ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reaction is also discussed elsewhere in the labeling:oBleeding [see Contraindications (4) and Warnings and Precautions (5.1) . oBleeding [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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. total of 16,782 patients were treated in the Phase III clinical trials (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Eptifibatide Therapy (PURSUET), Enhanced Suppression of the Platelet IIb/IIIa Receptor with Eptifibatide Therapy (ESPRET), and Eptifibatide to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II (EMPACT II)) [see Clinical Studies (14)]. These 16,782 patients had 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 PURSUET, EMPACT II, and ESPRET, data from the 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 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 g/dL. Minor bleeding included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with hemoglobin decrease of more than g/dL, and other hemoglobin decreases that were greater than g/dL but less than 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)Placebon (%)Eptifibatide Injection 180/2n (%)Patients46964679Major bleedingMinor bleedingRequiring transfusions+ 425 (9.3%)347 (7.6%)490 (10.4%)498 (10.8%) 604 (13.1%) 601 (12.8%)ESPRET (PCI) Placebo (%)Eptifibatide Injection 180/2/180n (%)Patients10241040Major bleedingMinor bleedingRequiring transfusions+ (0.4%)18 (2%)11 (1.1%)13 (1.3%)29 (3%)16 (1.5%)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.The majority of major bleeding reactions in the ESPRET study occurred at the vascular access site (1 and 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 PURSUET 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 major bleed in the EMPACT 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 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). 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 StudyPlacebon (%)Eptifibatide 180/2n (%)Patients 45774604Overall 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%)Note: Denominators are based on the total number of patients whose TIMI classification was resolved.In the PURSUET and ESPRET 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 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, patients in the placebo group, patient in the group treated with eptifibatide 180/1.3, and patients in the group treated with eptifibatide 180/2 experienced 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 EMPACT II study, intracranial hemorrhage was experienced by patient treated with eptifibatide 135/0.5, patients treated with eptifibatide 135/0.75, and 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 ESPRET study, there were hemorrhagic strokes, in the placebo group and in the eptifibatide group. In addition there was 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 single administration of eptifibatide (135 mcg/kg bolus followed by 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 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 injection-naive patients. These findings suggest acute thrombocytopenia after the administration of eptifibatide can develop as 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 PURSUET and EMPACT II studies, the incidence of thrombocytopenia (<100,000/mm3 or >=50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with eptifibatide and placebo. In the ESPRET study, the incidence was 0.6% in the placebo group and 1.2% in the eptifibatide 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 (19% and 19%, respectively, in PURSUET; 6% and 7%, respectively, in ESPRET). In PURSUET, the only serious nonbleeding adverse reaction that occurred at 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 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-treated patients. Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUET, EMPACT II, and ESPRIT studies, with no single reaction occurring in >0.5% of the study population (except for other in the ESPRET study).. CABG Angioplasty without CABG Angiography without angioplasty or CABG Medical therapy only 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 population of uncertain size, it is generally not possible to reliably estimate their frequency or establish 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)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term studies in animals have been performed to evaluate the carcinogenic potential of eptifibatide. Eptifibatide was not genotoxic in the Ames test, the mouse lymphoma cell (L 5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Administered by continuous intravenous infusion at total daily doses up to 72 mg/kg/day (about times the recommended maximum daily human dose on body surface area basis), eptifibatide had no effect on fertility and reproductive performance of male and female rats.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet.. 12.2 Pharmacodynamics. Infusion of eptifibatide into baboons caused dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than mcg/kg/min. In baboon model that is refractory to aspirin and heparin, doses of eptifibatide that inhibit aggregation prevented acute thrombosis with only modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatide, with complete inhibition at mcg/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model). Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with UA or NSTEMI and/or undergoing percutaneous coronary intervention. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, eptifibatide inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in dose- and concentration-dependent manner. The effect of eptifibatide was observed immediately after administration of 180 mcg/kg intravenous bolus. Table shows the effects of dosing regimens of eptifibatide used in the EMPACT II and PURSUET studies on ex vivo platelet aggregation induced by 20 micromolar ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRET on platelet aggregation have not been studied. Table 4: Platelet Inhibition and Bleeding TimePURSUET 180/2Inhibition of platelet aggregation 15 min after bolus 84%Inhibition of platelet aggregation at steady state>90%Bleeding-time prolongation at steady state<5xInhibition of platelet aggregation 4h after infusion discontinuation<50%Bleeding-time prolongation 6h after infusion discontinuation 1.4x180 mcg/kg bolus followed by continuous infusion of mcg/kg/min.The eptifibatide dosing regimen used in the ESPRET study included two 180 mcg/kg bolus doses given 10 minutes apart combined with continuous mcg/kg/min infusion. When administered alone, eptifibatide has no measurable effect on PT or aPTT. There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.. 12.3 Pharmacokinetics. The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to mcg/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of single 180 mcg/kg bolus combined with an infusion produces an early peak level, followed by small decline prior to attaining steady state (within to hours). This decline can be prevented by administering second 180 mcg/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma. Special Populations Geriatric Patients in clinical studies were older (range: 20 to 94 years) than those in the clinical pharmacology studies. Elderly patients with coronary artery disease demonstrated higher plasma levels and lower total body clearance of eptifibatide when given the same dose as younger patients. Limited data are available on lighter weight (<50 kg) patients over 75 years of age. Renal Impairment In patients with moderate to severe renal insufficiency (CrCl <50 mL/min using the Cockcroft-Gault equation), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels approximately doubled [see Use in Specific Populations (8.6) and Dosage and Administration (2)].Hepatic Impairment No studies have been conducted in patients with hepatic impairment. Gender Males and females have not demonstrated any clinically significant differences in the pharmacokinetics of eptifibatide.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Eptifibatide was studied in placebo-controlled, randomized studies. PURSUET evaluated patients with acute coronary syndromes: UA or NSTEMI. Two other studies, ESPRET and EMPACT II, evaluated patients about to undergo PCI. Patients underwent primarily balloon angioplasty in EMPACT II and intracoronary stent placement, with or without angioplasty, in ESPRET. 14.1 Non-ST-Segment Elevation Acute Coronary Syndrome. Non-ST-segment elevation acute coronary syndrome is defined as prolonged (>=10 minutes) symptoms of cardiac ischemia within the previous 24 hours associated with either ST-segment changes (elevations between 0.6 mm and mm or depression >0.5 mm), T-wave inversion (>1 mm), or positive CK-MB. This definition includes unstable angina and NSTEMI but excludes MI that is associated with waves or greater degrees of ST-segment elevation. PURSUET (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Eptifibatide Therapy) PURSUET was 726-center, 27-country, double-blind, randomized, placebo-controlled study in 10,948 patients presenting with UA or NSTEMI. Patients could be enrolled only if they had experienced cardiac ischemia at rest (>=10 minutes) within the previous 24 hours and had either ST-segment changes (elevations between 0.6 mm and mm or depression >0.5 mm), T-wave inversion (>1 mm), or increased CK-MB. Important exclusion criteria included history of bleeding diathesis, evidence of abnormal bleeding within the previous 30 days, uncontrolled hypertension, major surgery within the previous weeks, stroke within the previous 30 days, any history of hemorrhagic stroke, serum creatinine >2 mg/dL, dependency on renal dialysis, or platelet count <100,000/mm3. Patients were randomized to placebo, to eptifibatide 180 mcg/kg bolus followed by 2 mcg/kg/min infusion (180/2), or to eptifibatide 180 mcg/kg bolus followed by 1.3 mcg/kg/min infusion (180/1.3). The infusion was continued for 72 hours, until hospital discharge, or until the time of CABG, whichever occurred first, except that if PCI was performed, the eptifibatide infusion was continued for 24 hours after the procedure, allowing for duration of infusion up to 96 hours. The lower-infusion-rate arm was stopped after the first interim analysis when the active-treatment arms appeared to have the same incidence of bleeding.Patient age ranged from 20 to 94 (mean 63) years, and 65% were male. The patients were 89% Caucasian, 6% Hispanic, and 5% Black, recruited in the United States and Canada (40%), Western Europe (39%), Eastern Europe (16%), and Latin America (5%). This was real world study; each patient was managed according to the usual standards of the investigational site; frequencies of angiography, PCI, and CABG therefore differed widely from site to site and from country to country. Of the patients in PURSUET, 13% were managed with PCI during drug infusion, of whom 50% received intracoronary stents; 87% were managed medically (without PCI during drug infusion). The majority of patients received aspirin (75 to 325 mg once daily). Heparin was administered intravenously or subcutaneously, at the physicians discretion, most commonly as an intravenous bolus of 5000 units followed by continuous infusion of 1000 units/h. For patients weighing less than 70 kg, the recommended