Control Number: 118585

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20

PART II: SCIENTIFIC INFORMATION 21

PHARMACEUTICAL INFORMATION 21 CLINICAL TRIALS 22 DETAILED PHARMACOLOGY 27 TOXICOLOGY 28 REFERENCES 31

PART III: CONSUMER INFORMATION. 32

ANGIOMAX(r)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

ANGIOMAX (bivalirudin) is contraindicated in patients with:

• Hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.

• Uncontrollable active bleeding

• Major blood clotting disorders

• Acute gastric or duodenal ulcer

• Cerebral hemorrhage

• Severe cerebro-spinal trauma

• Bacterial endocarditis

• Severe uncontrolled hypertension

• Diabetic or hemorrhagic retinopathy

• Proximal use of spinal/epidural anesthesia

WARNINGS AND PRECAUTIONS

General

ANGIOMAX (bivalirudin) should not be administered intramuscularly.

There is no known antidote to ANGIOMAX. ANGIOMAX is hemodialysable (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Brachytherapy:

To date, no formal clinical trials have been conducted with ANGIOMAX as the principal anticoagulant when performing catheter-based brachytherapy (beta or gamma) to reduce the risk of in-stent restenosis. Therefore, ANGIOMAX is not recommended for use in brachytherapy procedures.

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

Cardiac Surgery:

When ANGIOMAX is used in cardiac surgery, techniques that allow blood or blood-based solutions to lie stagnant should be avoided. Local bivalirudin levels may decrease due to metabolism by proteases from blood exposed to wound or foreign surfaces, potentially leading to local clot formation. During surgery, blood should not be allowed to stand in grafts, and grafts should preferably be stored and tested for flow and leakage with saline, instead of blood. Care should be taken to avoid stasis in the internal mammary artery after harvest. Circulation throughout the cardiopulmonary bypass (CPB) circuit must be ensured with particular attention paid to bypass lines that are blood-filled and then clamped off, or lines that are intermittently used for perfusion.

Hematologic

Hemorrhage:

Bleeding may occur in conjunction with use of any anticoagulant drug. As with other anticoagulants, ANGIOMAX should be used with extreme caution in patients at increased risk of hemorrhage. Bleeding can occur at any site during therapy with ANGIOMAX. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site (see DRUG INTERACTIONS; and ADVERSE REACTIONS, Bleeding).

Immune

Immunogenicity/Re-exposure: In in vitro studies, ANGIOMAX exhibited no platelet aggregation response against sera from patients with a history of HIT/TS. Among 494 patients who received ANGIOMAX in clinical trials and were tested for antibodies, two had treatment-emergent positive bivalirudin antibody tests. Neither patient demonstrated clinical evidence of allergic or anaphylactic reactions, and repeat testing was not performed. Nine other patients who had initial positive tests were negative on repeat testing. Of fifteen healthy volunteers who were exposed to ANGIOMAX twice, none developed antibodies.

Special Populations

Pregnant Women:

There are no studies available evaluating ANGIOMAX in pregnant women.

Studies in rats and rabbits have demonstrated no evidence of impaired fertility or harm to the fetus attributable to bivalirudin at clinically relevant doses. Because animal reproduction studies are not always predictive of human response, ANGIOMAX should be used during pregnancy only if clearly indicated. In PCI, ANGIOMAX is intended for use with ASA (see INDICATIONS AND CLINICAL USE). Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, ANGIOMAX and ASA should be used together during pregnancy only with caution and if benefit is thought to outweigh risk.

Nursing Women:

It is not known whether ANGIOMAX 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.

Pediatrics (< 18 years of age):

The safety and efficacy of ANGIOMAX in children have not been established.

Geriatrics (> 65 years of age): In studies of patients undergoing PCI, 44% were $65 years of age, and 12% were > 75 years old. Elderly patients experienced more bleeding events than younger patients.

DRUG INTERACTIONS

Overview

In clinical trials in patients undergoing PCI, co-administration of ANGIOMAX (bivalirudin) with heparin, warfarin or thrombolytics was associated with increased risk of major bleeding events compared to patients not receiving these concomitant medications. The safety and effectiveness of ANGIOMAX have not been formally established when used in conjunction with GPIIb/IIIa inhibitors. In two clinical trials, however, it was noted that the apparent bleeding advantage of ANGIOMAX over heparin plus planned GPIIb/IIIa inhibitor (Table 1, 2, 9, 10; see also ADVERSE REACTIONS, Bleeding) was practically nullified when a GPIIb/IIIa inhibitor was added to ANGIOMAX therapy. No formal drug interaction studies have been carried out with bivalirudin. Clinical studies evaluating pharmacodynamic effects and providing preliminary safety information of various products when used in combination with ANGIOMAX have been carried out, including the adenosine diphosphate antagonist, ticlopidine, and the GPIIb/IIIa inhibitors, abciximab, tirofiban and eptifibatide. Although data are limited, precluding conclusions regarding efficacy and safety in combination with these agents, the results do not suggest interaction between ANGIOMAX and the individual drugs studied in respect of their pharmacodynamic activities. These results are not sufficient to conclude definitively that no interaction exists.

DOSAGE AND ADMINISTRATION PCI

The recommended dosage of ANGIOMAX is an intravenous (i.v.) bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hr for the duration of the PCI procedure, with optional continuation of the infusion for up to 4 hours post-procedure, at the discretion of the treating physician. After 4 hours, an additional i.v. infusion of ANGIOMAX may be initiated at a rate of 0.2 mg/kg/hr for up to 20 hours, if needed. ANGIOMAX is intended for use with ASA (300-325 mg daily) and has been studied only in patients receiving concomitant ASA.

