Perindopril-teva

INSTRUCTIONS for medical use of the medicinal product Perindopril-Teva (Perindopril-Teva)

Composition:

Active substance: perindopril (in the form of perindopril tromethamine);

1 tablet contains 2.5 mg, 5 mg, or 10 mg of perindopril tromethamine (corresponding to 1.7 mg, 3.4 mg, or 6.8 mg of perindopril, respectively);

Excipients: lactose monohydrate, maize starch, sodium hydrocarbonate, pregelatinized starch, povidone, magnesium stearate;

tablets of 2.5 mg: coating (Opadry II white 85F18422): polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), polyethylene glycol, talc;

tablets of 5 mg: coating (Opadry II green 85F210014): polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), polyethylene glycol, talc, indigo carmine (E 132), brilliant blue (E 133), iron oxide yellow (E 172), quinoline yellow (E 104);

tablets of 10 mg: coating (Opadry II green 85F210013): polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), polyethylene glycol, talc, indigo carmine (E 132), brilliant blue (E 133), iron oxide yellow (E 172), quinoline yellow (E 104).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

tablets of 2.5 mg: round, biconvex, film-coated tablets, white in color, with "T" imprinted on one side and smooth on the other;

tablets of 5 mg: biconvex capsule-shaped, film-coated tablets, light green in color, with "T" imprinted on one side and smooth on the other, with a break line on both sides;

tablets of 10 mg: round, biconvex, film-coated tablets, green in color, with "10" imprinted on one side and "T" on the other.

Pharmacotherapeutic group.

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

Pharmacological Properties.

Pharmacodynamics.

Perindopril is an angiotensin-converting enzyme inhibitor (ACE inhibitor) that converts angiotensin I into angiotensin II. The converting enzyme, or kinase, is an exopeptidase that enables angiotensin I to be transformed into the vasoconstrictive angiotensin II, and also causes the breakdown of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II concentration in plasma, which increases plasma renin activity (due to inhibition of the negative feedback on renin release) and reduces aldosterone secretion. Since ACE inactivates bradykinin, ACE inhibition also increases the activity of circulating and local kallikrein-kinin systems (and thus leads to activation of the prostaglandin system). This mechanism accounts for the antihypertensive effect of ACE inhibitors and partially explains the occurrence of certain adverse effects (e.g., cough).

Perindopril acts via its active metabolite – perindoprilat. Other metabolites do not inhibit ACE activity in vitro.

Arterial Hypertension

Perindopril effectively reduces arterial blood pressure in all stages of arterial hypertension (mild, moderate, and severe). Reduction in systolic and diastolic blood pressure is observed in patients both in the supine and standing positions.

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

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

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

Blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure is achieved within 1 month and is maintained without development of tachyphylaxis.

Discontinuation of treatment is not associated with a withdrawal syndrome.

Perindopril reduces left ventricular hypertrophy.

Perindopril exhibits vasodilatory properties. It improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries.

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

Heart Failure

Perindopril reduces cardiac workload by decreasing preload and afterload on the heart.

Studies involving patients with heart failure have demonstrated:

− reduction in filling pressure of the left and right ventricles;

− reduction in total peripheral vascular resistance;

− increased cardiac output and improved cardiac index.

In comparative studies, initial administration of 2.5 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure compared to placebo.

Patients with a History of Cerebrovascular Disease

In a study evaluating the benefits of long-term (4-year) perindopril treatment in preventing recurrent stroke in patients with a history of cerebrovascular disease, perindopril treatment (either as monotherapy or in combination with indapamide) reduced blood pressure (systolic/diastolic) by an average of 9.0/4.0 mm Hg and reduced the risk of recurrent stroke (both ischemic and hemorrhagic) compared to placebo (10.1% vs. 13.8%).

A significant reduction was also observed in the risk of:

• fatal or disabling stroke;
• major cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke;
• post-stroke dementia and severe post-stroke cognitive impairment;
• major coronary events, including non-fatal myocardial infarction or death due to ischemic heart disease.

These therapeutic benefits were observed in patients regardless of the presence or absence of arterial hypertension, age, sex, type of stroke, or presence of diabetes. Study results showed that after 5 years of treatment, one stroke could be prevented for every 23 patients treated, and one major cardiovascular complication could be prevented for every 18 patients.

