Skip to Content

COVERSYL ARGININE PLUS 10MG/2.5MG FILM-COATED TABLETS

Active substance(s): INDAPAMIDE / PERINDOPRIL ARGININE / INDAPAMIDE / PERINDOPRIL ARGININE / INDAPAMIDE / PERINDOPRIL ARGININE

View full screen / Print PDF » Download PDF ⇩

PDF Transcript

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
COVERSYL ARGININE PLUS 10 mg/2.5 mg, film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains 6.79 mg perindopril equivalent to 10 mg
perindopril arginine and 2.5 mg indapamide.
Excipient : lactose monohydrate
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
White, round film-coated tablet.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
COVERSYL ARGININE PLUS 10 mg/2.5 mg is indicated as substitution
therapy for treatment of essential hypertension, in patients already controlled
with perindopril and indapamide given concurrently at the same dose level.

4.2

Posology and method of administration
Oral route.

One COVERSYL ARGININE PLUS 10 mg/2.5 mg tablet per day as a single
dose, preferably to be taken in the morning, and before a meal.
Elderly (see section 4.4)
In elderly, the plasma creatinine must be adjusted in relation to age, weight
and gender. Elderly patients can be treated if renal function is normal and after
considering blood pressure response.
Patients with renal impairment (see section 4.4)
In severe and moderate renal impairment (creatinine clearance below 60
ml/min), treatment is contraindicated.
Usual medical follow-up will include frequent monitoring of creatinine and
potassium.
Patients with hepatic impairment (see sections 4.3, 4.4 and 5.2)
In severe hepatic impairment, treatment is contraindicated.
In patients with moderate hepatic impairment, no dose modification is
required.
Children and adolescents
COVERSYL ARGININE PLUS 10 mg/2.5 mg should not be used in children
and adolescents as the efficacy and tolerability of perindopril in children and
adolescents, alone or in combination, have not been established.

4.3

Contraindications

Linked to perindopril:
- Hypersensitivity to perindopril or any other ACE inhibitor
- History of angioedema (Quincke’s oedema) associated with previous ACE inhibitor
therapy
- Hereditary/idiopathic angioedema
- Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
- Concomitant use of Coversyl Arginine Plus 10mg/2.5mg 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).

Linked to indapamide:
- Hypersensitivity to indapamide or to any other sulfonamides
- Hepatic encephalopathy
- Severe hepatic impairment
- Hypokalaemia
- As a general rule, this medicine is inadvisable in combination with non-anti-arrhythmic
agents causing torsades de pointes (see section 4.5)
- Lactation (see section 4.6).
Linked to COVERSYL ARGININE PLUS 10 mg/2.5 mg:
- Hypersensitivity to any of the excipients

- Severe and moderate renal impairment (creatinine clearance below 60 ml/min)
Due to the lack of sufficient therapeutic experience, COVERSYL ARGININE PLUS
10 mg/2.5 mg should not be used in:
- Dialysis patients
- Patients with untreated decompensated heart failure.

4.4

Special warnings and precautions for use

Special warnings
Common to perindopril and indapamide:
Lithium:
The combination of lithium and the combination of perindopril and indapamide is usually not
recommended (see section 4.5).
Linked to perindopril:
Neutropenia/agranulocytosis:
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 preexisting 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, periodical monitoring of white blood cell counts is advised and patients should be
instructed to report any sign of infection (e.g. sore throat, fever).
Hypersensitivity/angioedema:
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported
rarely in patients treated with angiotensin converting enzyme inhibitors, including perindopril.
This may occur at any time during treatment. In such cases perindopril should be discontinued
promptly and appropriate monitoring should be instituted to ensure complete resolution of
symptoms prior to dismissing the patient. In those instances where swelling has been 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, appropriate therapy, which
may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to
ensure a patent airway, should be administered promptly.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of
angioedema compared to non-blacks.
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 desensitisation:
There have been isolated reports of patients experiencing sustained, life-threatening
anaphylactoid reactions while receiving ACE inhibitors during desensitisation treatment with