CARDIAC SURGERY

On-pump Cardiac Surgery

The recommended dosage of ANGIOMAX is an i.v. bolus of 1.0 mg/kg immediately followed by a 2.5 mg/kg/hr i.v. infusion. ANGIOMAX infusion may be terminated approximately 15 minutes prior to the anticipated end of cardiopulmonary bypass (CPB). The ACT may be used to check that the patient is anticoagulated following administration of ANGIOMAX. Infusion dose adjustment should not be necessary. For patients in whom hemofiltration is required during bypass, periodic ACT monitoring may be used (see DOSAGE AND ADMINISTRATION,

Dosing Pre- and Post-Cardiac Surgery, Medical Management Guidelines for Cardiac Surgery). If CPB is not terminated within 20 minutes or in patients who need to go back on bypass, a bivalirudin i.v. bolus of 0.5 mg/kg should be administered and a 2.5 mg/kg/hr i.v. infusion restarted and continued until 15 minutes prior to the anticipated end of CPB (See below DOSAGE AND ADMINISTRATION, Dosing Pre- and Post-Cardiac Surgery, Medical Management Guidelines for Cardiac Surgery for dosing of the CPB pump with ANGIOMAX).

Off-pump Cardiac Surgery

The recommended dosage of ANGIOMAX is an i.v. bolus of 0.75 mg/kg immediately followed by a 1.75 mg/kg/hr i.v. infusion for the duration of the procedure. The ACT may be used to check that the patient is anticoagulated following administration of ANGIOMAX. In clinical trials, investigators had the option to administer additional boluses of 0.1-0.5 mg/kg or make adjustments to the infusion rate in 0.25 mg/kg/hr increments if a higher level of anticoagulation was desired. The data suggest that infusion dose adjustments should not be necessary.

DOSAGE AND ADMINISTRATION, Dosing Pre- and Post-Cardiac Surgery, Medical Management Guidelines for Cardiac Surgery

For patients who may need to go on-pump, an additional ANGIOMAX i.v. bolus dose of 0.25 mg/kg should be administered to the systemic circulation and the infusion rate should be increased to 2.5 mg/kg/hr. In addition, see

for dosing of the pump.

Dosing Pre- and Post-Cardiac Surgery

ANGIOMAX may be used for anticoagulation up to 48 hours prior to surgery or in the postoperative phase up to 14 days after the procedure. An ANGIOMAX i.v. bolus of 0.1 mg/kg followed by an i.v. infusion of 0.2 mg/kg/hr may be administered, with aPTT monitoring to attain the clinically desired range of 1.5-2.5 times the baseline value.

Medical Management Guidelines for Cardiac Surgery:

CPB

Use of ANGIOMAX for anticoagulation during CPB requires little modification to the conventional bypass circuit setup. Before initiation of CPB, a bolus dose of 50 mg ANGIOMAX should be added to the circuit regardless of patient weight or volume of the prime. Either an open system or a closed system may be used for venous drainage. A closed system with venous reservoir bags generally has better flow characteristics with more internal mixing than a hardshell open venous reservoir. After completion of CPB, once it is clear that return to bypass support will not be needed, processing of the remaining circuit volume with a cell saver prior to a readministration to the patient is recommended. Provision to allow recirculation of the circuit following termination from CPB may be provided by administration of 50 mg of ANGIOMAX to the circuit followed by a continuous infusion of 50 mg/hr.

Cardioplegia

Crystalloid or blood-based cardioplegia may be used. If blood-based cardioplegia is used, blood should be obtained directly from the circuit and, after mixing with cardioplegia solution, should be immediately infused into the coronary system. If there are non-circulating portions of line between the pump and the patient, these lines should be flushed prior to cardioplegia administration. The cardioplegia setup can be circulated continuously by use of a connector. The volume of the cardioplegia circuit is typically 250 mL; for this volume, a continuous infusion of ANGIOMAX of 6.25 mg/hr will maintain anticoagulation within the circuit.

Hemofiltration

It is recommended that the ACT be measured frequently during hemofiltration to ensure the adequacy of anticoagulation.

Cell Saver

If a cell saver is used, an anticoagulant is necessary. A citrate-based solution (citrate phosphate dextrose [CPD], acid citrate dextrose [ACD], sodium citrate) is recommended.

DOSAGE ADJUSTMENT FOR PATIENTS WITH RENAL IMPAIRMENT

No reduction in the bolus dose of ANGIOMAX is needed regardless of the patient's baseline renal function. No infusion dose adjustment is required for patients with mild or moderate renal impairment undergoing either PCI or cardiac surgery. In PCI patients, reduction of the infusion rate to 1.0 mg/kg/hr should be considered if the creatinine clearance is less than 30 mL/min. If a PCI patient is dependent on hemodialysis, the infusion rate should be reduced to 0.25 mg/kg/hr. Patients with creatinine clearance below 30 mL/min have not been studied in cardiac surgery. See ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics for details regarding bivalirudin pharmacokinetics in patients with renal impairment. In patients with renal impairment, the ACT should be monitored with any dose alterations. ACT should be checked at 5 and 45 minutes. If ACT #250 seconds for renally-impaired patient, re- bolus and double the infusion rate to maintain ACT approximately 350 seconds. If ACT 250- 300 seconds in renally-impaired patient, re-bolus to maintain the ACT approximately 350 seconds. ANGIOMAX is hemodialysable (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

ADMINISTRATION

ANGIOMAX is intended for i.v. injection and infusion after dilution (see Reconstitution). The dose to be administered is adjusted according to the patient's weight, see Table 7.

