Perindopril 10 krka
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Perindopril 5 KRKA Perindopril 10 KRKA (Perindopril 5 KRKA Perindopril 10 KRKA)
Composition:
Active substance: perindopril;
1 tablet contains 5 mg or 10 mg of perindopril arginine, corresponding to 3.395 mg or 6.790 mg of perindopril, respectively;
Excipients: calcium chloride, hexahydrate; microcrystalline cellulose; microcrystalline cellulose, type 112; colloidal anhydrous silicon dioxide; magnesium stearate.
Dosage form. Tablets.
Main physicochemical properties:
5 mg tablets: white or almost white capsule-shaped tablets with a break line on both sides. On one side of the tablet, the marking V1 - V is imprinted on one side of the line and 1 on the other side of the line.
10 mg tablets: white or almost white round biconvex tablets with the marking V2 on one side of the tablet.
Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Perindopril. ATC code C09A A04.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action
Perindopril is an angiotensin-converting enzyme (ACE) inhibitor that inhibits the conversion of angiotensin I to angiotensin II. Angiotensin-converting enzyme (ACE), or kininase, is an exopeptidase that converts angiotensin I to angiotensin II and also mediates the breakdown of the vasodilatory agent bradykinin into an inactive heptapeptide. Inhibition of angiotensin-converting enzyme activity leads to a reduction in angiotensin II plasma concentration, increased plasma renin activity (due to suppression of negative feedback on renin release), and decreased aldosterone secretion. Since angiotensin-converting enzyme degrades bradykinin, inhibition of this enzyme results in increased activity of circulating and local kallikrein-kinin systems, and consequently, activation of the prostaglandin system. This mechanism contributes to the antihypertensive effect of ACE inhibitors and partially explains the occurrence of certain adverse effects (e.g., cough).
Perindopril is converted in the body to its active metabolite, perindoprilat. Other metabolites do not exhibit ACE-inhibiting activity under experimental conditions.
Clinical efficacy and safety
Arterial hypertension
Perindopril is effective in mild, moderate, and severe arterial hypertension. It reduces systolic and diastolic blood pressure both in the supine and standing positions.
Perindopril reduces total peripheral resistance, resulting in decreased systemic arterial pressure. Peripheral blood flow increases with virtually no change in heart rate. Renal blood flow usually increases, while glomerular filtration rate remains essentially unchanged.
The maximum antihypertensive effect develops within 4–6 hours after a single dose and lasts at least 24 hours: the T/R ratio (maximum/minimum effect over 24 hours) for perindopril ranges from 87% to 100%. Blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure occurs within one month and is maintained without tachyphylaxis.
Upon discontinuation of perindopril, no rebound effect occurs.
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 with a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.
Heart failure
Perindopril reduces cardiac workload by decreasing preload and afterload.
Studies in patients with heart failure have demonstrated:
- reduction in filling pressures of the right and left ventricles,
- reduction in systemic peripheral resistance,
- increase in cardiac index and improvement in cardiac output.
In comparative studies, initial administration of 2.5 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure compared to placebo.
Patients with a history of cerebrovascular disease
The PROGRESS study was a multicenter, international, double-blind, randomized, placebo-controlled trial that evaluated the benefits of 4 years of treatment with perindopril (as monotherapy or in combination with indapamide) in preventing recurrent stroke in patients with a history of cerebrovascular disease.
The primary endpoint was stroke.
After a 2-week run-in period of perindopril tert-butylamine 2 mg (equivalent to perindopril arginine 2.5 mg) once daily, followed by 2 weeks of 4 mg (equivalent to perindopril arginine 5 mg) once daily, 6105 patients were randomized into two groups: one group received placebo (n=3054), and the other received perindopril tert-butylamine 4 mg (equivalent to perindopril arginine 5 mg) as monotherapy or in combination with indapamide (n=3051). Indapamide was added to patients who had indications for diuretic therapy and no contraindications.
