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Active substance(s): PERINDOPRIL ARGININE

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Coversyl arginine 5 mg Orodispersible Tablets


Perindopril arginine.
One orodispersible tablet contains 3.395 mg perindopril corresponding to 5 mg
perindopril arginine.
Excipients with known effect:

0.2 mg aspartame.
For the full list of excipients, see section 6.1.


Orodispersible tablet.
White, round tablet.


Therapeutic indications
Treatment of hypertension.
Heart failure:
Treatment of symptomatic heart failure.
Stable coronary artery disease:
Reduction of risk of cardiac events in patients with a history of myocardial infarction
and/or revascularisation.


Posology and method of administration

The dose should be individualised according to the patient profile (see section 4.4) and blood
pressure response.

- Hypertension:
Coversyl arginine may be used in monotherapy or in combination with other classes of
antihypertensive therapy.
The recommended starting dose is 5 mg given once daily in the morning.
Patients with a strongly 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 function 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.
Special population:
Patients with 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 dose

ClCR 60

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 70 ml/min.
For patients on haemodialysis, the dose should be taken after dialysis.
Patients with hepatic impairment:
No dosage adjustment is necessary in patients with hepatic impairment (see sections 4.4 and
Paediatric population:
The safety and efficacy of perindopril in children 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.
Therefore, use in children and adolescents is not recommended.

Method of administration
For oral use.
Coversyl arginine is recommended to be taken once daily in the morning before a meal.




Hypersensitivity to the active substance, to any of the excipients listed in Section
6.1 or to any other ACE inhibitor;
History of angioedema associated with previous ACE inhibitor therapy;
Hereditary or idiopathic angioedema;
Second and third trimesters of pregnancy (see sections 4.4 and 4.6);
Concomitant use with Aliskiren in patients with diabetes mellitus or renal
impairment (GFR < 60 ml/min/1.73m²) (see sections 4.4 and 4.5).

Special warnings and precautions for use
Stable coronary artery disease:
If an episode of unstable angina pectoris (major or not) occurs during the first month
of perindopril treatment, a careful 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 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 with congestive heart failure who have normal or low blood
pressure, additional lowering of systemic blood pressure may occur with 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 cardiomyopathy:
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 cardiomyopathy.
Renal impairment:
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
function 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
Haemodialysis patients:
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.
Kidney transplantation:
There is no experience regarding the administration of Coversyl arginine in patients
with a recent kidney transplantation.
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 where 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.

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis:
Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL)
apheresis with dextran sulphate have experienced 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 experienced anaphylactoid reactions. In the same patients, these
reactions have been avoided when the ACE inhibitors were temporarily withheld, but
they reappeared upon inadvertent rechallenge.
Hepatic failure:
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
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in
patients receiving ACE inhibitors. In patients with normal renal function 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 function. 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
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
In patients undergoing major surgery or during anaesthesia with agents that 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). 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).
Diabetic patients:
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
The combination of perindopril and potassium-sparing drugs, potassium supplements
or potassium-containing salt substitutes is generally not recommended (see section
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
Hypotension, syncope, stroke, hyperkalaemia, and changes in renal function
(including acute renal failure) have been reported in susceptible individuals,
especially if combining medicinal products that affect this system. Dual blockade of
the renin-angiotensin-aldosterone system by combining an angiotensin converting
enzyme inhibitor (ACEI) with an angiotensin II receptor blocker (ARB) or aliskiren is
therefore not recommended.
Combination with aliskiren is contraindicated in patients with diabetes mellitus or
renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.3 and 4.5).

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE
inhibitor therapy is considered essential, 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.
Contains a source of phenylalanine. May be harmful for people with phenylketonuria.


Interaction with other medicinal products and other forms of interaction
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 as
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.
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-angiotensinaldosterone 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 as angioneurotic oedema (angioedema).
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, see 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 care:
Antidiabetic agents (insulins, oral hypoglycaemic agents):
Epidemiological studies have suggested that 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 combined
treatment and in patients with renal impairment.
Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive
dosage if necessary.
Non-potassium-sparing diuretics:
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 associated non-potassiumsparing diuretic.
In all cases, renal function (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 absence of hyperkalaemia and renal
A close monitoring of the kalaemia and creatinaemia is recommended in the first
month of the treatment once a week at the beginning and, monthly thereafter.
Non-steroidal anti-inflammatory medicinal products (NSAIDs) including aspirin ≥ 3
When ACE-inhibitors are administered simultaneously with non-steroidal antiinflammatory 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
function. The combination should be administered with caution, especially in the
elderly. Patients should be adequately hydrated and consideration should be given to
monitoring renal function after initiation of concomitant therapy, and periodically
Concomitant use which requires some care:
Antihypertensive agents and vasodilators:
Concomitant use of these agents may increase the hypotensive effects of perindopril.
Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may
further reduce blood pressure.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin):
Increased risk of angio-oedema, due to dipeptidyl peptidase IV (DPP-IV) decreased
activity by the gliptin, in patients co-treated with an ACE inhibitor.
Tricyclic antidepressants/Antipsychotics/Anaesthetics:
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


Fertility, pregnancy and lactation
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 second and
third trimesters 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 essential, 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
Exposure to ACE inhibitor therapy during the second and third trimesters is known to
induce human foetotoxicity (decreased renal function, oligohydramnios, skull
ossification retardation) and neonatal toxicity (renal failure, hypotension,
hyperkalaemia) (see section 5.3).

Should exposure to ACE inhibitors have occurred from the second trimester of
pregnancy, ultrasound check of renal function and skull is recommended. Infants
whose mothers have taken ACE inhibitors should be closely observed for
hypotension (see 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.


Effects on ability to drive and use machines
Coversyl arginine has no direct influence on the ability to drive and use 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
As a result the ability to drive or operate machinery may be impaired.


Undesirable effects
a. Summary of safety profile
The safety profile of perindopril is consistent with the safety profile of ACE
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, pruritis, rash, muscle cramps, and asthenia.
b. Tabulated list of adverse reactions
The following undesirable effects have been observed during clinical trials and/or
post-marketing use with perindopril and ranked under the following frequency:
Very common (≥1/10); common (≥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).


Undesirable Effects


System Organ
Blood and the
lymphatic System



Agranulocytosis or pancytopenia

Very rare

Haemoglobin decreased and haematocrit decreased

Very rare


Very rare


Undesirable Effects


System Organ
Haemolytic anaemia in patients with a congenital
deficiency of G-6PDH (see section 4.4)

Very rare


Very rare

Metabolism and
Hypoglycaemia (see sections 4.4 and 4.5)
Nutrition Disorders
Hyperkalaemia, reversible on discontinuation (see
section 4.4)





Mood disturbances


Sleep disorder


Nervous System














Very rare

Eye Disorders

Visual disturbances


Ear and labyrinth



Cardiac Disorders





Angina pectoris (see section 4.4)

Very rare


Very rare

Myocardial infarction, possibly secondary to
excessive hypotension in high risk patients (see
section 4.4)

Very rare

Vascular Disorders Hypotension (and effects related to hypotension)


Stroke possibly secondary to excessive
hypotension in high-risk patients (see section 4.4)
Thoracic and

Very rare








Undesirable Effects


System Organ
Eosinophilic pneumonia

Very rare


Very rare

Abdominal pain














Dry mouth



Very rare


Hepatitis either cytolytic or cholestatic (see section

Very rare

Skin and
Tissue Disorders






Urticaria (see section 4.4)


Angioedema of face, extremities, lips, mucous
membranes, tongue, glottis and/or larynx (see
section 4.4)


Photosensitivity reactions






Erythema multiforme
And Connective
Tissue Disorders

Very rare

Muscle cramps






Renal and Urinary

Renal insufficiency


Acute renal failure

Very rare

System and Breast

Erectile dysfunction


General Disorders Asthenia
and Administration
Chest pain
Site Condition



Undesirable Effects


System Organ
Oedema peripheral


Blood urea increased


Blood creatinine increased


Blood bilirubin increased


Hepatic enzyme increased




Injury, poisoning
and procedural
* Frequency calculated from clinical trials for adverse events detected from
spontaneous report
Clinical trials:
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 perindopriltreated patients, hypotension was observed 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)

Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. 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 Tel: Freephone 0808 100 3352 Website:


Limited data are available for overdose in humans. Symptoms associated with
overdose of ACE inhibitors may include hypotension, circulatory shock, electrolyte
disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia,
dizziness, anxiety, and cough.
The recommended treatment of overdose 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.




Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitor, plain, ATC code: C09A A04
Mechanism of action
Perindopril is an inhibitor of the enzyme that 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 that 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 through 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 as a rule, while the glomerular filtration rate (GFR) is usually
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.
Discontinuation of treatment does not lead to a rebound effect.
Perindopril reduces left ventricular hypertrophy.
In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves
large 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.

Heart failure:
Perindopril reduces cardiac work by a decrease in pre-load and after-load.
Studies in patients with 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 as compared to placebo.
Patients with stable coronary artery disease:
The EUROPA study was a multicentre, international, randomised, double-blind, placebocontrolled 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 cardiovascular 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.
Paediatric use:
The safety and efficacy of perindopril in children 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 assessment
in patients previously treated by other antihypertensive treatments, and decreased in naïve
More than 75% of children had systolic and diastolic blood pressure below the 95th percentile
at their last assessment.
The safety was satisfactory and consistent with the known safety profile of perindopril.


Pharmacokinetic properties

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 approximately 17 hours, resulting in steady-state within 4 days.
Special population
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).


Preclinical safety data
In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney,
with reversible damage.
No mutagenicity has been observed 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 observed. Fertility was not
impaired either in male or in female rats.
No carcinogenicity has been observed in long term studies in rats and mice.




List of excipients
Magnesium stearate (E470B),
Silica colloidal anhydrous (E551),
Spray dried lactose starch compound (lactose monohydrate 85%, maize starch 15%),
Aspartame (E951),
Acesulfame potassium (E950).


Not applicable


Shelf life
2 years


Special precautions for storage
Keep the container tightly closed in order to protect from moisture.


Nature and contents of container
5, 10, 14, 20, 30 or 50 tablets in a polypropylene tablet container equipped with a low
density polyethylene flow reducer and a low density polyethylene stopper containing
a white, silica desiccant gel.
Pack sizes :

1 x 5, 1 x 10, 1 x 14, 1 x 20, 1 x 30 or 1 x 50 tablets
2 x 30 or 2 x 50 tablets
3 x 30 tablets
4 x 30 tablets
10 x 50 tablets

Not all pack sizes may be marketed.


Special precautions for disposal
No special requirements.



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