Avancardo 5 mg/1,25 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

11-10-2019

Produktens egenskaper Produktens egenskaper (SPC)

27-05-2019

Aktiva substanser:
indapamidhemihydrat; perindoprilarginin
Tillgänglig från:
Actavis Group PTC ehf.
ATC-kod:
C09BA04
INN (International namn):
indapamidhemihydrat; perindopril arginine
Dos:
5 mg/1,25 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
perindoprilarginin 5 mg Aktiv substans; laktosmonohydrat Hjälpämne; indapamidhemihydrat 1,25 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 30 tabletter; Burk, 60 tabletter; Burk, 90 tabletter; Burk, 100 tabletter; Blister, 30 tabletter; Blister, 60 tabletter; Blister, 90 tabletter; Blister, 100 tabletter
Bemyndigande status:
Avregistrerad
Godkännandenummer:
51076
Tillstånd datum:
2016-01-14

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

11-10-2019

Produktens egenskaper Produktens egenskaper - engelska

27-05-2019

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

14-01-2016

Läs hela dokumentet

Package leaflet: Information for the user

Avancardo 5 mg/1.25 mg film-coated tablets

perindopril arginine/indapamide hemihydrate

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 Avancardo is and what it is used for

What you need to know before you take Avancardo

How to take Avancardo

Possible side effects

How to store Avancardo

Contents of the pack and other information

1.

What Avancardo is and what it is used for

Avancardo is a combination of two active ingredients, perindopril and indapamide. It is an

antihypertensive and is used in the treatment of high blood pressure (hypertension).

Perindopril belongs to a class of medicines called ACE inhibitors. These work by widening the blood

vessels, which makes it easier for your heart to pump blood through them. Indapamide is a diuretic.

Diuretics increase the amount of urine produced by the kidneys. However, indapamide is different

from other diuretics, as it only causes a slight increase in the amount of urine produced. Each of the

active ingredients reduces blood pressure and they work together to control your blood pressure.

2.

What you need to know before you take Avancardo

Do not take Avancardo

if you are allergic to perindopril or any other ACE inhibitor, or to indapamide or any other

sulphonamides 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 or tongue, 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 Avancardo in early pregnancy

- see “Pregnancy and breast-feeding”).

if you have a severe kidney disease or if you are receiving dialysis.

if you have severe liver disease or suffer from a condition called hepatic encephalopathy

(degenerative disease of the brain).

if you have low potassium levels in your blood.

if you are breast-feeding.

if you are suspected of having untreated decompensated heart failure (severe water retention,

difficulty in breathing).

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

lowering medicine containing aliskiren

if you have taken or are currently taking sacubitril/valsartan, a medicine used to treat a type of

long-term (chronic) heart failure in adults, as the risk of angioedema (rapid swelling under the

skin in an area such as the throat) is increased.

Warnings and precautions

Talk to your doctor before taking Avancardo:

if you suffer from a collagen disease (skin disease) such as systemic lupus erythematosus or

scleroderma,

if you have liver problems,

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 or problems with your kidneys,

if you have atherosclerosis (hardening of the arteries),

if you suffer from hyperparathyroidism (overactive parathyroid gland),

if you have diabetes,

if you suffer from gout,

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

if you take lithium or potassium-sparing diuretics (e.g. spironolactone, triamterene) as their use

with Avancardo should be avoided (see “Other medicines and Avancardo”).

if you are taking any of the following medicines, the risk of angioedema may be increased:

racecadotril, a medicine used to treat diarrhoea;

medicines used to prevent organ transplant rejection and for cancer (e.g., temsirolimus,

sirolimus, everolimus);

vildagliptin, a medicine used to treat diabetes.

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 Avancardo”

In rare instances some patients have had severe allergic reactions after taking ACE inhibitors such as

Avancardo. These reactions are more common in black people, and can result in an itchy rash and/or

the swelling of the face, lips, tongue and throat (angioedema). Severe allergic reactions may also affect

the gut and cause stomach pain (with or without nausea and vomiting) (intestinal angioedema).

You must tell your doctor if you think that you are (or might become) pregnant. Avancardo 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 and breast-feeding”).

If you develop a dry cough which is persistent for a long time, contact your doctor or pharmacist.

Avancardo may be less effective in lowering the blood pressure in black patients.

When you are taking Avancardo, you should also inform your doctor or the medical staff:

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

wasp stings,

if you are to undergo dialysis or LDL apheresis (which is removal of cholesterol from your

blood by a machine),

if you have had photosensitivity reactions,

if you are to undergo anaesthesia and/or surgery,

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

Athletes should be aware that Avancardo contains an active ingredient (indapamide hemihydrate)

which may give a positive reaction in drug tests.

Children and adolecents

Avancardo should not be given to children.

Other medicines and Avancardo

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

medicines.

You should avoid Avancardo with:

lithium (used to treat depression),

potassium supplements (including salt substitutes), potassium-sparing diuretics and other

medicines that can increase the amount of potassium in your blood (e.g. trimethoprim and co-

trimoxazole for infections caused by bacteria; ciclosporin, an immunosuppressant medicine

used to prevent organ transplant rejection; and heparin, a medicine used to thin blood to prevent

clots).

Your doctor may need to change your dose and/or to take other precautions:

If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the

headings “Do not take Avancardo” and “Warnings and precautions”)

Treatment with Avancardo can be affected by other medicines. Make sure to tell your doctor if you are

taking any of the following medicines as special care may be required:

baclofen (to treat muscle stiffness occurring in diseases such as multiple sclerosis),

non-steroidal anti-inflammatory drugs (e.g. ibuprofen) or high dose salicylates (e.g. aspirin),

medicines to treat diabetes such as insulin or metformin,

medicines used for heart rhythm problems (e.g. quinidine, hydroquinidine, disopyramide,

amiodarone, sotalol),

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

antidepressants, neuroleptics),

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) or to treat diabetes (vildagliptin). See section “Warnings and

precautions”

sultopride (for the treatment of psychoses),

bepridil (used to treat angina pectoris),

cisapride or diphemanil (used for the treatment of gastro-intestinal problems),

erythromycin by injection (an antibiotic),

halofantrine (used to treat certain types of malaria),

moxifloxacin, pentamidine, sparfloxacin (used to treat infections),

vincamine (used to treat symptomatic cognitive disorders in elderly including memory loss),

methadone (used for the treatment of opioid (narcotic) dependence),

terfenadine, astemizole or mizolastine (antihistamines for hay fever or allergies),

amphotericin B by injection (to treat severe fungal disease),

corticosteroids used to treat various conditions including severe asthma and rheumatoid arthritis,

stimulant laxatives (e.g. senna),

digoxin or other cardiac glycosides (for the treatment of heart problems),

tetracosactide (to treat Crohn’s disease),

allopurinol (for the treatment of gout),

medicines for the treatment of cancer,

immunosuppressants used for the treatment of auto-immune disorders or following transplant

surgery to prevent rejection (e.g. ciclosporin),

procainamide (for the treatment of an irregular heart beat),

other medicines for treating high blood pressure, including diuretics (medicines which increase

the amount of urine produced by the kidneys),

injectable gold (used to treat rhumatoid polyarthritis),

iodine contrast media (agents used for imaging examinations),

calcium including calcium supplements.

Avancardo with food and drink

It is preferable to take Avancardo before a meal.

Pregnancy, breast-feeding and fertility

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 Avancardo before you become pregnant or as soon as you know

you are pregnant and will advise you to take another medicine instead of Avancardo. Avancardo 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. Avancardo is

contraindicated 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

Avancardo usually does not affect alertness but different reactions such as dizziness or weakness in

relation to the decrease in blood pressure may occur in certain patients. If affected, your ability to

drive or to operate machinery may be impaired.

Avancardo 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.

Avancardo contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

3.

How to take Avancardo

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

if you are not sure.

The recommended dose is one tablet once a day.

Your doctor may decide to modify the dosage regimen if you suffer from renal impairment.

Take your tablet preferably in the morning and before a meal. Swallow the tablet with a glass of water.

If you take more Avancardo than you should

If you take too many tablets, contact your doctor or emergency department immediately. The most

likely effect in case of overdose is low blood pressure. If marked low blood pressure occurs

(symptoms such as dizziness or faintness), lying down with your legs raised can help.

If you forget to take Avancardo

It is important to take your medicine every day as regular treatment is more effective. However, If you

forget to take a dose of Avancardo, 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 Avancardo

As the treatment for high blood pressure 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.

If you experience any of the following, stop taking the medicinal product at once and tell your

doctor immediately:

A widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and

genitals (Stevens-Johnson syndrome), and a more severe form, causing extensive peeling of the

skin (toxic epidermal necrolysis)

Angioedema (symptoms include sudden wheeziness, swelling of the face or tongue)

Severe dizziness or fainting (due to low blood pressure)

Unusual fast or irregular heart beat.

In decreasing order of frequency, side effects can include:

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

Pins and needles, headache, dizziness, vertigo

Vision disturbances

Tinnitus (sensation of noises in the ears)

Light-headedness due to low blood pressure

Cough, shortness of breath

Gastro-intestinal disorders (nausea, epigastric pain, anorexia, vomiting, abdominal pain, taste

disturbances, dry mouth, dyspepsia or difficulty of digestion, diarrhoea, constipation)

Allergic reactions (such as skin rashes, itching)

Muscle cramps

Feeling of tiredness.

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

Mood swings, sleep disturbances

Bronchospasm (tightening of the chest, wheezing and shortness of breath)

Urticaria, allergic reactions, mainly dermatological, such as skin rashes, purpura (red pinpoints

on skin) in subjects with a predisposition to allergic and asthmatic reactions, purpura (red

pinpoints on skin), activation or worsening of systemic lupus erythematosus (a disease where

the body´s immune system attacs the body, which causes joint pain, skin rashes and fever)

Kidney problems

Impotence

Sweating.

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

High levels of calcium in the blood (hypercalcemia)

Psoriasis worsening.

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

Disorders of the blood, liver or pancreas

Confusion

Cardiovascular disorders (irregular heart beat, angina, heart attack)

Eosinophilic pneumonia (a rare type of pneumonia), rhinitis (blocked up or runny nose)

Severe skin manifestations such as erythema multiforme. Cases of photosensitivity reactions

(change in skin appearance) after exposure to the sun or artificial UVA have also been reported

Kidney failure (symptoms may be lower back pain and reduction in the volume of urine passed).

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

Discoloration, numbness and pain in fingers or toes (Raynaud’s phenomenon), life-threatening

irregular beat (Torsade de Pointes), fainting, abnormal ECG heart tracing, increased levels of

liver enzymes

Disorders of the blood and changes in laboratory parameters (blood tests) can occur. Your

doctor may need to give you blood tests to monitor your condition

In cases of hepatic insufficiency (liver problems), there is a possibility of onset of hepatic

encephalopathy (degenerative disease in the brain).

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 Avancardo

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

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 store blister packs above 30° C

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 Avancardo contains

The active substances are perindopril arginine and indapamide hemihydrate.

Each tablet contains 5 mg perindopril arginine and 1.25 mg indapamide hemihydrate.

The other ingredients are:

Tablet core:

Magnesium stearate, silica, hydrophobic colloidal, sodium starch glycolate,

glycerol dibehenate, maltodextrin, lactose monohydrate

Film-coating:

Poly(vinyl)alcohol (E1203), titanium dioxide (E171), macrogol (E1521), talc

(E553b), indigo carmine aluminium lake (E132), yellow iron oxide (E172)

What Avancardo looks like and contents of the pack

Avancardo 5 mg/1.25 mg film-coated tablets are blue, 8.5 mm x 4.3 mm oval, biconvex with

horizontal line on one side

Blister packs (OPA-Aluminium-PVC/Aluminium): 30, 60, 90 and 100 film-coated tablets

Tablet container (HDPE): 30, 60, 90 and 100 film-coated tablets

The tablet container contains two desiccants and is sealed with tamper evident foil and closed with

child-resistant closure, do not eat the desiccant.

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

2019-10-11<[To be completed nationally]>

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Perindopril (arginine)/Indapamide, film-coated tablets, SE/H/1426/002, 12.02.2019

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Avancardo 5 mg/1.25 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 5 mg perindopril arginine corresponding to 3.395 mg perindopril and

1.25 mg indapamide hemidydrate

Excipient with known effect:

Each film-coated tablet contains 84 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

Avancardo 5 mg/1.25 mg film-coated tablets are blue, 8.5 mm x 4.3 mm oval, biconvex with

horizontal line on one side

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of essential hypertension, Avancardo 5 mg/1.25 mg film-coated tablet is indicated in

patients whose blood pressure is not adequately controlled on perindopril alone.

4.2

Posology and method of administration

Posology

One Avancardo 5 mg/1.25 mg film-coated tablet per day as a single dose, preferably to be taken in the

morning, and before a meal.

When possible individual dose titration with the components is recommended. Avancardo

5 mg/1.25 mg film-coated tablet should be used when blood pressure is not adequately controlled on

Avancardo 2.5 mg/0.625 mg film-coated tablet (where available). When clinically appropriate, direct

change from monotherapy to Avancardo 5 mg/1.25 mg film-coated tablet may be considered.

Elderly (see section 4.4)

Treatment should be initiated after considering blood pressure response and renal function.

Patients with renal impairment (see section 4.4)

In severe renal impairment (creatinine clearance below 30 ml/min), treatment is contra-indicated.

In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), it is recommended to

start treatment with the adequate dosage of the free combination.

In patients with creatinine clearance greater than or equal to 60 ml/min, no dose modification is

required.

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.

Paediatric population

Avancardo 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.

Method of administration

Oral use.

4.3

Contraindications

Hypersensitivity to the active substances, any other ACE inhibitor, or any other sulphonamides

or to any of the excipients listed in section 6.1.

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)

The concomitant use of Avancardo 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).

Hepatic encephalopathy

Severe hepatic impairment

Hypokalaemia

Lactation (see section 4.6).

Severe renal impairment (creatinine clearance below 30 ml/min)

Due to the lack of sufficient therapeutic experience, Avancardo should not be used in:

Dialysis patients

Patients with untreated decompensated heart failure.

4.4

Special warnings and precautions for use

Avancardo

Lithium:

The combination of lithium with Avancardo is not recommended (see section 4.5).

Renal impairment:

In cases of severe renal impairment (creatinine clearance < 30 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 usually 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:

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

glucose-galactose malabsorption should not take this medicine.

Perindopril

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.

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, 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.

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 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

sulphate 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.

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 antihypertensive

treatments which have an established safety profile for use in pregnancy. When pregnancy is

diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate,

alternative therapy should be started (see sections 4.3 and 4.6).

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.

Paediatric population:

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 initial 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.

If Avancardo 5 mg/1.25 mg is prescribed to patients with known or suspected renal artery stenosis,

treatment should be started in a hospital setting at a low dose and renal function and potassium levels

should be monitored, since some patients have developed a functional renal insufficiency which was

reversed when treatment was stopped.

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 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

antidiabetic 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 hyperkalemia include those with renal

insufficiency, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, in

particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of

potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium

supplements or potassium-containing salt substitutes; or those patients taking other drugs associated

with increases in serum potassium (e.g. heparin, co-trimoxazole also known as

trimethoprim/sulfamethoxazole). The use of potassium supplements, potassium-sparing diuretics, or

potassium-containing salt substitutes particularly in patients with impaired renal function may lead to

a significant increase in serum potassium. Hyperkalemia 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).

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.

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 thiazide-related

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 which 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:

= (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 which may cause a positive

reaction in doping tests.

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).

Concomitant use contraindicated:

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:

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).

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 hypokalemia they should be used with

caution and with frequent monitoring of serum potassium and by ECG.

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 non-steroidal

anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2

inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.

Concomitant use of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening of

renal function, including possible acute renal failure, and an increase in serum potassium,

especially in patients with poor pre-existing renal 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.

Antidiabetic agents (insulin, hypoglycaemic sulphonamides): 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 sulphonamides. The onset of

hypoglycaemic episodes is very rare (improvement in glucose tolerance with a resulting

reduction in insulin requirements).

Torsades de pointes inducing drugs: Due to the risk of hypokalemia, 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, moxifloxacin, pentamidine, sparfloxacin, IV

vincamine, methadone, astemizole, terfenadine, mizolastine. 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:

-

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.

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.

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, Avancardo is not recommended during the first trimester of pregnancy. Avancardo is

contraindicated during the second and third trimesters of pregnancy.

Avancardo is contraindicated during lactation. A decision should therefore be made whether to

discontinue nursing or to discontinue Avancardo taking account the importance of this therapy for the

mother.

Pregnancy:

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 contraindicated 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 antihypertensive treatments which have an established

safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if

appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human

foetotoxicity (decreased renal 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).

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 hypoglycemia and thrombocytopenia in neonates have been

reported following exposure near term.

Breastfeeding:

Avancardo is contraindicated during breastfeeding.

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.

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

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.

Four percent of the patients on treatment with Avancardo 5 mg/1.25 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 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).

Blood and 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).

Metabolism and nutrition disorders:

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.

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.

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)

Vascular disorders:

Common:

Hypotension whether orthostatic or not (see section 4.4).

Not known:

Raynaud’s phenomenon.

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, epigastric pain, anorexia, vomiting, abdominal

pain, dysgeusia, dyspepsia, diarrhoea.

Very rare:

Pancreatitis.

Hepatobiliary 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.

Rare:

Psoriasis aggravation.

Very rare:

Erythema multiforme, toxic epidermal necrolysis, Steven-Johnson syndrome.

Cases of photosensitivity reactions have been reported (see section 4.4).

Musculoskeletal and connective tissue 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. 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. Elevated liver enzyme levels.

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

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

Avancardo is a combination of perindopril arginine salt, an angiotensin converting enzyme inhibitor,

and indapamide, a chlorosulphamoyl 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.

Mechanism of action

Avancardo:

Avancardo produces an additive synergy of the antihypertensive effects of the two components.

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.

Indapamide:

Indapamide is a sulphonamide derivative with an indole 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.

Pharmacodynamic effects

Avancardo:

In hypertensive patients regardless of age, perindopril/indapamide 2.5 mg/0.625 mg and

perindopril/indapamide 5 mg/1.25 mg exerts a dose-dependent antihypertensive effect on diastolic and

systolic arterial pressure whilst supine or standing.

This antihypertensive effect lasts for 24 hours. The reduction in blood pressure is obtained in less than

one month without tachyphylaxis; stopping treatment has no rebound effect. During clinical trials, the

concomitant administration of perindopril and indapamide produced antihypertensive effects of a

synergic nature in relation to each of the products administered alone.

PICXEL, a multicenter, 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/m

in male and > 100 g/m

in female) were randomised either to perindopril tert-butylamine

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 2 mg (equivalent to 2.5 mg perindopril arginine)/indapamide 0.625 mg (versus 20 %

with Enalapril 10 mg).

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 than those licensed for perindopril/indapamide 2.5 mg/0.625 mg

and perindopril/indapamide 5 mg/1.25 mg.

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.

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.

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.

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.

5.2

Pharmacokinetic properties

Avancardo:

The co-administration of perindopril and indapamide does not change their pharmacokinetic properties

by comparison to separate administration.

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 prodrug. Twenty seven percent of the administered perindopril dose reaches the

bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril

yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within

3 to 4 hours.

As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine

should be administered orally in a single daily dose in the morning before a meal.

It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.

The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of

perindoprilat to plasma proteins is 20 %, principally to angiotensin converting enzyme, but is

concentration-dependent.

Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is

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

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).

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.

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

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.

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

Tablet core:

Magnesium stearate

Silica, hydrophobic colloidal

Sodium starch glycolate (type A)

Glycerol dibehenate

Maltodextrin

Lactose monohydrate

Film-coating:

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Indigo Carmine Aluminium Lake (E132)

Yellow Iron Oxide (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

18 months

6.4

Special precautions for storage

Blister: Do not store above 30° C

HDPE bottle: No special storage conditions.

6.5

Nature and contents of container

OPA/Aluminium/PVC/Aluminium blister

HDPE bottle containing two desiccants sealed with tamper evident foil and closed with child-resistant

closure (PP).

Pack sizes:

Blister: 30, 60, 90 and 100 film-coated tablets

Tablet container: 30, 60, 90 and 100 film-coated tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

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

2019-05-27

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