BIVALIRUDIN: 839 Adverse Event Reports & Safety Profile

Bivalirudin for injection, USP contains bivalirudin which is a specific and reversible direct thrombin inhibitor. Bivalirudin is a synthetic, 20 amino acid peptide, with the 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 2,180 daltons (anhydrous free base peptide).

Figure

1: Structure formula for bivalirudin trifluoroacetate Bivalirudin for injection, USP is supplied as a sterile, white to off white lyophilized cake or powder, 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 mg to 280 mg based on a range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents .

Bivalirudin Trifluoroactetate Chemical

Structure

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 )

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.

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 )

REACTIONS Most common adverse reaction (>2%) was bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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%) patients undergoing PCI for treatment of unstable angina and randomized to bivalirudin for injection 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 for injection 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 for injection exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.

Among

494 subjects who received bivalirudin for injection 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 for injection: 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.

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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) (&lt;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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

INTERACTIONS In clinical trials in patients undergoing PCI/ percutaneous transluminal coronary angioplasty (PTCA), co-administration of bivalirudin for injection 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 )