KAL'CIJ-D3 NIKOMED FORTE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PERINDOPRIL

Perindopril is a medicinal product that contains perindopril in the form of tert-butylamine.

COMPOSITION

The active substance is perindopril; 1 tablet contains 2 mg or 4 mg, or 8 mg of perindopril in the form of tert-butylamine salt; excipients: calcium chloride hexahydrate, lactose monohydrate, crospovidone, microcrystalline cellulose, colloidal silicon dioxide, anhydrous magnesium stearate.

PHARMACEUTICAL FORM

Tablets.

MAIN PHYSICOCHEMICAL PROPERTIES

2 mg tablets: white or almost white, round, slightly biconvex, with beveled edges; 4 mg tablets: white or almost white, oval, slightly biconvex, with beveled edges and a notch on one side; 8 mg tablets: white or almost white, round, slightly biconvex, with beveled edges and a notch on one side.

PHARMACOTHERAPEUTIC GROUP

Angiotensin-converting enzyme inhibitors (ACE inhibitors), single-component. Perindopril. ATC code C09A A04.

PHARMACOLOGICAL PROPERTIES

PHARMACODYNAMICS

Mechanism of Action

Perindopril is an enzyme inhibitor that converts angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kinase, is an exopeptidase that makes it possible to convert angiotensin I into the vasoconstrictor angiotensin II, as well as to break down the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which increases the activity of renin in the blood serum (through a feedback mechanism) and reduces the secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also leads to an increase in the activity of the circulating and local kallikrein-kinin system (and thus also leads to the activation of the prostaglandin system). This mechanism of action causes a decrease in arterial blood pressure in ACE inhibitors and is partly responsible for the occurrence of some side effects (such as cough).

Perindopril acts through its active metabolite, perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE in experimental conditions.

PHARMACODYNAMIC EFFECT

Arterial Hypertension

Perindopril effectively reduces arterial blood pressure in all stages of arterial hypertension: mild, moderate, and severe; a decrease in systolic and diastolic blood pressure is observed in patients in both the supine and standing positions.

Perindopril reduces peripheral vascular resistance, which leads to a decrease in blood pressure. As a result, peripheral blood flow increases without affecting heart rate.

Usually, renal blood flow also increases, while the glomerular filtration rate (GFR) remains unchanged.

The maximum antihypertensive effect develops within 4-6 hours after a single dose and lasts for at least 24 hours: the T/R (minimum effectiveness/maximum effectiveness throughout the day) ratio of perindopril is 87-100%.

Blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure occurs within a month and is maintained without tachyphylaxis.

If perindopril is discontinued, there is no withdrawal effect.

Perindopril reduces left ventricular hypertrophy.

Clinical studies have shown that perindopril has vasodilating properties. It improves the elasticity of large arteries and reduces the ratio of wall thickness to vessel lumen for small arteries.

Combination therapy with a thiazide diuretic has an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.

HEART FAILURE

In experimental studies, congestive heart failure caused by coronary artery ligation has been shown to be reduced by perindopril, which reduces myocardial hypertrophy and excessive subendocardial collagen, restores the ratio of myosin to isoenzyme, and reduces the frequency of reperfusion arrhythmia.

Perindopril tert-butylamine facilitates heart function by reducing pre- and afterload on the heart.

Studies involving patients with heart failure have demonstrated:

• decreased filling pressure in the right and left ventricles,
• decreased systemic peripheral resistance,
• increased cardiac index and improved cardiac output,
• increased regional muscle blood flow in the myocardium.

In comparative studies, the initial appointment of 2 mg of perindopril to patients with heart failure of mild and moderate severity was not associated with any significant decrease in blood pressure compared to placebo.

CLINICAL EFFICACY AND SAFETY

Patients with stable ischemic heart disease (IHD)

EUROPA is an international multicenter randomized double-blind placebo-controlled clinical study that lasted 4 years. 12,218 patients aged 18 years and older were randomized to groups: 6,110 patients received 8 mg of perindopril and 6,108 patients received placebo. The study involved patients with confirmed IHD and without clinical symptoms of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization. Most patients in the study received perindopril in addition to standard therapy: antiplatelet agents, hypolipidemic agents, and beta-blockers.