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 nine 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. As with all parenteral drug products, i.v. mixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

RECONSTITUTION

ANGIOMAX is to be reconstituted with Water for Injection, USP as summarized below.

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 7. If the low-rate infusion is to be 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 7. 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.

OVERDOSAGE

Single bolus doses of ANGIOMAX up to 7.5 mg/kg have been reported without associated bleeding or adverse events. Discontinuation of ANGIOMAX (bivalirudin) leads to a gradual reduction in anticoagulant effects due to metabolism of the drug. There has been no experience of overdosage in human clinical trials. In case of overdosage, ANGIOMAX should be discontinued and the patient should be closely monitored for signs of bleeding. Supportive therapy should be instituted, as necessary. There is no known antidote to ANGIOMAX. ANGIOMAX is hemodialysable (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ANGIOMAX (bivalirudin) is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic peptide composed of twenty amino acids. 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, which allows fibrin to develop a covalently cross-linked framework, thus stabilising formed 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 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, and was not neutralized by products of the platelet release reaction. The clinical relevance of these findings is unknown. It also prolonged the aPTT, thrombin time (TT), and PT of normal human plasma in a concentration-dependent manner.

Pharmacodynamics

In healthy volunteers and patients undergoing routine angioplasty, bivalirudin exhibits linear dose-dependent and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of ANGIOMAX produces a prompt anticoagulant effect. Coagulation times return to the normal range approximately 1-2 hours following cessation of ANGIOMAX administration in patients with normal renal function. In 291 patients undergoing routine angioplasty, a positive correlation was observed between the dose of ANGIOMAX and the proportion of patients achieving ACT values of 300 or 350 seconds. In the subset of patients receiving ANGIOMAX at a dose of 1.0 mg/kg i.v. bolus plus 2.5 mg/kg/hr i.v. infusion for 4 hours, then followed by 0.2 mg/kg/hr, all patients reached maximal ACT values > 300 seconds. The correlation of various clotting tests with bivalirudin plasma concentration was studied in patients undergoing cardiac surgery. The data confirmed that, as during PCI, the activated clotting times were prolonged in a concentration-dependent manner during cardiac surgery.

Pharmacokinetics

Absorption:

Bivalirudin exhibits linear pharmacokinetics following i.v. administration to patients undergoing PTCA. In these patients, a mean steady state bivalirudin concentration of

12.3 +- 1.7 Fg/mL is achieved after administration of an i.v. bolus of 1 mg/kg followed by a 2.5 mg/kg/hr i.v. infusion given for 4 hours.

Distribution:

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

Excretion:

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 about 25 minutes. Bivalirudin is hemodialysable, with approximately 25% cleared by hemodialysis.

Special Populations and Conditions

Renal Insufficiency:

The disposition of bivalirudin was also studied in PTCA patients with mild and moderate renal impairment and in patients with severe renal impairment. Drug elimination was related to glomerular filtration rate (GFR), see Table 8.

For patients with renal impairment, the ACT should be monitored. In patients with renal impairment, the initial bolus dose should not be adjusted, however a reduction of the infusion dose to be administered may be required (see DOSAGE AND ADMINISTRATION, Dosage Adjustments for Patients with Renal Impairment).

Cardiac Surgery:

In a population of patients undergoing cardiac surgery utilizing CPB with normal renal function or mild/moderate renal dysfunction at baseline, the mean plasma bivalirudin concentration 5 minutes after administration of an i.v. bolus dose of 1.0 mg/kg followed by a 2.5 mg/kg/hr i.v. infusion was 13.3 +- 2.4 mg/mL. Bivalirudin levels were maintained at or above this concentration for the duration of infusion. Bivalirudin was eliminated with a clearance of 198 mL/min (2.34 mL/min/kg). Following termination of infusion, plasma bivalirudin concentrations declined biexponentially with an initial half-life of 27 minutes and a terminal half-life of 77 minutes. Temperature had no detectable effect on bivalirudin clearance. The clearance of bivalirudin was reduced by 20-30% in patients with mild or moderate renal impairment. The pharmacokinetics of bivalirudin in off-pump cardiac surgery patients was similar to that in on-pump surgery patients.

STORAGE AND STABILITY

ANGIOMAX dosage units are to be shipped and stored at controlled room temperature (20- 25oC). Do not freeze. Discard any unused portion of reconstituted solution remaining in the vial. 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.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ANGIOMAX (bivalirudin) is supplied as a sterile, lyophilized product in single-use, glass vials. Each vial of ANGIOMAX injection contains 250 mg of bivalirudin. Reconstitution of ANGIOMAX with 5 mL Water for Injection, USP yields a solution of pH 5.0-6.0 with the following composition: bivalirudin, 50 mg/mL; mannitol, 25 mg/mL; bound trifluoroacetate, 4-6 mg/mL; and sodium hydroxide to adjust pH to 5.0-6.0. Reconstituted material will be a clear to slightly opalescent, colourless to slightly yellow solution. Discard any unused portion of reconstituted solution remaining in the vial.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Bivalirudin is a synthetic peptide with the following attributes: Proper name: Bivalirudin Chemical name: 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 trifluoracetate (salt) hydrate Molecular formula and molecular mass: C98H138N24O33 *(C2HF3O2)x *(H2O)y 2180 daltons (anhydrous free base peptide) Structural formula:

