英文药名：BRILINTA(ticagrelor tablets) 中文药名：替卡格雷片 生产厂家：阿斯利康制药 药品介绍 替格瑞洛（ticagrelor）是由英国阿斯利康制药公司（AstraZeneca）研制开发的一种新的治疗急性冠状动脉综合症（acute coronary syndrome, ACS）的药物，该药于2011年7月20日被美国FDA批准上市，商品名为Brilinta。替格瑞洛通过防止血液中血小板结块的形成来预防血栓，从而有助于减少再次心血管事件的危险。 ACS包括一组心脏缺血症状，其原因包括不稳定型心绞痛或心脏病发作。Brilinta通过预防体内新的血栓形成来维持血流，有助于减少再次心血管事件的危险。 研究人员已对Brilinta联合阿司匹林治疗进行了研究。加框警告提示医务人员和病人，阿司匹林的剂量每日超过100 mg，会降低该药的有效性。 FDA药物评价与研究中心心血管和肾脏产品部主任诺曼（Norman Stockbridge）说：“在临床试验中，在预防心脏病发作和死亡方面，Brilinta比波立维（通用名：氯吡格雷）更有效，但这个优势见于联用每日1次维持剂量为75~100 mg的阿司匹林时。” 黑框警告还提示，与其他抗凝药一样，Brilinta增加出血发生率，并可引起显著的、有时是致命的出血。在临床试验中，服用Brilinta病人报告的最常见的不良反应是出血和呼吸困难。 Brilinta获准伴随着一项风险评估和减缓策略，后者是一项帮助确保该药的益处大于危险的计划。作为这个计划的一部分，公司必须对医师进行教育扩展，提醒他们有关使用较大剂量阿司匹林的危险。另外，在Brilinta配药时将配发用药指导，告知病人关于用药的最重要信息。该用药指导将在每次给每例病人调配处方时配发。 Brilinta由位于特拉华州威明顿的AstraZeneca制造。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BRILINTA safely and effectively. See full prescribing information for BRILINTA. BRILINTA® (ticagrelor) tablets, for oral use Initial U.S. Approval: 2011 WARNING: (A) BLEEDING RISK, and (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESSSee full prescribing information for complete boxed warning. BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding (5.1, 6.1). • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage (4.1, 4.2). • Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery (CABG) (5.1, 6.1). • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events (5.4) . ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. (2.1, 5.2, 14.1 ). RECENT MAJOR CHANGES Warnings and Precautions, Bradyarrhythmias (5.5)  09/2016 INDICATIONS AND USAGE BRILINTA is a P2Y12 platelet inhibitor 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. (1) DOSAGE AND ADMINISTRATION Initiate treatment with 180 mg oral loading dose following an ACS event. Continue treatment with 90 mg twice daily during the first year after an ACS event. After one year, administer 60 mg twice daily. (2.1) Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. (2.1, 5.2) DOSAGE FORMS AND STRENGTHS 60 mg and 90 mg tablets (3) CONTRAINDICATIONS • History of intracranial hemorrhage (4.1) • Active pathological bleeding (4.2) • Hypersensitivity to ticagrelor or any component of the product (4.3) WARNINGS AND PRECAUTIONS • Dyspnea was reported more frequently with BRILINTA than with control agents in clinical trials. Dyspnea resulting from BRILINTA is self-limiting. (5.3) • Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. (5.6) ADVERSE REACTIONS Most common adverse reactions are bleeding 12% and dyspnea 14%. (5.1, 5.3, 6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Avoid use with strong CYP3A inhibitors or CYP3A inducers. ( 7.1, 7.2) • Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects. (7.4) • Monitor digoxin levels with initiation of or any change in BRILINTA. (7.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 9/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 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 [see Clinical Studies (14.1)]. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing In the management of ACS, initiate BRILINTA treatment with a 180 mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Do not administer BRILINTA with another oral P2Y12 platelet inhibitor. Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg [see Warnings and Precautions (5.2) and Clinical Studies (14.1)]. A patient who misses a dose of BRILINTA should take one tablet (their next dose) at its scheduled time. 2.2 Administration For 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) [see Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side. BRILINTA (ticagrelor) 60 mg is supplied as a round, biconvex, pink, film-coated tablet marked with “60” above “T” on one side. 4 CONTRAINDICATIONS 4.1 History of Intracranial Hemorrhage BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population [see Clinical Studies (14.1)]. 4.2 Active Bleeding BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. 4.3 Hypersensitivity BRILINTA is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product. 