Bivalirudin

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

2 DOSAGE AND ADMINISTRATION The recommended dosage is a 0.75 mg/kg intravenous bolus dose followed immediately by a 1.75 mg/kg/h intravenous infusion for the duration of the procedure. Five minutes after the bolus dose, assess activated clotting time (ACT) to determine if an additional bolus of 0.3 mg/kg is needed. ( 2.1 ) Consider extending duration of infusion post-procedure up to 4 hours in patients with ST segment elevation MI. ( 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 a maintenance infusion of 1.75 mg/kg/h for the duration of the procedure. Five minutes after the bolus dose has been administered, assess activated clotting time (ACT) to determine if an additional bolus of 0.3 mg/kg is needed. Consider extending duration of infusion following PCI at 1.75 mg/kg/h for up to 4 hours post- procedure in patients with ST segment elevation MI (STEMI). 2.2 Dose Adjustment in Renal Impairment Bolus Dose: No reduction in the bolus dose is needed for any degree of renal impairment. Maintenance Infusion: In patients with creatinine clearance less than 30 mL/min (by Cockcroft Gault equation), reduce the infusion rate to 1 mg/kg/h. 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 Bivalirudin Injection is a ready-to-use sterile solution for intravenous use only. Inspection of Container Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Once removed from the refrigerator, Bivalirudin Injection may be stored at room temperature 20o to 25°C (68o to 77°F) for up to 72 hours [see How Supplied Storage and Handling ( 16.2 )] . Discard any unused portion. Drug Compatibilities No incompatibilities have been observed with administration sets. Do not administer the drugs listed in Table 1 in the same intravenous line with Bivalirudin Injection. Table 1. Drugs Not for Administration in the Same Intravenous Line with Bivalirudin Injection Alteplase Amiodarone HCl Amphotericin B Chlorpromazine HCl Diazepam Dobutamine Prochlorperazine Edisylate Reteplase Streptokinase Vancomycin HCl

3 DOSAGE FORMS AND STRENGTHS Injection, clear to slightly opalescent, colorless to yellow sterile solution: 250 mg of bivalirudin per 50 mL (5 mg/mL) in a single-dose vial. Ready-to-use. Each vial 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 a range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents . Injection: 250 mg/50 mL (5 mg/mL) in a single-dose vial. Ready-to-use. ( 3 )

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

6 ADVERSE REACTIONS Most common adverse reaction was bleeding (3.7%). To report SUSPECTED ADVERSE REACTIONS, contact MAIA Pharmaceuticals, Inc. at 1-888-877-9064 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 a 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 intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin greater than 3 g/dL or leading to a transfusion of greater than 2 units of blood. Immunogenicity/Re-Exposure As with all therapeutic proteins, 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 a history of HIT/HITTS. Among 494 subjects who received bivalirudin in clinical trials and were tested for antibodies, 2 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. 6.2 Postmarketing Experience Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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.

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 )

8 USE IN SPECIFIC POPULATIONS Geriatric patients: Increased bleeding risk possible. ( 8.5 ) Renal impairment: Reduce infusion dose and monitor ACT. ( 2.2 , 8.6 ) 8.1 Pregnancy Risk Summary There are no available data on use of bivalirudin in pregnant women to inform a 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) based on body surface area (BSA), respectively, revealed no evidence of fetal harm. All pregnancies have a 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 to 4% and 15 to 20%, respectively. Data Animal Data Reproductive 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 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. 8.2 Lactation Risk Summary It 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. 8.4 Pediatric Use The safety and effectiveness of bivalirudin 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 )] . The infusion dose of Bivalirudin Injection may need to be reduced, and anticoagulant status monitored in patients with renal impairment [see Dosage and Administration ( 2.2 )] .

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 a serine proteinase that plays a 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 a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V 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-Arg 3 -Pro 4 bond, resulting in recovery of thrombin active site functions.

11 DESCRIPTION Bivalirudin Injection contains bivalirudin trifluoroacetate, which is a specific and reversible direct thrombin inhibitor. Bivalirudin trifluoroacetate is a synthetic, 20 amino acid peptide salt, with the chemical name of D-phenylalanyl-L-prolyl-L-arginyl-L-prolylglycylglycylglycylglycyl-L-asparagylglycyl-L-α-aspartyl-L-phenylalanyl-L-α-glutamyl-L-α-glutamyl-L-isoleucyl-L-prolyl-L-α-glutamyl-L-α-glutamyl-L-tyrosyl-L-leucine trifluoroacetate. Each molecule of bivalirudin trifluoroacetate contains 1.7 to 2.6 equivalents of trifluoroacetic acid. The molecular formula of bivalirudin free base is C 98 H 138 N 24 O 33 and its molecular weight is 2180.32 Daltons (anhydrous free base peptide). The structural formula of bivalirudin free base is Figure 1: Structural Formula of Bivalirudin Bivalirudin Injection is supplied as a refrigerated, ready-to-use, sterile solution packaged in a 50 mL single-dose vial. Each milliliter of Bivalirudin Injection contains 5 mg bivalirudin (as trifluoroacetate salt)*, 0.8 mg sodium acetate trihydrate, 100 mg polyethylene glycol 400, and Water for Injection. The pH of Bivalirudin Injection may have been adjusted with sodium hydroxide and/or glacial acetic acid to 5.0 to 5.5. The solution is intended for intravenous administration at room temperature (20oC to 25°C/68oF to 77°F). *The range of bivalirudin trifluoroacetate is 5.4 to 5.6 mg based on a range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents. bivalirudin-spl-chemical-structure

10 OVERDOSAGE Cases of overdose of up to 10 times the recommended bolus or continuous infusion dose of bivalirudin have been reported in clinical trials and in postmarketing reports. A 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 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 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Bivalirudin Injection is supplied as a refrigerated, ready-to-use, clear to slightly opalescent, colorless to yellow, sterile solution in 250 mg/50 mL (5 mg/mL) single-dose, glass vials. The single-dose vials are available as follows: NDC 42023-622-01: Carton containing 1 Bivalirudin Injection single-dose vial NDC 42023-622-10: Carton containing 10 Bivalirudin Injection single-dose vials Each vial 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 a range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents. 16.2 Storage Store Bivalirudin Injection vials in the refrigerator between 2° to 8°C (36° to 46°F). Once removed from the refrigerator, Bivalirudin Injection may be stored at room temperature 20o to 25°C (68o to 77°F) for up to 72 hours [see Dosage and Administration ( 2.3 )] . Avoid excess heat.