Perindopril arginine Actavis 5 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

16-05-2019

Produktens egenskaper Produktens egenskaper (SPC)

16-05-2019

Aktiva substanser:
perindoprilarginin
Tillgänglig från:
Actavis Group PTC ehf.
ATC-kod:
C09AA04
INN (International namn):
perindopril arginine
Dos:
5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
perindoprilarginin 5 mg Aktiv substans; laktosmonohydrat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 5 tabletter; Blister, 120 tabletter; Blister, 100 tabletter; Blister, 90 tabletter; Blister, 60 tabletter; Blister, 50 tabletter; Blister, 30 tabletter; Blister, 20 tabletter; Blister, 14 tabletter; Blister, 10 tabletter; Burk, 30 tabletter; Burk, 500 tabletter; Burk, 90 tabletter; Burk, 60 tabletter
Bemyndigande status:
Avregistrerad
Godkännandenummer:
52058
Tillstånd datum:
2016-01-14

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

16-05-2019

Produktens egenskaper Produktens egenskaper - engelska

16-05-2019

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

02-03-2016

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Package leaflet: Information for the user

Perindopril arginine Actavis 5 mg film-coated tablets

Perindopril arginine

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Perindopril arginine Actavis is and what it is used for

What you need to know before you take Perindopril arginine Actavis

How to take Perindopril arginine Actavis

Possible side effects

How to store Perindopril arginine Actavis

Contents of the pack and other information

1.

What Perindopril arginine Actavis is and what it is used for

Perindopril arginine Actavis is an angiotensin converting enzyme (ACE) inhibitor. These work by

widening the blood vessels, which makes it easier for your heart to pump blood through them.

Perindopril arginine Actavis is used:

to treat high blood pressure (hypertension)

to treat heart failure (a condition where the heart is unable to pump enough blood to meet the

body’s needs)

to reduce the risk of cardiac events, such as heart attack, in patients with stable coronary artery

disease (a condition where the blood supply to the heart is reduced or blocked) and who have

already had a heart attack and/or an operation to improve the blood supply to the heart by

widening the vessels that supply it

2.

What you need to know before you take Perindopril arginine Actavis

Do not take Perindopril arginine Actavis

if you are allergic to perindopril, to any other ACE inhibitor or any of the other ingredients of

this medicine (listed in section 6)

if you have experienced symptoms such as wheezing, swelling of the face, tongue or throat,

intense itching or severe skin rashes with previous ACE inhibitor treatment or if you or a

member of your family have had these symptoms in any other circumstances (a condition called

angioedema)

if you are more than 3 months pregnant. (It is also better to avoid Perindopril arginine Actavis

in early pregnancy – see pregnancy section.)

if you have diabetes or impaired kidney function and you are treated with a blood pressure

lowering medicine containing aliskiren

Warnings and precautions

Talk to your doctor or pharmacist before taking Perindopril arginine Actavis

if you have aortic stenosis (narrowing of the main blood vessel leading from the heart) or

hypertrophic cardiomyopathy (heart muscle disease) or renal artery stenosis (narrowing of the

artery supplying the kidney with blood)

if you have any other heart problems

if you have liver problems

if you have kidney problems or if you are receiving dialysis

if you suffer from a collagen vascular disease (disease of the connective tissue) such as systemic

lupus erythematosus or scleroderma

if you have diabetes

if you are on a salt restricted diet or use salt substitutes which contain potassium

if you are to undergo anaesthesia and/or major surgery

if you are to undergo LDL apheresis (which is removal of cholesterol from your blood by a

machine)

if you are going to have desensitization treatment to reduce the effects of an allergy to bee or

wasp stings

if you have recently suffered from diarrhoea or vomiting, or are dehydrated

if you are taking any of the following medicines used to treat high blood pressure:

an angiotensin II receptor blocker (ARBs) (also known as sartans – for example valsartan,

telmisartan, irbesartan), in particular if you have diabetes-related kidney problems.

aliskiren.

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes

(e.g. potassium) in your blood at regular intervals.