Patients with Stable Ischemic Heart Disease

EUROPA is a 4-year, international, multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 12,218 patients aged 18 years and older were randomized: 6,110 patients received 8 mg of perindopril tert-butylamine, and 6,108 patients received placebo. The study included patients with confirmed ischemic heart disease and without clinical symptoms of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients in the study received perindopril in addition to standard therapy: antiplatelet agents, lipid-lowering drugs, and β-blockers.

The primary efficacy endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and/or cardiac arrest with successful resuscitation. Treatment with perindopril 8 mg once daily resulted in a significant absolute reduction of the primary endpoint by 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6] – p<0.001).

In patients with a history of myocardial infarction and/or revascularization, an absolute reduction of 2.2% in the primary endpoint was observed, corresponding to a relative risk reduction of 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.

Pharmacokinetics.

Absorption. After oral administration, perindopril is rapidly absorbed in the gastrointestinal tract, with peak plasma concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.

Perindopril is a prodrug. 27% of the absorbed perindopril is converted into the active metabolite perindoprilat. Additionally, five inactive metabolites are formed. Peak plasma concentration of perindoprilat is reached within 3–4 hours.

Since the presence of food in the stomach reduces the conversion of perindopril to perindoprilat and thus decreases bioavailability, perindopril should be administered orally as a single daily dose in the morning before meals.

A linear relationship exists between perindopril dose and its plasma concentration.

Distribution. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding of perindoprilat to plasma proteins is 20%, primarily to angiotensin-converting enzyme, but this value is dose-dependent.

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

Special Patient Groups. In elderly patients and in patients with heart or renal failure, the elimination rate of perindoprilat is reduced. In renal impairment, dosage adjustment is recommended according to the degree of renal dysfunction (based on creatinine clearance).

Perindoprilat is removed from the bloodstream by dialysis, with a clearance rate of 70 mL/min.

In liver cirrhosis, the kinetics of perindopril are altered, with hepatic clearance of the parent molecule reduced by half. However, the amount of perindoprilat formed remains unchanged; therefore, dosage adjustment is not necessary in this condition.

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 ischaemic heart disease.

Long-term treatment reduces the risk of myocardial infarction and heart failure.

Contraindications.

• Hypersensitivity to perindopril or to any component of the medicinal product, or to other ACE inhibitors.
• Angioedema (Quincke's oedema) in medical history related to previous treatment with ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Concomitant use of medicinal products containing the active substance aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate <60 mL/min/1.73 m²) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Pregnancy or planned pregnancy.
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
• Severe bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney.
• Concomitant use with sacubitril/valsartan; treatment with Perindopril-Teva may be initiated no sooner than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Clinical study data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher frequency of adverse reactions such as hypotension, hyperkalaemia, and impaired renal function (including acute renal failure), compared to use of a single medicinal product affecting the RAAS (see sections "Contraindications" and "Special precautions for use").

Medicinal products causing hyperkalaemia. Some medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, namely: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, and trimethoprim. Concomitant use of these medicinal products increases the risk of hyperkalaemia.

Concomitant use is contraindicated.

Aliskiren. Concomitant use of perindopril with aliskiren in patients with diabetes mellitus or patients with impaired renal function increases the risk of hyperkalaemia, worsening of renal function, and cardiovascular morbidity and mortality.

Extracorporeal treatment leading to contact of blood with negatively charged surfaces, such as high-flux dialysis or haemofiltration membranes (e.g., polyacrylonitrile membranes) or for low-density lipoprotein apheresis with dextran sulphate, may lead to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using dialysis membranes of another type or prescribing another class of antihypertensive medicinal products.

Sacubitril/valsartan. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as simultaneous inhibition of neprilysin and ACE may lead to an increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

Concomitant use not recommended.

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

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

Estramustine. Increased risk of adverse reactions such as angioedema.

Co-trimoxazole (trimethoprim/sulfamethoxazole). Patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly may have an increased risk of developing hyperkalaemia (see section "Special precautions for use").

Potassium-sparing diuretics, potassium-containing dietary supplements, or potassium-containing salt substitutes. Use of potassium-sparing diuretics (such as triamterene or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to hyperkalaemia (including fatal), especially in patients with renal impairment (additive hyperkalaemic effect). Therefore, combination of perindopril with the above-mentioned medicinal products is not recommended. If concomitant use of these agents is indicated, treatment should be conducted with caution and serum potassium levels should be monitored frequently (see section "Special precautions for use"). For use of spironolactone in heart failure, see "Concomitant use requiring special attention".

