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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use angiomax safely and effectively. See full prescribing information for angiomax . angiomax (bivalirudin) for injection, for intravenous use Initial Approval: 2000 _____ RECENT MAJOR CHANGES _____ Dosage and Administration ( ) 03/2016 Warnings and Precautions ( , ) 03/2016 _____ INDICATIONS AND USAGE _____ angiomax is a direct thrombin inhibitor indicated for use as an anticoagulant in patients: With unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). ( ) Undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as in the REPLACE-2 study.( ) With, or at risk of, heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS),undergoing PCI.

2 ( ) angiomax is intended for use with aspirin. ( ) Limitation of use Safety and effectiveness not established in patients with acute coronary syndromes who are not undergoing PTCA or PCI. ( ) _____ DOSAGE AND ADMINISTRATION _____ For patients who do not have HIT/HITTS PCI/PTCA: mg/kg intravenous (IV) bolus dose followedimmediately by a mg/kg/h IV infusion for the duration of the procedure. See FPI for remainder of monitoring and dosing information.( ) For patients who have HIT/HITTS PCI: mg/kg IV bolus dose followed immediately by a mg/kg/h IV infusion for the duration of the procedure. See FPI for remainder of monitoring and dosing information. ( ) For patients with STEMI _____ DOSAGE FORMS AND STRENGTHS _____ For injection: 250 mg of bivalirudin in a single-dose vial for reconstitution. (3) _____ CONTRAINDICATIONS _____ Active major bleeding (4) Hypersensitivity to bivalirudin or any product components (4) _____ WARNINGS AND PRECAUTIONS _____ Bleeding events: Hemorrhage can occur at any site.

3 Discontinue angiomax for an unexplained fall in blood pressure or hematocrit.( ) Acute Stent Thrombosis: Increased incidence of acute stent thrombosis in STEMI patients undergoing primary PCI. ( , ) Coronary artery brachytherapy: Risk of thrombus formation, including fatal outcomes, in gamma brachytherapy. ( ) Laboratory Test Interference: Bivalirudin interferes with INRmeasurements. ( ) _____ ADVERSE REACTIONS _____ Most common adverse reaction was bleeding (28%). Other adverse reactions (incidence > ) were headache, thrombocytopenia and fever. ( ) To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-800-264-4662 or FDA at 1-800-FDA-1088 or _____ DRUG INTERACTIONS_____ Heparin, warfarin, thrombolytics, or GPIs: Increased major bleeding risk with concomitant use. (7) _____ USE IN SPECIFIC POPULATIONS _____ Geriatric patients: Increased bleeding risk possible.

4 ( ) Renal impairment: Reduce infusion dose and monitor ACT. ( , ) See 17 for PATIENT COUNSELING INFORMATION Revised: 03/2016 Consider extending duration of infusion post-procedure up to 4 hours. ( ) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND Transluminal Coronary Angioplasty (PTCA) Coronary Intervention (PCI) with Limitation of Use 2 DOSAGE AND ADMINISTRATION in Renal for after Reconstitution3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND Stent Thrombosis in Patients with STEMI undergoing Artery Test Interference6 ADVERSE Trials Experience7 DRUG INTERACTIONS8 USE IN SPECIFIC Impairment10 OVERDOSAGE11 DESCRIPTION 12 CLINICAL PHARMACOLOGY Mechanism of Pharmacokinetics13 NONCLINICAL Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL PCI/PTCA16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed.

5 2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Percutaneous Transluminal Coronary Angioplasty (PTCA) angiomax (bivalirudin) is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). Percutaneous Coronary Intervention (PCI) angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the REPLACE-2 trial [see Clinical Studies ( )] is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). angiomax is indicated for patients with, or at risk of, heparin induced thrombocytopenia (HIT) or heparin induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI. Use with Aspirin angiomax in these indications is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin [see Dosage and Administration ( ) and Clinical Studies ( )].

6 Limitation of Use The safety and effectiveness of angiomax have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI. 2 DOSAGE AND ADMINISTRATION Recommended Dose angiomax is for intravenous administration only. angiomax is intended for use with aspirin (300-325 mg daily) and has been studied only in patients receiving concomitant aspirin. For patients who do not have HIT/HITTS The recommended dose of angiomax is an intravenous (IV) bolus dose of mg/kg, followed immediately by an infusion of mg/kg/h for the duration of the PCI/PTCA procedure. Five min after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of mg/kg should be given if needed. GPI administration should be considered in the event that any of the conditions listed in the REPLACE-2 clinical trial description [see Clinical Studies ( )] is present.

7 3 For patients who have HIT/HITTS The recommended dose of angiomax in patients with HIT/HITTS undergoing PCI is an IV bolus of mg/kg. This should be followed immediately by a continuous infusion at a rate of mg/kg/h for the duration of the procedure. For ongoing treatment post procedure angiomax infusion may be continued following PCI/PTCA for up to 4 hours post-procedure at the discretion of the treating physician. In patients with ST segment elevation myocardial infarction (STEMI) continuation of the angiomax infusion at a rate of mg/kg/h following PCI/PTCA for up to 4 hours post-procedure should be considered to mitigate risk of stent thrombosis [see Warnings and Precautions ( )]. After four hours, an additional IV infusion of angiomax may be initiated at a rate of mg/kg/h (low-rate infusion), for up to 20 hours, if needed. Dosing in Renal Impairment No reduction in the bolus dose is needed for any degree of renal impairment.

8 The infusion dose of angiomax may need to be reduced, and anticoagulant status monitored in patients with renal impairment. Patients with moderate renal impairment (30-59 mL/min) should receive an infusion of mg/kg/h. If the creatinine clearance is less than 30 mL/min, reduction of the infusion rate to 1 mg/kg/h should be considered. If a patient is on hemodialysis, the infusion rate should be reduced to mg/kg/h [see Use in Specific Population ( )]. Instructions for Administration angiomax is intended for intravenous bolus injection and continuous infusion after reconstitution and dilution. To each 250 mg vial, add 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Next, withdraw and discard 5 mL from a 50 mL infusion bag containing 5% Dextrose in Water or Sodium Chloride for Injection. Then add the contents of the reconstituted vial to the infusion bag containing 5% Dextrose in Water or Sodium Chloride for Injection to yield a final concentration of 5 mg/mL ( , 1 vial in 50 mL; 2 vials in 100 mL; 5 vials in 250 mL).

9 The dose to be administered is adjusted according to the patient s weight (see Table 1). If the low-rate infusion is used after the initial infusion, a lower concentration bag should be prepared. In order to prepare this lower concentration, reconstitute the 250 mg vial with 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Next, withdraw and discard 5 mL from a 500 mL infusion bag containing 5% Dextrose in Water or Sodium Chloride for Injection. Then add the contents of the reconstituted vial to the infusion bag containing 5% Dextrose in Water or Sodium Chloride for Injection to yield a final concentration of mg/mL. The infusion rate to be administered should be selected from the right-hand column in Table 1. 4 Table 1: Dosing Table Weight (kg) Using 5 mg/mL Concentration Using mg/mL Concentration Bolus mg/kg (mL) Infusion mg/kg/h (mL/h) Subsequent Low-rate Infusion mg/kg/h (mL/h) 43-47 7 16 18 48-52 20 53-57 8 19 22 58-62 9 21 24 63-67 10 23 26 68-72 28 73-77 11 26 30 78-82 12 28 32 83-87 13 30 34 88-92 36 93-97 14 33 38 98-102 15 35 40 103-107 16 37 42 108-112 44 113-117 17 40 46 118-122 18 42 48 123-127 19 44 50 128-132 52 133-137 20 47 54 138-142 21 49 56 143-147 22 51 58 148-152 60 5 angiomax should be administered via an intravenous line.

10 No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. The following drugs should not be administered in the same intravenous line with angiomax , since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with angiomax : alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin HCl. Dobutamine was compatible at concentrations up to 4 mg/mL but incompatible at a concentration of mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparations of angiomax containing particulate matter should not be used. Reconstituted material will be a clear to slightly opalescent, colorless to slightly yellow solution. Storage after Reconstitution Do not freeze reconstituted or diluted angiomax .