The primary efficacy endpoint was the composite assessment of the occurrence of cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest with subsequent successful resuscitation. Treatment with perindopril at a dose of 8 mg once daily led to a significant absolute reduction in the primary endpoint of the study by 1.9% (a reduction in relative risk by 20%, 95% CI [9.4; 28.6] - p < 0.001). In patients with a history of myocardial infarction and/or revascularization, an absolute reduction in the primary endpoint of 2.2% was observed, which corresponds to a reduction in relative risk by 22.4% (95% CI [12.0; 31.6] - p < 0.001) compared to placebo.

USE IN CHILDREN

The safety and efficacy of perindopril in children and adolescents under 18 years of age have not been established.

In an open clinical study without a comparison group, 62 children aged 2 to 15 years with a glomerular filtration rate of > 30 mL/min/1.73 m2 were prescribed perindopril at a mean dose of 0.07 mg/kg. The dose of the drug was adjusted individually, with an increase to a maximum of 0.135 mg/kg/day, depending on the patient's profile and blood pressure response to treatment. 59 patients participated in the study for 3 months, 36 patients continued treatment for at least 24 months (mean study duration 44 months). Systolic and diastolic blood pressure remained stable (from the moment of inclusion in the study to the last visit) in patients who were previously treated with other antihypertensive drugs and decreased in patients who were not previously treated. More than 75% of children had systolic and diastolic blood pressure below the 95th percentile during their last visit to the study. The safety profile of perindopril in children was consistent with the known safety profile of perindopril.

DATA FROM CLINICAL STUDIES ON DUAL BLOCKADE OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS)

The concomitant use of ACE inhibitors and angiotensin II receptor blockers has been studied in two large randomized controlled trials [ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].

ONTARGET - a study involving patients with cardiovascular or cerebrovascular disease in their history or type 2 diabetes with signs of target organ damage. VA NEPHRON-D - a study involving patients with type 2 diabetes and diabetic nephropathy.

The studies did not find a significant beneficial effect for patients with kidney disease and/or cardiovascular disease, while the risk of hyperkalemia, acute kidney injury, and/or hypotension increased compared to monotherapy with drugs that affect the RAAS. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

ALTITUDE (a study of aliskiren in type 2 diabetes using cardiovascular and kidney disease endpoints) - a study of the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and/or chronic kidney disease, cardiovascular disease. The study was stopped early due to an increased risk of adverse outcomes. Cardiovascular mortality, stroke, and reports of adverse events and serious complications (hyperkalemia, hypotension, and kidney dysfunction) were more frequent in the group receiving aliskiren compared to the placebo group.

PHARMACOKINETICS

ABSORPTION

After oral administration, perindopril is rapidly absorbed, with a maximum concentration in blood serum reached within 1 hour. The half-life of perindopril in blood serum is 1 hour.

Perindopril is a prodrug. 27% of the total amount of perindopril administered is determined in the blood as an active metabolite - perindoprilat. In addition to the active metabolite - perindoprilat, the drug forms 5 metabolites that are inactive. The maximum concentration of perindoprilat in blood serum is reached within 3-4 hours after administration.

Food intake reduces the conversion of perindopril to perindoprilat, thereby reducing its bioavailability. Therefore, the daily dose of perindopril is recommended to be taken once in the morning before meals.

A linear relationship is observed between the dose of perindopril and its concentration in blood plasma.

DISTRIBUTION

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. The binding of perindoprilat to blood plasma proteins is 20%, mainly to ACE, but this value is dose-dependent.

ELIMINATION

Perindoprilat is excreted in the urine. The terminal half-life of the unbound fraction is approximately 17 hours. The steady-state concentration in blood serum is reached within 4 days of starting treatment.

SPECIAL PATIENT GROUPS

ELDERLY

The elimination of perindoprilat is slowed down in elderly patients, as well as in patients with heart or kidney failure.

RENAL IMPAIRMENT

The dose should be adjusted for patients with renal impairment, taking into account the degree of impairment (creatinine clearance). The dialysis clearance of perindoprilat is 70 mL/min.

HEPATIC IMPAIRMENT

The kinetics of perindopril are altered in patients with liver cirrhosis: the hepatic clearance of perindopril is reduced by half. However, the amount of perindoprilat formed is not reduced. Therefore, such patients do not need to adjust the dose.

