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-(3,4difluorophenyl)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. The chemical structure of ticagrelor is: Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature. BRILINTA 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.

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The following adverse reactions are also discussed elsewhere in the labeling: Dyspnea [see WARNINGS AND PRECAUTIONS] 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 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 1 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. Figure 1: Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event
Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in the first 30 days. Table 1 : Non-CABG related bleeds (KM%)
  BRILINTA
N=9235 Clopidogrel
N=9186 Total (Major + Minor) 8.7

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Initiate BRILINTA treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily. After the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. ACS patients who have received a loading dose of clopidogrel may be started on BRILINTA. BRILINTA can be administered with or without food. A patient who misses a dose of BRILINTA should take one 90 mg tablet (their next dose) at its scheduled time. Administration Options For patients who are unable to swallow the tablet(s) whole, BRILINTA tablets can be crushed, mixed with water and drunk immediately. The glass should be refilled with water, stirred 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 [see CLINICAL PHARMACOLOGY].

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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 AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. CYP3A inducers Avoid use with potent inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Aspirin Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see WARNINGS AND PRECAUTIONS and Clinical Studies]. 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 CLINICAL PHARMACOLOGY]. Digoxin Digoxin Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in BRILINTA therapy [see CLINICAL PHARMACOLOGY]. 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. Read the Brilinta Drug Interactions Center for a complete guide to possible interactions Learn More »

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Acute Coronary Syndromes BRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). BRILINTA has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis [see Clinical Studies]. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily [see WARNINGS AND PRECAUTIONS and Clinical Studies].

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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]. Active Bleeding BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see WARNINGS AND 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 CLINICAL PHARMACOLOGY]. Hypersensitivity BRILINTA is contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product [see ADVERSE REACTIONS]. Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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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.

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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) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side. Bottles of 14 – NDC 0186-0777-28
Bottles of 60 – NDC 0186-0777-60
Bottles of 180 – NDC 0186-0777-18
100 count Hospital Unit Dose – NDC 0186-0777-39 Storage And Handling Store at 25°C (77°F); excursions permitted to 15°-30°C (59°- 86°F) [see USP controlled room temperature]. Distributed by: AstraZeneca LP, Wilmington, DE 19850. Issued: March 2015 Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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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 Discontinuation of BRILINTA below 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 of 75-100 mg [see DOSAGE AND ADMINISTRATION and Clinical Studies]. 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 to ticagrelor. Dyspnea In PLATO, 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, but occasionally required discontinuation (0.9% of patients taking BRILINTA versus 0.1% of patients taking clopidogrel). 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 the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent. 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 DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. Cytochrome CYP3A Potent Inducers Avoid use with potent CYP3A inducers, such as rifampin, phenytoin, carbamazepine, and phenobarbital [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. Patient Counseling Information See FDA-approved patient labeling (Medication Guide) Benefits and Risks

• Tell patients to take BRILINTA exactly as prescribed.
• Inform patients not to discontinue BRILINTA without discussing it with the prescribing physician.
• Tell patients daily doses of aspirin should not exceed 100 mg and to avoid taking any other medications that contain aspirin.
• Tell patients to read the Medication Guide.

Bleeding Inform patients that they:

• Will bleed and bruise more easily
• Will take longer than usual to stop bleeding
• Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.

Other Signs AND Symptoms Requiring Medical Attention

• Inform patients that BRILINTA can cause shortness of breath. Tell them to contact their doctor if they experience unexpected shortness of breath, especially if severe.

Invasive Procedures Instruct patients to:

• Inform physicians and dentists that they are taking BRILINTA before any surgery or dental procedure.
• Tell the doctor performing any surgery or dental procedure to talk to the prescribing physician before stopping BRILINTA.

Concomitant Medications Tell patients to list all prescription medications, over-the-counter medications or dietary supplements they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk (e.g. warfarin, heparin). Nonclinical Toxicology 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). Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m²basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m²basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. 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/m²basis) 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/m²basis). 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/m²basis). 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, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of BRILINTA in pediatric patients have not been established. Geriatric Use 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. 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 AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Renal Impairment No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see WARNINGS AND PRECAUTIONS]. Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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