Perindopril krka
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Perindopril KRKA (Perindopril KRKA)
Composition:
Active substance: perindopril;
1 tablet contains 4 mg or 8 mg of perindopril as the tert-butylamine salt;
Excipients: calcium chloride, hexahydrate; lactose monohydrate; crospovidone; microcrystalline cellulose; colloidal anhydrous silicon dioxide; magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties:
4 mg tablets: oval, slightly biconvex tablets of white to almost white color, beveled edges and a notch on one side;
8 mg tablets: round, slightly biconvex tablets of white to almost white color, beveled edges and a notch on one side.
Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Perindopril. ATC code C09AA04.
Pharmacological Properties.
Pharmacodynamics.
Perindopril is an ACE inhibitor that interferes with the conversion of angiotensin I to angiotensin II. Angiotensin-converting enzyme (ACE), or kinase, is an exopeptidase that converts angiotensin I into angiotensin II and also causes the breakdown of the vasodilatory agent bradykinin into an inactive heptapeptide. Inhibition of angiotensin-converting enzyme activity leads to reduced plasma concentrations of angiotensin II, 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 accounts for certain adverse effects (e.g., cough).
Perindopril is converted in the body into its active metabolite – perindoprilat. Other metabolites do not exhibit ACE-inhibiting activity under experimental conditions.
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, leading to a decrease in systemic arterial pressure. Peripheral blood flow increases with virtually no change in heart rate. Renal blood flow generally increases, while glomerular filtration rate remains practically unchanged.
The maximum antihypertensive effect develops 4–6 hours after a single dose and lasts at least 24 hours: the T/R ratio (maximum effect/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, there is no rebound effect.
Perindopril reduces left ventricular hypertrophy.
Clinical studies have demonstrated that perindopril has vasodilatory properties. It improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries.
Combination therapy with a thiazide diuretic produces an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.
Heart Failure
In experimental studies, congestive heart failure was induced by ligation of the coronary artery, and it was demonstrated that perindopril reduces myocardial hypertrophy and excessive subendocardial collagen accumulation, restores the myosin and isoenzyme ratio, and reduces the incidence of reperfusion arrhythmias.
Perindopril reduces cardiac workload by decreasing preload and afterload.
Studies involving patients with heart failure have demonstrated:
- reduction in filling pressures of the right and left ventricles,
- decreased systemic peripheral resistance,
- increased cardiac index and improved cardiac output,
- increased regional myocardial blood flow.
In comparative studies, initial administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure compared to placebo.
Clinical Efficacy and Safety
Patients with Stable Ischemic Heart Disease (IHD)
An international, multicenter, randomized, double-blind, placebo-controlled clinical trial, EUROPA, lasting 4 years, has been reported. The study included patients with confirmed ischemic heart disease and no clinical signs of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients 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 cardiac arrest with successful resuscitation. Treatment with perindopril 8 mg once daily was reported to reduce the primary endpoint by an absolute 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6] – p<0.001). In patients with a history of myocardial infarction and/or revascularization, an absolute reduction of 2.2% in the primary endpoint was observed, corresponding to a relative risk reduction of 22.4% (95% CI [12.0; 31.6] – p<0.001).
Use in Children
The safety and efficacy of perindopril in children and adolescents under 18 years of age have not been established.
An open-label clinical study involving 62 children aged 2 to 15 years has been reported. Perindopril was administered at a mean dose of 0.07 mg/kg with a glomerular filtration rate >30 mL/min/1.73 m². The dose was individually adjusted, increased up to a maximum of 0.135 mg/kg/day, depending on patient profile and blood pressure response. The mean duration of the study was 44 months. Systolic and diastolic blood pressure remained stable 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)
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)] evaluating concomitant use of ACE inhibitors and angiotensin II receptor blockers have been reported.
ONTARGET was a trial involving patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a trial involving patients with type 2 diabetes and diabetic nephropathy.
These trials did not demonstrate a significant beneficial effect on renal or cardiovascular morbidity and mortality compared to monotherapy; however, they showed an increased risk of hyperkalemia, acute kidney injury, and/or hypotension. Given the similar pharmacodynamic properties, these results are 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.