5 WARNINGS AND PRECAUTIONS 5.1 General Risk of Bleeding Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding [see Adverse Reactions (6.1)]. If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. 5.2 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 [see Dosage and Administration (2.1) and Clinical Studies (14.1)]. 5.3 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, 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. 5.4 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. 5.5 Bradyarrhythmias Due to observations of mostly asymptomatic ventricular pauses in an earlier clinical study, 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) were excluded from the main studies evaluating the safety and efficacy of BRILINTA. Therefore, due to the limited clinical experience in these patients, caution is advised [see Adverse Reactions (6.1)]. 5.6 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 [seeClinical Pharmacology (12.3)]. 6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: • Bleeding [ see Warnings and Precautions (5.1)] • Dyspnea [ see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. BRILINTA has been evaluated for safety in more than 27000 patients, including more than 13000 patients treated for at least 1 year. Bleeding in PLATO (Reduction in risk of thrombotic events in ACS) Figure 1 is a plot of time to the first non-CABG major bleeding event. Figure 1 – Kaplan-Meier estimate of time to first non-CABG PLATO-defined major bleeding event (PLATO) 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 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 PLATO Adverse reactions that occurred at a rate of 4% or more in PLATO are shown in Table 3. Table 3 - Percentage of patients reporting non-hemorrhagic adverse reactions at least 4% or more in either group and more frequently on BRILINTA (PLATO) BRILINTA N=9235 Clopidogrel N=9186   Dyspnea 13.8 7.8 Dizziness 4.5 3.9 Nausea 4.3 3.8 90 mg BID Bleeding in PEGASUS (Secondary Prevention in Patients with a History of Myocardial Infarction) Overall outcome of bleeding events in the PEGASUS study are shown in Table 4. Table 4 - Bleeding events (PEGASUS) BRILINTA + Aspirin N=6958 Aspirin Alone N=6996 n (%) patients with event Events /100 pt yrs n patients with event Events /100 pt yrs TIMI Major 115 (1.7) 0.78 54 (0.8) 0.34      Fatal 11 (0.2) 0.08 12 (0.2) 0.08      Intracranial hemorrhage 28 (0.4) 0.19 23 (0.3) 0.14 TIMI Major or Minor 168 (2.4) 1.15 72 (1.0) 0.45 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 Clopidogrel N=6996   Dyspnea 14.2 5.5 Dizziness 4.5 4.1 Diarrhea 3.3 2.5 60 mg BID Bradycardia In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month. PLATO and PEGASUS excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA 90 mg and clopidogrel patients, respectively. In PEGASUS, syncope was reported by 1.2% and 0.9% of patients on BRILINTA 60 mg and aspirin alone, respectively. Lab abnormalities Serum Uric Acid: In PLATO, serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA 90 mg and approximately 0.2 mg/dL on clopidogrel. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group). In PEGASUS, serum uric acid levels increased approximately 0.2 mg/dL from baseline on BRILINTA 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on BRILINTA than in patients on aspirin alone (1.5%,1.1%). Mean serum uric acid concentrations decreased after treatment was stopped. Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA 90 mg compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria. In PEGASUS, serum creatinine concentration increased by >50% in approximately 4% of patients receiving BRILINTA 60 mg, similar to aspirin alone. The frequency of renal related adverse events was similar for ticagrelor and aspirin alone regardless of age and baseline renal function. 7 DRUG INTERACTIONS 7.1 Strong CYP3A Inhibitors Strong CYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [see Clinical Pharmacology (12.3)]. 7.2 Strong CYP3A Inducers Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) [see Clinical Pharmacology (12.3)]. 7.3 Aspirin Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see Warnings and Precautions (5.2) and Clinical Studies (14.1)]. 7.4 Simvastatin, Lovastatin BRILINTA increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology (12.3)]. 7.5 Digoxin BRILINTA inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in BRILINTA therapy [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 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). 8.3 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 BRILINTA. 8.4 Pediatric Use The safety and effectiveness of BRILINTA in pediatric patients have not been established. 8.5 Geriatric Use In 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. 8.6 Hepatic Impairment Ticagrelor 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 [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE 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. Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG. 11 DESCRIPTION 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-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is: Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature. BRILINTA 90 mg tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow. BRILINTA 60 mg tablets for oral administration contain 60 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide black, and ferric oxide red. 12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 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 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 mg twice 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 [see Dosage and Administration (2)]. 12.3 Pharmacokinetics Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers. Absorption BRILINTA 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. 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 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. Specific Populations The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 5. Effects are modest and do not require dose adjustment. Figure 5 - Impact of intrinsic factors on the pharmacokinetics of ticagrelor 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 6 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. Figure 6 - Effect of co-administered drugs on the pharmacokinetics of ticagrelor 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 7. Figure 7 - Impact of BRILINTA on the pharmacokinetics of co-administered drugs 12.5 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. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 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. 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). 14 CLINICAL STUDIES 14.1 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 6 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. Table 6 - Patients with outcome events (KM%)(PLATO) BRILINTA N=9333 Clopidogrel N=9291 Hazard Ratio (95% CI) p-value Composite of CV death, MI, or stroke 9.8 11.7 0.84 (0.77, 0.92) 0.0003 CV death 2.9 4.0 0.74 Non-fatal MI 5.8 6.9 0.84 Non-fatal stroke 1.4 1.1 1.24 Secondary endpoints† CV death 4.0 5.1 0.79 (0.69, 0.91) 0.0013 MI ‡ 5.8 6.9 0.84 (0.75, 0.95) 0.0045 Stroke ‡ 1.5 1.3 1.17 (0.91, 1.52) 0.22 All-cause mortality 4.5 5.9 0.78 (0.69, 0.89) 0.0003 Dosed at 90 mg bid. Note: rates of first events for the components CV Death, MI and Stroke are the actual rates for first events for each component and do not add up to the overall rate of events in the composite endpoint. Including patients who could have had other non-fatal events or died. The Kaplan-Meier curve (Figure 8) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke in the overall study. Figure 8–Time to first occurrence of CV death, MI, or stroke (PLATO) The curves separate by 30 days [relative risk reduction (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. Some of these are shown in Figure 9. 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 exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below. Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., aspirin maintenance dose, use of PCI). Figure 9 –Subgroup analyses of (PLATO) Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. 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 10 shows overall results by median aspirin dose. Figure 10 shows results by region and dose. Figure 10 – CV death, MI, stroke by maintenance aspirin dose in the US and outside the US (PLATO) 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 7 for key baseline features. Table 7 - Baseline features (PEGASUS) Demographic % Patients <65 years 45% Diabetes 32% Multivessel disease 59% History of >1 MI 17% Chronic non-end stage renal disease 19% Stent 80% Prior P2Y12 platelet inhibitor therapy 89% Lipid lowering therapy 94% The Kaplan-Meier curve (Figure 11) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke. Figure 11 – Time to First Occurrence of CV death, MI or Stroke (PEGASUS) 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 8 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone. Table 8 - Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoints (PEGASUS)  BRILINTA  + Aspirin N=7045 Aspirin Alone N=7067 HR (95% CI) p-value n (patients with event) KM% n (patients with event) KM% Time to first CV death, MI, or stroke 487 7.8 578 9.0 0.84 (0.74, 0.95) 0.0043 CV Death 116 128 Myocardial infarction 283 336 Strokea  88 114 Subjects with events at any time CV Death 174 2.9 210 3.4 0.83 (0.68, 1.01) Myocardial infarction 285 4.5 338 5.2 0.84 (0.72, 0.98) Stroke  91 1.5 122 1.9 0.75 (0.57, 0.98) All-cause mortality 289 4.7 326 5.2 0.89 (0.76, 1.04) CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; KM = Kaplan-Meier percentage calculated at 36 months; MI = Myocardial infarction; N = Number of patients; 60 mg BID Primary endpoint For the components, the first-occurring component of the composite is included. The number of first events for the components CV Death, MI and Stroke are the actual number of first events for each component and do not add up to the number of events in the composite endpoint. Secondary endpoints In PEGASUS, the RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) were similar. The treatment effect of BRILINTA 60 mg over aspirin appeared similar across most pre-defined subgroups, see Figure 12. Figure 12 – Subgroup analyses of ticagrelor 60 mg (PEGASUS) Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. 16 HOW SUPPLIED/STORAGE AND HANDLING BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet with a “90” above “T” on one side: Bottles of 14 – NDC 0186-0777-28 Bottles of 60 – NDC 0186-0777-60 100 count Hospital Unit Dose – NDC 0186-0777-39 BRILINTA (ticagrelor) 60 mg is supplied as a round, biconvex, pink, film-coated tablet with a “60” above “T” on one side: Bottles of 60 – NDC 0186-0776-60 Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature]. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f7b3f443-e83d-4bf2-0e96-023448fed9a8 阿斯利康抗凝血药Brilique（替卡格雷）获欧盟批准用于伴有心脏病史患者的长期治疗 2016年2月22日，英国制药巨头阿斯利康（AZN）抗凝血药Brilique（ticagrelor，替卡格雷）在欧洲监管方面传来喜讯。欧盟委员会（EC）已批准Brilique 60mg新剂量，用于有心脏病发作史以及伴有高风险后续血栓事件的患者群体。 意见指出，在经过最初一年的Brilique 90mg+阿司匹林（aspirin）或其他双效抗血小板疗法后，Brilique 60mg新剂量可作为一种继续疗法开始治疗。 此次批准，使Brilique成为欧洲用于有心脏病史患者群体长期治疗的首个口服抗血小板药物。 在美国，Brilinta（ticagrelor，替卡格雷）60mg新剂量已于2015年9月获FDA批准，联合低剂量阿司匹林，用于患者心脏病发作一年后的长期治疗，以预防后续的心脏病发作、中风及心血管死亡事件。随着此次扩大适应症，Brilinta现在可用于急性冠脉综合征（ACS）或有心肌梗死（MI，也被称为心脏病发作）病史的患者，降低心脏病发作、中风及心血管死亡事件风险。 ticagrelor（替卡格雷）是一种口服抗血小板药物，其美国品牌名为Brilinta，欧洲品牌名为Brilique。ticagrelor属于可逆性血小板二磷酸腺苷（ADP）受体拮抗剂，旨在阻止血小板黏结在一起，避免形成可能导致心脏病发作和中风的血液凝块。 在美国，ticagrelor于2011年7月首次获FDA批准，用于急性冠脉综合征（ACS）成人患者的治疗。临床数据显示，在发生ACS事件之后至少12个月内，ticagrelor在降低心血管死亡方面疗效显著优于氯吡格雷（clopidogrel）。此外，ticagrelor也降低了已接受支架治疗ACS的患者群体中支架内血栓（ST）的发生率。 在ACS的临床管理中，ACS事件后第一年（12个月）内，ticagrelor的推荐维持剂量为90mg/每天2次。一年之后，有心脏病发作史的患者现在可以接受ticagrelor 60mg/每天2次的长期治疗，以预防进一步的心脏发作、中风及心血管死亡。 目前已知，患者在心脏病发作一年后，仍然存在发生后续心血管事件的风险。此次批准标志着一个重要里程碑，强调了ticagrelor在急性期和长期2方面降低患者后续心血管事件风险的重要作用。 Brilique/Brilinta扩大适应症的批准，是基于PEGASUS TIMI-54研究的数据，该研究是一项大规模预后研究，涉及超过2.1万例患者，这些患者在纳入研究之前1-3年内曾经历一次心脏病发作，研究调查了ticagrelor（60mg或90mg，每天2次）联合低剂量阿司匹林治疗方案长期预防心血管死亡、心脏发作和中风的疗效与安全性，并与安慰剂联合低剂量阿司匹林治疗方案进行了对比。 数据显示，与对照组相比，ticagrelor联合低剂量阿司匹林方案显著降低了心血管死亡、心脏发作及中风发生率，ticagrelor 60mg治疗组3年的事件发生率为7.77%，安慰剂对照组为9.04%。 目前，Brilinta/Brilique已获全球100多个国家批准，并被纳入12个主要的ACS临床治疗指南