Perindopril
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PERINDOPRES® (PERINDOPRES)
Composition:
Active substance: perindopril;
1 tablet contains 4 mg or 8 mg of perindopril tert-butylamine, equivalent to 3.338 mg or 6.676 mg of perindopril;
Excipients: lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide (hydrophobic), magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties: white or almost white tablets, flat cylindrical in shape, with beveled edges and a score line.
Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, single-component. Perindopril. ATC code C09A A04.
Pharmacological Properties.
Pharmacodynamics.
Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (angiotensin-converting enzyme – ACE). The converting enzyme, or kinase, is an exopeptidase that enables the conversion of angiotensin I into the vasoconstrictive angiotensin II, and also promotes 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 plasma renin activity (via a feedback mechanism) and reduces aldosterone secretion. Since ACE inactivates bradykinin, inhibition of ACE also leads to increased activity of the circulating and local kallikrein-kinin system (which also results in activation of the prostaglandin system). This mechanism of action underlies the blood pressure-lowering effect of ACE inhibitors and partially accounts for the occurrence of certain adverse effects (e.g., cough).
Perindopril tert-butylamine exerts its action via its active metabolite – perindoprilat. Other metabolites have no activity in inhibiting ACE under experimental conditions.
Arterial Hypertension.
Perindopril effectively reduces blood pressure in all stages of arterial hypertension: mild, moderate, and severe. Reduction in both systolic and diastolic blood pressure is observed in patients both in supine and standing positions.
Perindopril reduces peripheral vascular resistance, resulting in decreased blood pressure. As a consequence, peripheral blood flow increases without affecting heart rate.
Renal blood flow usually increases, while glomerular filtration rate remains mostly unchanged.
The maximum antihypertensive effect develops within 4–6 hours after a single dose and lasts at least 24 hours: the T/P ratio (minimum/maximum effect over 24 hours) of perindopril ranges from 87% to 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 has an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.
Heart Failure.
In experimental studies, congestive heart failure was induced by ligation of the coronary artery, after which it was demonstrated that Perindopres® reduces myocardial hypertrophy and excessive subendocardial collagen, restores the myosin to isoenzyme ratio, and reduces the incidence of reperfusion arrhythmias.
Perindopril tert-butylamine reduces cardiac workload by decreasing preload and afterload.
Studies involving patients with heart failure have demonstrated:
- reduction in filling pressure of the right and left ventricles;
- reduction in systemic peripheral resistance;
- increase in cardiac index and improvement in cardiac output;
- increase in regional blood flow in myocardial muscle.
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.
Pharmacokinetics.
Absorption.
After oral administration, perindopril is rapidly absorbed, 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 total administered perindopril is detected in blood as the active metabolite – perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five metabolites that are inactive. Peak plasma concentration of perindoprilat is reached within 3–4 hours after administration.
Food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability. Therefore, the daily dose of perindopril tert-butylamine is recommended to be taken once daily in the morning before a meal.
A linear relationship between perindopril dose and its plasma concentration is observed.
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, although 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 plasma concentration is achieved within 4 days of starting treatment.
Special Patient Groups.
Elimination of perindoprilat is slowed in elderly patients and in patients with heart or kidney failure. Dose adjustment is recommended for these patients based on the degree of organ dysfunction (creatinine clearance).
Dialysis clearance of perindoprilat – 70 mL/min.
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 results of the EUROPA study).
Contraindications.
- Hypersensitivity to the active substance or to any of the excipients, or to any other angiotensin-converting enzyme (ACE) inhibitor.
- History of angioedema associated with previous ACE inhibitor therapy.
- Idiopathic or hereditary angioedema.
- Concomitant use with medicinal products containing aliskiren in patients with renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) or in patients with diabetes mellitus (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
- Concomitant use with sacubitril/valsartan. Initiation of Perindopril® must not occur earlier 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").
- Extracorporeal treatment methods 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 solitary functioning kidney (see section "Special precautions for use").
- Pregnancy or planned pregnancy (see section "Use during pregnancy or breast-feeding").
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 use of a single agent acting on the RAAS (see sections "Contraindications" and "Special precautions for use").
Medicinal products increasing the risk of angioedema.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased 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 for use").
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (see section "Special precautions for use").
Medicinal products causing hyperkalemia.
Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Perindopril®. Certain medicinal products or therapeutic classes may cause hyperkalemia, including: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these agents increases the risk of hyperkalemia. Therefore, concomitant use of Perindopril® with these agents is not recommended. If concomitant use is necessary, it should be done with caution and with close monitoring of serum potassium levels.
Concomitant use contraindicated.
Aliskiren. Concomitant use of aliskiren and perindopril is contraindicated in patients with diabetes mellitus and in patients with impaired renal function due to increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality — not recommended in all other patient groups (see section "Special precautions for use").
Extracorporeal treatment methods that lead to blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) and for low-density lipoprotein apheresis with dextran sulfate, increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or an alternative class of antihypertensive agents.
Sacubitril/valsartan. Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as dual inhibition of neprilysin and ACE increases 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 for use").
Concomitant use not recommended.
Aliskiren. Concomitant use of aliskiren and perindopril is not recommended in any patients due to increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality; such concomitant use is contraindicated in patients with diabetes mellitus and in patients with impaired renal function.
Concomitant use of ACE inhibitors and angiotensin receptor blockers. Published 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 agents acting on the renin-angiotensin-aldosterone system. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in selected 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). In patients receiving concomitant co-trimoxazole (trimethoprim/sulfamethoxazole), the risk of hyperkalemia is increased (see section "Special precautions for use").
Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium salts. Hyperkalemia (including fatal cases) may occur, particularly in patients with renal impairment (additive hyperkalemic effect). These medicinal products are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use is necessary, it should be done with caution and with frequent monitoring of plasma potassium levels.
Lithium. Concomitant use of ACE inhibitors with lithium preparations may lead to reversible increases in plasma lithium concentrations and, consequently, increased risk of lithium toxicity. Concomitant use of perindopril with lithium preparations is not recommended. If such combination is necessary, plasma lithium levels must be closely monitored (see section "Special precautions for use").
Concomitant use requiring special attention.
Antidiabetic agents (insulin, oral hypoglycemic agents). Epidemiological studies suggest that concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment.
Baclofen. When used concomitantly, baclofen enhances the antihypertensive effect. Blood pressure monitoring and dose adjustment of antihypertensive agents may be required.
Diuretics. In patients receiving diuretics, particularly those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or increasing salt intake prior to starting perindopril tert-butylamine. Treatment should be initiated with low doses and gradually increased.
In arterial hypertension. If a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (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 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 (12.5–50 mg daily) is used concomitantly with low-dose ACE inhibitors, the following should be considered:
- There is a risk of hyperkalemia (possibly fatal) during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and a loop diuretic, if recommendations for use of this combination are not followed;
- Before initiating such combination, 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.
NSAIDs, including acetylsalicylic acid ≥3 g/day. The antihypertensive effect of ACE inhibitors may be reduced 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 increases the risk of worsening renal function, including acute renal failure, and elevated plasma potassium levels, particularly in patients with a history of renal impairment. Such combinations should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored immediately after starting combination therapy and periodically thereafter.
Racecadotril. ACE inhibitors (e.g., perindopril) may cause angioedema. This risk increases with concomitant use of racecadotril (a medicinal product used to treat acute diarrhea).
mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). In patients receiving concomitant mTOR inhibitors, the risk of angioedema is increased (see section "Special precautions for use").
Concomitant use requiring some attention.
Antihypertensive agents and vasodilators. Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril tert-butylamine. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may lead to additional reduction in blood pressure.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin). In patients receiving a combination of a gliptin and an ACE inhibitor, the risk of angioedema is increased because gliptins reduce dipeptidyl peptidase-IV (DPP-IV) activity.
Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special precautions for use").
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Gold. 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 preparations (sodium aurothiomalate).
Special precautions for use.
Stable ischemic heart disease.
If an episode of unstable angina (of any severity) occurred during the first month of treatment with perindopril, the benefit/risk ratio should be carefully assessed before deciding on continuing therapy.
Arterial hypotension.
ACE inhibitors may cause a reduction in blood pressure. Symptomatic arterial hypotension is less likely in patients with uncomplicated arterial hypertension and is more likely in patients with hypovolemia, those taking diuretics, those on a low-salt diet, patients on dialysis, patients with diarrhea or vomiting, and patients with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). 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 taking high doses of loop diuretics, have a history of hyponatremia, or have functional renal impairment. To reduce the risk of symptomatic arterial hypotension at the beginning of therapy and during dose titration, patients must be under close medical supervision (see sections "Method of administration and dosage" and "Adverse reactions"). 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 horizontal position and, if necessary, receive intravenous 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication for 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 predictable and usually does not require discontinuation of the drug. If arterial hypotension becomes symptomatic, dose reduction or discontinuation of the drug may become necessary.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy.
