DESCRIPTION SECTION.

11 DESCRIPTION Bivalirudin Injection contains bivalirudin which is specific and reversible direct thrombin inhibitor. Bivalirudin is synthetic, 20 amino acid peptide, with the chemical name of D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-L-asparagyl-glycyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-glutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-L-leucine (Figure 1). The molecular weight of bivalirudin is 2180 daltons (anhydrous free base peptide). The active pharmaceutical ingredient is in the form of bivalirudin trifluoroacetate as white to off-white powder.Figure 1: Structural Formula of BivalirudinBivalirudin Injection is supplied as frozen, premixed, iso-osmotic, sterile, nonpyrogenic 50 mL or 100 mL solution containing 250 mg or 500 mg respectively as bivalirudin (equivalent to an average of 275 or 550 mg bivalirudin trifluoroacetate) in the GALAXY single-dose container (PL 2040 Plastic). Sodium Chloride, USP has been added to adjust osmolality (0.9 g/100 mL).The approximate osmolality for Bivalirudin Injection is 300 mOsmol/kg.The pH of Bivalirudin Injection may have been adjusted with sodium hydroxide and/or hydrochloric acid to 5.2 to 6.0. The solution is intended for intravenous use at room temperature.The range of bivalirudin trifluoroacetate is 270 to 280 mg (250 mg strength) or 540 to 560 mg (500 mg strength) based on range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents.. Structural Formula of Bivalirudin.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS Most common adverse reaction was bleeding (3.7%). (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 trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In the BAT trials, 79 of the 2161 (3.7%) of subjects undergoing PCI for treatment of unstable angina and randomized to bivalirudin experienced major bleeding events which consisted of: intracranial bleeding, retroperitoneal bleeding, and clinically overt bleeding with decrease in hemoglobin >3 g/dL or leading to transfusion of >2 units of blood. 6.2 Immunogenicity As with all peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bivalirudin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.In in vitro studies, bivalirudin exhibited no platelet aggregation response against sera from patients with history of HIT/HITTS.Among 494 subjects who received bivalirudin in clinical trials and were tested for antibodies, subjects had treatment-emergent positive bivalirudin antibody tests. Neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests were negative on repeat testing.. 6.3 Postmarketing Experience Because postmarketing adverse reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of bivalirudin: fatal bleeding; hypersensitivity and allergic reactions including reports of anaphylaxis; lack of anticoagulant effect; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes; pulmonary hemorrhage; cardiac tamponade; and INR increased.

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 bivalirudin. Bivalirudin displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the in vitro human lymphocyte chromosomal aberration assay, the in vivo rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses of bivalirudin up to 150 mg/kg/day, about 1.6 times the dose on body surface area basis (mg/m2) of 50 kg person given the maximum recommended dose of 15 mg/kg/day.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is serine proteinase that plays central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.. 12.2 Pharmacodynamics In healthy volunteers and patients (with >=70% vessel occlusion undergoing routine PTCA), bivalirudin exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of bivalirudin produces an immediate anticoagulant effect. Coagulation times return to baseline approximately hour following cessation of bivalirudin administration. Bivalirudin also increases INR. Therefore INR measurements made in Bivalirudin Injection treated patients may not be useful for determining the appropriate dose of warfarin.In 291 patients with >=70% vessel occlusion undergoing routine PTCA, positive correlation was observed between the dose of bivalirudin and the proportion of patients achieving ACT values of 300 sec or 350 sec. At bivalirudin dose of mg/kg intravenous bolus plus 2.5 mg/kg/h intravenous infusion (1.4 times higher than the approved dose of 1.75 mg/kg/h) for hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec.. 12.3 Pharmacokinetics Bivalirudin exhibits linear pharmacokinetics following intravenous administration to patients undergoing PTCA. In these patients, mean steady state bivalirudin concentration of 12.3 +- 1.7 mcg/mL is achieved following an intravenous bolus of mg/kg and 4-hour 2.5 mg/kg/h intravenous infusion. DistributionBivalirudin does not bind to plasma proteins (except thrombin) or to red blood cells.EliminationBivalirudin has half- life of 25 minutes in PTCA patients with normal renal function. The total body clearance of bivalirudin in PTCA patients with normal renal function is 3.4 mL/min/kg. MetabolismBivalirudin is metabolized by proteolytic cleavage. ExcretionBivalirudin undergoes glomerular filtration. Tubular secretion and tubular reabsorption are also implicated in the excretion of bivalirudin, although the extent is unknown.Specific PopulationsPatients with Renal ImpairmentTotal body clearance was similar for PTCA patients with normal renal function and with mild renal impairment. Clearance was reduced by 21% in patients with moderate and severe renal impairment with half-life of 34 and 57 minutes, respectively. In dialysis patients, clearance was reduced by 70%, with half- life of 3.5 hours. Approximately 25% bivalirudin is cleared by hemodialysis.