The ALTITUDE trial (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 trial was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality, incidence of stroke, and reports of adverse events and serious complications (hyperkalemia, arterial hypotension, and renal function impairment) 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 total administered perindopril is detected in the 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 achieved 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 between perindopril dose and plasma concentration is observed.
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 the urine. The terminal 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 patients with renal impairment based on the degree of impairment (creatinine clearance).
The dialysis clearance of perindoprilat is 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 ischaemic heart disease.
To reduce the risk of myocardial infarction and heart failure (based on the EUROPA study results), long-term treatment should be administered.
Contraindications.
- Hypersensitivity to the active substance or to any other component of the medicinal product, or to other ACE inhibitors.
- History of angioedema associated with previous treatment with ACE inhibitors.
- Hereditary or idiopathic angioedema.
- Concomitant use with medicinal products containing the active substance aliskiren in patients with diabetes mellitus or patients with renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
- Concomitant use with sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
- Extracorporeal treatments leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
- Significant bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney (see section "Special precautions for use").
- Planned pregnancy and pregnancy.
- Paediatric age.
Interaction with other medicinal products and other forms of interaction.
Clinical study data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, 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 use of a single RAAS-acting agent (see sections "Contraindications" and "Special precautions for use").
Medicinal products causing hyperkalaemia
Certain medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, namely: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, and trimethoprim. Concomitant use of these medicinal products increases the risk of hyperkalaemia.
Concomitant use is contraindicated (see section "Contraindications")
Aliskiren
In patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalaemia, worsening of renal function, and cardiovascular morbidity and mortality is increased.
Extracorporeal treatment leading to blood contact with negatively charged surfaces, such as high-flux dialysis or haemofiltration membranes (e.g. polyacrylonitrile membranes) or for low-density lipoprotein apheresis with dextran sulphate, may increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using dialysis membranes of a different type or prescribing different classes of antihypertensive agents.
Sacubitril/valsartan
Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as dual inhibition of neprilysin and ACE may increase the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").
Concomitant use not recommended (see section "Special precautions for use")
Aliskiren: in any other patients, including those with diabetes mellitus or impaired renal function, the risk of hyperkalaemia, worsening of renal function, and cardiovascular morbidity and mortality is increased.
Concomitant use of ACE inhibitors and angiotensin receptor blockers: literature data indicate that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalaemia, and worsening of renal function (including acute renal failure) compared to monotherapy with RAAS-acting agents. Dual blockade (i.e. combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases under 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 co-trimoxazole (trimethoprim/sulfamethoxazole), there is a possible increased risk of hyperkalaemia (see section "Special precautions for use").
Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes
Although potassium levels usually remain within normal limits, hyperkalaemia may occur in some patients receiving perindopril. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Caution should also be exercised when perindopril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as the potassium-sparing diuretic amiloride. Therefore, concomitant use of perindopril with the above-mentioned agents is not recommended. However, if concomitant administration of these agents is necessary, they should be used with caution and serum potassium levels should be closely monitored.
Lithium. Concomitant use of ACE inhibitors with lithium-containing preparations may lead to reversible increases in plasma lithium concentrations and, consequently, an increased risk of lithium toxicity. Concomitant use of perindopril with lithium preparations is not recommended. If such use is clinically necessary, plasma lithium levels must be closely monitored (see section "Special precautions for use").
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 taking diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or 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 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 background diuretic therapy, ACE inhibitor therapy should be initiated at the lowest 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, the following should be observed:
- Failure to follow prescribing recommendations for this combination may result in hyperkalaemia (potentially fatal) in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and a loop diuretic;
- Hyperkalaemia and renal impairment must be excluded before initiating such combination therapy;
- Close monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment 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. This combination should be used cautiously, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored promptly after initiating combination therapy and periodically thereafter.
Racecadotril
ACE inhibitor therapy (e.g., perindopril) is known to induce angioedema. This risk may be increased when used concomitantly with racecadotril (a medicinal product used for the treatment of acute diarrhoea).
mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)
Patients receiving mTOR inhibitors may belong to a higher-risk group for developing angioedema (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. Concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional blood pressure reduction.
Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) (linagliptin, saxagliptin, sitagliptin, vildagliptin): in patients receiving a combination of a gliptin and an ACE inhibitor, there may be an increased risk of angioedema due to the gliptin's inhibition of DPP-IV activity.
Concomitant use of certain anaesthetics, 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 compounds: nitrate-like 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.
Before and during treatment with the drug, monitoring of blood pressure, kidney function, and plasma potassium levels is required.
Stable ischemic heart disease
If an episode of unstable angina (of any severity) occurs within the first month of perindopril treatment, the benefit-risk ratio should be carefully evaluated before deciding on continuing therapy.
Arterial hypotension
ACE inhibitors may cause a reduction in arterial blood pressure. Symptomatic arterial hypotension occurs less frequently in patients with uncomplicated arterial hypertension and is more likely in patients with hypovolemia, those taking diuretics, those on a low-salt diet, patients undergoing dialysis, patients with diarrhea or vomiting, or patients with severe renin-dependent hypertension. 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 heart failure who are taking high doses of loop diuretics, have hyponatremia, or have functional renal impairment. To reduce the risk of symptomatic arterial hypotension, patients should be under close medical supervision during initiation of therapy and dose titration. The same precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.
In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication 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 may cause additional reduction in systemic arterial pressure. This effect is expected and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, dose reduction or discontinuation of the drug may 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 stenosis or hypertrophic cardiomyopathy).
Renal function impairment
In patients with renal impairment (creatinine clearance < 60 mL/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section "Dosage and administration"), and subsequently based on the patient's response to treatment. Monitoring of potassium and creatinine levels is standard practice for such patients.
In patients with symptomatic heart failure, arterial 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 single kidney, treatment with ACE inhibitors has been associated with increased blood urea and serum creatinine levels, which usually return to normal after discontinuation of treatment. This is particularly relevant for patients with pre-existing renal impairment. In patients with concomitant renovascular hypertension, the risk of severe arterial hypotension and renal failure is increased. In 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 arterial hypotension; therefore, diuretics should be discontinued and renal function monitored during the first weeks of perindopril treatment.
In some patients with arterial hypertension, in whom no renovascular disease was detected before treatment, increases in blood urea and serum creatinine have developed, usually mild and transient, especially when perindopril was administered concomitantly with a diuretic. However, this is more characteristic in 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 who are receiving concomitant ACE inhibitor therapy, anaphylactoid reactions have occurred. Therefore, for such patients, it is necessary to consider either using a different type of dialysis membrane or switching to another class of antihypertensive drugs.
Patients after kidney transplantation
There is no experience with the use of perindopril in patients who have recently undergone kidney transplantation.
Renovascular hypertension
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 contributing factor. Loss of kidney 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 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 should be maintained 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 antihistamines may be helpful in alleviating 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 their condition is stabilized.
Patients with a history of angioedema unrelated to ACE inhibitor use are at increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").
Rare cases of intestinal angioedema have been reported in patients receiving ACE 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 C-1 esterase levels were normal. The diagnosis of intestinal angioedema was confirmed by abdominal computed tomography, ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be excluded 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 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 other neutral endopeptidase inhibitors (NEP) (e.g., racecadotril) and ACE inhibitors may also increase the risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, before initiating NEP inhibitor therapy (e.g., racecadotril) in patients taking perindopril, a careful benefit-risk assessment should be performed.
Patients receiving concomitant mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) may 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").
Anaphylactoid reactions during LDL apheresis
Rarely, life-threatening anaphylactoid reactions may occur in patients taking ACE inhibitors during low-density lipoprotein (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
In patients taking ACE inhibitors, anaphylactoid reactions may occur 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 resulting in death, have been reported during ACE inhibitor therapy. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevation of liver enzymes during ACE inhibitor therapy should discontinue the drug and receive appropriate medical evaluation and treatment.
