FDA label 181a08e6-b643-2524-e063-6294a90a6bd3

5 WARNINGS AND PRECAUTIONS Eptifibatide Injection can cause serious bleeding. If bleeding cannot be controlled, discontinue Eptifibatide Injection immediately. Minimize vascular and other traumas. If heparin is given concomitantly, monitor aPTT or ACT. ( 5.1 ) Thrombocytopenia: Discontinue Eptifibatide Injection and heparin. Monitor and treat condition appropriately. ( 5.2 ) 5.1 Bleeding Bleeding is the most common complication encountered during Eptifibatide Injection therapy. Administration of Eptifibatide Injection is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction Study group (TIMI) [see Adverse Reactions (6.1) ] . Most major bleeding associated with Eptifibatide Injection has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract. Minimize the use of arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes. When obtaining intravenous access, avoid non-compressible sites (e.g., subclavian or jugular veins). Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents Risk factors for bleeding include older age, a history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y 12 inhibitors). Concomitant treatment with other inhibitors of platelet receptor glycoprotein (GP) IIb/IIIa should be avoided. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT [see Dosage and Administration (2) ] . Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous Coronary Intervention (PCI) In patients undergoing PCI, treatment with Eptifibatide Injection is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, Eptifibatide infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first. Heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while Eptifibatide Injection is being infused. Prior to removing the sheath, it is recommended that heparin be discontinued for 3 to 4 hours and an aPTT of <45 seconds or ACT <150 seconds be achieved. In any case, both heparin and eptifibatide should be discontinued and sheath hemostasis should be achieved at least 2 to 4 hours before hospital discharge. If bleeding at access site cannot be controlled with pressure, infusion of eptifibatide and heparin should be discontinued immediately. 5.2 Thrombocytopenia There have been reports of acute, profound thrombocytopenia (immune-mediated and non-immune mediated) with Eptifibatide Injection. In the event of acute profound thrombocytopenia or a confirmed platelet decrease to <100,000/mm 3 , discontinue Eptifibatide Injection and heparin (unfractionated or low-molecular weight). Monitor serial platelet counts, assess the presence of drug-dependent antibodies, and treat as appropriate [see Adverse Reactions (6.1) ] . There has been no clinical experience with Eptifibatide Injection initiated in patients with a baseline platelet count <100,000/mm 3 . If a patient with low platelet counts is receiving Eptifibatide Injection, their platelet count should be monitored closely.

6 ADVERSE REACTIONS The following serious adverse reaction is also discussed elsewhere in the labeling: Bleeding [see Contraindications (4) and Warnings and Precautions (5.1) ] Bleeding and hypotension are the most commonly reported adverse reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 16,782 patients were treated in the Phase III clinical trials (PURSUET, ESPRET, and EMPACT II) [see Clinical Studies (14) ] . These 16,782 patients had a mean age of 62 years (range: 20-94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUET, EMPACT II, and ESPRET, data from the 3 studies were not pooled. Bleeding and hypotension were the most commonly reported adverse reactions (incidence ≥5% and greater than placebo) in the Eptifibatide Injection controlled clinical trial database. Bleeding The incidence of bleeding and transfusions in the PURSUET and ESPRET studies are shown in Table 2. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al. Table 2: Bleeding and Transfusions in the PURSUET and ESPRET Studies PURSUET (ACS) Placebo Eptifibatide Injection 180/2 n (%) n (%) Note: Denominator is based on patients for whom data are available. Patients 4696 4679 Major bleeding For major and minor bleeding, patients are counted only once according to the most severe classification. 425 (9.3%) 498 (10.8%) Minor bleeding 347 (7.6%) 604 (13.1%) Requiring transfusions Includes transfusions of whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization. 490 (10.4%) 601 (12.8%) ESPRET (PCI) Placebo Eptifibatide Injection 180/2/180 n (%) n (%) Patients 1024 1040 Major bleeding 4 (0.4%) 13 (1.3%) Minor bleeding 18 (2%) 29 (3%) Requiring transfusions 11 (1.1%) 16 (1.5%) The majority of major bleeding reactions in the ESPRET study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and Eptifibatide Injection groups, respectively). Bleeding at "other" locations occurred in 0.2% and 0.4% of patients, respectively. In the PURSUET study, the greatest increase in major bleeding in Eptifibatide Injection-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% versus 1.3%). Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in Eptifibatide Injection-treated patients compared to placebo-treated patients. Among patients experiencing a major bleed in the EMPACT II study, an increase in bleeding on Eptifibatide Injection versus placebo was observed only for the femoral artery access site (3.2% versus 2.8%). Table 3 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUET study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRET is not presented, as every patient underwent PCI in the ESPRET study and only 11 patients underwent CABG. Table 3: Major Bleeding by Procedures in the PURSUET Study Placebo Eptifibatide Injection 180/2 n (%) n (%) Note: Denominators are based on the total number of patients whose TIMI classification was resolved. Patients 4577 4604 Overall incidence of major bleeding 425 (9.3%) 498 (10.8%) Breakdown by procedure: CABG 375 (8.2%) 377 (8.2%) Angioplasty without CABG 27 (0.6%) 64 (1.4%) Angiography without angioplasty or CABG 11 (0.2%) 29 (0.6%) Medical therapy only 12 (0.3%) 28 (0.6%) In the PURSUET and ESPRET studies, the risk of major bleeding with Eptifibatide Injection increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg. Bleeding resulting in discontinuation of the study drug was more frequent among patients receiving Eptifibatide Injection than placebo (4.6% versus 0.9% in ESPRET, 8% versus 1% in PURSUET, 3.5% versus 1.9% in EMPACT II). Intracranial Hemorrhage and Stroke Intracranial hemorrhage was rare in the PURSUET, EMPACT II, and ESPRET clinical studies. In the PURSUET study, 3 patients in the placebo group, 1 patient in the group treated with Eptifibatide Injection 180/1.3, and 5 patients in the group treated with Eptifibatide Injection 180/2 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving Eptifibatide Injection 180/1.3, 0.7% in patients receiving Eptifibatide Injection 180/2, and 0.8% in placebo patients. In the EMPACT II study, intracranial hemorrhage was experienced by 1 patient treated with Eptifibatide Injection 135/0.5, 2 patients treated with Eptifibatide Injection 135/0.75, and 2 patients in the placebo group. The overall incidence of stroke was 0.5% in patients receiving 135/0.5 Eptifibatide Injection, 0.7% in patients receiving Eptifibatide Injection 135/0.75, and 0.7% in the placebo group. In the ESPRET study, there were 3 hemorrhagic strokes, 1 in the placebo group and 2 in the Eptifibatide Injection group. In addition there was 1 case of cerebral infarction in the Eptifibatide Injection group. Immunogenicity/Thrombocytopenia The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide Injection was nonantigenic in 412 patients receiving a single administration of Eptifibatide Injection (135-mcg/kg bolus followed by a continuous infusion of either 0.5 mcg/kg/min or 0.75 mcg/kg/min), and in 21 subjects to whom Eptifibatide Injection (135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to eptifibatide at higher doses has not been evaluated. In patients with suspected Eptifibatide Injection-related immune-mediated thrombocytopenia, IgG antibodies that react with the GP IIb/IIIa complex were identified in the presence of eptifibatide and in Eptifibatide Injection-naïve patients. These findings suggest acute thrombocytopenia after the administration of Eptifibatide Injection can develop as a result of naturally occurring drug-dependent antibodies or those induced by prior exposure to Eptifibatide Injection. Similar antibodies were identified with other GP IIb/IIIa ligand-mimetic agents. Immune-mediated thrombocytopenia with Eptifibatide Injection may be associated with hypotension and/or other signs of hypersensitivity. In the PURSUET and EMPACT II studies, the incidence of thrombocytopenia (<100,000/mm 3 or ≥50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with Eptifibatide Injection and placebo. In the ESPRET study, the incidence was 0.6% in the placebo group and 1.2% in the Eptifibatide Injection group. Other Adverse Reactions In the PURSUET and ESPRET studies, the incidence of serious nonbleeding adverse reactions was similar in patients receiving placebo or Eptifibatide Injection (19% and 19%, respectively, in PURSUET; 6% and 7%, respectively, in ESPRET). In PURSUET, the only serious nonbleeding adverse reaction that occurred at a rate of at least 1% and was more common with Eptifibatide Injection than placebo (7% versus 6%) was hypotension. Most of the serious nonbleeding adverse reactions consisted of cardiovascular reactions typical of a UA population. In the EMPACT II study, serious nonbleeding adverse reactions that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and Eptifibatide Injection-treated patients. Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUET, EMPACT II, and ESPRET studies, with no single reaction occurring in >0.5% of the study population (except for "other" in the ESPRET study). 6.2 Postmarketing Experience The following adverse reactions have been reported in post-approval use of Eptifibatide Injection in combination with heparin and aspirin. Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: cerebral, GI, and pulmonary hemorrhage. Fatal bleeding reactions have been reported. Acute profound thrombocytopenia, as well as immune-mediated thrombocytopenia, have been reported [see Adverse Reactions (6.1) ] .

<table width="80%" ID="table2"><caption>Table 2: Bleeding and Transfusions in the PURSUET and ESPRET Studies</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th colspan="3" align="center" styleCode="Lrule Botrule Rrule">PURSUET (ACS)</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Lrule Toprule Rrule">Placebo</th><th styleCode="Lrule Toprule Rrule">Eptifibatide Injection 180/2 </th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Lrule Rrule">n (%)</th><th styleCode="Lrule Rrule">n (%)</th></tr></thead><tfoot><tr><td colspan="3" align="left">Note: Denominator is based on patients for whom data are available.</td></tr></tfoot><tbody><tr><td styleCode="Lrule Rrule">Patients</td><td styleCode="Lrule Rrule">4696</td><td styleCode="Lrule Rrule">4679</td></tr><tr><td styleCode="Lrule Rrule">Major bleeding <footnote ID="table2a">For major and minor bleeding, patients are counted only once according to the most severe classification.</footnote></td><td styleCode="Lrule Rrule">425 (9.3%)</td><td styleCode="Lrule Rrule">498 (10.8%)</td></tr><tr><td styleCode="Lrule Rrule">Minor bleeding <footnoteRef IDREF="table2a"/></td><td styleCode="Lrule Rrule">347 (7.6%)</td><td styleCode="Lrule Rrule">604 (13.1%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Botrule Rrule">Requiring transfusions <footnote ID="table2b">Includes transfusions of whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization.</footnote></td><td styleCode="Lrule Rrule">490 (10.4%)</td><td styleCode="Lrule Rrule">601 (12.8%)</td></tr><tr><td colspan="3" align="center" styleCode="Lrule Botrule Rrule"><content styleCode="bold">ESPRET (PCI)</content></td></tr><tr><td styleCode="Lrule Rrule"/><td styleCode="Lrule Rrule"><content styleCode="bold">Placebo</content></td><td styleCode="Lrule Rrule"><content styleCode="bold"> Eptifibatide Injection </content> <content styleCode="bold">180/2/180</content></td></tr><tr styleCode="Lrule Rrule"><td styleCode="Lrule Rrule"/><td styleCode="Lrule Rrule"><content styleCode="bold">n (%)</content></td><td styleCode="Lrule Botrule Rrule"><content styleCode="bold">n (%)</content></td></tr><tr><td styleCode="Lrule Toprule Rrule">Patients</td><td styleCode="Lrule Toprule Rrule">1024</td><td styleCode="Lrule Rrule">1040</td></tr><tr><td styleCode="Lrule Rrule">Major bleeding <footnoteRef IDREF="table2a"/></td><td styleCode="Lrule Rrule">4 (0.4%)</td><td styleCode="Lrule Rrule">13 (1.3%)</td></tr><tr><td styleCode="Lrule Rrule">Minor bleeding <footnoteRef IDREF="table2a"/></td><td styleCode="Lrule Rrule">18 (2%)</td><td styleCode="Lrule Rrule">29 (3%)</td></tr><tr><td styleCode="Lrule Rrule">Requiring transfusions <footnoteRef IDREF="table2b"/></td><td styleCode="Lrule Rrule">11 (1.1%)</td><td styleCode="Lrule Botrule Rrule">16 (1.5%)</td></tr></tbody></table>

<table width="80%" ID="table3"><caption>Table 3: Major Bleeding by Procedures in the PURSUET Study</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Lrule Rrule">Placebo</th><th styleCode="Lrule Rrule">Eptifibatide Injection</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Lrule Rrule"/><th styleCode="Lrule Rrule">180/2</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Lrule Rrule">n (%)</th><th styleCode="Lrule Botrule Rrule">n (%)</th></tr></thead><tfoot><tr><td colspan="3" align="left">Note: Denominators are based on the total number of patients whose TIMI classification was resolved.</td></tr></tfoot><tbody><tr><td styleCode="Lrule Botrule Rrule">Patients</td><td styleCode="Lrule Botrule Rrule">4577</td><td styleCode="Lrule Botrule Rrule">4604</td></tr><tr><td styleCode="Lrule Botrule Rrule">Overall incidence of major bleeding</td><td styleCode="Lrule Botrule Rrule">425 (9.3%)</td><td styleCode="Lrule Botrule Rrule">498 (10.8%)</td></tr><tr><td styleCode="Lrule Rrule">Breakdown by procedure:</td><td styleCode=" Rrule"/><td styleCode="Lrule Rrule"/></tr><tr><td styleCode="Lrule"> CABG</td><td styleCode="Lrule"> 375 (8.2%)</td><td styleCode="Rrule Lrule"> 377 (8.2%)</td></tr><tr><td styleCode="Lrule"> Angioplasty without CABG</td><td styleCode="Lrule"> 27 (0.6%)</td><td styleCode="Lrule Rrule"> 64 (1.4%)</td></tr><tr><td styleCode="Lrule"> Angiography without angioplasty or CABG</td><td styleCode="Lrule"> 11 (0.2%)</td><td styleCode="Lrule Rrule"> 29 (0.6%)</td></tr><tr><td styleCode="Lrule Rrule"> Medical therapy only</td><td styleCode="Lrule"> 12 (0.3%)</td><td styleCode="Lrule Rrule"> 28 (0.6%)</td></tr></tbody></table>