Consumer medicine information

Bricalor

Ticagrelor

BRAND INFORMATION

Brand name

Bricalor

Active ingredient

Ticagrelor

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bricalor.

SUMMARY CMI

BRICALOR

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. WHY AM I USING BRICALOR?

BRICALOR film-coated tablets contains the active ingredient Ticagrelor. BRICALOR is used to a heart attack, or unstable angina (angina or chest pain that is not well controlled). For more information, see Section 1. Why am I using BRICALOR? in the full CMI.

2. What should I know before I take BRICALOR?

Do not use if you have ever had an allergic reaction to BRICALOR or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I take BRICALOR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BRICALOR and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take BRICALOR?

The starting dose is two tablets at the same time. This dose will usually be given to you in the hospital. After that, the usual dose is one tablet twice a day. Swallow each tablet whole with a drink of water. If you have trouble swallowing BRICALOR film-coated tablets you can crush them and mix with water. If you are using a nasogastric tube because you cannot swallow at all. More instructions can be found in Section 4. How do I take BRICALOR? in the full CMI.

5. What should I know while taking BRICALOR?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using BRICALOR.
  • Keep all of your doctor's appointments so that your progress can be checked. Your doctor will do regular tests (blood, urine or Magnetic Resonance Imaging (MRI)) to make sure the medicine is working and to prevent unwanted side effects. Your doctor will also use these tests to decide when you should stop taking BRICALOR.
Things you should not do
  • Do not stop taking BRICALOR without talking to your doctor. Take it for as long as your doctor keeps prescribing it. If you want to stop taking BRICALOR, talk to your doctor first.
  • Do not give this medicine to anyone else, even if they have symptoms that seem similar to yours.
Driving or using machines
  • BRICALOR is not likely to affect your ability to drive or use machines.
    You are being treated because you had a heart attack or unstable angina and you may experience dizziness and confusion. If you have these symptoms, you should be cautious while driving or using machines.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your medicine in the original container until it is time to take it.
  • Store it in a cool, dry place, below 25°C.

For more information, see Section 5. What should I know while taking BRICALOR? in the full CMI.

6. Are there any side effects?

Feeling short of breath This is very common (affects more than 1 in 10 people). It might be due to your heart disease or other cause, or it might be a side effect of BRICALOR. 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. Bruising, Nosebleed, Headache, Stomach pain, Constipation, diarrhoea or indigestion, Feeling of being sick, Rash, Inflamed stomach (gastritis), A tingling feeling, Fainting, Slow and/or irregular heart rate, Signs of irregular breathing (central sleep apnoea and Cheyne-Stokes respiration). This has been reported in a small number of patients taking BRICALOR (frequency cannot be estimated from the available data). Central sleep apnoea is associated with irregular breathing and may occur in patients with heart disease, stroke or other causes. Tell your doctor if you develop irregular breathing patterns such as speeding up, slowing down or short pauses in breathing. Your doctor will decide if you need further evaluation. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

BRICALOR

Active ingredient(s): [Ticagrelor]

Consumer Medicine Information (CMI)

This leaflet provides important information about using [BRICALOR]. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using [BRICALOR].

Where to find information in this leaflet:

1. Why am I using BRICALOR?
2. What should I know before I take BRICALOR?
3. What if I am taking other medicines?
4. How do I take BRICALOR?
5. What should I know while taking BRICALOR?
6. Are there any side effects?
7. Product details

1. Why am I using BRICALOR?

BRICALOR contains the active ingredient ticagrelor.

BRICALOR belongs to a group of medicines called anti-platelet medicines.

Platelets are very small cells in your blood that help to stop bleeding. When a blood vessel is damaged, they clump together to help form a blood clot. This stops bleeding. However, clots can also form inside a damaged blood vessel. This can be very dangerous because:

  • the clot can cut off the blood supply completely - this can cause a heart attack (myocardial infarction) or stroke.
  • the clot can partly block the blood vessels to the heart - this reduces the blood flow to the heart.
    This can cause chest pain which comes and goes (called 'unstable angina').

BRICALOR helps stop the clumping of platelets. This reduces the chance of a blood clot forming that can block a blood vessel. This means that BRICALOR reduces the chance of you having another heart attack, chest pain or stroke.

Your doctor will usually also tell you to take acetylsalicylic acid (aspirin). This is another medicine, which affects platelets.

You have been given BRICALOR because you have had:

  • a heart attack, or
  • unstable angina (angina or chest pain that is not well controlled).

Your doctor may prescribe this medicine for another use. Ask your doctor if you want more information.

BRICALOR is only available on a doctor's prescription.

There is no evidence that BRICALOR is addictive.

2. What should I know before I take BRICALOR?

Warnings

Do not take BRICALOR if:

  • You have an allergy to ticagrelor, or any of the ingredients listed at the end of the leaflet.
    Some of the symptoms of an allergic reaction may include, tightness of the chest, wheezing, coughing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body; rash, itching or hives.
  • you have problems with bleeding, such as bleeding in your stomach or gut from an ulcer.
  • you have moderate to severe liver disease.
  • you have had a stroke caused by bleeding in the brain or a history of bleeding in the brain.
  • 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).

Check with your doctor if you:

  • have allergies to any other medicines, foods, preservatives or dyes.
  • have an increased risk of bleeding because of:
    - a recent serious injury
    - recent surgery (including dental work)
    - recent bleeding from your stomach or gut (such as stomach ulcer or colon polyps)
    - you have a condition that affects blood clotting
  • have asthma or other lung problem or breathing difficulties
  • are due to have surgery (including dental work) at any time while taking BRICALOR.
    This is because of the increased risk of bleeding. Your doctor may want you to stop taking BRICALOR for a short time.
  • have or have had high uric Acid
  • have a low heart rate
  • have or have had any medical conditions.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

It is not recommended you take you take BRICALOR. Your doctor will discuss the risks and benefits of taking BRICALOR during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not recommended that you take BRICALOR. Your doctor will discuss the risks and benefits of taking BRICALOR during breast feeding.

Children

BRICALOR is not recommended for children under 18 years of age, as its safety and effectiveness in children have not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

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

  • rosuvastatin or more than 40 mg daily of simvastatin (used to treat high cholesterol).
  • rifampin (an antibiotic).
  • phenytoin, carbamazepine and phenobarbital (used to control seizures)
  • dexamethasone (used to treat inflammatory and auto immune conditions).
  • digoxin (used to treat heart failure).
  • cyclosporin (used to lessen your body's defences).
  • quinidine and diltiazem (used to treat abnormal heart rhythms).
  • adenosine (used to treat irregular heart rate).
  • ergotamine (used to treat migraine).
  • beta blockers and verapamil (used to treat high blood pressure).
  • morphine (used to relieve pain).

Tell your doctor or pharmacist if you are taking any medicines that may increase your risk of bleeding. These medicines include:

  • "Oral anticoagulants", often referred to as "blood thinners", which include aspirin, warfarin, clopidogrel and prasugrel.
  • "Fibrinolytics" and "thrombolytics", often referred to as "clot-dissolvers", which include streptokinase and tenecteplase.
  • Non-steroidal anti-inflammatory drugs (NSAIDs) often taken as pain killers such as ibuprofen and naproxen.
  • Selective serotonin reuptake inhibitors (SSRIs) taken as antidepressants such as paroxetine, sertraline and citalopram.

You may need different amounts of your medicines, or may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affects BRICALOR.

They will have more information on medicines to be careful with or avoid while taking BRICALOR.

4. How do I take BRICALOR?

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions in this leaflet, ask your doctor or pharmacist for help.

How much to take

The starting dose is two tablets at the same time. This dose will usually be given to you in the hospital. After that, the usual dose is one tablet twice a day.

BRICALOR film-coated tablets

Swallow each tablet whole with a drink of water.

If you have trouble swallowing BRICALOR film-coated tablets you can crush them and mix with water as follows:

  • Crush the tablet(s) to a fine powder using a mortar and pestle or other crushing device.
  • Add half a glass of water (approximately 100 mL) to the mortar and pestle/crushing device and stir before pouring the liquid into a glass and drinking immediately.
  • For the remaining medicine, add another 100 mL to mortar and pestle/crushing device and stir. Pour the liquid into a glass and drink it immediately. Make sure you also stir the liquid in the glass before you drink it

If you are using a nasogastric tube because you cannot swallow at all:

  • Crush tablets in mortar and pestle/crushing device to a fine powder.
  • Add 50 mL of water to the mortar and pestle/crushing device and stir before withdrawing the mixture into a syringe and administering the liquid through a nasogastric tube.
  • For the remaining medicine, add another 50 mL to mortar and pestle/crushing device and stir before withdrawing the mixture into the syringe and administering through a nasogastric tube.

When to take BRICALOR

It does not matter whether you take BRICALOR with food or on an empty stomach.

Take your doses at around the same time every day. For example, one in the morning and one in the evening.

Taking your tablets at the same time each day will have the best effect. It will also help you to remember when to take it. You can check the day when you last took a BRICALOR film-coated tablet by looking at days 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.

How long to take it

You should take BRICALOR for as long as your doctor tells you to.

If you forget to take BRICALOR

BRICALOR should be used regularly at the same time each day. If you miss your dose at the usual time, take your next dose as normal. Then go back to taking it as you would normally.

Do not take double the dose to make up for the dose you missed.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much BRICALOR

If you think that you have taken too much BRICALOR, may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you take too many BRICALOR tablets you may be at increased risk of bleeding.

5. What should I know while taking BRICALOR?

Things you must do

  • Take BRICALOR exactly as your doctor has told you to.
  • Tell all doctors, dentists and pharmacists who are treating you that you are taking BRICALOR.
  • If you are about to start taking any new medicines, tell your doctor and pharmacist that you are taking BRICALOR.
  • Tell your doctor if you become pregnant while you are taking BRICALOR.
  • Tell your doctor if you decide to breast feed your baby.

Things you should not do

  • Do not stop taking BRICALOR without talking to your doctor. Take it for as long as your doctor keeps prescribing it. If you want to stop taking BRICALOR, talk to your doctor first.
    This is because the benefits of BRICALOR are based on you taking it all the time. If you stop taking BRICALOR without talking to your doctor it may increase the chance of a heart attack or stroke or a blood clot forming.
  • Do not take BRICALOR to treat any other complaint unless your doctor advises you to.
  • Do not give this medicine to anyone else, even if they have symptoms that seem similar to yours.

Driving or using machines

Be careful driving or operating machinery.

BRICALOR is not likely to affect your ability to drive or use machines. You are being treated because you had a heart attack or unstable angina and you may experience dizziness and confusion. If you have these symptoms, you should be cautious while driving or using machines.

Looking after your medicine

Keep your tablets in the blister pack until it is time to take them.

If you take BRICALOR out of the blister pack it will not keep well.

Store it in a cool dry place below 30°C and away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

Ask your pharmacist what to do with any BRICALOR tablets you have left over if your doctor tells you to stop taking them, or you find that the expiry date has passed.

Do not take this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • A Feeling shortness of breath
    This is very common (affects more than 1 in 10 people). It might be due to your heart disease or other cause, or it might be a side effect of BRICALOR. 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.
  • Bruising
  • Nosebleed
  • Headache
  • Stomach pain
  • Constipation, diarrhoea or indigestion
  • Feeling of being sick
  • Rash
  • Inflamed stomach (gastritis)
  • A tingling feeling
  • Fainting
  • Slow and/or irregular heart rate
  • Signs of irregular breathing (central sleep apnoea and Cheyne-Stokes respiration)
    This has been reported in a small number of patients taking BRICALOR (frequency cannot be estimated from the available data). Central sleep apnoea is associated with irregular breathing and may occur in patients with heart disease, stroke or other causes. Tell your doctor if you develop irregular breathing patterns such as speeding up, slowing down or short pauses in breathing. Your doctor will decide if you need further evaluation.

Serious side effects

Serious side effectsWhat to do
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.
These are signs of a kind of stroke caused by bleeding into the brain. This is uncommon (affects less than 1 in 100 people).
Signs of bleeding, including:
  • Blood in your urine
  • Black stools or blood in your stools
  • Bleeding after surgery or from cuts and wounds that is more than normal
Some bleeding is common (affects less than 1 in 10 people). However, severe bleeding is uncommon (affects less than 1 in 100 people), but can be life threatening.
Signs of blood clotting, such as:
  • Fever and purplish spots on the skin or in the mouth, with or without yellowing of the skin or eyes, unexplained extreme tiredness or confusion
Signs of serious allergic reaction, such as:
  • tightness of the chest, wheezing, coughing or difficulty breathing.
  • swelling of the face, lips, tongue or other parts of the body.
  • severe skin reaction which may include rash, itching, redness, blistering or peeling of the skin.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

The level of uric acid in your blood may increase while taking BRICALOR.

Your doctor may order blood tests to monitor the level of uric acid in your blood.

Tell your doctor if you notice anything else that is making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

After using it

Storage

Keep your tablets in the blister pack until it is time to take them.

If you take BRICALOR out of the blister pack it will not keep well.

Keep it in a cool, dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom or near a sink. Do not leave it on a windowsill or in the car on hot days.

Heat and dampness can destroy some medicines. Keep it where young children cannot reach it.

A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Disposal

Ask your pharmacist what to do with any BRICALOR tablets you have left over if your doctor tells you to stop taking them, or you find that the expiry date has passed.

7. Product details

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

What BRICALOR contains:

Active ingredient
(main ingredient)		Ticagrelor 90 mg
Other ingredients (inactive ingredients)
  • Mannitol
  • Calcium hydrogen Phosphate Dihydrate
  • Croscarmellose sodium
  • Hyprolose
  • Magnesium stearate
  • Opadry complete film coating system 02B520003 yellow (111369)
  • PHARMACOR TICAGRELOR does not contain gluten.

Do not take this medicine if you are allergic to any of these ingredients.

What BRICALOR looks like

BRICALOR are round, biconvex, light yellow to yellow, film coated tablet debossed with “90” on one side and “A” over “049” on other side.

BRICALOR 90 mg is available in calendar blisters (with sun/moon symbols) in cartons of 14, 28 and 56 tablets.

Who distributes BRICALOR

Pharmacor Australia Pty Ltd.
Suite 803, Level 8 Tower A,
The Zenith 821 Pacific Highway
CHATSWOOD, NSW, 2067
www.pharmacor.com.au

Australian Registration Number

BRICALOR Tablets 90 mg
AUST R 288019

This leaflet was prepared in 08/2024

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Bricalor

Active ingredient

Ticagrelor

Schedule

S4

 

1 Name of Medicine

Ticagrelor.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 90 mg ticagrelor.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
Round, biconvex, light yellow to yellow, film coated tablet debossed with "90" on one side and "A" over "049" on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Bricalor, in combination with aspirin, is indicated for the prevention of atherothrombotic events (cardiovascular death, myocardial infarction and stroke) in adult 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).

4.2 Dose and Method of Administration

Bricalor treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.
Patients taking Bricalor should take aspirin daily unless specifically contraindicated. Following an initial dose of aspirin, Bricalor should be used with a recommended maintenance dose of aspirin 100 mg daily. If required, the aspirin maintenance dose may vary from 75-150 mg according to clinical need.

Missed dose.

Lapses in therapy should be avoided. A patient who misses a dose of Bricalor 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.
Physicians who desire to switch patients with a prior ACS event from existing anti-platelet therapy to Bricalor should administer the first dose of Bricalor 24 hours following the last dose of the other anti-platelet medication.

Premature discontinuation.

Treatment is recommended for at least 12 months unless discontinuation of Bricalor is clinically indicated. In patients with ACS, premature discontinuation with any anti-platelet therapy, including Bricalor, could result in an increased risk of cardiovascular death, or myocardial infarction due to the patient's underlying disease.

Administration.

For oral use. Bricalor can be taken with or without food.
For patients who are unable to swallow the tablet(s) whole, Bricalor tablets (90 mg and 2 x 90 mg) 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.
For oral administration of crushed tablets, crush Bricalor tablets using mortar and pestle or a similar device. Adding approximately 100 mL of water to the mortar/crushing device and stir for approximately 1 minute before transferring the dispersion to a glass/dosing cup and administer. Add another 100 mL of water to the mortar/crushing device and stir for approximately ½ minute to ensure that all the remaining powder is dispersed before transferring this to the glass/dosing cup. Stir the contents of the glass again for approximately ½ minute and administer the remaining water/dispersed tablet.
For administration via a nasogastric tube (CH8 or greater), crush the tablets as stated above and use approximately 50 mL of water to disperse the crushed powder before withdrawing the dispersion into a suitable syringe. Then administer the full contents of the syringe via the nasogastric tube. Add another 50 mL to the mortar/crushing device and stir for approximately ½ minute to ensure that all the remaining powder is dispersed, before withdrawing the dispersion into the syringe and administering via the nasogastric tube. Refill the syringe with approximately 25 mL of water and shake before flushing any remaining contents from the nasogastric tube into the stomach.

Special populations.

Paediatric patients.

Safety and efficacy in children below the age of 18 years have not been established. Bricalor is not indicated in a paediatric population (see Section 5.1 Pharmacodynamic Properties).

Elderly.

No dose adjustment is required.

Patients with renal impairment.

No dose adjustment is necessary for patients with renal impairment "No information is available concerning treatment of patients on renal dialysis and therefore Bricalor is not recommended in these patients".

Patients with hepatic impairment.

No dose adjustment is necessary for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with severe hepatic impairment and there is limited information on treatment of patients with moderate hepatic impairment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Hypersensitivity to ticagrelor or any of the excipients.
Active pathological bleeding.
History of intracranial haemorrhage (see Section 4.4 Special Warnings and Precautions for Use).
Moderate to severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as co-administration may lead to a substantial increase in exposure to ticagrelor (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Bleeding risk.

In the PLATO study, the 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 ACS treated with ticagrelor and aspirin showed an increased risk of non-CABG major bleeding and also more generally in bleeds requiring medical attention i.e. major + minor PLATO bleeds, but not fatal or life-threatening bleeds (see Section 4.8 Adverse Effects (Undesirable Effects)). In the PHILO and PLATO studies, a statistically significant higher incidence of 'minor bleeding' events was reported for ticagrelor compared to clopidogrel in the Asian/Japanese population. The incidence of 'major bleeding' events was similar for both treatment groups in the PLATO Asian subpopulation, whereas it was numerically higher for the ticagrelor group compared to clopidogrel group in the PHILO study (see Section 4.8 Adverse Effects (Undesirable Effects)).
As with other anti-platelet agents, Bricalor prolongs bleeding time and should be used with caution in patients who may be at risk of increased bleeding. Therefore, the use of Bricalor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. If clinically indicated, Bricalor should be used with caution in the following patient groups:
Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders or active or recent gastrointestinal bleeding) or who are at increased risk of trauma. The use of Bricalor is contraindicated in patients with active pathological bleeding in those with a history of intracranial haemorrhage, and in patients with moderate to severe hepatic impairment (see Section 4.3 Contraindications).
Patients with concomitant administration of drugs that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants (e.g. warfarin) and/or fibrinolytics/thrombolytics within 24 hours of ticagrelor dosing).
Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of ticagrelor with desmopressin did not decrease template bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events.
Anti-fibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may augment haemostasis. Bricalor 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 Bricalor before any surgery is scheduled and before any new medicinal product is taken. If a patient requires surgery, physicians should consider each patient's clinical profile as well as the benefits and risks of continued antiplatelet therapy when determining when discontinuation of Bricalor treatment should occur.
Because of the reversible binding of ticagrelor, restoration of platelet aggregation occurs faster with ticagrelor compared to clopidogrel. In the OFFSET study (see Section 5.1 Pharmacodynamic Properties), mean IPA for ticagrelor 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 anti-platelet therapy must be temporarily discontinued due to surgery or trauma).
In patients undergoing coronary bypass grafting (CABG) in PLATO, those on ticagrelor had a non-statistically significant higher rate of major bleeding compared with those on clopidogrel when the drug was stopped within 1 day prior to surgery but a similar rate of major bleeds compared with those on clopidogrel after stopping therapy 2 or more days before surgery.
Based on the results in PLATO, if a CABG procedure is planned the bleeding risk with ticagrelor is numerically increased compared to that seen with clopidogrel when therapy is discontinued within 96 hours prior to the procedure.
If a patient is to undergo elective surgery and antiplatelet effect is not desired, Bricalor should be discontinued 5 days prior to surgery.

Patients with prior ischaemic stroke.

The PLATO study included ACS patients with prior ischaemic stroke. In the absence of data, caution is advised for treatment with Bricalor beyond one year.

Use in hepatic impairment.

The Cmax 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 ticagrelor was similar between the two groups. No dose adjustment is needed for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with severe hepatic impairment and there is limited experience with ticagrelor in patients with moderate hepatic impairment. Therefore, use of Bricalor is contraindicated in patients with moderate to severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).

Bradyarrhythmia.

Holter ECG monitoring has shown an increased frequency of mostly asymptomatic ventricular pauses during treatment with ticagrelor compared with clopidogrel. In Phase 3 studies evaluating the safety and efficacy of ticagrelor, 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 atrioventricular (AV) block or bradycardic-related syncope) have been excluded from ticagrelor outcome studies. Therefore, due to the limited clinical experience in these patients, caution is advised (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Bradyarrhythmic events and AV blocks have been reported in the post-marketing setting in patients taking ticagrelor (see Section 4.8 Adverse Effects (Undesirable Effects)), primarily in patients with ACS, where cardiac ischaemia and concomitant drugs reducing the heart rate or affecting cardiac conduction are potential confounders. The patient's clinical condition and concomitant medication should be assessed as potential causes prior to adjusting treatment.
In addition, caution should be exercised when administering ticagrelor concomitantly with drugs 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 drugs known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).
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 congestive 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 Pharmacodynamic Properties, Clinical trials, Holter substudy).

Renal dialysis.

As there is no safety and efficacy data for ticagrelor in patients undergoing renal dialysis, caution should be used with these patients as ticagrelor is not expected to be dialyzable.

Dyspnoea.

Dyspnoea, usually mild to moderate in intensity and often resolving without need for treatment discontinuation, is reported by 13.8% of patients treated with ticagrelor in PLATO and by 7.8% treated with clopidogrel. Discontinuations due to dyspnoea were reported in 0.9% of patients taking ticagrelor and 0.1% of patients taking clopidogrel (see Section 4.8 Adverse Effects (Undesirable Effects), Discontinuation).
Patients with asthma/chronic obstructive pulmonary disorder (COPD) may have an increased absolute risk of experiencing dyspnoea with Bricalor. Bricalor should be used with caution in patients with a 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 Bricalor should be stopped.

Creatinine elevations.

Creatinine levels may increase during treatment with ticagrelor (see Section 4.8 Adverse Effects (Undesirable Effects), Lab abnormalities, Creatinine elevations). The mechanism has not been elucidated. Renal function should be checked after one month and thereafter according to routine medical practice paying special attention to patients ≥ 75 years and patients with moderate/severe renal impairment and those receiving concomitant treatment with an Angiotensin II Receptor Blocker (ARB).

Uric acid increase and gout.

Hyperuricaemia and gout may occur during treatment with Bricalor (see Section 4.8 Adverse Effects (Undesirable Effects)). Caution is advised in patients with a history of hyperuricaemia or gout.

Central sleep apnoea.

Central sleep apnoea including Cheyne-Stokes respiration has been reported in the post-marketing setting in patients taking ticagrelor. If central sleep apnoea is suspected, further clinical assessment may be considered.

Thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) has been reported very rarely with the use of ticagrelor. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition and requires prompt treatment, including plasmapheresis.

Others.

Based on the relationship observed in the PLATO study between maintenance aspirin dose and relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high dose maintenance dose aspirin (> 300 mg) is not recommended (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In PLATO, patients weighing < 60 kg were at greater risk of cardiovascular events and slightly higher risk of major bleeding compared with patients weighing ≥ 60 kg (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

Discontinuations.

Patients who require discontinuation of Bricalor are at increased risk for cardiac events. Premature discontinuation of treatment should be avoided. If Bricalor 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 Dose and Method of Administration).

Use in the elderly.

Higher exposures to ticagrelor and the active metabolite were observed in elderly (≥ 65 years) subjects compared to younger subjects. These differences are not considered clinically significant. No dose adjustment is needed for elderly patients.
In PLATO, patients ≥ 65 years or ≥ 75 years of age were at greater risk of cardiovascular events and slightly higher risk of major bleeding compared with younger patients (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

Paediatric use.

The safety and efficacy of ticagrelor has not been established in patients under 18 years of age.
Bricalor is not indicated in a paediatric population (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties).

Effects on laboratory tests.

Platelet function tests to diagnose heparin-induced thrombocytopenia.

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 P2Y12-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 Bricalor, 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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.

Effects of other drugs on ticagrelor.

Drugs metabolised by CYP3A4.

Ketoconazole and other strong CYP3A4 inhibitors.

Co-administration of ketoconazole with ticagrelor increased the ticagrelor Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atanazavir) would be expected to have similar effects and their concomitant use with Bricalor is contraindicated.

Diltiazem and other moderate CYP3A4 inhibitors.

Co-administration of ticagrelor with diltiazem increased the ticagrelor Cmax by 69% and AUC by 174% and decreased the active metabolite Cmax 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, fluconazole, and verapamil) would be expected to have a similar effect as diltiazem leading to increased exposure to ticagrelor, therefore caution is advised.

Rifampicin and other CYP3A4 inducers.

Co-administration of rifampicin with ticagrelor decreased the ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax of its active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to Bricalor as well and may result in reduced efficacy of Bricalor.

Cyclosporin (PgP and CYP3A inhibitor).

Co-administration of cyclosporin (600 mg dose) with ticagrelor (180 mg) as a single oral dose in healthy male volunteers increased ticagrelor Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 33% and Cmax was decreased by 15% in the presence of cyclosporin. Caution is advised when cyclosporin and ticagrelor are coadministered.
Others.

Morphine.

Delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, has been reported in patients treated with morphine. This interaction may be related to reduced gastrointestinal motility, and therefore apply to other opioids (e.g. fentanyl). The clinical relevance is unknown, but data indicate the potential for reduced ticagrelor efficacy in patients co-administered ticagrelor and morphine. In patients with ACS, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Effects of ticagrelor on other drugs.

Drugs metabolised by CYP3A4.

Simvastatin.

Co-administration of ticagrelor with simvastatin increased the simvastatin Cmax by 81% and AUC by 56% and increased simvastatin acid Cmax by 64% and AUC by 52% with some individual increases equal to 2 to 3-fold. There was no effect of simvastatin on ticagrelor plasma levels. There is the potential for an increase in simvastatin-related adverse reactions such as myopathy and rhabdomyolysis with co-administration; no cases of rhabdomyolysis were reported when ticagrelor was co-administered with simvastatin 40 mg daily or lower. Therefore, concomitant use of ticagrelor with doses of simvastatin greater than 40 mg daily is not recommended.
A similar effect on other statins metabolised by CYP3A4 cannot be excluded.

Atorvastatin.

Co-administration of atorvastatin and ticagrelor increased the atorvastatin acid Cmax by 23% and AUC by 36%. Similar increases in AUC and Cmax were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.

Other.

Ticagrelor is a mild CYP3A4 inhibitor. Co-administration of Bricalor and CYP3A4 substrates with narrow therapeutic indices (i.e. ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these drugs.
Drugs metabolised by CYP2C9.

Tolbutamide.

Co-administration of ticagrelor with tolbutamide resulted in no change in the plasma levels of either drug, which suggest that ticagrelor is not a CYP2C9 inhibitor and unlikely to alter the CYP2C9 mediated metabolism of drugs like warfarin and tolbutamide.
Oral contraceptives. Co-administration of ticagrelor and levonorgestrel and ethinyl estradiol increased the ethinyl estradiol exposure approximately 20% but did not alter the PK of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are co-administered with Bricalor.
P-glycoprotein (P-gp) substrates (including digoxin and cyclosporin). Concomitant administration of ticagrelor increased the digoxin Cmax 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 Cmax and AUC of ticagrelor and its active metabolite were not affected. Concomitant administration of ticagrelor had a minor effect on the AUC (Gmean ratio 1.12 [90% CI; 105.75-119.20]) and Cmax (Gmean ratio 1.05 [90% CI; 98.67-111.81] of cyclosporin. Appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent drugs like digoxin and cyclosporin concomitantly with ticagrelor.
No data are available on concomitant use of Bricalor with potent P-gp inhibitors (e.g. verapamil, quinidine) that may increase ticagrelor exposure.

Other concomitant therapy.

In clinical studies, ticagrelor was commonly administered with aspirin, heparin, low molecular weight heparin, intravenous GpIIb/IIIa inhibitors, proton pump inhibitors, statins, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers as needed for concomitant conditions. These studies did not produce any evidence of clinically significant adverse interactions. Due to potential pharmacodynamic interactions, caution should be exercised with the concomitant administration of Bricalor and medicinal products known to alter haemostasis.

Adenosine.

Based on the mechanism of action of ticagrelor, patients may transiently experience increased dyspnoea in association with a bolus dose of adenosine while taking ticagrelor (see Section 5.1 Pharmacodynamic Properties, Mechanism of action).

Aspirin.

Clinical pharmacology interaction studies showed that co-administration of ticagrelor with aspirin did not have any effect on ticagrelor or its active metabolite plasma levels.

Heparin and enoxaparin.

Clinical pharmacology interaction studies showed that co-administration of ticagrelor with heparin did not have any effect on ticagrelor or its 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 heparin had no effect on enoxaparin based on factor Xa assay.

Non-steroidal anti-inflammatory drugs (NSAIDs).

Concomitant administration with chronic NSAIDs has not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs and ticagrelor should be co-administered with caution (see Section 4.4 Special Warnings and Precautions for Use, Bleeding risk).

Clopidogrel and prasugrel.

Ticagrelor and clopidogrel or prasugrel should not be co-administered.
Concomitant administration with clopidogrel has not been studied. Switching from clopidogrel to ticagrelor results in an absolute IPA increase of 26.4% and switching from ticagrelor to clopidogrel results in an absolute IPA decrease of 24.5%. Patients can be switched from clopidogrel to ticagrelor without interruption of anti-platelet effect (see Section 5.1 Pharmacodynamic Properties, Phamacodyamic effects, Switching data).

Drugs known to induce bradycardia.

Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with drugs 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 drugs known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).

Selective serotonin reuptake inhibitors (SSRIs).

Due to reports of cutaneous bleeding abnormalities with SSRIs, caution is advised when administering SSRIs with Bricalor as this may increase the risk of bleeding. In PLATO, there was no increase in major bleeding in patients taking ticagrelor concomitantly with SSRIs.

Rosuvastatin.

Ticagrelor might affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. Although the exact mechanism is not known, in some cases, concomitant use of ticagrelor and rosuvastatin led to renal function decrease, increased CK level and rhabdomyolysis.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Ticagrelor was found to have no effect on fertility of female rats at oral doses up to 200 mg/kg per 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 (about 16 times the maximum human therapeutic exposure).
Ticagrelor had no effect on foetal development at oral doses up to 100 mg/kg per day in rats (about 5 times the maximum human therapeutic exposure) and up to 42 mg/kg per 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 (just under 5 times the maximum human therapeutic exposure).
(Category B1)
No clinical data on exposed pregnancies are available for ticagrelor.
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Because animal reproduction studies are not always predictive of a human response, Bricalor is not recommended for use during pregnancy.
 It is not known whether ticagrelor is excreted in human milk. Studies in rats have shown that ticagrelor and active metabolites are excreted in the milk. The use of Bricalor during breastfeeding is not recommended.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of ticagrelor on the ability to drive and use machines have been performed. Bricalor is expected to have no or negligible influence on the ability to drive and use machines. During treatment with ticagrelor dizziness and confusion have been reported. Therefore, patients who experience these symptoms should be cautious while driving or using machines.

4.8 Adverse Effects (Undesirable Effects)

The safety profile of ticagrelor in patients with ACS (UA, NSTEMI and STEMI) was evaluated in PLATO study, which compared patients treated with ticagrelor (loading dose of 180 mg of ticagrelor and a maintenance dose of 90 mg bd) to patients treated with clopidogrel (300-600 mg loading dose followed by 75 mg od maintenance dose) both given in combination with aspirin and other standard therapies.
Median treatment duration for ticagrelor was 277 days. See Figure 1.
The most commonly reported adverse drug reactions in patients treated with ticagrelor were bleeding and dyspnoea, (also see Section 4.4 Special Warnings and Precautions for Use). In PLATO, headache, and epistaxis and these events occurred at higher rates than in the clopidogrel treatment group. Serious adverse events were reported in a similar frequency between ticagrelor (20.2%) and clopidogrel (20.3%) treated patients. The most frequent serious adverse events observed were cardiac failure (1.1% vs 1.0%), non-cardiac chest pain (0.9% vs 0.9%) and dyspnoea (0.7% vs 0.4%).

Discontinuation.

In PLATO, the ticagrelor group had a higher discontinuation rate due to AEs than clopidogrel (7.4% vs 5.4%). The difference was driven mainly by dyspnoea (0.9% vs 0.1%) and epistaxis (0.4% vs 0.1%). The ticagrelor and clopidogrel groups had a similar discontinuation rate due to other AEs. The discontinuation rate due to serious adverse events was 2.8% for ticagrelor and 2.4% for clopidogrel.

Bleeding events.

PLATO study. Overall outcome of bleeding events in the PLATO study are shown in Table 1.
Bleeding unrelated to any procedure: as shown in Table 1 PLATO-defined 'major' and 'major + minor' non-procedural bleeding was more frequent with ticagrelor. Discontinuation of treatment due to non-procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p < 0.001). Clinically important locations for 'major + minor' bleeding in rank order by frequency were (ticagrelor vs clopidogrel): intracranial (27 vs 14 events), pericardial (11 vs 11), retroperitoneal (3 vs 3), intraocular (2 vs 4) and intra-articular (2 vs 1). Other common locations were in rank order of frequency: gastrointestinal (170 vs 135 events), epistaxis (116 vs 61), urinary (45 vs 37), subcutaneous/dermal (43 vs 38) and haemoptysis (13 vs 7).
There was no difference with ticagrelor compared to clopidogrel for fatal non-procedural bleeding.
Bleeding category definitions.

PLATO 'major fatal/life-threatening'.

Fatal bleeding, or intracranial, or intrapericardial with cardiac tamponade, or 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 minor.

Requires medical intervention to stop or treat bleeding.

PLATO major other.

Significantly disabling, or clinically apparent with 30-50 g/L decrease in haemoglobin, or 2-3 red cell units transfused.
Bleeding events reported in PLATO were also mapped to the TIMI (thrombolysis in myocardial infarction) scale, to facilitate comparison with other similar studies. The following TIMI bleeding definitions were used:

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.
Minimal bleeds included all other bleeds not requiring intervention or treatment (e.g. bruising, bleeding gums, oozing from injection sites, etc); these were collected but not adjudicated.
PLATO definitions are more inclusive when compared to TIMI definitions of bleeding. Compared to TIMI, the PLATO definitions feature lower thresholds to capture bleeding events during both acute and chronic phases of ACS.
In PLATO, time to first PLATO-defined 'total major' bleeding for ticagrelor did not differ significantly from that of clopidogrel. The event rate for bleeding was higher for both treatment arms during the first 30 days compared to the remainder of the study; most events occurred during this period. There were few fatal bleeding events in the study, 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel 75 mg once daily. When minor bleeding was included, combined PLATO-defined major and minor bleeding events were significantly higher on ticagrelor than on clopidogrel. Minimal bleeding rates on ticagrelor were higher than on clopidogrel. Overall rates of TIMI-defined bleeding events did not differ significantly between ticagrelor and clopidogrel.
Patients ≥ 65 or ≥ 75 years of age had a slightly higher rate of major bleeding in both treatment arms. For patients ≥ 75 years of age, the rate of major bleeding was 12.1% on ticagrelor vs 11.8% on clopidogrel. For patients < 75 years of age, the rate of major bleeding was 10.1% on ticagrelor vs 9.8% on clopidogrel. Similar differences were seen in patients ≥ 65 years compared with those < 65 years.
In addition, patients weighing < 60 kg had a slightly higher rate of major bleeding in both treatment arms. For patients weighing < 60 kg, the rate of major bleeding was 11.2% on ticagrelor vs 13.3% on clopidogrel. For patients weighing ≥ 60 kg, the rate of major bleeding was 10.3% on ticagrelor vs 9.9% on clopidogrel.
In the Asian subpopulation of PLATO the rate of minor bleeding events reported with ticagrelor treatment was 7.0% compared to 4.1% on clopidogrel [HR 1.74 (95% CI: 1.02, 2.97)]. For major bleeding the incidence for the ticagrelor and clopidogrel groups was 10.1% and 9.3% respectively [HR 1.07 (95% CI: 0.73, 1.59)].

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 1 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.
Among ticagrelor-treated patients in PLATO, there were similar rates of haemorrhagic stroke between those with a history of prior TIA or ischaemic stroke and those without prior TIA or ischaemic stroke: 2/564 (0.35%) vs 21/8762 (0.24%).

Gastrointestinal bleeding and fatal gastrointestinal bleeding.

Total major GI bleeding was higher on ticagrelor than clopidogrel (1.3% vs 1%) however fatal/life threatening GI bleeding rates were similar and fatal GI bleeding events were less on ticagrelor (0 vs 5 events).
PHILO study. In PHILO, an exploratory study with a design similar to that of the PLATO study, minor bleeding events were reported in a higher proportion of Japanese subjects in the ticagrelor group compared with the clopidogrel group (15.2% (59/387) vs 9.2% (35/380) [HR 1.75 (95% CI: 1.15, 2.67]). For major bleeding the incidence in patients on ticagrelor was 10.3% compared to clopidogrel 6.8% [HR 1.54 (95% CI: 0.94, 2.53)].

Dyspnoea.

Dyspnoea is reported by patients treated with ticagrelor. Most reported dyspnoea AEs were mild to moderate in intensity and often resolved without the need of treatment discontinuation. Dyspnoea adverse events (AEs) (dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal, and nocturnal dyspnoea), when combined, were reported in 13.8% of patients taking ticagrelor and in 7.8% taking clopidogrel in the PLATO study. The study did not exclude patients with underlying CHF, COPD or asthma. Most of the dyspnoea AEs were mild to moderate in intensity. Dyspnoea serious adverse events were reported in 0.7% taking ticagrelor and 0.4% taking clopidogrel. More patients taking ticagrelor 0.9% discontinued study drug than did patients taking clopidogrel 0.1% due to dyspnoea. Dyspnoea was usually reported in the initial phase of treatment; the time to the first dyspnoea AE was numerically shorter with ticagrelor (median of 20 days) than with clopidogrel (median of 33 days) during treatment with study medication.
Compared with clopidogrel, patients with asthma/COPD treated with ticagrelor may have an increased risk of experiencing non-serious dyspnoea (3.29% ticagrelor versus 0.53% clopidogrel) and serious dyspnoea (0.38% ticagrelor versus 0.00% clopidogrel).
Approximately 30% of all dyspnoea resolved within 7 days. 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 of dyspnoea with ticagrelor is due to new or worsening heart or lung disease.
In patients who underwent pulmonary function testing in the clinical program, there was no indication of an adverse effect of ticagrelor on pulmonary function.
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 ticagrelor is due to new or worsening heart or lung disease. There was no indication of an adverse effect of ticagrelor on pulmonary function (see Section 4.4 Special Warnings and Precautions for Use).
In PLATO, the CV benefit of ticagrelor was maintained in patients who reported dyspnoea.

Lab abnormalities.

Uric acid elevations.

In PLATO, serum uric acid concentration increased to more than upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. Mean serum uric acid concentration increased approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel and after treatment was stopped, decreased to approximately 7% on ticagrelor but with no decrease observed for clopidogrel. The hyperuricaemia AEs reported were 0.5% for ticagrelor vs 0.2% for clopidogrel. Of these AEs 0.05% for ticagrelor vs 0.02% for clopidogrel were considered causally related by investigators. For gouty arthritis, the AEs reported were 0.2% for ticagrelor vs 0.1% for clopidogrel; none of these adverse events were assessed as causally related by investigators.

Creatinine elevations.

In PLATO, serum creatinine concentration significantly increased by > 30% in 25.5% of patients receiving ticagrelor compared to 21.3% of patients receiving clopidogrel and by > 50% in 8.3% of patients receiving ticagrelor compared to 6.7% of patients receiving clopidogrel. Creatinine elevations by > 50% were more pronounced in patients > 75 years (ticagrelor 13.6% versus clopidogrel 8.8%), in patients with severe renal impairment at baseline (ticagrelor 17.8% versus clopidogrel 12.5%) and in patients receiving concomitant treatment with ARBs (ticagrelor 11.2% versus clopidogrel 7.1%). The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Signs of reversibility on discontinuation were observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for related serious AEs. Within these subgroups renal-related serious AEs and adverse AEs leading to discontinuation of study drug were similar between treatment groups. The totality of renal AEs reported were 4.9% for ticagrelor vs 3.8% for clopidogrel, however a similar percent of patients reported events considered by the investigators as causally related to treatment; 54 (0.6%) for ticagrelor and 43 (0.5%) for clopidogrel.
The following adverse events have been identified following studies with ticagrelor (see Table 3).

Tabulated list of adverse drug reactions.

Adverse drug reactions from the clinical studies with ticagrelor are listed by MedDRA system organ class (SOC) and frequency category (see Table 4). 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, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000).

Postmarketing experience.

The following adverse reactions have been identified during post-approval use of ticagrelor. 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 Contraindications).

Skin and subcutaneous tissue disorders.

Rash.

Blood disorders.

Thrombotic thrombocytopenic purpura (see Section 4.4 Special Warnings and Precautions for Use).

Cardiac disorders.

Bradyarrhythmia, AV block (see Section 4.4 Special Warnings and Precautions for Use).

Nervous system disorders.

Central sleep apnoea including Cheyne-Stokes respiration (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Ticagrelor is well tolerated in single doses up to 900 mg. GI 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.
In the event of overdose, observe for these potential adverse effects and consider ECG monitoring.
There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not dialysable (see Section 5.2 Pharmacokinetic Properties, Special populations, Patients with renal impairment). Treatment of overdose should follow local standard medical practice. The expected effect of excessive Bricalor dosing is prolonged duration of bleeding risk associated with platelet inhibition. If bleeding occurs appropriate supportive measures should be taken.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bricalor contains ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct acting selective and reversibly binding P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y12 dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding but when bound to the P2Y12 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 death, myocardial infarction or stroke.
Ticagrelor has an additional mechanism of action, which involves inhibition of 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. However, a link between the observed increases in adenosine and clinical outcomes (e.g. morbidity-mortality) has not been clearly elucidated. Ticagrelor has no clinically significant direct effect on adenosine receptors (A1, A2A, A2B, A3) and is not metabolised to adenosine.

Pharmacodynamic effects.

Onset of action.

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 (see Figure 2). Ninety percent 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.

Offset of effect.

After the ticagrelor and the active metabolite concentrations decline to a level less than that required for receptor saturation, IPA gradually decreases with declining plasma concentrations. Since ticagrelor binds reversibly, the recovery of platelet function does not depend on replacement of platelets. Ticagrelor 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.
Median final extent IPA measured after the last dose of ticagrelor is approximately 20-30% higher for ticagrelor compared to clopidogrel. However, by 24 hours post-dose, %IPA is similar between ticagrelor and clopidogrel, indicating that patients who miss a dose of ticagrelor would have an IPA level comparable to those treated with once daily clopidogrel. In addition, %IPA is lower for ticagrelor from 72 hours through 7 days compared with clopidogrel. Mean %IPA for ticagrelor at 72 hours (Day 3) post last dose was comparable to clopidogrel at Day 5, and %IPA for ticagrelor at Day 5 was similar to clopidogrel at Day 7, which is not statistically different from placebo, (see Figure 3).

Responders to ticagrelor.

The IPA induced by ticagrelor has less variability at peak plasma concentrations of ticagrelor and the active metabolite at peak plasma concentrations observed with the 90 mg twice daily dose compared to clopidogrel 75 mg once daily. Patients with stable coronary artery disease 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 ticagrelor as compared to clopidogrel. In non-responders to clopidogrel, the IPA response to ticagrelor was observed to be higher and more consistent. Ticagrelor treatment resulted in consistently higher IPA compared with clopidogrel, and this was apparent post dose for both responders and non-responders.

Switching data.

Patients can be switched from clopidogrel to ticagrelor without interruption of anti-platelet effect. Patients switching from 75 mg clopidogrel once daily to ticagrelor 90 mg twice daily results in an absolute IPA increase of 26.4% and switching from ticagrelor to clopidogrel results in an absolute IPA decrease of 24.5% (also see Section 4.2 Dose and Method of Administration).

Adenosine mechanism (ENT-1).

Ticagrelor increased plasma adenosine concentrations in ACS patients. 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 P2Y12 antagonism. Adenosine has been linked to the cardio-protective effect of preconditioning. Ticagrelor has been shown to augment adenosine-induced dyspnoea in healthy volunteers (see Section 4.4 Special Warnings and Precautions for Use).

Clinical trials.

PLATO study.

The clinical evidence for the efficacy of ticagrelor is derived from the PLATO [PLATelet Inhibition and Patient Outcomes] study, a randomised, double-blind comparison of ticagrelor to clopidogrel, both given in combination with aspirin and other standard therapy.
The PLATO study was a Phase 3 randomised, double-blind, parallel group, efficacy and safety study with 18,624 patients comparing ticagrelor with clopidogrel for prevention of atherothrombotic events (cardiovascular [CV] death, myocardial infarction [MI] and stroke) in patients with acute coronary syndromes (unstable angina, non ST elevation myocardial infarction [NSTEMI] or ST elevation myocardial infarction [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 could have been medically managed, treated with percutaneous coronary intervention (PCI) (with or without stent) or coronary artery bypass graft (CABG).
Patients were excluded from participation in the study for any of the following: 1) Active bleeding, history of previous intracranial bleed, gastrointestinal (GI) bleed within the past 6 months, major surgery within 30 days. 2) Moderate or severe liver disease. 3) Patient required dialysis. 4) Oral anticoagulation therapy that could not be stopped. 5) Fibrinolytic therapy in the 24 hours prior to randomisation, or planned fibrinolytic treatment following randomization. 6) Known clinically important anaemia or thrombocytopenia. 7) Increased risk of bradycardic events unless treated with a pacemaker. 8) A need for chronic concomitant oral strong CYP3A inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers.
Patients were randomised to receive a loading dose of 180 mg of ticagrelor followed by a maintenance dose of 90 mg of ticagrelor twice daily or clopidogrel 75 mg once daily, with an initial loading dose of 300 mg. Patients were to receive concomitant aspirin 75-100 mg daily. For patients not previously on aspirin a loading dose of 160 mg to 500 mg was allowed.
The patient population was 92% Caucasian, 28% female, 42% greater than 65 years of age with 15% greater than 75 years of age. Concomitant medications taken post-randomisation included beta-blockers (86%), lipid-lowering agents (93%) and ACE inhibitors (79%).
Planned treatment duration was a minimum of 6 months to a maximum of 12 months. Mean exposure to study drug in PLATO was 246 days for ticagrelor; median exposure was 276 days (interquartile range 177-365 days). Patients who prematurely discontinued study drug, but did not withdraw from the study, continued to be followed for study endpoint events. Study visits were scheduled 1, 3, 6, 9 and 12 months following randomisation. Enrolment was stopped based on primary endpoint projections. To ensure 6 months minimum treatment, patients continued on-trial until their next scheduled visit at 6, 9 or 12 months, which became their final visit. Of the randomised patients, 18,062 (98%) completed the study. Patients were considered to have completed the study if they had a final visit (81.9% for ticagrelor, 81.2% for clopidogrel) died (4.4% for ticagrelor, 5.6% for clopidogrel), or were followed-up/alive (vital status collected when contacted, but patient did not want to continue participation in the study (10.4% for ticagrelor, 10.5% for clopidogrel). The most common reason for premature termination of study participation was withdrawal of informed consent (2.9%). There were 2 patients on the ticagrelor arm (none on clopidogrel) for whom vital status was unknown at the end of the study period.
The primary endpoint was time to first occurrence of any event from the composite of death from vascular causes, MI and stroke. Planned accrual of 1,780 primary endpoint events in PLATO provided 90% power to detect a relative risk reduction of 13.5% with ticagrelor compared with clopidogrel over a 12-month period given an event rate of 11% in the clopidogrel group at 12 months.
Ticagrelor reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI population (see Figure 4 and Table 5). Primary and secondary efficacy endpoints were hierarchically tested in the sequence shown in Table 5.
Ticagrelor is superior to clopidogrel in the prevention of thrombotic events (RRR 16%, ARR 1.9%, NNT = 54) of the composite efficacy endpoint (cardiovascular (CV) death, myocardial infarction (MI) or stroke) over 12 months. The difference in treatments was driven by cardiovascular death and myocardial infarction with no significant difference in the rate of strokes (1.5% on ticagrelor vs 1.3% on clopidogrel). Ticagrelor demonstrated a statistically significant relative risk reduction of 16% (ARR 1.1%) for MI and a 21% relative risk reduction (ARR 1.1%) for CV death. Treating 91 patients with ticagrelor instead of clopidogrel will prevent 1 CV death.
The superiority of ticagrelor over clopidogrel 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. Figure 4 reveals that the estimate of the risk to the first occurrence of any event in the composite efficacy endpoint for ticagrelor and clopidogrel continues to diverge at 12 months.
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 of ticagrelor over clopidogrel appears consistent across multiple patient subgroups by demographic characteristics including weight, gender, medical history, concomitant therapy, and by final index event diagnosis (STEMI, NSTEMI, and UA). The benefits associated with ticagrelor 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.
Patients ≥ 65 years or ≥ 75 years of age had a higher rate of major CV events in both treatment arms. For patients ≥ 75 years of age, the rate of major CV events was 15.9% on ticagrelor vs 16.9% on clopidogrel. For patients < 75 years of age, the rate of major CV events was 8.1% on ticagrelor vs9.8% on clopidogrel. Similar differences were seen in patients ≥ 65 years compared with those < 65 years.
In addition, patients weighing < 60 kg had a higher rate of major CV events in both treatment arms. For patients weighing < 60 kg, the rate of major CV events was 12.4% on ticagrelor vs 16.4% on clopidogrel. For patients weighing ≥ 60 kg, the rate of major CV events was 9.0% on ticagrelor vs 10.4% on clopidogrel.
In the PLATO Asian subpopulation, the efficacy result for the primary endpoint (ticagrelor 13.0% vs clopidogrel 16.2%; HR 0.82 [95% CI: 0.59, 1.14]) was consistent with the overall efficacy results in the PLATO population, as were the secondary composite endpoints.
A weakly significant treatment interaction was observed with region whereby the hazard ratio (HR) for the primary endpoint favours ticagrelor in the rest of world but favours clopidogrel in North America, which represented approximately 10% of the overall population studied (interaction p-Value = 0.045). The explanation for this apparent treatment-by-region interaction observed in PLATO is uncertain. It could be due to chance, however additional analyses suggest that the efficacy of ticagrelor 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 ticagrelor is used with a low maintenance dose of aspirin 75-150 mg (see Section 5.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
Ticagrelor demonstrated a statistically significant relative risk reduction (RRR) in the primary composite endpoint (cardiovascular (CV) death, myocardial infarction (MI) or stroke) in acute coronary syndromes (ACS) patients planned for invasive management (RRR 16%, absolute risk reduction (ARR) 1.7%, p = 0.0025). In a pre-specified, exploratory analysis, ticagrelor 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 fewer definite stent thromboses among patients treated with ticagrelor compared to clopidogrel (73 vs 107, RRR 32%, ARR 0.6%; nominal p = 0.0123).
Ticagrelor demonstrated a statistically significant RRR of 16% (p = 0.0001, ARR 2.1%) for the composite of all-cause mortality, MI and stroke compared to clopidogrel.
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 ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase, and 2.2% and 1.6% respectively, after 1 month.
The increase in ventricular pauses in the acute phase of ACS was more pronounced in ticagrelor patients with history of congestive heart failure (CHF) (9.2% vs 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% vs 2.1% for ticagrelor patients with and without CHF history respectively; and 3.8% versus 1.4% with clopidogrel. There were no adverse clinical consequences associated with this imbalance (including pacemaker insertions) in this population of patients.
Genetic substudy. In the PLATO genotyping substudy of 10,285 patients ticagrelor findings were consistent with overall PLATO findings. Ticagrelor was more efficacious than clopidogrel in reducing major CV events irrespective of CYP2C19 and ABCB1 polymorphisms. Similar to the overall PLATO study, total PLATO 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 to clopidogrel in patients with one or more CYP2C19 loss of function alleles, but was similar to clopidogrel in patients with no loss of function allele.

Renal.

The PLATO study included 15,202 ACS patients who had serum creatinine levels available at baseline. Of these patients, 3237 (21.2%) had chronic kidney disease (CKD) (defined as Creatinine Clearance < 60 mL/min by the Cockcroft-Gault equation). In patients with CKD, treatment with ticagrelor resulted in a statistically significant reduction in major CV events compared with clopidogrel and absolute risk reduction with ticagrelor increased as renal function declined. No significant difference in major bleeding was observed between ticagrelor and clopidogrel irrespective of renal function, while numerically more non-procedure related bleeding was observed with ticagrelor.

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.

PHILO study.

This was an exploratory randomised, double-blind, parallel group, multicentre trial to assess the efficacy and safety of ticagrelor compared to clopidogrel in Asian/Japanese patients with non-ST or ST-elevation acute coronary syndrome (ACS) for whom PCI is planned, unlike PLATO where patients intended for medical management were also included.
A total of 800 patients, from 3 countries [Japan, South Korea and Taiwan; most were Japanese (723/800; 90%)], were randomised to one of two treatment groups: ticagrelor 90 mg tablet twice daily orally, with an initial loading dose of 180 mg or clopidogrel 75 mg once daily orally, with an initial loading dose of 300 mg in clopidogrel-naïve patients. All patients also received aspirin) 75-100 mg daily during the treatment period in the study.
The duration of study treatment was 6-12 months. At the end of follow up, the incidence of the primary efficacy endpoint, a composite of CV death/MI [excluding silent MI]/stroke, was 36/401 (10.2% per year) in the ticagrelor group compared to 25/400 (8.1% per year) in the clopidogrel group. The hazard ratio (ticagrelor/clopidogrel) was 1.47 (95% CI 0.88, 2.44).

5.2 Pharmacokinetic Properties

Ticagrelor demonstrates linear pharmacokinetics. Exposure to ticagrelor and active metabolite AR-C124910XX are approximately dose proportional.

Absorption.

Absorption of ticagrelor is rapid with a median Tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with a median Tmax of approximately 2.5 hours. The Cmax and AUC of ticagrelor and the active metabolite increased in an approximately proportional manner with dose over the dose range studied (30-1,260 mg).
The mean absolute bioavailability of ticagrelor was estimated to be 36%, (range 25.4% to 64.0%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax or the AUC of the active metabolite, but resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite Cmax. These small changes are considered of minimal clinical significance; therefore, Bricalor can be given with or without food.
Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and the active metabolite). Compared to whole tablets, the geometric least-squares (LS) mean concentrations of ticagrelor were higher at 0.5 hour and 1 hour following administration of crushed tablets suspended in water and dispersed tablets suspended in water administered via NGT, respectively. At two hours post-dose the geometric LS mean concentrations following administration of the crushed tablet suspended in water and the dispersed tablet suspended in water administered via NGT were similar to the geometric LS mean concentration following administration of the whole tablet. The geometric LS mean concentrations of the major metabolite of ticagrelor, AR-C124910XX, were higher, compared with whole tablets, following administration of crushed tablets suspended in water at 0.5 hour and 1 hour post-dose, respectively, and higher at 0.5 hour, 1 hour and 2 hours post-dose respectively following administration of dispersed tablets suspended in water administered via a NGT.

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 P-glycoprotein weak inhibitors.
The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 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 radiolabelled 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 t1/2 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.

Clearance of ticagrelor.

The systemic clearance of ticagrelor is 14.2 L/h.

Special populations.

Elderly.

Higher exposures to ticagrelor (approximately 60% for both Cmax and AUC) and the active metabolite (approximately 50% for both Cmax and AUC) were observed in elderly (≥ 65 years) subjects compared to younger subjects. These differences are not considered clinically significant. No dose adjustment is needed for elderly patients.

Paediatric.

Ticagrelor has not been evaluated in a paediatric population. (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties).

Gender.

Higher exposures to ticagrelor (approximately 52% and 37% for Cmax and AUC, respectively) and the active metabolite (approximately 50% for both Cmax and AUC) were observed in women compared to men. These differences are not considered clinically significant.

Body weight.

Body weight was determined to have less than 20% change in the population mean clearance for both ticagrelor and the active metabolite at the 10th or 90th percentile of the body weight distribution compared to the population mean clearance at the median. This small effect on the clearance is not considered clinically relevant. Accordingly, no dose adjustment is necessary for ticagrelor based on weight.

Smoking.

Habitual smoking increased population mean clearance of ticagrelor by approximately 22%. This effect on the clearance is not considered clinically relevant.

Patients with renal impairment.

Exposure to ticagrelor was approximately 20% lower and exposure to the active metabolite was approximately 17% higher as measured by AUC in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) compared to subjects with normal renal function. The IPA effect of ticagrelor was similar between the two groups, however there was more variability observed in individual response in patients with severe renal impairment. These differences are not considered clinically significant.
No dosing adjustment is needed in patients with renal impairment.
No information is available concerning treatment of patients of renal dialysis.

Patients with hepatic impairment.

The Cmax 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 ticagrelor was similar between the two groups. These differences are not considered clinically significant. No dose adjustment is needed for patients with mild hepatic impairment.
No studies have specifically been conducted with ticagrelor in patients with moderate or severe hepatic impairment. No pharmacokinetic information is available in patients with moderate hepatic impairment. Therefore, Bricalor is contraindicated for use in patients with moderate or severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Ethnicity.

Patients of Asian descent have a 39% higher mean bioavailability of ticagrelor compared to Caucasian patients. Patients self-identified as Black had an 18% lower bioavailability of ticagrelor compared to Caucasian patients. The exposure in patients self-identified as Hispanic or Latino was similar to that in Caucasians. In clinical pharmacology studies, the exposure (Cmax and AUC) to ticagrelor in Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

5.3 Preclinical Safety Data

Genotoxicity.

Ticagrelor showed no genotoxic potential in assays for gene mutations (bacterial reverse mutation, mouse lymphoma TK) and chromosomal damage (rat micronucleus in vivo).

Carcinogenicity.

No compound-related tumours were observed in a 2-year mouse study at oral doses up to 250 mg/kg/day (ca. 18-fold maximum human therapeutic exposure to ticagrelor). There was no increase in tumours in male rats oral doses up to 120 mg/kg/day (ca. 15-fold maximum human therapeutic exposure). Increases in uterine adenocarcinomas and hepatocellular adenomas/adenocarcinomas and decreases in pituitary adenomas and mammary fibroadenomas were observed in female rats at more than 25 times maximum human therapeutic exposure to ticagrelor, with no change in tumour incidence seen at around 8 times maximum human therapeutic exposure. The uterine tumours seen only in rats were hypothesised to result from a 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, calcium hydrogen phosphate dehydrate, croscarmellose sodium, hyprolose, magnesium stearate, Opadry complete film coating system 02B520003 yellow (111369).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

PVC-PVdC/Alu calendar blister (with sun/moon symbols) in cartons of 14 (1 x 14 tablets sample pack), 28 (2 x 14 tablets), 56 (4 x 14 tablets). Not all pack sizes are marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Ticagrelor is a white or off-white to pale pink crystalline powder. The log P (octanol/water) has been measured to > 4.0 at pH 7.4. The molecule has no pKa values within physiological range and does not demonstrate pH dependent solubility. It is non-hygroscopic, exhibiting no significant increase in water content after exposure at 40°C/75% RH.

Chemical structure.


Chemical name (IUPAC): (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.

CAS number.

274693-27-5.
Molecular weight: 522.57.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes