Prenesa®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Prenessa® (Prenessa®)

Composition:

Active substance: perindopril;

1 tablet contains 2 mg or 4 mg or 8 mg of perindopril as the tert-butylamine salt;

Excipients: calcium chloride hexahydrate, lactose monohydrate, crospovidone, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

2 mg tablets: white to almost white, round, slightly biconvex, with bevelled edges;

4 mg tablets: white to almost white, oval, slightly biconvex, with bevelled edges and a notch on one side;

8 mg tablets: white to almost white, round, slightly biconvex, with bevelled edges and a notch on one side.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kininase, is an exopeptidase that enables the conversion of angiotensin I into vasoconstrictive angiotensin II, and also causes the breakdown of the vasodilator bradykinin into inactive heptapeptide. Inhibition of ACE leads to a decrease in angiotensin II concentration in blood plasma, which increases serum renin activity (via feedback mechanism) and reduces aldosterone secretion. Since ACE inactivates bradykinin, inhibition of ACE also leads to increased activity of circulating and local kallikrein-kinin system (and thus also leads to activation of the prostaglandin system). This mechanism of action underlies the antihypertensive effect of ACE inhibitors and partially accounts for the occurrence of certain adverse effects (e.g., cough).

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

Pharmacodynamic Effect

Arterial Hypertension

Perindopril effectively reduces arterial blood pressure at 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 usually increases, while glomerular filtration rate (GFR) typically remains unchanged.

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

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

Upon discontinuation of perindopril, there is no rebound effect.

Perindopril reduces left ventricular hypertrophy.

Clinical studies have demonstrated that perindopril has vasodilatory properties. It improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries.

Combination therapy with a thiazide diuretic produces 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 was induced by coronary artery ligation, and it was demonstrated that perindopril reduces myocardial hypertrophy and excessive subendocardial collagen, restores the myosin to isoenzyme ratio, and reduces the incidence of reperfusion arrhythmias.

Perindopril tert-butylamine eases the workload of the heart by reducing both preload and afterload.

Studies involving patients with heart failure have demonstrated:

• reduction in filling pressure of the right and left ventricles,
• reduction in systemic vascular resistance,
• increase in cardiac index and improvement in cardiac output,
• increase in regional myocardial blood flow.

In comparative studies, initial administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction 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 trial that lasted 4 years. A total of 12,218 patients aged 18 years and older were randomized: 6,110 patients received 8 mg of perindopril and 6,108 patients received placebo. The study included patients with confirmed IHD 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 mortality, non-fatal myocardial infarction, and/or cardiac arrest with successful resuscitation. Treatment with perindopril 8 mg once daily resulted in a statistically significant absolute reduction in 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.

In an open-label clinical study without a comparator group, 62 children aged 2 to 15 years with glomerular filtration rate >30 mL/min/1.73 m² received perindopril at a mean dose of 0.07 mg/kg. The dose was individually adjusted, increased up to a maximum of 0.135 mg/kg/day depending on patient profile and blood pressure response to treatment. Fifty-nine patients participated in the study for 3 months, and 36 patients continued treatment for at least 24 months (mean study duration was 44 months). Systolic and diastolic blood pressure remained stable (from study entry to last visit) in patients previously treated with other antihypertensive agents and decreased in those not previously treated. More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last study visit. The safety profile in children was consistent with the known safety profile of perindopril.

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

Concomitant use of ACE inhibitors and angiotensin II receptor blockers was investigated in two large-scale randomized controlled trials [ONTARGET (Ongoing Telmisartan Alone and Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].

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

The studies did not demonstrate significant beneficial effects on kidney and/or cardiovascular disease outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings 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 (Aliskiren Trial in Type 2 Diabetes with Cardiovascular and Renal Disease Endpoints) was a study assessing 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 and cardiovascular disease. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality, incidence of stroke, and reports of adverse events and serious complications (hyperkalemia, arterial hypotension, and impaired renal function) were more frequent in the aliskiren group compared to the placebo group.