O O O O O O O O

O O O O

H2N-CH-C-N-CH-C-NH-CH-C-N-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-

CH2 CH2 CH2

CH2 CH2 CH2

H H H H CH2

H CH2

-NH-CH-C-NH-CH-C-NH-CH-C-N-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-OH

CH2

CH CH2 CH2

CH2

CH2

CH2

CH2

CH2 C

CH2 C

CH3 CH2 CH2 CH3

CH2 C

CH2 C

CH CH3 CH3

O OH

O OH

O OH

O OH OH

Physicochemical properties: Bivalirudin is a white to off-white powder, with a pH of approximately 3 when dissolved in water without buffering. The compound's solubility is >= 140 mg/mL at pH 4.6-5.6. Bivalirudin is insoluble (<=0.1 mg/mL) in acetonitrile, chloroform, octanol and ethyl acetate. It is sparingly soluble (>=0.1 mg/mL, <=1.0 mg/mL) in acetone and sec- butanol, and soluble (>=1.0 mg/mL, <=10.0 mg/mL) in water, pH 3.3-4.0. It is freely soluble (>=10.0 mg/mL) in methanol (gels), ethanol (gels), and water at pH of 2.2 (gels), 2.4-3.1, 4.3-4.5, 4.6-5.6.

CLINICAL TRIALS

Study demographics and trial design PCI

ANGIOMAX (bivalirudin) has been evaluated in four interventional cardiology trials reporting 11,422 patients. Stents were deployed in 6,062 of the patients in these trials - mainly in trials performed since 1995. PTCA, atherectomy or other procedures were performed in the remaining patients. ANGIOMAX plus provisional platelet GPIIb/IIIa inhibition was evaluated versus heparin plus planned GPIIb/IIIa inhibition in 6010 patients undergoing PCI in the double-blind, randomized, multi-centre REPLACE-2 trial (Randomized Evaluation in PCI linking ANGIOMAX to reduced Clinical Events). Patients were aged 25-95 years with body weights 35-199 kg. Indications for PCI included unstable angina (35% of patients), myocardial infarction (MI) within 7-days prior to intervention (8%), stable angina (25%) and positive ischemic stress test (24%). Stents were deployed in 85% of patients, balloon angioplasty, atherectomy and other procedures were performed in 15%. Pretreatment with ASA (given in 99%) and thienopyridines (86%) was based on protocol recommendations. Pretreatment with other anticoagulants was allowed by protocol. ANGIOMAX was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/hr infusion for the duration of the procedure. At investigator discretion, the infusion could be continued following the procedure for up to 4 hours. The median infusion duration was 44 minutes. Heparin was administered as a 65 U/kg bolus. Abciximab and eptifibatide were given according to manufacturers' instructions. Both randomised groups could be given "provisional" treatments with GPIIb/IIIa inhibitors during the PCI at investigator discretion, but under double-blind conditions. Provisional treatment with GPIIb/IIIa inhibitors was requested in 5.2% of patients randomised to heparin plus GPIIb/IIIa (they were given placebo) and in 7.2% patients randomised to ANGIOMAX (they were given abciximab or eptifibatide according to pre- randomisation investigator choice and patient stratification). Reasons for provisional treatment included new or suspected thrombus, dissection with decreased flow and decreased Thrombosis In Myocardial Infarction (TIMI) flow (0-2) or slow reflow. The ACT (measured by a Hemochron(r) device) was checked 5 minutes after the first bolus of study medication. For patients randomised to ANGIOMAX, the median 5-minute ACT was 358 seconds (interquartile range 320-400 seconds) and the ACT was <225 seconds in 3%. For patients randomised to heparin plus GPIIb/IIIa inhibitors, the median 5-minute ACT was 317 seconds (interquartile range 263-373 seconds) and the ACT was <225 seconds in 12%. At the end of the procedure, median ACT values were 344 seconds (ANGIOMAX group) and 276 seconds (heparin plus GPIIb/IIIa inhibitor group). ANGIOMAX was also evaluated in patients with unstable angina undergoing PTCA in two randomised, double-blind, multicenter studies with identical protocols (the BAT trial, Bivalirudin Angioplasty Trial). Overall, 4312 patients with unstable angina, including 741 patients (17%) with post-MI angina, were treated in a 1:1 randomised fashion with ANGIOMAX or heparin. Patients evaluated had a median age of 63 years (range 29-90 years) and a median weight of 80 kg (range 39-120 kg), with 68% male, and 91% Caucasian. Twenty-three percent of patients were treated with open-label heparin within one hour prior to randomisation. All patients were administered ASA 300-325 mg prior to PTCA, and daily thereafter. Patients randomised to ANGIOMAX were started on an i.v. infusion of ANGIOMAX of 2.5 mg/kg/hr in a double-blind fashion. Within 5 minutes after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an i.v. bolus. The infusion was continued for 4 hours, then the infusion was changed, under double-blind conditions, to ANGIOMAX at 0.2 mg/kg/hr for up to an additional 20 hours, with patients receiving this infusion for an average of 14 hours. The ACT was checked at 5 minutes and at 45 minutes following commencement of the ANGIOMAX infusion. If on either occasion the ACT was < 350 seconds, an additional double-blinded bolus of placebo was administered. The ANGIOMAX dose was not titrated to ACT. Median ACT values (and observed values between the 5th and 95th percentile) were: 345 seconds (240-595 seconds) at 5 minutes, and 346 seconds (269-583 seconds) at 45 minutes after initiation of dosing. Patients randomised to heparin were given a loading dose of 175 IU/kg in a double-blind fashion as an i.v. bolus 5 minutes before the planned procedure, after commencement of an initial infusion of heparin at 15 IU/kg/hr. The infusion was continued for 4 hours. After 4 hours, the heparin infusion was changed, under double-blind conditions, to remain at heparin 15 IU/kg/hr for up to 20 additional hours. The ACT was checked at 5 minutes and at 45 minutes following commencement of the infusion. If on either occasion the ACT was < 350 seconds, an additional double-blind bolus of heparin at 60 IU/kg was administered. Once the target ACT was achieved for heparin patients, no further ACT measurements were performed. 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, pre-defined as "procedural failure", had occurred. The use of open-label heparin after administration of test drug was similar between ANGIOMAX and heparin treatment groups, at about 20% in both groups.

