Eptifibatide

5 WARNINGS AND PRECAUTIONS • Eptifibatide can cause serious bleeding. If bleeding cannot be controlled, discontinue eptifibatide immediately. Minimize vascular and other traumas. If heparin is given concomitantly, monitor aPTT or ACT. (5.1) • Thrombocytopenia: Discontinue eptifibatide and heparin. Monitor and treat condition appropriately. (5.2) 5.1 Bleeding Bleeding is the most common complication encountered during eptifibatide therapy. Administration of eptifibatide 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 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 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 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. In the event of acute profound thrombocytopenia or a confirmed platelet decrease to <100,000/mm 3 , discontinue eptifibatide 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 initiated in patients with a baseline platelet count <100,000/mm 3 . If a patient with low platelet counts is receiving eptifibatide, 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 Baxter Healthcare at 1-866-888-2472 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 (PURSUIT, ESPRIT, and IMPACT 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 PURSUIT, IMPACT II, and ESPRIT, 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 controlled clinical trial database. Bleeding The incidence of bleeding and transfusions in the PURSUIT and ESPRIT 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 PURSUIT and ESPRIT Studies Note: Denominator is based on patients for whom data are available. PURSUIT (ACS) Placebo n (%) Eptifibatide 180/2 n (%) Patients Major bleeding For major and minor bleeding, patients are counted only once according to the most severe classification. Minor bleeding Requiring transfusions Includes transfusions of whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization. 4696 425 (9.3%) 347 (7.6%) 490 (10.4%) 4679 498 (10.8%) 604 (13.1%) 601 (12.8%) ESPRIT (PCI) Placebo n (%) Eptifibatide 180/2/180 n (%) Patients Major bleeding Minor bleeding Requiring transfusions 1024 4 (0.4%) 18 (2%) 11 (1.1%) 1040 13 (1.3%) 29 (3%) 16 (1.5%) The majority of major bleeding reactions in the ESPRIT study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and eptifibatide groups, respectively). Bleeding at “other” locations occurred in 0.2% and 0.4% of patients, respectively. In the PURSUIT study, the greatest increase in major bleeding in eptifibatide-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-treated patients compared to placebo-treated patients. Among patients experiencing a major bleed in the IMPACT II study, an increase in bleeding on eptifibatide 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 PURSUIT study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRIT is not presented, as every patient underwent PCI in the ESPRIT study and only 11 patients underwent CABG. Table 3: Major Bleeding by Procedures in the PURSUIT Study Placebo n (%) Eptifibatide 180/2 n (%) Patients Overall incidence of major bleeding Breakdown by procedure: CABG Angioplasty without CABG Angiography without angioplasty or CABG Medical therapy only 4577 425 (9.3%) 375 (8.2%) 27 (0.6%) 11 (0.2%) 12 (0.3%) 4604 498 (10.8%) 377 (8.2%) 64 (1.4%) 29 (0.6%) 28 (0.6%) Note: Denominators are based on the total number of patients whose TIMI classification was resolved. In the PURSUIT and ESPRIT studies, the risk of major bleeding with eptifibatide 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 than placebo (4.6% versus 0.9% in ESPRIT, 8% versus 1% in PURSUIT, 3.5% versus 1.9% in IMPACT II). Intracranial Hemorrhage and Stroke Intracranial hemorrhage was rare in the PURSUIT, IMPACT II, and ESPRIT clinical studies. In the PURSUIT study, 3 patients in the placebo group, 1 patient in the group treated with eptifibatide 180/1.3, and 5 patients in the group treated with eptifibatide 180/2 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving eptifibatide 180/1.3, 0.7% in patients receiving eptifibatide 180/2, and 0.8% in placebo patients. In the IMPACT II study, intracranial hemorrhage was experienced by 1 patient treated with eptifibatide 135/0.5, 2 patients treated with eptifibatide 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, 0.7% in patients receiving eptifibatide 135/0.75, and 0.7% in the placebo group. In the ESPRIT study, there were 3 hemorrhagic strokes, 1 in the placebo group and 2 in the eptifibatide group. In addition there was 1 case of cerebral infarction in the eptifibatide group. Immunogenicity/Thrombocytopenia The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide was nonantigenic in 412 patients receiving a single administration of eptifibatide (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 (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-related immune-mediated thrombocytopenia, IgG antibodies