This therapy was administered in addition to standard treatment for stroke and/or arterial hypertension or any other pathological condition.
All patients enrolled in the study had a history of cerebrovascular disease (stroke or transient ischemic attack) within the past 5 years. Blood pressure was not an inclusion criterion: 2916 patients had arterial hypertension, and 3189 had normal blood pressure.
After a mean follow-up of 3.9 years, systolic/diastolic blood pressure decreased on average by 9.0/4.0 mm Hg, and the risk of recurrent stroke (both ischemic and hemorrhagic) was significantly reduced by 28% (95% CI [17;38], p<0.0001) compared to placebo (10.1% vs. 13.8%).
Significant reductions were also observed in the risk of:
- fatal or disabling stroke (4% vs. 5.9%, corresponding to a 33% risk reduction);
- total major cardiovascular events, defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (15% vs. 19.8%, corresponding to a 26% risk reduction);
- post-stroke dementia (1.4% vs. 2.1%, corresponding to a 34% risk reduction) and severe post-stroke cognitive impairment (1.6% vs. 2.8%, corresponding to a 45% risk reduction);
- major coronary events, including non-fatal myocardial infarction or death due to ischemic heart disease (3.8% vs. 5%, corresponding to a 26% risk reduction).
These therapeutic benefits were observed regardless of the presence or absence of arterial hypertension, age, sex, type of stroke, or diabetes. The PROGRESS study results showed that after 5 years of treatment, one stroke could be prevented in every 23 patients, and one major cardiovascular complication could be avoided in every 18 patients.
Patients with stable ischemic heart disease (IHD)
EUROPA was an international, multicenter, randomized, double-blind, placebo-controlled clinical trial lasting 4 years. A total of 12,218 patients aged 18 years and older were randomized: 6110 received 8 mg of perindopril and 6108 received placebo. Patients enrolled had confirmed ischemic heart disease without clinical signs of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients in the study received perindopril as an adjunct 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 resuscitated cardiac arrest. Treatment with 8 mg of perindopril (equivalent to perindopril arginine 10 mg) once daily resulted in a significant absolute reduction of 1.9% in the primary endpoint (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, the absolute reduction in the primary endpoint was 2.2%, corresponding to a 22.4% relative risk reduction (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, non-comparative clinical study, 62 children aged 2 to 15 years with a glomerular filtration rate >30 mL/min/1.73 m² were administered perindopril at a mean dose of 0.07 mg/kg. The dose was individually adjusted, increasing up to a maximum of 0.135 mg/kg/day depending on patient profile and blood pressure response. Fifty-nine patients participated in the study for 3 months, and 36 continued treatment for at least 24 months (mean study duration: 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 previously untreated. 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 trial data on dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ACE inhibitors and angiotensin II receptor blockers was evaluated 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 included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D included patients with type 2 diabetes and diabetic nephropathy.
These trials did not demonstrate significant beneficial effects on renal and/or cardiovascular outcomes or mortality. In contrast, compared to monotherapy, there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension. Given the similarity in 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 Using Cardiovascular and Renal Disease Endpoints) evaluated 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, stroke incidence, and reports of adverse events and serious complications (hyperkalemia, arterial hypotension, and renal dysfunction) were more frequent in the aliskiren group 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 administered dose is detected in blood as the active metabolite, perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five inactive metabolites. Peak plasma 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 plasma concentration.
Distribution
The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Plasma protein binding of perindoprilat is 20%, primarily to angiotensin-converting enzyme, 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 plasma concentration is achieved within 4 days of starting treatment.
Special patient populations
Elimination of perindoprilat is slowed in elderly patients and in patients with heart or kidney failure. 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.
Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of perindopril is halved. However, the amount of perindoprilat formed is not reduced. Therefore, dose adjustment is not required in these patients (see sections "Special precautions" and "Dosage and administration").
Clinical characteristics.
Indications.
- Arterial hypertension.
- Heart failure.
- Prevention of recurrent stroke in patients with cerebrovascular disease.
