Bleeding

Along with dyspnea, bleeding was a commonly observed adverse reaction in both the PLATO* and PEGASUS clinical trials.

Bleeding in the PLATO trial

Bleeding in the PEGASUS trial

Bleeding in the PLATO clinical trial

PLATO

SAFETY END POINTS: PLATO-DEFINED NON–CABG-RELATED BLEEDING1

BRILINTA® (ticagrelor) tablets additional secondary efficacy end points
  • About half of the Non–CABG-related Major Bleeding events were in the first 30 days1

IMPORTANT SAFETY INFORMATION FOR BRILINTA® (ticagrelor) 60-mg AND 90-mg TABLETS
WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

A. BLEEDING RISK
  • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding
  • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
  • Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery

PLATO

SAFETY END POINTS: PLATO-DEFINED CABG-RELATED BLEEDING1

BRILINTA® (ticagrelor) tablets CABG-related bleeding rates vs clopidogrel
  • PLATO did not show an advantage for BRILINTA 90 mg compared with clopidogrel for CABG-related Bleeding1
  • Rates of Major Fatal/Life-threatening CABG-related Bleeding were similar between BRILINTA 90 mg and clopidogrel when study drug was withheld 1-5 days before CABG surgery1
  • When antiplatelet therapy was stopped 5 days before CABG, Major Bleeding occurred in 75% of patients receiving BRILINTA 90 mg and 79% of patients receiving clopidogrel1

PLATO used the following bleeding severity categorization: PLATO Minor Bleed: requires medical intervention to stop or treat bleeding. PLATO Major Bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (eg, intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in Hct of at least 9%); transfusion of 2 or more units. PLATO Major Bleed, Fatal/Life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in Hct of at least 15%); transfusion of 4 or more units. Fatal: a bleeding event that directly led to death within 7 days.

Hb=hemoglobin; Hct=hematocrit.

Bleeding in the PEGASUS clinical trial

PEGASUS

SAFETY END POINTS: TIMI BLEEDING1

BRILINTA® (ticagrelor) tablets bleeding rates in PEGASUS

TIMI Major: Fatal Bleeding or any intracranial bleeding or clinically overt signs of hemorrhage associated with a drop in Hb of ≥5 g/dL or a fall in Hct of ≥15%. Fatal: a bleeding event that directly led to death within 7 days. TIMI Minor: clinically apparent with 3-5 g/dL decrease in Hb.

Additional Safety

See additional safety information for dyspnea and other adverse reactions.

1975408-3218312 Last Updated 10/16

IMPORTANT SAFETY INFORMATION FOR BRILINTA® (ticagrelor) 60-mg AND 90-mg TABLETS

WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS A. BLEEDING RISK

  • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding
  • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
  • Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery 
  • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

  • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided

CONTRAINDICATIONS

  • BRILINTA is contraindicated in patients with a history of intracranial hemorrhage or active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with hypersensitivity (eg, angioedema) to ticagrelor or any component of the product

WARNINGS AND PRECAUTIONS

  • Dyspnea was reported in about 14% of patients treated with BRILINTA, more frequently than in patients treated with control agents. Dyspnea resulting from BRILINTA is often self-limiting
  • Discontinuation of BRILINTA will increase the risk of MI, stroke, and death. When possible, interrupt therapy with BRILINTA for 5 days prior to surgery that has a major risk of bleeding. If BRILINTA must be temporarily discontinued, restart as soon as possible
  • Ticagrelor can cause ventricular pauses. Bradyarrhythmias including AV block have been reported in the post-marketing setting. PLATO and PEGASUS excluded patients at increased risk of bradyarrhythmias not protected by a pacemaker, and they may be at increased risk of developing bradyarrhythmias with ticagrelor
  • Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor and there are no studies of BRILINTA in these patients

ADVERSE REACTIONS

  • The most common adverse reactions associated with the use of BRILINTA included bleeding and dyspnea: In PLATO, for BRILINTA vs clopidogrel, non-CABG PLATO-defined major bleeding (3.9% vs 3.3%) and dyspnea (14% vs 8%); in PEGASUS, BRILINTA vs aspirin alone, TIMI Total Major bleeding (1.7% vs 0.8%) and dyspnea (14% vs 6%)

DRUG INTERACTIONS

  • Avoid use with strong CYP3A inhibitors and strong CYP3A inducers. BRILINTA is metabolized by CYP3A4/5. Strong inhibitors substantially increase ticagrelor exposure and so increase the risk of adverse events. Strong inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor
  • Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse events
  • Monitor digoxin levels with initiation of, or change in, BRILINTA therapy

INDICATIONS

BRILINTA is indicated to reduce the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction. For at least the first 12 months following ACS, it is superior to clopidogrel.

BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

DOSING

In the management of ACS, initiate BRILINTA treatment with a 180-mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg.

Please read full Prescribing Information , including Boxed WARNINGS, and Medication Guide  .

*The PLATO study compared BRILINTA (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter) for the prevention of thrombotic CV events (CV death, MI, or stroke) in 18,624 patients with ACS (UA, NSTEMI, STEMI). Patients were treated for at least 6 months and up to 12 months. Patients were excluded if they had a previous intracranial hemorrhage, gastrointestinal bleeding within 6 months, had a known bleeding diathesis or coagulation disorder, or required treatment with anticoagulants. BRILINTA and clopidogrel were studied with aspirin and other standard therapies.

The PEGASUS-TIMI 54 trial compared BRILINTA (90 mg twice daily or 60 mg twice daily) vs placebo, each given with low-dose aspirin, for the prevention of thrombotic CV events (CV death, MI, or stroke) in 21,162 patients ≥50 years of age with a history of MI
(1 to 3 years prior to randomization) and at least 1 risk factor for thrombotic CV events. Patients were treated for at least 12 months and up to 48 months with a median follow-up time of 33 months. Patients were excluded if they required renal dialysis, had a previous intracranial hemorrhage, had gastrointestinal bleeding within 6 months, had a known bleeding diathesis or coagulation disorder, or required treatment with anticoagulants. Only the 60-mg dose strength is approved for use in patients with a history of MI 1 year after an ACS event.

REFERENCE:

  1. BRILINTA [package insert]. Wilmington, DE: AstraZeneca; 2016.

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