There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not expected to be dialyzable. Treatment of overdose should follow local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken.
Platelet transfusion did not reverse the antiplatelet effect of BRILINTA in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding.
Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.
BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population.
Active BleedingBRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage .
HypersensitivityBRILINTA is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.
The following adverse reactions are also discussed elsewhere in the labeling:
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)
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 event | 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) |
| 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)
| 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 event | 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) |
| 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 PLATOAdverse 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 |
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 |
| 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 PEGASUSAdverse 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 |
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 AcidIn 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 CreatinineIn 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 ExperienceThe 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.
Immune system disorders: Hypersensitivity reactions including angioedema.
Skin and subcutaneous tissue disorders: Rash
BRILINTA is indicated to reduce the rate of cardiovascular death, 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.
The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.
The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 3, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours.
The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.
As shown in Figure 4, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 4 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.
Figure 3 – Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel
Figure 4 – Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mgtwice daily, or clopidogrel 75 mg daily
Transitioning from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4% and from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect.
Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
AbsorptionBRILINTA can be taken with or without food. Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0– 4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).
The mean absolute bioavailability of ticagrelor is about 36% (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC.
BRILINTA as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0 – 4.0) for ticagrelor and 2.0 hours (range 1.0 –8.0) for AR-C124910XX.
DistributionThe steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
MetabolismCYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.
ExcretionThe primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.
There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day, delayed development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred.
In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis).
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS General Risk Of BleedingDrugs 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 DoseIn 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 75100 mg.
DyspneaIn 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.
In a substudy of PLATO, 199 subjects underwent pulmonary function testing irrespective of whether they reported dyspnea. 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 BRILINTADiscontinuation 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.
BradyarrhythmiasTicagrelor can cause ventricular pauses. Bradyarrhythmias including AV block have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2nd or 3rd degree AV block or bradycardia-related syncope not protected by a pacemaker were excluded from PLATO and PEGASUS and may be at increased risk of developing bradyarrhythmias with ticagrelor.
Severe Hepatic ImpairmentAvoid 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.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients daily doses of aspirin should not exceed 100 mg and to avoid taking any other medications that contain aspirin.
Advise patients that they:
Advise patients to contact their doctor if they experience unexpected shortness of breath, especially if severe.
Advise patients to inform physicians and dentists that they are taking BRILINTA before any surgery or dental procedure.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisTicagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8-fold the MRHD based on AUC) was not carcinogenic in female rats.
MutagenesisTicagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.
Impairment Of FertilityTicagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15-fold the MRHD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC).
Use In Specific Populations Pregnancy Pregnancy Category C:There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day, delayed development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred.
In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis).
Nursing MothersIt is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from BRILINTA, a decision should be made whether to discontinue nursing or to discontinue BRILINTA.
Pediatric UseThe safety and effectiveness of BRILINTA in pediatric patients have not been established.
Geriatric UseIn PLATO and PEGASUS, about half of patients in each study were ≥65 years of age and about 15% were ≥75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.
Hepatic ImpairmentTicagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of BRILINTA in patients with severe hepatic impairment. There is limited experience with BRILINTA in patients with moderate hepatic impairment; consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor. No dosage adjustment is needed in patients with mild hepatic impairment.
Renal ImpairmentNo dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied.
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.
Do not administer BRILINTA with another oral P2Y12 platelet inhibitor.
Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. A patient who misses a dose of BRILINTA should take one tablet (their next dose) at its scheduled time.
AdministrationFor patients who are unable to swallow tablets whole, BRILINTA tablets can be crushed, mixed with water and drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater).
The following adverse reactions are also discussed elsewhere in the labeling:
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)
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 event | 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) |
| 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)
| 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 event | 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) |
| 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 PLATOAdverse 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 |
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 |
| 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 PEGASUSAdverse 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 |
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 AcidIn 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 CreatinineIn 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 ExperienceThe 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.
Immune system disorders: Hypersensitivity reactions including angioedema.
Skin and subcutaneous tissue disorders: Rash
DRUG INTERACTIONS Strong CYP3A InhibitorsStrong 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 InducersStrong 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).
AspirinUse of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA.
Simvastatin, LovastatinBRILINTA increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg.
DigoxinBRILINTA inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in BRILINTA therapy.
