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 afterthe bolus dose has been administered, an activated clotting time (ACT) should be performed andan 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

Drug Compatibilities

No incompatibilities have been observed with administration sets.

Do not be administer the drugs listed in Table 2 in the same intravenous line with bivalirudin for injection.

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 8º 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.

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)] .

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 trialsof another drug and may not reflect the rates observed in practice.

In the BAT trials, 79 of the 2,161 (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 observedincidence of antibody (including neutralizing antibody) positivity in an assay may be influencedby several factors including assay methodology, sample handling, timing of sample collection,concomitant medications, and underlying disease. For these reasons, comparison of the incidenceof antibodies to bivalirudin for injection in the studies described below with the incidence ofantibodies in other studies or to other products may be misleading.

In in vitro studies, bivalirudin for injection exhibited no platelet aggregation response against serafrom patients with a history of HIT/HITTS.

Among 494 subjects who received bivalirudin for injection in clinical trials and were tested forantibodies, 2 subjects had treatment-emergent positive bivalirudin antibody tests. Neither subjectdemonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was notperformed. 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 uncertainsize, it is not always possible to reliably estimate their frequency or establish a causalrelationship to drug exposure.

The following adverse reactions have been identified during postapproval use of bivalirudin forinjection: fatal bleeding; hypersensitivity and allergic reactions including reports of anaphylaxis;lack of anticoagulant effect; thrombus formation during PCI with and without intracoronarybrachytherapy, including reports of fatal outcomes; pulmonary hemorrhage; cardiac tamponade;and INR increased.

8.1 Pregnancy

Risk Summary

There are no data available on use of bivalirudin for injection in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Reproduction studies in rats and rabbits administered subcutaneously doses up to 1.6 times and 3.2 times the maximum recommended human dose (MRHD) of 15 mg/kg/day based on body surface area (BSA) during organogenesis respectively,revealed no evidence of fetal harm.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population isunknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Reproductive studies have been performed in rats at subcutaneous doses up to 150 mg/kg/day(1.6 times the maximum recommended human dose based on body surface area) and rabbits at subcutaneous doses up to 150 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). These studies revealed no harm to the fetus attributable to bivalirudin.

At 500 mg/kg/day (equivalent to 5.4 times the maximum recommended human dose based onbody surface area) subcutaneously, litter sizes and live fetuses in rats were reduced. Fetal skeletal variations were also noted. Some of these changes could be attributed to maternal toxicity observed at high doses.

There is no study covering the peri-natal period because of the potential complications of drug induced hemorrhage during delivery.

8.2 Lactation

Risk Summary

It is not known whether bivalirudin is present in human milk. No data are available on the effects on the breastfed child or on milk production.

Bivalirudin was administered to lactating rats in reproduction studies (see Data). Thedevelopmental and health benefits of breastfeeding should be considered along with the mother’sclinical need for bivalirudin for injection and any potential adverse effects on the breastfed child from bivalirudin for injection or from the underlying maternal condition.

Data

Animal Data

Reproduction studies conducted in lactating female rats dosed subcutaneously daily with bivalirudin at doses up to 150 mg/kg/day (1.6 times the maximum recommended human dose,based on body surface area) from day 2 through day 20 of lactation revealed no adversedevelopmental outcomes to the pups.

8.4 Pediatric Use

The safety and effectiveness of bivalirudin for injection in pediatric patients have not been established.

8.5 Geriatric Use

In studies of patients undergoing PCI, 44% were ≥65 years of age and 12% of patients were ≥75 years old. Elderly patients experienced more bleeding events than younger patients.

8.6 Renal Impairment

The disposition of bivalirudin for injection was studied in PTCA patients with mild, moderateand severe renal impairment. The clearance of bivalirudin for injection was reduced approximately 21% in patients with moderate and severe renal impairment and was reduced approximately 70% in dialysis-dependent patients. [see Clinical Pharmacology (12.3)]. Reduce the infusion dose of bivalirudin for injection and monitor the anticoagulant status morefrequently in patients with renal impairment creatinine clearance less than 30mL/min (by Cockcroft Gault equation) [see Dosage and Administration (2.2)].

12.1 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-Arg3-Pro4 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.

12.2 Pharmacodynamics

In healthy volunteers and patients (with ≥70% vessel occlusion undergoing routine PTCA), bivalirudin exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of bivalirudin producesan immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hourfollowing cessation of bivalirudin administration. Bivalirudin for injection also increase INR. Therefore INR measurements made in bivalirudin for injection treated patients may not be useful for determining the appropriate dose of warfarin.

In 291 patients with ≥70% vessel occlusion undergoing routine PTCA, a positive correlation was observed between the dose of bivalirudin and the proportion of patients achieving ACT values of 300 sec or 350 sec. At a bivalirudin dose of 1 mg/kg IV bolus plus 2.5 mg/kg/h IV infusion for 4 hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec.

12.3 Pharmacokinetics

Bivalirudin exhibits linear pharmacokinetics following IV administration to patients undergoing PTCA. In these patients, a mean steady state bivalirudin concentration of 12.3 ± 1.7 mcg/mL is a chieved following an IV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion.

Distribution

Bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells.

Elimination

Bivalirudin has a half-life of 25 minutes in PTCA patients with normal renal function. The totalbody clearance of bivalirudin in PTCA patients with normal renal function is 3.4 mL/min/kg.

Metabolism

Bivalirudin is metabolized by proteolytic cleavage.

Excretion

Bivalirudin undergoes glomerular filtration. Tubular secretion and tubular reabsorption are also implicated in the excretion of bivalirudin, although the extent is unknown.

Specific Populations

Patients with Renal Impairment

Total body clearance was similar for PTCA patients with normal renal function and with mildrenal impairment. Clearance was reduced by 21% in patients with moderate and severe renal impairment with a half-life of 34 and 57 minutes, respectively.

In dialysis patients, clearance was reduced by 70%, with a half-life of 3.5 hours. Approximately25% bivalirudin is cleared by hemodialysis.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of bivalirudin. Bivalirudin displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the in vitro human lymphocyte chromosomal aberration assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses of bivalirudin up to 150 mg/kg/day, about 1.6 times the dose on a body surface area basis (mg/m2) of a 50 kg person given the maximum recommended dose of 15 mg/kg/day.

16.1 How Supplied

Bivalirudin for injection is supplied as a sterile, lyophilized powder in single-dose, glass vials. Each vial contains 250 mg of bivalirudin equivalent to an average of 275 mg of bivalirudin trifluoroacetate*.

*The range of bivalirudin trifluoroacetate is 270 to 280 mg based on a range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents.

Package of 10 Single-dose Vials NDC 55111-652-37

16.2 Storage

Store bivalirudin for injection dosage units at 20 to 25°C (68 to 77°F); [see USP Controlled Room Temperature].