Angiomax

Cardinal Health
The Medicines Company

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 U.S. Approval: 2000 INDICATIONS AND USAGEAngiomax is a direct thrombin inhibitor indicated for use as an anticoagulant in patients: With unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). ( 1.1 ) Undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as in the REPLACE-2 study. ( 1.2 ) With, or at risk of, heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS), undergoing PCI. ( 1.2 ) Angiomax is intended for use with aspirin. ( 1.3 ) Limitation of use Safety and effectiveness not established in patients with acute coronary syndromes who are not undergoing PTCA or PCI. ( 1.4 ) DOSAGE AND ADMINISTRATION For patients who do not have HIT/HITTS PCI/PTCA: 0.75 mg/kg intravenous (IV) bolus dose followed by a 1.75 mg/kg/h IV infusion for the duration of the procedure. ( 2.1 ) Perform activated clotting time (ACT) test 5 minutes post-bolus dose. If needed, give an additional bolus of 0.3 mg/kg. ( 2.1 ) After PCI/PTCA, IV infusion may be continued for up to 4 hours, after which a rate of 0.2 mg/kg/h can be used for up to 20 more hours, if needed. ( 2.1 ) Consider glycoprotein IIb/IIIa inhibitor (GPI) administration with procedural complications. ( 2.1 , 14.1 ) For patients who have HIT/HITTS The recommended dose of Angiomax in patients with HIT/HITTS undergoing PCI is an IV bolus of 0.75 mg/kg. This should be followed by an infusion at a rate of 1.75 mg/kg/h for the duration of the procedure. ( 2.1 ) After PCI/PTCA, IV infusion may be continued for up to 4 hours, after which a rate of 0.2 mg/kg/h can be used for up to 20 more hours, if needed. ( 2.1 ) For patients with Renal Impairment No reduction in bolus dose required. Consider reduction of the rate of infusion to 1 mg/kg/h for CrCL 0.5%) were headache, thrombocytopenia and fever. ( 6.1 )  To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-800-264-4662 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONSHeparin, warfarin, thrombolytics, or GPIs: Increased major bleeding risk with concomitant use. ( 7 ) USE IN SPECIFIC POPULATIONS Pediatric patients: Safety and efficacy not established. ( 8.4 ) Geriatric patients: Elderly patients may experience more bleeding than younger patients. ( 8.5 ) Renal impairment: Reduce infusion dose and monitor ACT. ( 2.2 , 8.6 ) See 17 for PATIENT COUNSELING INFORMATION Revised: 06/2010

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 ANGIOMAX INDICATIONS AND USAGE
  • 1.1  Percutaneous Transluminal Coronary Angioplasty (PTCA)
  • 1.2  Percutaneous Coronary Intervention (PCI)
  • 1.3  Use with Aspirin
  • 1.4  Limitation of Use
• 2 ANGIOMAX DOSAGE AND ADMINISTRATION
  • 2.1  Recommended Dose
  • 2.2  Dosing in Renal Impairment
  • 2.3  Instructions for Administration
  • 2.4  Storage after Reconstitution
• 3 DOSAGE FORMS AND STRENGTHS
• 4 ANGIOMAX CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1  Bleeding Events
  • 5.2  Coronary Artery Brachytherapy
• 6 ANGIOMAX ADVERSE REACTIONS
  • 6.1  Clinical Trials Experience
  • 6.2  Immunogenicity/Re-Exposure
  • 6.3  Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6  Renal Impairment
• 10 OVERDOSAGE
• 11 ANGIOMAX DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1  PCI/PTCA
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1  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).

1.2  Percutaneous Coronary Intervention (PCI)

Angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the REPLACE-2 trial [see Clinical Studies ( 14.1 )] 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.

1.3  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 ( 2.1 ) and Clinical Studies ( 14.1 )].

1.4  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

2.1  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 0.75 mg/kg, followed 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 [see Clinical Studies ( 14.1 )] is present.

For patients who have HIT/HITTS

The recommended dose of Angiomax 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

Continuation of the Angiomax infusion following PCI/PTCA for up to 4 hours post-procedure is optional, at the discretion of the treating physician. After four hours, an additional IV infusion of Angiomax may be initiated at a rate of 0.2 mg/kg/h (low-rate infusion), for up to 20 hours, if needed.

2.2  Dosing in Renal Impairment

No reduction in the bolus dose is needed for any degree of renal impairment. 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 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 [see Use In Specific Population ( 8.6 )].

2.3  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. Each reconstituted vial should be further diluted in 50 mL of 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 bag, reconstitute the 250 mg vial with 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 500 mL of 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.

Angiomax 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 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 12.5 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.