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Bivalirudin Angioplasty Trial (BAT) In the BAT studies, patients with unstable angina undergoing PCI were randomized 1:1 to 1 mg/kg bolus of bivalirudin and then 2.5 mg/kg/h for four hours and then 0.2 mg/kg/h for 14 20 hours or to 175 IU/kg bolus of heparin followed by an 18-24 hour infusion of 15 IU/kg/h infusion. Additional heparin but not bivalirudin could be administered for ACT 350 seconds. The studies were designed to demonstrate the superiority of bivalirudin to heparin on the occurrence of any of the following during hospitalization up to seven days of death, MI, abrupt closure of the dilated vessel, or clinical deterioration requiring revascularization or placement of an aortic balloon pump. The 4312 subjects ranged in age from 29-90 (median 63) years. 68% were male, and 91% were Caucasian. Median weight was 80 kg (39-120 kg). 741 (17%) subjects had post-MI angina. Twenty-three percent of patients were treated with heparin within one hour prior to randomization. The studies did not demonstrate that bivalirudin was statistically superior to heparin for reducing the risk of death, MI, abrupt closure of the dilated vessel, or clinical deterioration requiring revascularization or placement of an aortic balloon pump, but the occurrence of these events was similar in both treatment groups. Study outcomes are shown in Table 2.Table 2: Incidences of In-hospital Endpoints in BAT TrialEndpointBivalirudin (n=2161)HEPARIN(n=2151)Primary endpointA composite of death or MI or clinical deterioration of cardiac origin requiring revascularization or placement of an aortic balloon pump or angiographic evidence of abrupt vessel closure 7.9%9.3% Death, MI, revascularization6.2%7.9% Death0.2%0.2% MI3.3%4.2%AT-BAT Trial (NCT 00043940)This was single-arm open-label study in which 51 subjects with heparin-induced thrombocytopenia (HIT) or heparin induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI. The majority of patients achieved adequate ACT at the time of device activation and no major bleeding was reported. Two patients developed thrombocytopenia.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Bivalirudin Injection is contraindicated in patients with:oSignificant active bleedingoHypersensitivity to Bivalirudin Injection or its components [see Adverse Reactions (6.2)].. oSignificant active bleeding. oHypersensitivity to Bivalirudin Injection or its components [see Adverse Reactions (6.2)].. oSignificant active bleeding (4)oHypersensitivity to bivalirudin or its components (4). oSignificant active bleeding (4). oHypersensitivity to bivalirudin or its components (4).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is serine proteinase that plays central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oThe recommended dosage is 0.75 mg/kg intravenous bolus dose followed immediately by 1.75 mg/kg/h intravenous infusion for the duration of the procedure. Five minutes after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed. (2.1)oConsider extending duration of infusion post-procedure up to hours in patients with ST segment elevation MI (STEMI). (2.1). oThe recommended dosage is 0.75 mg/kg intravenous bolus dose followed immediately by 1.75 mg/kg/h intravenous infusion for the duration of the procedure. Five minutes after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed. (2.1). oConsider extending duration of infusion post-procedure up to hours in patients with ST segment elevation MI (STEMI). (2.1). 2.1 Recommended Dosage The recommended dose of Bivalirudin Injection is an intravenous bolus dose of 0.75 mg/kg, followed immediately by maintenance infusion of 1.75 mg/kg/h for the duration of the procedure. Five minutes after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.Consider extending duration of infusion following PCI at 1.75 mg/kg/h for up to hours post-procedure in patients with ST segment elevation MI (STEMI).. 2.2 Dose Adjustment in Renal Impairment Bolus DoseNo reduction in the bolus dose is needed for any degree of renal impairment. Maintenance InfusionIn patients with creatinine clearance less than 30 mL/min (by Cockcroft Gault equation), reduce the infusion rate to mg/kg/h. Monitor anticoagulant status in patients with renal impairment.In patients on hemodialysis, reduce the infusion rate to 0.25 mg/kg/h [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].. 