Brilinta Adverse Reactions

Summary of the safety profile: The safety profile of Ticagrelor (BRILINTA) has been evaluated in a large development programme where more than 58,000 patients and healthy volunteers have received ticagrelor. Data on adverse drug reactions identified in clinical studies or from post-marketing experience with ticagrelor are presented as follows including information from clinical studies specific to the approved indications (PLATO, PEGASUS, THEMIS and THALES). For information on those studies see Pharmacology: Pharmacodynamics under Actions.
In PLATO, patients on Ticagrelor (BRILINTA) had a higher incidence of discontinuation of study drug due to adverse events than patients on clopidogrel (7.4% for ticagrelor 90 mg twice daily vs. 5.4% for clopidogrel 75 mg once daily).
In PEGASUS, patients on Ticagrelor (BRILINTA) had a higher incidence of discontinuation of study drug due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg twice daily with ASA vs. 8.5% for ASA therapy alone).
In THEMIS patients who had undergone PCI, discontinuation of study drug due to adverse events was 21.3% for Ticagrelor (BRILINTA) in combination with ASA vs. 13.0% for ASA alone.
In THALES, patients on Ticagrelor (BRILINTA) in combination with ASA had a higher incidence of discontinuation of study drug due to adverse events compared to ASA therapy alone (9.7% for ticagrelor 90 mg twice daily in combination with ASA vs. 7.6% for ASA therapy alone).
The most commonly reported adverse drug reactions in patients treated with ticagrelor were bleeding and dyspnoea (see also Precautions).
Tabulated list of adverse drug reactions: Adverse drug reactions determined from clinical studies with Ticagrelor (BRILINTA) are listed by MedDRA System Organ Class (SOC) and frequency category in Table 5. Within each SOC and frequency category, adverse drug reactions are presented in order of decreasing seriousness. Frequency categories are defined according to the following conventions: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000), Very rare (<1/10,000), Not known (cannot be estimated from the available data). (See Table 5.)

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Postmarketing experience: The following adverse reactions have been identified during post-approval use of Ticagrelor (BRILINTA). Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency.
Blood disorders: Thrombotic Thrombocytopenic Purpura (see Precautions).
Cardiac disorders: Bradyarrhythmia, AV block (see Precautions).
Immune system disorders: Hypersensitivity reactions including angioedema (see Contraindications).
Nervous system disorders: Central sleep apnoea including Cheyne-Stokes respiration (see Precautions).
Skin and subcutaneous tissue disorders: Rash.
Description of selected adverse drug reactions: Bleeding findings in PLATO: Overall outcome of bleeding events in the PLATO Study are shown in Table 6. (See Table 6.)

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In PLATO, time to first PLATO-defined Total Major bleeding for Ticagrelor (BRILINTA) did not differ significantly from that of clopidogrel. There were few fatal bleeding events in the study, 20 (0.2%) for Ticagrelor (BRILINTA) 90 mg twice daily 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 (BRILINTA) than on clopidogrel. Overall rates of TIMI-defined bleeding events did not differ significantly between Ticagrelor (BRILINTA) and clopidogrel.
CABG-related bleeding: In PLATO, 42% of the 1584 patients (12% of cohort) who underwent CABG surgery had a PLATO-defined Major Fatal/Life-threatening bleeding with no difference between the treatment groups. Fatal CABG bleeding occurred in 6 patients in each treatment group (see Precautions).
Non-CABG related bleeding and non-procedural related bleeding: Ticagrelor (BRILINTA) and clopidogrel did not differ in non-CABG PLATO-defined Major Fatal/Life-threatening bleeding, but PLATO-defined Total Major, TIMI Major, and TIMI Major + Minor bleeding were more common with ticagrelor. Similarly, when removing all procedure related bleeding, more bleeding occurred with ticagrelor than with clopidogrel (Table 6). Discontinuation of treatment due to non-procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p<0.001).
Age, gender, weight, ethnicity, geographic region, concurrent conditions, concomitant therapy, and medical history, including a previous stroke or transient ischaemic attack, all did not predict either overall or non-procedural PLATO-defined Major bleeding. Thus, no particular group was identified at risk for any subset of bleeding.
Intracranial bleeding: There were more intracranial non-procedural bleeds with ticagrelor (n=27 bleeds in 26 patients, 0.3%) than with clopidogrel (n=14 bleeds, 0.2%), of which 11 bleeds with ticagrelor and 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.
Bleeding findings in PEGASUS: Overall outcome of bleeding events in the PEGASUS Study are shown in Table 7. (See Table 7.)

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In PEGASUS, TIMI Major bleeding for Ticagrelor (BRILINTA) 60 mg twice daily was higher than for ASA alone. No increased bleeding risk was seen for fatal bleeding and only a minor increase was observed in intracranial haemorrhages, as compared to ASA therapy alone. There were few fatal bleeding events in the study, 11 (0.3%) for Ticagrelor (BRILINTA) 60 mg and 12 (0.3%) for ASA therapy alone. The observed increased risk of TIMI Major bleeding with Ticagrelor (BRILINTA) 60 mg was primarily due to a higher frequency of Other TIMI Major bleeding driven by events in the gastrointestinal SOC.
Increased bleeding patterns similar to TIMI Major were seen for TIMI Major or Minor and PLATO-defined Major and PLATO-defined Major or Minor bleeding categories (see Table 7). Discontinuation of treatment due to bleeding was more common with Ticagrelor (BRILINTA) 60 mg compared to ASA therapy alone (6.2% and 1.5%, respectively). The majority of these bleedings were of less severity (classified as TIMI Requiring medical attention), e.g. epistaxis, bruising, and haematomas.
The bleeding profile of Ticagrelor (BRILINTA) 60 mg was consistent across multiple pre-defined subgroups (e.g. by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy, and medical history) for TIMI Major, TIMI Major or Minor, and PLATO-defined Major bleeding events.
Intracranial bleeding: Spontaneous ICHs were reported in similar rates for Ticagrelor (BRILINTA) 60 mg and ASA therapy alone (n=13, 0.2% in both treatment groups). Traumatic and procedural ICHs showed a minor increase with Ticagrelor (BRILINTA) 60 mg treatment, (n=15, 0.2%) compared with ASA therapy alone (n=10, 0.1%). There were 6 fatal ICHs with Ticagrelor (BRILINTA) 60 mg and 5 fatal ICHs with ASA therapy alone. The incidence of intracranial bleeding was low in both treatment groups given the significant comorbidity and cardiovascular risk factors of the population under study.
Bleeding findings in THEMIS patients who had undergone PCI: The bleeding events in THEMIS patients who had undergone PCI are shown in Table 8. (See Table 8.)

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There were few fatal bleeding events, 6 for Ticagrelor (BRILINTA) in combination with ASA and 6 for ASA therapy alone. The number of patients with intracranial haemorrhages was 33 for Ticagrelor (BRILINTA) in combination with ASA and 31 for ASA alone.
Discontinuation of study drug due to bleeding in patients who had undergone PCI was more common with Ticagrelor (BRILINTA) in combination with ASA compared to ASA alone (4.7% and 1.3%, respectively). Epistaxis and increased tendency to bruise were the most common bleeding events resulting in the discontinuation of Ticagrelor (BRILINTA).
Bleeding findings in THALES: Overall outcome of bleeding events in the THALES study are shown in Table 9. (See Table 9.)

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In THALES, the rate of GUSTO Severe bleeding for Ticagrelor (BRILINTA) 90 mg twice daily in combination with ASA was higher than for ASA alone. A similar bleeding pattern was observed for the GUSTO Severe or Moderate bleeding category (see Table 9). Due to the low number of GUSTO Severe bleeding events, no conclusion can be drawn regarding bleeding risk across subgroups. Discontinuation of treatment due to bleeding was more common with Ticagrelor (BRILINTA) 90 mg with ASA compared to ASA therapy alone (2.9% and 0.6%, respectively).
Intracranial bleeding and fatal bleeding: In total, there were 21 intracranial haemorrhages (ICHs) (19 spontaneous, 1 traumatic, 1 procedural) for Ticagrelor (BRILINTA) 90 mg with ASA and 6 ICHs (3 spontaneous, 2 traumatic, 1 procedural) for ASA alone. Fatal bleedings occurred in 11 patients (10 fatal ICHs, 1 fatal gastro-intestinal bleed) for Ticagrelor (BRILINTA) 90 mg with ASA and in 2 patients (2 fatal ICHs) for ASA alone.
Dyspnoea: In PLATO, dyspnoea adverse events were reported in 13.8% of patients taking ticagrelor 90 mg twice daily and in 7.8% of patients taking clopidogrel 75 mg once daily. Most reported dyspnoea adverse events were mild to moderate in intensity and often resolved without the need of treatment discontinuation. Dyspnoea was usually reported in the initial phase of treatment and 87% of the patients who reported dyspnoea experienced a single episode. Dyspnoea serious adverse events were reported in 0.7% taking ticagrelor and 0.4% taking clopidogrel. Patients who reported dyspnoea tended to be older and more frequently had dyspnoea, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), or asthma at baseline. PLATO data do not suggest that the higher frequency with Ticagrelor (BRILINTA) is due to new or worsening heart or lung disease. There was no indication of an adverse effect of Ticagrelor (BRILINTA) on pulmonary function (see Precautions).
In PEGASUS, dyspnoea was reported in 14.2% of patients taking Ticagrelor (BRILINTA) 60 mg twice daily and in 5.5% of patients taking ASA alone. As in PLATO, most reported dyspnoea was mild to moderate in intensity (see Precautions).
In THEMIS patients who had undergone PCI, dyspnoea was reported in 22.0% of patients taking Ticagrelor (BRILINTA) twice daily in combination with ASA and in 7.5% of patients taking ASA alone. Most reported dyspnoea was mild to moderate in intensity (see Precautions).
In THALES, dyspnoea led to study drug discontinuation in 1.0% and 0.2% of patients taking Ticagrelor (BRILINTA) 90 mg in combination with ASA vs. ASA alone, respectively.