Eptifibatide

1 INDICATIONS AND USAGE Eptifibatide injection is a platelet aggregation inhibitor indicated for: Treatment of acute coronary syndrome (ACS) managed medically or with percutaneous coronary intervention (PCI) (1.1) Treatment of patients undergoing PCI (including intracoronary stenting) (1.2) 1.1 Acute Coronary Syndrome (ACS) Eptifibatide injection is indicated to decrease the rate of a combined endpoint of death or new myocardial infarction (MI) in patients with ACS (unstable angina [UA]/non-ST-elevation myocardial infarction [NSTEMI]), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI). 1.2 Percutaneous Coronary Intervention (PCI) Eptifibatide injection is indicated to decrease the rate of a combined endpoint of death, new MI, or need for urgent intervention in patients undergoing PCI, including those undergoing intracoronary stenting [see Clinical Studies (14.1, 14.2) ] .

2 DOSAGE AND ADMINISTRATION Before infusion of eptifibatide, the following laboratory tests should be performed to identify pre-existing hemostatic abnormalities: hematocrit or hemoglobin, platelet count, serum creatinine, and PT/aPTT. In patients undergoing PCI, the activated clotting time (ACT) should also be measured. The activated partial thromboplastin time (aPTT) should be maintained between 50 and 70 seconds unless PCI is to be performed. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT. ACS or PCI: 180 mcg/kg I.V. bolus as soon as possible after diagnosis followed by infusion at 2 mcg/kg/min. (2.1 , 2.2) PCI: Add a second 180 mcg/kg bolus at 10 minutes. (2.2) In patients with creatinine clearance less than 50 mL/min, reduce the infusion to 1 mcg/kg/min. ( 2.1 , 2.2 , 2.3 ) 2.1 Dosage in Acute Coronary Syndrome (ACS) Indication Normal Renal Function Creatinine Clearance less than 50 mL/min Patients with ACS 180 mcg/kg intravenous (I.V.) bolus as soon as possible after diagnosis, followed by continuous infusion of 2 mcg/kg/min 180 mcg/kg I.V. bolus as soon as possible after diagnosis, followed by continuous infusion of 1 mcg/kg/min Infusion should continue until hospital discharge or initiation of coronary artery bypass graft surgery (CABG), up to 72 hours If a patient is to undergo PCI, the infusion should be continued until hospital discharge or for up to 18 to 24 hours after the procedure, whichever comes first, allowing for up to 96 hours of therapy Aspirin, 160 to 325 mg, should be given daily Eptifibatide injection should be given concomitantly with heparin dosed to achieve the following parameters: During Medical Management : Target aPTT 50 to 70 seconds If weight greater than or equal to 70 kg, 5,000 units bolus followed by infusion of 1,000 units/h. If weight less than 70 kg, 60 units/kg bolus followed by infusion of 12 units/kg/h. During PCI : Target ACT 200 to 300 seconds If heparin is initiated prior to PCI, additional boluses during PCI to maintain an ACT target of 200 to 300 seconds. Heparin infusion after the PCI is discouraged. 2.2 Dosage in Percutaneous Coronary Intervention (PCI) Indication Normal Renal Function Creatinine Clearance less than 50 mL/min Patients with PCI 180 mcg/kg I.V. bolus immediately before PCI followed by continuous infusion of 2 mcg/kg/min and a second bolus of 180 mcg/kg (given 10 minutes after the first bolus) 180 mcg/kg I.V. bolus immediately before PCI followed by continuous infusion of 1 mcg/kg/min and a second bolus of 180 mcg/kg (given 10 minutes after the first bolus) Infusion should be continued until hospital discharge, or for up to 18 to 24 hours, whichever comes first. A minimum of 12 hours of infusion is recommended. In patients who undergo CABG surgery, eptifibatide infusion should be discontinued prior to surgery. Aspirin, 160 to 325 mg, should be given 1 to 24 hours prior to PCI and daily thereafter. Eptifibatide injection should be given concomitantly with heparin to achieve a target ACT of 200 to 300 seconds. Administer 60 units/kg bolus initially in patients not treated with heparin within 6 hours prior to PCI. Additional boluses during PCI to maintain ACT within target. Heparin infusion after the PCI is strongly discouraged. Patients requiring thrombolytic therapy should discontinue eptifibatide injection. 2.3 Important Administration Instructions Inspect eptifibatide injection for particulate matter and discoloration prior to administration, whenever solution and container permit. May administer eptifibatide injection in the same intravenous line as alteplase, atropine, dobutamine, heparin, lidocaine, meperidine, metoprolol, midazolam, morphine, nitroglycerin, or verapamil. Do not administer eptifibatide injection through the same intravenous line as furosemide. May administer eptifibatide injection in the same I.V. line with 0.9% NaCl or 0.9% NaCl/5% dextrose. With either vehicle, the infusion may also contain up to 60 mEq/L of potassium chloride. Withdraw the bolus dose(s) of eptifibatide injection from the 10 mL vial into a syringe. Administer the bolus dose(s) by I.V. push. Immediately following the bolus dose administration, initiate a continuous infusion of eptifibatide. When using an intravenous infusion pump, administer eptifibatide injection undiluted directly from the 100 mL vial. Spike the 100 mL vial with a vented infusion set. Center the spike within the circle on the stopper top. Discard any unused portion left in the vial. Administer eptifibatide injection by volume according to patient weight (see Table 1). Table 1: Eptifibatide Injection Dosing Charts by Weight Patient Weight 180 mcg/kg Bolus Volume 2 mcg/kg/min Infusion Volume (CrCl greater than or equal to 50 mL/min) 1 mcg/kg/min Infusion Volume (CrCl less than 50 mL/min) (kg) (lb) (from 2 mg/mL vial) (from 2 mg/mL 100 mL vial) (from 0.75 mg/mL 100 mL vial) (from 2 mg/mL 100 mL vial) (from 0.75 mg/mL 100 mL vial) 37 to 41 81 to 91 3.4 mL 2 mL/h 6 mL/h 1 mL/h 3 mL/h 42 to 46 92 to 102 4 mL 2.5 mL/h 7 mL/h 1.3 mL/h 3.5 mL/h 47 to 53 103 to 117 4.5 mL 3 mL/h 8 mL/h 1.5 mL/h 4 mL/h 54 to 59 118 to 130 5 mL 3.5 mL/h 9 mL/h 1.8 mL/h 4.5 mL/h 60 to 65 131 to 143 5.6 mL 3.8 mL/h 10 mL/h 1.9 mL/h 5 mL/h 66 to 71 144 to 157 6.2 mL 4 mL/h 11 mL/h 2 mL/h 5.5 mL/h 72 to 78 158 to 172 6.8 mL 4.5 mL/h 12 mL/h 2.3 mL/h 6 mL/h 79 to 84 173 to 185 7.3 mL 5 mL/h 13 mL/h 2.5 mL/h 6.5 mL/h 85 to 90 186 to 198 7.9 mL 5.3 mL/h 14 mL/h 2.7 mL/h 7 mL/h 91 to 96 199 to 212 8.5 mL 5.6 mL/h 15 mL/h 2.8 mL/h 7.5 mL/h 97 to 103 213 to 227 9 mL 6 mL/h 16 mL/h 3 mL/h 8 mL/h 104 to 109 228 to 240 9.5 mL 6.4 mL/h 17 mL/h 3.2 mL/h 8.5 mL/h 110 to 115 241 to 253 10.2 mL 6.8 mL/h 18 mL/h 3.4 mL/h 9 mL/h 116 to 121 254 to 267 10.7 mL 7 mL/h 19 mL/h 3.5 mL/h 9.5 mL/h >121 >267 11.3 mL 7.5 mL/h 20 mL/h 3.7 mL/h 10 mL/h

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 Eugia US LLC at 1-866-850-2876 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 to 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. * For major and minor bleeding, patients are counted only once according to the most severe classification. † Includes transfusions of whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization. PURSUIT (ACS) Placebo n (%) Eptifibatide 180/2 n (%) Patients 4696 4679 Major bleeding * 425 (9.3%) 498 (10.8%) Minor bleeding * 347 (7.6%) 604 (13.1%) Requiring transfusions † 490 (10.4%) 601 (12.8%) ESPRIT (PCI) Placebo n (%) Eptifibatide 180/2/180 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 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 Note: Denominators are based on the total number of patients whose TIMI classification was resolved. Placebo n (%) Eptifibatide 180/2 n (%) 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 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 (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) ] .

7 DRUG INTERACTIONS Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. Avoid concomitant use with other glycoprotein (GP) IIb/IIIa inhibitors. (7.1) 7.1 Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. Concomitant treatment with other inhibitors of platelet receptor GP IIb/IIIa should be avoided.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Eptifibatide injection is a clear, colorless, sterile, non-pyrogenic solution free from visible particles and is supplied as follows: 75 mg per 100 mL (0.75 mg / mL) 100 mL Single-Dose Vials, packaged individually NDC 55150-218-99 20 mg per 10 mL (2 mg / mL) 10 mL Single-Dose Vials, packaged individually NDC 55150-219-10 200 mg per 100 mL (2 mg / mL) 100 mL Single-Dose Vials, packaged individually NDC 55150-220-99 16.2 Storage Vials should be stored refrigerated at 2° to 8°C (36° to 46°F). Vials may be transferred to room temperature storage* for a period not to exceed 2 months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with a "DISCARD BY" date (2 months from the transfer date or the labeled expiration date, whichever comes first). * Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light until administration. The vial stoppers are not made with natural rubber latex.