hymenoptera (bees, wasps) venom. ACE inhibitors should be used with caution in allergic
patients treated with desensitisation, and avoided in those undergoing venom immunotherapy.
However these reactions could be prevented by temporary withdrawal of ACE inhibitor for at
least 24 hours before treatment in patients who require both ACE inhibitors and
desensitisation.
Anaphylactoid reactions during LDL apheresis:
Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis
with dextran sulfate have experienced life-threatening anaphylactoid reactions. These
reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each
apheresis.
Haemodialysis patients:
Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes
(e.g., AN 69®) and treated concomitantly with an ACE inhibitor. In these patients
consideration should be given to using a different type of dialysis membrane or a different
class of antihypertensive agent.
Potassium-sparing diuretics, potassium salts:
The combination of perindopril and potassium-sparing diuretics, potassium salts is usually 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 ACEinhibitors, 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 function, electrolytes
and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in
patients with diabetic nephropathy.

Pregnancy:
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).
Linked to indapamide:
When liver function is impaired, thiazide diuretics and thiazide-related diuretics may cause
hepatic encephalopathy. Administration of the diuretic should be stopped immediately if this
occurs.
Photosensitivity:
Cases of photosensitivity reactions have been reported with thiazides and related thiazides
diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is
recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary,
it is recommended to protect exposed areas to the sun or to artificial UVA.
Precautions for use
Common to perindopril and indapamide:

Renal impairment:
In cases of severe and moderate renal impairment (creatinine clearance < 60 ml/min),
treatment is contraindicated.
In certain hypertensive patients without pre-existing apparent renal lesions and for whom
renal blood tests show functional renal insufficiency, treatment should be stopped and
possibly restarted either at a low dose or with one constituent only.
In these patients usual medical follow-up will include frequent monitoring of potassium and
creatinine, after two weeks of treatment and then every two months during therapeutic
stability period. Renal failure has been reported mainly in patients with severe heart failure or
underlying renal failure including renal artery stenosis.
The drug is not recommended in case of bilateral renal artery stenosis or a single functioning
kidney.
Hypotension and water and electrolyte depletion:
There is a risk of sudden hypotension in the presence of pre-existing sodium depletion (in
particular in individuals with renal artery stenosis). Therefore systematic testing should be
carried out for clinical signs of water and electrolyte depletion, which may occur with an
intercurrent episode of diarrhoea or vomiting. Regular monitoring of plasma electrolytes
should be carried out in such patients.
Marked hypotension may require the implementation of an intravenous infusion of isotonic
saline.
Transient hypotension is not a contraindication to continuation of treatment. After
re-establishment of a satisfactory blood volume and blood pressure, treatment can be started
again either at a reduced dose or with only one of the constituents.
Potassium levels:
The combination of perindopril and indapamide does not prevent the onset of hypokalaemia
particularly in diabetic patients or in patients with renal failure. As with any antihypertensive
agent containing a diuretic, regular monitoring of plasma potassium levels should be carried
out.
Excipients:
COVERSYL ARGININE PLUS 10 mg/2.5 mg should not be administered to patients with
rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption.
Linked to perindopril:
Cough:
A dry cough has been reported with the use of angiotensin converting enzyme inhibitors. It is
characterised by its persistence and by its disappearance when treatment is withdrawn. An
iatrogenic aetiology should be considered in the event of this symptom. If the prescription of
an angiotensin converting enzyme inhibitor is still preferred, continuation of treatment may be
considered.
Children and adolescents:
The efficacy and tolerability of perindopril in children and adolescents, alone or in
combination, have not been established.
Risk of arterial hypotension and/or renal insufficiency (in cases of cardiac insufficiency,
water and electrolyte depletion, etc...):
Marked stimulation of the renin-angiotensin-aldosterone system has been observed
particularly during marked water and electrolyte depletions (strict sodium-free diet or
prolonged diuretic treatment), in patients whose blood pressure was initially low, in cases of
renal artery stenosis, congestive heart failure or cirrhosis with oedema and ascites.

