Brilinta Adverse Reactions

Clinical Trials Experience: The following adverse reactions are also discussed elsewhere in the labeling: Bleeding (see Warnings and Precautions); Dyspnea (see Warnings and Precautions).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
BRILINTA has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year.
Bleeding: PLATO used the following bleeding severity categorization: Major bleed - fatal/life-threatening: Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.
Major bleed - other: Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
Minor bleed: Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).
Minimal bleed: All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.
Figure 11 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG and other procedures, but the risk persists during later use of antiplatelet therapy. (See Figure 11.)


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Annualized rates of bleeding are summarized in Table 4 as follows. About half of the bleeding events were in the first 30 days. (See Table 4.)


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As shown in Table 4, BRILINTA was associated with a somewhat greater risk of non-CABG bleeding than was clopidogrel. No baseline demographic factor altered the relative risk of bleeding with BRILINTA compared to clopidogrel.
In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Table 5. Rates were very high but similar for BRILINTA and clopidogrel. (See Table 5.)


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Although the platelet inhibition effect of BRILINTA has a faster offset than clopidogrel in in vitro tests and BRILINTA is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of BRILINTA compared to clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.
No data exists with BRILINTA regarding a hemostatic benefit of platelet transfusions.
Drug Discontinuation: In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for BRILINTA and 5.4% for clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of BRILINTA patients and 1.0% of clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of BRILINTA and 0.1% of clopidogrel patients.
Common Adverse Events: A variety of non-hemorrhagic adverse events occurred in PLATO at rates of 3% or more. These are shown in Table 6. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common on BRILINTA or clearly related to the drug's pharmacologic effect (dyspnea). (See Table 6.)


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Bleeding in PEGASUS (Secondary Prevention in Patients with a History of Myocardial Infarction): Overall outcome of bleeding events in the PEGASUS study are shown in Table 7. (See Table 7.)


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The bleeding profile of BRILINTA 60 mg compared to aspirin alone was consistent across multiple pre-defined subgroups (e.g., by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy, stent, and medical history) for TIMI Major and TIMI Major or Minor bleeding events.
Other Adverse Reactions in PEGASUS: Adverse reactions that occurred in PEGASUS at rates of 3% or more are shown in Table 8. (See Table 8.)


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Bradycardia: In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month.
PLATO and PEGASUS excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker).
In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA 90mg and clopidogrel patients, respectively. In PEGASUS, syncope was reported by 1.2% and 0.9% of patients on BRILINTA 60 mg twice daily and aspirin alone, respectively.
Postmarketing Experience: The following adverse reactions have been identified during post-approval use of 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 and lymphatic system disorders: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of BRILINTA. TTP is a serious condition which can occur after a brief exposure (<2 weeks) and requires prompt treatment.
Immune system disorders: Hypersensitivity reactions including angioedema (see Contraindications).
Skin and subcutaneous tissue disorders: Rash.
Gynecomastia: In PLATO, gynecomastia was reported by 0.23% of men on BRILINTA and 0.05% on clopidogrel.
Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO.
Lab abnormalities: Serum Uric Acid: Serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA and approximately 0.2 mg/dL on clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group).
In PEGASUS, serum uric acid levels increased approximately 0.2 mg/dL from baseline on Brilinta 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on BRILINTA than in patients on aspirin alone (1.5%, 1.1%). Mean serum uric acid concentrations decreased after treatment was stopped.
Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy or oliguria.
In PEGASUS, serum creatinine concentration increased by >50% in approximately 4% of patients receiving BRILINTA 60 mg, similar to aspirin alone. The frequency of renal related adverse events was similar for ticagrelor and aspirin alone regardless of age and baseline renal function. (See Table 9.)


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