POM: Prescription only medicine
This information is intended for use by health professionals
two.5 mg film-coated tablets
Coversyl Arginine 5 mg film-coated tablets
Coversyl Arginine 10 mg film-coated tablets
One film-coated tablet contains 1.6975 mg perindopril corresponding to
two.5 mg perindopril arginine.
Excipient with known effect: 36.29 mg lactose monohydrate.
One film-coated tablet contains
three.395 mg perindopril corresponding to 5 mg perindopril arginine.
Excipient with known effect: 72.58 mg lactose monohydrate.
One film-coated tablet contains
six.790 mg perindopril corresponding to 10 mg perindopril arginine.
through known effect: 145.16 mg lactose monohydrate.
For a full list of excipients,
view section 6.1.
White, ball, convex, film-coated tablet.
Light-green, rod-shaped film-coated tablet engraved with on one face and scored on both edges. The tablet can be divided into equal doses.
Green, round, biconvex, film-coated tablet engraved with on one face and on the other face.
Treatment of hypertension.
Treatment of symptomatic
Stable coronary artery disease:
Reduction of risk of cardiac events in patients with a history of myocardial infarction and/or revascularisation.
The dose should be individualised according to the patient profile (see section 4.4) and blood pressure response.
Coversyl Arginine may be used in monotherapy or in combination with other classes of antihypertensive therapy (see sections 4.3, 4.4, 4.5 and 5.1)
suggested starting dose is 5 mg given once daily in the morning.
Patients with a intensely activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and/or volume depletion, cardiac decompensation or severe hypertension) may experience an excessive drop in blood pressure following the initial dose. A starting dose of 2.5 mg is recommended in such patients and the initiation of treatment should take place under medical supervision.
The dose may be increased to 10 mg once daily after one month of treatment.
Symptomatic hypotension may occur following initiation of therapy with Coversyl Arginine; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.
If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with Coversyl Arginine (see section 4.4).
In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Coversyl Arginine should be initiated with a 2.5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of Coversyl Arginine should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.
In elderly patients treatment should be initiated at a dose of 2.5 mg which may be progressively increased to 5 mg after one month then to 10 mg if necessary depending on renal function (see table below).
Symptomatic heart failure:
It is recommended that Coversyl Arginine, generally associated with a non-potassium-sparing diuretic and/or digoxin and/or a beta-blocker, be introduced under close medical supervision with a recommended starting dose of 2.5 mg taken in the morning. This dose may be increased after 2 weeks to 5 mg once daily if tolerated. The dose adjustment should be based on the clinical response of the individual patient.
In severe heart failure and in other patients considered to be at high risk (patients with impaired renal function and a tendency to have electrolyte disturbances, patients receiving simultaneous treatment with diuretics and/or treatment with vasodilating agents), treatment should be initiated under careful supervision (see section 4.4).
Patients at high risk of symptomatic hypotension e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy should have these conditions corrected, if possible, prior to therapy with Coversyl Arginine. Blood pressure, renal
work and serum potassium should be monitored closely, both before and during treatment with Coversyl Arginine (see section 4.4).
Stable coronary artery disease:
Coversyl Arginine should be introduced at a dose of 5 mg once daily for two weeks, then increased to 10 mg once daily, depending on renal function and provided that the 5 mg dose is well tolerated.
Elderly patients should receive 2.5 mg once daily for one week, then 5 mg once daily the next week, before increasing the dose up to 10 mg once daily depending on renal function (see Table 1 “Dosage adjustment in renal impairment”). The dose should be increased only if the previous lower dose is well tolerated.
Patients via renal impairment:
Dosage in patients with renal impairment should be based on creatinine clearance as outlined in table 1 below:
Table 1: dosage adjustment in renal impairment
Creatinine clearance (ml/min)
Recommended carry outse
5 mg per day
30 < ClCR < 60
2.5 mg per day
15 < ClCR < 30
2.5 mg every other day
Haemodialysed patients *
ClCR < 15
2.5 mg on the day of dialysis
* Dialysis clearance of perindoprilat is
For patients on haemodialysis, the executese should be taken after dialysis.
Patients via hepatic impairment:
No dosage adjustment is necessary in patients with hepatic impairment (see sections 4.4 and 5.2).
The safety and efficacy of perindopril in
sonren and adolescents aged below 18 years have not been established.
Currently available data are described in section 5.1 but no recommendation on a posology can be made.
usage in children and adolescents is not recommended.
For oral use.
Coversyl Arginine is
suggested to be taken once daily in the morning before a meal.
• Hypersensitivity to the active substance, to any of the excipients or to any other ACE inhibitor;
• History of angioedema associated with previous ACE inhibitor therapy (see section 4.4);
• Hereditary or idiopathic angioedema;
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6);
• Concomitant use of Coversyl Arginine with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1);
• Concomitant use with sacubitril/valsartan (see sections 4.4 and 4.5);
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5);
• Significant bilateral renal artery stenosis or stenosis of the artery to a single
working kidney (see section 4.4).
Stable coronary artery disease:
If an episode of unstable angina pectoris (major or not) occurs during the first month of perindopril treatment, a automobileeful appraisal of the benefit/risk should be performed before treatment continuation.
ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see sections 4.5 and 4.8). In patients with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored (see sections 4.2 and 4.8). Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
In some patients
through congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur
through Coversyl Arginine.
This effect is anticipated and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of Coversyl Arginine may be necessary.
Aortic and mitral valve stenosis / hypertrophic automobilediomyopathy:
As with other ACE inhibitors, Coversyl Arginine should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic
Renal special needs:
In cases of renal impairment (creatinine clearance < 60 ml/min) the initial perindopril dosage should be adjusted according to the patient’s creatinine clearance (see section 4.2) and then as a function of the patient’s response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients (see section 4.8).
In patients with symptomatic heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal
work should be monitored during the first weeks of Coversyl Arginine therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when Coversyl Arginine has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Coversyl Arginine may be required.
Anaphylactoid reactions have been reported in patients dialysed with high flux membranes, and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.
There is no experience regarding the administration of Coversyl Arginine in patients
through a recent kidney transplantation.
There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single
working kidney are treated with ACE inhibitors (see section 4.3). Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported rarely in patients treated with ACE inhibitors, including Coversyl Arginine (see section 4.8). This may occur at any time during therapy.
In such cases, Coversyl Arginine should promptly be discontinued and appropriate monitoring should be initiated and continued until complete resolution of symptoms has occurred. In those instances
whereby swelling was confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
The combination of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section 4.3). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema (see section 4.5). Hence, a careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients on perindopril.
Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus):
Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).
Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis:
Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate have observed life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactic reactions during desensitisation:
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have saw anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up (see section 4.8).
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal
work and no other complicating factors, neutropenia occurs rarely.
Perindopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal
work. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever).
ACE inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
As with other ACE inhibitors, perindopril may be less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
In patients undergoing major surgery or during anaesthesia with agents
who produce hypotension, Coversyl Arginine may block angiotensin II formation secondary to compensatory renin release. The treatment should be discontinued one day prior to the surgery. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole).
The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. If concomitant use of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see section 4.5).
In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).
The combination of lithium and perindopril is generally not recommended (see section 4.5).
Potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes:
The combination of perindopril and potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes is generally not recommended (see section 4.5).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal
work, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be
usaged concomitantly in patients with diabetic nephropathy.
Patients with primary hyperaldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of this product is not recommended.
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered
vital, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency should not take this medicinal product.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Drugs inducing hyperkalaemia
Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such
under the name of ciclosporin or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalaemia.
Concomitant use contra-indicated (see section 4.3):
In diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.
Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis with dextran sulfate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
The concomitant use of perindopril with sacubitril/valsartan is contra-indicated as the concomitant inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be started until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see section 4.3 and 4.4).
Concomitant use not recommended (see section 4.4):
In patients other than diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.
Concomitant therapy with ACE inhibitor and angiotensin-receptor blocker:
It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy with ACE inhibitor and angiotensin-receptor blocker is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g., by combining an ACE-inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function, potassium levels, and blood pressure.
Risk of increased adverse effects such
under the name of angioneurotic oedema (angioedema).
Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see section 4.4).
Potassium-sparing diuretics (e.g. triamterene, amiloride…), potassium salts:
Hyperkalaemia (potentially lethal), especially in conjunction with renal impairment (additive hyperkalaemic effects).
The combination of perindopril with the above-mentioned drugs is not recommended (see section 4.4). If concomitant use is nonetheless indicated, they should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone in heart failure, watch below.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Use of perindopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).
Concomitant use which requires special automotivee:
Antidiabetic agents (insulins, oral hypoglycaemic agents):
Epidemiological studies have suggested
who concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose lowering effect with risk of hypoglycaemia.
This phenomenon appeared to be more likely to occur during the first weeks of merged treatment and in patients with renal impairment.
Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive dosage if necessary.
Patients on diuretics, and especially those who are volume and/or salt depleted, may experience excessive reduction in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and progressive doses of perindopril.
In arterial hypertension, when prior diuretic therapy can have caused salt/volume depletion, either the diuretic must be discontinued before initiating the ACE inhibitor, in which case a non-potassium-sparing diuretic can be thereafter reintroduced or the ACE inhibitor must be initiated with a low dosage and progressively increased.
In diuretic-treated congestive heart failure, the ACE inhibitor should be initiated at a very low dosage, possibly after reducing the dosage of the
under the name ofsociated non-potassium-sparing diuretic.
In all cases, renal
work (creatinine levels) must be monitored during the first few weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone, spironolactone):
With eplerenone or spironolactone at doses between 12.5 mg to 50 mg by day and with low doses of ACE inhibitors:
In the treatment of class II-IV heart failure (NYHA) with an ejection fraction < 40%, and previously treated with ACE inhibitors and loop diuretics, risk of hyperkalaemia, potentially lethal, especially in case of non-observance of the prescription recommendations on this combination.
Before initiating the combination, check the
lack of hyperkalaemia and renal impairment.
A close monitoring of the kalaemia and creatininaemia is recommended in the first month of the
therapy once a week at the beginning and, monthly thereafter.
Non-steroidal anti-inflammatory medicinal products (NSAIDs) including
under the name ofpirin ≥ 3 g/day:
When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal
work. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal
work after initiation of concomitant therapy, and periodically thereafter.
ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk may be elevated when
usaged concomitantly with racecadotril (a drug used against acute diarrhea).
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)
Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see section 4.4).
Concomitant use which requires some
Antihypertensive agents and vasodilators:
usage of these agents may increase the hypotensive effects of perindopril. Concomitant
usage with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin):
Increased risk of angioedema, due to dipeptidyl peptidase IV (DPP-IV) decreased activity by the gliptin, in patients co-treated with an ACE inhibitor.
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4).
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including perindopril.
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded.
Unless continued ACE inhibitor therapy is considered
vital, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal
work, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal
work and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see also sections 4.3 and 4.4).
Because no information is available regarding the use of Coversyl Arginine during breast-feeding, Coversyl Arginine is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
There was no effect on reproductive performance or fertility.
Coversyl Arginine has no direct influence on the ability to drive and
usage machines but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication.
As a result the ability to drive or operate machinery may be impaired.
a. Summary of safety and security profile
The safety profile of perindopril is consistent with the safety profile of ACE inhibitors:
The most frequent adverse events reported in clinical trials and observed with perindopril are: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, dysgeusia, dyspepsia, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia.
b. Tabulated list of adverse reactions
The following undesirable effects have been saw during clinical trials and/or post-marketing use with perindopril and ranked under the following frequency:
ubiquitous (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data).
System Organ Class
Blood and the lymphatic System Disorders
Agranulocytosis or pancytopenia
Haemoglobin decreased and haematocrit decreased
Haemolytic anaemia in patients with a congenital deficiency of G-6PDH (see section 4.4)
Metabolism and Nutrition Disorders
Hypoglycaemia (see sections 4.4 and 4.5)
Hyperkalaemia, reversible on discontinuation (see section 4.4)
Nervous System disorders
Ear and labyrinth disorders
Angina pectoris (see section 4.4)
Myocardial infarction, possibly secondary to excessive hypotension in high risk patients (see section 4.4)
Hypotension (and effects related to hypotension)
Stroke possibly secondary to excessive hypotension in high-risk patients (see section 4.4)
Respiratory, Thoracic and Mediastinal Disorders
Hepatitis either cytolytic or cholestatic (see section 4.4)
Skin and Subcutaneous Tissue Disorders
Urticaria (see section 4.4)
Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (see section 4.4)
Musculoskeletal And Connective Tissue Disorders
Renal and Urinary Disorders
Acute renal failure
Reproductive System and Breast Disorders
General Disorders and Administration Site Condition
Blood urea increased
Blood creatinine increased
Blood bilirubin increased
Hepatic enzyme increased
Injury, poisoning and procedural complications
* Frequency calculated from
scientific trials for adverse events detected from spontaneous report
Cases of SIADH have been reported with other ACE inhibitors. SIADH can be considered
under the name of a very rare but possible complication
under the name ofsociated with ACE inhibitor therapy including perindopril.
During the randomised period of the EUROPA study, only serious adverse events were collected. Few patients experienced serious adverse events: 16 (0.3%) of the 6122 perindopril patients and 12 (0.2%) of the 6107 placebo patients. In perindopril-treated patients, hypotension was experienced in 6 patients, angioedema in 3 patients and sudden cardiac arrest in 1 patient. More patients withdrew for cough, hypotension or other intolerance on perindopril than on placebo, 6.0% (n=366) versus 2.1% (n=129) respectively.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is essential. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Limited data are available for overdosage in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
The recommended treatment of overdosage is intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Perindopril may be removed from the general circulation by haemodialysis (see section 4.4). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
Pharmacotherapeutic group: ACE inhibitor, plain, ATC code: C09A A04
Mechanism of action
Perindopril is an inhibitor of the enzyme
who converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system).
It is possible
who this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (e.g. cough).
Perindopril acts using its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.
Clinical efficacy and safety
Perindopril is active in all grades of hypertension: mild, moderate, severe; a reduction in systolic and diastolic blood pressures in both supine and standing positions is observed.
Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction. As a consequence, peripheral blood flow increases, with no effect on heart rate.
Renal blood flow increases
under the name of a rule, while the glomerular filtration rate (GFR) is usually unchanged.
The antihypertensive activity is maximal between 4 and 6 hours after a single dose and is sustained for at least 24 hours: trough effects are about 87-100 % of peak effects.
The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achieved within a month and persists without the occurrence of tachyphylaxis.
therapy does not lead to a rebound effect.
Perindopril reduces left ventricular hypertrophy.
In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves substantial artery elasticity and decreases the media: lumen ratio of small arteries.
An adjunctive therapy with a thiazide diuretic produces an additive-type of synergy. The combination of an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia induced by the diuretic treatment.
Perindopril reduces automotivediac work by a decrease in pre-load and after-load.
Studies in patients
through heart failure have demonstrated:
– decreased left and right ventricular filling pressures,
– reduced total peripheral vascular resistance,
– increased cardiac output and improved cardiac index.
In comparative studies, the first administration of 2.5 mg of perindopril arginine to patients with mild to moderate heart failure was not associated with any significant reduction of blood pressure
under the name of compared to placebo.
Patients with stable coronary artery disease:
The EUROPA study was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial lasting 4 years.
Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised to 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) (n=6110) or placebo (n=6108).
The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overall, 90% of the patients had a previous myocardial infarction and/or a previous coronary revascularisation. Most of the patients received the study medication on top of conventional therapy including platelet inhibitors, lipid lowering agents and beta-blockers.
The main efficacy criterion was the composite of automobilediovascular mortality, non-fatal myocardial infarction and/or cardiac arrest with successful resuscitation. The treatment with 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) once daily resulted in a significant absolute reduction in the primary endpoint of 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 revascularisation, an absolute reduction of 2.2% corresponding to a RRR of 22.4% (95%CI [12.0; 31.6] – p<0.001) in the primary endpoint was observed by comparison to placebo.
The safety and efficacy of perindopril in kidren and adolescents aged below 18 years have not been established.
In an open, non-comparative clinical study in 62 hypertensive children aged from 2 to 15 years with a glomerular filtration rate > 30 ml/min/1.73 m2, patients received perindopril with an average dose of 0.07 mg/kg. The dose was individualised according to the patient profile and blood pressure response up to a maximum dose of 0.135 mg/kg/day.
59 patients completed the period of three months, and 36 patients completed the extension period of the study, i.e. were followed at least 24 months (mean study duration: 44 months).
Systolic and diastolic blood pressure remained stable from the inclusion to the last
under the name ofsessment in patients previously treated by other antihypertensive treatments, and decreased in naïve patients.
More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last
under the name ofsessment.
The safety was consistent with the known safety profile of perindopril.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
scientific trial data:
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ compromise. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was saw.
Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be
usaged concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour. The plasma half-life of perindopril is equal to 1 hour.
Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours.
As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal.
It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.
The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of perindoprilat to plasma proteins is 20%, principally to angiotensin converting enzyme, but is concentration-dependent.
Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is
up to 17 hours, resulting in steady-state within 4 days.
Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure. Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance).
Dialysis clearance of perindoprilat is equal to 70 ml/min.
Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is reduced by half. However, the quantity of perindoprilat formed is not reduced and therefore no dosage adjustment is required (see sections 4.2 and 4.4).
In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible compromise.
No mutagenicity has been
witnessed in in vitro or in vivo studies.
Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of embryotoxicity or teratogenicity. However, angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects on late foetal development, resulting in foetal death and congenital effects in rodents and rabbits: renal lesions and an increase in peri- and postnatal mortality have been
witnessed. Fertility was not impaired either in male or in female rats.
No carcinogenicity has been
witnessed in long term studies in rats and mice.
Hydrophobic colloidal silica
Sodium starch glycolate (type A)
Copper chlorophyllin (not
Keep the container tightly closed in order to
preserve from moisture.
White polypropylene tablet container equipped with a polyethylene flow reducer and a white opaque stopper containing a desiccant gel.
Box of 5, 10, 14, 20, 28, 30, 50, 60 (60 or 2 containers of 30), 84 (84 or 3 containers of 28), 90 (90 or 3 containers of 30), 100 (100 or 2 containers of 50), 120 (120 or 4 containers of 30) or 500 tablets (500 or 10 containers of 50).
Not all pack sizes may be
No one-of-a-kind requirements.
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