The blocking of this system with an angiotensin converting enzyme inhibitor may therefore
cause, particularly at the time of the first administration and during the first two weeks of
treatment, a sudden drop in blood pressure and/or an increase in plasma levels of creatinine,
showing a functional renal insufficiency. Occasionally this can be acute in onset, although
rare, and with a variable time to onset.
In such cases, the treatment should then be initiated at a lower dose and increased
progressively.
Elderly:
Renal function and potassium levels should be tested before the start of treatment. The dose is
subsequently adjusted according to blood pressure response, especially in cases of water and
electrolyte depletion, in order to avoid sudden onset of hypotension.
Patients with known atherosclerosis:
The risk of hypotension exists in all patients but particular care should be taken in patients
with ischaemic heart disease or cerebral circulatory insufficiency, with treatment being started
at a low dose.
Renovascular hypertension:
The treatment for renovascular hypertension is revascularisation. Nonetheless, angiotensin
converting enzyme inhibitors can be beneficial in patients presenting with renovascular
hypertension who are awaiting corrective surgery or when such a surgery is not possible.
Treatment with COVERSYL ARGININE PLUS 10 mg/2.5 mg is not appropriate in patients
with known or suspected renal artery stenosis because treatment should be started in a
hospital setting at a dose lower than the COVERSYL ARGININE PLUS 10 mg/2.5 mg one.
Other populations at risk:
In patients with severe cardiac insufficiency (grade IV) or in patients with insulin dependent
diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment with
COVERSYL ARGININE PLUS 10 mg/2.5 mg is not appropriate because treatment should be
started under medical supervision with a reduced initial dose. Treatment with beta-blockers in
hypertensive patients with coronary insufficiency should not be stopped: the ACE inhibitor
should be added to the beta-blocker.
Diabetic patients:
The glycaemia levels should be closely monitored in diabetic patients previously treated with
oral anti-diabetic drugs or insulin, namely during the first month of treatment with an ACE
inhibitor.
Ethnic differences:
As with other angiotensin converting enzyme inhibitors, perindopril is apparently 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.
Surgery / anaesthesia:
Angiotensin converting enzyme inhibitors can cause hypotension in cases of anaesthesia,
especially when the anaesthetic administered is an agent with hypotensive potential.
It is therefore recommended that treatment with long-acting angiotensin converting enzyme
inhibitors such as perindopril should be discontinued where possible one day before surgery.
Aortic or mitral valve stenosis / hypertrophic cardiomyopathy:
ACE inhibitors should be used with caution in-patient with an obstruction in the outflow tract
of the left ventricle.
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 4.8).
Hyperkalaemia:
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 potassiumcontaining 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).
Linked to indapamide:
Water and electrolyte balance:
Sodium levels:
These should be tested before treatment is started, then at regular intervals. All diuretic
treatment can cause a reduction in sodium levels, which may have serious consequences.
Reduction in sodium levels can be initially asymptomatic and regular testing is therefore
essential. Testing should be more frequent in elderly and cirrhotic patients (see sections 4.8
and 4.9).
Potassium levels:
Potassium depletion with hypokalaemia is a major risk with thiazide diuretics and thiaziderelated diuretics. The risk of onset of lowered potassium levels (< 3.4 mmol/l) should be
prevented in some high risk populations such as elderly and/or malnourished subjects,
whether or not they are taking multiple medications, cirrhotic patients with oedema and
ascites, coronary patients and patients with heart failure.
In such cases hypokalaemia increases the cardiac toxicity of cardiac glycosides and the risk of
rhythm disorders.
Subjects presenting with a long QT interval are also at risk, whether the origin is congenital or
iatrogenic. Hypokalaemia, as with bradycardia, acts as a factor that favours the onset of
severe rhythm disorders, in particular torsades de pointes, which may be fatal.
In all cases more frequent testing of potassium levels is necessary. The first measurement of
plasma potassium levels should be carried out during the first week following the start of
treatment.
If low potassium levels are detected, correction is required.
Calcium levels:
Thiazide diuretics and thiazide-related diuretics may reduce urinary excretion of calcium and
cause a mild and transient increase in plasma calcium levels. Markedly raised levels of
calcium may be related to undiagnosed hyperparathyroidism. In such cases the treatment
should be stopped before investigating the parathyroid function.
Blood glucose:
Monitoring of blood glucose is important in diabetic patients, particularly when potassium
levels are low.

