FDA label 3b3e6616-35cc-e0b9-e063-6394a90a76ac

WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND TICAGRELOR TABLETS EFFECTIVENESS A. BLEEDING RISK Ticagrelor tablets, like other antiplatelet agents, can cause significant, sometimes fatal bleeding ( 5.1 , 6.1 ). Do not use ticagrelor tablets in patients with active pathological bleeding or a history of intracranial hemorrhage ( 4.1 , 4.2 ). Do not start ticagrelor tablets in patients undergoing urgent coronary artery bypass graft surgery (CABG) ( 5.1 , 6.1 ). If possible, manage bleeding without discontinuing ticagrelor tablets. Stopping ticagrelor tablets increases the risk of subsequent cardiovascular events ( 5.4 ). B. ASPIRIN DOSE AND TICAGRELOR TABLETS EFFECTIVENESS Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor tablets and should be avoided ( 2.1 , 5.2 , 14.1 ). WARNING: (A) BLEEDING RISK, and (B) ASPIRIN DOSE AND TICAGRELOR TABLETS EFFECTIVENESS See full prescribing information for complete boxed warning. BLEEDING RISK Ticagrelor tablets, like other antiplatelet agents, can cause significant, sometimes fatal bleeding. ( 5.1 , 6.1 ) Do not use ticagrelor tablets in patients with active pathological bleeding or a history of intracranial hemorrhage. ( 4.1 , 4.2 ) Do not start ticagrelor tablets in patients undergoing urgent coronary artery bypass graft surgery (CABG). ( 5.1 , 6.1 ) If possible, manage bleeding without discontinuing ticagrelor tablets. Stopping ticagrelor tablets increases the risk of subsequent cardiovascular events. ( 5.4 ) ASPIRIN DOSE AND TICAGRELOR TABLETS EFFECTIVENESS Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor tablets and should be avoided. ( 2.1 , 5.2 , 14.1 )

5 WARNINGS AND PRECAUTIONS Dyspnea was reported more frequently with ticagrelor tablets than with control agents in clinical trials. Dyspnea resulting from ticagrelor tablets is self-limiting. ( 5.3 ) Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. ( 5.6 ) Laboratory Test Interference: False negative platelet functional test results have been reported for Heparin Induced Thrombocytopenia (HIT). Ticagrelor tablets are not expected to impact PF4 antibody testing for HIT ( 5.7 ). 5.1 General Risk of Bleeding Drugs that inhibit platelet function including ticagrelor tablets increase the risk of bleeding [see Adverse Reactions ( 6.1 )]. If possible, manage bleeding without discontinuing ticagrelor tablets. Stopping ticagrelor tablets 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 ticagrelor tablets with maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor tablets. Therefore, after the initial loading dose of aspirin, use ticagrelor tablets 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 ticagrelor tablets 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 ticagrelor tablets and 0.1% of clopidogrel patients in PLATO and 4.3% of ticagrelor tablets 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 ticagrelor tablets, no specific treatment is required; continue ticagrelor tablets without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of ticagrelor tablets, consider prescribing another antiplatelet agent. 5.4 Discontinuation of Ticagrelor Tablets Discontinuation of ticagrelor tablets will increase the risk of myocardial infarction, stroke, and death. If ticagrelor tablets must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with ticagrelor tablets for five days prior to surgery that has a major risk of bleeding. Resume ticagrelor tablets as soon as hemostasis is achieved. 5.5 Bradyarrhythmias Ticagrelor can cause ventricular pauses [see Adverse Reactions ( 6.1 ) ] . Bradyarrhythmias including AV block have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2 nd or 3 rd degree AV block or bradycardia-related syncope not protected by a pacemaker were excluded from PLATO and PEGASUS and may be at increased risk of developing bradyarrhythmias with ticagrelor. 5.6 Severe Hepatic Impairment Avoid use of ticagrelor tablets in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of ticagrelor tablets patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3 )]. 5.7 Laboratory Test Interferences False negative functional tests for Heparin Induced Thrombocytopenia (HIT) Ticagrelor tablets have 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 P2Y 12 -receptor on the healthy donor platelets in the test by ticagrelor in the affected patient’s serum/plasma. Information on concomitant treatment with ticagrelor tablets is required for interpretation of HIT functional tests. Based on the mechanism of ticagrelor interference, ticagrelor tablets are not expected to impact PF4 antibody testing for HIT.