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 vascular diseases receiving immunosuppressants, allopurinol, or procainamide, or in combination with these risk factors, especially in the presence of existing renal impairment. Serious infections may develop in such patients, which in isolated cases do not respond to intensive antibiotic therapy. 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 (e.g., sore throat, fever).
Racial factor
ACE inhibitors are more likely to cause angioedema in black patients than in patients of other races. As with other ACE inhibitors, perindopril is less effective in reducing blood pressure in black patients compared to patients of other races, possibly due to lower plasma renin levels in black patients with arterial hypertension, particularly among African-American populations.
Cough
Cough has been reported during ACE inhibitor therapy. The cough is typically non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of 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 arterial hypotension occurs and is thought to be due to this mechanism, the patient's condition can be normalized by increasing circulating blood volume.
Hyperkalemia
Elevated serum potassium levels have been observed in some patients during ACE inhibitor therapy, including perindopril. 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 drugs that increase serum potassium levels (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole).
The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with 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 antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy.
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, potassium-containing dietary supplements, or potassium-containing salt substitutes is not recommended.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment (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 should only be performed under specialist supervision 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, the use of this medicinal product is not recommended.
Excipients
The drug contains lactose; therefore, perindopril is not recommended for patients with rare hereditary intolerance to galactose, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.
Use during pregnancy or breastfeeding.
Pregnancy. The use of ACE inhibitors is contraindicated during pregnancy and in women planning pregnancy.
Women planning pregnancy should be switched to alternative antihypertensive therapy with a proven safety profile in pregnancy. ACE inhibitor therapy must be discontinued immediately upon confirmation of pregnancy, and alternative therapy should be initiated if necessary.
Epidemiological data on teratogenic risk during first-trimester use of ACE inhibitors are inconclusive, but a small increase in risk cannot be excluded. Except when continuation of ACE inhibitor therapy is considered necessary, women planning pregnancy should be prescribed alternative antihypertensive therapy with an established safety profile during pregnancy.
If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately, and alternative treatment initiated if necessary.
The effects of ACE inhibitor therapy during the second and third trimesters are due to fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If ACE inhibitors have been used from the second trimester of pregnancy, ultrasound examination is recommended to assess kidney function and skull ossification. Newborns whose mothers received ACE inhibitors should be closely monitored for hypotension (see sections "Contraindications" and "Special precautions for use").
Breastfeeding period. Perindopril is contraindicated during breastfeeding due to lack of data on its passage into breast milk. Alternative therapy with a better-studied safety profile should be used during breastfeeding.
Fertility. No effect on reproductive capacity or fertility has been observed.
Ability to affect reaction speed when driving or operating machinery.
Perindopril has no direct effect on the ability to drive or operate machinery. However, individual reactions related to reduced blood pressure may occur in some patients, particularly at the beginning of treatment or when used concomitantly with other antihypertensive drugs. As a result, reaction speed when driving or operating machinery may be reduced.
Method of Administration and Dosage
The drug is intended for oral administration in adults.
Perindopril is recommended to be taken once daily in the morning before meals. The tablet can be divided into equal doses using the score line.
Dosage should be individually adjusted for each patient depending on the indication, patient profile, and blood pressure levels (see section "Special Considerations").
Arterial Hypertension
Perindopril can be prescribed as monotherapy or in combination with antihypertensive drugs 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 (especially those with renovascular hypertension, fluid and electrolyte imbalances, heart failure, or severe arterial hypertension, as well as elderly patients) are at risk of developing symptomatic hypotension (first-dose hypotension); therefore, an initial dose of 2 mg under medical supervision, possibly in a hospital setting, is recommended.
After 1 month of treatment, the dose may be increased to the maximum dose of 8 mg once daily.
Symptomatic hypotension may occur at the beginning of perindopril therapy, especially in patients receiving diuretics. Such patients should be treated with caution due to possible volume and/or salt depletion. If possible, diuretic therapy should be discontinued 2–3 days before initiating perindopril.
For patients with arterial hypertension in whom discontinuation of diuretics is not feasible, treatment with perindopril should be initiated at a daily dose of 2 mg. In these patients, renal function and serum potassium levels should be monitored. Further dose escalation of perindopril should be based on blood pressure response, and diuretic therapy may be resumed if necessary.