Uric acid:
Tendency to gout attacks may be increased in hyperuricaemic patients.
Renal function and diuretics:
Thiazide diuretics and thiazide-related diuretics are only fully effective when renal function is
normal or only slightly impaired (creatinine levels lower than approximately 25 mg/l, i.e.
220 µmol/l for an adult).
In the elderly the value of plasma creatinine levels should be adjusted to take account of the
age, weight and sex of the patient, according to the Cockroft formula:
clcr = (140 - age) x body weight / 0.814 x plasma creatinine level
with: age expressed in years
body weight in kg
plasma creatinine level in micromol/l
This formula is suitable for an elderly male and should be adapted for women by multiplying
the result by 0.85.
Hypovolaemia, resulting from the loss of water and sodium caused by the diuretic at the start
of treatment, causes a reduction in glomerular filtration. It may result in an increase in blood
urea and creatinine levels. This transitory functional renal insufficiency is of no adverse
consequence in patients with normal renal function but may however worsen a pre-existing
renal impairment.
Athletes:
Athletes should note that this product contains an active substance that may cause a positive
reaction in doping tests.

4.5

Interaction with other medicinal products and other forms of interaction

Common to perindopril and indapamide:
Concomitant use not recommended:
Lithium: reversible increases in serum lithium concentrations and toxicity have been
reported during concomitant administration of lithium with ACE inhibitors.
Concomitant use of thiazide diuretics may further increase lithium levels and enhance
the risk of lithium toxicity with ACE inhibitors. Use of perindopril combined with
indapamide 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:
- Baclofen: Potentiation of antihypertensive effect. Monitoring of blood pressure and
renal function, and dose adaptation of the antihypertensive if necessary.
- Non-steroidal anti-inflammatory medicinal products (included acetylsalicylic acid
at high doses): when ACE-inhibitors are administered simultaneously with nonsteroidal 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 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 thereafter.
Concomitant use which requires some care:
- Imipramine-like
antidepressants
(tricyclics),
neuroleptics:
Increased
antihypertensive effect and increased risk of orthostatic hypotension (additive
effect).
- Corticosteroids, tetracosactide: Reduction in antihypertensive effect (salt and water
retention due to corticosteroids).
- other antihypertensive agents : Use of other antihypertensive medicinal products
with perindopril/indapamide could result in additional blood pressure lowering
effect.
Linked to perindopril:
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosteronesystem (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).
Concomitant use not recommended:
- Potassium-sparing diuretics (spironolactone, triamterene, alone or in combination),
potassium (salts): ACE inhibitors attenuate diuretic induced potassium loss.
Potassium sparing diuretics e.g. spironolactone, triamterene, or amiloride,
potassium supplements, or potassium-containing salt substitutes may lead to
significant increases in serum potassium (potentially lethal). If concomitant use is
indicated because of documented hypokalaemia they should be used with caution
and with frequent monitoring of serum potassium and by ECG.
Concomitant use which requires special care:
- Antidiabetic agents (insulin, hypoglycaemic sulfonamides): Reported with
captopril and enalapril.
The use of angiotensin converting enzyme inhibitors may increase the
hypoglycaemic effect in diabetics receiving treatment with insulin or with
hypoglycaemic sulfonamides. The onset of hypoglycaemic episodes is very rare
(improvement in glucose tolerance with a resulting reduction in insulin
requirements).
Concomitant use which requires some care:
- Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or
procainamide: Concomitant administration with ACE inhibitors may lead to an
increased risk for leucopenia.
- Anaesthetic drugs: ACE inhibitors may enhance the hypotensive effects of certain
anaesthetic drugs.
- Diuretics (thiazide or loop diuretics): Prior treatment with high dose diuretics may
result in volume depletion and in a risk of hypotension when initiating therapy with
perindopril.

