BIVALIRUDIN

Bivalirudin for Injection contains bivalirudin which is a specific and reversible direct thrombin inhibitor. Bivalirudin is a synthetic, 20 amino acid peptide, with 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. The active pharmaceutical ingredient is in the form of bivalirudin trifluoroacetate as a white to off-white powder. The chemical name for bivalirudin trifluoroacetate is 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 trifluoroacetate (Figure 1). The molecular weight of bivalirudin is 2180 daltons (anhydrous free base peptide). Figure 1 Structural Formula for Bivalirudin Trifluoroacetate Bivalirudin for Injection is supplied as a sterile white lyophilized cake, in single-dose vials. Each vial contains 250 mg bivalirudin, equivalent to an average of 275 mg of bivalirudin trifluoroacetate*, 125 mg mannitol, and sodium hydroxide to adjust the pH to 5 to 6 (equivalent of approximately 12.5 mg sodium). When reconstituted with Sterile Water for Injection, the product yields a clear to opalescent, colorless to slightly yellow solution, pH 5 to 6. * The range of bivalirudin trifluoroacetate is 270 to 280 mg based on a range of trifluoroacetic acid composition of 1.9 to 2.6 equivalents. structure

Bivalirudin for Injection is indicated for use as 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 for 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 (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS). ( 1 )

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 has been administered, an activated clotting time (ACT) should be performed and an additional bolus dose of 0.3 mg/kg should be given if needed. Extending duration of infusion post-procedure up to 4 hours should be considered in patients with ST segment elevation MI (STEMI). ( 2.1 ) 2.1 Recommended Dosage Bivalirudin for injection has been studied only in patients receiving concomitant aspirin. The recommended dose of bivalirudin for injection is an intravenous bolus dose of 0.75 mg/kg, followed immediately by an 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. Extended duration of infusion following PCI at 1.75 mg/kg/h for up to 4 hours post-procedure should be considered 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. 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 Preparation and Administration Bivalirudin for injection is intended for intravenous bolus injection and continuous infusion after reconstitution and dilution. Preparation Instructions for Bolus Injection and Continuous Infusion To each 250 mg vial, add 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Withdraw and discard 5 mL from a 50 mL infusion bag containing 5% Dextrose in Water or 0.9% Sodium Chloride for Injection. Add the contents of the reconstituted vial to the infusion bag containing 5% Dextrose in Water or 0.9% Sodium Chloride for Injection to yield a final concentration of 5 mg/mL (e.g., 1 vial in 50 mL; 2 vials in 100 mL; 5 vials in 250 mL). Adjust the dose to be administered according to the patient's weight (see Table 1). Table 1 Dosing Table Weight (kg) Using 5 mg/mL Concentration Bolus Infusion 0.75 mg/kg 1.75 mg/kg/h (mL) (mL/h) 43-47 7 16 48-52 7.5 17.5 53-57 8 19 58-62 9 21 63-67 10 23 68-72 10.5 24.5 73-77 11 26 78-82 12 28 83-87 13 30 88-92 13.5 31.5 93-97 14 33 98-102 15 35 103-107 16 37 108-112 16.5 38.5 113-117 17 40 118-122 18 42 123-127 19 44 128-132 19.5 45.5 133-137 20 47 138-142 21 49 143-147 22 51 148-152 22.5 52.5 Drug Compatibilities No incompatibilities have been observed with administration sets. Do not administer the drugs listed in Table 2 in the same intravenous line with Bivalirudin for injection. Table 2. Drugs Not for Administration in the Same Intravenous Line with Bivalirudin for injection Alteplase Amiodarone HCl Amphotericin B Chlorpromazine HCl Diazepam Dobutamine Prochlorperazine Edisylate Reteplase Streptokinase Vancomycin HCl Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparations of bivalirudin for injection containing particulate matter should not be used. Reconstituted material will be a clear to slightly opalescent, colorless to slightly yellow solution. 2.4 Storage after Reconstitution Do not freeze reconstituted or diluted bivalirudin for injection. Reconstituted material may be stored at 2° to 8°C for up to 24 hours. Diluted bivalirudin for injection with a concentration of between 0.5 mg/mL and 5 mg/mL is stable at room temperature for up to 24 hours. Discard any unused portion of reconstituted solution remaining in the vial.

Bivalirudin is contraindicated in patients with: Active major bleeding; Hypersensitivity (e.g., anaphylaxis) to bivalirudin or its components [see Adverse Reactions ( 6.3 )] . Active major bleeding ( 4 ) Hypersensitivity to bivalirudin or its components ( 4 )

Most common adverse reaction (>2%) was bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hainan Shuangcheng Pharmaceuticals Co., Ltd. at 1-732-346-6655 or the 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%) patients 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 a decrease in hemoglobin >3 g/dL or leading to a 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 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. 6.3 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 postapproval 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.

In clinical trials in patients undergoing PCI/percutaneous transluminal coronary angioplasty (PTCA), 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 )