrolyte levels, 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.

Primary Hyperaldosteronism

Patients with primary hyperaldosteronism are generally not responsive to antihypertensive drugs whose action is based on inhibition of the RAAS. Therefore, the use of perindopril 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 blood volume, which may occur during diuretic therapy, strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe arterial hypertension with high renin activity. In patients at increased risk of developing symptomatic arterial hypotension, blood pressure, renal function, and serum potassium levels should be carefully monitored during therapy with this combination.

A similar approach applies to patients with angina pectoris and cerebrovascular diseases, in whom pronounced 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, blood volume should be replenished by intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not a contraindication for further use of this combination. After restoration of blood volume and blood pressure, treatment can be continued.

Mitral Stenosis, Aortic Stenosis, Hypertrophic Obstructive Cardiomyopathy

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

Impaired Renal Function

Patients with renal failure (creatinine clearance < 60 ml/min) are recommended to have an individual selection of perindopril and amlodipine doses. Such patients require regular monitoring of serum potassium and creatinine levels.

In patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, therapy with ACE inhibitors may lead to an increase in serum urea and creatinine levels, 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 concentration may occur, especially with the simultaneous use of perindopril 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. With the progression of this syndrome, 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 use of this combination should be discontinued and the patient’s condition should be monitored.

Ethnic Differences

Patients of the Black race develop angioedema more often than representatives of other races when taking 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. Perhaps this difference is 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 by the specified mechanism, blood pressure should be maintained by replenishing the 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), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, or 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 (e.g., heparin, co-trimoxazole). 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 with regular monitoring of serum potassium levels.

Patients with Diabetes Mellitus

When using this combination in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be carefully monitored during the first month of therapy.

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. Calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure due to a possible increased risk of adverse cardiovascular events and mortality.

Hepatic Insufficiency

In patients with impaired liver function, the T_1/2 and AUC of amlodipine increase. Dosing recommendations for amlodipine have not been established. Amlodipine should be started at the lowest doses and precautions should be taken, both at the beginning of treatment and when increasing the dose. In patients with severe hepatic insufficiency, 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.

Renal Failure

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

Perindopril + Amlodipine

Special instructions regarding amlodipine and perindopril also apply to the combination of these active substances.

Concomitant use of this combination with lithium preparations, potassium-sparing diuretics, potassium-containing substitutes, or dantrolene is not recommended.

With caution

Renal artery stenosis (including bilateral), solitary functioning kidney, hepatic insufficiency, renal insufficiency, 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 allergic 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, desensitizing therapy, LDL apheresis, aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy, use in Black patients, non-ischemic CHF NYHA functional class III-IV, elderly age.

Effect on the ability to drive vehicles and mechanisms

Although no negative effect on the ability to drive vehicles or other complex mechanisms has been observed during the use of this combination, 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.

Drug Interactions

Perindopril

Clinical trial data show that dual blockade of the RAAS as a result of 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.

Drugs causing hyperkalemia

Some drugs may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists (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 less than 60 ml/min/1.73 m² body surface area). The risk of hyperkalemia, worsening of renal function, cardiovascular morbidity and mortality increases.

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. If a patient requires extracorporeal therapy, the possibility of using another type of dialysis membrane or another class of antihypertensive drugs should be considered.

Concomitant use with combined medicinal products containing valsartan + sacubitril

Concomitant use of perindopril with the combination of valsartan + sacubitril is contraindicated, because 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.

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 of renal function and increased frequency of cardiovascular morbidity and mortality.

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 of renal function (including acute renal failure) compared to situations where only one drug affecting the RAAS is used. The use of dual blockade of the RAAS (e.g., simultaneous use of ACE inhibitors and ARBs) should be limited to individual cases with strict monitoring of renal function, plasma potassium levels, and blood pressure.

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.

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

Hyperkalemia (possibly fatal), especially in case of impaired renal function (additive effects associated with hyperkalemia).

The combination of perindopril with the above-mentioned drugs is not recommended. If, nevertheless, concomitant use is indicated, they should be used with precautions and regular monitoring of serum potassium levels.

Features of the use of spironolactone in chronic heart failure are described later in the text (see the subsection “Combinations requiring special attention”).

Lithium preparations

Reversible increases in plasma lithium levels and associated 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.

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 losses before starting perindopril therapy, and also 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.

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

In all cases, renal function (creatinine concentration) should be monitored in 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 per day and low doses of ACE inhibitors: when treating chronic heart failure 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.

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

When ACE inhibitors are used concomitantly with NSAIDs (acetylsalicylic acid at a dose that has 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 need to 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 undergoing alteplase thrombolytic therapy for acute ischemic stroke may have an increased risk of developing angioedema.

Combination requiring attention

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

When used concomitantly with ACE inhibitors, the risk of angioedema increases due to the reduction in dipeptidyl peptidase-IV (DPP-IV) activity caused by the gliptin.

Sympathomimetics

May reduce the antihypertensive effect of ACE inhibitors.

Gold preparations

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

Allopurinol, immunosuppressants, 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 with ACE inhibitors may lead to a hypotensive effect.

Amlodipine

Combinations not recommended

Dantrolene (IV administration )

Cases of fatal ventricular fibrillation and collapse have been observed in laboratory animals during the use of verapamil and IV 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.

Combination 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 (particularly 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 such as 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. Therefore, clinical monitoring and dose adjustment may be required. In patients taking amlodipine concomitantly with clarithromycin, there is an increased risk of arterial hypotension. Close monitoring of patients taking perindopril concomitantly with clarithromycin should be conducted.

Combination 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 during concomitant use of these drugs, 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 other populations, except for patients who have undergone kidney transplantation, in whom variability in the increase of cyclosporine trough plasma concentrations was noted (on average from 0 to 40%). Consideration should be given to monitoring cyclosporine plasma concentration in patients after kidney transplantation during concomitant use with amlodipine. If necessary, the cyclosporine dose should be reduced.

Simvastatin

Concomitant administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. In patients taking amlodipine, simvastatin intake 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 intake of amlodipine and consumption of grapefruit or grapefruit juice is not recommended, due to the possible increase in amlodipine bioavailability in some patients, which, in turn, may lead to an enhancement of the blood pressure-lowering effects.

Perindopril + amlodipine

Combination requiring special attention

Baclofen possible enhancement of the antihypertensive effect. Blood pressure and renal function should be monitored, and if necessary, adjustment of the amlodipine dose is required.

Combination requiring attention

Antihypertensive agents (e.g., beta-blockers) and vasodilators possible enhancement of the antihypertensive effect of perindopril and amlodipine. 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 as a result of corticosteroid action).

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

Amifostine: possible enhancement of the antihypertensive effect of amlodipine.

Tricyclic antidepressants, antipsychotics, general anesthetics: enhancement of the antihypertensive effect and increased risk of orthostatic hypotension.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.