Like other ACE inhibitors, perindopril tert-butylamine 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 case of renal impairment (creatinine clearance < 60 mL/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section "Method of administration and dosage"), and subsequently based on the patient's response to treatment. For such patients, regular monitoring of serum potassium and creatinine levels is generally recommended (see section "Adverse reactions").
In patients with symptomatic heart failure, arterial hypotension occurring at the beginning of ACE inhibitor therapy may lead to deterioration of renal function, in some cases resulting in acute renal failure, which is usually reversible.
In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, treatment with ACE inhibitors has been associated with increases in blood urea nitrogen and serum creatinine levels, which usually return to normal after discontinuation of treatment. This is particularly relevant for patients with renal impairment. In the presence of concomitant renovascular hypertension, the risk of severe arterial hypotension and renal failure is increased. Treatment of such patients should be initiated under close medical supervision, starting with low doses and cautious dose titration.
Due to these recommendations, diuretic therapy may predispose to arterial hypotension; therefore, diuretics should be discontinued and renal function should be monitored during the first weeks of treatment with perindopril tert-butylamine.
In some patients with arterial hypertension, in whom no renovascular disease was detected prior to treatment initiation, increases in blood urea and serum creatinine have occurred, usually mild and transient, especially when perindopril tert-butylamine was administered concomitantly with a diuretic. However, this is more common in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril tert-butylamine may become necessary.
Patients undergoing hemodialysis.
In patients undergoing hemodialysis using high-flux polyacrylonitrile membranes and receiving concomitant ACE inhibitor therapy, anaphylactoid reactions have occurred. Therefore, a decision should be made regarding the use of another type of dialysis membrane or another class of antihypertensive medicinal products for such patients.
Patients after kidney transplantation.
Experience with the use of perindopril tert-butylamine in patients after recent kidney transplantation surgery is lacking.
Renovascular hypertension.
When ACE inhibitors are prescribed to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, the risk of hypotension and renal failure increases (see section "Contraindications"). Diuretic therapy may be a predisposing factor. Loss of renal function 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 tert-butylamine (see section "Adverse reactions"). 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 complete resolution of symptoms. In isolated cases where swelling is limited to the face and lips, the condition usually improves without treatment. Administration of antihistamine medicinal products may be helpful in relieving symptoms.
Angioedema involving laryngeal edema may be fatal. In cases where swelling involves the tongue, glottis, or larynx, causing airway obstruction, emergency treatment must be initiated immediately, which may include administration of adrenaline and/or securing airway patency. Patients should remain under close medical supervision until complete resolution of symptoms and stabilization of condition.
Patients with a history of angioedema unrelated to ACE inhibitor use are at increased risk of angioedema during ACE inhibitor therapy (see section "Contraindications").
Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients experienced 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 established by abdominal computed tomography or ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema must be excluded during differential diagnosis in patients with abdominal pain who are taking ACE inhibitors.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, 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 neutral endopeptidase (NEP) inhibitors, such as racecadotril, and ACE inhibitors also increases 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 therapy with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) belong to a group at increased risk of developing angioedema, e.g., airway or tongue swelling, with or without respiratory impairment (see section "Interaction with other medicinal products and other forms of interaction").
Caution should be exercised when initiating therapy with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis.
Rarely, life-threatening anaphylactoid reactions may occur in patients taking ACE inhibitors during LDL apheresis using dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.
Anaphylactoid reactions during desensitization therapy.
In patients taking ACE inhibitors, anaphylactoid reactions, which may be life-threatening, may occur during desensitization therapy with medicinal products containing bee venom. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy, but reactions may recur if provocation tests are performed carelessly.
Hepatic impairment.
Rare cases of a syndrome beginning with cholestatic jaundice and progressing to rapidly progressing liver necrosis, sometimes fatal, have been reported in patients receiving ACE inhibitors. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevation of liver enzymes while receiving an ACE inhibitor should discontinue the drug and undergo appropriate medical evaluation and treatment (see section "Adverse reactions").
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 in the absence of other risk factors. Perindopril should be administered with great caution to patients with collagenoses, during immunosuppressive therapy, with allopurinol or procainamide, or in combination with these risk factors, especially in the presence of 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 count is recommended. Patients should be informed that they must report any signs of infection (sore throat, fever).
Racial factor.
ACE inhibitors cause angioedema more frequently 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 these patients.
Cough.
Cough has been reported during therapy with ACE inhibitors.
The cough is non-productive, persistent, and resolves after discontinuation of the drug. Cough associated with ACE inhibitor use should be considered in the differential diagnosis of cough.
Surgery/anesthesia.
The drug may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or receiving anesthetic 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.
Hyperkalemia.
Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, particularly perindopril. ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. In patients with normal renal function, this effect is usually mild. Risk factors for hyperkalemia include: renal impairment, worsening renal function, 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, potassium-containing salt substitutes, or other medicinal products that increase serum potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists or angiotensin receptor blockers. 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 levels. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution, and careful monitoring of serum potassium levels and renal function is required. If concomitant use of perindopril and any of these 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 medicinal products, potassium-containing dietary supplements, or potassium-containing salt substitutes.
Concomitant use of perindopril with potassium-sparing medicinal products or potassium-containing dietary supplements is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Dual blockade of the RAAS.
Reports have been received regarding the occurrence of arterial hypotension, syncope, stroke, hyperkalemia, and renal impairment (including acute renal failure), particularly with concomitant use of medicinal products affecting the RAAS. Combination of an ACE inhibitor (ACEI) with an angiotensin II receptor blocker (ARB) or aliskiren, considering dual blockade of the renin-angiotensin-aldosterone system, is not recommended.
If dual blockade therapy with two RAAS blockers is considered absolutely necessary, it should only occur under specialist supervision and with frequent 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 generally do not respond to antihypertensive drugs acting via suppression of the renin-angiotensin system. Therefore, use of this medicinal product is not recommended in such patients.
Concomitant use with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Excipients.
This medicinal product contains 59.0/118.0 mg monohydrate lactose. Use with caution in patients with diabetes mellitus. Perindopril tert-butylamine is not recommended for patients with rare hereditary galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.
Use during pregnancy or breastfeeding.
Pregnancy. Use of ACE inhibitors is contraindicated during pregnancy (see section "Contraindications"). The drug must not be used in pregnant women or women planning pregnancy. If continued treatment with ACE inhibitors is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive drugs with established safety data during pregnancy. If pregnancy is confirmed during treatment, the drug must 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, a slight increase in risk cannot be excluded. It is known that ACE inhibitor use during the second and third trimesters of pregnancy leads to fetotoxicity and neonatal toxicity.
If a woman took an ACE inhibitor during the second trimester of pregnancy, ultrasound evaluation of fetal renal function and skull ossification is recommended. Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored due to the potential for arterial hypotension.
Breastfeeding. Perindopril tert-butylamine is not recommended during breastfeeding due to lack of data on its passage into breast milk. During breastfeeding, alternative treatment with a better-studied safety profile should be considered, especially during breastfeeding of a newborn or premature infant.
Fertility. No effect on reproductive capacity or fertility has been observed.
Ability to influence reaction speed when driving or operating machinery.
Perindopril tert-butylamine does not have a direct effect on the ability to drive or operate machinery. However, individual reactions associated with reduced blood pressure may occur in some patients, particularly at the beginning of treatment or during concomitant use with other antihypertensive medicinal products. As a result, the ability to drive or operate machinery may be reduced.
Dosage and Administration
For oral use.
Perindopres® 4 mg and 8 mg tablets may be divided in half to achieve doses of 2 mg and 4 mg.
The tablets should be taken once daily in the morning before meals.
Dosage should be individualized according to blood pressure levels (see section "Special Instructions").
Arterial hypertension.
Perindopril tert-butylamine may be administered 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 (particularly patients with renovascular hypertension, fluid and electrolyte imbalance, cardiac decompensation, or severe hypertension) may experience excessive reduction in arterial pressure after the first dose. Such patients should start treatment with a dose of 2 mg under medical supervision.
The dose may be increased to 8 mg once daily after one month of treatment.
Symptomatic arterial hypotension may occur at the beginning of perindopril tert-butylamine therapy, especially in patients concurrently receiving diuretics. Treatment with perindopril should be initiated cautiously in such patients due to possible volume and/or salt depletion.
If possible, diuretic therapy should be discontinued 2–3 days before initiating perindopril tert-butylamine treatment (see section "Special Instructions").
For patients with arterial hypertension who cannot discontinue diuretics, treatment should be initiated with a dose of 2 mg. Renal function and serum potassium levels should be monitored in these patients. Subsequent 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 mg, which may be increased to 4 mg after one month of treatment, and then, if necessary, to 8 mg, depending on renal function (see Table 1).
Heart failure.
In 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 morning dose of 2 mg. After 2 weeks, if well tolerated, the dose should be increased to 4 mg once daily. Dosage should be individualized according to the patient's clinical status.
Patients with severe heart failure and other high-risk patients (patients with impaired renal function and tendency to electrolyte disturbances, patients receiving concomitant therapy with diuretics and/or vasodilators) should start treatment under close medical supervision (see section "Special Instructions").
In patients at high risk of symptomatic arterial hypotension—such as those with electrolyte deficiency, with or without hyponatremia, those with hypovolemia, or those receiving intensive diuretic therapy—correction of these conditions should be attempted, if possible, prior to initiating treatment. Arterial pressure, renal function, and serum potassium levels must be closely monitored both before and during treatment (see section "Special Instructions").
Prevention of recurrent stroke in patients with cerebrovascular disease.
The recommended initial dose is 2 mg (½ tablet of Perindopres® 4 mg) once daily in the morning. After 2 weeks of treatment, the dose should be increased to 4 mg (1 tablet of Perindopres® 4 mg) once daily in the morning.
If after 2 weeks of treatment with Perindopres® 4 mg the patient requires additional blood pressure control, indapamide may be added at a dose of 1 tablet daily. Treatment may be initiated anytime from 2 weeks to several years after the initial stroke.
Prevention of cardiovascular complications in patients with documented stable ischemic heart disease.
Treatment should be initiated with Perindopres® 4 mg (1 tablet once daily in the morning). After 2 weeks, if well tolerated and depending on renal function, the dose should be increased to 8 mg.
Elderly patients should start treatment with a dose of 2 mg (½ tablet of Perindopres® 4 mg) once daily in the morning; after one week, the dose should be increased to 4 mg (1 tablet of Perindopres® 4 mg); after 2 weeks, depending on renal function, the dose should be increased to 8 mg (Perindopres® 8 mg, 1 tablet daily) (see Table 1). Dose escalation is possible only if the previous dose is well tolerated.
Special patient groups. Dosing for patients with renal impairment should be based on creatinine clearance as shown in Table 1.
Table 1.
Dosage adjustment in renal impairment
| Creatinine clearance (ml/min) |
Recommended dosage |
| ClCR ≥ 60 |
4 mg once daily |
| 30 < ClCR < 60 |
2 mg once daily |
| 15 < ClCR < 30 |
2 mg every other day |
| Patients undergoing hemodialysis1 |
|
| ClCR < 15 |
2 mg on dialysis day |
1The dialysis clearance of perindoprilate is 70 mL/min. The dose should be administered to patients undergoing hemodialysis after the hemodialysis session.
Patients with hepatic impairment.
Dose adjustment of the medicinal product is not required in patients with hepatic impairment (see sections "Special warnings and precautions for use" and "Pharmacokinetics").
Children.
The efficacy and safety of use in children have not been studied; therefore, perindopril tert-butylamine is not recommended for use in pediatric patients.
Overdose.
There is insufficient information regarding perindopril overdose. Symptoms associated with overdose of ACE inhibitors may 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 head elevation. Infusion of angiotensin II and/or intravenous administration of catecholamines should be provided if possible. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special warnings and precautions for use"). In cases of treatment-resistant bradycardia, implantation of an artificial pacemaker may be indicated. Continuous monitoring of vital signs, serum electrolyte concentrations, and serum creatinine 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, paraesthesia, vertigo, visual disturbances, tinnitus, arterial hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, skin rash, muscle cramps, asthenia.
Patients should be advised to consult a physician if signs of anuria/oliguria, hot flushes, depression, darkening of urine, nausea, vomiting, muscle cramps, or confusion occur, as these may indicate the development of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
The adverse reactions listed below have been observed during clinical trials and the post-marketing period with perindopril. The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10,000, <1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).
