Brilinta Adverse Reactions

Summary of the safety profile: In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone).
The most commonly reported adverse drug reactions in patients treated with ticagrelor were bleeding and dyspnoea (see "Precautions").
60 mg: The safety profile of ticagrelor has been evaluated in three large randomized phase 3 outcome trials (PLATO, PEGASUS and THEMIS) including more than 58,000 patients of which more than 32,000 patients were exposed to ticagrelor (see "Pharmacology: Pharmacodynamics under Actions").
In the subgroup of THEMIS patients with history of PCI, discontinuation of study drug due to adverse events was higher for ticagrelor (21.3%) in combination with ASA versus ASA alone (13.0%). The most common adverse events leading to study discontinuation reported at higher rates with ticagrelor compared to ASA alone were dyspnoea, increased tendency to bruise, epistaxis and ecchymosis (see "Precautions").
90 mg: The safety profile of ticagrelor 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 and THALES) (see "Pharmacology: Pharmacodynamics under Actions").
In THALES, patients on ticagrelor 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). 
Tabulated list of adverse reactions: The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 5).
Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 5.)

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Description of selected adverse reactions: Bleeding: Bleeding findings in PLATO: Overall outcome of bleeding rates in the PLATO study are shown in Table 6. (See Table 6.)

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Ticagrelor and clopidogrel did not differ in rates of PLATO Major Fatal/Life-threatening bleeding, PLATO total Major bleeding, TIMI Major bleeding, or TIMI Minor bleeding (Table 6). However, more PLATO combined Major + Minor bleeding occurred with ticagrelor compared with clopidogrel. Few patients in PLATO had fatal bleeds: 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel (see "Precautions").
Age, sex, weight, race, 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 Major bleeding. Thus, no particular group was identified at risk for any subset of bleeding.
CABG-related bleeding: In PLATO, 42% of the 1584 patients (12% of cohort) who underwent coronary artery bypass graft (CABG) surgery had a PLATO Major Fatal/Life-threatening bleeding with no difference between 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 and clopidogrel did not differ in non-CABG PLATO-defined Major Fatal/Life-threatening bleeding, but PLATO-defined Total Major, TIMI Major, and TIMI Major + Minor bleeding were more common with ticagrelor. Similarly, when removing all procedure related bleeds, more bleeding occurred with ticagrelor than with clopidogrel (Table 6). Discontinuation of treatment due to non-procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p<0.001).
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.
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 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 60 mg and 12 (0.3%) for ASA therapy alone. The observed increased risk of TIMI Major bleeding with ticagrelor 60 mg was primarily due to a higher frequency of Other TIMI Major bleedings driven by events in the gastrointestinal SOC.
Increased bleeding patterns similar to TIMI Major were seen for TIMI Major or Minor and PLATO Major and PLATO Major or Minor bleeding categories (see Table 6). Discontinuation of treatment due to bleeding was more common with ticagrelor 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 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 Major bleeding events.
Intracranial bleeding: Spontaneous ICHs were reported in similar rates for ticagrelor 60 mg and ASA therapy alone (n=13, 0.2% in both treatment groups). Traumatic and procedural ICHs showed a minor increase with ticagrelor 60 mg treatment, (n=15, 0.2%) compared with ASA therapy alone (n=10, 0.1%). There were 6 fatal ICHs with ticagrelor 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 CV risk factors of the population under study.
60 mg: Bleeding findings in THEMIS patients who had undergone PCI: The primary safety endpoint in the THEMIS study was the 'TIMI Major Bleeding' events. The safety analysis included also the PLATO and BARC bleeding classifications.
In THEMIS, the rate of TIMI Major bleeding was higher for ticagrelor twice daily than for ASA alone (Kaplan-Meier estimate at 36 months: 2.2% vs. 1.2%, respectively, p <0.0001). This higher incidence was characterized by a greater number of fatal bleedings (17 for ticagrelor vs. 10 for ASA) and intracranial haemorrhages (70 for ticagrelor vs. 46 for ASA alone). Most of the intracranial haemorrhages reported in the ticagrelor treatment arm were traumatic events (N=41), most commonly reported in subdural location (see "Precautions").
In the subgroup of patients with a history of PCI, the incidence of TIMI Major bleeding was also higher for ticagrelor compared to ASA alone (Table 8). There were few fatal bleeding events, 6 for ticagrelor in combination with ASA and 6 for ASA therapy alone. The number of patients with intracranial haemorrhages was 33 for ticagrelor in combination with ASA and 31 for ASA alone, corresponding to KM percentages of 0.7% and 0.6%, respectively, p=0.4545. The rate of fatal bleeding and intracranial haemorrhage was however similar in both treatment arms. Among the cases of ICH reported with ticagrelor, 23 were traumatic and 10 were spontaneous. The observed increased risk of TIMI Major bleeding with ticagrelor was therefore primarily due to a higher frequency of events within the system organ class (SOC) gastrointestinal disorders; and injury, poisoning and procedural complications. (See Table 8.)

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Discontinuation of study drug due to bleeding events in patients with a history of PCI was more common with ticagrelor 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 treatment.
Bleeding in Patient Subpopulations: The bleeding profile of ticagrelor was generally consistent across multiple pre-defined subgroups (e.g., by age, gender, weight, ethnicity, geographic region, concurrent conditions, concomitant therapy, and medical history).
90 mg: 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 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 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 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 BRILINTA 90 mg with ASA and in 2 patients (2 fatal ICHs) for ASA alone.
Other Adverse Events: Dyspnoea: Dyspnoea, a sensation of breathlessness, is reported by patients treated with ticagrelor. In PLATO, dyspnoea adverse events (AEs) (dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea), when combined, was reported by 13.8% of patients treated with ticagrelor and by 7.8% of patients treated with clopidogrel. In 2.2% of patients taking ticagrelor and by 0.6% taking clopidogrel investigators considered the dyspnoea causally related to treatment in the PLATO study and few were serious (0.14% ticagrelor; 0.02% clopidogrel), (see "Precautions"). Most reported symptoms of dyspnoea were mild to moderate in intensity, and most were reported as a single episode early after starting treatment.
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). In absolute terms, this risk was higher than in the overall PLATO population. Ticagrelor should be used with caution in patients with history of asthma and/or COPD (see "Precautions").
About 30% of episodes resolved within 7 days. PLATO included patients with baseline congestive heart failure, chronic obstructive pulmonary disease (COPD), or asthma; these patients, and the elderly, were more likely to report dyspnoea. For Brilinta, 0.9% of patients discontinued study drug because of dyspnoea compared with 0.1% taking clopidogrel. The higher incidence of dyspnoea with ticagrelor is not associated with new or worsening heart or lung disease (see "Precautions"). Ticagrelor does not affect tests of pulmonary function.
In PEGASUS, dyspnoea was reported in 14.2% of patients taking ticagrelor 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"). Patients who reported dyspnoea tended to be older and more frequently had dyspnoea, COPD or asthma at baseline.
60 mg: In the THEMIS study protocol, adverse event collection was limited to serious adverse events, discontinuations due to adverse events and adverse events of interest. Adverse event data collected in the THEMIS trial appears consistent with data from PLATO and PEGASUS trials.
In THEMIS, patients who had undergone PCI, dyspnoea was reported in 22.0% of patients taking ticagrelor 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").
90 mg: In THALES, dyspnoea led to study drug discontinuation in 1.0% and 0.2% of patients taking ticagrelor 90 mg in combination with ASA vs. ASA alone, respectively.
Investigations: 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. The corresponding numbers in PEGASUS were 9.1%, 8.8% and 5.5% for ticagrelor 90 mg, 60 mg and placebo, respectively. 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. In PEGASUS, a reversible increase in mean serum uric acid levels of 6.3% and 5.6% was found for ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In PLATO, the frequency of gouty arthritis was 0.2% for ticagrelor vs. 0.1% for clopidogrel. The corresponding numbers for gout/gouty arthritis in PEGASUS were 1.6%, 1.5% and 1.1% for ticagrelor 90 mg, 60 mg and placebo, respectively.