Pharmacokinetics

Absorption

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

Perindopril is a prodrug. 27% of the total administered perindopril is detected in blood as the active metabolite—perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five inactive metabolites. Peak serum concentration of perindoprilat is reached 3–4 hours after administration.

Food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability. Therefore, the daily dose of perindopril should be taken once daily in the morning before a meal.

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. Perindoprilat binding to plasma proteins is 20%, primarily to ACE, but this value is dose-dependent.

Elimination

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

Special Patient Groups

Elderly

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

Renal Impairment

Dose adjustment is recommended for patients with renal impairment based on the degree of impairment (creatinine clearance). Dialysis clearance of perindoprilat is 70 mL/min.

Hepatic Impairment

Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of perindopril is reduced by half. However, the amount of perindoprilat formed is not reduced. Therefore, dose adjustment is not required in these patients.

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 myocardial infarction and heart failure (based on the EUROPA study results).

Contraindications.

• Hypersensitivity to the active substance or to any other component of the medicinal product, or to other ACE inhibitors.
• History of angioedema associated with previous treatment with ACE inhibitors (see section "Special precautions").
• Hereditary or idiopathic angioedema.
• Concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
• Pregnancy or planned pregnancy.
• Concomitant use with sacubitril/valsartan therapy (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
• Extracorporeal treatments leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
• Significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Clinical data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single agent acting on the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special precautions").

Medicinal products causing hyperkalemia

Certain medicinal products or therapeutic classes may lead to hyperkalemia, including: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, and trimethoprim. Concomitant use of these medicinal products increases the risk of hyperkalemia.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren

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

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

Sacubitril/valsartan

Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as dual inhibition of neprilysin and ACE may increase the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions").

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

Aliskiren

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

Concomitant use of ACE inhibitors and angiotensin receptor blockers

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

Estramustine

Increased risk of adverse reactions such as angioedema.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

In patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole), there is a possible increased risk of hyperkalemia (see section "Special precautions").

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

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

Lithium

Concomitant use of ACE inhibitors with lithium preparations may result in reversible increases in serum lithium concentration and, consequently, an increased risk of lithium toxicity. The use of perindopril with lithium preparations is not recommended. If such combination therapy is deemed necessary, serum lithium levels must be closely monitored (see section "Special precautions").

Concomitant use requiring special attention

Antidiabetic agents (insulin, oral hypoglycemic agents)

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

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

Diuretics not containing potassium

In patients receiving diuretics, especially those with impaired 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 increasing 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 deficiency, the diuretic should be discontinued before initiating 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 congestive heart failure on background diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.

In any case, renal function (creatinine levels) 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 ACE inhibitors, the following should be observed:

• Failure to follow recommendations for use of this combination may result in hyperkalemia (potentially fatal) in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and a loop diuretic;
• Before initiating such combination therapy, absence of hyperkalemia and renal impairment should be confirmed;
• Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

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

The antihypertensive effect of ACE inhibitors may be attenuated when used concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, or nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including the development of acute renal failure, and elevated plasma potassium levels, particularly in patients with a history of renal impairment. This combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored shortly after initiating combination therapy and periodically thereafter.

Racecadotril

ACE inhibitors (e.g., perindopril) are known to induce angioedema. This risk may be increased when used concomitantly with racecadotril (a medicinal product used for the treatment of acute diarrhea).

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

Patients receiving mTOR inhibitors concomitantly may have an increased risk of angioedema (see section "Special precautions").

Concomitant use requiring some attention

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

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

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

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold compounds: nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and arterial hypotension) are rarely observed in patients receiving ACE inhibitors, including perindopril, concomitantly with injectable gold compounds (sodium aurothiomalate).

Special precautions for use.

Before and during treatment with the medicinal product, monitoring of blood pressure, renal function, and plasma potassium levels is required.

Stable ischaemic heart disease (IHD)

If an episode of unstable angina (of any severity) occurs during the first month of treatment with perindopril, careful consideration of the risk-benefit ratio should be undertaken before deciding on continuation of therapy.