See also information under the heading “Do not take Perindopril arginine Actavis”.

if you are taking any of the following medicines, the risk of angioedema (rapid swelling under

the skin in area such as the throat) is increased:

racecadotril (used to treat diarrhea)

sirolimus, everolimus, temsirolimus and other drugs belonging to the class of so-called

mTor inhibitors (used to avoid rejection of transplanted organs)

if you are of black origin since you may have a higher risk of angioedema and this medicine

may be less effective in lowering you blood pressure than in non-black patients.

Angioedema

Angioedema (a severe allergic reaction with swelling of the face, lips, tongue or throat with difficulty

in swallowing or breathing) has been reported in patients treated with ACE inhibitors, including

Perindopril arginine Actavis. This may occur at any time during treatment. If you develop such

symptoms, you should stop taking Perindopril arginine Actavis and see a doctor immediately. See also

section 4.

You must tell your doctor if you think that you are (or might become) pregnant. Perindopril arginine

Actavis is not recommended in early pregnancy, and must not be taken if you are more than 3 months

pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

Children and adolescents

The use of perindopril in children and adolescents up to the age of 18 years is not recommended.

Other medicines and Perindopril arginine Actavis

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

Treatment with Perindopril arginine Actavis can be affected by other medicines. These include:

other medicines for high blood pressure, including angiotensin II receptor blocker (ARB) or

aliskiren (see also information under the headings “Do not take Perindopril arginine Actavis”

and “Warnings and precautions” or diuretics (medicines which increase the amount of urine

produced by the kidneys)

potassium-sparing drugs (e.g. triamterene, amiloride), potassium supplements or

potassium-containing salt substitutes, other drugs which can increase potassium in your body:

heparin (medicines used to thin blood)

trimethoprim and co-trimoxazole also known as trimethoprim/sulfamethoxazole (for the

treatment of infections)

potassium-sparing drugs used in treatment of heart failure: eplerenone and spironolactone at

doses between 12.5 mg to 50 mg per day

lithium for mania or depression

non-steroidal anti-inflammatory drugs (e.g. ibuprofen) for pain relief or high dose aspirin

medicines to treat diabetes (such as insulin or metformin)

baclofen (used to treat muscle stiffness on diseases such as multiple sclerosis)

medicines to treat mental disorders such as depression, anxiety, schizophrenia etc. (e.g. tricyclic

antidepressants, antipsychotics)

medicines, which is most often used to treat diarrhea (racecadotril) or avoid rejection of

transplanted organs (sirolimus, everolimus, temsirolimus and other drugs belonging to the class

of so-called mTor inhibitors). See section “Warnings and precautions”

immunosuppressants (medicines which reduce the defence mechanism of the body) used for the

treatment of auto-immune disorders or following transplant surgery (e.g. ciclosporin,

tacrolimus)

estramustine (used in cancer therapy)

allopurinol (for the treatment of gout)

procainamide (for the treatment of an irregular heartbeat)

vasodilators including nitrates (products that make the blood vessels become wider)

medicines used for the treatment of low blood pressure, shock or asthma (e.g. ephedrine,

noradrenaline or adrenaline)

gold salts, especially with intravenous administration (used to treat rheumatoid polyarthritis)

Perindopril arginine Actavis with food and drink

It is preferable to take Perindopril arginine Actavis before a meal.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

Pregnancy

You must tell your doctor if you think that you are (or might become) pregnant. Your doctor will

normally advise you to stop taking Perindopril arginine Actavis before you become pregnant or as

soon as you know you are pregnant and will advise you to take another medicine instead of

Perindopril arginine Actavis. Perindopril arginine Actavis is not recommended in early pregnancy, and

must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if

used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Perindopril arginine Actavis

is not recommended for mothers who are breast-feeding, and your doctor may choose another

treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born

prematurely.

Driving and using machines

Perindopril arginine Actavis usually does not affect alertness but dizziness or weakness due to low

blood pressure may occur in certain patients. If you are affected in this way, your ability to drive or to

operate machinery may be impaired.