Table 2.
| System organ classes according to MedDRA |
Adverse reactions |
Frequency |
| Eye disorders |
Visual disturbance |
Common |
| Ear and labyrinth disorders |
Tinnitus |
Common |
| Respiratory, thoracic and mediastinal disorders |
Cough |
Common |
| Dyspnoea |
Common |
|
| Bronchospasm |
Uncommon |
|
| Eosinophilic pneumonia |
Rare |
|
| Rhinitis |
Rare |
|
| Gastrointestinal disorders |
Abdominal pain |
Common |
| Constipation |
Common |
|
| Diarrhoea |
Common |
|
| Disturbance of taste (dysgeusia) |
Common |
|
| Dyspepsia |
Common |
|
| Nausea |
Common |
|
| Vomiting |
Common |
|
| Dry mouth |
Uncommon |
|
| Pancreatitis |
Rare |
|
| Hepatobiliary disorders |
Cytolytic or cholestatic hepatitis (see section "Special precautions") |
Rare |
| Renal and urinary disorders |
Renal failure |
Uncommon |
| Acute renal failure |
Rare |
|
| Anuria/oliguria |
Very rare |
|
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Very rare |
| Metabolism and nutrition disorders |
Hypoglycaemia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction") |
Uncommon* |
| Hyperkalaemia, which resolves after discontinuation of the medicinal product (see section "Special precautions") |
Uncommon* |
|
| Hyponatraemia |
Uncommon* |
|
| Nervous system disorders |
Dizziness |
Common |
| Headache |
Common |
|
| Paraesthesia |
Common |
|
| Vertigo |
Common |
|
| Somnolence |
Uncommon* |
|
| Syncope |
Uncommon* |
|
| Confusion |
Rare |
|
| Psychiatric disorders |
Mood changes |
Uncommon |
| Sleep disorders |
Uncommon |
|
| Depression |
Uncommon |
|
| Cardiac disorders |
Palpitations |
Uncommon* |
| Tachycardia |
Uncommon* |
|
| Angina pectoris (see section "Special precautions") |
Rare |
|
| Arrhythmia |
Rare |
|
| Myocardial infarction may occur due to excessive reduction in blood pressure in patients with high risk (see section "Special precautions") |
Rare |
|
| Vascular disorders |
Hypotension (and related symptoms) |
Common |
| Vasculitis |
Uncommon* |
|
| Stroke may occur due to excessive reduction in blood pressure in patients with high risk (see section "Special precautions") |
Rare |
|
| Hot flushes |
Very rare |
|
| Raynaud's phenomenon |
Frequency not known |
|
| Blood and lymphatic system disorders |
Eosinophilia |
Uncommon* |
| Agranulocytosis or pancytopenia |
Rare |
|
| Decreased haemoglobin and haematocrit levels |
Rare |
|
| Leucopenia/neutropenia |
Rare |
|
| Haemolytic anaemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency (see section "Special precautions") |
Rare |
|
| Thrombocytopenia |
Rare |
|
| Immune system disorders |
Hypersensitivity reactions, including anaphylactoid reactions (see section "Special precautions") |
Uncommon |
| Skin and subcutaneous tissue disorders |
Pruritus |
Common |
| Skin rashes |
Common |
|
| Urticaria (see section "Special precautions") |
Uncommon |
|
| Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (see section "Special precautions") |
Uncommon |
|
| Photosensitivity reactions |
Uncommon* |
|
| Pemphigoid |
Uncommon* |
|
| Hyperhidrosis |
Uncommon |
|
| Worsening of psoriasis symptoms |
Very rare* |
|
| Multiform erythema |
Rare |
|
| Musculoskeletal and connective tissue disorders |
Muscle cramps |
Common |
| Arthralgia |
Uncommon* |
|
| Myalgia |
Uncommon* |
|
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
| General disorders |
Asthenia |
Common |
| Chest pain |
Uncommon* |
|
| Malaise |
Uncommon* |
|
| Peripheral oedema |
Uncommon* |
|
| Hyperthermia |
Uncommon* |
|
| Laboratory findings |
Increased blood urea nitrogen |
Uncommon* |
| Elevated plasma creatinine |
Uncommon* |
|
| Elevated plasma bilirubin levels |
Very rare |
|
| Elevated liver enzymes |
Very rare |
|
| Injury, poisoning and procedural complications |
Falls |
Uncommon* |
*The frequency of adverse reactions identified from spontaneous reports is calculated based on clinical trial data.
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions after marketing authorization of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.
Packaging.
10 tablets in a blister pack; 3 blisters per carton.
Prescription status. Prescription only.
Manufacturer. JSC "Pharmaceutical Company "Darnytsia".
Manufacturer's address and location of operations.
13, Borispilska Street, Kyiv, 02093, Ukraine.