In elderly patients, treatment should be initiated at a dose of 2 mg, which may be increased to 4 mg after 1 month of treatment, and subsequently, if needed and depending on renal function, up to 8 mg (see table below).
Heart Failure
In patients with heart failure, perindopril is usually prescribed concomitantly with a potassium-wasting 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 the drug is well tolerated, the dose may be increased to 4 mg once daily. Dosage 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, predisposition to electrolyte imbalances, or those receiving concomitant therapy with diuretics and/or vasodilators) should be initiated under close medical supervision (see section "Special Considerations").
In patients at high risk of developing symptomatic hypotension—particularly those with electrolyte depletion with or without hyponatremia, hypovolemia, or those receiving intensive diuretic therapy—correction of these conditions should be attempted, if possible, prior to initiating perindopril therapy. Blood pressure, renal function, and serum potassium levels should be closely monitored before and during perindopril treatment (see section "Special Considerations").
Prevention of Cardiovascular Complications in Patients with Documented Stable Ischemic Heart Disease
The initial dose of perindopril is 4 mg once daily in the morning. After 2 weeks, provided the drug is well tolerated and considering renal function, the dose should be increased to 8 mg once daily.
In elderly patients, treatment should be initiated at a dose of 2 mg once daily for the first week, followed by 4 mg once daily during the second week. After 1 week, the dose may be increased to 8 mg once daily. Dose escalation is permissible only if the previous lower dose is well tolerated.
Prevention of Recurrent Stroke in Patients with Cerebrovascular Disease
The initial dose of perindopril in patients with a history of cerebrovascular disease is 2 mg once daily in the morning. After 2 weeks of treatment, the dose should be increased to 4 mg daily and maintained for another 2 weeks before initiating indapamide.
Careful monitoring of blood pressure is required.
Perindopril may be prescribed in combination with indapamide, or treatment may be switched to a fixed-dose combination of perindopril and indapamide, either before or during perindopril therapy.
Treatment may be initiated at any time from 2 weeks to several years after the initial stroke.
Patients with Renal Impairment
Dosage in patients with renal insufficiency depends on creatinine clearance.
| Creatinine clearance (mL/min) |
Recommended dose |
| ClCr ≥ 60 |
4 mg/day |
| 30 < ClCr < 60 |
2 mg/day |
| 15 < ClCr < 30 |
2 mg every other day |
| Patients on hemodialysis *, ClCr < 15 |
2 mg on dialysis day |
* Dialysis clearance of perindoprilat is 70 mL/min. Perindopril should be administered to patients undergoing hemodialysis after the hemodialysis session.
Patients with hepatic impairment
Patients with hepatic impairment do not require dose adjustment (see sections "Pharmacokinetics" and "Special precautions").
Children.
The efficacy and safety of use in children (under 18 years of age) have not been established. Therefore, perindopril is not recommended for use in children.
Overdose.
Information regarding perindopril overdose is limited. Symptoms associated with overdose of ACE inhibitors may include: arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
In case of overdose, intravenous administration of 0.9% (9 mg/mL) sodium chloride solution is recommended. If arterial hypotension occurs, the patient should be placed in a supine position with low head elevation. If possible, infusion of angiotensin II and/or intravenous administration of catecholamines should be provided. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special precautions"). In cases of treatment-resistant bradycardia, artificial cardiac pacing is indicated. Continuous monitoring of vital signs, serum electrolyte concentrations, and serum creatinine levels is required.
Adverse Reactions
The safety profile of perindopril corresponds to the safety profile of ACE inhibitors.
The most commonly observed adverse reactions during clinical studies with perindopril are: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, hypotension, cough, dyspnea, abdominal pain, constipation, diarrhea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, skin rash, muscle cramps, asthenia.
During clinical studies and post-marketing use of perindopril, the following adverse reactions have been observed with the following frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
| Body systems |
Adverse reactions |
Frequency |
|
| Blood and lymphatic system disorders |
Eosinophilia |
Uncommon |
|
| Leukopenia/neutropenia |
Very rare |
||
| Agranulocytosis or pancytopenia |
Very rare |
||
| Decreased hemoglobin and hematocrit levels |
Very rare |
||
| Thrombocytopenia |
Very rare |
||
| Hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency1) |
Very rare |
||
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Uncommon |
|
| Metabolism and nutrition disorders |
Hyperkalemia1), reversible after 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 |
||
| Syncope |
Uncommon* |
||
| Confusion |
Very rare |
||
| Vertigo |
Common |
||
| Eye disorders |
Visual disturbances |
Common |
|
| Ear and labyrinth disorders |
Tinnitus |
Common |
|
| Cardiac disorders |
Palpitations |
Uncommon* |
|
| Tachycardia |
Uncommon* |
||
| Angina pectoris1) |
Very rare |
||
| Myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients1) |
Very rare |
||
| Arrhythmia |
Very rare |
||
| Vascular disorders |
Stroke may occur due to excessive reduction in blood pressure in high-risk patients |
Very rare |
|
| Raynaud's phenomenon |
Not known |
||
| Hypotension (and associated symptoms) |
Common |
||
| Vasculitis |
Uncommon* |
||
| Flushing |
Uncommon |
||
| Respiratory, thoracic and mediastinal disorders |
Cough |
Common |
|
| Dyspnea |
Common |
||
| Bronchospasm |
Uncommon |
||
| Eosinophilic pneumonia |
Very rare |
||
| Rhinitis |
Very rare |
||
| Hepatobiliary disorders |
Cytolytic or cholestatic hepatitis1) |
Very rare |
|
| Gastrointestinal disorders |
Abdominal pain |
Common |
|
| Nausea |
Common |
||
| Vomiting |
Common |
||
| Dyspepsia |
Common |
||
| Diarrhea |
Common |
||
| Constipation |
Common |
||
| Taste disturbances (dysgeusia) |
Common |
||
| Dry mouth |
Uncommon |
||
| Pancreatitis |
Very rare |
||
| Skin and subcutaneous tissue disorders |
Rash |
Common |
|
| Pruritus |
Common |
||
| Hyperhidrosis |
Uncommon |
||
| Worsening of psoriasis symptoms |
Uncommon |
||
| Pemphigoid |
Uncommon* |
||
| Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria1) |
Uncommon |
||
| Photosensitivity reactions |
Uncommon* |
||
| Multiform erythema |
Very rare |
||
| Musculoskeletal and connective tissue disorders |
Muscle cramps |
Common |
|
| Arthralgia |
Uncommon* |
||
| Myalgia |
Uncommon* |
||
| Renal and urinary disorders |
Renal failure |
Uncommon |
|
| Acute renal failure |
Uncommon |
||
| Anuria/oliguria |
Uncommon |
||
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
|
| General disorders |
Peripheral edema |
Uncommon* |
|
| Chest pain |
Uncommon* |
||
| Asthenia |
Common |
||
| Malaise |
Uncommon* |
||
| Hyperthermia |
Uncommon* |
||
| Investigations |
Increased blood urea levels |
Uncommon* |
|
| Increased blood creatinine levels |
Uncommon* |
||
| Increased blood bilirubin levels |
Uncommon |
||
| Elevated liver enzymes |
Uncommon |
||
| Injury, poisoning and procedural complications |
Falls |
Uncommon* |
|
*Frequency was calculated from clinical trial data for adverse reactions identified based on spontaneous reports.
- See section "Special precautions".
- See sections "Special precautions" 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 (0.3%) experienced serious adverse reactions. Among patients receiving perindopril, hypotension was observed in 6 patients, angioneurotic edema in 3 patients, and sudden cardiac arrest in 1 patient. Among patients who discontinued the study, 6.0% (n = 366) reported cough, arterial hypotension, or any other intolerance to perindopril, compared with 2.1% (n = 129) of patients receiving placebo.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.
Shelf life. 3 years.
Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture. Keep out of reach and sight of children.
Packaging. 10 tablets in a blister; 3 or 9 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and location of operations.
Šmarješka cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.