2.4  Storage after Reconstitution

Do not freeze reconstituted or diluted Angiomax. Reconstituted material may be stored at 2-8°C for up to 24 hours. Diluted Angiomax 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.

3 DOSAGE FORMS AND STRENGTHS

Angiomax is supplied as a sterile, lyophilized powder in single-use, glass vials. After reconstitution, each vial delivers 250 mg of Angiomax.

4 CONTRAINDICATIONS

Angiomax is contraindicated in patients with:

• Active major bleeding;
• Hypersensitivity (e.g., anaphylaxis) to Angiomax or its components [see Adverse Reactions ( 6.3 )].

5 WARNINGS AND PRECAUTIONS

5.1  Bleeding Events

Although most bleeding associated with the use of Angiomax 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 Angiomax administration [see Adverse Reactions ( 6.1 )]. Angiomax should be used with caution in patients with disease states associated with an increased risk of bleeding.

5.2  Coronary Artery Brachytherapy

An increased risk of thrombus formation, including fatal outcomes, has been associated with the use of Angiomax in gamma brachytherapy.

If a decision is made to use Angiomax 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 ( 6.3 )].

6 ADVERSE REACTIONS

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.

Bleeding

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

In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, double-blind studies comparing Angiomax to heparin, Angiomax 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 Angiomax group than in the heparin group.

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 Angiomax 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.

Serious, non-bleeding adverse events were experienced in 2% of 2161 Angiomax-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 Angiomax- 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.

6.2  Immunogenicity/Re-Exposure

In in vitro studies, Angiomax exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.

Among 494 subjects who received Angiomax 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 Angiomax: 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.

7 DRUG INTERACTIONS

In clinical trials in patients undergoing PCI/PTCA, co-administration of Angiomax with heparin, warfarin, thrombolytics, or GPIs was associated with increased risks of major bleeding events compared to patients not receiving these concomitant medications.

There is no experience with co-administration of Angiomax and plasma expanders such as dextran.

8 USE IN SPECIFIC POPULATIONS

8.1 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 Angiomax. 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.

Angiomax is intended for use with aspirin [see Indications and Usage ( 1.3 )]. Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, Angiomax and aspirin should be used together during pregnancy only if clearly needed.

8.3 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 Angiomax is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of Angiomax 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. Patients treated with Angiomax experienced fewer bleeding events in each age stratum, compared to heparin.

8.6  Renal Impairment

The disposition of Angiomax was studied in PTCA patients with mild, moderate and severe renal impairment. The clearance of Angiomax was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients. [see Clinical Pharmacology ( 12.3 )].

The infusion dose of Angiomax may need to be reduced, and anticoagulant status monitored in patients with renal impairment [see Dosage and Administration ( 2.2 )].

10 OVERDOSAGE

Single bolus doses of Angiomax up to 7.5 mg/kg have been reported without associated bleeding or other adverse reactions. In cases of overdosage, treatment with Angiomax should be immediately discontinued and the patient monitored closely for signs of bleeding. Angiomax is hemodialyzable [see Clinical Pharmacology ( 12.3 )]. There is no known antidote to Angiomax.

11 DESCRIPTION

Angiomax is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic, 20 amino acid peptide. The chemical name 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 (salt) hydrate (Figure 1). The molecular weight of Angiomax is 2180 daltons (anhydrous free base peptide).

Angiomax is supplied in single-use vials as a white lyophilized cake, which is sterile. Each vial contains 250 mg bivalirudin, 125 mg mannitol, and sodium hydroxide to adjust the pH to 5-6 (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 5-6.

Figure 1. Structural Formula for Bivalirudin

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Angiomax 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 Angiomax to thrombin is reversible as thrombin slowly cleaves the Angiomax-Arg₃-Pro₄ bond, resulting in recovery of thrombin active site functions.

In in vitro studies, Angiomax 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), Angiomax exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of Angiomax produces an immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hour following cessation of Angiomax administration.

In 291 patients with ≥70% vessel occlusion undergoing routine PTCA , a positive correlation was observed between the dose of Angiomax and the proportion of patients achieving ACT values of 300 sec or 350 sec. At an Angiomax 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

Angiomax exhibits linear pharmacokinetics following IV administration to patients undergoing PTCA. In these patients, a mean steady state Angiomax 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. Angiomax does not bind to plasma proteins (other than thrombin) or to red blood cells. Angiomax 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 Angiomax 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).

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Angiomax. Angiomax 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 Angiomax 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.

14 CLINICAL STUDIES

14.1  PCI/PTCA

Angiomax has been evaluated in five randomized, controlled interventional cardiology trials reporting 11,422 patients. Stents were deployed in 6062 of the patients in these trials - mainly in trials performed since 1995. Percutaneous transluminal coronary angioplasty, atherectomy or other procedures were performed in the remaining patients.

REPLACE-2 Trial

This was a randomized, double-blind, multicenter study reporting 6002 (intent-to-treat) patients undergoing PCI. Patients were randomized to treatment with Angiomax with the "provisional" use of platelet glycoprotein IIb/IIIa inhibitor (GPI) or heparin plus planned use of GPI. GPIs were added on a "provisional" basis to patients who were randomized to Angiomax in the following circumstances:

• decreased TIMI flow (0 to 2) or slow reflow;
• dissection with decreased flow;
• new or suspected thrombus;
• persistent residual stenosis;
• distal embolization;
• unplanned stent;
• suboptimal stenting;
• side branch closure;
• abrupt closure; clinical instability; and
• prolonged ischemia.

During the study, one or more of these circumstances occurred in 12.7% of patients in the Angiomax with provisional GPI arm. GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI arm (62.2% of eligible patients).

Patients ranged in age from 25-95 years (median, 63); weight ranged from 35-199 kg (median 85.5); 74.4% were male and 25.6% were female. Indications for PCI included unstable angina (35% of patients), myocardial infarction within 7 days prior to intervention (8% of patients), stable angina (25%) and positive ischemic stress test (24%). Stents were deployed in 85% of patients. Ninety-nine percent of patients received aspirin and 86% received thienopyridines prior to study treatment.

Angiomax was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration of the procedure. The activated clotting time (ACT - measured by a Hemochron^® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 0.3 mg/kg was given. At investigator discretion, the infusion could be continued following the procedure for up to 4 hours. The median infusion duration was 44 min. Heparin was administered as a 65 U/kg bolus. The activated clotting time (ACT - measured by a Hemochron^® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 20 units/kg was given. GPIs (either abciximab or eptifibatide) were given according to manufacturers' instructions. Both randomized groups could be given "provisional" treatments during the PCI at investigator discretion, but under double-blind conditions. "Provisional" treatment with GPI was requested in 5.2% of patients randomized to heparin plus GPI (they were given placebo) and 7.2% patients randomized to Angiomax with provisional GPI (they were given abciximab or eptifibatide according to pre-randomization investigator choice and patient stratification).

The percent of patients reaching protocol-specified levels of anticoagulation was greater in the Angiomax with provisional GPI group than in the heparin plus GPI group. For patients randomized to Angiomax with provisional GPI, the median 5 min ACT was 358 sec (interquartile range 320-400 sec) and the ACT was <225 sec in 3%. For patients randomized to heparin plus GPI, the median 5 min ACT was 317 sec (interquartile range 263-373 sec) and the ACT was <225 sec in 12%. At the end of the procedure, median ACT values were 334 sec (Angiomax group) and 276 sec (heparin plus GPI group).

For the composite endpoint of death, MI, or urgent revascularization adjudicated under double-blind conditions, the frequency was higher (7.6%)(95% confidence interval 6.7%-8.6%) in the Angiomax with "provisional" GPI arm when compared to the heparin plus GPI arm (7.1%)(95% confidence interval 6.1%-8.0%). However, major hemorrhage was reported significantly less frequently in the Angiomax with provisional GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study outcomes are shown in Table 7.

At 12 months' follow-up, mortality was 1.9% among patients randomized to Angiomax with "provisional" GPIs and 2.5% among patients randomized to heparin plus GPI.

Bivalirudin Angioplasty Trial (BAT)

Angiomax was evaluated in patients with unstable angina undergoing PTCA in two randomized, double-blind, multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1) a new onset of severe or accelerated angina or rest pain within the month prior to study entry or (2) angina or ischemic rest pain which developed between four hours and two weeks after an acute myocardial infarction (MI). Overall, 4312 patients with unstable angina, including 741 (17%) patients with post-MI angina, were treated in a 1:1 randomized fashion with Angiomax or heparin. Patients ranged in age from 29-90 (median 63) years, their weight was a median of 80 kg (39-120 kg), 68% were male, and 91% were Caucasian. Twenty-three percent of patients were treated with heparin within one hour prior to randomization. All patients were administered aspirin 300-325 mg prior to PTCA and daily thereafter. Patients randomized to Angiomax were started on an intravenous infusion of Angiomax (2.5 mg/kg/h). Within 5 min after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an intravenous bolus. The infusion was continued for 4 hours, then the infusion was changed under double-blinded conditions to Angiomax (0.2 mg/kg/h) for up to an additional 20 hours (patients received this infusion for an average of 14 hours). The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blinded bolus of placebo was administered. The Angiomax dose was not titrated to ACT. Median ACT values were: ACT in sec (5^th percentile-95^th percentile): 345 sec (240-595 sec) at 5 min and 346 sec (range 269-583 sec) at 45 min after initiation of dosing. Patients randomized to heparin were given a loading dose (175 IU/kg) as an intravenous bolus 5 min before the planned procedure, with immediate commencement of an infusion of heparin (15 IU/kg/h). The infusion was continued for 4 hours. After 4 hours of infusion, the heparin infusion was changed under double-blinded conditions to heparin (15 IU/kg/h) for up to 20 additional hours. The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blind bolus of heparin (60 IU/kg) was administered. Once the target ACT was achieved for heparin patients, no further ACT measurements were performed. All ACTs were determined with the Hemochron^® device. The protocol allowed use of open-label heparin at the discretion of the investigator after discontinuation of blinded study medication, whether or not an endpoint event (procedural failure) had occurred. The use of open-label heparin was similar between Angiomax and heparin treatment groups (about 20% in both groups).

The studies were designed to demonstrate the safety and efficacy of Angiomax in patients undergoing PTCA as a treatment for unstable angina as compared with a control group of similar patients receiving heparin during and up to 24 hours after initiation of PTCA. The primary protocol endpoint was a composite endpoint called procedural failure, which included both clinical and angiographic elements measured during hospitalization. The clinical elements were: the occurrence of death, MI, or urgent revascularization, adjudicated under double-blind conditions. The angiographic elements were: impending or abrupt vessel closure. The protocol-specified safety endpoint was major hemorrhage.

The median duration of hospitalization was 4 days for both the Angiomax and the heparin treatment groups. The rates of procedural failure were similar in the Angiomax and heparin treatment groups. Study outcomes are shown in Table 8.

AT-BAT Trial

This was a single-group open-label study which enrolled 51 patients with heparin-induced thrombocytopenia (HIT) or heparin induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI. Evidence for the diagnosis of HIT/HITTS was based on a clinical history of a decrease of platelets in patients after heparin administration [new diagnosis or history of clinically suspected or objectively documented HIT/HITTS defined as either: 1) HIT: positive heparin-induced platelet aggregation (HIPA) or other functional assay where the platelet count has decreased to <100,000/mL (minimum 30% from prior to heparin), or has decreased to <150,000/mL (minimum 40% from prior to heparin), or has decreased as above within hours of receiving heparin in a patient with a recent, previous exposure to heparin; 2) HITTS: thrombocytopenia as above plus arterial or venous thrombosis diagnosed by physician examination/laboratory and/or appropriate imaging studies]. Patients ranged in age from 48-89 years (median 70); weight ranged from 42-123 kg (median 76); 50% were male and 50% were female. Angiomax was administered as either 1 mg/kg bolus followed by 2.5 mg/kg/h (high dose in 28 patients) or 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion (lower dose in 25 patients) for up to 4 hours. Ninety-eight percent of patients received aspirin, 86% received clopidogrel and 19% received GPIs.

The median ACT values at the time of device activation were 379 sec (high dose) and 317 sec (lower dose). Following the procedure, 48 of the 51 patients (94%) had TIMI grade 3 flow and stenosis <50%. One patient died during a bradycardic episode 46 hours after successful PCI, another patient required surgical revascularization, and one patient experienced no flow requiring a temporary intra-aortic balloon.

Two of the fifty-one patients with the diagnosis of HIT/HITTS developed thrombocytopenia after receiving Angiomax and GPIs.

16 HOW SUPPLIED/STORAGE AND HANDLING

Angiomax is supplied as a sterile, lyophilized powder in single-use, glass vials. After reconstitution, each vial delivers 250 mg of Angiomax.

NDC 65293-001-01

Store Angiomax dosage units at 20-25°C (68-77°F). Excursions to 15-30°C permitted. [See USP Controlled Room Temperature.]

17 PATIENT COUNSELING INFORMATION

Advise patients to watch carefully for any signs of bleeding or bruising and to report these to their health care provider when they occur.

Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter medications or herbal products, prior to Angiomax use. Examples of other medications that should not be taken with Angiomax are warfarin and heparin.

Manufactured by:
BenVenue Laboratories
Bedford, OH

Distributed by:
ICS
Louisville, KY

Marketed by:
The Medicines Company
Parsippany, NJ 07054
For information call: (800) 264-4662

U.S. Patent 5,196,404

Hemochron^® is a registered trademark of International Technidyne Corporation, Edison, NJ.

06/2010

PRINCIPAL DISPLAY PANEL

Angiomax^®

For Injection 250 mg

Bivalirudin

5 Single Use Vials