Perindopril arginine Actavis contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor

before taking this medicinal product.

3.

How to take Perindopril arginine Actavis

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

Swallow your tablet with a glass of water, preferably at the same time each day, in the morning, before

a meal. Your doctor will decide on the correct dose for you.

Perindopril arginine Actavis 5 mg tablets can be divided into equal doses.

The recommended dosages are as follows:

High blood pressure: the usual starting and maintenance dose is 5 mg once daily. After one month, this

can be increased to 10 mg once a day if required. 10 mg a day is the maximum recommended dose for

high blood pressure.

If you are 65 or older, the usual starting dose is 2.5 mg once a day. After a month this can be increased

to 5 mg once a day and then if necessary to 10 mg once daily.

Heart failure: the usual starting dose is 2.5 mg once daily. After two weeks, this can be increased to

5 mg once a day, which is the maximum recommended dose for heart failure.

Stable coronary artery disease: the usual starting dose is 5 mg once daily. After two weeks, this can be

increased to 10 mg once daily, which is the maximum recommended dose in this indication. If you are

65 or older, the usual starting dose is 2.5 mg once a day. After a week this can be increased to 5 mg

once a day and after a further week to 10 mg once daily.

Use in children and adolescents

Use in children and adolescents is not recommended.

If you take more Perindopril arginine Actavis than you should

If you take too many tablets, contact your nearest accident and emergency department or tell your

doctor immediately. The most likely effect in case of overdose is low blood pressure which can make

you feel dizzy or faint. If this happens, lying down with the legs raised can help.

If you forget to take Perindopril arginine Actavis

It is important to take your medicine every day as regular treatment works better. However, if you

forget to take a dose of Perindopril arginine Actavis, take the next dose at the usual time. Do not take a

double dose to make up for a forgotten dose.

If you stop taking Perindopril arginine Actavis

As the treatment with Perindopril arginine Actavis is usually life-long, you should discuss with your

doctor before stopping this medicinal product.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking the medicinal product and see a doctor immediately, if you experience any of the

following side effects:

swelling of the face, lips, mouth, tongue or throat, difficulty in breathing (angioedema) (see

section 3 “Warnings and precautions”) (uncommon – may affect up to 1 in 100 people)

severe dizziness or fainting due to low blood pressure (common – may affect up to 1 in 10

people)

unusual fast or irregular heart beat, chest pain (angina) or heart attack (very rare – may affect up

to 1 in 10,000 people)

weakness of arms or legs, or problems speaking which could be sign of a possible stroke (very

rare - may affect up to 1 in 10,000 people)

sudden wheeziness, chest pain, shortness of breath, or difficulty in breathing (bronchospasm)

(uncommon - may affect up to 1 in 100 people)

inflamed pancreas which may cause severe abdominal and back pain accompanied with feeling

very unwell (very rare - may affect up to 1 in 10,000 people)

yellowing of the skin or eyes (jaundice) which could be a sign of hepatitis (very rare - may

affect up to 1 in 10,000 people)

skin rash which often starts with red itchy patches on your face, arms or legs (erythema

multiforme) (very rare - may affect up to 1 in 10,000 people)

Tell your doctor if you notice any of the following side effects:

Common (may affect up to 1 in 10 people):

dizziness,

headache,

pins and needles,

vertigo,

vision disturbances,

tinnitus (sensation of noises in the ears),

cough,

shortness of breath (dyspnoea),

gastrointestinal disorders (nausea, vomiting, abdominal pain, taste disturbances, dyspepsia or

difficulty of digestion, diarrhoea, constipation),

allergic reactions (such as skin rashes, itching),

muscle cramps,

feeling of weakness.

Uncommon (may affect up to 1 in 100 people):

excess of eosinophils (a type of white blood cells),

change in laboratory parameters: hypoglycaemia (very low blood sugar level) in case of diabetic

patients, high blood level of potassium reversible on discontinuation, low level of sodium,

increased blood urea, and increased blood creatinine.

mood swings,

sleep disturbances,

somnolence,

fainting,

palpitations,

tachycardia,

vasculitis (inflammation of blood vessels),

dry mouth,

photosensitivity reaction (increased sensitivity of the skin to sun),

formation of blister clusters over the skin,

sweating,

arthralgia (joint pain),

myalgia (muscle pain),

kidney problems,

impotence,

chest pain,

malaise,

oedema peripheral,

fever,

intense itching or severe skin rashes,

fall,

Rare (may affect up to 1 in 1,000 people):

changes in laboratory parameters: increased level of liver enzymes, high level of serum

bilirubin,

psoriasis worsening.

Very rare (may affect up to 1 in 10,000 people):

changes in blood values such as a lower number of white and red blood cells, lower

haemoglobin, lower number of blood platelets.

confusion,

eosinophilic pneumonia (a rare type of pneumonia),

rhinitis (blocked up or runny nose),

acute renal failure.

Not known (frequency cannot be estimated from available data):

discoloration, numbness and pain in fingers or toes (Raynaud’s phenomenon).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety of

this medicine.

5.

How to store Perindopril arginine Actavis

Keep this medicine out of the sight and reach of children.

Blisters: Do not store above 30°C. Store in original package in order to protect from moisture.

Tablet container: Keep the bottle tightly closed in order to protect from moisture.

Do not use this medicine after the expiry date which is stated on the label, carton or bottle after

“EXP”. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Perindopril arginine Actavis contains

The active substance is perindopril arginine. Each tablet contains 5 mg perindopril arginine.

The other ingredients are:

Tablet core:

Magnesium stearate, silica, hydrophobic colloidal, sodium starch glycolate

(type A), glycerol dibehenate, maltodextrin, lactose monohydrate

Film-coating:

Polyvinyl alcohol-part. hydrolyzed (E1203), titanium dioxide (E171), macrogol

(E1521), talc (E553b)

What Perindopril arginine Actavis looks like and contents of the pack

Perindopril arginine Actavis 5 mg film-coated tablets are white, oval, biconvex with side score and

with two dots on one side. The tablet can be divided into equal doses.

The tablet container contains a desiccant, do not eat the desiccant

Pack sizes:

Blister packs (OPA/Al/PVC/Al): 5, 10, 14, 20, 30, 50, 60, 90, 100 and 120 film-coated tablets

Tablet container (HDPE): 30, 60, 90 and 500 film-coated tablets

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

This medicinal product is authorised in the Member States of the EEA under the following

names:

[To be completed nationally]

This leaflet was last revised in <{MM/YYYY}> <{month YYYY

}>.

05/2019

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Perindopril arginine Actavis 5 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg perindopril arginine equivalent to 3.395 mg perindopril.

Excipient with known effect:

Each film-coated tablet contains 70.78 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

Perindopril arginine Actavis 5 mg film-coated tablets are white, 8 x 4 mm oval, biconvex with side

scores and with two dots on one side. The tablet can be divided into equal doses.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hypertension:

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.

4.2

Posology and method of administration

Posology

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

response.

Hypertension:

Perindopril arginine Actavis may be used in monotherapy or in combination with other classes of

anti-hypertensive therapy (see sections 4.3, 4.4, 4.5 and 5.1).

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 Perindopril arginine Actavis;

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 Perindopril

arginine Actavis (see section 4.4).

In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Perindopril

arginine Actavis should be initiated with a 2.5 mg dose. Renal function and serum potassium should

be monitored. The subsequent dosage of Perindopril arginine Actavis 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 Perindopril arginine Actavis, 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 Perindopril arginine

Actavis. Blood pressure, renal function and serum potassium should be monitored closely, both before

and during treatment with Perindopril arginine Actavis (see section 4.4).

Stable coronary artery disease:

Perindopril arginine Actavis 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

≥ 60

5 mg per day

30 < Cl

< 60

2.5 mg per day

15 < Cl

< 30

2.5 mg every other day

Haemodialysed patients*

< 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 5.2).

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.

It is recommended that Perindopril arginine Actavis is taken once daily in the morning before a meal.

4.3

Contraindications

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);

The concomitant use of Perindopril arginine Actavis with aliskiren-containing products is

contraindicated in patients with diabetes mellitus or renal impairment (GFR

< 60 ml/min/1.73 m

) (see sections 4.5 and 5.1).

4.4

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.

Hypotension:

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 with congestive heart failure who have normal or low blood pressure, additional

lowering of systemic blood pressure may occur with Perindopril arginine Actavis. This effect is

anticipated and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic,

a reduction of dose or discontinuation of Perindopril arginine Actavis may be necessary.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy:

As with other ACE inhibitors, Perindopril arginine Actavis 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 Perindopril arginine Actavis 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 Perindopril

arginine Actavis 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

Perindopril arginine Actavis may be required.

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 anti-hypertensive agent.

Kidney transplantation:

There is no experience regarding the administration of Perindopril arginine Actavis in patients with a

recent kidney transplantation.

Hypersensitivity/Angioedema:

Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been

reported rarely in patients treated with ACE inhibitors, including Perindopril arginine Actavis (see

section 4.8). This may occur at any time during therapy

.

In such cases, Perindopril arginine Actavis

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.

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

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 4.8).

Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia:

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).

Race:

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:

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.

Surgery/Anaesthesia:

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension,

Perindopril arginine Actavis 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.

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, inter-current 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).

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).

Lithium:

The combination of lithium and perindopril is generally not recommended (see section 4.5).

Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes:

The combination of perindopril and potassium sparing diuretics, 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 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).

Excipients:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or

glucose-galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Racecadotril:

ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk may be elevated when

used 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).

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk

for hyperkalaemia (see section 4.4).

Drugs inducing hyperkalaemia

Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: potassium salts,

potassium-sparing diuretics, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or

tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalaemia.

Dual blockade of the renin angiotensin aldosterone system (RAAS):

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).

Concomitant use not recommended (see section 4.4):

Estramustine:

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

Lithium:

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.

Baclofen:

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-potassium-sparing 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 impairment.

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 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 anti-hypertensive 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:

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 angioedema, 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:

Sympathomimetics may reduce the anti-hypertensive effects of ACE inhibitors.

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.

4.6

Fertility, pregnancy and lactation

Pregnancy:

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

inhibitor 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 also sections 4.3 and 4.4).

Breastfeeding:

Because no information is available regarding the use of Perindopril arginine Actavis during

breast-feeding, Perindopril arginine Actavis is not recommended and alternative treatments with better

established safety profiles during breast-feeding are preferable, especially while nursing a newborn or

preterm infant.

Fertility:

There was no effect on reproductive performance or fertility

4.7

Effects on ability to drive and use machines

Perindopril arginine Actavis 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 anti-hypertensive medication.

As a result the ability to drive or operate machinery may be impaired.

4.8

Undesirable effects

Summary of the safety 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.

Tabulated list of adverse reactions

The following undesirable effects have been observed during treatment with perindopril and ranked

under the following frequency:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000

to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

MedDRA

System Organ Class

Undesirable effects

Frequency

Eosinophilia

Uncommon*

Agranulocytosis or pancytopenia

Very rare

Haemoglobin decreased and haematocrit

decreased

Very rare

Leucopenia/neutropenia

Very rare

Haemolytic anaemia in patients with a

congenital deficiency of G-6PDH (see section

4.4)

Very rare

Blood and lymphatic system

disorders

Thrombocytopenia

Very rare

Hypoglycaemia (see sections 4.4 and 4.5)

Uncommon*

Metabolism and nutrition

disorders

Hyperkalaemia, reversible on discontinuation

Uncommon*

(see section 4.4)

Hyponatraemia

Uncommon*

Mood disturbances

Uncommon

Psychiatric disorders

Sleep disorder

Uncommon

Dizziness

Common

Headache

Common

Paraesthesia

Common

Vertigo

Common

Somnolence

Uncommon*

Syncope

Uncommon*

Nervous System disorders

Confusion

Very rare

Eye Disorders

Visual disturbances

Common

Ear and labyrinth disorders

Tinnitus

Common

Palpitations

Uncommon*

Tachycardia

Uncommon*

Angina pectoris (see section 4.4)

Very rare

Arrhythmia

Very rare

Cardiac Disorders

Myocardial infarction, possibly secondary to

excessive hypotension in high risk patients (see

section 4.4)

Very rare

Hypotension (and effects related to hypotension)

Common

Vasculitis

Uncommon*

Stroke possibly secondary to excessive

hypotension in high-risk patients (see section

4.4)

Very rare

Vascular Disorders

Raynaud’s phenomenon

Not known

Cough

Common

Dyspnoea

Common

Bronchospasm

Uncommon

Eosinophilic pneumonia

Very rare

Respiratory, thoracic and

mediastinal disorders

Rhinitis

Very rare

Abdominal pain

Common

Constipation

Common

Diarrhoea

Common

Dysgeusia

Common

Dyspepsia

Common

Nausea

Common

Vomiting

Common

Dry mouth

Uncommon

Gastrointestinal Disorders

Pancreatitis

Very rare

Hepatobiliary disorders

Hepatitis either cytolytic or cholestatic (see

section 4.4)

Very rare

Pruritis

Common

Rash

Common

Urticaria (see section 4.4)

Uncommon

Angioedema of face, extremities, lips, mucous

membranes, tongue, glottis and/or larynx (see

section 4.4)

Uncommon

Photosensitivity reactions

Uncommon*

Pemphigoid

Uncommon*

Hyperhidrosis

Uncommon

Psoriasis aggravation

Rare

Skin and subcutaneous tissue

disorders

Erythema multiforme

Very rare

Muscle cramps

Common

Musculoskeletal and

connective tissue disorders

Arthralgia

Uncommon*

Myalgia

Uncommon*

Renal insufficiency

Uncommon

Renal and urinary disorders

Acute renal failure

Very rare

Reproductive system and

breast Disorders

Erectile dysfunction

Uncommon

Asthenia

Common

Chest pain

Uncommon*

Malaise

Uncommon*

Oedema peripheral

Uncommon*

General disorders and

administration site condition

Pyrexia

Uncommon*

Blood urea increased

Uncommon*

Blood creatinine increased

Uncommon*

Blood bilirubin increased

Rare

Investigations

Hepatic enzyme increased

Rare

Injury, poisoning and

procedural complications

Fall

Uncommon*

* 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 perindopril-treated 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) respectively.

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 national reporting system

listed in Appendix V.

4.9

Overdose

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.

5.

PHARMACOLOGICAL PROPERTIES

5.1

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

Hypertension:

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 unchanged.

The anti-hypertensive 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, 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 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 population:

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 m

, 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 patients.

More than 75% of children had systolic and diastolic blood pressure below the 95

percentile at their

last assessment.

The safety was consistent with the known safety profile of perindopril.

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 the 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

Absorption

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

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.

Distribution

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.

Elimination

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).

5.3

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

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.

No carcinogenicity has been observed in long-term studies in rats and mice.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Magnesium stearate

Silica, hydrophobic colloidal

Sodium starch glycolate (type A)

Glycerol dibehenate

Maltodextrin

Lactose monohydrate

Film-coating:

Polyvinyl alcohol part. hydrolyzed (E1203)

Titanium dioxide (E171)

Macrogol 3350 (E1521)

Talc (E553b)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

18 months

6.4

Special precautions for storage

Blisters: Do not store above 30°C. Store in original package in order to protect from moisture.

HDPE bottle: Keep the bottle tightly closed in order to protect from moisture.

6.5

Nature and contents of container

OPA/Aluminium/PVC/Aluminium blister

HDPE bottle containing 2 desiccants, sealed with foil and closed with child-resistant closure (PP).

Pack sizes:

Blister: 5, 10, 14, 20, 30, 50, 60, 90, 100 and 120 film-coated tablets

HDPE bottle: 30, 60, 90 and 500 film-coated tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2019-05-16

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