Brilinta

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Ticagrelor 90 mg;  ;  ;  
Available from:
AstraZeneca Limited
INN (International Name):
Ticagrelor 90 mg
Dosage:
90 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Ticagrelor 90 mg       Excipient: Calcium hydrogen phosphate Hyprolose Hypromellose Iron oxide yellow Macrogol 400 Magnesium stearate Mannitol Purified talc Purified water   Sodium starch glycolate Titanium dioxide
Units in package:
Blister pack, PVC/PVDC/Al sample blister sheet, 14 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Ajinomoto OmniChem SA
Therapeutic indications:
BRILINTA, co-administered with acetylsalicylic acid (aspirin), is indicated for the prevention of atherothrombotic events (cardiovascular death, myocardial infarction and stroke) · in patients with Acute Coronary Syndromes (unstable angina [UA], non ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG). · in patients with a history of myocardial infarction (MI occurred at least one year ago) and a high risk of developing an atherothrombotic event.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVDC/Al sample blister sheet - 14 tablets - 36 months from date of manufacture stored at or below 30°C - Blister pack, PVC-PVDC/AL blister sheet - 56 tablets - 36 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-8784
Authorization date:
2011-03-24

Brilinta

CMI 310715

Copyright

1(6)

Brilinta

TM

Ticagrelor 60 mg or 90 mg Film Coated Tablets.

CONSUMER MEDICINE INFORMATION

What is in this leaflet

This leaflet answers some of the common questions people ask about Brilinta. It does not contain all

the information that is known about Brilinta.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you taking Brilinta

against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Brilinta is used for

Brilinta in combination with aspirin is to be used in adults only. You have been given Brilinta

because you have had:

a heart attack, or

unstable angina (angina or chest pain that is not well controlled)

Brilinta reduces the chances of having another heart attack or of dying from a disease related to your

heart or blood vessels.

How Brilinta works

Brilinta contains the active substance called ticagrelor. This belongs to a group of medicines called

anti-platelet medicines.

Brilinta affects cells called ‘platelets’ (also called thrombocytes). These very small blood cells help

stop bleeding by clumping together to plug tiny holes in blood vessels that are cut or damaged.

However, platelets can also form clots inside diseased blood vessels in the heart and brain. This can

be very dangerous because:

the clot can cut off the blood supply completely - this can cause a heart attack (myocardial

infarction), or

the clot can partly block the blood vessels to the heart - this reduces the blood flow to the heart

and can cause chest pain which comes and goes (called ‘unstable angina’)

Brilinta helps stop the clumping of platelets. This reduces the chance of a blood clot forming that can

reduce blood flow.

This medicine is only available with a doctor’s prescription.

Before you use Brilinta

When you must not use it

Do not take Brilinta if:

You are allergic to ticagrelor or any of the other ingredients of Brilinta (listed in Product

Description)

You are bleeding now You have severe liver disease

You are taking any of the following medicines: ketoconazole (used to treat fungal infections),

clarithromycin (used to treat bacterial infections), nefazodone (an antidepressant), ritonavir and

atazanavir (used to treat HIV infection and AIDS)

You have had a stroke caused by bleeding in the brain

Brilinta

CMI 310715

Copyright

2(6)

Do not take Brilinta if any of the above applies to you. If you are not sure, talk to your doctor or

pharmacist before taking Brilinta.

Take special care with Brilinta

Check with your doctor, pharmacist or dentist before taking Brilinta if:

You have an increased risk of bleeding because of:

- a recent serious injury

- recent surgery (including dental work)

- you have a condition that affects blood clotting

- recent bleeding from your stomach or gut (such as a stomach ulcer or colon ‘polyps’).

You are due to have surgery (including dental work) at any time while taking Brilinta. This is

because of the increased risk of bleeding. Your doctor may want you to stop taking Brilinta 5

days prior to surgery

Your heart rate is abnormally low (usually lower than 60 beats per minute) and you do not

already have in place a device that paces your heart (pacemaker)

You have asthma or other lung problem or breathing difficulties

You have had a blood test that showed more than the usual amount of uric acid

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or dentist before

taking Brilinta.

Children and adolescents

Brilinta is not recommended for children and adolescents under 18 years.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

This

includes

medicines

that

without

prescription,

dietary

supplements

herbal

remedies. This is because Brilinta can affect the way some medicines work and some medicines

can have an effect on Brilinta.

Tell your doctor or pharmacist if you are taking any of the following medicines:

more

than

daily

either

simvastatin

lovastatin

(medicines

used

treat

high

cholesterol)

rifampicin (an antibiotic), phenytoin, carbamazepine and phenobarbital (used to control seizures),

digoxin (used to treat heart failure), cyclosporin (used to lessen your body’s defences), quinidine

and diltiazem (used to treat abnormal heart rhythms), beta blockers and verapamil (used to treat

high blood pressure)

In particular, tell your doctor or pharmacist if you are taking any of the following medicines that

increase your risk of bleeding:

‘oral anticoagulants’ often referred to as ’blood thinners’ which include warfarin

non-steroidal anti-inflammatory drugs (abbreviated as NSAIDs) often taken as pain killers such

as ibuprofen and naproxen

selective serotonin reuptake inhibitors (abbreviated as SSRIs) taken as antidepressants such as

paroxetine, sertraline and citalopram

other medicines such as ketoconazole (used to treat fungal infections), clarithromycin (used to

treat bacterial infections), nefazodone, (an antidepressant), ritonavir and atazanavir (used to treat

HIV infection and AIDS), cisapride (used to treat heartburn), ergot alkaloids (used to treat

migraines and headaches)

Brilinta

CMI 310715

Copyright

3(6)

Also tell your doctor that you are taking Brilinta, because if your doctor gives you fibrinolytics, often

called ‘clot dissolvers’, such as streptokinase or alteplase, you may have an increased risk of

bleeding.

Taking Brilinta with food and drink

You can take Brilinta with or without food.

Pregnancy and breast-feeding

It is not recommended to use Brilinta if you are pregnant or may become pregnant. Women should

use appropriate contraceptive measures to avoid pregnancy while taking this medicine. Talk to your

doctor before taking Brilinta if you are breast-feeding. Your doctor will discuss with you the benefits

and risks of taking Brilinta during this time.

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.

Driving and using machines

Brilinta is not likely to affect your ability to drive or use machines. If you feel dizzy while taking

Brilinta, be careful while driving or using machines

How to take Brilinta

Always take Brilinta exactly as your doctor has told you. You should check with your doctor or

pharmacist if you are not sure.

How much to take

The dose of Brilinta you take will depend on your condition. Your doctor will tell you the correct dose

to use.

If you had a recent heart attack or unstable angina (angina or chest pain that is not well controlled).

The starting dose is two tablets at the same time (loading dose of 180 mg). This dose will usually be

given to you in the hospital. After this starting dose, the usual dose is one tablet of 90 mg twice a day

for 12 months unless your doctor tells you differently. After one year your doctor may continue your

treatment with a lower dose of 60 mg tablet twice a day.

If you had a heart attack over a year ago, the usual dose is one 60 mg tablet twice a day. Continue

taking Brilinta as long as your doctor tells you.

Take Brilinta around the same time every day (for example, one tablet in the morning and one in the

evening).

Your doctor will usually also tell you to take low dose aspirin. This is a substance present in many

medicines used to prevent blood clotting. Your doctor will tell you how much to take (usually between

75-150 mg daily).

How to take Brilinta

You can take the tablet with or without food

You can check when you last took a tablet of Brilinta by looking on the blister. There is a sun

(for the morning) and a moon (for the evening). This will tell you whether you have taken the

dose.

If you have trouble swallowing

If you have trouble swallowing the tablet(s) you can crush them and mix with water as follows:

crush the tablet(s) to a fine powder

Brilinta

CMI 310715

Copyright

4(6)

pour the powder into half a glass of water

stir and drink immediately

to make sure that there is no medicine left, rinse the empty glass with another half a glass of

water and drink it

If you take more Brilinta than you should

If you take more Brilinta than you should, talk to a doctor or go to hospital straight away. Take the

medicine pack with you. You may be at increased risk of bleeding.

If you forget to take Brilinta

If you forget to take a dose, just take your next dose as normal

Do not take a double dose (two doses at the same time) to make up for the forgotten dose.

If you stop taking Brilinta

Do not stop taking Brilinta without talking to your doctor. Take Brilinta on a regular basis and for as

long as your doctor keeps prescribing it. If you stop taking Brilinta, it may increase your chances of

having another heart attack or dying from a disease related to your heart or blood vessels. If you

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

Side Effects

Like all medicines, Brilinta can cause side effects, although not everybody gets them. The following

side effects may happen with this medicine.

See a doctor straight away if you notice any of the following – you may need urgent medical

treatment:

Bleeding into the brain or inside the skull is an uncommon side effect, and may cause

signs of a stroke such as:

- sudden numbness or weakness of your arm, leg or face, especially if only on one side of the

body

- sudden confusion, difficulty speaking or understanding others

- sudden difficulty in walking or loss of balance or co-ordination

- suddenly feeling dizzy or sudden severe headache with no known cause.

Bleeding – some bleeding is common. However, severe bleeding is uncommon, but can be life

threatening. Bleeding of many different kinds can be increased, for example:

- bleeding that is severe or that you cannot control

- unexpected bleeding or bleeding that lasts a long time

- blood in your urine

- black stools or red blood in your stools

- visual disturbance caused by blood in your eye

- coughing up or vomiting blood

- bleeding into joints causing painful swelling

Discuss with your doctor if you notice any of the following:

Feeling short of breath - this is very common (affects more than 10 in 100 people). It might be

due to your heart disease or another cause, or it might be a side effect of Brilinta. Brilinta

related breathlessness is generally mild and characterised as a sudden, unexpected hunger for

air usually occurring at rest and may appear in the first weeks of therapy and for many people

Brilinta

CMI 310715

Copyright

5(6)

may disappear while treatment is continued. If you have asthma or COPD, this is more likely. If

your feeling of shortness of breath gets worse or lasts a long time, tell your doctor. Your doctor

will decide if it needs treatment or further investigations.

