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Brilinta

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Brilinta




Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are also discussed elsewhere in the labeling:

Clinical Trials Experience

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 27000 patients, including more than 13000 patients treated for at least 1 year.

Bleeding in PLATO (Reduction in Risk of Thrombotic Events in ACS)

Figure 1 is a plot of time to the first non-CABG major bleeding event.

Figure 1 : Kaplan-Meier estimate of time to first non-CABG PLATO-defined major bleeding event (PLATO)

Kaplan-Meier estimate of time to first non-CABG PLATO-defined major bleeding event - Illustration

Frequency of bleeding in PLATO is summarized in Tables 1 and 2. About half of the Non-CABG major bleeding events were in the first 30 days .

Table 1 : Non-CABG related bleeds (PLATO)

  BRILINTA*
N=9235
n (%) patients with event
Clopidogrel
N=9186
n (%) patients with event
PLATO Major + Minor 713 (7.7) 567 (6.2)
  Major 362 (3.9) 306 (3.3)
     Fatal/Life-threatening 171 (1.9) 151 (1.6)
     Fatal 15 (0.2) 16 (0.2)
     Intracranial hemorrhage (Fatal/Life-threatening) 26 (0.3) 15 (0.2)
* 90 mg BID

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 (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (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 hematocrit (Hct) of at least 15%); transfusion of 4 or more units.

Fatal: A bleeding event that directly led to death within 7 days.

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 Figure 2 and Table 2.

Figure 2 : ‘Major fatal/life-threatening' CABG-related bleeding by days from last dose of study drug to CABG procedure (PLATO)

Major fatal/life-threatening’ CABG-related bleeding by days from last dose of study drug to CABG procedure - Illustration

X-axis is days from last dose of study drug prior to CABG.

The PLATO protocol recommended a procedure for withholding study drug prior to CABG or other major surgery without unblinding. If surgery was elective or non-urgent, study drug was interrupted temporarily, as follows: If local practice was to allow antiplatelet effects to dissipate before surgery, capsules (blinded clopidogrel) were withheld 5 days before surgery and tablets (blinded ticagrelor) were withheld for a minimum of 24 hours and a maximum of 72 hours before surgery. If local practice was to perform surgery without waiting for dissipation of antiplatelet effects capsules and tablets were withheld 24 hours prior to surgery and use of aprotinin or other haemostatic agents was allowed. If local practice was to use IPA monitoring to determine when surgery could be performed both the capsules and tablets were withheld at the same time and the usual monitoring procedures followed. T Ticagrelor; C Clopidogrel.

Table : 2 CABG-related bleeding (PLATO)

  BRILINTA*
N=770
n (%) patients with event
Clopidogrel
N=814
n (%) patients with event
PLATO Total Major 626 (81.3) 666 (81.8)
Fatal/Life-threatening 337 (43.8) 350 (43.0)
Fatal 6 (0.8) 7 (0.9)
* 90 mg BID

PLATO Major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (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 hematocrit (Hct) of at least 15%); transfusion of 4 or more units.

When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.

Other Adverse Reactions in PLATO

Adverse reactions that occurred at a rate of 4% or more in PLATO are shown in Table 3.

Table 3 : Percentage of patients reporting non-hemorrhagic adverse reactions at least 4% or more in either group and more frequently on BRILINTA (PLATO)

  BRILINTA*
N=9235
Clopidogrel
N=9186
Dyspnea 13.8 7.8
Dizziness 4.5 3.9
Nausea 4.3 3.8
* 90 mg BID

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 4.

Table 4 : Bleeding events (PEGASUS)

  BRILINTA* + Aspirin
N=6958
Aspirin Alone
N=6996
n (%) patients with event Events / 100 pt yrs n (%) patients with event Events / 100 pt yrs
TIMI Major 115 (1.7) 0.78 54 (0.8) 0.34
Fatal 11 (0.2) 0.08 12 (0.2) 0.08
Intracranial hemorrhage 28 (0.4) 0.19 23 (0.3) 0.14
TIMI Major or Minor 168 (2.4) 1.15 72 (1.0) 0.45
* 60 mg BID

TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥ 5 g/dL, or a fall in hematocrit (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 hemoglobin.

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 5.

Table 5 : Non-hemorrhagic adverse reactions reported in > 3.0% of patients in the ticagrelor 60 mg treatment group (PEGASUS)

  BRILINTA* + Aspirin
N=6958
Aspirin Alone
N=6996
Dyspnea 14.2 5.5
Dizziness 4.5 4.1
Diarrhea 3.3 2.5
*60 mg BID

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 90 mg and clopidogrel patients, respectively. In PEGASUS, syncope was reported by 1.2% and 0.9% of patients on BRILINTA 60 mg and aspirin alone, respectively.

Lab Abnormalities

Serum Uric Acid

In PLATO, serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA 90 mg and approximately 0.2 mg/dL on clopidogrel. 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 90 mg 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.

Read the Brilinta (ticagrelor tablets for oral administration) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Strong CYP3A Inhibitors

Strong CYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [see CLINICAL PHARMACOLOGY].

Strong CYP3A Inducers

Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) [see CLINICAL PHARMACOLOGY].

Aspirin

Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see WARNINGS AND PRECAUTIONS and Clinical Studies].

Simvastatin, Lovastatin

BRILINTA increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see CLINICAL PHARMACOLOGY].

Digoxin

BRILINTA inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in BRILINTA therapy [see CLINICAL PHARMACOLOGY].

Read the Brilinta Drug Interactions Center for a complete guide to possible interactions

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 9/18/2015

Side Effects
Interactions

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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