Arterial hypotension

ACE inhibitors may cause a reduction in blood pressure. Symptomatic arterial hypotension is less common in patients with uncomplicated arterial hypertension and is more likely to occur in patients with hypovolaemia, those receiving diuretics, those on a low-salt diet, patients undergoing dialysis, patients with diarrhoea or vomiting, or 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 is more likely 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 hyponatraemia, or have functional renal impairment. To reduce the risk of symptomatic arterial hypotension during initiation of therapy and dose titration, patients should be under close medical supervision (see sections "Posology and method of administration" and "Undesirable effects"). The same precautions apply to patients with ischaemic heart disease or cerebrovascular disease, 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 with low head elevation and, if necessary, receive an intravenous infusion of 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication for further treatment, which can usually be continued without difficulty after restoration of blood volume and normalization of blood pressure.

In some patients with congestive heart failure and normal or low blood pressure, perindopril may cause a further 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.

Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy

Like other ACE inhibitors, perindopril should be administered with caution in patients with mitral valve stenosis or left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Renal impairment

In patients with renal impairment (creatinine clearance < 60 mL/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section "Posology and method of administration") and subsequently based on the patient's response to treatment. Monitoring of potassium and creatinine levels is standard practice in such patients (see section "Undesirable effects").

In patients with symptomatic heart failure, arterial hypotension occurring at the beginning of ACE inhibitor therapy may lead to deterioration in renal function, and in some cases to acute renal failure, which is usually reversible.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, increases in serum urea and creatinine levels have been observed during ACE inhibitor therapy, which usually return to normal after discontinuation of treatment. This is particularly relevant in patients with pre-existing renal impairment. The risk of severe arterial hypotension and renal failure is increased in patients with concomitant renovascular hypertension. Such patients should be started on treatment under close medical supervision with low doses and cautious dose titration. Since diuretic therapy may predispose to arterial hypotension, diuretics should be discontinued and renal function monitored during the first weeks of perindopril treatment.

In some patients with arterial hypertension without previously diagnosed renovascular disease, increases in serum urea and creatinine levels have been observed, usually mild and transient, particularly when used concomitantly with diuretics. However, this is more common in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril may become necessary.

Patients undergoing haemodialysis

In patients undergoing haemodialysis with high-flux polyacrylonitrile membranes and receiving concomitant ACE inhibitor therapy, anaphylactoid reactions have occurred. Therefore, for such patients, a decision should be made regarding the use of an alternative type of dialysis membrane or an alternative class of antihypertensive agents.

Patients after kidney transplantation

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

Renovascular hypertension

The use of ACE inhibitors in 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 predisposing factor. Renal dysfunction may manifest as minimal changes in serum creatinine levels even in patients with stenosis of one renal artery.

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril (see section "Undesirable effects"). This may occur at any time during treatment. In such cases, the drug must be discontinued immediately and appropriate monitoring of the patient should be instituted until symptoms have completely resolved. In isolated cases where swelling is limited to the face and lips, the condition usually improves without treatment. Antihistamines may be helpful in relieving symptoms.

Angioedema involving laryngeal swelling may be fatal. In cases where swelling involves the tongue, glottis, or larynx, causing airway obstruction, emergency treatment is required, which may include administration of adrenaline and/or securing airway patency. Patients should remain under close medical supervision until symptoms have completely resolved and their condition is stabilized.

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

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. 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 levels were normal. The diagnosis of intestinal angioedema was confirmed by computed tomography of the abdomen, ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain in patients receiving ACE inhibitors.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. After discontinuation of sacubitril/valsartan, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Concomitant use of other neutral endopeptidase inhibitors (NEP) (e.g., racecadotril) with ACE inhibitors may also increase the risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, a careful benefit-risk assessment should be performed before initiating NEP inhibitor therapy (e.g., racecadotril) in patients receiving perindopril.

Patients receiving concomitant mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) may belong to a group at increased risk of angioedema (e.g., airway or tongue swelling, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction").

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

Rarely, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Anaphylactoid reactions during desensitization therapy

Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy with agents containing bee venom. These reactions can be avoided by temporarily discontinuing the ACE inhibitor, but may recur if provocation tests are performed carelessly.