that react with the GP IIb/IIIa complex were identified in the presence of eptifibatide and in eptifibatide-naïve patients. These findings suggest acute thrombocytopenia after the administration of eptifibatide can develop as a result of naturally occurring drug-dependent antibodies or those induced by prior exposure to eptifibatide. Similar antibodies were identified with other GP IIb/IIIa ligand-mimetic agents. Immune-mediated thrombocytopenia with eptifibatide may be associated with hypotension and/or other signs of hypersensitivity. In the PURSUIT and IMPACT 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 and placebo. In the ESPRIT study, the incidence was 0.6% in the placebo group and 1.2% in the eptifibatide group. Other Adverse Reactions In the PURSUIT and ESPRIT studies, the incidence of serious nonbleeding adverse reactions was similar in patients receiving placebo or eptifibatide (19% and 19%, respectively, in PURSUIT; 6% and 7%, respectively, in ESPRIT). In PURSUIT, the only serious nonbleeding adverse reaction that occurred at a rate of at least 1% and was more common with eptifibatide 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 IMPACT II study, serious nonbleeding adverse reactions that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo and eptifibatide-treated patients. Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUIT, IMPACT II, and ESPRIT studies, with no single reaction occurring in >0.5% of the study population (except for “other” in the ESPRIT study). 6.2 Postmarketing Experience The following adverse reactions have been reported in post-approval use of eptifibatide 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 cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 2: Bleeding and Transfusions in the PURSUIT and ESPRIT Studies</caption><col width="33%"/><col width="33%"/><col width="33%"/><tfoot><tr><td align="left" colspan="3" valign="top">Note: Denominator is based on patients for whom data are available.</td></tr></tfoot><tbody><tr styleCode="Toprule"><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">PURSUIT (ACS)</content> <content styleCode="bold">Placebo</content> <content styleCode="bold">n (%)</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Eptifibatide</content> <content styleCode="bold">180/2</content> <content styleCode="bold">n (%)</content> </paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph> Patients Major bleeding<footnote ID="_Ref534615054">For major and minor bleeding, patients are counted only once according to the most severe classification.</footnote> Minor bleeding<footnoteRef IDREF="_Ref534615054"/> Requiring transfusions<footnote ID="_Ref534615166">Includes transfusions of whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization.</footnote> </paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>4696 425 (9.3%) 347 (7.6%) 490 (10.4%) </paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>4679 498 (10.8%) 604 (13.1%) 601 (12.8%)</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph><content styleCode="bold">ESPRIT (PCI) Placebo n (%)</content></paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Eptifibatide</content> <content styleCode="bold">180/2/180</content> <content styleCode="bold">n (%)</content></paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule Lrule " valign="top"><paragraph> Patients Major bleeding<footnoteRef IDREF="_Ref534615054"/><sup/> Minor bleeding<footnoteRef IDREF="_Ref534615054"/><sup/> Requiring transfusions<footnoteRef IDREF="_Ref534615166"/> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1024 4 (0.4%) 18 (2%) 11 (1.1%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1040 13 (1.3%) 29 (3%) 16 (1.5%) </paragraph></td></tr></tbody></table>

<table cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 3: Major Bleeding by Procedures in the PURSUIT Study</caption><col width="59%"/><col width="18%"/><col width="23%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo n (%)</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Eptifibatide</content> <content styleCode="bold">180/2</content> <content styleCode="bold">n (%)</content> </paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Patients Overall incidence of major bleeding</paragraph><paragraph> Breakdown by procedure: CABG Angioplasty without CABG Angiography without angioplasty or CABG Medical therapy only</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>4577 425 (9.3%)</paragraph><paragraph> 375 (8.2%) 27 (0.6%) 11 (0.2%) 12 (0.3%)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>4604 498 (10.8%)</paragraph><paragraph> 377 (8.2%) 64 (1.4%) 29 (0.6%) 28 (0.6%)</paragraph></td></tr><tr><td colspan="3" styleCode="Botrule Toprule " valign="middle"><paragraph>Note: Denominators are based on the total number of patients whose TIMI classification was resolved.</paragraph></td></tr></tbody></table>