HIT/TS

Heparin-induced thrombocytopenia with or without thrombosis (HIT/TS) is an adverse immune reaction to systemic heparin exposure characterized by the formation of antibodies to complexes formed between heparin and platelet factor 4 (HPF-4) leading to platelet activation and intense thrombin generation. The clinical picture of HIT/TS is recognized by the association between thrombocytopenia, seropositivity for HPF-4 antibodies, and a predisposition to intravascular thrombosis. Patients with cardiovascular disease are frequently exposed to heparin and may form HPF-4 antibodies. Such patients are at risk of thrombosis when exposed to heparin during interventional or surgical procedures. It is estimated that the incidence of HIT following heparin exposure during cardiac surgery is 1- 3%. Prior to cardiac surgery, approximately 5-13% of patients have HPF-4 antibodies; the presence of these antibodies preoperatively has been shown to represent an independent risk factor for adverse outcomes such as death, organ dysfunction and prolonged hospitalization in patients administered heparin during cardiac surgery.

CHOOSE (patients with or at risk of HIT/TS) and EVOLUTION (non-HIT/TS patients) Trials in CARDIAC SURGERY The results of four trials provided clinical substantiation that ANGIOMAX is a safe and effective anticoagulant for use in patients with or at risk of HIT/TS undergoing cardiac surgery. Each of the two CHOOSE efficacy studies in patients with or at risk of HIT/TS undergoing on- or off- pump cardiac surgery included 50 prospective patients administered bivalirudin compared to approximately 50 historical control patients. Patients were considered to be with or at risk of HIT/TS if they had a new diagnosis or a documented history of HIT/TS. This was defined by a positive platelet aggregation assay, functional assay, or immunoassay for HPF-4 antibodies, and/or thrombocytopenia (platelet count decreased 50% or more from baseline) associated with heparin use. In addition patients with HIT plus any evidence of arterial or venous thrombosis (HITTS) were eligible for inclusion. The two EVOLUTION safety studies were each conducted in 150 non-HIT/TS patients undergoing on- or off-pump cardiac surgery, randomized 2:1, bivalirudin to heparin/protamine. Patients in the CHOOSE and EVOLUTION studies had a median age ranging from 64-67 years, 69-74% were male and 87-93% were Caucasian in the two treatment groups. The median weight ranged from 77-88 kg with a corresponding Body Mass Index (BMI) of 27-29. In the on-pump studies, patients were dosed with a bivalirudin i.v. bolus of 1.0 mg/kg followed by an i.v. infusion of 2.5 mg/kg/hr; patients undergoing off-pump surgery were dosed with an i.v. bolus of 0.75 mg/kg followed by an i.v. infusion of 1.75 mg/kg/hr.

Study results

PCI

In the REPLACE-2 trial, the primary protocol endpoint was a composite of three efficacy variables measured 30 days post-procedure, (death, MI, and urgent revascularization), and one safety variable, (in-hospital major hemorrhage), adjudicated under double-blind conditions. The rates of this composite endpoint were similar in the ANGIOMAX and heparin plus GPIIb/IIIa inhibitor treatment groups. The secondary composite ischemic endpoint of death, MI or urgent revascularisation was reported with similar incidence in both groups. Major hemorrhage was reported significantly less frequently in patients randomised to ANGIOMAX. Study outcomes are shown in Table 9.

#

: p<0.001 vs. heparin + GPIIb/IIIa inhibitor

In the BAT trial, the studies were designed to demonstrate the safety and efficacy of ANGIOMAX in patients undergoing PTCA as a treatment for unstable angina. The primary pre- specified endpoint was a composite endpoint called "procedural failure", which included both clinical and angiographic elements measured during hospitalisation. The clinical elements were the occurrence of death, MI, or urgent revascularisation, while the angiographic elements were identified as impending or abrupt vessel closure. The pre-specified safety endpoint was major hemorrhage. The median duration of hospitalisation was 4 days for both the ANGIOMAX and heparin treatment groups. The rates of so-called procedural failure were similar in the ANGIOMAX and heparin treatment groups. Study outcomes are shown in Table 10 below for the intent-to-treat population.

1. The protocol specified primary endpoint (a composite of death or MI or clinical deterioration of cardiac origin requiring revascularisation or placement of an aortic balloon pump or angiographic evidence of abrupt vessel closure).

2. Defined as: Q-wave MI; CK-MB elevation $ 2xULN, new ST- or T-wave abnormality, and chest pain $ 30 min; OR new LBBB with chest pain

$

30 min and/or elevated CK-MB enzymes; OR elevated CK-MB and new ST- or T-wave abnormality without chest pain; OR elevated CK-MB.

Defined as: any revascularisation procedure, including angioplasty, CABG, stenting, or placement of an intra-aortic balloon pump.