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 )] Most common adverse reactions are bleeding 12% and dyspnea 14%. ( 5.1 , 5.3 , 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Ticagrelor tablets have 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) Ticagrelor 90 mg BID 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. No baseline demographic factor altered the relative risk of bleeding with ticagrelor 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) Ticagrelor 90 mg BID N=770 Clopidogrel N=814 n (%) patients with event n (%) patients with event PLATO Total Major 626 (81.3) 666 (81.8) Fatal/Life-threatening 337 (43.8) 350 (43.0) Fatal 6 (0.8) 7 (0.9) PLATO Major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (Hct) of at least 9%); transfusion of 2 or more units. PLATO Major bleed, fatal/life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in hematocrit (Hct) of at least 15%); transfusion of 4 or more units. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of ticagrelor 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 ticagrelor (PLATO) Ticagrelor 90 mg BID N=9235 Clopidogrel N=9186 Dyspnea 13.8 7.8 Dizziness 4.5 3.9 Nausea 4.3 3.8 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) Ticagrelor 60 mg BID + 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. The bleeding profile of ticagrelor 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) Ticagrelor 60 mg BID + Aspirin N=6958 Aspirin Alone N=6996 Dyspnea 14.2 5.5 Dizziness 4.5 4.1 Diarrhea 3.3 2.5 Bradycardia In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with ticagrelor (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, 2 nd or 3 rd 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 ticagrelor 90 mg and clopidogrel patients, respectively. In PEGASUS, syncope was reported by 1.2% and 0.9% of patients on ticagrelor 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 ticagrelor 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 ticagrelor 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on ticagrelor 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 ticagrelor 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 ticagrelor 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. figure1 figure2 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ticagrelor tablets. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of ticagrelor tablets. 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 ( 4.3 ) ] . Skin and subcutaneous tissue disorders: Rash

<table width="100%" border="1"><caption> Table 1 - Non-CABG related bleeds (PLATO)</caption><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule"/><td align="center" styleCode="Botrule Rrule Toprule"><paragraph><content styleCode="bold"> Ticagrelor <footnote ID="L90b00994-214a-45f3-b8e9-b07b3a7b2b04">90 mg BID</footnote></content></paragraph><paragraph><content styleCode="bold">N=9235</content></paragraph></td><td align="center" styleCode="Botrule Rrule Toprule"><paragraph><content styleCode="bold"> Clopidogrel</content></paragraph><paragraph><content styleCode="bold">N=9186</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"/><td align="center" styleCode="Botrule Rrule"><content styleCode="bold"> n (%) patients with event</content></td><td align="center" styleCode="Botrule Rrule"><content styleCode="bold"> n (%) patients with event</content></td></tr><tr><td styleCode="Botrule Lrule Rrule"> PLATO Major + Minor</td><td align="center" styleCode="Botrule Rrule"> 713 (7.7)</td><td align="center" styleCode="Botrule Rrule">567 (6.2) </td></tr><tr><td styleCode="Botrule Lrule Rrule"> Major</td><td align="center" styleCode="Botrule Rrule"> 362 (3.9)</td><td align="center" styleCode="Botrule Rrule"> 306 (3.3)</td></tr><tr><td styleCode="Botrule Lrule Rrule"> Fatal/Life-threatening </td><td align="center" styleCode="Botrule Rrule"> 171 (1.9)</td><td align="center" styleCode="Botrule Rrule"> 151 (1.6)</td></tr><tr><td styleCode="Botrule Lrule Rrule"> Fatal</td><td align="center" styleCode="Botrule Rrule"> 15 (0.2)</td><td align="center" styleCode="Botrule Rrule"> 16 (0.2)</td></tr><tr><td styleCode="Botrule Lrule Rrule"> Intracranial hemorrhage (Fatal/Life-threatening)</td><td align="center" styleCode="Botrule Rrule"> 26 (0.3)</td><td align="center" styleCode="Botrule Rrule"> 15 (0.2)</td></tr><tr><td colspan="3" styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">PLATO Minor bleed:</content>requires medical intervention to stop or treat bleeding. </paragraph><paragraph><content styleCode="bold">PLATO Major bleed:</content>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. </paragraph><paragraph><content styleCode="bold">PLATO Major bleed, fatal/life-threatening:</content>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. </paragraph><paragraph><content styleCode="bold">Fatal:</content>A bleeding event that directly led to death within 7 days. </paragraph></td></tr></tbody></table>