- Prevention of cardiovascular complications in patients with documented stable ischaemic heart disease. Long-term treatment reduces the risk of myocardial infarction and heart failure (based on the EUROPA trial results).
Contraindications.
- Hypersensitivity to the active substance or to any other ingredient of the medicinal product, or to other ACE inhibitors.
- History of angioedema associated with previous therapy with ACE inhibitors (see section "Special precautions").
- Hereditary or idiopathic angioedema.
- Pregnancy or women planning pregnancy (see section "Use during pregnancy or breast-feeding").
- Concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or with renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
- Concomitant use with sacubitril/valsartan. The medicinal product must not be used within 36 hours before or after the last dose of sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
- Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
- Severe bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney (see section "Special precautions").
Interaction with other medicinal products and other forms of interaction.
Clinical trial 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, hyperkalaemia, 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 increasing the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions"). Initiation of sacubitril/valsartan therapy 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 of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (see section "Special precautions").
Medicinal products causing hyperkalaemia
Although serum potassium levels usually remain within normal limits, some medicinal products or therapeutic classes may cause hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Concomitant administration of these agents increases the risk of hyperkalaemia. Therefore, concomitant use of these agents is not recommended. If concomitant use is necessary, they should be used with caution and serum potassium levels should be closely monitored.
Concomitant use is contraindicated (see section "Contraindications")
Aliskiren
In patients with diabetes mellitus or renal impairment, the risk of hyperkalaemia, worsening renal function, and cardiovascular morbidity and mortality is increased.
Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as high-flux dialysis or haemofiltration membranes (e.g., polyacrylonitrile membranes) or dextran sulfate-based low-density lipoprotein apheresis, 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.
Concomitant use is not recommended (see section "Special precautions")
Aliskiren: In all other patients, including those with diabetes or renal impairment, the risk of hyperkalaemia, worsening renal function, and cardiovascular morbidity and mortality is increased.
Concomitant use of ACE inhibitors and angiotensin II 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 II receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents acting on the RAAS. Dual blockade (i.e., combination of an ACE inhibitor with an angiotensin II receptor blocker) may be considered in individual cases under close monitoring of renal function, serum potassium, and blood pressure.
Estramustine: Increased risk of adverse reactions such as angioedema.
Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium salts.
Risk of hyperkalaemia (potentially fatal), especially in patients with renal impairment (additive hyperkalaemic effect). These agents are not recommended for concomitant use with perindopril. However, if concomitant administration is necessary, they should be used with caution and serum potassium levels should be closely monitored. For use of spironolactone in heart failure, see section "Concomitant use requiring special attention".
Lithium
Concomitant use of ACE inhibitors with lithium preparations may result in reversible increases in plasma lithium concentrations and, consequently, increased risk of lithium toxicity. Concomitant use of perindopril with lithium is not recommended. If such combination is necessary, plasma lithium levels must be closely monitored (see section "Special precautions").
Concomitant use requiring special attention
Antidiabetic agents (insulin, oral hypoglycaemic agents)
Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may enhance the hypoglycaemic effect, increasing the risk of hypoglycaemia. This phenomenon is most likely to occur during the first weeks of combination therapy and in patients with renal impairment.
Baclofen: Enhanced antihypertensive effect. Blood pressure should be monitored and antihypertensive dosage adjusted if necessary.
Diuretics not containing potassium
In patients receiving diuretics, particularly those with disturbed water and 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 volume, or increasing salt intake prior to starting perindopril therapy. Treatment should be initiated with low doses and gradually increased.
In arterial hypertension, if a previously prescribed diuretic may have caused fluid/electrolyte depletion, it should be discontinued prior to 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 possible dose, possibly after reducing the diuretic dose.
In all cases, 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 in patients with NYHA class II–IV heart failure and ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, there is a risk of hyperkalaemia (potentially fatal), especially if recommendations for use of this combination are not followed. Before initiating such combination therapy, absence of hyperkalaemia and renal impairment should be confirmed. Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day. Concomitant use of ACE inhibitors with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, or non-selective NSAIDs may reduce the antihypertensive effect. 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. Such combinations should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored immediately after initiating combination therapy and periodically thereafter.
