Bivalirudin In 0.9% Sodium Chloride

Percutaneous Transluminal Coronary Angioplasty (PTCA)

Bivalirudin In 0.9% Sodium Chloride^® (bivalirudin) is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).

Percutaneous Coronary Intervention (PCI)

Bivalirudin In 0.9% Sodium Chloride with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the

REPLACE-2 trial is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI).

Bivalirudin In 0.9% Sodium Chloride 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

Bivalirudin In 0.9% Sodium Chloride in these indications is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin.

Limitation Of Use

The safety and effectiveness of Bivalirudin In 0.9% Sodium Chloride have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

Recommended Dose

Bivalirudin In 0.9% Sodium Chloride is for intravenous administration only.

Bivalirudin In 0.9% Sodium Chloride 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 Bivalirudin In 0.9% Sodium Chloride 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 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 0.3 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 is present.

For Patients Who Have HIT/HITTS

The recommended dose of Bivalirudin In 0.9% Sodium Chloride in patients with HIT/HITTS undergoing PCI is an IV bolus of 0.75 mg/kg. This should be followed by a continuous infusion at a rate of 1.75 mg/kg/h for the duration of the procedure.

For Ongoing Treatment Post Procedure

Bivalirudin In 0.9% Sodium Chloride 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 Bivalirudin In 0.9% Sodium Chloride infusion at a rate of 1.75 mg/kg/h following PCI/PTCA for up to 4 hours postprocedure should be considered to mitigate risk of stent thrombosis..

After four hours, an additional IV infusion of Bivalirudin In 0.9% Sodium Chloride may be initiated at a rate of 0.2 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. The infusion dose of Bivalirudin In 0.9% Sodium Chloride 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 1.75 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 0.25 mg/kg/h.

Instructions For Administration

Bivalirudin In 0.9% Sodium Chloride 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 0.9% Sodium Chloride for Injection. Then 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). 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 0.9% Sodium Chloride for Injection. Then 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 0.5 mg/mL. The infusion rate to be administered should be selected from the right-hand column in Table 1.

Table 1: Dosing Table

Bivalirudin In 0.9% Sodium Chloride should be administered via an intravenous line. 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 Bivalirudin In 0.9% Sodium Chloride, since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with Bivalirudin In 0.9% Sodium Chloride: 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 12.5 mg/mL.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparations of Bivalirudin In 0.9% Sodium Chloride 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 Bivalirudin In 0.9% Sodium Chloride. Reconstituted material may be stored at 2-8°C for up to 24 hours. Diluted Bivalirudin In 0.9% Sodium Chloride 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 In 0.9% Sodium Chloride is contraindicated in patients with:

• Active major bleeding;
• Hypersensitivity (e.g., anaphylaxis) to Bivalirudin In 0.9% Sodium Chloride or its components.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Bleeding Events

Although most bleeding associated with the use of Bivalirudin In 0.9% Sodium Chloride in PCI/PTCA occurs at the site of arterial puncture, hemorrhage can occur at any site. An unexplained fall in blood pressure or hematocrit should lead to serious consideration of a hemorrhagic event and cessation of Bivalirudin In 0.9% Sodium Chloride administration. Bivalirudin In 0.9% Sodium Chloride should be used with caution in patients with disease states associated with an increased risk of bleeding.

Acute Stent Thrombosis In Patients With STEMI Undergoing PCI

Acute stent thrombosis (AST) (<4 hours) has been observed at a greater frequency in Bivalirudin In 0.9% Sodium Chloride 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 an Bivalirudin In 0.9% Sodium Chloride 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.

Coronary Artery Brachytherapy

An increased risk of thrombus formation, including fatal outcomes, has been associated with the use of Bivalirudin In 0.9% Sodium Chloride in gamma brachytherapy.

If a decision is made to use Bivalirudin In 0.9% Sodium Chloride 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.

Laboratory Test Interference

Bivalirudin In 0.9% Sodium Chloride affects International Normalized Ratio (INR), therefore INR measurements made in patients who have been treated with Bivalirudin In 0.9% Sodium Chloride may not be useful for determining the appropriate dose of warfarin.

Nonclinical Toxicology

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. Â 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.

Use In Specific Populations

Pregnancy

Pregnancy Category B

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 evidence of impaired fertility or harm to the fetus attributable to bivalirudin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Bivalirudin In 0.9% Sodium Chloride is intended for use with aspirin. Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, Bivalirudin In 0.9% Sodium Chloride and aspirin should be used together during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether bivalirudin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Bivalirudin In 0.9% Sodium Chloride is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Bivalirudin In 0.9% Sodium Chloride in pediatric patients have not been established.

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. Patients treated with Bivalirudin In 0.9% Sodium Chloride experienced fewer bleeding events in each age stratum, compared to heparin.

Renal Impairment

The disposition of Bivalirudin In 0.9% Sodium Chloride was studied in PTCA patients with mild, moderate and severe renal impairment. The clearance of Bivalirudin In 0.9% Sodium Chloride was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysisdependent patients. The infusion dose of Bivalirudin In 0.9% Sodium Chloride may need to be reduced, and anticoagulant status monitored in patients with renal impairment.

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.

Bleeding

In 6010 patients undergoing PCI treated in the REPLACE-2 trial, Bivalirudin In 0.9% Sodium Chloride patients exhibited statistically significantly lower rates of bleeding, transfusions, and thrombocytopenia as noted in Table 2.

Table 2: Major Hematologic Outcomes REPLACE-2 (Safety Population)

In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, doubleblind studies comparing Bivalirudin In 0.9% Sodium Chloride to heparin, Bivalirudin In 0.9% Sodium Chloride patients exhibited lower rates of major bleeding and lower requirements for blood transfusions. The incidence of major bleeding is presented in Table 3. The incidence of major bleeding was lower in the Bivalirudin In 0.9% Sodium Chloride group than in the heparin group.

Table 3: Major Bleeding and Transfusions in BAT Trial (all patients)*

In the AT-BAT study, of the 51 patients with HIT/HITTS, 1 patient who did not undergo PCI had major bleeding during CABG on the day following angiography. Nine patients had minor bleeding (mostly due to access site bleeding), and 2 patients developed thrombocytopenia.

Other Adverse Reactions

Adverse reactions, other than bleeding, observed in clinical trials were similar between the Bivalirudin In 0.9% Sodium Chloride treated patients and the control groups.

Adverse reactions (related adverse events) seen in clinical studies in patients undergoing PCI and PTCA are shown in Tables 4 and 5.

Table 4: Most Frequent (>0.2%) Treatment-related Adverse Events (reactions)(through 30 days) in the REPLACE-2 Safety Population

Table 5: Adverse Reactions Other Than Bleeding Occurring In ≥ 5% of Patients in Either Treatment Group in BAT Trial

Serious, non-bleeding adverse events were experienced in 2% of 2161 Bivalirudin In 0.9% Sodium Chloride-treated patients and 2% of 2151 heparin-treated patients. The following individual serious non-bleeding adverse events were rare (>0.1% to <1%) and similar in incidence between Bivalirudin In 0.9% Sodium Chloride- and heparin-treated patients. These events are listed by body system: Body as a Whole: fever, infection, sepsis; Cardiovascular: hypotension, syncope, vascular anomaly, ventricular fibrillation; Nervous: cerebral ischemia, confusion, facial paralysis; Respiratory: lung edema; Urogenital: kidney failure, oliguria. In the BAT trial, there was no causality assessment for adverse events.

Immunogenicity/Re-Exposure

In in vitro studies, Bivalirudin In 0.9% Sodium Chloride exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.

Among 494 subjects who received Bivalirudin In 0.9% Sodium Chloride 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.

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 In 0.9% Sodium Chloride: 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.

Cases of overdose of up to 10 times the recommended bolus or continuous infusion dose of Bivalirudin In 0.9% Sodium Chloride have been reported in clinical trials and in postmarketing reports. A number of the reported overdoses were due to failure to adjust the infusion dose of bivalirudin in persons with renal dysfunction including persons on hemodialysis. Bleeding, as well as deaths due to hemorrhage, have been observed in some reports of overdose. In cases of suspected overdosage, discontinue Bivalirudin In 0.9% Sodium Chloride immediately and monitor the patient closely for signs of bleeding. There is no known antidote to Bivalirudin In 0.9% Sodium Chloride. Bivalirudin In 0.9% Sodium Chloride is hemodialyzable.

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 produces an immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration.

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.

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 achieved following an IV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion. Bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells. Bivalirudin is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with a half-life in patients with normal renal function of 25 min.

The disposition of bivalirudin was studied in PTCA patients with mild, moderate, and severe renal impairment. Drug elimination was related to glomerular filtration rate (GFR). Total body clearance was similar for patients with normal renal function and with mild renal impairment (60-89 mL/min). Clearance was reduced in patients with moderate and severe renal impairment and in dialysis-dependent patients (see Table 6 for pharmacokinetic parameters).

Bivalirudin is hemodialyzable, with approximately 25% cleared by hemodialysis.

Table 6: PK Parameters in Patients with Renal Impairment*