Defined as the occurrence of any of the following: intracranial $

bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin

3 g/dL or leading to a transfusion of $ 2 units of blood. In evaluating the efficacy and safety of ANGIOMAX in these clinical studies, the relatively high initial bolus dose of heparin (175 IU/kg) used in the comparator group should be noted. This is reflected by the mean ACT values reported in these studies of 377 seconds for ANGIOMAX- treated patients at 5 minutes after initiation of therapy, compared to 414 seconds with heparin; and 380 seconds for ANGIOMAX-treated patients at 45 minutes after initiation, compared to 418 seconds in those treated with heparin. Mean baseline ACT values were virtually identical for both groups at 145 and 144 seconds, respectively.

CHOOSE (patients with or at risk of HIT/TS) and EVOLUTION (non-HIT/TS patients) Trials in CARDIAC SURGERY In the CHOOSE and EVOLUTION trials, the primary endpoint was procedural success, defined as the absence of death, Q-wave MI, repeat coronary revascularization, and stroke at Day 7 or discharge, whichever occurred first. Procedural success rates were similar in the ANGIOMAX and the comparator groups in the CHOOSE and EVOLUTION studies at Day 7/discharge and at Day 30 (see Table 11). The incidences of death, Q-wave MI, revascularization and stroke were few and were similar in the treatment groups. The clinical trial data indicated that any of the commonly used activated clotting tests may be used to ensure that the patient is adequately anticoagulated following administration of ANGIOMAX.

1. Investigator-reported Q-wave MI data were used for the CHOOSE studies because data from the historical cohort could not be adjudicated

2. Q-wave MI data adjudicated by an independent Clinical Events Committee are used for these studies

3. Defined as absence of death, Q-wave MI, stroke and revascularization

DETAILED PHARMACOLOGY

Human Pharmacokinetics:

In healthy volunteers, ANGIOMAX (bivalirudin) was administered as a 15 minute i.v. infusion at a range of doses.

N/D: not detectable

Bivalirudin plasma concentrations were measured using an ELISA antibody based assay that detected bivalirudin and some bivalirudin metabolites. Further studies have been carried out in patients with varying degrees of renal impairment undergoing PTCA at the dose of 1.0 mg/kg i.v. bolus, plus 2.5 mg/kg/hr i.v. infusion for 4 hours followed by 0.5 mg/kg/hr for a further 4 hours, and in severely renally impaired patient volunteers where a bolus of 1.0 mg/kg and infusion of 0.5 mg/kg/hr for 10 hours was given, see Table 13 below. Plasma and urine levels of bivalirudin were detected by an LC/MS based method validated to quantify only intact bivalirudin.

These data indicate that patients with moderate and severe renal impairment exhibit about 20% reduction in renal clearance. The half-life was prolonged in these patients. Therefore, in patients with severe renal impairment (GFR <30 mL/min), ACT should be monitored and a reduction in the infusion dose should be considered (see DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Renal Impairment). An additional study of subjects with normal to severely impaired renal function (as determined by insulin clearance), demonstrated that plasma clearance of ANGIOMAX is proportional to glomerular filtration rate at all levels of renal function. The study also demonstrated that ANGIOMAX is hemodialysable.

TOXICOLOGY

Bivalirudin was administered to animals for up to 28 days by continuous i.v. infusion at dose levels of up to 80 times the clinically recommended dose of 15 mg/kg/day. Toxicological effects observed were directly related to the route of administration and to the anticoagulant activity of bivalirudin, such as local injection site phlebitis and hemorrhage, and internal organ hemorrhage. Bivalirudin caused no signs of toxicity at clinically relevant doses administered by either repeated i.v. injection or continuous infusion for up to 28 days. The relative anticoagulant activity of various species is reported below in Table 14.

Acute Toxicity:

Mouse:

No overt toxicity was observed within a 14-day observation period at i.v. and subcutaneous (s.c.) doses up to and including 200 mg/kg.

Rat:

An acute single dose i.v. study in rats assessed doses up to 200 mg/kg, when administered in

10 mL/kg saline infusion, and included a 14-day observation period. This study showed enlargement of the thymus gland and submandibular lymph nodes in both sexes. Acute toxicity was also observed, including death, respiratory distress, piloerection and vascular congestion of the lungs. Findings were observed at all dose levels. Another study, examining a 100 mg/kg single i.v. dose, administered in 2 mL/kg saline infusion, with a 14-day follow-up observation period, reported no adverse effects.

Monkey

: No mortality or adverse effects attributable to bivalirudin were observed in two monkeys administered doses up to 42 mg/kg over a four hour period by i.v. infusion.

Subchronic and Chronic Toxicity:

Rat:

Continuous i.v. infusion for 7 to 28 days at doses from 25 to 1200 mg/kg/day caused no adverse effects at 25 mg/kg/day. Mortality was observed at doses of 250 mg/kg/day for 28 days (2 of 30 animals) and 500 mg/kg/day for 28 days (2 of 10 animals) and above. At 500, 1000, and 1200 mg/kg/day, in addition to mortality, hemorrhage of internal organs was observed. A dose of 75 mg/kg/day and above for 28 days produced phlebitis at the injection site accompanied by effects in the spleen (enlargement), liver (sinusoidal histiocytosis/necrosis), and bone marrow (myeloid hypercellularity).

Monkey:

Clinical signs, body weight, and food consumption appeared normal in cynomolgus monkeys following continuous i.v. infusion for 14 or 28 days at doses of 15 and 45 mg/kg/day.