heparin bolus dose was 60 units/kg followed by continuous infusion of 12 units/kg/h. target aPTT of 50 to 70 seconds was recommended. total of 1250 patients underwent PCI within 72 hours after randomization, in which case they received intravenous heparin to maintain an ACT of 300 to 350 seconds. The primary endpoint of the study was the occurrence of death from any cause or new MI (evaluated by blinded Clinical Endpoints Committee) within 30 days of randomization. Compared to placebo, eptifibatide administered as 180 mcg/kg bolus followed by 2 mcg/kg/min infusion significantly (p=0.042) reduced the incidence of endpoint events (see Table 6). The reduction in the incidence of endpoint events in patients receiving eptifibatide was evident early during treatment, and this reduction was maintained through at least 30 days (see Figure 1). Table also shows the incidence of the components of the primary endpoint, death (whether or not preceded by an MI) and new MI in surviving patients at 30 days.Table 5: Clinical Events in the PURSUET StudyDeath or MI Placebo (n=4739) (%) Eptifibatide(180 mcg/kg bolus then mcg/kg/min infusion) (n=4722) (%) p-value days 359 (7.6%) 279 (5.9%) 0.001 days 552 (11.6%) 477 (10.1%) 0.016 30 days Death or MI (primary endpoint) 745 (15.7%) 672 (14.2%) 0.042 Death 177 (3.7%) 165 (3.5%) Nonfatal MI 568 (12%) 507 (10.7%) Figure 1: Kaplan-Meier Plot of Time to Death or Myocardial Infarction Within 30 Days of Randomization in the PURSUET StudyTreatment with eptifibatide prior to determination of patient management strategy reduced clinical events regardless of whether patients ultimately underwent diagnostic catheterization, revascularization (i.e., PCI or CABG surgery) or continued to receive medical management alone. Table shows the incidence of death or MI within 72 hours.Table 6: Clinical Events (Death or MI) in the PURSUET Study Within 72 Hours of RandomizationPlaceboEptifibatide (180 mcg/kg bolus then mcg/kg/min infusion) Overall patient population n=4739 n=4722 At 72 hours 7.6% 5.9% Patients undergoing early PCI n=631 n=619 Pre-procedure (nonfatal MI only) 5.5% 1.8% At 72 hours 14.4% 9% Patients not undergoing early PCI n=4108 n=4103 At 72 hours 6.5% 5.4% All of the effect of eptifibatide was established within 72 hours (during the period of drug infusion), regardless of management strategy. Moreover, for patients undergoing early PCI, reduction in events was evident prior to the procedure. An analysis of the results by sex suggests that women who would not routinely be expected to undergo PCI receive less benefit from eptifibatide (95% confidence limits for relative risk of 0.94 to 1.28) than do men (0.72 to 0.9). This difference may be true treatment difference, the effect of other differences in these subgroups, or statistical anomaly. No differential outcomes were seen between male and female patients undergoing PCI (see results for ESPRET). Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUET trial (96.9% of the initial enrollment). This follow-up included 4566 patients who received eptifibatide at the 180/2 dose. As reported by the investigators, the occurrence of death from any cause or new MI for patients followed for at least 165 days was reduced from 13.6% with placebo to 12.1% with eptifibatide 180/2.. Death or MI (primary endpoint) Death Nonfatal MI - At 72 hours - Pre-procedure (nonfatal MI only) - At 72 hours - At 72 hours Graph 1. 14.2 Percutaneous Coronary Intervention (PCI). EMPACT II (Eptifibatide to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II) EMPACT II was multicenter, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included history of bleeding diathesis, major surgery within weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy. Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent PCI for ongoing ACS. Patients were randomly assigned to of treatment regimens, each incorporating bolus dose initiated immediately prior to PCI followed by continuous infusion lasting 20 to 24 hours: 1) 135 mcg/kg bolus followed by continuous infusion of 0.5 mcg/kg/min of eptifibatide (135/0.5); 2) 135 mcg/kg bolus followed by continuous infusion of 0.75 mcg/kg/min of eptifibatide (135/0.75); or 3) matching placebo bolus followed by matching placebo continuous infusion. Each patient received aspirin and an intravenous heparin bolus of 100 units/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an ACT of 300 to 350 seconds. The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least dose of study drug. As shown in Table 7, each eptifibatide regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose eptifibatide group. As in the PURSUET study, the effects of eptifibatide were seen early and persisted throughout the 30-day period.Table 7: Clinical Events in the EMPACT II StudyPlacebon (%)Eptifibatide (135 mcg/kg bolus then 0.5 mcg/kg/min infusion)n (%)Eptifibatide (135 mcg/kg bolus then 0.75 mcg/kg/min infusion) (%)Patients 12851300 1286 Abrupt Closure 65 (5.1%)36 (2.8%) 43 (3.3%) p-value versus placebo0.003 0.03 Death, MI, or Urgent Intervention 24 hours 123 (9.6%)86 (6.6%) 89 (6.9%) p-value versus placebo 0.006 0.014 48 hours 131 (10.2%)99 (7.6%) 102 (7.9%) p-value versus placebo 0.021 0.045 30 days (primary endpoint) 149 (11.6%)118 (9.1%) 128 (10%) p-value versus placebo 0.035 0.179 Death or MI 30 days 110 (8.6%)89 (6.8%) 95 (7.4%) p-value versus placebo 0.102 0.272 months 151 (11.9%)136 (10.6%) 130 (10.3%) p-value versus placebo 0.297 0.182 Kaplan-Meier estimate of event rate.ESPRET (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Eptifibatide Therapy) The ESPRET study was multicenter, double-blind, randomized, placebo-controlled study conducted in the United States and Canada that enrolled 2064 patients undergoing elective or urgent PCI with intended intracoronary stent placement. Exclusion criteria included MI within the previous 24 hours, ongoing chest pain, administration of any oral antiplatelet or oral anticoagulant other than aspirin within 30 days of PCI (although loading doses of thienopyridine on the day of PCI were encouraged), planned PCI of saphenous vein graft or subsequent staged PCI, prior stent placement in the target lesion, PCI within the previous 90 days, history of bleeding diathesis, major surgery within weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy. Patient age ranged from 24 to 93 (mean 62) years, and 73% of patients were male. The study enrolled 90% Caucasian, 5% African American, 2% Hispanic, and 1% Asian patients. Patients received wide variety of stents. Patients were randomized either to placebo or eptifibatide administered as an intravenous bolus of 180 mcg/kg followed immediately by continuous infusion of mcg/kg/min, and second bolus of 180 mcg/kg administered 10 minutes later (180/2/180). Eptifibatide infusion was continued for 18 to 24 hours after PCI or until hospital discharge, whichever came first. Each patient received at least dose of aspirin (162 to 325 mg) and 60 units/kg of heparin as bolus (not to exceed 6000 units) if not already receiving heparin infusion. Additional boluses of heparin (10 to 40 units/kg) could be administered in order to reach target ACT between 200 and 300 seconds. The primary endpoint of the ESPRET study was the composite of death, MI, urgent target vessel revascularization (UTVR), and bailout to open-label eptifibatide due to thrombotic complication of PCI (TBO) (e.g., visible thrombus, no reflow, or abrupt closure) at 48 hours. MI, UTVR, and TBO were evaluated by blinded Clinical Events Committee. As shown in Table 8, the incidence of the primary endpoint and selected secondary endpoints was significantly reduced in patients who received eptifibatide. treatment benefit in patients who received eptifibatide was seen by 48 hours and at the end of the 30-day observation period.Table 8: Clinical Events in the ESPRET Study Placebo (n=1024) Eptifibatide (n=1040) Relative Risk (95% CI) p-value Death, MI, UTVR, or Thrombotic Bailout 48 hours (primary endpoint) 108 (10.5%) 69 (6.6%) 0.629 (0.471, 0.84) 0.0015 30 days 120 (11.7%) 78 (7.5%) 0.64 (0.488, 0.84) 0.0011 Death, MI, or UTVR 48 hours 95 (9.3%) 62 (6%) 0.643 (0.472, 0.875) 0.0045 30 days (key secondary endpoint) 107 (10.4%) 71 (6.8%) 0.653 (0.49, 0.871) 0.0034 Death or MI 48 hours 94 (9.2%) 57 (5.5%) 0.597 (0.435, 0.82) 0.0013 30 days 104 (10.2%) 66 (6.3%) 0.625 (0.465, 0.84) 0.0016 Eptifibatide was administered as 180 mcg/kg boluses at times and 10 minutes and an infusion at mcg/kg/min.The need for thrombotic bailout was significantly reduced with eptifibatide at 48 hours (2.1% for placebo, 1% for eptifibatide; p=0.029). Consistent with previous studies of GP IIb/IIIa inhibitors, most of the benefit achieved acutely with eptifibatide was in the reduction of MI. Eptifibatide reduced the occurrence of MI at 48 hours from 9% for placebo to 5.4% (p=0.0015) and maintained that effect with significance at 30 days. There was no treatment difference with respect to sex in ESPRET. Eptifibatide reduced the incidence of the primary endpoint in both men (95% confidence limits for relative risk: 0.54, 1.07) and women (0.24, 0.72) at 48 hours. Follow-up (12-month) mortality data were available for 2024 patients (1017 on eptifibatide) enrolled in the ESPRET trial (98.1% of the initial enrollment). Twelve-month clinical event data were available for 1964 patients (988 on eptifibatide), representing 95.2% of the initial enrollment. As shown in Table 9, the treatment effect of eptifibatide seen at 48 hours and 30 days appeared preserved at months and year. Most of the benefit was in reduction of MI.Table 9: Clinical Events at Months and Year in the ESPRET StudyPlacebo (n=1024) Eptifibatide (n=1040) Hazard Ratio(95% CI)Death, MI, or Target Vessel Revascularization months 187 (18.5%) 146 (14.3%) 0.744 (0.599, 0.924) year 222 (22.1%) 178 (17.5%) 0.762 (0.626, 0.929)Death, MI months 117 (11.5%) 77 (7.4%) 0.631 (0.473, 0.841) year 126 (12.4%) 83 (8%) 0.63 (0.478, 0.832)Percentages are Kaplan-Meier event rates.. 1) 135 mcg/kg bolus followed by continuous infusion of 0.5 mcg/kg/min of eptifibatide (135/0.5); 2) 135 mcg/kg bolus followed by continuous infusion of 0.75 mcg/kg/min of eptifibatide (135/0.75); or p-value versus placebo. 24 hours p-value versus placebo 48 hours p-value versus placebo 30 days (primary endpoint) p-value versus placebo 30 days p-value versus placebo 6 months p-value versus placebo Placebo (n=1024) Eptifibatide (n=1040) Relative Risk (95% CI) p-value. Death, MI, UTVR, or Thrombotic Bailout 48 hours (primary endpoint) 108 (10.5%) 69 (6.6%) 0.629 (0.471, 0.84) 0.0015 30 days 120 (11.7%) 78 (7.5%) 0.64 (0.488, 0.84) 0.0011 Death, MI, or UTVR. 48 hours 95 (9.3%) 62 (6%) 0.643 (0.472, 0.875) 0.0045 30 days (key secondary endpoint) 107 (10.4%) 71 (6.8%) 0.653 (0.49, 0.871) 0.0034 Death or MI. 48 hours 94 (9.2%) 57 (5.5%) 0.597 (0.435, 0.82) 0.0013 30 days 104 (10.2%) 66 (6.3%) 0.625 (0.465, 0.84) 0.0016 6 months 1 year 6 months 1 year.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Treatment with eptifibatide is contraindicated in patients with: oA history of bleeding diathesis, or evidence of active abnormal bleeding within the previous 30 days oSevere hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy oMajor surgery within the preceding weeks oHistory of stroke within 30 days or any history of hemorrhagic stroke oCurrent or planned administration of another parenteral GP IIb/IIIa inhibitor oDependency on renal dialysis oHypersensitivity to eptifibatide or any component of the product (hypersensitivity reactions that occurred included anaphylaxis and urticaria) oA history of bleeding diathesis, or evidence of active abnormal bleeding within the previous 30 days oSevere hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy oMajor surgery within the preceding weeks oHistory of stroke within 30 days or any history of hemorrhagic stroke oCurrent or planned administration of another parenteral GP IIb/IIIa inhibitor oDependency on renal dialysis oHypersensitivity to eptifibatide or any component of the product (hypersensitivity reactions that occurred included anaphylaxis and urticaria) oBleeding diathesis or bleeding within the previous 30 days (4) oSevere uncontrolled hypertension (4) oMajor surgery within the preceding weeks (4) oStroke within 30 days or any history of hemorrhagic stroke (4)oCoadministration of another parenteral GP IIb/IIIa inhibitor (4) oDependency on renal dialysis (4) oKnown hypersensitivity to any component of the product (4) oBleeding diathesis or bleeding within the previous 30 days (4) oSevere uncontrolled hypertension (4) oMajor surgery within the preceding weeks (4) oStroke within 30 days or any history of hemorrhagic stroke (4). oCoadministration of another parenteral GP IIb/IIIa inhibitor (4) oDependency on renal dialysis (4) oKnown hypersensitivity to any component of the product (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Eptifibatide is cyclic heptapeptide containing amino acids and mercaptopropionyl (des-amino cysteinyl) residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N6-(aminoiminomethyl)-N2-(3-mercapto-1-oxopropyl)-L-lysylglycyl-L--aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic (1->6)-disulfide. Eptifibatide binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation.The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is:Eptifibatide Injection is clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use with an empirical formula of C35H49N11O9S2 molecular weight of 832. Each 10 mL vial contains mg/mL of eptifibatide injection and each 100 mL vial contains either 0.75 mg/mL of eptifibatide injection or mg/mL of eptifibatide injection. Each vial of either size also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.. Figure 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Before infusion of eptifibatide injection, 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 IV bolus as soon as possible after diagnosis followed by infusion at mcg/kg/min. (2.1, 2.2) PCI: Add second 180 mcg/kg bolus at 10 minutes. (2.2) In patients with creatinine clearance less than 50 mL/min, reduce the infusion to mcg/kg/min. (2.1, 2.2, 2.3). ACS or PCI: 180 mcg/kg IV bolus as soon as possible after diagnosis followed by infusion at mcg/kg/min. (2.1, 2.2) PCI: Add second 180 mcg/kg bolus at 10 minutes. (2.2) In patients with creatinine clearance less than 50 mL/min, reduce the infusion to 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 (IV) bolus as soon as possible after diagnosis, followed by continuous infusion of mcg/kg/min 180 mcg/kg IV bolus as soon as possible after diagnosis, followed by continuous infusion of mcg/kg/min oInfusion should continue until hospital discharge or initiation of coronary artery bypass graft surgery (CABG), up to 72 hours oIf 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 oAspirin, 160 mg to 325 mg, should be given dailyEptifibatide injection should be given concomitantly with heparin dosed to achieve the following parameters: During Medical Management: Target aPTT 50 to 70 seconds oIf weight greater than or equal to 70 kg, 5000-unit bolus followed by infusion of 1000 units/h. oIf 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 oIf heparin is initiated prior to PCI, additional boluses during PCI to maintain an ACT target of 200 to 300 seconds.oHeparin infusion after the PCI is discouraged.. oInfusion should continue until hospital discharge or initiation of coronary artery bypass graft surgery (CABG), up to 72 hours oIf 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 oAspirin, 160 mg to 325 mg, should be given daily. During Medical Management: Target aPTT 50 to 70 seconds oIf weight greater than or equal to 70 kg, 5000-unit bolus followed by infusion of 1000 units/h. oIf 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 oIf heparin is initiated prior to PCI, additional boluses during PCI to maintain an ACT target of 200 to 300 seconds.. oHeparin infusion after the PCI is discouraged.. 2.2 Dosage in Percutaneous Coronary Intervention (PCI) IndicationNormal Renal FunctionCreatinine Clearance less than 50 mL/minPatients withPCI180 mcg/kg IV bolus immediately before PCI followed by continuous infusion of mcg/kg/min and second bolus of 180 mcg/kg (given 10 minutes after the first bolus) 180 mcg/kg IV bolus immediately before PCI followed by continuous infusion of mcg/kg/min and second bolus of 180 mcg/kg (given 10 minutes after the first bolus) oInfusion should be continued until hospital discharge, or for up to 18 to 24 hours, whichever comes first. minimum of 12 hours of infusion is recommended. oIn patients who undergo CABG surgery, eptifibatide infusion should be discontinued prior to surgery. oAspirin, 160 mg to 325 mg, should be given to 24 hours prior to PCI and daily thereafter.oEptifibatide injection should be given concomitantly with heparin to achieve target ACT of 200 to 300 seconds. Administer 60-units/kg bolus initially in patients not treated with heparin within hours prior to PCI. oAdditional boluses during PCI to maintain ACT within target. oHeparin infusion after the PCI is strongly discouraged. Patients requiring thrombolytic therapy should discontinue eptifibatide injection. oInfusion should be continued until hospital discharge, or for up to 18 to 24 hours, whichever comes first. minimum of 12 hours of infusion is recommended. oIn patients who undergo CABG surgery, eptifibatide infusion should be discontinued prior to surgery. oAspirin, 160 mg to 325 mg, should be given to 24 hours prior to PCI and daily thereafter.. oEptifibatide injection should be given concomitantly with heparin to achieve target ACT of 200 to 300 seconds. Administer 60-units/kg bolus initially in patients not treated with heparin within hours prior to PCI. oAdditional boluses during PCI to maintain ACT within target. oHeparin infusion after the PCI is strongly discouraged. 2.3 Important Administration Instructions 1.Inspect eptifibatide injection for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.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. 3.May administer eptifibatide injection in the same IV 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. 4.Withdraw the bolus dose(s) of eptifibatide injection from the 10 mL vial into syringe. Administer the bolus dose(s) by IV push. 5.Immediately following the bolus dose administration, initiate continuous infusion of eptifibatide injection. When using an intravenous infusion pump, administer eptifibatide injection undiluted directly from the 100 mL vial. Spike the 100 mL vial with vented infusion set. Center the spike within the circle on the stopper top. 6.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 WeightPatient Weight 180 mcg/kg Bolus Volume mcg/kg/min Infusion Volume (CrCl greater than or equal to 50 mL/min) mcg/kg/min Infusion Volume (CrCl less than 50 mL/min) (kg) (lb)(from mg/mL vial) (from mg/mL 100 mL vial) (from 0.75 mg/mL 100 mL vial)(from mg/mL 100 mL vial) (from 0.75 mg/mL 100 mL vial)37 to 41 81 to 91 3.4 mL2 mL/h mL/h1 mL/h mL/h42 to 4692 to 102 mL2.5 mL/h7 mL/h1.3 mL/h 3.5 mL/h47 to 53 103 to 117 4.5 mL3 mL/h8 mL/h1.5 mL/h mL/h54 to 59 118 to 130 mL3.5 mL/h9 mL/h1.8 mL/h 4.5 mL/h60 to 65 131 to 143 5.6 mL3.8 mL/h10 mL/h1.9 mL/h mL/h66 to 71 144 to 157 6.2 mL4 mL/h11 mL/h2 mL/h 5.5 mL/h72 to 78 158 to 172 6.8 mL4.5 mL/h12 mL/h2.3 mL/h mL/h79 to 84 173 to 185 7.3 mL5 mL/h13 mL/h2.5 mL/h 6.5 mL/h85 to 90 186 to 198 7.9 mL5.3 mL/h14 mL/h2.7 mL/h mL/h91 to 96 199 to 212 8.5 mL5.6 mL/h15 mL/h2.8 mL/h 7.5 mL/h97 to 103 213 to 227 mL6 mL/h16 mL/h3.0 mL/h mL/h104 to 109228 to 2409.5 mL6.4 mL/h17 mL/h3.2 mL/h 8.5 mL/h110 to 115241 to 25310.2 mL6.8 mL/h18 mL/h3.4 mL/h mL/h116 to 121254 to 26710.7 mL7 mL/h19 mL/h3.5 mL/h 9.5 mL/h>121>26711.3 mL7.5 mL/h20 mL/h3.7 mL/h 10 mL/h. 1.Inspect eptifibatide injection for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.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. 3.May administer eptifibatide injection in the same IV 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. 4.Withdraw the bolus dose(s) of eptifibatide injection from the 10 mL vial into syringe. Administer the bolus dose(s) by IV push. 5.Immediately following the bolus dose administration, initiate continuous infusion of eptifibatide injection. When using an intravenous infusion pump, administer eptifibatide injection undiluted directly from the 100 mL vial. Spike the 100 mL vial with vented infusion set. Center the spike within the circle on the stopper top. 6.Discard any unused portion left in the vial. Administer eptifibatide injection by volume according to patient weight (see Table 1).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. oInjection: 20 mg of eptifibatide in 10 mL (2 mg/mL), for intravenous bolus.oInjection: 75 mg of eptifibatide in 100 mL (0.75 mg/mL), for intravenous infusion.oInjection: 200 mg of eptifibatide in 100 mL (2 mg/mL), for intravenous infusion.. oInjection: 20 mg of eptifibatide in 10 mL (2 mg/mL), for intravenous bolus.. oInjection: 75 mg of eptifibatide in 100 mL (0.75 mg/mL), for intravenous infusion.. oInjection: 200 mg of eptifibatide in 100 mL (2 mg/mL), for intravenous infusion.. o20 mg/10 mL (2 mg/mL) in single-dose vial for bolus injection (3) o75 mg/100 mL (0.75 mg/mL) in single-dose vial for infusion (3) o200 mg/100 mL (2 mg/mL) in single-dose vial for infusion (3) o20 mg/10 mL (2 mg/mL) in single-dose vial for bolus injection (3) o75 mg/100 mL (0.75 mg/mL) in single-dose vial for infusion (3) o200 mg/100 mL (2 mg/mL) in single-dose vial for infusion (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oCoadministration 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) oCoadministration 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. The PURSUET and EMPACT II clinical studies enrolled patients up to the age of 94 years (45% were age 65 and over; 12% were age 75 and older). There was no apparent difference in efficacy between older and younger patients treated with eptifibatide. The incidence of bleeding complications was higher in the elderly in both placebo and eptifibatide groups, and the incremental risk of eptifibatide-associated bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUET study; no such limitation was stipulated in the ESPRET study [see Adverse Reactions (6.1)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied Eptifibatide injection is supplied as sterile solution as follows: NDCEptifibatide InjectionPackage Factor67457-629-1020 mg/10 mL vial1s67457-630-10200 mg/100 mL vial1s67457-631-1075 mg/100 mL vial1s. 16.2 Storage. Vials should be stored refrigerated at to 8C (36 to 46F). Vials may be transferred to room temperature storage for period not to exceed months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with DISCARD BY date (2 months from the transfer date or the labeled expiration date, whichever comes first). Protect from light until administration. Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Eptifibatide injection is platelet aggregation inhibitor indicated for: oTreatment of acute coronary syndrome (ACS) managed medically or with percutaneous coronary intervention (PCI) (1.1)oTreatment of patients undergoing PCI (including intracoronary stenting) (1.2) oTreatment of acute coronary syndrome (ACS) managed medically or with percutaneous coronary intervention (PCI) (1.1). oTreatment of patients undergoing PCI (including intracoronary stenting) (1.2) 1.1 Acute Coronary Syndrome (ACS). Eptifibatide injection is indicated to decrease the rate of 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 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to inform the doctor or healthcare provider about any medical conditions, medications, and allergies.Manufactured for:Mylan Institutional LLCMorgantown, WV 26505 U.S.AManufactured by:Mylan Laboratories LimitedBangalore, IndiaMAY 2021.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term studies in animals have been performed to evaluate the carcinogenic potential of eptifibatide. Eptifibatide was not genotoxic in the Ames test, the mouse lymphoma cell (L 5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Administered by continuous intravenous infusion at total daily doses up to 72 mg/kg/day (about times the recommended maximum daily human dose on body surface area basis), eptifibatide had no effect on fertility and reproductive performance of male and female rats.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There has been only limited experience with overdosage of eptifibatide. There were patients in the EMPACT II study, patients in the PURSUET study, and no patients in the ESPRET study who received bolus doses and/or infusion doses more than double those called for in the protocols. None of these patients experienced an intracranial bleed or other major bleeding.Eptifibatide was not lethal to rats, rabbits, or monkeys when administered by continuous intravenous infusion for 90 minutes at total dose of 45 mg/kg (about to times the recommended maximum daily human dose on body surface area basis). Symptoms of acute toxicity were loss of righting reflex, dyspnea, ptosis, and decreased muscle tone in rabbits and petechial hemorrhages in the femoral and abdominal areas of monkeys.From in vitro studies, eptifibatide is not extensively bound to plasma proteins and thus may be cleared from plasma by dialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel. NDC 67457-629-10Eptibatide Injection20 mg/10 mL(2 mg/mL)(20 mg/10 mL vial for weight-adjusted bolus dosing)FOR INTRAVENOUS USE ONLYSterileMylanRx onlySingle-Dose Vial. Carton-20.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of eptifibatide in pediatric patients have not been studied.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Infusion of eptifibatide into baboons caused dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than mcg/kg/min. In baboon model that is refractory to aspirin and heparin, doses of eptifibatide that inhibit aggregation prevented acute thrombosis with only modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatide, with complete inhibition at mcg/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model). Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with UA or NSTEMI and/or undergoing percutaneous coronary intervention. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, eptifibatide inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in dose- and concentration-dependent manner. The effect of eptifibatide was observed immediately after administration of 180 mcg/kg intravenous bolus. Table shows the effects of dosing regimens of eptifibatide used in the EMPACT II and PURSUET studies on ex vivo platelet aggregation induced by 20 micromolar ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRET on platelet aggregation have not been studied. Table 4: Platelet Inhibition and Bleeding TimePURSUET 180/2Inhibition of platelet aggregation 15 min after bolus 84%Inhibition of platelet aggregation at steady state>90%Bleeding-time prolongation at steady state<5xInhibition of platelet aggregation 4h after infusion discontinuation<50%Bleeding-time prolongation 6h after infusion discontinuation 1.4x180 mcg/kg bolus followed by continuous infusion of mcg/kg/min.The eptifibatide dosing regimen used in the ESPRET study included two 180 mcg/kg bolus doses given 10 minutes apart combined with continuous mcg/kg/min infusion. When administered alone, eptifibatide has no measurable effect on PT or aPTT. There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to mcg/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of single 180 mcg/kg bolus combined with an infusion produces an early peak level, followed by small decline prior to attaining steady state (within to hours). This decline can be prevented by administering second 180 mcg/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma. Special Populations Geriatric Patients in clinical studies were older (range: 20 to 94 years) than those in the clinical pharmacology studies. Elderly patients with coronary artery disease demonstrated higher plasma levels and lower total body clearance of eptifibatide when given the same dose as younger patients. Limited data are available on lighter weight (<50 kg) patients over 75 years of age. Renal Impairment In patients with moderate to severe renal insufficiency (CrCl <50 mL/min using the Cockcroft-Gault equation), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels approximately doubled [see Use in Specific Populations (8.6) and Dosage and Administration (2)].Hepatic Impairment No studies have been conducted in patients with hepatic impairment. Gender Males and females have not demonstrated any clinically significant differences in the pharmacokinetics of eptifibatide.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Available data on eptifibatide use in pregnant women from published literature and the pharmacovigilance database are insufficient to establish drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated myocardial infarction can be fatal to the pregnant woman and fetus (see Clinical Considerations). In animal reproduction studies, there was no evidence of adverse developmental effects when eptifibatide was administered intravenously to pregnant rats and rabbits at approximately times the recommended maximum daily human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Myocardial infarction is medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of eptifibatide on the fetus.Data Animal Data Embryo-fetal development studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats during the period of organogenesis at total daily doses of up to 72 mg/kg/day (about times the recommended maximum daily human dose on body surface area basis) and in pregnant rabbits during the period of organogenesis at total daily doses of up to 36 mg/kg/day (also about times the recommended maximum daily human dose on body surface area basis). These studies revealed no evidence of harm to the fetus due to eptifibatide.

SPL UNCLASSIFIED SECTION.

1.1 Acute Coronary Syndrome (ACS). Eptifibatide injection is indicated to decrease the rate of 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).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oGeriatric Use: Risk of bleeding increases with age. (8.5) oGeriatric Use: Risk of bleeding increases with age. (8.5) 8.1 Pregnancy. Risk Summary Available data on eptifibatide use in pregnant women from published literature and the pharmacovigilance database are insufficient to establish drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated myocardial infarction can be fatal to the pregnant woman and fetus (see Clinical Considerations). In animal reproduction studies, there was no evidence of adverse developmental effects when eptifibatide was administered intravenously to pregnant rats and rabbits at approximately times the recommended maximum daily human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Myocardial infarction is medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of eptifibatide on the fetus.Data Animal Data Embryo-fetal development studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats during the period of organogenesis at total daily doses of up to 72 mg/kg/day (about times the recommended maximum daily human dose on body surface area basis) and in pregnant rabbits during the period of organogenesis at total daily doses of up to 36 mg/kg/day (also about times the recommended maximum daily human dose on body surface area basis). These studies revealed no evidence of harm to the fetus due to eptifibatide.. 8.2 Lactation Risk Summary There are no available data on the presence of eptifibatide in human milk, the effects on the breastfed infant, or the effects on milk production. As eptifibatide is peptide, it is likely to be destroyed in the infants gastrointestinal tract and not absorbed orally by the breastfed infant. 8.4 Pediatric Use. Safety and effectiveness of eptifibatide in pediatric patients have not been studied.. 8.5 Geriatric Use. The PURSUET and EMPACT II clinical studies enrolled patients up to the age of 94 years (45% were age 65 and over; 12% were age 75 and older). There was no apparent difference in efficacy between older and younger patients treated with eptifibatide. The incidence of bleeding complications was higher in the elderly in both placebo and eptifibatide groups, and the incremental risk of eptifibatide-associated bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUET study; no such limitation was stipulated in the ESPRET study [see Adverse Reactions (6.1)]. 8.6 Renal Impairment. Approximately 50% of eptifibatide is cleared by the kidney in patients with normal renal function. Total drug clearance is decreased by approximately 50% and steady-state plasma eptifibatide concentrations are doubled in patients with an estimated CrCl <50 mL/min (using the Cockcroft-Gault equation). Therefore, the infusion dose should be reduced to mcg/kg/min in such patients [see Dosage and Administration (2)]. The safety and efficacy of eptifibatide in patients dependent on dialysis has not been established.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oEptifibatide 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) oThrombocytopenia: Discontinue eptifibatide and heparin. Monitor and treat condition appropriately. (5.2) oEptifibatide 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) oThrombocytopenia: 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, history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y12 inhibitors). Concomitant treatment with other inhibitors of platelet receptor glycoprotein (GP) IIb/IIIa should be avoided. In patient 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 to 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 to 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 confirmed platelet decrease to <100,000/mm3, 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 baseline platelet count <100,000/mm3. If patient with low platelet counts is receiving eptifibatide, their platelet count should be monitored closely.