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.
Concomitant use of certain anaesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to further reduction in blood pressure (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) occur rarely 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.
Hypotension
ACE inhibitors may cause a reduction in blood pressure. Symptomatic hypotension is less common in patients with uncomplicated hypertension and is more likely to occur in patients with hypovolemia, in those receiving diuretics, on a low-salt diet, in patients on dialysis, in patients with diarrhea or vomiting, or in patients with severe renin-dependent hypertension (see sections "Special precautions for use" and "Side effects"). Symptomatic hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic hypotension is most likely in patients with more severe degrees of heart failure who are receiving high doses of loop diuretics, have hyponatremia, or have functional renal impairment. To reduce the risk of symptomatic hypotension at the beginning of therapy and during dose titration, patients must be under close medical supervision (see sections "Dosage and administration" and "Side effects"). The same precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.
In case of hypotension, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication 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 with normal or low blood pressure, perindopril may cause 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 be necessary.
Stenosis of aortic and mitral valves / hypertrophic cardiomyopathy
As with other ACE inhibitors, perindopril should be administered with caution in patients with mitral valve stenosis or left ventricular outflow tract obstruction (aortic sten0sis 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 "Dosage and administration"), and subsequently adjusted based on the patient's response to treatment. Monitoring of potassium and creatinine levels is standard practice for such patients (see section "Side effects").
In patients with symptomatic heart failure, hypotension occurring at the beginning of ACE inhibitor therapy may lead to deterioration of 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 solitary kidney, increases in blood urea and serum creatinine levels have been observed during ACE inhibitor therapy; these changes usually return to normal after discontinuation of treatment. This is particularly relevant for patients with pre-existing renal impairment. The risk of severe hypotension and renal failure is increased in patients with concomitant renovascular hypertension. For such patients, treatment should be initiated under close medical supervision with low doses and cautious dose titration. Given the above, diuretic therapy may predispose to hypotension; therefore, diuretics should be discontinued and renal function should be monitored during the first weeks of perindopril therapy.
In some patients with hypertension, in whom no renovascular disease was detected before the start of treatment, increases in blood urea and serum creatinine levels have occurred, usually mild and transient, especially when perindopril was administered concomitantly with a diuretic. However, this is more typical for patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril may become necessary.
Patients undergoing hemodialysis
In patients undergoing hemodialysis with high-flux polyacrylonitrile membranes and receiving concomitant ACE inhibitor therapy, anaphylactoid reactions have occurred. Such patients should use a different type of dialysis membrane or be prescribed another class of antihypertensive agents.
Patients after kidney transplantation
There is no experience with the use of perindopril in patients after recent kidney transplantation.
Renovascular hypertension
When ACE inhibitors are administered 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 the artery of one kidney.
Hypersensitivity / angioedema
Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported in patients during ACE inhibitor therapy, including perindopril. This may occur at any time during treatment. In such cases, the drug must be discontinued immediately and appropriate monitoring of the patient's condition should be maintained until symptoms completely resolve. In isolated cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment. Administration of antihistamines may be helpful in reducing symptoms.
Angioedema involving laryngeal edema 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 the 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 inhibitor therapy. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C1 esterase 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 should be considered in the differential diagnosis of abdominal pain in patients taking ACE inhibitors.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan therapy should not begin earlier than 36 hours after the last dose of perindopril. After discontinuation of sacubitril/valsartan therapy, 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 (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised 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 with dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.
Anaphylactoid reactions during desensitization therapy
Anaphylactoid reactions may occur in patients taking ACE inhibitors during desensitization therapy with agents 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 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 "Side effects").