Internal organ hemorrhage was identified in some animals receiving 150 mg/kg/day over 14 days. Anticoagulant activities maintained during the study were approximately 85, 200, and 350 percent above baseline levels at the three doses tested, respectively. In a 28-day study, myocardial degeneration and/or necrosis were noted in 2 monkeys receiving the highest dose of 150 mg/kg/day. The lesions were associated with mild hemorrhage and appeared to occur during the last 7 to 10 days of the 28-day treatment period. No cardiac lesions were evident in monkeys treated with bivalirudin at 150 mg/kg/day for 14 days.

Special Studies:

Bivalirudin, when administered subcutaneously once/week at 1 mg/kg for 3 weeks was considered non-antigenic in guinea pigs. No antibodies cross-reacting with bivalirudin were detected in monkeys receiving i.v. doses up to 100 mg/kg and up to 150 mg/kg/day for 14 days by continuous infusion. Bivalirudin at 10 mg/mL did not cause hemolysis or plasma protein flocculation of human blood

in vitro.

Carcinogenesis and Genotoxicity:

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.

Reproductive and Developmental Toxicity:

Rat:

Reproductive toxicity, as defined by adverse effects on mating and fertility indices, was

observed only at dose levels associated with toxicity, i.e. 150 and 500 mg/kg/day. Developmental toxicity, i.e. adverse fetal effects, was observed only at maternally toxic doses of 150 and 500 mg/kg/day. No teratogenic effects were evident at any doses evaluated.

Rabbit:

Neither maternal nor developmental adverse effects were observed up to and including bivalirudin doses of 150 mg/kg/day.

REFERENCES

1. Bennett-Guerrero E, Slaughter TF, White WD, et al. Preoperative anti-PF4/heparin antibody level predicts adverse outcome after cardiac surgery. J Thorac Cardiovasc Surg 2005; 130:1567-1572.

2. Bittl JA, Strony J, Brinker JA, Ahmed WH et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. New Engl J Med 1995; 333:764-76.

3. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407:258-64.

4. Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006; 131:533-539.

5. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg 2007; 83:572-577.

6. Koster A, Spiess B, Jurmann M, et al. Bivalirudin provides rapid, effective and reliable anticoagulation during off-pump coronary revascularization: results of the "EVOLUTION-OFF" trial. Anesth Analg 2006; 103:540-544.

7. Kress DC, McDonald ML, Aronson S, et al. The impact of heparin PF4 antibody complexes on cardiac surgical outcomes: novel findings [abstract]. Abstract presented at: CHEST 2005, American College of Chest Physicians (ACCP); October 29 - November 3, 2005; Montreal, Quebec, Canada.

8. Lee DH, Warkentin TE. Frequency of heparin-induced thrombocytopenia. Chapter 4 In: Warkentin TE and Greinacher A (eds): Heparin-Induced Thrombocytopenia, Third Ed., NY: Marcel Dekker Inc.; 2004, pp. 107-148.

9. Lincoff AM, et al. Bivalirudin and Provisional Glycoprotein IIb/IIIa Blockade Compared with Heparin and Planned Glycoprotein IIb/IIIa Blockade During Percutaneous Coronary Intervention: REPLACE-2 Randomized Trial. JAMA 2003; 289:853-863.

10. Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990; 29:7101.

11. Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: Effect of renal function, dose, and gender. Clin Pharmacol Ther 2002; 71:433-439.

12. Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol 2000; 12:33F-36F.

13. Reddan D, et al. Anticoagulation in acute cardiac care patients with chronic kidney disease. Am Heart J 2003; 145:586-94.

14. Smedira NG, Dyke CM, Koster A, et al. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 2006; 131:686-692.

15. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery.

Ann Thorac Surg 2003; 76(6):2121-31.

PART III: CONSUMER INFORMATION

PrANGIOMAX(r)

Bivalirudin for Injection

This leaflet is part III of a three-part "Product Monograph" published when ANGIOMAX was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about ANGIOMAX. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

ANGIOMAX is an anticoagulant, a medication that prevents blood

from clotting. It is used in patients undergoing Percutaneous Coronary Intervention (PCI), a procedure that unblocks narrowed coronary arteries without having to perform surgery or during cardiac (heart) surgery called a Coronary Artery Bypass Graft (CABG) (sometimes referred to as "bypass" surgery). Heparin is also a drug that prevents blood from clotting and is commonly used in patients with cardiovascular disease during PCI or cardiac surgery. Rarely, a patient can develop antibodies to heparin that put them at risk for developing a clot if exposed to heparin. ANGIOMAX is used instead of heparin in these cases when these patients must undergo PCI or cardiac surgery.

What it does:

ANGIOMAX is a direct thrombin-inhibitor that prevents blood

from clotting during and after PCI or cardiac surgery.

When it should not be used:

ANGIOMAX should not be used in patients with:

A history of any allergic or other severe reaction to ANGIOMAX or any of its components (see 'What the nonmedicinal ingredients are' below)

Uncontrollable active bleeding

Major blood clotting disorders

Acute stomach or intestinal ulcer

Bleeding in the brain

Severe trauma to the brain or spine

Inflammation of the heart valves or inner layer of the heart wall caused by bacterial infections

Severe uncontrolled high blood pressure

An eye problem called "retinopathy" caused by diabetes or bleeding

Use of spinal/epidural anaesthesia

What the medicinal ingredient is:

Bivalirudin

What the nonmedicinal ingredients are:

Mannitol, sodium hydroxide, trifluoroacetate

What dosage forms it comes in:

ANGIOMAX is available as a powder (250 mg) for intravenous

(IV) injection after dilution.