2.3 Instructions for Administration Thawing and Inspection of Plastic ContaineroThaw frozen container at room temperature (25C/ 77F) or under refrigeration (5C/41F). Do not thaw by immersion in water baths or by microwave irradiation.oDo not add supplemental medication.oParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check for minute leaks by squeezing container firmly. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection the solution remains cloudy or if an insoluble precipitate is noted, if there are any leaks, or if any seals or outlet ports are not intact, the container should be discarded.oDo not refreeze thawed Bivalirudin Injection. Thawed solution is stable for 14 days under refrigeration (5C/41F) or 24 hours at room temperature (25C/77F). Discard any unused portion.Drug CompatibilitiesNo incompatibilities have been observed with administration sets. Do not administer the drugs listed in Table in the same intravenous line with Bivalirudin Injection.Table Drugs Not for Administration in the Same Intravenous Line with Bivalirudin InjectionAlteplaseAmiodarone HClAmphotericin BChlorpromazine HClDiazepamDobutamineProchlorperazine EdisylateReteplaseStreptokinaseVancomycin HCl. oThaw frozen container at room temperature (25C/ 77F) or under refrigeration (5C/41F). Do not thaw by immersion in water baths or by microwave irradiation.. oDo not add supplemental medication.. oParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check for minute leaks by squeezing container firmly. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection the solution remains cloudy or if an insoluble precipitate is noted, if there are any leaks, or if any seals or outlet ports are not intact, the container should be discarded.. oDo not refreeze thawed Bivalirudin Injection. Thawed solution is stable for 14 days under refrigeration (5C/41F) or 24 hours at room temperature (25C/77F). Discard any unused portion.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Injection, clear and colorless solution:o250 mg of bivalirudin per 50 mL (5 mg/mL) in single-dose GALAXY container supplied as frozen, premixed, iso-osmotic, sterile, nonpyrogenic solution. Ready to use. Each container contains 250 mg of bivalirudin equivalent to an average of 275 mg bivalirudin trifluoroacetate. The range of bivalirudin trifluoroacetate is 270 to 280 mg based on range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents.o500 mg of bivalirudin per 100 mL (5 mg/mL) in single-dose GALAXY container supplied as frozen, premixed, iso-osmotic, sterile, nonpyrogenic solution. Ready to use. Each container contains 500 mg of bivalirudin equivalent to an average of 550 mg bivalirudin trifluoroacetate+.+The range of bivalirudin trifluoroacetate is 540 to 560 mg based on range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents. o250 mg of bivalirudin per 50 mL (5 mg/mL) in single-dose GALAXY container supplied as frozen, premixed, iso-osmotic, sterile, nonpyrogenic solution. Ready to use. Each container contains 250 mg of bivalirudin equivalent to an average of 275 mg bivalirudin trifluoroacetate. o500 mg of bivalirudin per 100 mL (5 mg/mL) in single-dose GALAXY container supplied as frozen, premixed, iso-osmotic, sterile, nonpyrogenic solution. Ready to use. Each container contains 500 mg of bivalirudin equivalent to an average of 550 mg bivalirudin trifluoroacetate+.. Injection, clear and colorless solution in single dose containers. Ready to use:o250 mg of bivalirudin per 50 mL (5 mg/mL) (3)o500 mg of bivalirudin per 100 mL (5 mg/mL) (3). Injection, clear and colorless solution in single dose containers. Ready to use:. o250 mg of bivalirudin per 50 mL (5 mg/mL) (3). o500 mg of bivalirudin per 100 mL (5 mg/mL) (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS In clinical trials in patients undergoing PCI, co-administration of bivalirudin with heparin, warfarin, thrombolytics, or GPIs was associated with increased risks of major bleeding events compared to patients not receiving these concomitant medications.. Heparin, warfarin, thrombolytics, or GPIs: Increased major bleeding risk with concomitant use. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use In studies of patients undergoing PCI, 44% were >=65 years of age and 12% of patients were >=75 years old. Elderly patients experienced more bleeding events than younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Bivalirudin Injection is supplied as frozen, premixed, iso-osmotic, sterile, nonpyrogenic single-dose solution packaged in the GALAXY container. When thawed, clear and colorless solution is obtained. The single-dose GALAXY plastic containers are available as follows:CodeNDCContainerSizeNumber of Containers/Carton2G3567NDC 0338-9572-24GALAXY single-dose50 mL24 count carton of 250 mg/50 mL (5 mg/mL) GALAXY containers2G3566NDC 0338-9576-12GALAXY single-dose100 mL12 count carton of 500 mg/100 mL (5 mg/mL) GALAXY containersThe 250 mg and 500 mg strength drug products contain 250 mg or 500 mg respectively as bivalirudin (equivalent to an average of 275 or 550 mg bivalirudin trifluoroacetate).The range of bivalirudin trifluoroacetate is 270 to 280 mg (250 mg strength) or 540 to 560 mg (500 mg strength) based on range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents.. 16.2 Storage GALAXY containers should be stored frozen at or below -20C/-4F.Product containers may be fragile in the frozen state.