Brilinta

Ticagrelor.

Each tablet contains 90 mg of ticagrelor.
Each tablet contains 60 mg of ticagrelor.
BRILINTA contains ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically, it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C₂₃H₂₈F₂N₆O₄S and its molecular weight is 522.57.
Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.
Excipients/Inactive Ingredients: 90 mg film coated tablet: Core: Mannitol (E421), Dibasic calcium phosphate, Magnesium stearate, Sodium starch glycolate, Hydroxypropyl cellulose.
Coating: Talc, Titanium dioxide (E171), Ferric oxide yellow (E172), Polyethylene glycol 400, Hypromellose.
60 mg film coated tablet: Core: Mannitol (E421), Dibasic calcium phosphate, Magnesium stearate, Sodium starch glycolate, Hydroxypropyl cellulose.
Coating: Titanium dioxide (E171), Ferric oxide black (E172), Ferric oxide red (E172), Polyethylene glycol 400, Hypromellose.

Pharmacology: Mechanism of Action: Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
Pharmacodynamics: 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 ticagrelor 180 mg or clopidogrel 600 mg. As shown in Figure 1, 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 2, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in figure 2 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. (See Figures 1 and 2.)


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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 (see Dosage & Administration).
Adenosine mechanism (ENT-1): Ticagrelor increased plasma adenosine concentrations in ACS patients and has been shown to augment several physiological responses to adenosine. Adenosine is a vasodilator; ticagrelor has been shown to augment adenosine-induced coronary blood flow increases in healthy volunteers and ACS patients. Adenosine is an endogenous platelet inhibitor; ticagrelor has been shown to augment adenosine-mediated inhibition of platelet aggregation in addition to platelet inhibition due to its P2Y12 antagonism. Adenosine has been linked to the cardioprotective effect of preconditioning; ticagrelor has been shown to reduce infarct size via an adenosine-mediated mechanism in a rat model of reperfusion injury. Adenosine also induces dyspnoea; ticagrelor has been shown to augment adenosine-induced dyspnoea in healthy volunteers. Thus, the dyspnoea observed in some patients taking ticagrelor (see Adverse Reactions) may partly or completely be mediated by adenosine.
Pharmacokinetics: Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
Absorption: 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 can be taken with or without food.
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 the active metabolite), 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.
Distribution: The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
Metabolism: CYP3A4 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 (P-gp) substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.
Excretion: The 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.
Special Populations: The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 3. Effects are modest and do not require dose adjustment. (See Figure 3.)


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Pediatric: Ticagrelor has not been evaluated in a pediatric population (see Precautions).
Body Weight: No dose adjustment is necessary for ticagrelor based on weight.
Smoking: Habitual smoking increased population mean clearance of ticagrelor by approximately 22% when compared to non-smokers. No dose adjustment is necessary for ticagrelor based on smoking status.
Renal impairment: In patients with end stage renal disease on haemodialysis AUC and Cmax of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately prior to dialysis (49% and 61%, respectively) showing that ticagrelor is not dialysable. Exposure of the active metabolite increased to a lesser extent (AUC 13-14% and Cmax 17-36%). The inhibition of platelet aggregation (IPA) effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to subjects with normal renal function
Effects of Other Drugs on BRILINTA : CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 4 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g. cyclosporine) increase ticagrelor exposure. (See Figure 4.)


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Effects of BRILINTA on Other Drugs: In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 5. (See Figure 5.)


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Pharmacogenetics: In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the BRILINTA arm did not depend on CYP2C19 loss of function status.
Toxicology: Nonclinical Toxicology: Carcinogenesis: Ticagrelor 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 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.
Mutagenesis: Ticagrelor 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 Fertility: Ticagrelor 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).
Clinical Studies: Acute Coronary Syndromes and Secondary Prevention after Myocardial Infarction: PLATO: PLATO was a randomized double-blind study comparing BRILINTA (N=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS), who presented within 24 hours of onset of the most recent episode of chest pain or symptoms. The study's primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke.
Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients with previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent.
All patients randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Patients in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if clopidogrel therapy had not already been given. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment. Patients were treated for at least 6 months and for up to 12 months.
PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years. Median exposure to study drug was 277 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO.
Table 1 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality. (See Table 1 and Figure 6.)


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The curves separate by 30 days (RRR 12%) and continue to diverge throughout the 12 month treatment period (RRR 16%). Among 11289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated "definite") than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.009). The results were similar for drug-eluting and bare metal stents.
A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Many of these are shown in Figure 6. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two marked exceptions: A finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further as follows.
Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (eg, final diagnosis, aspirin maintenance dose, use of PCI). (See Figure 7.)