Neutropenia / agranulocytosis / thrombocytopenia / anemia
Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen diseases receiving immunosuppressive therapy, allopurinol, or procainamide, or in combination with these risk factors, especially in the presence of existing renal impairment. Serious infections, sometimes unresponsive to intensive antibiotic therapy, may occasionally develop in such patients. If perindopril is prescribed to such patients, periodic monitoring of white blood cell count is recommended, and patients should be informed to report any signs of infection (sore throat, fever).
Racial characteristics
ACE inhibitors cause angioedema more frequently in patients of Black race than in patients of other races. As with other ACE inhibitors, perindopril is less effective in reducing blood pressure in patients of Black race compared to patients of other races, possibly due to lower plasma renin levels in Black patients with hypertension.
Cough
Cough has been reported during ACE inhibitor therapy. The cough is non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/anesthesia
Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or anesthesia with hypotensive agents. The drug should be discontinued one day before surgery. If hypotension occurs and is thought to be due to this mechanism, the patient's condition can be corrected by increasing circulating blood volume.
Hyperkalemia
Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal impairment, worsening renal function, advanced age (over 70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and particularly mineralocorticoid receptor antagonists or angiotensin receptor blockers.
The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with renal impairment, may lead to significant increases in serum potassium levels. Hyperkalemia may result in serious, sometimes fatal, arrhythmias. If concomitant use of perindopril and any of the above-mentioned agents is considered appropriate, 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").
Diabetic patients
Patients with diabetes mellitus receiving oral hypoglycemic 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, hyperkalemia, 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 sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
If dual RAAS blockade therapy is considered absolutely necessary, it may be performed only under specialist supervision and with 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 hyperaldosteronism
Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via inhibition of the RAAS. Therefore, use of this medicinal product is not recommended.
Pregnancy
ACE inhibitors should not be initiated during pregnancy. If continuation of ACE inhibitor therapy is not considered necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Use during pregnancy or breastfeeding
Pregnancy
The medicinal product is contraindicated in pregnant women or women who may become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.
If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.
If ACE inhibitors were used during the second trimester of pregnancy, ultrasound assessment of fetal renal and cranial function is recommended.
Newborns whose mothers received ACE inhibitors should be closely monitored for possible hypotension (see sections "Contraindications" and "Special precautions for use").
Breastfeeding
As there is no information on the use of perindopril during breastfeeding, perindopril is not recommended, and alternative therapy with a better-established safety profile during breastfeeding is preferable, especially for newborns or premature infants.
Fertility
No effect on reproductive capacity or fertility has been observed.
Ability to influence reaction speed when driving or operating machinery
Perindopril has no effect or a negligible effect on the ability to drive or operate machinery; however, individual reactions related to low blood pressure may occur in some patients, particularly at the beginning of treatment or in combination with other antihypertensive drugs. As a result, the ability to drive or operate machinery may be impaired.
Administration and Dosage.
Dosage
The dose should be individually adjusted for each patient depending on the indication, patient profile, and blood pressure levels (see section "Special Instructions").
Arterial Hypertension
Perindopril may be prescribed as monotherapy or in combination with antihypertensive agents of other classes (see sections "Pharmacokinetics", "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Special Instructions").
The recommended initial dose is 5 mg once daily in the morning.
Patients with high RAAS activity (particularly those with renovascular hypertension, fluid and electrolyte imbalance, heart failure, or severe arterial hypertension) may experience excessive hypotension after the initial dose. For such patients, the recommended initial dose is 2.5 mg under medical supervision, if necessary – in a hospital setting.
After 1 month of treatment, the dose may be increased to the maximum dose of 10 mg once daily.
Symptomatic hypotension may occur at the beginning of perindopril therapy, especially in patients receiving diuretics. Such patients should start perindopril treatment cautiously, as they may have water and/or salt deficiency. If possible, diuretic therapy should be discontinued 2–3 days before initiating perindopril (see section "Special Instructions").
For patients with arterial hypertension in whom diuretic therapy cannot be discontinued, perindopril treatment should be initiated at a daily dose of 2.5 mg. 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 2.5 mg, which may be increased to 5 mg after 1 month of treatment, and then, if necessary and depending on renal function – up to 10 mg (see table below).