CLINICAL CHARACTERISTICS

INDICATIONS

• Arterial hypertension.
• Heart failure.
• Prevention of recurrent stroke in patients with cerebrovascular disease.
• Prevention of cardiovascular complications in patients with documented stable ischemic heart disease.

Long-term treatment reduces the risk of developing myocardial infarction and heart failure (according to the results of the EUROPA study).

CONTRAINDICATIONS

• Increased sensitivity to the active substance or to any other component of the drug, as well as to other ACE inhibitors.
• History of angioedema associated with previous treatment with ACE inhibitors (see "Special Instructions").
• Hereditary or idiopathic angioedema.
• Concomitant use with drugs containing the active substance aliskiren, in patients with diabetes or with renal impairment (creatinine clearance < 60 mL/min) (see "Special Instructions" and "Interactions with Other Medicinal Products and Other Forms of Interaction").
• Pregnancy or planning pregnancy.
• Concomitant use with sacubitril/valsartan therapy (see "Special Instructions" and "Interactions with Other Medicinal Products and Other Forms of Interaction").
• Extracorporeal treatments that lead to contact between blood and negatively charged surfaces (see "Interactions with Other Medicinal Products and Other Forms of Interaction").
• Significant bilateral stenosis of the renal arteries or stenosis of the artery of a single functioning kidney (see "Special Instructions").

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Clinical data indicate that dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher frequency of adverse reactions, such as hypotension, hyperkalemia, and decreased renal function (including acute kidney injury), compared to the use of one drug that affects the RAAS (see "Pharmacodynamics", "Contraindications", and "Special Instructions").

Drugs that cause hyperkalemia

Certain drugs or classes of drugs may cause hyperkalemia, namely: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. Concomitant use of these drugs increases the risk of hyperkalemia.

Concomitant use is contraindicated (see "Contraindications")

Aliskiren

In patients with diabetes or patients with impaired renal function, the risk of hyperkalemia, worsening renal function, and cardiovascular disease and mortality is increased.

Extracorporeal treatments that lead to contact between blood and negatively charged surfaces, such as high-flux membranes for dialysis or hemofiltration (e.g., polyacrylate membranes) and for low-density lipoprotein apheresis with dextran sulfate, may increase the risk of developing severe anaphylactoid reactions (see "Contraindications"). In case of necessity of such treatment, it is recommended to consider the possibility of using dialysis membranes of a different type or prescribing different classes of antihypertensive drugs.

Sacubitril/valsartan

Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as concomitant inhibition of neprilysin and ACE may increase the risk of developing angioedema. Sacubitril/valsartan therapy should not be started until at least 36 hours after the last dose of perindopril. Perindopril therapy should not be started until at least 36 hours after the last dose of sacubitril/valsartan (see "Contraindications" and "Interactions with Other Medicinal Products and Other Forms of Interaction").

Concomitant use is not recommended (see "Special Instructions")

Aliskiren

In patients with diabetes or patients with impaired renal function, the risk of hyperkalemia, worsening renal function, and cardiovascular disease and mortality is increased.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers

According to the literature, in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin II receptor blockers was associated with an increased frequency of hypotension, syncope, hyperkalemia, and decreased renal function (including acute kidney injury) compared to monotherapy with RAAS-acting drugs. Dual blockade (i.e., the combination of an ACE inhibitor with an angiotensin II receptor blocker) may be used in individual cases and under close monitoring of renal function, potassium levels, and blood pressure.

Estramustine

The risk of adverse reactions, such as angioedema (angioedema), is increased.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

In patients who are concomitantly using co-trimoxazole (trimethoprim/sulfamethoxazole), there is a possible increased risk of developing hyperkalemia (see "Special Instructions").

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes

Although potassium usually remains within normal limits, in some patients receiving perindopril, hyperkalemia may occur. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in potassium levels in the blood serum. It is also necessary to exercise caution when concomitantly using perindopril with other agents that increase potassium levels in the blood serum, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic. Therefore, concomitant use of perindopril with the above-mentioned drugs is not recommended. However, if concomitant use of these substances is necessary, they should be used with caution and with close monitoring of potassium levels in the blood serum.

Lithium

When ACE inhibitors are used with lithium preparations, a reversible increase in lithium concentration in the blood serum and, accordingly, an increased risk of its toxic effects are possible. It is not recommended to use perindopril with lithium preparations. If such use is necessary, it is mandatory to closely monitor lithium levels in the blood serum (see "Special Instructions").

Concomitant use requiring special attention

Antidiabetic agents (insulin, oral hypoglycemic agents)

Epidemiological studies suggest that concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may lead to an increased risk of hypoglycemia. This phenomenon is most likely to occur in the first weeks of combination therapy and in patients with renal impairment.

Baclofen

Enhances the antihypertensive effect. If necessary, blood pressure and the dose of antihypertensive agents should be monitored and adjusted.

Diuretics that do not contain potassium

In patients taking diuretics, especially those with impaired water and electrolyte balance, excessive hypotension may occur after starting treatment with an ACE inhibitor. The likelihood of developing a hypotensive effect is reduced by discontinuing the diuretic, increasing blood volume, or consuming salt before starting perindopril therapy. Treatment should be started with low doses and gradually increased.

In cases of arterial hypertension, when a previously prescribed diuretic may have caused water and electrolyte deficiency, it is necessary to discontinue the diuretic before starting perindopril treatment (in such cases, diuretic intake may be resumed over time), or it is necessary to prescribe an ACE inhibitor at a low dose with gradual increase.

In the case of congestive heart failure on the background of diuretic therapy, ACE inhibitor therapy should be started with a minimal dose, possibly after reducing the dose of the diuretic.

In any case, it is necessary to monitor renal function (creatinine levels) during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone)

In the case of concomitant use of eplerenone or spironolactone at doses of 12.5 mg to 50 mg per day with low doses of ACE inhibitors, it is necessary:

• in the event of non-compliance with the recommendations for the appointment of this combination, there is a risk of developing hyperkalemia (possibly fatal) during treatment of patients with heart failure of NYHA class II-IV and a left ventricular ejection fraction of less than 40% who have previously been treated with an ACE inhibitor and a loop diuretic;
• before prescribing such a combination, it is necessary to ensure the absence of hyperkalemia and impaired renal function;
• it is recommended to conduct careful monitoring of potassium and creatinine levels weekly during the first month of treatment and monthly thereafter.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day

May weaken the antihypertensive effect of ACE inhibitors, such as NSAIDs, including acetylsalicylic acid in anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening renal function, including the possibility of acute kidney injury, and increased potassium levels in the blood plasma, especially in patients with pre-existing renal impairment. Such a combination should be prescribed with caution, especially in elderly patients. Patients should restore fluid balance, and it is also necessary to pay attention to monitoring renal function immediately after prescribing combination therapy and periodically thereafter.

Rasagiline

It is known that treatment with ACE inhibitors (such as perindopril) may cause the development of angioedema. This risk may increase when used in combination with rasagiline (a drug used to treat acute diarrhea).

mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)

Patients who concomitantly use mTOR inhibitors may belong to a group with an increased risk of developing angioedema (e.g., angioedema of the airways or tongue, with respiratory disorders or without) (see "Interactions with Other Medicinal Products and Other Forms of Interaction").

Concomitant use requiring some attention

Antihypertensive agents and vasodilators: concomitant use of antihypertensive agents may increase the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may contribute to additional blood pressure reduction.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): in patients who are prescribed a combination of gliptin and ACE inhibitor, there is a possible increased risk of developing angioedema due to the fact that gliptin reduces the activity of dipeptidyl peptidase-IV (DPP-IV).

Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotic agents with ACE inhibitors may lead to further blood pressure reduction (see "Special Instructions").

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

Gold preparations: a nitrate-like reaction (symptoms are flushing of the face, nausea, vomiting, and hypotension) rarely occurs in patients who concomitantly take ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate).

SPECIAL INSTRUCTIONS

Before starting and during treatment with the drug, it is necessary to monitor blood pressure, renal function, and potassium levels in the blood plasma.

Stable IHD

In the event that a patient experiences an episode of unstable angina (of any severity) during the first month of perindopril treatment, it is necessary to carefully weigh the risk/benefit ratio before deciding whether to continue treatment.

Arterial Hypotension

Taking ACE inhibitors can cause a decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated arterial hypertension and is more likely in patients with hypovolemia, those taking diuretics, on a low-sodium diet, on dialysis, with diarrhea or vomiting, or with severe renin-dependent arterial hypertension (see "Interactions with Other Medicinal Products and Other Forms of Interaction" and "Adverse Reactions"). Symptomatic hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal impairment. The development of symptomatic hypotension is most likely in patients with more severe heart failure who are taking high doses of loop diuretics, have hyponatremia, or have functional renal impairment.

To reduce the risk of symptomatic hypotension during the initiation of therapy and dose adjustment, patients should be under close medical supervision (see "Dosage and Administration" and "Adverse Reactions"). Similar precautions exist for patients with IHD or cerebrovascular disease, in whom excessive blood pressure reduction may cause myocardial infarction or stroke.

If hypotension occurs, the patient should be placed in a horizontal position with a low headboard, and if necessary, 0.9% (9 mg/mL) sodium chloride solution should be administered intravenously. Transient hypotension is not a contraindication to further use of the drug, which can usually be used without any obstacles after fluid volume and blood pressure have been restored.

In some patients with congestive heart failure with normal or reduced blood pressure, perindopril may cause additional blood pressure reduction. This effect is predictable and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, it may be necessary to reduce the dose or discontinue the drug.

Aortic and Mitral Valve Stenosis/Hypertrophic Cardiomyopathy

As with other ACE inhibitors, perindopril should be prescribed with caution to patients with mitral valve stenosis or outflow obstruction from the left ventricle (aortic stenosis or hypertrophic cardiomyopathy).

Renal Impairment

In the case of renal impairment (creatinine clearance < 60 mL/min), the initial dose of perindopril should be prescribed according to the patient's creatinine clearance (see "Dosage and Administration"), and then according to the patient's response to treatment. Monitoring of potassium and creatinine levels is a standard practice for such patients (see "Adverse Reactions").

In patients with symptomatic heart failure, hypotension that occurs at the start of ACE inhibitor therapy may lead to impaired renal function, sometimes with the development of acute kidney injury, which is usually reversible.

In some patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single functioning kidney, ACE inhibitors have been observed to increase levels of urea and creatinine in the blood serum, which usually return to normal after discontinuation of treatment. This is especially true for patients with renal impairment. In the presence of concomitant renovascular hypertension, the risk of severe hypotension and kidney failure increases. For such patients, treatment should be started under close medical supervision (see "Special Instructions").

In some patients with arterial hypertension, in whom no renovascular disease was detected before the start of treatment, an increase in urea and creatinine levels in the blood serum was observed, usually minor and temporary, especially when used in combination with a diuretic. However, this is more characteristic of patients with pre-existing renal impairment. It may be necessary to reduce the dose and/or discontinue the diuretic and/or perindopril.

Patients on Hemodialysis

In patients undergoing hemodialysis using high-flux polyacrylate membranes and concomitant ACE inhibitor therapy, anaphylactoid reactions have occurred. Therefore, for such patients, it is necessary to decide on the use of a different type of dialysis membrane or a different class of antihypertensive drugs.

Patients after Kidney Transplantation

There is no experience with the use of perindopril in patients who have recently undergone kidney transplantation.

Renovascular Hypertension

In the case of ACE inhibitor therapy in patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single functioning kidney, the risk of hypotension and kidney failure increases (see "Contraindications"). A favorable factor may be treatment with diuretics. Loss of kidney function may manifest as minimal changes in creatinine levels in the blood serum, even in patients with stenosis of the artery of one kidney.

Hypersensitivity/Angioedema

Rare cases of angioedema of the face, limbs, lips, mucous membranes, tongue, glottis, and/or larynx have been reported in patients taking ACE inhibitors, including perindopril (see "Adverse Reactions"). This can occur at any time during treatment. In such cases, the drug should be discontinued immediately, and the patient should be placed under close medical supervision until the symptoms have completely disappeared. In those individual cases where edema is limited to the face and lips, the patient's condition usually improves without treatment. The appointment of antihistamines may be useful for reducing symptoms.

Angioedema associated with edema of the glottis may be fatal. In cases where edema spreads to the tongue, glottis, or larynx, causing airway obstruction, emergency therapy is necessary, which may include the administration of adrenaline and/or ensuring the patency of the airways. Patients should be under close medical supervision until the symptoms that have occurred have completely disappeared and their condition has stabilized.

Patients who have a history of angioedema not associated with ACE inhibitor therapy are at increased risk of developing angioedema when taking an ACE inhibitor (see "Contraindications").

Rare cases of intestinal angioedema have been reported in patients taking ACE inhibitors. In these patients, abdominal pain (with or without nausea and vomiting) was observed; in some cases, there was no preceding angioedema of the face, and the C-1 esterase level was normal. The diagnosis of intestinal angioedema was established during computed tomography of the abdominal cavity or ultrasound examination, or during surgical intervention. After discontinuation of ACE inhibitor therapy, the symptoms of angioedema disappeared. Intestinal angioedema should be excluded during differential diagnosis in patients with abdominal pain who are taking ACE inhibitors.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of developing angioedema (see "Contraindications"). Sacubitril/valsartan therapy should not be started until at least 36 hours after the last dose of perindopril. Perindopril therapy should not be started until at least 36 hours after the last dose of sacubitril/valsartan (see "Contraindications" and "Interactions with Other Medicinal Products and Other Forms of Interaction"). Concomitant use of other neprilysin inhibitors (e.g., rasagiline) and ACE inhibitors may also increase the risk of developing angioedema (see "Interactions with Other Medicinal Products and Other Forms of Interaction"). Therefore, before starting treatment with neprilysin inhibitors (e.g., rasagiline), patients taking perindopril should undergo a careful assessment of the risk/benefit ratio.

Patients who concomitantly use mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) may belong to a group with an increased risk of developing angioedema (e.g., angioedema of the airways or tongue, with respiratory disorders or without) (see "Interactions with Other Medicinal Products and Other Forms of Interaction").

Anaphylactoid Reactions during Lipoprotein Apheresis

Rarely, in patients taking ACE inhibitors, anaphylactoid reactions may occur during lipoprotein apheresis with dextran sulfate. The development of anaphylactoid reactions can be avoided if ACE inhibitor therapy is temporarily discontinued before each apheresis procedure.

Anaphylactic Reactions during Desensitization Therapy

In patients taking ACE inhibitors during desensitization therapy with drugs containing bee venom, anaphylactoid reactions may occur. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy, but reactions may recur with careless conduct of provocative tests.

Liver Impairment

Cases have been reported where, against the background of ACE inhibitor therapy, a syndrome develops that begins with cholestatic jaundice and progresses to rapid liver necrosis and sometimes fatal outcome. The mechanism of development of this syndrome is unknown. Patients who develop jaundice or a significant increase in liver enzymes during ACE inhibitor therapy should discontinue the drug and receive appropriate medical examination and treatment (see "Adverse Reactions").

Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia

Among patients taking ACE inhibitors, cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been registered. In patients with normal renal function and without other risk factors, neutropenia occurs rarely. Perindopril should be prescribed with extreme caution to patients with collagen diseases, during immunosuppressive therapy, allopurinol, or procainamide, or in combination with these factors, especially in the presence of pre-existing renal impairment. Sometimes, in these patients, serious infections may develop that do not respond to intensive antibiotic therapy. If perindopril is prescribed to such patients, it is recommended to periodically monitor the white blood cell count in the blood, and patients should be informed that they should report any signs of infectious disease (sore throat, fever).

Racial Characteristics

ACE inhibitors are more likely to cause angioedema in patients of the Negroid race than in representatives of other races. Like other ACE inhibitors, perindopril is less effective in reducing blood pressure in patients of the Negroid race than in patients of other races, which may be due to the low level of renin in the blood of patients with arterial hypertension of this race.

Cough

There have been reports of coughing during ACE inhibitor therapy. The cough is characterized as non-productive, persistent, and stops after discontinuation of the drug. Cough caused by ACE inhibitors should be considered during differential diagnosis of cough.

Surgery/Anesthesia

Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients during surgery or anesthesia with drugs that cause hypotension. The drug should be discontinued 1 day before surgery. If hypotension occurs, which is believed to be caused by this mechanism, the patient's condition can be normalized by increasing the volume of circulating blood.

Hyperkalemia

In some patients taking ACE inhibitors, including perindopril, an increase in potassium levels in the blood serum has been observed. Risk factors for hyperkalemia include renal impairment, worsening renal function, age (over 70 years), diabetes, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride) or potassium supplements, or potassium-containing salt substitutes; or patients taking other drugs that increase potassium levels in the blood serum (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole).

The use of potassium-containing salt substitutes, potassium-sparing diuretics, or potassium supplements, especially in patients with impaired renal function, may lead to a significant increase in potassium levels in the blood serum. Hyperkalemia can cause the development of serious, sometimes life-threatening arrhythmias. If concomitant use of perindopril and any of the above-mentioned substances is considered necessary, they should be used with caution and with frequent monitoring of potassium levels in the blood serum (see "Interactions with Other Medicinal Products and Other Forms of Interaction").

Patients with Diabetes

Patients with diabetes who are taking perindopril should have their blood glucose levels closely monitored during the first month of therapy, especially when taking oral hypoglycemic agents or insulin (see "Interactions with Other Medicinal Products and Other Forms of Interaction").

Lithium

Concomitant use of lithium and perindopril is not recommended (see "Interactions with Other Medicinal Products and Other Forms of Interaction").

Potassium-Sparing Preparations, Potassium Supplements, or Potassium-Containing Salt Substitutes

Concomitant use of perindopril with potassium-sparing preparations or potassium supplements is not recommended (see "Interactions with Other Medicinal Products and Other Forms of Interaction").

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

There are data that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute kidney injury). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see "Interactions with Other Medicinal Products and Other Forms of Interaction"). If treatment with dual blockade of the RAAS is considered absolutely necessary, it can only be performed under the supervision of a specialist and with frequent close monitoring of renal function, electrolyte levels, and blood pressure.

Primary Aldosteronism

Patients with primary hyperaldosteronism usually do not respond to treatment with antihypertensive drugs that act by inhibiting the RAAS. Therefore, the appointment of this drug is not recommended.

Excipients

The drug contains lactose, so it is not recommended for patients with rare hereditary galactose intolerance, glucose-galactose malabsorption syndrome, or lactase deficiency Lapp.

USE DURING PREGNANCY OR BREASTFEEDING

Pregnancy: the use of ACE inhibitors is contraindicated during pregnancy.

Women planning pregnancy should be transferred to alternative antihypertensive therapy with a proven safety profile for pregnant women. After pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately, and if necessary, alternative therapy should be prescribed.

Epidemiological data on the risk of teratogenic effects when using ACE inhibitors during the first trimester of pregnancy are not conclusive, but some increase in risk cannot be excluded. Except in cases where continuation of ACE inhibitor therapy is considered necessary, women planning pregnancy should be prescribed alternative antihypertensive therapy with a proven safety profile for use during pregnancy.

If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately, and if necessary, alternative therapy should be started.

It is known that ACE inhibitor therapy during the second and third trimesters causes fetotoxicity (renal dysfunction, oligohydramnios, delayed ossification of the skull) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If ACE inhibitors were used during the second trimester of pregnancy, it is recommended to perform an ultrasound examination to check renal function and skull condition. Newborns whose mothers used ACE inhibitors should be closely monitored for hypotension (see "Contraindications" and "Special Instructions").

Breastfeeding: perindopril is not recommended during breastfeeding due to the lack of data on its penetration into breast milk. During breastfeeding, it is desirable to prescribe alternative therapy with a more studied safety profile, especially during breastfeeding of a newborn or premature infant.

Fertility: no effect on reproductive ability or fertility has been detected.

ABILITY TO INFLUENCE THE RATE OF REACTION WHEN DRIVING VEHICLES OR OPERATING OTHER MECHANISMS

Perindopril does not have a direct effect on the ability to drive vehicles or operate other mechanisms. However, in some patients, individual reactions associated with a decrease in blood pressure may occur, especially at the beginning of treatment or when used in combination with other antihypertensive drugs. As a result, the reaction rate when driving vehicles or operating other mechanisms may be reduced.

DOSAGE AND ADMINISTRATION

The drug is intended for oral administration in adults.

It is recommended to use perindopril once a day in the morning before meals.

The dose should be adjusted individually for each patient, taking into account the indication for use, patient profile, and blood pressure indicators (see "Special Instructions").

Arterial Hypertension

Perindopril can be prescribed as monotherapy or in combination with drugs from other classes of antihypertensive agents.

The recommended initial dose is 4 mg once a day, in the morning.

Patients with high RAAS activity (especially patients with renovascular arterial hypertension, water and electrolyte imbalance, heart failure, or severe arterial hypertension, as well as elderly patients) are recommended to start with a dose of 2 mg under medical supervision, if necessary, in a hospital setting, due to the possibility of rapid blood pressure reduction (hypotension of the first dose).

After 1 month of treatment, the dose can be increased to a maximum dose of 8 mg once a day.

At the beginning of perindopril therapy, symptomatic hypotension may occur, especially in patients taking diuretics. Such patients should start treatment with perindopril with caution, as they may have a deficiency of water and/or salt. If possible, diuretic therapy should be discontinued 2-3 days before starting perindopril treatment (see "Special Instructions").

For patients with arterial hypertension, if diuretic therapy cannot be discontinued, perindopril treatment should be started with a dose of 2 mg once a day. In such patients, it is necessary to monitor renal function and potassium levels in the blood serum. Further dose increases of perindopril should be made based on blood pressure indicators, and if necessary, diuretic therapy may be resumed.

Elderly patients should start treatment with a dose of 2 mg, which can be increased to 4 mg after 1 month of treatment, and then, if necessary, to 8 mg, taking into account renal function (see the table below).

*Dialysis clearance of perindoprilat - 70 mL/min. Patients on hemodialysis should take perindopril after dialysis.

Patients with Liver Impairment

Patients with liver impairment do not require dose adjustment of the drug (see "Pharmacokinetics" and "Special Instructions").

CHILDREN

The efficacy and safety of perindopril in children (under 18 years of age) have not been studied, so perindopril is not recommended for children.

OVERDOSAGE

There is insufficient information about perindopril overdose. Symptoms associated with ACE inhibitor overdose may include hypotension, circulatory shock, electrolyte imbalance, kidney failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough.

In case of overdose, it is recommended to administer 0.9% (9 mg/mL) sodium chloride solution intravenously. If hypotension occurs, the patient should be placed in a horizontal position with a low headboard. If possible, angiotensin II and/or catecholamines should be administered intravenously. Perindopril can be removed from the systemic circulation by hemodialysis (see "Special Instructions"). In case of resistant bradycardia, the use of a pacemaker is indicated. It is necessary to establish continuous monitoring of vital signs, electrolyte levels, and creatinine levels in the blood serum.

Adverse Reactions

The safety profile of perindopril corresponds to the safety profile of ACE inhibitors.

The most frequent adverse reactions observed during perindopril treatment in clinical trials were: dizziness, headache, paresthesia, vertigo, vision disturbances, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, diarrhea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, skin rash, muscle cramps, asthenia.

During clinical trials and post-marketing experience with perindopril, the following adverse reactions were reported with the following frequencies: very common (≥ 1/10); common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000); not known (cannot be estimated from the available data).

Clinical Trials

During the randomization period in the EUROPA study, information was collected only on serious adverse reactions. In a small number of patients, serious adverse reactions were found: 16 (0.3%) of 6122 patients in the perindopril group and 12 (0.2%) of 6107 patients in the placebo group. Among patients receiving perindopril, hypotension was observed in 6 patients, angioneurotic edema in 3 patients, and sudden cardiac arrest in 1 patient. Patients who discontinued participation in the study, 6.0% (n = 366) complained of cough, arterial hypotension, or any other intolerance to perindopril compared to 2.1% (n = 129) of patients who received placebo.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf Life

3 years.

Storage Conditions

Store at a temperature not exceeding 30 °C in the original packaging to protect from moisture. Store in a place inaccessible to children.

Packaging

10 tablets in a blister pack; 3 or 6 or 9 blister packs in a carton box.

Marketing Authorization Holder

By prescription.

Manufacturer

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's Address

Smajrjeska cesta 6, 8501 Novo mesto, Slovenia.

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Nuno Tavares Lopes

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• Country of registration
  Ukraine
• Active substance
  calcium carbonatecholecalciferol (vitamin d3)
• Prescription required
  No
• Manufacturer
  Asker Kontrakt Manufekcering AS
• This information is for reference only and does not constitute medical advice. Always consult a licensed doctor before taking any medication. Oladoctor is not responsible for medical decisions based on this content.

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