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Regional Differences: Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable.
A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome.
Aspirin Dose: The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were different in US sites from sites outside of the US. About 8% of non-US investigators administered aspirin doses above 100 mg, and about 2% administered doses above 300 mg. In the US, 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored BRILINTA when used with low maintenance doses (≤100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 8 shows overall results by median aspirin dose. Figure 8 shows results by region and dose. (See Figure 8.)


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Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI.
Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of BRILINTA.
PEGASUS: The PEGASUS TIMI-54 study was a 21162-patient, randomized, double-blind, placebo-controlled, parallel-group study. Two doses of ticagrelor, either 90 mg twice daily or 60 mg twice daily, co-administered with 75-150 mg of aspirin, were compared to aspirin therapy alone in patients with history of MI. The primary endpoint was the composite of first occurrence of CV death, non-fatal MI and non-fatal stroke. CV death and all-cause mortality were assessed as secondary endpoints.
Patients were eligible to participate if they were ≥50 years old, with a history of MI 1 to 3 years prior to randomization, and had at least one of the following risk factors for thrombotic cardiovascular events: age ≥65 years, diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min. Patients could be randomized regardless of their prior ADP receptor blocker therapy or a lapse in therapy. Patients requiring or who were expected to require renal dialysis during the study were excluded. Patients with any previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. A small number of patients with a history of stroke were included. Based on information external to PEGASUS, 102 patients with a history of stroke (90 of whom received study drug) were terminated early and no further such patients were enrolled.
Patients were treated for at least 12 months and up to 48 months with a median follow up time of 33 months.
Patients were predominantly male (76%) Caucasian (87%) with a mean age of 65 years, and 99.8% of patients received prior Aspirin therapy. See Table 2 for key baseline features. (See Table 2.)


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The Kaplan-Meier curve (Figure 9) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke. (See Figure 9.)


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Both the 60 mg and 90 mg regimens of BRILINTA in combination with aspirin were superior to aspirin alone in reducing the incidence of CV death, MI or stroke. The absolute risk reductions for BRILINTA plus aspirin vs. aspirin alone were 1.27% and 1.19% for the 60 and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea.
Table 3 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone. (See Table 3.)


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In PEGASUS, the RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) was similar. The treatment effect of BRILINTA 60 mg twice daily over aspirin was consistent across pre-defined subgroups, see Figure 10. (See Figure 10).


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BRILINTA 90 mg: BRILINTA 90 mg co-administered with ASA 75-100 mg is indicated for the prevention of thrombotic events (cardiovascular death, myocardial infarction and stroke) in patients with acute coronary syndromes (ACS) [unstable angina, non-ST elevation myocardial infarction (NSTEMI) or ST elevation myocardial infarction (STEMI)] including patients managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG).
BRILINTA 60 mg: BRILINTA 60 mg is indicated for the prevention of thrombotic events (cardiovascular death, myocardial infarction and stroke) in patients with a history of myocardial infarction (MI occurred at least one year ago) and a high risk of developing a thrombotic event and have at least 1 of the following risk factors: Age ≥65 years; Diabetes mellitus requiring medication; Documented history of a second prior presumed spontaneous MI (>1 year ago); Documented history of angiographic evidence of multivessel CAD (stenosis ≥50% in 2 major coronary artery territories [ie. left anterior descending, ramus intermedius, left circumflex, right coronary artery], involving the main vessel, a major branch, or a bypass graft); Chronic, non-end stage renal dysfunction (creatinine clearance calculated by Cockroft Gault equation <60 ml/min).

Posology: Patients taking Brilinta should also take a daily low maintenance dose of ASA 75-100 mg, unless specifically contraindicated.
Acute coronary syndromes: Brilinta treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.
History of myocardial infarction: Brilinta 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event. Treatment may be started without interruption as continuation therapy after the initial one-year treatment with Brilinta 90 mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in ACS patients with a high risk of an atherothrombotic event. Treatment can also be initiated up to 2 years from the MI, or within one year after stopping previous ADP receptor inhibitor treatment. There are limited data on the efficacy and safety of Brilinta beyond 3 years of extended treatment.
Missed dose: Lapses in therapy should also be avoided. A patient who misses a dose of Brilinta should take only one tablet (their next dose) at its scheduled time.
Special populations: Elderly: No dose adjustment is required in elderly.
Renal impairment: No dose adjustment is necessary for patients with renal impairment.
Hepatic impairment: Ticagrelor has not been studied in patients with severe hepatic impairment and its use in these patients is therefore contraindicated. Only limited information is available in patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor should be used with caution. No dose adjustment is necessary for patients with mild hepatic impairment.
Paediatric population: The safety and efficacy of ticagrelor in children below the age of 18 years have not been established. No data are available.
Method of administration: For oral use.
Brilinta can be administered with or without food.
For patients who are unable to swallow the tablet(s) whole, the tablets can be crushed to a fine powder and mixed in half a glass of water and drunk immediately. The glass should be rinsed with a further half glass of water and the contents drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture.

There is currently no known treatment to reverse the effects of BRILINTA and ticagrelor is not 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 infusion 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.

History of Intracranial Hemorrhage: BRILINTA is contraindicated in patients with a history of intracranial hemorrrhage (ICH) because of a high risk of recurrent ICH in this population (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Active Bleeding: BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage (see Warnings, Precautions and Adverse Reactions).
Severe Hepatic Impairment: BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins (see Pharmacology under Actions).
Hypersensitivity: BRILINTA is contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product (see Adverse Reactions).
Co-administration with strong CYP3A4 inhibitors: Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as co-administration may lead to a substantial increase in exposure to ticagrelor.

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 planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery.
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG or other surgical procedures in the setting of BRILINTA.
If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events.
ASPIRIN DOSE AND BRILINTA EFFECTIVENESS: Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75-100 mg per day.

General Risk of Bleeding: Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding.
BRILINTA increased the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding. Fatal and life-threatening bleeding rates were not increased (see Adverse Reactions).
In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDs]).
When possible, discontinue BRILINTA five days prior to surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding.
If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events (see Warnings and Adverse Reactions).
Concomitant Aspirin Maintenance Dose: In PLATO, use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Therefore, after the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a maintenance dose of aspirin 75-100 mg (see Dosage & Administration and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Moderate Hepatic Impairment: BRILINTA has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure of ticagrelor.
Dyspnea: Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment. If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption.
In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no significant difference between treatment groups for FEV1. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.
Discontinuation of BRILINTA: Avoid interruption of BRILINTA treatment. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of BRILINTA will increase the risk of myocardial infarction, stent thrombosis and death.
Strong Inhibitors of Cytochrome CYP3A: Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole (see Interactions and Pharmacology under Actions).
Cytochrome CYP3A Potent Inducers: Avoid use with potent CYP3A inducers, such as rifampin, phenytoin, carbamazepine, and phenobarbital (see Interactions and Pharmacology under Actions).
Surgery: Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken.
In PLATO patients undergoing coronary artery bypass grafting (CABG), ticagrelor had more bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery. If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 7 days prior to surgery.
Patients with prior ischaemic stroke: ACS patients with prior ischaemic stroke can be treated with Brilinta for up to 12 months (PLATO study).
In PEGASUS, patients with history of MI with prior ischaemic stroke were not included. Therefore, in the absence of data, treatment beyond one year is not recommended in these patients.
Hepatic impairment: Use of ticagrelor is contraindicated in patients with severe hepatic impairment. There is limited experience with ticagrelor in patients with moderate hepatic impairment, therefore, caution is advised in these patients.
Patients at risk for bradycardic events: Holter ECG monitoring has shown an increased frequency of mostly asymptomatic ventricular pauses during treatment with ticagrelor compared with clopidogrel. Patients with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic related syncope) have been excluded from the main studies evaluating the safety and efficacy of ticagrelor. Therefore, due to the limited clinical experience, ticagrelor should be used with caution in these patients.
In addition, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).
During the Holter substudy in PLATO, more patients had ventricular pauses ≥3 seconds with ticagrelor than with clopidogrel during the acute phase of their ACS. The increase in Holter-detected ventricular pauses with ticagrelor was higher in patients with chronic heart failure (CHF) than in the overall study population during the acute phase of ACS, but not at one month with ticagrelor or compared to clopidogrel. There were no adverse clinical consequences associated with this imbalance (including syncope or pacemaker insertion) in this patient population.
Creatinine elevations: Creatinine levels may increase during treatment with ticagrelor. The mechanism has not been elucidated. Renal function should be checked according to routine medical practice. In patients with ACS, it is recommended that renal function is also checked one month after initiating the treatment with ticagrelor, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an angiotensin receptor blocker (ARB).
Uric acid increase: Hyperuricaemia may occur during treatment with ticagrelor. Caution is advised in patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged.
Other: Based on a relationship observed in PLATO between maintenance ASA dose and relative efficacy of ticagrelor compared to clopidogrel, coadministration of ticagrelor and high maintenance dose ASA (>300 mg) is not recommended.
Premature discontinuation: Premature discontinuation with any antiplatelet therapy, including Brilinta, could result in an increased risk of cardiovascular (CV) death, MI or stroke due to the patient's underlying disease. Therefore, premature discontinuation of treatment should be avoided.
Laboratory Test Interferences: False negative functional tests for Heparin Induced Thrombocytopenia (HIT): BRILINTA has been reported to cause false negative results in platelet functional tests (to include, but may not be limited to, the heparin-induced platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to inhibition of the P2Y12-receptor on the healthy donor platelets in the test by ticagrelor in the affected patient's serum/plasma. Information on concomitant treatment with BRILINTA is required for interpretation of HIT functional tests. Based on the mechanism of BRILINTA interference, BRILINTA is not expected to impact PF4 antibody testing for HIT.
Hepatic Impairment: BRILINTA has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, BRILINTA is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment (see Contraindications, Warnings, Precautions and Pharmacology under Actions).
Renal Impairment: No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied (see Pharmacology under Actions).
Use in Children: The safety and effectiveness of BRILINTA in pediatric patients have not been established.
Use in Elderly: In PLATO, 43% of patients were ≥65 years of age and 15% were ≥75 years of age.
The relative risk of bleeding was similar in both treatment and age groups.
No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

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. The lowest dose was 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 Mothers: It 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 drug BRILINTA.

Clinical Trials Experience: The following adverse reactions are also discussed elsewhere in the labeling: Bleeding (see Warnings and Precautions); Dyspnea (see Warnings and Precautions).
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 10000 patients, including more than 3000 patients treated for more than 1 year.
Bleeding: PLATO used the following bleeding severity categorization: Major bleed - fatal/life-threatening: Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.
Major bleed - other: Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
Minor bleed: Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).
Minimal bleed: All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.
Figure 11 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG and other procedures, but the risk persists during later use of antiplatelet therapy. (See Figure 11.)


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Annualized rates of bleeding are summarized in Table 4 as follows. About half of the bleeding events were in the first 30 days. (See Table 4.)


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As shown in Table 4, BRILINTA was associated with a somewhat greater risk of non-CABG bleeding than was clopidogrel. 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 Table 5. Rates were very high but similar for BRILINTA and clopidogrel. (See Table 5.)


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Although the platelet inhibition effect of BRILINTA has a faster offset than clopidogrel in in vitro tests and BRILINTA is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of BRILINTA compared to clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.
No data exists with BRILINTA regarding a hemostatic benefit of platelet transfusions.
Drug Discontinuation: In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for BRILINTA and 5.4% for clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of BRILINTA patients and 1.0% of clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of BRILINTA and 0.1% of clopidogrel patients.
Common Adverse Events: A variety of non-hemorrhagic adverse events occurred in PLATO at rates of 3% or more. These are shown in Table 6. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common on BRILINTA or clearly related to the drug's pharmacologic effect (dyspnea). (See Table 6.)


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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 7. (See Table 7.)


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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 8. (See Table 8.)


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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 90mg and clopidogrel patients, respectively. In PEGASUS, syncope was reported by 1.2% and 0.9% of patients on BRILINTA 60 mg twice daily and aspirin alone, respectively.
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.
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 (see Contraindications).
Skin and subcutaneous tissue disorders: Rash.
Gynecomastia: In PLATO, gynecomastia was reported by 0.23% of men on BRILINTA and 0.05% on clopidogrel.
Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO.
Lab abnormalities: Serum Uric Acid: Serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA and approximately 0.2 mg/dL on clopidogrel in PLATO. 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 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. (See Table 9.)


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Effects of other drugs: Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5. Ticagrelor is also a p-glycoprotein (P-gp) substrate.
CYP3A inhibitors: Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) (see Warnings, Precautions and Pharmacology under Actions).
CYP3A inducers: Avoid use with potent inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) (see Warnings, Precautions and Pharmacology under Actions).
Aspirin: Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA (see Warnings, Precautions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Effect of BRILINTA on other drugs: Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.
Simvastatin, lovastatin: BRILINTA will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg (see Pharmacology under Actions).
Digoxin: Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in BRILINTA therapy (see Pharmacology under Actions).
Other Concomitant Therapy: BRILINTA can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton-pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.
Cyclosporine (Pgp and CYP3A inhibitor): Coadministration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3 fold and 2.8 fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of cyclosporine. No data are available on concomitant use of ticagrelor with other active substances that also are potent Pgp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) that also may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution.
Oral contraceptives: Coadministration of ticagrelor and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are coadministered with ticagrelor.
Medicinal products known to induce bradycardia: Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).
Others: Clinical pharmacology interaction studies showed that coadministration of ticagrelor with heparin, enoxaparin and ASA or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or the active metabolite or on ADP induced platelet aggregation compared with ticagrelor alone. If clinically indicated, medicinal products that alter haemostasis should be used with caution in combination with ticagrelor. A 2 fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3 x 200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients.
A delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, has been observed in patients with ACS treated with morphine (35% reduction in ticagrelor exposure). This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced ticagrelor efficacy in patients co-administered ticagrelor and morphine. In patients with ACS, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Incompatibilities: Not applicable.

Do not store above 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC24 - ticagrelor ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.

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