Symptomatic 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 2.5 mg taken in the morning. After 2 weeks, if the drug is well tolerated, the dose may be increased to 5 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 (with impaired renal function and predisposition to electrolyte disturbances, patients receiving concomitant diuretic and/or vasodilator therapy) should be initiated under close medical supervision (see section "Special Instructions").
In 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, correction of these conditions should be performed, if possible, before initiating perindopril therapy. Blood pressure, renal function, and serum potassium levels should be carefully monitored before and during perindopril treatment (see section "Special Instructions").
Prevention of Recurrent Stroke in Patients with Cerebrovascular Disease
The recommended initial dose is 2.5 mg once daily in the morning. After 2 weeks of treatment, increase the dose to 5 mg once daily in the morning.
If after 2 weeks of treatment with 5 mg the patient requires additional blood pressure control, indapamide may be added at a dose of 1 tablet daily. Treatment may be initiated at any time from 2 weeks to several years after the initial stroke.
Prevention of Cardiovascular Complications in Patients with Documented Stable Ischemic Heart Disease
Long-term treatment with perindopril 10 mg (1 tablet daily) reduces the risk of myocardial infarction and heart failure (based on results of the 4-year EUROPA study). Treatment should be initiated with 5 mg of perindopril (1 tablet daily in the morning). After 2 weeks, if well tolerated, the dose should be increased to 10 mg for long-term maintenance therapy with perindopril 10 mg once daily in the morning.
In elderly patients with documented ischemic heart disease, treatment should be initiated with a dose of 2.5 mg once daily in the morning; after 1 week, increase the dose to 5 mg; after 2 weeks, if well tolerated and depending on renal function, increase the dose to 10 mg and initiate long-term therapy.
Stable Ischemic Heart Disease
The initial dose of perindopril is 5 mg once daily in the morning. After 2 weeks, if well tolerated and considering renal function, increase the dose to 10 mg once daily.
In elderly patients, initially prescribe the drug at a dose of 2.5 mg once daily for the first week, then 5 mg once daily during the following week. After 1 week, increase the dosage to 10 mg once daily (see Table 1 "Dosage in Patients with Renal Impairment"). Dose escalation is permitted only if the previous lower dose is well tolerated.
Special Patient Groups
Patients with Impaired Renal Function
Dosage in patients with renal impairment depends on creatinine clearance.
Table 1. Dosage in Patients with Renal Impairment
| Creatinine clearance (mL/min) |
Recommended dose |
| ClCr ≥ 60 |
5 mg/day |
| 30 < ClCr < 60 |
2.5 mg/day |
| 15 < ClCr < 30 |
2.5 mg every other day |
| Patients undergoing hemodialysis *, ClCr < 15 |
2.5 mg on dialysis day |
*The dialysis clearance of perindoprilat is 70 mL/min. Perindopril should be administered to patients undergoing hemodialysis after the hemodialysis session.
Patients with hepatic insufficiency
Dose adjustment is not required in patients with hepatic insufficiency (see sections "Pharmacokinetics" and "Special precautions").
Administration method
The drug is intended for oral administration in adults.
It is recommended to take perindopril once daily in the morning before meals.
Children.
The efficacy and safety of perindopril in children (under 18 years of age) have not been established. Current available data are described in the section "Pharmacodynamics", but dosage recommendations cannot be provided. Therefore, perindopril is not recommended for use in children.
Overdose.
There is insufficient information regarding perindopril overdose. Symptoms associated with ACE inhibitor overdose 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 mg/mL (9%) sodium chloride solution 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 catecholamines should be provided if possible. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special precautions"). In case of treatment-resistant bradycardia, temporary cardiac pacing 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 reported adverse reactions during clinical trials with perindopril include: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, rash, maculopapular eruptions, muscle cramps, and asthenia.