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Bivalirudin Injection is an anticoagulant for use in patients undergoing percutaneous coronary intervention (PCI) including patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome.. Bivalirudin Injection is direct thrombin inhibitor indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) including patients with heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise patients to watch carefully for any signs of bleeding or bruising and to report these to their health care provider when they occur.Baxter and Galaxy are registered trademarks of Baxter International Inc.Baxter Healthcare CorporationDeerfield, IL 60015 USA07-19-01-820.

LACTATION SECTION.

8.2 Lactation Risk SummaryIt is not known whether bivalirudin is present in human milk. No data are available on the effects of bivalirudin on the breastfed child or on milk production. Bivalirudin was administered to lactating rats in reproduction studies (see Data ). The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Bivalirudin Injection and any potential adverse effects on the breastfed infant from Bivalirudin Injection or from the underlying maternal condition.DataAnimal DataReproduction studies conducted in lactating female rats dosed subcutaneously daily with bivalirudin at doses up to 150 mg/kg/day (1.6 times the maximum recommended human dose, based on body surface area) from day through day 20 of lactation revealed no adverse developmental outcomes to the pups.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oGeriatric patients: Increased bleeding risk possible. (8.5)oRenal impairment: Reduce infusion dose and monitor ACT. (2.2, 8.6). oGeriatric patients: Increased bleeding risk possible. (8.5). oRenal impairment: Reduce infusion dose and monitor ACT. (2.2, 8.6). 8.1 Pregnancy Risk SummaryThere are no available data on use of bivalirudin in pregnant women to inform drug-associated risk of adverse developmental outcomes. Reproduction studies in rats and rabbits administered subcutaneously (SC) doses up to 1.6 times and 3.2 times the maximum recommended human dose (MRHD) of 15 mg/kg/day based on body surface area (BSA) during organogenesis, respectively, revealed no evidence of fetal harm. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataReproductive studies have been performed in rats at subcutaneous doses up to 150 mg/kg/day, (1.6 times the maximum recommended human dose based on body surface area) and rabbits at subcutaneous doses up to 150 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). These studies revealed no harm to the fetus attributable to bivalirudin.At 500 mg/kg/day (equivalent to 5.4 times the maximum recommended human dose based on body surface area) subcutaneously, litter sizes and live fetuses in rats were reduced. Fetal skeletal variations were also noted. Some of these changes could be attributed to maternal toxicity observed at high doses. There is no study covering the peri-natal period because of the potential complications of drug-induced hemorrhage during delivery.. 8.2 Lactation Risk SummaryIt is not known whether bivalirudin is present in human milk. No data are available on the effects of bivalirudin on the breastfed child or on milk production. Bivalirudin was administered to lactating rats in reproduction studies (see Data ). The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Bivalirudin Injection and any potential adverse effects on the breastfed infant from Bivalirudin Injection or from the underlying maternal condition.DataAnimal DataReproduction studies conducted in lactating female rats dosed subcutaneously daily with bivalirudin at doses up to 150 mg/kg/day (1.6 times the maximum recommended human dose, based on body surface area) from day through day 20 of lactation revealed no adverse developmental outcomes to the pups.. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use In studies of patients undergoing PCI, 44% were >=65 years of age and 12% of patients were >=75 years old. Elderly patients experienced more bleeding events than younger patients.. 8.6 Renal Impairment The disposition of bivalirudin was studied in PTCA patients with mild, moderate and severe renal impairment. The clearance of bivalirudin was reduced approximately 21% in patients with moderate and severe renal impairment and was reduced approximately 70% in dialysis-dependent patients [see Clinical Pharmacology (12.3)]. Reduce the infusion dose of Bivalirudin Injection and monitor the anticoagulant status more frequently in patients with renal impairment creatine clearance less than 30mL/min (by Cockcroft Gault equation) [see Dosage and Administration (2.2)].

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 bivalirudin. Bivalirudin displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the in vitro human lymphocyte chromosomal aberration assay, the in vivo rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses of bivalirudin up to 150 mg/kg/day, about 1.6 times the dose on body surface area basis (mg/m2) of 50 kg person given the maximum recommended dose of 15 mg/kg/day.

OVERDOSAGE SECTION.

10 OVERDOSAGE Cases of overdose of up to 10 times the recommended bolus or continuous infusion dose of Bivalirudin Injection have been reported in clinical trials and in postmarketing reports. number of the reported overdoses were due to failure to adjust the infusion dose of bivalirudin in persons with renal dysfunction including persons on hemodialysis [see Dosage and Administration (2.2)]. Bleeding, as well as deaths due to hemorrhage, have been observed in some reports of overdose. In cases of suspected overdosage, discontinue Bivalirudin Injection immediately and monitor the patient closely for signs of bleeding. There is no known antidote to bivalirudin. Bivalirudin is hemodialyzable [see Clinical Pharmacology (12.3)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Container LabelNDC 0338-9572-24Bivalirudin in 0.9% SodiumChloride Injection250 mg per 50 mL(5 mg mL)For intravenous use only. Do Not Dilute.Code 2G3567GALAXYSterile Nonpyrogenic50 mL Single Dose ContainerDiscard unused portionEach 50 mL contains: 250 mg bivalirudin equivalent to an average of 275 mgbivalirudin trifluoroacetate; 450 mg sodium chloride, USP; and Water for Injection,USP. pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.Usual Dose: See prescribing information.Cautions: Do not add supplemental medication or additives.Rx onlyStore frozen at or below -20C/-4F. Thaw at room temperature (25C/77F) orunder refrigeration (5C/41F). Product should not be thawed by immersion in waterbaths or by microwave irradiation. Do not force thaw. Thawed solution is stable for14 days under refrigeration or 24 hours at room temperature.Do not refreeze.PL 2040 PlasticBaxter LogoBaxter Healthcare CorporationDeerfield, IL 60015 USABaxter and Galaxy are registered trademarks of Baxter International Inc.Made in USA07-34-00-0054Container LabelNDC 0338-9576-12Bivalirudin in 0.9% SodiumChloride Injection500 mg per 100 mL(5 mg mL)For intravenous use only. Do Not Dilute. Code 2G3566GALAXY Sterile Nonpyrogenic100 mL Single Dose ContainerDiscard unused portionEach 100 mL contains: 500 mg bivalirudin equivalent to an average of550 mg bivalirudin trifluoroacetate; 900 mg sodium chloride, USP; and Waterfor Injection, USP. pH may have been adjusted with sodium hydroxide and/orhydrochloric acid.Usual Dose: See prescribing information.Cautions: Do not add supplemental medication or additives.Rx onlyStore frozen at or below -20C/-4F. Thaw at room temperature (25C/77F) orunder refrigeration (5C/41F). Product should not be thawed by immersion inwater baths or by microwave irradiation. Do not force thaw. Thawed solutionis stable for 14 days under refrigeration or 24 hours at room temperature.Do not refreeze.Baxter LogoPL 2040 PlasticBaxter Healthcare CorporationDeerfield, IL 60015 USABaxter and Galaxy are registered trademarks of Baxter International Inc.Made in USA07-34-00-0055. Bivalirudin Representative Container Label 0338-9572-24. Bivalirudin Representative Container Label 0338-9576-12.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics In healthy volunteers and patients (with >=70% vessel occlusion undergoing routine PTCA), bivalirudin exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of bivalirudin produces an immediate anticoagulant effect. Coagulation times return to baseline approximately hour following cessation of bivalirudin administration. Bivalirudin also increases INR. Therefore INR measurements made in Bivalirudin Injection treated patients may not be useful for determining the appropriate dose of warfarin.In 291 patients with >=70% vessel occlusion undergoing routine PTCA, positive correlation was observed between the dose of bivalirudin and the proportion of patients achieving ACT values of 300 sec or 350 sec. At bivalirudin dose of mg/kg intravenous bolus plus 2.5 mg/kg/h intravenous infusion (1.4 times higher than the approved dose of 1.75 mg/kg/h) for hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Bivalirudin exhibits linear pharmacokinetics following intravenous administration to patients undergoing PTCA. In these patients, mean steady state bivalirudin concentration of 12.3 +- 1.7 mcg/mL is achieved following an intravenous bolus of mg/kg and 4-hour 2.5 mg/kg/h intravenous infusion. DistributionBivalirudin does not bind to plasma proteins (except thrombin) or to red blood cells.EliminationBivalirudin has half- life of 25 minutes in PTCA patients with normal renal function. The total body clearance of bivalirudin in PTCA patients with normal renal function is 3.4 mL/min/kg. MetabolismBivalirudin is metabolized by proteolytic cleavage. ExcretionBivalirudin undergoes glomerular filtration. Tubular secretion and tubular reabsorption are also implicated in the excretion of bivalirudin, although the extent is unknown.Specific PopulationsPatients with Renal ImpairmentTotal body clearance was similar for PTCA patients with normal renal function and with mild renal impairment. Clearance was reduced by 21% in patients with moderate and severe renal impairment with half-life of 34 and 57 minutes, respectively. In dialysis patients, clearance was reduced by 70%, with half- life of 3.5 hours. Approximately 25% bivalirudin is cleared by hemodialysis.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere are no available data on use of bivalirudin in pregnant women to inform drug-associated risk of adverse developmental outcomes. Reproduction studies in rats and rabbits administered subcutaneously (SC) doses up to 1.6 times and 3.2 times the maximum recommended human dose (MRHD) of 15 mg/kg/day based on body surface area (BSA) during organogenesis, respectively, revealed no evidence of fetal harm. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataReproductive studies have been performed in rats at subcutaneous doses up to 150 mg/kg/day, (1.6 times the maximum recommended human dose based on body surface area) and rabbits at subcutaneous doses up to 150 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). These studies revealed no harm to the fetus attributable to bivalirudin.At 500 mg/kg/day (equivalent to 5.4 times the maximum recommended human dose based on body surface area) subcutaneously, litter sizes and live fetuses in rats were reduced. Fetal skeletal variations were also noted. Some of these changes could be attributed to maternal toxicity observed at high doses. There is no study covering the peri-natal period because of the potential complications of drug-induced hemorrhage during delivery.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage The recommended dose of Bivalirudin Injection is an intravenous bolus dose of 0.75 mg/kg, followed immediately by maintenance infusion of 1.75 mg/kg/h for the duration of the procedure. Five minutes after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.Consider extending duration of infusion following PCI at 1.75 mg/kg/h for up to hours post-procedure in patients with ST segment elevation MI (STEMI).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oBleeding events: Bivalirudin increases the risk of bleeding. Its anticoagulant effect subsides approximately one hour after discontinuation. (5.1, 6.1, 12.2)oThrombotic risk with coronary artery brachytherapy: An increased risk of thrombus formation, including fatal outcomes, in gamma brachytherapy. (5.3). oBleeding events: Bivalirudin increases the risk of bleeding. Its anticoagulant effect subsides approximately one hour after discontinuation. (5.1, 6.1, 12.2). oThrombotic risk with coronary artery brachytherapy: An increased risk of thrombus formation, including fatal outcomes, in gamma brachytherapy. (5.3). 5.1 Bleeding Events Bivalirudin increases the risk of bleeding [see Adverse Reactions (6.1)]. Bivalirudins anticoagulant effect subsides approximately one hour after discontinuation [see Clinical Pharmacology (12.2)].. 5.3 Thrombotic Risk with Coronary Artery Brachytherapy An increased risk of thrombus formation, including fatal outcomes, has been associated with the use of bivalirudin in gamma brachytherapy [see Adverse Reactions (6.3)].