Hepatic impairment

Rare cases of a syndrome beginning with cholestatic jaundice and progressing rapidly to fulminant hepatic necrosis, sometimes fatal, have been reported during ACE inhibitor therapy. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes during ACE inhibitor therapy should discontinue the drug and receive appropriate medical evaluation and treatment (see section "Undesirable effects").

Neutropenia/agranulocytosis/thrombocytopenia/anaemia

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anaemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, during immunosuppressive therapy, allopurinol, or procainamide therapy, or in combination of these risk factors, especially in the presence of existing renal impairment. Serious infections, occasionally unresponsive to intensive antibiotic therapy, may develop in such patients. If perindopril is prescribed to such patients, periodic monitoring of white blood cell counts is recommended, and patients should be advised to report any signs of infection (e.g., sore throat, fever).

Racial characteristics

ACE inhibitors are more likely to cause angioedema in black patients than in patients of other races. Like other ACE inhibitors, perindopril is less effective in reducing blood pressure in black patients than in patients of other races, possibly due to lower plasma renin levels in hypertensive black patients.

Cough

Cough has been reported during therapy with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of chronic cough.

Surgery/anesthesia

Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or receiving anaesthetic agents that cause hypotension. The drug should be discontinued one day before surgery. If arterial hypotension occurs and is considered to be due to this mechanism, the patient's condition can be normalized by increasing circulating blood volume.

Hyperkalaemia

Elevated serum potassium concentrations have been observed in some patients receiving ACE inhibitors, including perindopril. Risk factors for hyperkalaemia include renal impairment, worsening renal function, advanced age (over 70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes; or patients receiving other drugs that increase serum potassium (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole).

The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalaemia may result in serious, sometimes fatal, arrhythmias. If concomitant use of perindopril with any of the above-mentioned agents is considered necessary, they should be used with caution and with frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Patients with diabetes mellitus

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Lithium

Concomitant use of lithium and perindopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes

Concomitant use of perindopril with potassium-sparing agents or potassium-containing dietary supplements is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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, hyperkalaemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual blockade therapy with two RAAS inhibitors is considered absolutely necessary, it should be performed only under specialist supervision with frequent and careful monitoring of renal function, electrolytes, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via inhibition of the RAAS. Therefore, the use of this medicinal product is not recommended.

Excipients

The medicinal product contains lactose; therefore, perindopril is not recommended for patients with rare hereditary conditions of galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp-type lactase deficiency.

Use during pregnancy or breastfeeding

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

Women planning pregnancy should be switched to an alternative antihypertensive therapy with a well-established safety profile in pregnancy. ACE inhibitor therapy must be discontinued immediately upon confirmation of pregnancy, and alternative therapy should be initiated if necessary.

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive, but a slight increase in risk cannot be excluded. Except when continuation of ACE inhibitor therapy is considered essential, women planning pregnancy should be prescribed alternative antihypertensive therapy with a well-established safety profile during pregnancy.

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

It is known that ACE inhibitor therapy during the second and third trimesters of pregnancy causes foetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). If ACE inhibitors have been used from the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull ossification. Newborns whose mothers received ACE inhibitors should be closely monitored for hypotension (see sections "Contraindications" and "Special precautions for use").

Breastfeeding: Perindopril is not recommended during breastfeeding due to lack of data on its excretion in breast milk. During breastfeeding, alternative therapy with a better-established safety profile is preferred, especially when nursing a newborn or preterm infant.

Fertility: No effect on reproductive capacity or fertility has been observed.

Ability to drive and use machines

Perindopril has no direct effect on the ability to drive or operate machinery. However, individual reactions related to a reduction in blood pressure may occur in some patients, particularly at the beginning of treatment or during concomitant use with other antihypertensive agents. As a result, the ability to react when driving or operating machinery may be reduced.

Method of Administration and Dosage

The medication is intended for oral use in adults.

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

The dose should be individually adjusted for each patient depending on the indication, patient profile, and blood pressure levels (see section "Special Warnings and Precautions for Use").

Arterial Hypertension

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

The recommended initial dose is 4 mg once daily in the morning.

Patients with high activity of the renin-angiotensin-aldosterone system (RAAS) (particularly those with renovascular hypertension, fluid and electrolyte imbalances, heart failure, severe arterial hypertension, or elderly patients) are at risk of developing a sudden drop in blood pressure (first-dose hypotension). Therefore, an initial dose of 2 mg under medical supervision, possibly in a hospital setting, is recommended.

After 1 month of treatment, the dose may be increased to the maximum dose of 8 mg once daily.

Symptomatic hypotension may occur at the beginning of perindopril therapy, especially in patients taking diuretics. Such patients should be treated with caution due to possible volume and/or salt depletion. If possible, diuretic therapy should be discontinued 2–3 days before initiating perindopril (see section "Special Warnings and Precautions for Use").

For patients with arterial hypertension in whom diuretic therapy cannot be discontinued, treatment with perindopril should be initiated at a dose of 2 mg once daily. Renal function and serum potassium levels should be monitored in these patients. Further dose escalation of perindopril should be based on blood pressure response, and diuretic therapy may be resumed if necessary.

In elderly patients, treatment should be initiated at a dose of 2 mg, which may be increased to 4 mg after 1 month of treatment, and subsequently, if necessary and depending on renal function, up to 8 mg (see table below).

Heart Failure

In patients with heart failure, perindopril 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 mg taken in the morning. After 2 weeks, if the drug is well tolerated, the dose may be increased to 4 mg once daily. The dose should be individually adjusted according to the patient's clinical status.

Treatment of patients with severe heart failure and other high-risk patients (those with impaired renal function and predisposition to electrolyte disturbances; patients receiving concomitant therapy with diuretics and/or vasodilators) should be initiated under close medical supervision (see section "Special Warnings and Precautions for Use").

Patients at high risk of symptomatic hypotension, particularly 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 should be carefully monitored both before and during treatment (see section "Special Warnings and Precautions for Use").

Prevention of Recurrent Stroke in Patients with Cerebrovascular Disease

The initial dose of perindopril in patients with a history of cerebrovascular disease is 2 mg once daily in the morning. After 2 weeks of treatment, the dose should be increased to 4 mg daily and maintained for another 2 weeks before initiating indapamide.

Careful monitoring of blood pressure is required.

Perindopril may be prescribed in combination with indapamide, or treatment may be switched to a fixed-dose combination of perindopril and indapamide, either before or during perindopril therapy.

Treatment should be initiated within 2 weeks to several years after the initial stroke.

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

The initial dose of perindopril is 4 mg once daily in the morning. After 2 weeks, provided the drug is well tolerated and depending on renal function, the dose should be increased to 8 mg once daily.

In elderly patients, treatment should be initiated at a dose of 2 mg once daily in the morning for the first week, followed by 4 mg once daily during the second week. After 2 weeks, provided the drug is well tolerated and depending on renal function, the dose should be increased to 8 mg. Dose escalation is only permitted if the previous dose was well tolerated.

Patients with Renal Impairment

Dosing in patients with renal insufficiency depends on creatinine clearance.

Creatinine clearance (mL/min)	Recommended dose
ClCr ≥ 60	4 mg/day
30 < ClCr < 60	2 mg/day
15 < ClCr < 30	2 mg every other day
Patients on hemodialysis *, ClCr < 15	2 mg on dialysis day

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

Patients with hepatic impairment

Patients with hepatic impairment do not require dose adjustment (see sections "Pharmacokinetics" and "Special precautions").

Children.

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

Overdose.

Information regarding perindopril overdose is limited. Symptoms associated with overdose of ACE inhibitors may include: arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough.

In case of overdose, intravenous administration of 0.9% (9 mg/mL) sodium chloride solution is recommended. If arterial hypotension occurs, the patient should be placed in a supine position with low head elevation. If possible, infusion of angiotensin II and/or intravenous administration of catecholamines should be provided. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special precautions"). 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 necessary.

Adverse Reactions

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors.

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

The following adverse reactions have been observed during clinical trials and post-marketing use of perindopril, with the following frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Body Systems	Adverse Reactions	Frequency
Blood and lymphatic system	Eosinophilia	Uncommon*
	Leukopenia/neutropenia	Very rare
	Agranulocytosis or pancytopenia	Very rare
	Decreased hemoglobin and hematocrit levels	Very rare
	Thrombocytopenia	Very rare
	Hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency1)	Very rare
Endocrine system	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)	Uncommon
Metabolism and nutrition disorders	Hyperkalemia1), reversible after discontinuation of the drug	Uncommon*
	Hypnatremia	Uncommon*
	Hypoglycemia2)	Uncommon*
Psychiatric disorders	Mood disturbances	Uncommon
	Sleep disturbances	Uncommon
	Depression	Uncommon
Nervous system	Dizziness	Common
	Headache	Common
	Somnolence	Uncommon*
	Paresthesia	Common
	Fainting	Uncommon*
	Confusion	Very rare
	Vertigo	Common
Eye disorders	Visual disturbances	Common
Ear and labyrinth disorders	Tinnitus	Common
Cardiac disorders	Palpitations	Uncommon*
	Tachycardia	Uncommon*
	Angina pectoris1)	Very rare
	Myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients1)	Very rare
	Arrhythmia	Very rare
Vascular disorders	Stroke may occur due to excessive reduction in blood pressure in high-risk patients	Very rare
	Raynaud's phenomenon	Unknown
	Hypotension (and associated symptoms)	Common
	Vasculitis	Uncommon*
	Flushing	Uncommon
Respiratory, thoracic and mediastinal disorders	Cough	Common
	Dyspnea	Common
	Bronchospasm	Uncommon
	Eosinophilic pneumonia	Very rare
	Rhinitis	Very rare
Hepatobiliary disorders	Cytolytic or cholestatic hepatitis1)	Very rare
Gastrointestinal disorders	Abdominal pain	Common
	Nausea	Common
	Vomiting	Common
	Dyspepsia	Common
	Diarrhea	Common
	Constipation	Common
	Taste disturbances (dysgeusia)	Common
	Dry mouth	Uncommon
	Pancreatitis	Very rare
Skin and subcutaneous tissue disorders	Rash	Common
	Pruritus	Common
	Hyperhidrosis	Uncommon
	Worsening of psoriasis symptoms	Uncommon
	Pemphigoid	Uncommon*
	Angioedema of the face, limbs, lips, mucous membranes, tongue, glottis and/or larynx, urticaria1)	Uncommon
	Photosensitivity reactions	Uncommon*
	Multiform erythema	Very rare
Musculoskeletal and connective tissue disorders	Muscle cramps	Common
	Arthralgia	Uncommon*
	Myalgia	Uncommon*
Renal and urinary disorders	Renal failure	Uncommon
	Acute renal failure	Uncommon
	Anuria/oliguria	Uncommon
Reproductive system and breast disorders	Erectile dysfunction	Uncommon
General disorders	Peripheral edema	Uncommon*
	Chest pain	Uncommon*
	Asthenia	Common
	Malaise	Uncommon*
	Hyperthermia	Uncommon*
Laboratory investigations	Increased blood urea levels	Uncommon*
	Increased blood creatinine levels	Uncommon*
	Increased blood bilirubin levels	Uncommon
	Elevated liver enzymes	Uncommon
Injury, poisoning and procedural complications	Falls	Uncommon*

*Frequency was calculated based on clinical trial data for adverse reactions identified from spontaneous reports.

1. See section "Special warnings and precautions for use".
2. See sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction".

Clinical trials

During the randomization period of the EUROPA study, information was collected only on serious adverse reactions. 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. 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 the study due to adverse events: 6.0% (n = 366) reported cough, arterial hypotension, or any other intolerance to perindopril, compared to 2.1% (n = 129) of patients receiving placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through 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. Keep out of the reach and sight of children.

Packaging. 10 tablets in a blister; 3, 6, or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.