Dyspnea

Understanding dyspnea and treatment considerations

In clinical trials, about 14% of patients treated with BRILINTA developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment, but led to study drug discontinuation in 0.9% of BRILINTA and 0.1% of clopidogrel patients in PLATO* and 4.3% of BRILINTA 60 mg and 0.7% on aspirin alone patients in PEGASUS.

If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent.

Patients should not stop taking BRILINTA without first consulting you or the doctor who prescribed BRILINTA. It is important to remind your patients why you prescribed BRILINTA.

Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment1

Incidence of Dyspnea in PLATO trial1-3

BRILINTA 90 mg + aspirin

(n=9235)

Clopidogrel + aspirin

(n=9186)

Overall Rate of Dyspnea

14%

8%

Mild Dyspnea

9.6%

5.5%

Moderate Dyspnea

4.5%

2.4%

Severe Dyspnea

0.4%

0.2%

Discontinuation Due to Dyspnea

0.9%

0.1%


Patients may be counted in more than 1 event category. Patients with multiple events in the same category being tabulated are counted only once within that category.2

Dyspnea was prospectively evaluated in the PLATO trial. At enrollment, PLATO investigators were asked to record whether there was a history of dyspnea and/or current dyspnea and record occurrences of dyspnea as adverse events or serious adverse events (AEs/SAEs) throughout the trial.3

Incidence of Dyspnea in PEGASUS trial1

BRILINTA 60 mg + aspirin

(n=6958)

Aspirin alone

(n=6996)

Overall Rate of Dyspnea

14%

6%

Discontinuation Due to Dyspnea

4.3%

0.7%

Dyspnea resulting from BRILINTA often resolved during continued treatment.1

  • In PLATO, dyspnea was reported in 14% of patients treated with BRILINTA 90 mg and in 8% of patients taking clopidogrel. In PEGASUS, dyspnea was reported in 14% of patients treated with BRILINTA 60 mg and in 6% of patients taking aspirin alone
  • If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption if possible
  • In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent

IN PLATO

Median time to onset of dyspnea in the BRILINTA group was 23 days (vs 43 days for the clopidogrel group)3

  • In PLATO, onset of dyspnea was more likely to occur within 7 days of initiation in the BRILINTA group (vs the clopidogrel group)3
  • If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption, if possible1
  • In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent1

Pulmonary function testing in a PLATO substudy1

  • In a substudy of 199 patients from PLATO who underwent pulmonary function testing irrespective of whether they reported dyspnea: — No indication of an adverse effect on pulmonary function after one month or after at least 6 months of chronic treatment

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

Additional Safety

See additional safety information for bleeding 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.

REFERENCES:

  1. BRILINTA [package insert]. Wilmington, DE: AstraZeneca LP; 2016.
  2. Data on file, 2908300. AstraZeneca Pharmaceuticals LP.
  3. Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;32(23):2945-2953.

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