Does Brilinta (ticagrelor) cause side effects?

Brilinta (ticagrelor) is a P2Y12 platelet inhibitor indicated to reduce the risk of cardiovascular death, heart attack (myocardial infarction), and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction (MI). 

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.

Common side effects of Brilinta include

Serious side effects of Brilinta include

  • severe liver impairment. 

Drug interactions of Brilinta include strong CYP3A inhibitors such as ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin because they substantially increase Brilinta exposure and so increase the risk of shortness of breath, bleeding, and other adverse events.

  • Strong CYP3A inducers such as rifampin, phenytoin, carbamazepine and phenobarbital substantially reduce Brilinta exposure and so decrease the efficacy of Brilinta.
  • Use of Brilinta with aspirin maintenance doses above 100 mg reduced the effectiveness of Brilinta.
  • Brilinta increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A.
  • Avoid simvastatin and lovastatin doses greater than 40 mg.
  • Brilinta inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in Brilinta therapy. 

There are no adequate and well-controlled studies of Brilinta use in pregnant women. Brilinta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 

It is unknown if Brilinta or its active metabolites are excreted in human milk. Because many drugs are excreted in breast milk, and because of the potential for serious adverse reactions in nursing infants from Brilinta, a decision should be made whether to discontinue breastfeeding or to discontinue Brilinta.

What are the important side effects of Brilinta (ticagrelor)?

General Risk of Bleeding

  • Drugs that inhibit platelet function including Brilinta increase the risk of bleeding. If possible, manage bleeding without discontinuing Brilinta. Stopping Brilinta increases the risk of subsequent cardiovascular events

Concomitant Aspirin Maintenance Dose

  • In PLATO the use of Brilinta with maintenance doses of aspirin above 100 mg decreased the effectiveness of Brilinta. Therefore, after the initial loading dose of aspirin, use Brilinta with a maintenance dose of aspirin of 75-100 mg

Dyspnea

  • 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.
  • There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.
  • 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.

Discontinuation of Brilinta

  • Discontinuation of Brilinta will increase the risk of myocardial infarction, stroke, and death.
  • If Brilinta must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible.
  • When possible, interrupt therapy with Brilinta for five days prior to surgery that has a major risk of bleeding.
  • Resume Brilinta as soon as hemostasis is achieved.

Severe Hepatic Impairment

Avoid use of Brilinta in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of Brilinta patients with severe hepatic impairment

What is the dosage of ticagrelor?

Initiate treatment with 180 mg oral loading dose following an ACS event. Brilinta safely and effectively. See full prescribing information for Continue treatment with 90 mg twice daily during the first year after an ACS Brilinta. event. After one year, administer 60 mg twice daily. Use Brilinta with a daily maintenance dose of aspirin of 75-100 mg.

Brilinta (ticagrelor) side effects list for healthcare professionals

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

  • Bleeding
  • Dyspnea

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 32,000 patients.

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 (PLATO) - 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
Clopidogrel
N=9186
n (%) patients with eventn (%) patients with event
PLATO Major + Minor713 (7.7)567 (6.2)
  Major362 (3.9)306 (3.3)
    Fatal/Life-threatening171 (1.9)151 (1.6)
    Fatal15 (0.2)16 (0.2)
    Intracranial hemorrhage (Fatal/Life-threatening)26 (0.3)15 (0.2)
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.
* 90 mg BID

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 (PLATO) - 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
Clopidogrel
N=814
n (%) patients with eventn (%) patients with event
PLATO Total Major626 (81.3)666 (81.8)
  Fatal/Life-threatening337 (43.8)350 (43.0)
  Fatal6 (0.8)7 (0.9)
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.
* 90 mg BID

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
Dyspnea13.87.8
Dizziness4.53.9
Nausea4.33.8
* 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*
N=6958
Placebo
N=6996
Events / 1000 patient yearsEvents / 1000 patient years
TIMI Major83
  Fatal11
  Intracranial hemorrhage21
TIMI Major or Minor115
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.
* 60 mg BID

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*
N=6958
Placebo
N=6996
Dyspnea14.2%5.5%
Dizziness4.5%4.1%
Diarrhea3.3%2.5%
*60 mg BID

Bleeding In THEMIS (Prevention Of Major CV Events In Patients With CAD And Type 2 Diabetes Mellitus)

The Kaplan-Meier curve of time to first TIMI Major bleeding event is presented in Figure 3.

Figure 3 - Time to first TIMI Major bleeding event (THEMIS)

Time to first TIMI Major bleeding event (THEMIS) - Illustration
T = Ticagrelor; P = Placebo; N = Number of patients

The bleeding events in THEMIS are shown below in Table 6.

Table 6 - Bleeding events (THEMIS)

Brilinta
N=9562
Placebo
N=9531
Events / 1000 patient yearsEvents / 1000 patient years
TIMI Major94
TIMI Major or Minor125
TIMI Major or Minor or Requiring medical attention4618
Fatal bleeding10
Intracranial hemorrhage32

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, PEGASUS and THEMIS 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).

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.

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 or establish a causal relationship to drug exposure.

  • 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.
  • Skin and subcutaneous tissue disorders: Rash

What drugs interact with Brilinta (ticagrelor)?

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).

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).

Aspirin

  • Use of Brilinta with aspirin maintenance doses above 100 mg reduced the effectiveness of Brilinta.

Opioids

  • As with other oral P2Y12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying.
  • Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

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.

Digoxin

  • Brilinta inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in Brilinta therapy.

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Medically Reviewed on 1/26/2021
References
FDA Prescribing Information

Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.