The adverse reactions observed during clinical trials and post-marketing use of perindopril are listed below, categorized by frequency of occurrence: 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); not known (cannot be estimated from the available data).
| System Organ Classes |
Adverse Reactions |
Frequency |
|
| Blood and lymphatic system disorders |
Eosinophilia |
Uncommon* |
|
| Agranulocytosis or pancytopenia |
Very rare |
||
| Decreased hemoglobin and hematocrit levels |
Very rare |
||
| Leukopenia/neutropenia |
Very rare |
||
| Hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency1 |
Very rare |
||
| Thrombocytopenia |
Very rare |
||
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Uncommon |
|
| Metabolism and nutrition disorders |
Hyperkalemia1, reversible upon discontinuation of the drug |
Uncommon* |
|
| Hypokalemia |
Uncommon* |
||
| Hypoglycemia2 |
Uncommon* |
||
| Psychiatric disorders |
Mood changes |
Uncommon |
|
| Sleep disturbances |
Uncommon |
||
| Depression |
Uncommon |
||
| Nervous system disorders |
Dizziness |
Common |
|
| Headache |
Common |
||
| Somnolence |
Uncommon* |
||
| Paresthesia |
Common |
||
| Loss of consciousness |
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 |
||
| Arrhythmia |
Very rare |
||
| Myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients1 |
Very rare |
||
| Vascular disorders |
Hypotension (and associated symptoms) |
Common |
|
| Vasculitis |
Uncommon* |
||
| Flushing |
Uncommon* |
||
| Stroke may occur due to excessive reduction in blood pressure in high-risk patients |
Very rare |
||
| Raynaud's phenomenon |
Unknown |
||
| Respiratory, thoracic and mediastinal disorders |
Cough |
Common |
|
| Dyspnea |
Common |
||
| Bronchospasm |
Uncommon |
||
| Eosinophilic pneumonia |
Very rare |
||
| Rhinitis |
Very rare |
||
| Gastrointestinal disorders |
Abdominal pain |
Common |
|
| Nausea |
Common |
||
| Vomiting |
Common |
||
| Dyspepsia |
Common |
||
| Diarrhea |
Common |
||
| Constipation |
Common |
||
| Taste disturbance (dysgeusia) |
Common |
||
| Dry mouth |
Uncommon |
||
| Pancreatitis |
Very rare |
||
| Hepatobiliary disorders |
Cytolytic or cholestatic hepatitis1 |
Very rare |
|
| Skin and subcutaneous tissue disorders |
Rash |
Common |
|
| Pruritus |
Common |
||
| Urticaria1 |
Uncommon |
||
| Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria1 |
Uncommon |
||
| Photosensitivity reactions |
Uncommon* |
||
| Pemphigoid |
Uncommon* |
||
| Hyperhidrosis |
Uncommon |
||
| Worsening of psoriasis symptoms |
Uncommon |
||
| Multiform erythema |
Very rare |
||
| Musculoskeletal and connective tissue disorders |
Muscle cramps |
Common |
|
| Arthralgia |
Uncommon* |
||
| Myalgia |
Uncommon* |
||
| Renal and urinary disorders |
Renal impairment |
Uncommon |
|
| Acute renal failure |
Uncommon |
||
| Anuria/oliguria |
Uncommon |
||
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
|
| General disorders |
Asthenia |
Common |
|
| Chest pain |
Uncommon* |
||
| Malaise |
Uncommon* |
||
| Peripheral edema |
Uncommon* |
||
| Hyperthermia |
Uncommon* |
||
| Investigations |
Increased blood urea nitrogen |
Uncommon* |
|
| Increased serum creatinine |
Uncommon* |
||
| Increased serum bilirubin |
Uncommon |
||
| Elevated liver enzymes |
Uncommon |
||
| Injury, poisoning and procedural complications |
Fall |
Uncommon* |
|
*Frequency was calculated from clinical trial data for adverse reactions identified based on spontaneous reporting.
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 randomized 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, 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 medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions. The medicinal product does not require special storage conditions. 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.