Lithium. When ACE inhibitors are used concomitantly with lithium-containing medicinal products, reversible increases in serum lithium concentration and lithium toxicity have been reported. Therefore, combined therapy with perindopril and lithium-containing medicinal products is not recommended. If such use is necessary, plasma lithium levels must be monitored carefully (see section "Special precautions for use").

Concomitant use requiring special attention.

Antidiabetic agents (insulin, oral hypoglycaemic agents). According to epidemiological studies, concomitant use of ACE inhibitors and antidiabetic agents (insulin, hypoglycaemic agents) may enhance the glucose-lowering effect with a risk of hypoglycaemia. This effect usually occurs during the first weeks of combination therapy and in cases of renal impairment.

Baclofen. Antihypertensive effect is enhanced. Blood pressure should be monitored and antihypertensive dosage adjusted if necessary.

Diuretics. In patients taking diuretics, particularly those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake prior to starting perindopril therapy. Treatment should be initiated with low doses and gradually increased.

In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte depletion, the diuretic should be discontinued before starting ACE inhibitor therapy (in such cases, diuretic therapy may be resumed later), or the ACE inhibitor should be initiated at a low dose with gradual dose escalation.

In chronic heart failure on background diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.

In any case, renal function (creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone is used concomitantly with low doses of an ACE inhibitor, it should be noted that:

• in patients with NYHA class II-IV heart failure and ejection fraction <40%, previously treated with an ACE inhibitor and a loop diuretic, there is a risk of hyperkalaemia (possibly fatal), especially if recommendations for use of this combination are not followed;
• before prescribing such a combination, absence of hyperkalaemia and renal impairment should be confirmed;
• careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥3 g/day. Concomitant use of ACE inhibitors and nonsteroidal anti-inflammatory drugs (acetylsalicylic acid at analgesic doses, COX-2 inhibitors, and nonselective NSAIDs) may result in reduced antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may lead to worsening of renal function, including development of acute renal failure, and increased serum potassium levels, particularly in patients with a history of renal impairment. Such combination should be used with caution, especially in elderly patients. Adequate hydration should be provided and renal function monitored after initiation and periodically during such combination therapy.

Racecadotril. ACE inhibitors (e.g., perindopril) are known to cause angioedema. This risk may be increased when used concomitantly with racecadotril (a medicinal product used to treat acute diarrhoea).

mTOR (mammalian target of rapamycin) inhibitors (e.g., sirolimus, everolimus, temsirolimus). In patients receiving concomitant mTOR inhibitors, there may be an increased risk of angioedema (see section "Special precautions for use").

Concomitant use requiring attention.

Antihypertensive agents and vasodilators. Concomitant use of these agents may enhance the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may further reduce blood pressure.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin). In patients receiving a combination of a gliptin and an ACE inhibitor, there may be an increased risk of angioedema due to the gliptin's inhibition of dipeptidyl peptidase-IV (DPP-IV) activity.

Tricyclic antidepressants/antipsychotics/anaesthetics. Concomitant use of certain anaesthetic agents, tricyclic antidepressants, and antipsychotics with ACE inhibitors may lead to further reduction in blood pressure.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold preparations. Rarely, when an ACE inhibitor, including perindopril, is used concomitantly with injectable gold preparations (sodium aurothiomalate), reactions similar to those observed with nitrates (flushing, nausea, vomiting, and arterial hypotension) may occur.

Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates. Perindopril may be used concomitantly with acetylsalicylic acid (when used as a thrombolytic), thrombolytics, beta-blockers, and/or nitrates.

Special precautions for use.

Stable ischemic heart disease. If an episode of unstable angina (of any severity) occurred during the first month of perindopril treatment, the benefit-risk ratio should be carefully assessed before deciding on continuing therapy.

Arterial hypotension. Angiotensin-converting enzyme (ACE) inhibitors may cause a reduction in blood pressure. Symptomatic arterial hypotension is rare in patients with uncomplicated arterial hypertension and is more likely to occur in patients with hypovolemia, those receiving diuretics, those on a low-salt diet, patients undergoing dialysis, or patients with diarrhea or vomiting, as well as in patients with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects"). Symptomatic arterial hypotension has been observed in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic arterial hypotension is most likely in patients with more severe degrees of heart failure who are receiving high doses of loop diuretics, have hyponatremia, or have functional renal impairment. Patients at increased risk of symptomatic arterial hypotension should be closely monitored by a physician at the beginning of therapy and during dose titration (see sections "Dosage and administration" and "Undesirable effects"). The same precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication to further use of the drug, which can usually be continued without difficulty after restoration of blood volume and blood pressure elevation.

In some patients with congestive heart failure and normal or low blood pressure, perindopril tert-butylamine may cause additional reduction in systemic arterial pressure. This effect is expected and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, dose reduction or discontinuation of the drug may become necessary.

Valvular stenosis (aortic and mitral valves) / hypertrophic cardiomyopathy. As with other ACE inhibitors, perindopril tert-butylamine should be administered with caution to patients with mitral valve stenosis or left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Renal function impairment. In patients with impaired renal function (creatinine clearance <60 mL/min), the initial dose of perindopril should be adjusted according to creatinine clearance (see section "Dosage and administration"), and subsequently based on the patient's clinical response to treatment. In these patients, monitoring of serum potassium and creatinine concentrations is mandatory.

In patients with symptomatic heart failure, arterial hypotension occurring at the beginning of ACE inhibitor therapy may lead to further deterioration of renal function. In such cases, acute renal failure, usually reversible, has been reported.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, ACE inhibitors may increase blood urea and serum creatinine levels; these effects usually disappear after discontinuation of the drug. The likelihood of such events is particularly high in patients with renal impairment. The presence of renovascular hypertension increases the risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under close medical supervision with low doses and careful titration. Since diuretics may promote the development of arterial hypotension, their use should be discontinued during the first weeks of treatment with perindopril tert-butylamine, and renal function should be monitored.

In some patients with arterial hypertension who had no evidence of renovascular disease before treatment initiation, administration of perindopril, particularly when combined with diuretics, may lead to increased blood urea and serum creatinine levels, which are usually mild and transient. The likelihood of such adverse reactions is higher in patients with impaired renal function. In such cases, dose reduction and/or discontinuation of diuretics and/or perindopril tert-butylamine may be necessary.

Patients undergoing hemodialysis. Anaphylactoid reactions have been reported in patients undergoing dialysis with high-flux membranes while concurrently receiving ACE inhibitor therapy. These patients should either switch to a different type of dialysis membrane or receive antihypertensive therapy from another drug class.

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

Renovascular hypertension. Administration of ACE inhibitors to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney increases the risk of hypotension and renal failure (see section "Contraindications"). Concomitant diuretic therapy may be a contributing factor. Loss of kidney function may manifest with minimal changes in serum creatinine levels even in patients with stenosis of one renal artery.

Hypersensitivity reactions / angioedema. Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported in patients receiving ACE inhibitors, including perindopril (see section "Undesirable effects"). Angioedema may develop at any time during treatment. In such cases, perindopril must be discontinued immediately and the patient should be closely monitored until symptoms completely resolve. When swelling is limited to the face and lips, the condition usually resolves spontaneously, although antihistamines may help relieve symptoms.

Angioedema associated with laryngeal edema may be fatal. Swelling of the tongue, glottis, or larynx may lead to airway obstruction. In such cases, emergency treatment is required. Immediate emergency measures should be taken, which may include administration of adrenaline and/or securing airway patency. The patient must remain under close medical supervision until symptoms have completely and stably resolved.

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

Intestinal angioedema has been rarely reported in patients receiving ACE inhibitor therapy. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C1 esterase inhibitor levels were normal. The diagnosis of intestinal angioedema was established by abdominal computed tomography, ultrasound, or during surgery. Symptoms of angioedema resolved after discontinuation of ACE inhibitors. Intestinal angioedema should not be excluded from the differential diagnosis in patients presenting with abdominal pain while receiving ACE inhibitors.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of Perindopril-Teva. Treatment with Perindopril-Teva may be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Anaphylactic reactions during desensitization therapy. Anaphylactoid reactions, potentially life-threatening, may occur in patients receiving ACE inhibitors during desensitization therapy (e.g., with bee venom-containing preparations). These reactions can be avoided by temporarily discontinuing ACE inhibitors, but may recur if provocation tests are performed carelessly.

Hepatic impairment. Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is not fully understood. Patients who develop jaundice or marked elevations in liver enzymes while receiving ACE inhibitors should discontinue the drug and receive appropriate medical care.

Neutropenia/agranulocytosis/thrombocytopenia/anemia. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other complicating factors. Perindopril should be used with extreme caution in patients with collagenosis, those receiving immunosuppressive therapy, allopurinol, or procainamide, and especially when these factors are combined, particularly in the presence of renal impairment. Severe infections, which may not respond to intensive antibiotic therapy, may develop in some such patients. Periodic monitoring of white blood cell counts is recommended in patients receiving perindopril, and patients should be warned to report any signs of infection (e.g., sore throat, fever).

Racial origin. ACE inhibitors are more likely to cause angioedema in black patients than in patients of other races. As with other ACE inhibitors, perindopril is less effective in reducing blood pressure in black patients with arterial hypertension compared to patients of other races, possibly due to lower plasma renin levels in these patients.

Cough. A dry, persistent cough may occur during ACE inhibitor therapy and resolves after discontinuation of the drug. This ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/anesthesia. During surgery or anesthesia with agents that cause arterial hypotension, perindopril may block the secondary formation of angiotensin II in response to compensatory renin release. Treatment should be discontinued one day before surgery. If arterial hypotension occurs and is considered to be due to this mechanism, circulating blood volume should be increased.

Serum potassium levels. Increased serum potassium levels have been observed in some patients receiving ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal impairment or worsening renal function, age (>70 years), diabetes mellitus, hypoaldosteronism, concomitant illnesses, especially dehydration, acute heart failure, and metabolic acidosis.

ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. This effect is usually minor in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function and/or those receiving potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics (spironolactone, eplerenone, triamterene, or amiloride), other drugs that increase serum potassium (e.g., heparin, trimethoprim, or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor antagonists. Caution is required when using potassium-sparing diuretics and angiotensin receptor antagonists in patients receiving ACE inhibitors. Serum potassium levels and renal function should be monitored in such patients (see section "Interaction with other medicinal products and other forms of interaction").

Hyperkalemia may lead to serious, sometimes fatal, arrhythmias. If treatment with the above-mentioned drugs is necessary, they should be used with caution and regular monitoring of serum potassium levels is required (see section "Interaction with other medicinal products and other forms of interaction").

Patients with diabetes mellitus. In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy.

Lithium. Concomitant use of lithium and perindopril is generally not recommended.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual RAAS blockade by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be performed only under specialist supervision with frequent and careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Primary aldosteronism. Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via inhibition of the renin-angiotensin system. Therefore, use of this medicinal product is not recommended.

Excipients.

Lactose. Since the drug contains lactose, it should not be administered to patients with rare hereditary intolerance to galactose, glucose-galactose malabsorption, or absolute lactase deficiency.

Sodium. This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy. The drug is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, treatment should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on the risk of teratogenic effects associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive; therefore, an increased risk cannot be excluded. It is known that ACE inhibitor use during the second and third trimesters of pregnancy causes fetotoxicity and neonatal toxicity.

If a woman has taken an ACE inhibitor during the second trimester of pregnancy, ultrasound assessment of fetal kidney function and skull bones is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be closely monitored for possible arterial hypotension.

Breastfeeding. Use of perindopril tert-butylamine during breastfeeding is not recommended due to lack of data on its passage into breast milk. During breastfeeding, it is preferable to prescribe alternative treatment with a better-investigated safety profile, especially when nursing a newborn or premature infant.

Effect on reproductive function. There are no data on the effect of perindopril on human reproductive function.

Ability to affect reaction speed when driving or operating machinery.

Perindopril does not have a direct effect on the ability to drive or operate machinery. However, individual reactions related to reduced blood pressure may occur in some patients, especially at the beginning of treatment or when combined with other antihypertensive drugs. As a result, the ability to drive or operate machinery may be impaired.

Dosage and Administration

For oral use.

Perindopril tert-butylamine is recommended to be taken once daily in the morning before meals.

The dose should be individually adjusted for each patient depending on the patient's profile, blood pressure levels, and response to treatment. 5 mg tablets may be divided into two equal doses.

Arterial Hypertension

Perindopril tert-butylamine may be prescribed as monotherapy or in combination with antihypertensive agents of other classes.

The recommended initial dose is 5 mg once daily in the morning.

In patients with high RAAS activity (particularly those with renovascular hypertension, sodium depletion and/or dehydration, cardiac decompensation, or severe arterial hypertension), an excessive reduction in blood pressure may occur after the first dose. The initial recommended dose for such patients is 2.5 mg, and treatment initiation should be under medical supervision.

The dose may be increased to 10 mg once daily after one month of treatment.

Symptomatic hypotension may occur at the beginning of perindopril therapy, especially in patients concurrently taking diuretics. In such patients, perindopril therapy should be initiated cautiously, as they may have a deficiency of water and/or salt.

If possible, diuretic therapy should be discontinued 2–3 days before starting treatment with perindopril tert-butylamine.

For patients with arterial hypertension in whom discontinuation of diuretic therapy is not feasible, perindopril tert-butylamine treatment should be initiated at a dose of 2.5 mg. In these patients, renal function and serum potassium levels should be monitored. Further dose escalation of perindopril tert-butylamine should be based on blood pressure response. If necessary, diuretic therapy may be resumed.

Elderly patients should start treatment with a dose of 2.5 mg, which may be gradually increased to 5 mg after one month of treatment, and then, if necessary, to 10 mg, depending on renal function (see table).

Heart Failure

For patients with heart failure, perindopril tert-butylamine is usually prescribed concomitantly with a potassium-depleting diuretic and/or digoxin and/or a β-blocker. Treatment should be initiated under close medical supervision with an initial dose of 2.5 mg taken in the morning. After 2 weeks, if well tolerated, the dose should be increased to 5 mg once daily. The dose should then be individually adjusted based on the patient's clinical response.

Patients with severe heart failure and other high-risk patients (those with impaired renal function and predisposition to electrolyte imbalances, or those receiving concomitant therapy with diuretics and/or vasodilators) should start treatment under close medical supervision (see section "Special Warnings and Precautions for Use").

Patients at high risk of symptomatic arterial hypotension—specifically those with electrolyte deficiency, with or without hyponatremia, hypovolemia, or those who have received intensive diuretic therapy—should have these conditions corrected, if possible, prior to initiating perindopril. Blood pressure, renal function, and serum potassium levels must be carefully monitored both before and during perindopril treatment (see section "Special Warnings and Precautions for Use").

Prevention of Recurrent Stroke in Patients with Cerebrovascular Disease

The recommended initial dose is 2.5 mg once daily in the morning. After 2 weeks of treatment, the dose should be increased to 5 mg once daily in the morning.

If after 2 weeks of treatment with 5 mg perindopril the patient requires additional blood pressure control, indapamide may be added at a dose of 1 tablet daily. Treatment may be initiated at any time from 2 weeks to several years after the initial stroke.

Prevention of Cardiovascular Complications in Patients with Documented Stable Ischemic Heart Disease

Long-term treatment reduces the risk of myocardial infarction and heart failure. Treatment should be initiated with perindopril 5 mg (once daily in the morning). After 2 weeks, if well tolerated and depending on renal function, the dose should be increased to 10 mg (once daily in the morning).

In elderly patients with documented ischemic heart disease, treatment should be initiated with a dose of 2.5 mg once daily in the morning; after one week, the dose should be increased to 5 mg; after 2 weeks, if well tolerated and depending on renal function, the dose should be increased to 10 mg (once daily) to begin long-term treatment.

Patients with Renal Impairment

Doses for patients with renal impairment should be determined based on creatinine clearance (see table).

Dose Adjustment in Renal Impairment

Creatinine clearance (ml/min)	Recommended dose
ClCR ≥ 60	5 mg once daily
30 < ClCR < 60	2.5 mg once daily
15 < ClCR < 30	2.5 mg every two days
Patients undergoing hemodialysis*
ClCR < 15	2.5 mg on dialysis days

*The dialysis clearance of perindoprilat is 70 mL/min. Patients undergoing hemodialysis should take the dose of perindopril after hemodialysis.

Patients with hepatic impairment

Patients with hepatic impairment do not require dose adjustment.

Children.

The safety and efficacy of perindopril in children have not been established. Therefore, perindopril tosilate is not recommended for use in children (under 18 years of age).

Overdose.

Data regarding perindopril overdose are limited. Possible symptoms associated with overdose of ACE inhibitors include arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough, etc.

In case of overdose, intravenous administration of 0.9% sodium chloride solution (9 mg/mL) is recommended. If arterial hypotension occurs, the patient should be placed in a supine position with low elevation of the head. If possible, infusion of angiotensin II and/or intravenous administration of catecholamines should be performed. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special instructions"). In case of treatment-resistant bradycardia, use of an artificial pacemaker is indicated. Continuous monitoring of vital signs, serum electrolyte concentrations, and creatinine levels is required.

Adverse reactions.

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors. The most commonly reported adverse reactions during clinical trials with perindopril include: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, arterial hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, dysgeusia, dyspepsia, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia.

Adverse reactions are categorized by frequency as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders. Uncommon*: eosinophilia; very rare: decreased haemoglobin and haematocrit, thrombocytopenia, leucopenia/neutropenia, agranulocytosis or pancytopenia, haemolytic anaemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency.

Endocrine disorders. Rare: syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders. Uncommon*: hypoglycaemia, hyperkalaemia (resolves after discontinuation of the drug), hyponatraemia.

Psychiatric disorders. Uncommon: mood changes, sleep disturbances, depression.

Nervous system disorders. Common: headache, dizziness, vertigo, paraesthesia; uncommon*: somnolence, loss of consciousness; very rare: confusion.

Eye disorders. Common: visual disturbances.

Ear and labyrinth disorders. Common: tinnitus.

Cardiac disorders. Uncommon*: palpitations, tachycardia; very rare: arrhythmia, angina pectoris, myocardial infarction (may occur due to excessive reduction in blood pressure in high-risk patients).

Vascular disorders. Common: arterial hypotension and related effects; uncommon*: vasculitis; rare: flushing; very rare: stroke (may occur due to excessive reduction in blood pressure in high-risk patients); frequency not known: Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders. Common: cough, dyspnoea; uncommon: bronchospasm; very rare: eosinophilic pneumonia, rhinitis.

Gastrointestinal disorders. Common: nausea, vomiting, abdominal pain, dysgeusia, dyspepsia, diarrhoea, constipation; uncommon: dry mouth; very rare: pancreatitis.

Hepatobiliary disorders. Very rare: cytolytic or cholestatic hepatitis.

Skin and subcutaneous tissue disorders. Common: rash, pruritus; uncommon: angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria; uncommon*: photosensitivity reactions, pemphigoid, hyperhidrosis; rare: exacerbation of psoriasis; very rare: erythema multiforme.

Musculoskeletal and connective tissue disorders. Common: muscle cramps; uncommon*: arthralgia, myalgia.

Renal and urinary disorders. Uncommon: renal impairment; rare: anuria/oliguria, acute renal failure.

Reproductive system and breast disorders. Uncommon: erectile dysfunction.

General disorders and administration site conditions. Common: asthenia; uncommon*: chest pain, malaise, peripheral oedema, hyperthermia.

Investigations. Uncommon*: increased blood urea nitrogen, increased plasma creatinine; rare: increased plasma liver enzymes and bilirubin.

Injury, poisoning and procedural complications. Uncommon*: falls.

* Frequency of adverse reactions identified from spontaneous reports, calculated based on clinical trial data.

Clinical trials. During the randomization period in the EUROPA study, only serious adverse events were recorded. A small number of patients experienced serious adverse reactions: 16 (0.3%) out of 6122 patients in the perindopril group and 12 (0.2%) out of 6107 patients in the placebo group. In patients receiving perindopril, hypotension was observed in 6 patients, angioedema in 3 patients, and sudden cardiac arrest in 1 patient. Among patients who discontinued the study, 6.0% (n=366) reported cough, arterial hypotension, or any other intolerance to perindopril compared to 2.1% (n=129) of patients receiving placebo.

Shelf life. 28 months.

After first opening of the container – 6 months.

Storage conditions.

Store in a tightly closed container to protect from light and moisture. No special temperature storage conditions are required. Keep out of the reach of children.

Packaging.

30 tablets per container; 1 container per carton.

Prescription category. Prescription only.

Manufacturer.

Pharmaceutical Works Teva Ltd.

Manufacturer's address and location of its business operations.

Unit 1; H-4042 Debrecen, Pallagi str. 13, Hungary.

Date of last review.