bivalirudin 250 MG Injection [Angiomax]

INDICATIONS AND USAGE 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 )

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 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 is for intravenous administration only. Bivalirudin for Injection has been studied only in patients receiving concomitant aspirin. The recommended dose of Bivalirudin for Injection is an intravenous (IV) 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 30mL/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 0.75 mg/kg (mL) Infusion 1.75 mg/kg/h (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 8ºC 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.

WARNINGS AND PRECAUTIONS Bleeding events: Bivalirudin for injection increases the risk of bleeding. ( 5.1 , 6.1 , 12.2 ) Acute Stent Thrombosis: Increased incidence of acute stent thrombosis in STEMI patients undergoing primary PCI. ( 2.1 , 5.2 ) Thrombotic Risk with Coronary Artery Brachytherapy: An increased risk of thrombus formation, including fatal outcomes, in gamma brachytherapy. ( 5.3 ) 5.1 Bleeding Events Bivalirudin for injection increases the risk of bleeding [see Adverse Reactions ( 6.1 )] . An unexplained fall in blood pressure or hematocrit should lead to serious consideration of a hemorrhagic event and cessation of bivalirudin for injection administration. Monitor patients receiving bivalirudin for injection for signs and symptoms of bleeding. Monitor patients with disease states associated with an increased risk of bleeding more frequently for bleeding. 5.2 Acute Stent Thrombosis in Patients with STEMI Undergoing PCI Acute stent thrombosis (AST) (<4 hours) has been observed at a greater frequency in bivalirudin for injection treated patients (1.2%, 36/2889) compared to heparin treated patients (0.2%, 6/2911) with STEMI undergoing primary PCI. Among patients who experienced an AST, one fatality (0.03%) occurred in a bivalirudin for injection treated patient and one fatality (0.03%) in a heparin treated patient. These patients have been managed by Target Vessel Revascularization (TVR). Patients should remain for at least 24 hours in a facility capable of managing ischemic complications and should be carefully monitored following primary PCI for signs and symptoms consistent with myocardial ischemia. 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 for injection in gamma brachytherapy. If a decision is made to use bivalirudin for injection during brachytherapy procedures, maintain meticulous catheter technique, with frequent aspiration and flushing, paying special attention to minimizing conditions of stasis within the catheter or vessels [see Adverse Reactions ( 6.1 )].

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

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. In in vitro studies, bivalirudin inhibited both soluble (free) and clot-bound thrombin, was not neutralized by products of the platelet release reaction, and prolonged the activated partial thromboplastin time (aPTT), thrombin time (TT), and prothrombin time (PT) of normal human plasma in a concentration-dependent manner. The clinical relevance of these findings is unknown.