Bivalirudin

75 mg/kg/h intravenous infusion for the duration of the procedure. 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).

1 Recommended Dosage Bivalirudin has been studied only in patients receiving concomitant aspirin. 75 mg/kg/h for the duration of the procedure. 3 mg/kg should be given if needed. 75 mg/kg/h for up to 4 hours post-procedure should be considered in patients with ST segment elevation MI (STEMI).

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. 3 )] . 3 Instructions for Preparation and Administration Bivalirudin 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. 9% Sodium Chloride for Injection. , 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 ). 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.

Table 2:

Drugs Not for Administration in the Same Intravenous Line with Bivalirudin 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 containing particulate matter should not be used. Reconstituted material will be a clear to slightly opalescent, colorless to slightly yellow solution. 4 Storage after Reconstitution Do not freeze reconstituted or diluted Bivalirudin.

Reconstituted material may be stored at 2° to 8°C for up to 24 hours. 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.

6 ADVERSE REACTIONS Most common adverse reaction (>2%) was bleeding. 1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. gov/medwatch. 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.

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 greater than 3 g/dL or leading to a transfusion of greater than 2 units of blood.

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. 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.

5 WARNINGS AND PRECAUTIONS • Bleeding Events: Bivalirudin increases the risk of bleeding. 2 ) • Acute Stent Thrombosis: Increased incidence of acute stent thrombosis in STEMI patients undergoing primary PCI. 2 ) • Thrombotic Risk with Coronary Artery Brachytherapy: An increased risk of thrombus formation, including fatal outcomes, in gamma brachytherapy.

1 )] . An unexplained fall in blood pressure or hematocrit should lead to serious consideration of a hemorrhagic event and cessation of bivalirudin administration. Monitor patients receiving bivalirudin for signs and symptoms of bleeding.

Monitor patients with disease states associated with an increased risk of bleeding more frequently for bleeding. 2%, 6/2911) with STEMI undergoing primary PCI. 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. 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.

3) ] .

1) ] . • Active major bleeding ( 4 ) • Hypersensitivity to bivalirudin or its components ( 4 )