- Gold: 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.
Linked to indapamide:
Concomitant use which requires special care:
- Torsades de pointes inducing drugs: Due to the risk of hypokalaemia, indapamide
should be administered with caution when associated with medicinal products that
induced torsades de pointes such as class IA antiarrhythmic agents (quinidine,
hydroquinidine, disopyramide); class III antiarrhythmic agents (amiodarone,
dofetilide, ibutilide, bretylium, sotalol); some neuroleptics (chlorpromazine,
cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides
(amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol,
haloperidol), other neuroleptics (pimozide); other substances such as bepridil,
cisapride, diphemanil, IV erythromycin, halofantrine, mizolastine, moxifloxacin,
pentamidine, sparfloxacin, IV vincamine, methadone, astemizole, terfenadine.
Prevention of low potassium levels and correction if necessary: monitoring of the
QT interval.
- Potassium-lowering drugs: amphotericin B (IV route), glucocorticoids and
mineralocorticoids (systemic route), tetracosactide, stimulant laxatives: Increased
risk of low potassium levels (additive effect). Monitoring of potassium levels, and
correction if necessary; particular consideration required in cases of treatment with
cardiac glycosides. Non-stimulant laxatives should be used.
- Cardiac glycosides: Low potassium levels favour the toxic effects of cardiac
glycosides. Potassium levels and ECG should be monitored and treatment
reconsidered if necessary.
Concomitant use which requires some care:
- Metformin: Lactic acidosis due to metformin caused by possible functional renal
insufficiency linked to diuretics and in particular to loop diuretics. Do not use
metformin when plasma creatinine levels exceed 15 mg/l (135 micromol/l) in men
and 12 mg/l (110 micromol/l) in women.
- Iodinated contrast media: In cases of dehydration caused by diuretics, there is an
increased risk of acute renal insufficiency, particularly when high doses of
iodinated contrast media are used. Rehydration should be carried out before the
iodinated compound is administered.
- Calcium (salts): Risk of increased levels of calcium due to reduced elimination of
calcium in the urine.
- Ciclosporin: Risk of increased creatinine levels with no change in circulating levels
of ciclosporin, even when there is no salt and water depletion.
4.6

Fertility, pregnancy and lactation

Given the effects of the individual components in this combination product on pregnancy and
lactation,
COVERSYL ARGININE PLUS 2.5mg/0.625mg is not recommended during the first
trimester of pregnancy. COVERSYL ARGININE PLUS 2.5mg/0.625mg is contraindicated
during the second and third trimesters of pregnancy.
COVERSYL ARGININE PLUS 2.5mg/0.625mg is contraindicated during lactation. A
decision should therefore be made whether to discontinue nursing or to discontinue

COVERSYL ARGININE PLUS 2.5mg/0.625mg taking account the importance of this
therapy for the mother.
Pregnancy:
Linked to 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 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 started.
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).
Linked to indapamide:
Prolonged exposure to thiazide during the third trimester of pregnancy can reduce maternal
plasma volume as well as uteroplacental blood flow, which may cause a foeto-placental
ischemia and growth retardation. Moreover, rare cases of hypoglycaemia and
thrombocytopenia in neonates have been reported following exposure near term.
Breastfeeding:
COVERSYL ARGININE PLUS 2.5mg/0.625mg is contra-indicated during lactation.
Linked to perindopril:
Because no information is available regarding the use of perindopril during breastfeeding,
perindopril is not recommended and alternative treatments with better established safety
profiles during breast-feeding are preferable, especially while nursing a newborn or preterm
infant.
Linked to indapamide:
Indapamide is excreted in human milk. Indapamide is closely related to thiazide diuretics
which have been associated, during breast-feeding, with decrease or even suppression of milk
lactation. Hypersensitivity to sulfonamide-derived drugs, hypokalaemia and nuclear icterus
might occur.

4.7

Effects on ability to drive and use machines
Linked to perindopril, indapamide and COVERSYL ARGININE PLUS
10 mg/2.5 mg:

Neither the two active substances nor COVERSYL ARGININE PLUS
10 mg/2.5 mg affect alertness 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.

4.8

Undesirable effects
The administration of perindopril inhibits the renin-angiotensin-aldosterone axis and
tends to reduce the potassium loss caused by indapamide. 6 percent of the patients on
treatment with COVERSYL ARGININE PLUS 10 mg/2.5 mg experience
hypokalaemia (potassium level < 3.4 mmol/l).
The following undesirable effects could be observed during treatment 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).
Blood and the lymphatic system disorders:
Very rare:
Thrombocytopenia, leucopenia/neutropenia, agranulocytosis, aplastic
anaemia, haemolytic anaemia.
Anaemia (see section 4.4) has been reported with angiotensin
converting enzyme inhibitors in specific circumstances (patients who have had
kidney transplants, patients undergoing haemodialysis).
Psychiatric disorders:
Uncommon: mood or sleep disturbances.
Nervous system disorders:
Common: Paraesthesia, headache, dizziness, vertigo.
Very rare: Confusion.
Not known: Syncope
Eye disorders:
Common: Vision disturbance.
Ear and labyrinth disorders:
Common: Tinnitus.
Vascular disorders:
Common: Hypotension whether orthostatic or not (see section 4.4).
Cardiac disorders:
Very rare: Arrhythmia including bradycardia, ventricular tachycardia, atrial
fibrillation, angina pectoris and myocardial infarction possibly secondary to excessive
hypotension in high-risk patients (see section 4.4).
Not known: Torsade de pointes (potentially fatal) (see sections 4.4 and 4.5).