WARNINGS AND PRECAUTIONS

ANGIOMAX (bivalirudin) should not be administered into muscle.

BEFORE you use ANGIOMAX talk to your doctor or pharmacist if:

You are at risk of experiencing bleeding

You are pregnant, planning on becoming pregnant or are breast feeding

The safety and effectiveness of ANGIOMAX in brachytherapy (a type of radiation therapy) has not been studied. Therefore, ANGIOMAX is not recommended for use in brachytherapy procedures.

As with any drug that prevents blood from clotting, bleeding may occur during or after your PCI or cardiac surgery. You may be at an increased risk for bleeding if you are elderly, female or are being given other drugs also known to cause bleeding like heparin or warfarin. Early signs of bleeding include nose or gum bleeds, blood in urine or stool, bruising easily and/or the appearance of a rash of round, red spots under the skin. If you are concerned about your risk for bleeding or experience any of these symptoms after your PCI or cardiac surgery, talk to your doctor immediately.

In patients undergoing cardiac surgery it is often necessary to receive a blood transfusion. This is true whether the doctor uses ANGIOMAX or heparin during your medical procedure. In patients undergoing PCI, the need for transfusions is less common.

The safety and effectiveness of ANGIOMAX has not been studied in children.

INTERACTIONS WITH THIS MEDICATION

No formal drug interaction studies have been carried out with bivalirudin. Use of ANGIOMAX together with heparin, warfarin, thrombolytics (drugs that break up blood clots) or glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors (drugs that prevent platelets from binding together) is associated with an increased risk of bleeding events.

ANGIOMAX is administered via an intravenous line from a glass bottle or polyvinyl chloride bags.

PROPER USE OF THIS MEDICATION

ANGIOMAX is only administered by trained medical professionals through an intravenous line.

ANGIOMAX will be administered to you after it has been dissolved in sterile water and diluted to a final concentration of 5 mg/mL.

Usual dose:

The dose of ANGIOMAX you will receive will be based on your

weight and will depend on what procedure, PCI or cardiac surgery, you are going to have.

PCI:

ANGIOMAX should be given as an IV bolus dose of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hr for the entire procedure. Your doctor may decide to continue it for 4 hours and then up to

20 hours after your procedure but at a reduced dose. ANGIOMAX

is intended for use with acetylsalicylic acid (ASA). If you have severe kidney disease, the infusion dose may have to be reduced to

1.0 mg/kg/hr. If you are on dialysis, the infusion rate should be reduced to 0.25 mg/kg/hr.

Cardiac Surgery:

On-pump Cardiac Surgery:

ANGIOMAX should be given as an IV bolus dose of 1.0 mg/kg followed by an infusion of 2.5 mg/kg/hr. ANGIOMAX infusion may be terminated approximately 15 minutes prior to the anticipated end of cardiopulmonary bypass (CPB). If CPB is not terminated within 20 minutes or if you need to go back on bypass, a bivalirudin IV bolus of 0.5 mg/kg should be administered and a 2.5 mg/kg/hr i.v. infusion restarted and continued until 15 minutes prior to the anticipated end of CPB.

Off-pump Cardiac Surgery:

ANGIOMAX should be given as an IV bolus dose of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hr for the duration of the procedure.

Patients with severe kidney disease have not been studied in cardiac surgery using ANGIOMAX.

Overdose:

Overdosage with ANGIOMAX may result in increased bleeding or adverse events. If overdose occurs, ANGIOMAX should be

discontinued and the patient should be monitored closely for signs of bleeding. Supportive therapy to treat any symptoms should be

started as needed. Once the administration of ANGIOMAX has

been stopped, there is a gradual reduction in the risk for bleeding as the body breaks down the drug. There is no known antidote to ANGIOMAX. ANGIOMAX is removed from the blood by dialysis.

sleeping, and vomiting.

In clinical studies during and after cardiac surgery, common side effects with ANGIOMAX were: anxiety, constipation, fluid build- up in the chest cavity, nausea, and vomiting.

Rare side effects:

Other side effects that occurred rarely with ANGIOMAX included: decreased platelet count, hives, and rash.

During routine medical use with ANGIOMAX, the following side effects have been reported: clot formation during PCI, and fatal bleeding.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Side effects that have been observed with ANGIOMAX have also been observed with other drugs that prevent blood clotting such as heparin. Although the adverse events listed below have been reported when ANGIOMAX was used, it does not necessarily mean that ANGIOMAX caused the event. The side effects listed below are for your information and if you have any concerns or think you are experiencing an adverse reaction, talk to your doctor or pharmacist immediately.

Common side effects:

In clinical studies during and after PCI, common side effects reported with ANGIOMAX were: angina, collapsed lung,

indigestion, nausea, nervousness, pain at the injection site, trouble

MORE INFORMATION

This is not a complete list of side effects. For any unexpected effects while taking ANGIOMAX, contact your doctor or pharmacist.

This document plus the full product monograph, prepared for health professionals can be found at: http://www.oryxpharma.com

or by contacting the sponsor, Oryx Pharmaceuticals Inc., at: 1-866-260-6291

This leaflet was prepared by Oryx Pharmaceuticals Inc. (A Subsidiary of Filiale d'Arrow Pharmaceuticals Inc.)

Last revised: March 11, 2008

HOW TO STORE IT

Store at controlled room temperature (20 - 25degC). Do not freeze. Discard any unused portion of the reconstituted solution remaining in the vial.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate Health Products and Food Branch

Health Canada

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.