Other possible side effects

Very common (may affect more than 10 in 100 people)

An increase in the level of uric acid in the blood (as seen in tests)

Bleeding caused by blood disorder

Common (may affect up to 1 in 10 people)

Bruising, bleeding into the skin

Nosebleed

Feeling dizzy or like the room is spinning

Diarrhoea

Feeling sick (nausea)

Itching

Severe pain and swelling in your joints – these are signs of gout

Feeling dizzy or light headed, or having blurred vision – these are signs of low blood pressure

Bleeding after surgery or from cuts (e.g. while shaving) and wounds that is more than normal

Bleeding from your stomach lining (ulcer)

Bleeding gums

Uncommon (may affect up to 1 in 100 people)

Confusion

Blood in your eye

Vaginal

bleeding

that

heavier,

happens

different

times,

than

your

normal period

(menstrual) bleeding

Bleeding from a tumour

Blood in your ear

Bleeding into joints and muscles causing painful swelling

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please

tell your doctor or pharmacist, but do not stop taking Brilinta until you have spoken to them.

How to store Brilinta

Keep out of the reach and sight of children.

Do not use Brilinta after the expiry date, which is stated on the blister and carton after EXP. The

expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how

to dispose of medicines no longer required. These measures will help to protect the environment.

Product description

What Brilinta contains

The active substance is ticagrelor. Each film-coated tablet contains 60 or 90 mg of ticagrelor.

The other ingredients are:

Tablet

core:

mannitol,

calcium

hydrogen

phosphate

dihydrate,

sodium

starch

glycolate,

hydroxypropyl-cellulose , magnesium stearate

Tablet film coating: hypromellose , titanium dioxide , talc (90 mg only), polyethylene glycol 400,

and ferric oxide yellow (90 mg only), ferric oxide black (60 mg only) ferric oxide red (60 mg only).

Brilinta

CMI 310715

Copyright

6(6)

What Brilinta looks like and contents of the pack

60mg: Film-coated tablet (tablet): The tablets are round, biconvex, pink, film-coated marked with a

“60” above “T” on one side and plain on the other.

90mg: Film-coated tablet (tablet): The tablets are round, biconvex, yellow, film-coated marked with a

“90” above “T” on one side and plain on the other.

Brilinta 60 mg and 90 mg are available in calendar blisters (with sun/moon symbols) in cartons of 14

and 56 tablets.

Marketed by

AstraZeneca Limited

P299 Private Bag 92175, Auckland 1142.

Telephone: (09) 306 5650.

Trademarks herein are the property of the AstraZeneca Group.

© This CMI is copyrighted to AstraZeneca Limited and may be reproduced but not altered in any way.

31 July 2015

RILINTA

Data Sheet 120619

Copyright

NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

RILINTA

60 mg film-coated tablets

RILINTA

90 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

60 mg: each tablet contains 60 mg ticagrelor.

90 mg: each tablet contains 90 mg ticagrelor.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

60 mg - Round, biconvex, pink, film coated tablets, marked with “60” above “T” on one side

and plain on the other.

90 mg - Round, biconvex, yellow, film coated tablets, marked with ‘90’ above ‘T’ on one side

and plain on the other.

4.

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

RILINTA

, co-administered with acetylsalicylic acid (aspirin), is indicated for the prevention of

atherothrombotic events (cardiovascular death, myocardial infarction and stroke)

in patients with Acute Coronary Syndromes (unstable angina [UA], non ST elevation

Myocardial

Infarction

[NSTEMI]

elevation

Myocardial

Infarction

[STEMI]);

including patients managed medically, and those who are managed with percutaneous

coronary

intervention

(PCI)

coronary

artery

by-pass

grafting

(CABG).

in patients with a history of myocardial infarction (MI occurred at least one year ago)

and a high risk of developing an atherothrombotic event.

For further information, please refer to section 5.1.

4.2

DOSE AND METHOD OF ADMINISTRATION

Acute Coronary Syndromes

In patients with Acute Coronary Syndromes, B

RILINTA

treatment should be initiated with a

single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.

Treatment is recommended for at least 12 months unless discontinuation of B

RILINTA

clinically indicated (see section 5.1). After one year, patients initiated on 90 mg twice daily

may continue treatment with 60 mg twice daily without interruption.

RILINTA

Data Sheet 120619

Copyright

Patients taking B

RILINTA

should also take a daily low maintenance dose of aspirin of 75 -150

mg, unless specifically contraindicated. An initial loading dose of aspirin is recommended for

patients with ACS (see section 5.1).

History of Myocardial Infarction (MI occurred at least one year ago)

In patients with a history of Myocardial Infarction (MI occurred at least one year ago) no loading

dose of B

RILINTA

is required and the recommended dose is 60 mg twice daily.

Long term treatment is recommended unless discontinuation of B

RILINTA

is clinically indicated

(see section 5.1).

Patients taking B

RILINTA

should also take a daily low maintenance dose of aspirin of 75-

150 mg, unless specifically contraindicated.

Patients may start treatment with B

RILINTA

60 mg twice daily, regardless of their previous anti-

platelet regimen, and irrespective if there has been a lapse in therapy or not.

Patients should discontinue their current anti-platelet therapy before initiating B

RILINTA

with low

dose aspirin at the next scheduled dose.

Patients initiated on B

RILINTA

90 mg twice daily at the time of the acute event, after one year,

may continue treatment with 60 mg twice daily without interruption.

Dosage Considerations

Premature discontinuation

Premature discontinuation with any antiplatelet therapy, including B

RILINTA

, could result in an

increased risk of cardiovascular death, myocardial infarction, or stroke due to the patient’s

underlying disease (see section 4.4). Therefore premature discontinuation of treatment should

be avoided.

Missed dose

Lapses in therapy should also be avoided. A patient who misses a dose of B

RILINTA

should

take their next dose at its scheduled time.

Switching

In patients having an ACS event, the loading dose of 180 mg should be given as soon as

possible regardless of any previous antiplatelet treatment.

Physicians who desire to switch patients with a prior ACS event, to B

RILINTA

should administer

the first dose of B

RILINTA

24 hours following the last dose of the other antiplatelet medication.

Method of administration

For oral use. B

RILINTA

can be administered with or without food. For patients who are unable

to swallow the tablet(s) whole, B

RILINTA

tablets can be crushed to a fine powder and mixed in

half a glass of water and drunk immediately. The glass should be rinsed with a further half

glass of water and the contents drunk. The mixture can also be administered via a nasogastric

tube (CH8 or greater). It is important to flush the nasogastric tube through with water after

administration of the mixture.

Special populations

Elderly population

No dose adjustment is required in the elderly (see section 5.2).

RILINTA

Data Sheet 120619

Copyright

Renal impairment

No dose adjustment is necessary for patients with renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment. B

RILINTA

has not

been studied in patients with severe hepatic impairment and there is limited information on

treatment of patients with moderate hepatic impairment. Use in patients with severe hepatic

impairment is therefore contraindicated (see section 4.3, 4.4 and 5.2).

Paediatric population

The safety and efficacy of B

RILINTA

in children below the age of 18 have not been established.

4.3

CONTRAINDICATIONS

Hypersensitivity to the ticagrelor or any of the excipients listed in section 6.1 (see

section 4.8).

Active pathological bleeding

History of intracranial haemorrhage (see section 4.8)

Severe hepatic impairment (see sections 4.2, 4.4 and 5.2)

Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole,

clarithromycin,

nefazodone,

ritonavir

atazanavir)

contraindicated,

co-administration may lead to a substantial increase in exposure to ticagrelor (see

sections 4.5).

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Bleeding risk

phase

pivotal

trial

(PLATO

[PLATelet

Inhibition

Patient

Outcomes],

18,624 patients) key exclusion criteria included an increased risk for bleeding, clinically

important thrombocytopenia or anaemia, previous intracranial bleed, gastrointestinal bleed

within the past 6 months or major surgery within the past 30 days. Patients with acute coronary

syndromes treated with B

RILINTA

and aspirin showed an increased risk of non-CABG major

bleeding and also more generally in bleeds requiring medical attention i.e. Major or Minor

PLATO bleeds, but not Fatal or Life-threatening bleeds (see section 4.8).

Therefore, the use of B

RILINTA

in patients at known increased risk for bleeding should be

balanced against the benefit in terms of prevention of atherothrombotic events. If clinically

indicated,

RILINTA

should

used

with

caution

following

patient

groups:

Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery,

coagulation disorders, active or recent gastrointestinal bleeding, or moderate hepatic

impairment) or who are at increased risk of trauma. The use of B

RILINTA

contraindicated in patients with active pathological bleeding, in those with a history of

intracranial haemorrhage and in patients with severe hepatic impairment (see

section 4.3).

Patients with concomitant administration of medicinal products that may increase the

risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral

anticoagulants, and/or fibrinolytics within 24 hours of B

RILINTA

dosing).

Platelet transfusion did not reverse the antiplatelet effect of B

RILINTA

in healthy volunteers and

is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of B

RILINTA

with desmopressin did not decrease template-bleeding time, desmopressin is unlikely to be

effective in managing clinical bleeding events.

RILINTA

Data Sheet 120619

Copyright

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa

therapy may increase haemostasis. B

RILINTA

may be resumed after the cause of bleeding has

been identified and controlled.

Surgery

Patients should be advised to inform physicians and dentists that they are taking B

RILINTA

before any surgery is scheduled and before any new medicinal product is taken.

Because of the reversible binding of B

RILINTA

, restoration of platelet aggregation occurs faster

with B

RILINTA

compared to clopidogrel. In the OFFSET study, mean Inhibition of Platelet

Aggregation (IPA) for B

RILINTA

at 72 hours post-dose was comparable to mean IPA for

clopidogrel at 120 hours post-dose. The more rapid offset of effect may predict a reduced risk

of bleeding complications, e.g. in settings where antiplatelet therapy must be temporarily

discontinued due to surgery or trauma.

In PLATO patients undergoing coronary artery bypass grafting (CABG), B

RILINTA

had more

bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major

bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery (see

section 4.8).

If a patient is to undergo elective surgery and antiplatelet effect is not desired, B

RILINTA

should

be discontinued 5 days prior to surgery (see section 5.1).

Patients with prior ischaemic stroke

ACS patients with prior ischaemic stroke can be treated with B

RILINTA

for up to 12 months

(PLATO study).

In PEGASUS, patients with a history of MI with prior ischaemic stroke were not included.

Therefore, in the absence of data caution is advised for treatment beyond one year.

Patients with moderate hepatic impairment

There is limited experience with B

RILINTA

in patients with moderate hepatic impairment

therefore caution is advised in these patients. Use of B

RILINTA

is contraindicated in patients

with severe hepatic impairment (see section 4.2, 4.3 and 5.2).

Patients at risk for bradyarrhythmia

Holter ECG monitoring has shown an increased frequency of mostly asymptomatic ventricular

pauses during treatment with ticagrelor compared with clopidogrel. Bradyarrhythmic events

have been reported in the postmarketing setting. In phase 3 studies evaluating the safety and

efficacy of B

RILINTA

, bradyarrhythmic events were reported in a similar frequency for ticagrelor

and comparators (placebo, clopidogrel and aspirin). Patients with an increased risk of

bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or

3rd degree AV block or bradycardic-related syncope) have been excluded from B

RILINTA

outcome studies. Therefore, due to the limited clinical experience in these patients, caution is

advised (also see section 5.1).

In addition, caution should be exercised when administering B

RILINTA

concomitantly with

medicinal products known to induce bradycardia. However no evidence of clinically significant

adverse reactions was observed in the PLATO trial after concomitant administration with one

or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium

channel blockers diltiazem and verapamil, and 4% digoxin) (see section 4.5).

RILINTA

Data Sheet 120619

Copyright

During the Holter substudy in PLATO, more patients had ventricular pauses

3 seconds with

ticagrelor than with clopidogrel during the acute phase of their ACS. The increase in

Holter-detected ventricular pauses with ticagrelor was higher in patients with chronic heart

failure (CHF) than in the overall study population during the acute phase of ACS, but not at

one month with ticagrelor or compared to clopidogrel. There were no adverse clinical

consequences associated with this imbalance (including syncope or pacemaker insertion) in

this patient population (see section 5.1).

Dyspnoea

Dyspnoea, usually mild to moderate in intensity and often resolving without need for treatment

discontinuation, is reported in patients treated with B

RILINTA

. Patients with asthma/COPD may

have an increased absolute risk of experiencing dyspnoea with B

RILINTA

(see section 4.8).

Ticagrelor should be used with caution in patients with history of asthma and/or COPD. The

mechanism has not been elucidated. If a patient reports new, prolonged or worsened

dyspnoea this should be investigated fully and if not tolerated, treatment with B

RILINTA

should

be stopped.

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura has been reported very rarely with the use of B

RILINTA

TTP is a serious condition and requires prompt treatment.

Interference with Laboratory Tests

Platelet function tests to diagnose Heparin induced thrombocytopenia (HIT)

False negative results in platelet function test for heparin induced thrombocytopenia (HIT) have

been reported in patients administered ticagrelor. This is related to inhibition of the

receptor on the healthy donor platelets in the test by ticagrelor in the patient’s

sera/plasma. Information on concomitant treatment with ticagrelor is required for interpretation

of HIT platelet function tests.

Before considering discontinuation of ticagrelor, the benefit and risk of continued treatment

should be assessed, taking both the prothrombotic state of HIT and the increased risk of

bleeding with concomitant anticoagulant and ticagrelor treatment into consideration.

Other

Based on a relationship observed in the PLATO study between maintenance aspirin dose and

relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high

maintenance dose aspirin (>300 mg) is not recommended (see section 5.1).

Discontinuation

Patients who require discontinuation of B

RILINTA

are at increased risk for cardiac events or

stroke. Premature discontinuation of treatment should be avoided. If B

RILINTA

must be

temporarily stopped due to an adverse event(s), it should be re-initiated as soon as possible

when the benefits outweigh the risks of the adverse event or when the adverse event has come

to resolution (see section 4.2).

4.5

INTERACTION WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTION

Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also

a P-gp substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates.

RILINTA

Data Sheet 120619

Copyright

Effects of other medicinal products on B

RILINTA

Medicinal products metabolised by CYP3A4

Ketaconazole (Strong CYP3A4 inhibitors)

Co-administration of ketoconazole with ticagrelor increased the ticagrelor C

and AUC

equal to 2.4-fold and 7.3-fold, respectively. The C

and AUC of the active metabolite were

reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin,

nefazodone, ritonavir and atazanavir) would be expected to have similar effects and

therefore concomitant use with B

RILINTA

is contraindicated (see section 4.3 ).

Diltiazem (Moderate CYP3A4 inhibitors)

Co-administration of diltiazem and ticagrelor increased the ticagrelor C

by 69% and AUC

by 174%, and decreased the active metabolite C

by 38% and AUC was unchanged.

There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4

inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to

have a similar effect and can as well be co-administered with B

RILINTA

Rifampicin and Other CYP3A Inducers

Co-administration of rifampicin with ticagrelor decreased ticagrelor C

and AUC by 73% and

86%, respectively. The C

of the active metabolite was unchanged and the AUC was

decreased by 46%, respectively. Other CYP3A4 inducers (e.g. phenytoin, carbamazepine and

phenobarbital)

would

expected

decrease

exposure

RILINTA

well.

Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and

efficacy of ticagrelor therefore their concomitant use with B

RILINTA

is discouraged.

Cyclosporine (PgP and CYP3A inhibitor)

Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor C

and AUC

equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased

by 32% and C

was decreased by 15% in the presence of cyclosporine. There was no effect

of ticagrelor on cyclosporine blood levels.

Others

Clinical pharmacology interaction studies showed that co-administration of ticagrelor with

heparin, enoxaparin, and aspirin did not have any effect on ticagrelor or the active metabolite

plasma levels. Co-administration of ticagrelor and heparin had no effect on heparin based on

activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) assays.

Co-administration of ticagrelor and enoxaparin had no effect on enoxaparin based on factor

Xa assay.

No data are available on concomitant use of B

RILINTA

with other medicines that also are potent

P-glycoprotein (P-gp) inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine)

that also may increase ticagrelor exposure. If the association cannot be avoided, their

concomitant use should be made with caution.

Delayed and decreased exposure to oral P2Y

inhibitors, including ticagrelor and its active

metabolite, has been reported in patients treated with morphine (approximately 35% reduction

in ticagrelor). This interaction may be related to reduced gastrointestinal motility, and therefore

apply to other opioids. The clinical relevance is unknown.

RILINTA

Data Sheet 120619

Copyright

Effects of B

RILINTA

on other medicinal products

Medicinal products metabolised by CYP3A4

Simvastatin

Co-administration of ticagrelor with simvastatin increased simvastatin C

by 81% and AUC

by 56% and increased simvastatin acid C

by 64% and AUC by 52% with some individual

increases equal to 2 to 3-fold. Co-administration of ticagrelor with doses of simvastatin

exceeding 40 mg daily could cause adverse effects of simvastatin and should be weighed

against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels.

RILINTA

may have similar effect on lovastatin, but is not expected to have a clinically

meaningful effect on other statins. The concomitant use of ticagrelor with doses of

simvastatin or lovastatin greater than 40 mg is not recommended.

Atorvastatin

Co-administration of atorvastatin and ticagrelor increased atorvastatin acid C

by 23% and

AUC by 36%. Similar increases in AUC and C

were observed for all atorvastatin acid

metabolites. These increases are not considered clinically significant.

A similar effect on other statins metabolised by CYP3A4 cannot be excluded. Patients in

PLATO receiving ticagrelor took a variety of statins, with no concern of an association with

statin safety among the 93% of the PLATO cohort taking these medicinal products.

Other

Ticagrelor is a mild CYP3A4 inhibitor. Co-administration of ticagrelor and CYP3A4 substrates

with narrow therapeutic indices (i.e. cisapride or ergot alkaloids) is not recommended, as

ticagrelor may increase the exposure to these medicinal products.

Medicinal products metabolised by CYP2C9 - Tolbutamide

Co-administration of ticagrelor with tolbutamide resulted in no change in the plasma levels of

either medicinal product, which suggest that ticagrelor is not a CYP2C9 inhibitor and unlikely

to alter the CYP2C9 mediated metabolism of medicinal products like warfarin and tolbutamide.

Oral contraceptives

Co-administration of ticagrelor and levonorgestrel and ethinyl oestradiol increased ethinyl

oestradiol

exposure

approximately

20% but

alter

pharmacokinetics

levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when

levonorgestrel and ethinyl oestradiol are co-administered with B

RILINTA

Digoxin (P-gp substrate)

Concomitant administration of ticagrelor increased the digoxin C

by 75% and AUC by 28%.

The mean trough digoxin levels were increased about 30% with ticagrelor co-administration

with some individual maximum increases to 2 fold. In the presence of digoxin, the C

AUC of ticagrelor and its active metabolite were not affected. Therefore, appropriate clinical

and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp

dependent medicinal products like digoxin concomitantly with ticagrelor.

Medicinal products known to induce bradycardia

Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution

should be exercised when administering B

RILINTA

concomitantly with medicinal products

known to induce bradycardia (see section 4.4). However no evidence of clinically significant

adverse reactions was observed in the PLATO trial after concomitant administration with one

or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium

channel blockers diltiazem and verapamil and 4% digoxin).

RILINTA

Data Sheet 120619

Copyright

Other concomitant therapy

In clinical studies, B

RILINTA

was commonly administered with aspirin, proton pump inhibitors,

statins, beta-blockers, angiotensin converting enzyme inhibitors and angiotensin receptor

blockers as needed for concomitant conditions for long-term and also heparin, low molecular

weight heparin and intravenous GpIIb/IIIa inhibitors for short durations (see section 5.1). No

evidence of clinically significant adverse interactions with these medicinal products was

observed.

Co-administration of ticagrelor with heparin, enoxaparin or desmopressin had no effect on

activated partial thromboplastin time (aPTT), activated coagulation time (ACT) or factor Xa

assays.

However,

potential

pharmacodynamic

interactions,

caution

should

exercised with the concomitant administration of B

RILINTA

with medicinal products known to

alter haemostasis.

Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and

citalopram), caution is advised when administering SSRIs with ticagrelor as this may increase

the risk of bleeding.

4.6

FERTILITY, PREGNANCY AND LACTATION

Pregnancy

Women of childbearing potential

Women of childbearing potential should use appropriate contraceptive measures to avoid

pregnancy during B

RILINTA

therapy.

Pregnancy

There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies

in animals have shown reproductive toxicity (see section 5.3). B

RILINTA

is not recommended

during pregnancy.

Breastfeeding

It is not known whether this medicinal product is excreted in human milk. Studies in rats have

shown excretion of ticagrelor and its active metabolites in milk. The use of B

RILINTA

during

breastfeeding is not recommended.

Fertility

RILINTA

had no effect on male or female fertility in animals (see section 5.3).

4.7

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No studies on the effects of B

RILINTA

on the ability to drive and use machines have been

performed. B

RILINTA

is expected to have no or negligible influence on the ability to drive and

use machines. During treatment with B

RILINTA

, dizziness and confusion have been reported.

Therefore, patients who experience these symptoms should be cautious while driving or using

machines.

4.8

UNDESIRABLE EFFECTS

Summary of the safety profile

The safety profile of B

RILINTA

has been evaluated in two large phase 3 outcome trials (PLATO

PEGASUS)

including

more

than

39,000

patients

(see

section

5.1).

The relevant adverse drug reactions observed in these studies are discussed below.

RILINTA

Data Sheet 120619

Copyright

The safety of B

RILINTA

in patients with acute coronary syndromes (UA, NSTEMI and STEMI)

was evaluated in the PLATO study, which compared patients treated with B

RILINTA

90 mg twice

daily to patients treated with clopidogrel 75 mg once daily, both given in combination with

acetylsalicylic acid (aspirin) and other standard therapies. Median treatment duration for

RILINTA

was 277 days. In PLATO, patients on B

RILINTA

had a higher incidence of

discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%).

The safety of B

RILINTA

in patients with history of MI (MI occurred at least one year ago) and

high risk of developing a thrombotic event was evaluated in the PEGASUS study, which

compared patients treated with B

RILINTA

60 mg twice daily or 90 mg twice daily combined with

aspirin to aspirin therapy alone and other standard therapies. Median treatment duration for

RILINTA

60 mg was 29.4 months. In PEGASUS, patients on B

RILINTA

had a higher incidence

of discontinuation due to adverse events compared to aspirin therapy alone (16.1% for

ticagrelor 60 mg with aspirin vs. 8.5% for aspirin therapy alone).

The most commonly reported adverse drug reactions in patients treated with ticagrelor were

bleeding and dyspnoea (also see section 4.4).

Tabulated summary of adverse drug reactions

Adverse drug reactions from the PLATO and PEGASUS clinical studies with B

RILINTA

(Table 1)

are listed by MedDRA System Organ Class (SOC) and frequency category. Within each SOC

and frequency category, adverse drug reactions are presented in order of decreasing

seriousness. Frequency categories are defined according to the following conventions: 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).

Table 1

Adverse Drug reactions observed in PLATO and PEGASUS phase 3

clinical studies

System Organ Classification

Very Common

Common

Uncommon

Neoplasms benign, malignant

and

unspecified

(including

cysts and polyps)

Tumour bleedings

Blood

and

lymphatic

system

disorders

Blood

disorder

bleedings

Metabolism

and

nutrition

disorders

Hyperuricaemia

Gout

Psychiatric disorders

Confusion

Nervous system disorders

Dizziness

Syncope

Intracranial

haemorrhage

Eye disorders

Eye haemorrhage

Ear and labyrinth disorders

Vertigo

Ear haemorrhage

Vascular disorders

Hypotension

Respiratory,

thoracic

and

mediastinal disorders

Dyspnoea

Respiratory

system

bleedings

Gastrointestinal disorders

Gastrointestinal

haemorrhage

Diarrhoea, Nausea

Retroperitoneal

haemorrhage

RILINTA

Data Sheet 120619

Copyright

System Organ Classification

Very Common

Common

Uncommon

Skin and subcutaneous tissue

disorders

Subcutaneous or

dermal bleeding

Pruritus

Musculoskeletal connective

tissue and bone

Muscular

bleedings

Renal and urinary disorders

Urinary tract

bleeding

Reproductive system and

breast disorders

Reproductive

system bleedings

Investigations

Blood creatinine

increased

Injury, poisoning and

procedural complications

Post procedural

haemorrhage,

Traumatic bleedings

Frequencies derived from lab observations (uric acid increases to >ULN from baseline below or within reference

range. Creatinine increases of >50% from baseline) and not crude adverse event report frequency.

e.g., bleeding from bladder cancer, gastric cancer, colon cancer.

e.g., increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis.

e.g., conjunctival, retinal, intraocular bleeding.

e.g., epistaxis, haemoptysis.

e.g., gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage.

e.g., ecchymosis, skin haemorrhage, petechiae.

e.g., haemarthrosis, muscle haemorrhage.

e.g., haematuria, cystitis haemorrhagic.

e.g., vaginal haemorrhage, haematospermia, postmenopausal haemorrhage.

e.g., contusion, traumatic haematoma, traumatic haemorrhage.

i.e. spontaneous, procedure related or traumatic intracranial haemorrhage.

Description of selected adverse drug reactions

Bleeding findings in PLATO

Overall outcome of bleeding events in the PLATO study are shown in Table 2.

Table 2 –Analysis of Overall Bleeding Events, Kaplan-Meier estimate of bleeding rates

by treatment at 12 months (PLATO)

Safety Endpoints

B

RILINTA

90 mg twice daily

N=9235

Clopidogrel

75mg once

dailyN=9186

p-value

KM%

Hazard Ratio

(95% CI)

KM%

PLATO-defined bleeding categories

Primary Safety Endpoint

PLATO-defined Total Major

11.6

1.04

(0.95, 1.13)

11.2

0.4336

Secondary Endpoints

PLATO Fatal/Life-Threatening

1.03

(0.90, 1.16)

0.6988

PLATO Total Major or Minor

16.1

1.11

(1.03, 1.20)

14.6

0.0084

PLATO Non-CABG Major

1.19

(1.02, 1.38)

0.0264

PLATO Non-Procedural Major

1.31

(1.08, 1.60)

0.0058

PLATO Non-Procedural Major or Minor

1.39

(1.21, 1.60)

0.0001

RILINTA

Data Sheet 120619

Copyright

TIMI-defined bleeding categories

TIMI Major

1.03

(0.93, 1.15)

0.5669

TIMI Major or Minor

11.4

1.05

(0.96, 1.15)

10.9

0.3272

Bleeding category definitions:

PLATO Major Fatal/Life-threatening: Fatal bleeding, OR any intracranial bleeding, OR intrapericardial with cardiac tamponade,

OR with hypovolaemic shock or severe hypotension requiring pressors/inotropes or surgery OR clinically apparent with >50 g/L

decrease in haemoglobin, OR ≥4 red cell units transfused.

PLATO Major Other: Significantly disabling, OR, clinically apparent with 30-50 g/L decrease in haemoglobin or 2-3 red cell units

transfused.

PLATO Minor: Requires medical intervention to stop or treat bleeding.

TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of haemorrhage associated with a drop in

haemoglobin (Hgb) of ≥50 g/L, or when Hgb is not available, a fall in haematocrit (Hct) of

≥15%..

TIMI Minor: Clinically apparent with 30-50 g/L decrease in haemoglobin.

In PLATO, time to first PLATO-defined Total Major bleeding for B

RILINTA

did not differ

significantly from that of clopidogrel. There were few fatal bleeding events in the study, 20

(0.2%) for B

RILINTA

90mg twice daily and 23 (0.3%) for clopidogrel 75mg once daily. When

minor bleeding was included, combined PLATO-defined Major and Minor bleeding events were

significantly higher on B

RILINTA

than on clopidogrel. Overall rates of TIMI-defined bleeding

events did not differ significantly between B

RILINTA

and clopidogrel.

CABG-related bleeding: In PLATO, 42% of the 1584 patients (12% of cohort) who underwent

coronary

artery

bypass

graft

(CABG)

surgery

PLATO-defined

Major

Fatal/Life-

threatening bleeding with no difference between the treatment groups. Fatal CABG bleeding

occurred in 6 patients in each treatment group (see section 4.4).

Non-CABG related bleeding and non-procedural related bleeding: B

RILINTA

and clopidogrel did

not differ in non-CABG PLATO-defined Major Fatal/Life-threatening bleeding, but PLATO-

defined Total Major, TIMI Major, and TIMI Major + Minor bleeding were more common with

ticagrelor. Similarly, when removing all procedure related bleeds, more bleeding occurred with

ticagrelor than with clopidogrel (Table 2). Discontinuation of treatment due to non-procedural

bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p<0.001).

Age, gender, weight, ethnicity, geographic region, concurrent conditions, concomitant therapy,

and medical history, including a previous stroke or transient ischaemic attack, all did not predict

either overall or non-procedural PLATO-defined Major bleeding. Thus no particular group was

identified at risk for any subset of bleeding.

Intracranial bleeding: There were more intracranial non-procedural bleeds with ticagrelor

(n=27 bleeds in 26 patients, 0.3%) than with clopidogrel (n=14 bleeds, 0.2%), of which

11 bleeds with ticagrelor and one with clopidogrel were fatal. There was no difference in

overall fatal bleeds. The percentage of intracranial bleeding was low in both treatment groups

given the significant comorbidity and cardiovascular risk factors of the population under study.

Bleeding findings in PEGASUS

Overall outcome of bleeding events in the PEGASUS study are shown in Table 3.

RILINTA

Data Sheet 120619

Copyright

Table 3 – Analysis of Overall Bleeding Events, Kaplan-Meier estimate of bleeding rates

by treatment at 36 months (PEGASUS)

Safety Endpoints

BRILINTA 60 mg twice

daily with Aspirin

N=6958

Aspirin alone

N=6996

p-value

KM%

Hazard

Ratio

(95% CI)

KM%

TIMI-defined bleeding categories

TIMI Major

2.32

(1.68, 3.21)

<0.0001

Fatal

1.00

(0.44, 2.27)

1.0000

1.33

(0.77, 2.31)

0.3130

Other TIMI Major

3.61

(2.31, 5.65)

<0.0001

TIMI Major or Minor

2.54

(1.93, 3.35)

<0.0001

TIMI Major or Minor or

Requiring medical attention

16.6

2.64

(2.35, 2.97)

<0.0001

PLATO-defined bleeding categories

PLATO Major

2.57

(1.95, 3.37)

<0.0001

Fatal/Life-threatening

2.38

(1.73, 3.26)

<0.0001

Other PLATO Major

3.37

(1.95, 5.83)

<0.0001

PLATO Major or Minor

15.2

2.71

(2.40, 3.08)

<0.0001

Bleeding category definitions:

TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of haemorrhage associated with a drop in

haemoglobin (Hgb) of ≥50 g/L, or when Hgb is not available, a fall in haematocrit (Hct) of 15%.

Fatal: A bleeding event that directly led to death within 7 days.

ICH: Intracranial haemorrhage.

Other TIMI Major: Non-fatal non-ICH TIMI Major bleeding.

TIMI Minor: Clinically apparent with 30-50 g/L decrease in haemoglobin.

TIMI Requiring medical attention: Requiring intervention, OR leading to hospitalisation, OR prompting evaluation.

PLATO Major Fatal/life-threatening: Fatal bleeding, OR any intracranial bleeding, OR intrapericardial with cardiac tamponade,

OR with hypovolaemic shock or severe hypotension requiring pressors/inotropes or surgery OR clinically apparent with >50 g/L

decrease in haemoglobin, OR ≥4 red cell units transfused.

PLATO Major Other: Significantly disabling, OR clinically apparent with 30-50 g/L decrease in haemoglobin, OR 2-3 red cell

units transfused.

PLATO Minor: Requires medical intervention to stop or treat bleeding.

In PEGASUS, TIMI Major bleeding for B

RILINTA

60 mg twice daily was higher than for aspirin

alone. No increased bleeding risk was seen for fatal bleeding and only a minor increase was

observed in intracranial haemorrhages, as compared to aspirin therapy alone. There were few

fatal bleeding events in the study, 11 (0.3%) for B

RILINTA

60 mg and 12 (0.3%) for aspirin

therapy alone. The observed increased risk of TIMI Major bleeding with B

RILINTA

60 mg was

primarily due to a higher frequency of Other TIMI Major bleeding driven by events in the

gastrointestinal SOC.

RILINTA

Data Sheet 120619

Copyright

Increased bleeding patterns similar to TIMI Major were seen for TIMI Major or Minor and

PLATO-defined Major and PLATO-defined Major or Minor bleeding categories (see Table 3).

Discontinuation of treatment due to bleeding was more common with B

RILINTA

60 mg

compared to aspirin therapy alone (6.2% and 1.5%, respectively). The majority of these

bleedings were of less severity (classified as TIMI Requiring medical attention), e.g. epistaxis,

bruising and haematomas.

The bleeding profile of B

RILINTA

60 mg was consistent across multiple pre-defined subgroups

(e.g. by age, gender, weight, race, geographic region, concurrent conditions, concomitant

therapy and medical history) for TIMI Major, TIMI Major or Minor, and PLATO-defined Major

bleeding events.

Intracranial bleeding: Spontaneous ICHs were reported in similar rates for B

RILINTA

60 mg and

aspirin therapy alone (n=13, 0.2% in both treatment groups). Traumatic and procedural ICHs

showed a minor increase with B

RILINTA

60 mg treatment, (n=15, 0.2%) compared with aspirin

therapy alone (n=10, 0.1%). There were 6 fatal ICHs with B

RILINTA

60 mg and 5 fatal ICHs

with aspirin therapy alone. The incidence of intracranial bleeding was low in both treatment

groups given the significant comorbidity and cardiovascular risk factors of the population under

study.

Dyspnoea

In PLATO, dyspnoea adverse events were reported in 13.8% of patients taking ticagrelor 90

mg twice daily and in 7.8% in patients taking clopidogrel 75 mg once daily. Most reported

dyspnoea adverse events were mild to moderate in intensity and often resolved without the

need of treatment discontinuation. Dyspnoea was usually reported in the initial phase of

treatment and 87% of the patients who reported dyspnoea experienced a single episode.

Dyspnoea serious adverse events were reported in 0.7% taking ticagrelor and 0.4% taking

clopidogrel. Patients who reported dyspnoea tended to be older and more frequently had

dyspnoea, CHF, COPD, or asthma at baseline. PLATO data do not suggest that the higher

frequency with B

RILINTA

is due to new or worsening heart or lung disease. There was no

indication of an adverse effect of B

RILINTA

on pulmonary function (see section 4.4).

In PEGASUS, dyspnoea was reported in 14.2% of patients taking B

RILINTA

60 mg twice daily

and in 5.5% of patients taking aspirin alone. As in PLATO, most reported dyspnoea was mild

to moderate in intensity (see section 4.4).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of B

RILINTA

Because these reactions are reported voluntarily from a population of an unknown size, it is

not always possible to reliably estimate their frequency.

Immune system disorders: Hypersensitivity reactions including angioedema (see section 4.3)

Skin and subcutaneous tissue disorders: Rash

Blood disorders: Thrombotic Thrombocytopenic Purpura (see section 4.4)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

RILINTA

Data Sheet 120619

Copyright

4.9

OVERDOSE

There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not

dialysable (see section 5.2). Treatment of overdose should follow local standard medical

practice. The expected effect of excessive B

RILINTA

dosing is prolonged duration of bleeding

risk associated with platelet inhibition. If bleeding occurs appropriate supportive measures

should be taken.

Ticagrelor is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was

dose-limiting in a single ascending dose study. Other clinically meaningful adverse effects

which may occur with overdose include dyspnoea and ventricular pauses (see section 4.8).

In the event of overdose, observe for these potential adverse reactions and consider ECG

monitoring.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764 766).

5.

PHARMACOLOGICAL PROPERTIES

5.1

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code:

B01AC24

Mechanism of action

RILINTA

contains ticagrelor a member of the chemical class cyclopentyltriazolopyrimidines

(CPTP), which is an oral, direct acting selective and reversibly binding P2Y

receptor

antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y

dependent platelet

activation and aggregation. Ticagrelor does not prevent ADP binding but when bound to the

receptor prevents ADP-induced signal transduction. Since platelets participate in the

initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of

platelet function has been shown to reduce the risk of cardiovascular events such as CV death,

myocardial infarction or stroke.

Ticagrelor has an additional mechanism of action, increasing local endogenous adenosine

levels by inhibiting equilibrative nucleoside transporter-1 (ENT-1). Adenosine is formed locally

at sites of hypoxia and tissue damage through degradation of released adenosine tri- and di-

phosphate (ATP and ADP). As adenosine degradation is essentially restricted to the

intracellular space, inhibition of ENT-1 by ticagrelor prolongs the half-life of adenosine and

thereby increases its local extracellular concentration providing enhanced local adenosine

responses. Ticagrelor has no clinically significant direct effect on adenosine receptors (A

) and is not metabolised to adenosine. Adenosine has been documented to have

a number of effects that include: vasodilation, cardioprotection, platelet inhibition, modulation

of inflammation and induction of dyspnoea, which may contribute to the clinical profile of

ticagrelor.

Pharmacodynamic effects

Onset of Action

The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-

week study examining both acute and chronic platelet inhibition effects in response to 20 µM

ADP as the platelet aggregation agonist in patients with stable coronary artery disease (CAD)

RILINTA

Data Sheet 120619

Copyright

on aspirin. The onset was evaluated following a loading dose of 180 mg ticagrelor or 600 mg

clopidogrel.

Ticagrelor demonstrates a rapid onset of pharmacological effect as demonstrated by a mean

IPA for ticagrelor at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA

effect of 87.9% to 89.6% by 2-4 hours post dose. 90% of patients had final extent IPA >70% by

2 hours post dose. The high IPA effect of ticagrelor between 87%-89% was maintained

between 2-8 hours.

Figure 1 - Mean final extent Inhibition (±SE) of Platelet Aggregation (IPA) following

single oral doses of 180 mg BRILINTA or 600 mg clopidogrel in patients with stable CAD

Offset of Effect

The offset was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg

once daily, again in response to 20 µM ADP. After the B

RILINTA

concentrations decline to a

level less than that required for receptor saturation, IPA gradually decreases with declining

plasma concentrations. Since B

RILINTA

binds reversibly, the recovery of platelet function does

not depend on replacement of platelets. B

RILINTA

has a faster rate of offset of IPA as compared

to clopidogrel as determined by the slope of offset from 4-72 hours after last dose (see section

4.4).

Median final extent IPA measured after the last dose of B

RILINTA

is approximately 20-30%

higher for B

RILINTA

compared to clopidogrel. However, by 24 hours post-dose, %IPA is similar

between B

RILINTA

and clopidogrel, and is lower for B

RILINTA

from 72 hours through 7 days

compared with the clopidogrel. Mean %IPA for B

RILINTA

at 72 hours (Day 3) post last dose

was comparable to clopidogrel at Day 5, and %IPA for B

RILINTA

at Day 5 was similar to

clopidogrel at Day 7, which is not statistically different from placebo.

Treatment:

BRILINTA

Clop idogrel

IP A ( % ) Ind uc e d by 2 0 uM A DP

0

10

20

30

40

50

60

70

80

90

100

Time (hour)

0

1

2

3

4

5

6

7

8

RILINTA

Data Sheet 120619

Copyright

Figure 2 - Mean final extent Inhibition (±SE) of Platelet Aggregation (IPA) following the

last maintenance dose of 90 mg B

RILINTA

or 75 mg clopidogrel or placebo

Brilinta

58.4%

32.8%

19.5%

9.7%

7.3%

Clopidogrel

51.8%

41.3%

29.1%

20.8%

11.6%

Placebo

2.6%

1.4%

2.6%

1.0%

6.0%

Responders to B

RILINTA

IPA induced by B

RILINTA

has less variability at peak plasma concentrations of B

RILINTA

observed with the 90 mg twice daily dose compared to clopidogrel 75 mg once daily. Patients

with stable CAD predetermined to have low IPA response to clopidogrel (non-responders), and

given a concomitant dose of aspirin, exhibited higher mean IPA response after administration

of B

RILINTA

as compared to clopidogrel. In non-responders to clopidogrel, the IPA response

to B

RILINTA

was observed to be higher and more consistent. B

RILINTA

treatment resulted in

consistently higher IPA compared with clopidogrel, and this was apparent post dose for both

responders and non-responders.

Switching data

Switching from clopidogrel 75 mg once daily to B

RILINTA

90 mg twice daily results in an

absolute IPA increase of 26.4% and switching from B

RILINTA

to clopidogrel results in an

absolute IPA decrease of 24.5%. Patients can be switched from clopidogrel to B

RILINTA

without interruption of anti-platelet effect (see section 4.2).

Adenosine mechanism (ENT-1)

Ticagrelor increased plasma adenosine concentrations in ACS patients and has been shown

to augment several physiological responses to adenosine. Adenosine is a vasodilator;

ticagrelor has been shown to augment adenosine-induced coronary blood flow increases in

healthy volunteers and ACS patients. Adenosine is an endogenous platelet inhibitor; ticagrelor

has been shown to augment adenosine-mediated inhibition of platelet aggregation in addition

to platelet inhibition due to its P2Y

antagonism. Adenosine has been linked to the cardio-

protective effect of preconditioning; ticagrelor has been shown to reduce infarct size via an

adenosine-mediated mechanism in a rat model of reperfusion injury. Adenosine also induces

dyspnoea; ticagrelor has been shown to augment adenosine-induced dyspnoea in healthy

volunteers. Thus, the dyspnoea observed in some patients taking ticagrelor (see section 4.8)

may partly be mediated by adenosine.

RILINTA

Data Sheet 120619

Copyright

Clinical efficacy and safety

The clinical evidence for the efficacy of B

RILINTA

is derived from two phase 3 trials:

The PLATO [PLATelet Inhibition and Patient Outcomes] study, a comparison of

RILINTA

to clopidogrel, both given in combination with aspirin and other standard

therapy.

The PEGASUS TIMI-54 [PrEvention with TicaGrelor of SecondAry Thrombotic Events

in High-RiSk AcUte Coronary Syndrome Patients] study, a comparison of B

RILINTA

treatment combined with aspirin to aspirin therapy alone.

PLATO study (Acute Coronary Syndromes)

The PLATO Study was a 18,624 patient randomised, double-blind, parallel group, phase 3,

efficacy and safety study of B

RILINTA

compared with clopidogrel for prevention of thrombotic

events (CV death, MI and stroke) in patients with ACS (unstable angina, non ST elevation MI

[NSTEMI] or ST elevation MI [STEMI]).

The study was comprised of patients who presented within 24 hours of onset of the most recent

episode of chest pain or symptoms. Patients were randomised to receive clopidogrel (75 mg

once daily, with an initial loading dose of 300 mg), or a loading dose of 180 mg of B

RILINTA

followed by a maintenance dose of 90 mg of B

RILINTA

twice daily. Patients could have been

medically managed, treated with PCI or CABG.

Figure 3 - Kaplan-Meier plot and analysis of the primary clinical composite endpoint of

CV Death, MI and Stroke in PLATO (full analysis set)

RILINTA

reduced the occurrence of the primary composite endpoint compared to clopidogrel

in both the UA/NSTEMI and STEMI population.

9 3 3 3

9 2 9 1

8 6 2 8

8 5 2 1

8 4 6 0

8 3 6 2

8 2 1 9

8 1 2 4

6 7 4 3

6 6 5 0

5 1 6 1

5 0 9 6

4 1 4 7

4 0 7 4

8 0 %

1 1 .

6 7 %

9 5 %

7 7 ,

p - v a l

< 0 .

0 0 1

c a g r e l

( T)

8 6 4 /

9 3 3 3 ]

o p i

d o g r e l

( C)

1 0 1 4 /

9 2 9 1 ]

Kaplan-Meier Percentage (%)

Da y s

r om Ra n d om i

s a t

1 2 0

1 8 0

2 4 0

3 0 0

3 6 0

RILINTA

Data Sheet 120619

Copyright

Table 4 – Analysis of primary and secondary efficacy endpoints in PLATO (full analysis

set)

Primary Endpoint

Patients with

Events

B

RILINTA

90 mg

twice

daily

(%)

N=9333

Clopidogrel

75 mg once

daily

(%)

N=9291

Relative

Risk

Reduction

a

(%)

Hazard Ratio

(95% CI)

p-value

Composite of CV

Death/MI (excl. silent

MI)/Stroke

10.9

0.84(0.77,0.92)

p=0.0003

CV death

0.79(0.69,0.91)

p=0.0013

MI (excl. silent MI)

0.84(0.75,0.95)

p=0.0045

Stroke

1.17(0.91,1.52)

p=0.2249

Secondary Endpoints

Composite of CV

Death/MI (excl. silent

MI)/Stroke – intent to

invasively manage

a

10.0

0.84(0.75,0.94)

p=0.0025

Composite of all-cause

mortality/MI (excl. silent

MI)/Stroke

11.5

0.84(0.77,0.92)

p=0.0001

Composite of CV

Death/Total

MI/Stroke/SRI

/TIA

Other ATE

13.8

15.7

0.88(0.81,0.95)

p=0.0006

All-cause mortality

0.78(0.69,0.89)

p=0.0003**

RRR = (1-Hazard Ratio) x 100%. Values with a negative relative risk reduction indicate a relative risk increase

**nominal p-value.

SRI = Severe Recurrent Cardiac Ischaemia.

RI = Recurrent Cardiac Ischaemia.

TIA = Transient Ischemic Attack.

ATE = Arterial Thrombotic events.

RILINTA

is superior to clopidogrel in the prevention of thrombotic events (relative risk reduction

[RRR] 16%, absolute risk reduction [ARR] 1.9%, NNT =54) of the composite efficacy endpoint

(CV death, MI and stroke) over 12 months. The difference in treatments was driven by CV

death and MI with no difference on strokes. B

RILINTA

demonstrated a statistically significant

RRR of 16% (ARR 1.1%) for MI and a 21% relative risk reduction (ARR 1.1%) for CV death.

Treating 91 patients with B

RILINTA

instead of clopidogrel will prevent 1 CV death.

RILINTA

showed superiority to clopidogrel in preventing the composite endpoint (CV death,

MI, or stroke). This result appeared early (ARR 0.6% and RRR of 12% at 30 days), with a

constant treatment effect over the entire 12 month period, yielding ARR 1.9% per year with

RRR of 16%. This suggests it is appropriate to treat for at least 12 months (see section 4.2).

In PLATO, a large number of subgroup comparisons were conducted for the primary efficacy

endpoint to assess the robustness and consistency of the overall benefit. The treatment effect

RILINTA

over

clopidogrel

appears

consistent

across

multiple

patient

subgroups

demographic characteristics including weight, gender, medical history, concomitant therapy,

and by final index event diagnosis (STEMI, NSTEMI, and UA).

A weakly significant treatment interaction was observed with region whereby the hazard ratio

for the primary endpoint favours B

RILINTA

in the rest of world but favours clopidogrel in North

RILINTA

Data Sheet 120619

Copyright

America, which represented approximately 10% of the overall population studied (interaction

p-value=0.045).

This apparent treatment-by-region interaction observed in PLATO could plausibly be attributed

to chance, at least in part. Additional analyses suggest that the efficacy of

RILINTA

relative

to clopidogrel is associated with aspirin dose during maintenance therapy. The data show

greater efficacy of ticagrelor compared to clopidogrel when used in conjunction with low

maintenance dose aspirin (75-150 mg). The relative efficacy of ticagrelor versus clopidogrel

when used with high doses of aspirin (>300 mg) is less certain. Based on this observed

relationship between maintenance aspirin dose and relative efficacy of ticagrelor compared to

clopidogrel, it is recommended that

RILINTA

is used with a low maintenance dose of aspirin

75-150 mg (see sections 4.2 and 4.4).

The benefits associated with

RILINTA

were also independent of the use of other acute and

long-term cardiovascular therapies, including heparin, low molecular weight heparin (LMWH),

intravenous GpIIb/IIIa inhibitors, lipid-lowering drugs, beta-blockers, angiotensin-converting

enzyme (ACE) inhibitors, angiotensin II receptor antagonists and proton pump inhibitors (see

section 4.5).

RILINTA

demonstrated a statistically significant RRR in the composite endpoint of CV death,

MI and stroke in ACS patients planned for invasive management (RRR 16%, ARR 1.7%,

p=0.0025). In an exploratory analysis,

RILINTA

demonstrated a RRR of the primary

composite endpoint in ACS patients intended for medical management (RRR 15%, ARR 2.3%,

nominal p=0.0444). Consistent with the primary endpoint of the study, the effect in these two

groups was driven by CV death and MI with no effect on stroke. In patients receiving stents

there were numerically fewer definite stent thromboses among patients treated with ticagrelor

compared to clopidogrel (73 vs. 107, RRR 32%, ARR 0.6%, nominal p=0.0123).

RILINTA

demonstrated a statistically significant RRR of 16% (ARR 2.1%) for the composite of

all-cause mortality, MI and stroke compared to clopidogrel.

The final secondary endpoint (all-cause mortality) was evaluated.

RILINTA

demonstrated a

RRR of 22% for all-cause mortality compared to clopidogrel at a nominal significance level of

p=0.0003 and an ARR of 1.4%.

Holter Substudy

To study the occurrence of ventricular pauses and other arrhythmic episodes during PLATO,

investigators performed Holter monitoring in a subset of nearly 3000 patients, of whom

approximately 2000 had recordings both in the acute phase of their ACS and after one month.

The primary variable of interest was the occurrence of ventricular pauses ≥3 seconds. More

patients had ventricular pauses with B

RILINTA

(6.0%) than with clopidogrel (3.5%) in the acute

phase; and 2.2% and 1.6%, respectively, after 1 month (see section 4.4). The increase in

ventricular pauses in the acute phase of ACS was more pronounced in ticagrelor patients with

history of CHF (9.2% versus 5.4% in patients without CHF history; for clopidogrel patients,

4.0% in those with versus 3.6% in those without CHF history). This imbalance did not occur

at one month: 2.0% versus 2.1% for ticagrelor patients with and without CHF history

respectively;

and 3.8%

versus

1.4% with

clopidogrel.

There

were

adverse

clinical

consequences

associated

with

this

imbalance

(including

pacemaker

insertions)

this

population of patients.

PLATO genetic substudy

In PLATO, 10,285 patients provided genetic samples for genotype determination of CYP2C19

and ABCB1 loci. An analysis provided these associations of genotype groupings on efficacy

and safety outcomes in PLATO. The superiority of ticagrelor over clopidogrel in reducing major

RILINTA

Data Sheet 120619

Copyright

CV events was not significantly affected by patient CYP2C19 or ABCB1 genotype. Similar to

the overall PLATO study, Total Major Bleeding did not differ between ticagrelor and clopidogrel,

regardless of CYP2C19 or ABCB1 genotype. Non-CABG PLATO Major bleeding was

increased with ticagrelor compared clopidogrel in patients with one or more CYP2C19 LOF

allele, but was similar to clopidogrel in patients with no loss of function allele.

Combined efficacy and safety composite

A combined efficacy and safety composite (CV death, MI, stroke, or PLATO-defined ‘Total

Major’ bleeding) supports the clinical benefit of ticagrelor compared to clopidogrel (RRR 8%,

ARR 1.4%, HR 0.92; p=0.0257) over 12 months after ACS events.

PEGASUS Study (History of Myocardial Infarction)

The PEGASUS TIMI-54 study was a 21,162 patient, event-driven, randomised, double blind,

placebo controlled, parallel group, international multicentre study to assess the prevention of

thrombotic events with ticagrelor given at 2 doses (either 90 mg twice daily or 60 mg twice

daily) combined with low dose aspirin (75-150 mg daily) compared to aspirin therapy alone

(75-150 mg daily) in patients with history of MI and additional risk factors for atherothrombosis.

Risk Factors

Patients were eligible to participate if they were aged 50 years or over, with a history of MI (1 to

3 years prior to randomisation), and had at least one of the following risk factors for

atherothrombosis:

age ≥65 years

diabetes mellitus requiring medication

a second prior MI

evidence of multivessel CAD

chronic non-end-stage renal dysfunction.

RILINTA

Data Sheet 120619

Copyright

Figure 4 - Kaplan-Meier plot and analysis of primary clinical composite endpoint of CV

Death, MI and Stroke in PEGASUS (full analysis set)

Days from Randomization

Cumulative %

1080

1200

1320

Ticagrelor 60 mg bd

Placebo

Patients with events

KM% at 36 months

Hazard Ratio (95% CI)

p-value

7045

487 ( 6.9%)

7.8%

0.84 (0.74, 0.95)

0.0043

7067

578 ( 8.2%)

9.0%

N at risk

Ti 60 mg 7045

6948

6857

6784

6711

6357

5904

4926

3698

2055

Placebo 7067

6950

6842

6761

6658

6315

5876

4899

3646

2028

RILINTA

Data Sheet 120619

Copyright

Table 5 - Analysis of primary and secondary efficacy endpoints in PEGASUS (full

analysis set)

BRILINTA 60 mg twice daily+

Aspirin

N = 7045

Aspirin alone

N = 7067

p-value

Characteristic

Patients

with

events

KM %

HR

(95% CI)

Patients

with events

KM %

Primary endpoint

Composite of CV

Death/MI /stroke

487 (6.9%)

7.8%

0.84

(0.74, 0.95)

578 (8.2%)

9.0%

0.0043 (s)

CV death

174 (2.5%)

2.9%

0.83

(0.68, 1.01)

210 (3.0%)

3.4%

0.0676

285 (4.0%)

4.5%

0.84

(0.72, 0.98)

338 (4.8%)

5.2%

0.0314

Stroke

91 (1.3%)

1.5%

0.75

(0.57, 0.98)

122 (1.7%)

1.9%

0.0337

Secondary endpoint

CV death

174 (2.5%)

2.9%

0.83

(0.68, 1.01)

210 (3.0%)

3.4%

All-cause

mortality

289 (4.1%)

4.7%

0.89

(0.76, 1.04)

326 (4.6%)

5.2%

Hazard ratio and p-values are calculated separately for ticagrelor vs. aspirin alone from Cox proportional hazards

model with treatment group as the only explanatory variable.

Kaplan-Meier percentage calculated at 36 months.

Note: the number of first events for the components CV Death, MI and stroke are the actual number of first events

for each component and do not add up to the number of events in the composite endpoint

(s) Indicates statistical significance.

CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; KM - Kaplan-Meier; MI = Myocardial infarction;

N = Number of patients.

Both 60 mg twice daily and 90 mg twice daily regimens of B

RILINTA

, in combination with aspirin,

were superior to aspirin alone in the prevention of thrombotic events (composite endpoint: CV

death, MI and stroke), with a consistent treatment effect over the entire study period, yielding

a 16% RRR and 1.27% ARR for ticagrelor 60 mg and a 15% RRR and 1.19% ARR for ticagrelor

90 mg.

Although the efficacy profile of ticagrelor 90 mg and 60 mg were similar, there is evidence that

the lower dose has a better tolerability and safety profile in relation to risk of the bleeding and

dyspnoea.

Therefore,

RILINTA

60 mg

twice

daily

co-administered

with

aspirin

recommended for the prevention of thrombotic events (CV death, MI and stroke) in patients

with a history of myocardial infarction (MI occurred at least one year ago) and a high risk of

developing a thrombotic event.

Relative to aspirin alone, B

RILINTA

60 mg twice daily significantly reduced the primary

composite endpoint of CV death, MI and stroke. Each of the components contributed to the

reduction in the primary composite endpoint (CV death 17% RRR, MI 16% RRR, and stroke

25% RRR).

RILINTA

Data Sheet 120619

Copyright

Treating 79 patients for up to 36 months with B

RILINTA

60 mg twice daily in combination with

aspirin instead of aspirin therapy alone will prevent one primary composite endpoint event.

The benefit of ticagrelor seen on the primary composite endpoint was also reflected across the

two secondary endpoints, with a numerical decrease in both CV death and all-cause mortality

for ticagrelor 60 mg combined with aspirin compared to aspirin therapy alone, but this did not

reach statistical significance (see Table 5).

The RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and

onwards (16% RRR) was similar. This effect was consistent throughout the study, with

duration up to 48 months (median 33 months). The consistency of RRR over time suggests

that it is appropriate to continue treatment with ticagrelor as long as the patient remains at high

risk of developing thrombotic events (see section 4.2).

The treatment effect of B

RILINTA

60 mg twice daily over aspirin was consistent across major

subgroups, see Figure 5.

Figure 5 – Hazard ratios and rates of the primary clinical composite end point of CV

Death, MI and Stoke by patient subgroup in PEGASUS (full analysis set)

RILINTA

Data Sheet 120619

Copyright

The treatment effect of B

RILINTA

60 mg twice daily over aspirin therapy alone was consistent

across multiple patient subgroups, based on demographic characteristics including weight,

gender, medical history and region.

The benefits associated with B

RILINTA

were also independent of the use of other cardiovascular

therapies including lipid-lowering drugs, beta-blockers, angiotensin-converting enzyme (ACE)

inhibitors, angiotensin II receptor antagonists, calcium channel blockers, nitrates and proton

pump inhibitors (see section 4.5).

5.2

PHARMACOKINETIC PROPERTIES

Ticagrelor demonstrates linear pharmacokinetics and exposure to ticagrelor and the active

metabolite (AR-C124910XX) are approximately dose proportional up to 1260 mg.

Absorption

Absorption of ticagrelor is rapid with a median t

of approximately 1.5 hours. The formation

of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with a

median t

of approximately 2.5 hours. Following oral administration of ticagrelor 90 mg under

fasted conditions, C

is 529 ng/ml and AUC is 3451 ng*h/ml. The metabolite parent ratios

are 0.28 for C

and 0.42 for AUC.

The mean absolute bioavailability of ticagrelor was estimated to be 36% (range 25.4% to

64.0%). Ingestion of a high-fat meal resulted in a 21% increase in ticagrelor AUC and

22% decrease in the active metabolite C

but had no effect on ticagrelor C

or the AUC of

the active metabolite. These small changes are considered of minimal clinical significance;

therefore, ticagrelor can be given with or without food.

Ticagrelor

crushed

tablets

mixed

water,

given

orally

administered

through

nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and C

within 80-

125% for ticagrelor and the active metabolite). Initial exposure (0.5 and 1 hour post-dose) from

crushed ticagrelor tablets mixed in water was higher compared to whole tablets, with a

generally identical concentration profile thereafter (2 to 48 hours).

Distribution

The steady state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and the active

metabolite is extensively bound to human plasma protein (>99.0%).

Metabolism

CYP3A is the major enzyme responsible for ticagrelor metabolism and the formation of the

active metabolite and their interactions with other CYP3A substrates ranges from activation

through to inhibition. Ticagrelor and the active metabolite are weak P-glycoprotein inhibitors.

The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in

vitro binding to the platelet P2Y

ADP-receptor. The systemic exposure to the active

metabolite is approximately 30-40% of that obtained for ticagrelor.

Excretion

The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabeled

ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in

faeces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both

less than 1% of the dose. The primary route of elimination for the active metabolite is mostly

via biliary secretion. The mean t

was approximately 6.9 hours (range 4.5-12.8 hours) for

ticagrelor and 8.6 hours (range 6.5-12.8 hours) for the active metabolite.

RILINTA

Data Sheet 120619

Copyright

Special populations

Elderly

Higher exposures to ticagrelor (approximately 60% for both C

and AUC) and the active

metabolite (approximately 50% for both C

and AUC) were observed in elderly (≥ 65 years)

subjects compared to younger subjects. These differences are not considered clinically

significant (see section 4.2).

Paediatric

RILINTA

has not been evaluated in a paediatric population (see section 4.2 ).

Gender

Higher exposures to ticagrelor (approximately 52% and 37% for C

and AUC, respectively)

and the active metabolite (approximately 50% for both C

and AUC) were observed in women

compared to men. These differences are not considered clinically significant.

Renal impairment

Exposure to ticagrelor was approximately 20% lower and exposure to the active metabolite

was approximately 17% higher in patients with severe renal impairment compared to subjects

with normal renal function. The IPA effect of B

RILINTA

was similar between the two groups,

however there was more variability observed in individual response in patients with severe

renal impairment.

In patients with end stage renal disease on haemodialysis AUC and C

of B

RILINTA

90 mg

administered on a day without dialysis were 38% and 51% higher respectively compared to

subjects with normal renal function. A similar increase in exposure was observed when

RILINTA

administered

immediately

prior

dialysis

showing

that

RILINTA

dialysable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of

RILINTA

was independent of dialysis in patients with end stage renal disease and similar to

subjects with normal renal function.

No dosing adjustment is needed in patients with renal impairment.

Hepatic impairment

and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment

compared to matched healthy subjects, respectively, however the IPA effect of BRILINTA was

similar between the two groups. Ticagrelor has not been studied in patients with severe

hepatic impairment and there is no pharmacokinetic information in patients with moderate

hepatic impairment (see section 4.2, 4.3 and 4.4).

Ethnicity

Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian

patients. Patients self-identified as Black had an 18% lower bioavailability of ticagrelor

compared to Caucasian patients. In clinical pharmacology studies, the exposure (C

AUC) to ticagrelor in Japanese subjects was approximately 40% (20% after adjusting for body

weight) higher compared to that in Caucasians. The exposure in patients self-identified as

Hispanic or Latino was similar to that in Caucasians.

5.3

PRECLINICAL SAFETY DATA

Preclinical data for ticagrelor and its major metabolite have not demonstrated unacceptable

risk for adverse effects for humans based on conventional studies of safety pharmacology,

single and repeated dose toxicity and genotoxic potential.

RILINTA

Data Sheet 120619

Copyright

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels

similar or above to clinical exposure levels and with possible relevance to clinical use were as

follows: GI toxicity and gastrointestinal irritation.

No compound-related tumours were observed in a 2-year mouse study at oral doses up to 250

mg/kg/day (>18-fold the maximum human therapeutic exposure). There was no increase in

tumours in male rats at oral doses up to 120 mg/kg/day (>15-fold the maximum human

therapeutic exposure). There was an increase in uterine adenocarcinomas and hepatocellular

adenomas plus adenocarcinomas and a decrease in pituitary adenomas and mammary

fibroadenomas in female rats only exposed to high doses (>25-fold the maximum human

therapeutic exposures). No change in tumour incidence was observed at 60 mg/kg/day (8-fold

difference to the maximum human therapeutic exposure). The uterine tumours seen only in

rats were found to be the result of a non-genotoxic endocrine effect of hormonal imbalance

present in rats given high doses of ticagrelor. The benign liver tumours are considered

secondary to the response by the liver to the metabolic load placed on the liver from the high

doses of ticagrelor.

Ticagrelor has been tested in a range of in vitro and in vivo tests, and was not shown to be

genotoxic.

Ticagrelor was found to have no effect on fertility of female rats at oral doses up to 200

mg/kg/day (approximately 20 times the maximum human therapeutic exposure) and had no

effect on fertility of male rats at doses up to 180 mg/kg/day (15.7 times the maximum human

therapeutic exposure).

Ticagrelor had no effect on foetal development at oral doses up to 100 mg/kg/day in rats (5.1

times the maximum human therapeutic exposure) and up to 42 mg/kg/day in rabbits

(equivalent to the maximum human therapeutic exposure). Ticagrelor had no effects on

parturition or postnatal development in rats at doses up to 60 mg/kg/day (4.6 times the

maximum human therapeutic exposure).

6.

PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

60 mg film coated tablet

Core

Mannitol (E421)

Dibasic calcium phosphate

Magnesium stearate

Sodium starch glycolate

Hydroxypropyl-cellulose

Coating

Titanium dioxide (E171)

Ferric oxide black (E172)

Ferric oxide red (E172)

Polyethylene glycol 400

Hypromellose

90 mg film coated tablet

Core

Mannitol (E421)

RILINTA

Data Sheet 120619

Copyright

Dibasic calcium phosphate

Magnesium stearate

Sodium starch glycolate

Hydroxypropyl-cellulose

Coating

Talc

Titanium dioxide (E171)

Ferric oxide yellow (E172)

Polyethylene glycol 400

Hypromellose (E464)

6.2

INCOMPATIBILITIES

Not applicable.

6.3

SHELF LIFE

3 years.

6.4

SPECIAL PRECAUTIONS FOR STORAGE

Do not store above 30°C.

6.5

NATURE AND CONTENTS OF CONTAINER

PVC-PVDC/Al transparent calendar blister (with sun/moon symbols) of 14 tablets; cartons of

14 tablets (1 blister) and 56 tablets (4 blisters).

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL

Return unused and expired medicines to your local pharmacy for disposal.

7

MEDICINE SCHEDULE

Prescription Medicine.

8.

SPONSOR

AstraZeneca Limited

P299 Private Bag 92175

Auckland 1142

Telephone: (09) 306 5650

9.

DATE OF FIRST APPROVAL

RILINTA

60 mg: 18 November 2016

RILINTA

90 mg: 18 August 2011

RILINTA

Data Sheet 120619

Copyright

10.

DATE OF REVISION OF THE TEXT

12 June 2019

CDS 1 May 2019

BRILINTA is a registered trademark of the AstraZeneca group of companies.

© AstraZeneca 2019

Doc ID-004039921 v2.0

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Caution in patients at increased risk of trauma added.

Table 1 – new footnote regarding intracranial haemorrhage

Similar products

Search alerts related to this product

Share this information