Respiratory, thoracic and mediastinal disorders:
Common:
A dry cough has been reported with the use of angiotensin converting enzyme
inhibitors. It is characterised by its persistence and by its disappearance when
treatment is withdrawn. An iatrogenic aetiology should be considered in the presence
of this symptom. Dyspnoea.
Uncommon: Bronchospasm.
Very rare: Eosinophilic pneumonia, rhinitis.
Gastrointestinal disorders:
Common: Constipation, dry mouth, nausea, vomiting, abdominal pain, dysgeusia,
dyspepsia, diarrhoea.
Very rare: Pancreatitis.
Hepato-biliary disorders:
Very rare: Hepatitis either cytolytic or cholestatic (see section 4.4).
Not known: In case of hepatic insufficiency, there is a possibility of onset of hepatic
encephalopathy (see sections 4.3 and 4.4).
Skin and subcutaneous tissue disorders:
Common: Rash, pruritus, maculopapular eruptions.
Uncommon:
- Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or
larynx, urticaria (see section 4.4).
- Hypersensitivity reactions, mainly dermatological, in subjects with a
predisposition to allergic and asthmatic reactions.
- Purpura.
Possible aggravation of pre-existing acute disseminated lupus erythematosus.
Very rare: erythema multiforme, toxic epidermic necrolysis, Steven Johnson
syndrome.
Cases of photosensitivity reactions have been reported (see section 4.4).
Musculoskeletal, connective tissue and bone disorders:
Common: Muscle cramps.
Renal and urinary disorders:
Uncommon: Renal insufficiency.
Very rare: Acute renal failure.
Reproductive system and breast disorders:
Uncommon: Impotence.
General disorders and administration site conditions:
Common: Asthenia.
Uncommon: Sweating.
Investigations:
Not known:
- Electrocardiogram QT prolonged (see sections 4.4 and 4.5).
- Blood glucose increased and blood uric acid increased during treatment.
- Elevated liver enzyme levels.
- Slight increase in urea and in plasma creatinine levels, reversible when treatment
is stopped. This increase is more frequent in cases of renal artery stenosis, arterial
hypertension treated with diuretics, renal insufficiency.

Metabolism and nutrition disorder:
Rare : Hypercalcemia.
Not known:
- Potassium depletion with hypokalaemia particularly serious in certain high risk
populations (see section 4.4).
- Increased levels of potassium, usually transitory.
- Hyponatraemia with hypovolaemia responsible for dehydration and orthostatic
hypotension.

4.9

Overdose
The most likely adverse reaction in cases of overdose is hypotension,
sometimes associated with nausea, vomiting, cramps, dizziness, sleepiness,
mental confusion, oliguria which may progress to anuria (due to
hypovolaemia). Salt and water disturbances (low sodium levels, low potassium
levels) may occur.
The first measures to be taken consist of rapidly eliminating the product(s)
ingested by gastric lavage and/or administration of activated charcoal, then
restoring fluid and electrolyte balance in a specialised centre until they return
to normal.
If marked hypotension occurs, this can be treated by placing the patient in a
supine position with the head lowered. If necessary an intravenous infusion of
isotonic saline may be given, or any other method of volaemic expansion may
be used.
Perindoprilat, the active form of perindopril, can be dialysed (see section 5.2).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: perindopril and diuretics, ATC code: C09BA04
COVERSYL ARGININE PLUS 10 mg/2.5 mg is a combination of perindopril arginine salt,
an angiotensin converting enzyme inhibitor, and indapamide, a chlorosulfamoyl diuretic. Its
pharmacological properties are derived from those of each of the components taken
separately, in addition to those due to the additive synergic action of the two products when
combined.
Pharmacological mechanism of action
Linked to perindopril:
Perindopril is an inhibitor of the angiotensin converting enzyme (ACE inhibitor) which
converts angiotensin I to angiotensin II, a vasoconstricting substance; in addition the enzyme
stimulates the secretion of aldosterone by the adrenal cortex and stimulates the degradation of
bradykinin, a vasodilatory substance, into inactive heptapeptides.
This results in:

-

a reduction in aldosterone secretion,
an increase in plasma renin activity, since aldosterone no longer exercises negative
feedback,
a reduction in total peripheral resistance with a preferential action on the vascular bed in
muscle and the kidney, with no accompanying salt and water retention or reflex
tachycardia, with chronic treatment.

The antihypertensive action of perindopril also occurs in patients with low or normal renin
concentrations.
Perindopril acts through its active metabolite, perindoprilat. The other metabolites are
inactive.
Perindopril reduces the work of the heart:
- by a vasodilatory effect on veins, probably caused by changes in the metabolism of
prostaglandins : reduction in pre-load,
- by reduction of the total peripheral resistance: reduction in afterload.
Studies carried out on patients with cardiac insufficiency have shown:
- a reduction in left and right ventricular filling pressures,
- a reduction in total peripheral vascular resistance,
- an increase in cardiac output and an improvement in the cardiac index,
- an increase in regional blood flow in muscle.
Exercise test results also showed improvement.
Linked to indapamide:
Indapamide is a sulfonamide derivative with an in-dole ring, pharmacologically related to the
thiazide group of diuretics. Indapamide inhibits the reabsorption of sodium in the cortical
dilution segment. It increases the urinary excretion of sodium and chlorides and, to a lesser
extent, the excretion of potassium and magnesium, thereby increasing urine output and having
an antihypertensive action.
Characteristics of antihypertensive action
Linked to COVERSYL ARGININE PLUS 10 mg/2.5 mg:
In hypertensive patients regardless of age, COVERSYL ARGININE PLUS 10 mg/2.5 mg
exerts a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure
whilst supine or standing.
PICXEL, a multicentre, randomised, double blind active controlled study has assessed on
echocardiography the effect of perindopril/indapamide combination on LVH versus enalapril
monotherapy.
In PICXEL, hypertensive patients with LVH (defined as left ventricular mass index (LVMI) >
120 g/m2 in male and > 100 g/m2 in female) were randomised either to perindopril tertbutylamine 2 mg (equivalent to 2.5 mg perindopril arginine)/indapamide 0.625 mg or to
enalapril 10 mg once a day for a one-year treatment. The dose was adapted according to blood
pressure control, up to perindopril tert-butylamine 8 mg (equivalent to 10 mg perindopril
arginine) and indapamide 2.5 mg or enalapril 40 mg once a day. Only 34% of the subjects
remained treated with perindopril tert-butylamine 2mg (equivalent to 2.5 mg perindopril
arginine)/indapamide 0.625mg (versus 20% with Enalapril 10mg).
At the end of treatment, LVMI had decreased significantly more in the
perindopril/indapamide group
(-10.1 g/m²) than in the enalapril group (-1.1 g/m²) in the all randomised patients population.
The between group difference in LVMI change was -8.3 (95% CI (-11.5,-5.0), p < 0.0001).
A better effect on LVMI was reached with perindopril 8 mg (equivalent to 10 mg perindopril
arginine)/indapamide 2.5 mg dose.

Regarding blood pressure, the estimated mean between-group differences in the randomised
population were -5.8 mmHg (95% CI (-7.9, -3.7), p < 0.0001) for systolic blood pressure and
-2.3 mmHg (95% CI (-3.6,-0.9), p = 0.0004) for diastolic blood pressure respectively, in
favour of the perindopril/indapamide group.
Linked to perindopril:
Perindopril is active in all grades of hypertension: mild to moderate or severe. A reduction in
systolic and diastolic arterial pressure is observed in the lying and standing position.
The antihypertensive activity after a single dose is maximal at between 4 and 6 hours and is
maintained over 24 hours.
There is a high degree of residual blocking of angiotensin converting enzyme at 24 hours,
approximately 80%.
In patients who respond, normalised blood pressure is reached after one month and is
maintained without tachyphylaxis.
Withdrawal of treatment has no rebound effect on hypertension.
Perindopril has vasodilatory properties and restores elasticity of the main arterial trunks,
corrects histomorphometric changes in resistance arteries and produces a reduction in left
ventricular hypertrophy.
If necessary, the addition of a thiazide diuretic leads to an additive synergy.
The combination of an angiotensin converting enzyme inhibitor with a thiazide diuretic
decreases the hypokalaemia risk associated with the diuretic alone.
Linked to indapamide:
Indapamide, as monotherapy, has an antihypertensive effect which lasts for 24 hours. This
effect occurs at doses at which the diuretic properties are minimal.
Its antihypertensive action is proportional to an improvement in arterial compliance and a
reduction in total and arteriolar peripheral vascular resistance.
Indapamide reduces left ventricular hypertrophy.
When a dose of thiazide diuretic and thiazide-related diuretics is exceeded, the
antihypertensive effect reaches a plateau, whereas the adverse effects continue to increase. If
the treatment is ineffective, the dose should not be increased.
Furthermore, it has been shown that in the short-term, mid-term and long-term in
hypertensive patients, indapamide :
- has no effect on lipid metabolism : triglycerides, LDL-cholesterol and HDL-cholesterol,
- has no effect on carbohydrate metabolism, even in diabetic hypertensive patients.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) clinical 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
damage. 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 observed.
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 used
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.

5.2

Pharmacokinetic properties
Linked to COVERSYL ARGININE PLUS 10 mg/2.5 mg:
The co-administration of perindopril and indapamide does not change their
pharmacokinetic properties by comparison to separate administration.
Linked to perindopril:
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 pro-drug. 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 salt 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.
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).
Linked to indapamide:
Indapamide is rapidly and completely absorbed from the digestive tract.

The peak plasma level is reached in humans approximately one hour after oral
administration of the product. Plasma protein binding is 79 %.
The elimination half-life is between 14 and 24 hours (average 18 hours).
Repeated administration does not produce accumulation. Elimination is mainly
in the urine (70 % of the dose) and faeces (22 %) in the form of inactive
metabolites.
The pharmacokinetics are unchanged in patients with renal insufficiency.

5.3

Preclinical safety data
Perindopril/indapamide combination has slightly increased toxicity than that
of its components. Renal manifestations do not seem to be potentiated in the
rat. However, the combination produces gastro-intestinal toxicity in the dog
and the toxic effects on the mother seem to be increased in the rat (compared
to perindopril).
Nonetheless, these adverse effects are shown at dose levels corresponding to a
very marked safety margin by comparison to the therapeutic doses used.
Related to perindopril:
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 fetal development, resulting in fetal death and congenital effects in rodents
and rabbits: renal lesions and an increase in peri- and postnatal mortality have
been observed.
No carcinogenicity has been observed in long-term studies in rats and mice.
Related to indapamide:
The highest doses administered orally to different animal species (40 to 8000
times the therapeutic dose) have shown an exacerbation of the diuretic
properties of indapamide. The major symptoms of poisoning during acute
toxicity studies with indapamide administered intravenously or intraperitoneally were related to the pharmacological action of indapamide, i.e.
bradypnoea and peripheral vasodilation.
Indapamide has been tested negative concerning mutagenic and carcinogenic
properties.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Core:
Lactose monohydrate
Magnesium stearate (E470B)
Maltodextrin
Silica colloidal anhydrous (E551)
Sodium starch glycolate (type A)
Film-coating:
Glycerol (E422)
Hypromellose (E464)
Macrogol 6000
Magnesium stearate (E470B)
Titanium dioxide (E171)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life

3 years.
6.4

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

6.5

Nature and contents of container
14, 20, 28, 30 or 50 tablets in polypropylene tablet container equipped with a
low density polyethylene flow reducer and a low density polyethylene stopper
containing a white desiccant gel.
Pack sizes:
1 x 14, 1 x 20, 1 x 28, 1 x 30 or 1 x 50 tablets

2 x 28, 2 x 30 or 2 x 50 tablets
3 x 30 tablets
10 x 50 tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER

Les Laboratoires Servier
50, rue Carnot
92284 Suresnes cedex
France

8

MARKETING AUTHORISATION NUMBER(S)
PL 05815/0071

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/02/2009

10

DATE OF REVISION OF THE TEXT
15/12/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide