Update to section 4.2 Posology and method of administration to include the following text:

Discontinuation of ASA may be considered after 3 months in patients with ACS who have undergone a percutaneous coronary intervention (PCI) procedure and have an increased risk of bleeding. In that case, ticagrelor as single antiplatelet therapy should be continued for 9 months (see section 4.4).

Update to section 4.4 Special warnings and precautions for use to include the following text:

In two randomised controlled studies (TICO and TWILIGHT) in patients with ACS who have undergone a PCI procedure with a drug-eluting stent, discontinuing ASA after 3 months dual antiplatelet therapy with ticagrelor and ASA (DAPT), and continuing with ticagrelor as single antiplatelet therapy (SAPT) for 9 and 12 months, respectively, has been shown to decrease the risk of bleeding with no observed increase in risk of major adverse cardiovascular events (MACE) compared with continued DAPT. The decision to discontinue ASA after 3 months and continue with ticagrelor as single antiplatelet therapy for 9 months in patients with an increased risk of bleeding should be based on clinical judgment considering the risk of bleeding versus the risk of thrombotic events (see section 4.2).

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[…]

4.       Possible side effects

[…]

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

• Abnormally Low heart rate (usually lower than 60 beats per minute)

[…]

6.       Contents of the pack and other information

[…]

This leaflet was last revised in 03/2022 12/2021

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.

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[…]

2.            QUALITATIVE AND QUANTITATIVE COMPOSITION

[…]

Brilique contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium‑free’.

For the full list of excipients, see section 6.1.

[…]

4.       CLINICAL PARTICULARS

[…]

4.4     Special warnings and precautions for use

[…]

Patients at risk for bradycardic events

[…]

Bradyarrhythmic events and AV blocks have been reported in the post-marketing setting in patients taking ticagrelor (see section 4.8), primarily in patients with ACS, where cardiac ischemia 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.

[…]

Sodium

Brilique contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium‑free’.

[…]

4.8     Undesirable effects

[…]

Table 1 – Adverse reactions by frequency and system organ class (SOC)

[…]

10.     DATE OF REVISION OF THE TEXT

03 March 2022 15 November 2021

Inserted text, Deleted text

[..]

6. Contents of the pack and other information

[..]

Marketing Authorisation Holder and Manufacturer

[..]

 This leaflet was last revised in 11/2021 12/2021

Inserted text

[..]

4.5         Interaction with other medicinal products and other forms of interaction

[..]

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 CPK level and rhabdomyolysis.

[..]

4.8         Undesirable effects

[..]

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

[..]

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

[..]

10.      DATE OF REVISION OF THE TEXT

15 November 2021

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[..]

1.       What Brilique is and what it is used for

[..]

Other medicines and Brilique

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because Brilique can affect the way some medicines work and some medicines can have an effect on Brilique.

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

• rosuvastatin (a medicine to treat high cholesterol)

[..]

4.       Possible side effects

[..]

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

[..]

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

[..]

6.       Contents of the pack and other information

[..]

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

[..]

United Kingdom

AstraZeneca UK Ltd

Tel: +44 1582 836 836

This leaflet was last revised in 09/2021 11/2021

Inserted text; Deleted text

[..]

4.4 Special warnings and precautions for use

[..]

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 should be considered.

[..]

Inserted text; Deleted text

[..]

2. What you need to know before you take Brilique

[..]

Warnings and precautions

Talk to your doctor or pharmacist before taking Brilique 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.

4.2 Posology and method of administration

[..]

Paediatric population

The safety and efficacy of ticagrelor in children below the age of 18 years have not been established. There is no relevant use of ticagrelor in children with sickle cell disease (see sections 5.1 and 5.2). No data are available.

[..]

5.1 Pharmacodynamic properties

[..]

Paediatric population

In a randomised, double-blind, parallel-group Phase III study (HESTIA 3), 193 paediatric patients (ages 2 to less than 18 years) with sickle cell disease were randomised to receive either placebo or ticagrelor at doses of 15 mg to 45 mg twice daily depending on body weight. Ticagrelor resulted in a median platelet inhibition of 35% at pre-dose and 56% at 2 hours post-dose at steady state.

Compared to placebo, there was no treatment benefit of ticagrelor on the rate of vaso-occlusive crises.

[..]

5.2 Pharmacokinetic properties

[..]

Paediatric population

Limited data are available in children with sickle cell disease Ticagrelor has not been evaluated in a paediatric population (see sections 4.2 and 5.1).

In the HESTIA 3 study, patients aged 2 to less than 18 years weighing ≥ 12 to ≤ 24 kg, > 24 to ≤ 48 kg and > 48 kg, were administered ticagrelor as paediatric dispersible 15 mg tablets at doses of respectively 15, 30 and 45 mg twice daily. Based on population pharmacokinetic analysis, the mean AUC ranged from 1095 ng*h/mL to 1458 ng*h/mL and the mean C_max ranged from 143 ng/mL to 206 ng/mL at steady state.

SmPC (Inserted text)

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4.4      Special warnings and precautions for use

Bleeding risk

[..]

• Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding) or who are at increased risk of trauma.

[..]

4.8         Undesirable effects

[..]

Tabulated list of adverse reactions

[..]

Table 1 – Adverse reactions by frequency and system organ class (SOC)

[..]

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

[..]

10.       DATE OF REVISION OF THE TEXT

[..]

25^th March 2021

Addition of warning relating to interference with platelet function tests to diagnose heparin induced thrombocytopenia (HIT), update of HPRA adverse event reporting details, update to date of revision

Blue = Addition

Red = Deletion

2.            What you need to know before you take Brilique

Warnings and Precautions

…..

If you are taking both Brilique and heparin:

• Your doctor may require a sample of your blood for diagnostic tests if they suspect a rare platelet disorder caused by heparin. It is important that you inform your doctor that you are taking both Brilique and heparin, as Brilique may affect the diagnostic test.

 4.         Possible side effects

Reporting of side effects

UK

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie  

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

…..

6.            Contents of the pack and other information

Marketing Authorisation Holder and Manufacturer

…..

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom

AstraZeneca UK Ltd

Tel: + 44 1582 836 836

Ireland

AstraZeneca Pharmaceuticals (Ireland) DAC

Tel: + 353 1609 7100

Malta

Associated Drug Co. Ltd

Tel: + 356 2277 8000

This leaflet was last revised in September 2019.

Section 4.5:       Addition of Thrombotic Thrombocytopenic Purpura wording.

Section 4.8:       Thrombotic Thrombocytopenic Purpura (unknown) side effect added to AE table.

Section 10:         date updated.

Additional minor editorial revisions were made throughout the SmPC.  

Section 2:           addition of sodium content wording.

Section 4.2:        deletion of wording for renal dialysis.

Section 4.4:        updated wording for bradycardia added.

Section 4.4:        Addition of ‘stroke’ for premature discontinuation.

Section 4.9:        wording for dialysis clarified.

Section 5.2:        haemodialysis wording added to the ‘Renal impairment’ subheading.

Section 10:         date updated.

Additional minor editorial revisions were made throughout the SmPC.  

Section 4.4

Surgery

Change from 7 to 5 days where ticagrelor should be discontinued prior to surgery 

Section 10

Date of revision changed to 26th July 2018.

Section 4.5          Editorial changes to placement of information on grapefruit juice. Addditional information relating to interaction between morphine and oral P2Y12 inhibitors, including ticagrelor and its active metabolite.

Section 4.8          Addition of comma and update UK ADR reporting details in line with latest version.

Section 5.3          Addition of comma.

Section 10           Updated date of revision.

Section 4.4: updated to include information on platelet transfusion

Section 4.4: updated spelling of ‘ischaemic’

Section 4.9: updated to include information on platelet transfusion

Section 5.1: updated spelling of ‘ischaemic’ and minor editorial change

Section 10 : updated date of revision

Section 1 – Addition of 60mg details.

Section 2 – Addition of 60mg details.

Section 3 – Addition of 60mg details.

Section 4.1 – Update indication to include history of myocardial infarction.

Section 4.2 – Update section to include history of myocardial infarction posology for 60mg strength. Update information about moderate hepatic impairment.

Section 4.3 – Remove moderate hepatic impairment as a contraindication.

Section 4.4 – Update to ‘Bleeding risk’ section. Addition of sections on ‘Patients with prior ischemic stroke’ and ‘Hepatic impairment’. Update to ‘Dyspnoea’ section. Update to ‘Uric acid increase’ section and addition of section of ‘Premature discontinuation’. Editorial changes to improve readability.

Section 4.5 – Amendment of ‘Brilique’ to ‘ticagrelor’ where relevant. Editorial changes to improve readability.

Section 4.6 – Amendment of ‘Brilique’ to ‘ticagrelor’ where relevant.

Section 4.7 – Addition of confusion to section.

Section 4.8 – Extensive update to section based on all available Brilique data. Amendment of ‘Brilique’ to ‘ticagrelor’ where relevant. Editorial changes to improve readability.

Section 4.9 – Amendment of ‘Brilique’ to ‘ticagrelor’ where relevant.

Section 5.1 – Addition of PEGASUS clinical safety and efficacy data. Editorial changes to improve readability.

Section 5.2 – Update to ‘Absorption’, ‘Hepatic impairment’ and ‘Ethnicity’ sections.

Section 6.1 – Addition of 60mg details. Editorial changes to improve readability.

Section 6.5 – Addition of 60mg details.

Section 6.6 – Addition of disposal information.

Section 8 – Addition of 60mg details.

Section 10 – Change to date of revision.

Section 1 – Change “film coated” to “film-coated”.

Section 2 – Change “film coated” to “film-coated”.

Section 4.1 – Editorial amendments.

Section 4.2 – Editorial amendments.

Section 4.3 – Remove reference to section 4.4.

Section 4.4 – Editorial amendments and remove repeated interaction information.

Section 4.5 – Editorial clarifications.

Section 4.6 – Change “Breast feeding” to “Breast-feeding”.

Section 4.7 – Clarification around effect on ability to drive and use machines.

Section 4.8 – Editorial amendments, amendment of Maltese ADR reporting address in line with updated Appendix V.

Section 4.9 – Editorial amendments.

Section 5.1 – Editorial amendments.

Section 5.2 – Editorial amendments.

Section 5.3 – Corrections to typographical errors.

Section 6.1 – Editorial amendments in line with QRD.

Section 7 – Correction to MAH address.

Section 9 – Addition of Date of Latest Renewal.
Section 10 – Update to date of revision

- Section 4.2 Addition of method of administration for crushed tablets

- Section 4.5 Removal of Dexamethasone as a CYP3A inducers
- Section 4.8 Update to new Irish agency details and minor editorial changes

- Section 5.1 Additional mechanism of action - adenosine pathway

- Section 5.2 Pharmacokinetic properties for crushed administration route

- Section 10 Revision date

Section 4.5 – Interaction with other medicinal products and other forms of interaction: Added information on grapefruit juice

Section 4.7 – Effects on ability to drive and use machines: Added additional language regarding dizziness and confusion.

Section 4.8 - Undesirable effects: Added language about post-marketing experience to the Tabulated list of adverse reactions

Added a new footnote to Intracranial haemorrhage in Table 1 to list fatal intracranial bleedings have been reported during post-marketing.

Section 10 - Updated date of revision

Section 4.2

Changes in titles for Special Populations.

Section 4.3

Addition of excipient list reference.

Section 4.8

Addition of hypersensitivity into ADR table.

Section 10

Date of revision updated to 24^th October 2012.