<table width="100%" border="1"><caption>Table 2 - CABG-related bleeding (PLATO) </caption><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule"/><td align="center" styleCode="Botrule Rrule Toprule"><paragraph><content styleCode="bold">Ticagrelor <footnote ID="Ld89748a5-a34b-49ad-892d-57ea793e14b1">90 mg BID</footnote></content></paragraph><paragraph><content styleCode="bold">N=770</content></paragraph></td><td align="center" styleCode="Botrule Rrule Toprule"><paragraph><content styleCode="bold">Clopidogrel</content></paragraph><paragraph><content styleCode="bold">N=814 </content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"/><td align="center" styleCode="Botrule Rrule"><content styleCode="bold"> n (%) patients with event</content></td><td align="center" styleCode="Botrule Lrule Rrule"><content styleCode="bold">n (%) patients with event </content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> PLATO Total Major</td><td align="center" styleCode="Botrule Rrule"> 626 (81.3)</td><td align="center" styleCode="Botrule Rrule">666 (81.8) </td></tr><tr><td styleCode="Botrule Lrule Rrule"> Fatal/Life-threatening</td><td align="center" styleCode="Botrule Rrule"> 337 (43.8)</td><td align="center" styleCode="Botrule Rrule"> 350 (43.0)</td></tr><tr><td styleCode="Botrule Lrule Rrule"> Fatal</td><td align="center" styleCode="Botrule Rrule"> 6 (0.8)</td><td align="center" styleCode="Botrule Rrule"> 7 (0.9)</td></tr><tr><td colspan="3" styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">PLATO Major bleed:</content>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. </paragraph><paragraph><content styleCode="bold">PLATO Major bleed, fatal/life-threatening:</content>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. </paragraph></td></tr></tbody></table>

<table width="100%"><caption>Table 3 - Percentage of patients reporting non-hemorrhagic adverse reactions at least 4% or more in either group and more frequently on ticagrelor (PLATO) </caption><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule"/><td align="center" styleCode="Botrule Rrule Toprule"><paragraph><content styleCode="bold">Ticagrelor <footnote ID="Lf3670cc3-e001-4efb-b838-f54afd754ef7">90 mg BID</footnote></content></paragraph><paragraph><content styleCode="bold">N=9235</content></paragraph></td><td align="center" styleCode="Botrule Rrule Toprule"><paragraph><content styleCode="bold">Clopidogrel</content></paragraph><paragraph><content styleCode="bold">N=9186 </content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule"> Dyspnea</td><td align="center" styleCode="Botrule Rrule">13.8 </td><td align="center" styleCode="Botrule Rrule"> 7.8</td></tr><tr><td styleCode="Botrule Lrule Rrule"> Dizziness</td><td align="center" styleCode="Botrule Rrule">4.5</td><td align="center" styleCode="Botrule Rrule"> 3.9</td></tr><tr><td styleCode="Botrule Lrule Rrule"> Nausea</td><td align="center" styleCode="Botrule Rrule">4.3</td><td align="center" styleCode="Botrule Rrule"> 3.8</td></tr></tbody></table>