ReoPro®
`Abciximab
`
`For intravenous administration
`DESCRIPTION:
`Abciximab, ReoPro®, is the Fab fragment of the chimeric human-murine monoclonal
`antibody 7E3. Abciximab binds to the glycoprotein (GP) lib/Ilia receptor of human
`platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin ( av~3)
`receptor found on platelets and vessel wall endothelial and smooth muscle cells.
`
`The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell
`culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a
`series of steps involving specific viral inactivation and removal procedures, digestion
`with papain and column chromatography.
`
`ReoPro® is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use.
`Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of
`0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water
`for Injection. No preservatives are added.
`
`CLINICAL PHARMACOLOGY:
`General- Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member
`of the integrin family ~f .adhesion receptors and the major platelet surface receptor
`involved in platelet aggregation. Abciximab inhibits platelet aggregation by preventing
`the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to
`GPIIb/IIIa receptor sites on activated platelets. The mechanism of action is thought to
`involve steric hindrance and/or conformational effects to block access of large molecules
`to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic
`acid) binding site of GPIIb/IIIa.
`
`Abciximab binds with similar affinity to the vitronectin receptor, also known as the av~3
`integrin. The vitronectin receptor mediates the procoagulant properties of platelets and
`the proliferative properties of vascular endothelial and smooth muscle cells. In in vitro
`studies using a model cell line derived from melanoma cells, Abciximab blocked av~3-
`mediated effects including cell adhesion (IC5o = 0.34 ~g/mL). At concentrations which,
`in vitro, provide > 80% GPIIb/IIIa receptor blockade, but above the in vivo therapeutic
`range, Abciximab more effectively blocked the burst of thrombin generation that
`followed platelet activation than select comparator antibodies which inhibit GPIIb/IIIa
`alone (1). The relationship ofthese in vitro data to clinical efficacy is unknown.
`
`Abciximab also binds to the activated Mac-1 receptor on monocytes and neutrophils (2).
`In in vitro studies, Abciximab and 7E3 IgG blocked Mac-1 receptor function as
`evidenced by inhibition of monocyte adhesion (3). In addition, the degree of activated
`Mac-1 expression on circulating leukocytes and the numbers of circulating leukocyte(cid:173)
`platelet complexes has been shown to be reduced in patients treated with Abciximab
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`compared to control patients ( 4 ). The relationship of these in vitro data to clinical
`efficacy is uncertain.
`
`Pre-clinical experience- Maximal inhibition of platelet aggregation was observed when
`::::: 80% of GPIIb/IIIa receptors were blocked by Abciximab. In non-human primates,
`Abciximab bolus doses of 0.25 mg!kg generally achieved a blockade of at least 80% of
`platelet receptors and fully inhibited platelet aggregation. Inhibition of platelet function
`was temporary following a bolus dose, but receptor blockade could be sustained at;::: 80%
`by continuous intravenous infusion. The inhibitory effects of Abciximab were
`substantially reversed by the transfusion of platelets in monkeys. The antithrombotic
`efficacy of prototype antibodies [murine 7E3 Fab and F(ab')2] and Abciximab was
`evaluated in dog, monkey and baboon models of coronary, carotid, and femoral artery
`thrombosis. Doses of the murine version of 7E3 or Abciximab sufficient to produce
`high-grade (2:. 80%) GPIIb/IIIa receptor blockade prevented acute thrombosis and yielded
`lower rates of thrombosis compared with aspirin and/or heparin.
`
`Pharmacokinetics-
`free plasma
`intravenous bolus administration,
`Following
`concentrations of Abciximab decrease rapidly with an initial half-life of less than 10
`minutes and a second phase half-life of about 30 minutes, probably related to rapid
`binding to the platelet GPIIb/IIIa receptors. Platelet function generally recovers over the
`course of 48 hours (5,6), although Abciximab remains in the circulation for 15 days or
`more in a platelet-bound state. Intravenous administration of a 0.25 mg/kg bolus dose of
`Abciximab followed by continuous infusion of 10 j.!g/min (or a weight-adjusted infusion
`of 0.125 j.!g/kg/min to a maximum of 10 j.!g/min) produces approximately constant free
`plasma concentrations throughout the infusion. At the termination of the infusion period,
`free plasma concentrations fall rapidly for approximately six hours then decline at a
`slower rate.
`
`Pharmacodynamics-
`Intravenous administration in humans of single bolus doses of
`Abciximab from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of
`platelet function as measured by ex vivo platelet aggregation in response to adenosine
`diphosphate (ADP) or by prolongation of bleeding time. At the two highest doses (0.25
`and 0.30 mg/kg) at two hours post injection (the first time point evaluated), over 80% of
`the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 j.!M
`ADP was almost abolished. The median bleeding time increased to over 30 minutes at
`both doses compared with a baseline value of approximately five minutes.
`
`Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a
`continuous infusion of 10 j.!g/min for periods of 12 to 96 hours produced sustained
`high-grade GPIIb/IIIa receptor blockade (2: 80%) and inhibition of platelet function (ex
`vivo platelet aggregation in response to 5 j.!M or 20 j.!M ADP less than 20% of baseline
`and bleeding time greater than 30 minutes) for the duration of the infusion in most
`patients. Similar results were obtained when a weight-adjusted infusion dose (0.125
`j.!g/kg/min to a maximum of 10 j.!g/min) was used in patients weighing up to 80 kg.
`Results in patients who received the 0.25 mg!kg bolus followed by a 5 j.tg/min infusion
`for 24 hours showed a similar initial receptor blockade and inhibition of platelet
`
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`aggregation, but the response was not maintained throughout the infusion period. The
`onset of Abciximab-mediated platelet inhibition following a 0.25 mglk:g bolus and 0.125
`flg/kg/min infusion was rapid and platelet aggregation was reduced to less than 20% of
`baseline in 8 of 10 patients at 10 minutes after treatment initiation.
`
`Low levels of GPIIb/IIIa receptor blockade are present for more than 10 days following
`cessation of the infusion. After discontinuation of Abciximab infusion, platelet function
`returns gradually to normal. Bleeding time returned to :$; 12 minutes within 12 hours
`following the end of infusion in 15 of20 patients (75%), and within 24 hours in 18 of20
`patients (90%). Ex vivo platelet aggregation in response to 5 flM ADP returned to~ 50%
`of baseline within 24 hours following the end of infusion in 11 of 32 patients (34%) and
`within 48 hours in 23 of 32 patients (72%). In response to 20 flM ADP, ex vivo platelet
`aggregation returned to~ 50% of baseline within 24 hours in 20 of 32 patients (62%) and
`within 48 hours in 28 of 32 patients (88% ).
`
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`CLINICAL STUDIES:
`Abciximab has been studied in four Phase 3 clinical trials, all of which evaluated the
`effect of Abciximab in patients undergoing percutaneous coronary intervention (PCI): in
`patients at high risk for abrupt closure of the treated coronary vessel (EPIC), in a broader
`group of patients (EPILOG), in unstable angina patients not responding to conventional
`medical
`therapy (CAPTURE), and
`in patients suitable for either conventional
`angioplasty/atherectomy or primary stent implantation (EPILOG Stent; EPISTENT).
`Percutaneous intervention included balloon angioplasty, atherectomy, or stent placement.
`All trials involved the use of various, concomitant heparin dose regimens and, unless
`contraindicated, aspirin (325 mg) was administered orally two hours prior to the planned
`procedure and then once daily.
`
`EPIC was a multicenter, double-blind, placebo-controlled trial of Abciximab in patients
`undergoing percutaneous transluminal coronary angioplasty or atherectomy (PTCA) who
`were at high risk for abrupt closure of the treated coronary vessel (7). Patients were
`allocated to treatment with: 1) Abciximab bolus plus infusion for 12 hours; 2) Abciximab
`bolus plus placebo infusion, or; 3) placebo bolus plus infusion. All patients received
`concomitant heparin (10,000 to 12,000 U bolus followed by an infusion for 12 hours).
`
`The primary endpoint was the composite of death, myocardial infarction (MI), or urgent
`intervention for recurrent ischemia within 30 days of randomization. The primary
`endpoint event rates in the Abciximab bolus plus infusion group were reduced mostly in
`the first 48 hours and this benefit was sustained through 30 days (7), 6 months (8), and
`three years (9).
`
`EPILOG was a randomized, double-blind, multicenter, placebo-controlled trial which
`evaluated Abciximab in a broad population of patients undergoing PCI (excluding
`patients with myocardial infarction and unstable angina meeting the EPIC high risk
`criteria) (I 0).
`Study procedures emphasized discontinuation of heparin after the
`procedure with early femoral arterial sheath removal and careful access site management
`(see PRECAUTIONS). EPILOG was a three-arm trial comparing Abciximab plus
`standard-dose heparin, Abciximab plus low-dose heparin, and placebo plus standard-dose
`heparin. Abciximab and heparin infusions were weight-adjusted in all arms. The
`Abciximab bolus plus infusion regimen was: 0.25 mg/kg bolus followed by a
`0.125 f..lg/kg/min infusion (to a maximum of 10 f..lg/min) for 12 hours. The heparin
`regimen was either a standard-dose regimen (initial I 00 U/kg bolus, target ACT 2 300
`seconds) or a low-dose regimen (initial 70 U/kg bolus, target ACT 2 200 seconds).
`
`The primary endpoint of the EPILOG trial was the composite of death or MI occurring
`within 30 days of PCI. The composite of death, MI, or urgent intervention was an
`important secondary endpoint. The endpoint events in the Abciximab treatment group
`were reduced mostly in the first 48 hours and this benefit was sustained through 30 days
`and six months (1 0) and one year ( 11 ). The (Kaplan-Meier) endpoint event rates at 30
`days are shown in Table I.
`
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`Table 1
`ENDPOINT EVENT RATES AT 30 DAYS -EPILOG TRIAL
`
`Placebo + Abciximab + Abciximab +
`Standard Dose
`Standard
`Low Dose
`Heparin
`Dose Heparin
`Heparin
`(n=939)
`(n=918)
`(n=935)
`
`Number of Patients(%)
`
`Death or Ml3
`
`p-value vs. placebo
`
`85 (9.1)
`
`38 (4.2)
`
`<0.001
`
`Death, Ml, or urgent intervention3
`
`109 (11.7)
`
`49 (5.4)
`
`<0.001
`
`35 (3.8)
`
`<0.001
`
`48 (5.2)
`
`<0.001
`
`p-value vs. placebo
`
`Components of Composite Endpointsb
`
`Death
`
`Acute myocardial infarctions in surviving
`patients
`
`Urgent interventions in surviving patients
`without an acute myocardial infarction
`
`7 (0.8)
`
`78 (8.4)
`
`4 (0.4)
`
`34 (3.7)
`
`3 (0.3)
`
`32 (3.4)
`
`24 (2.6)
`
`II (1.2)
`
`13 (1.4)
`
`a Patients who experienced more than one event in the first 30 days are counted only once.
`b Patients are counted only once under the most serious component (death > acute MI >
`urgent intervention).
`
`At the six-month follow up visit, the event rate for death, MI, or repeat (urgent or
`non-urgent) intervention remained lower in the Abciximab treatment arms (22.3% and
`22.8%, respectively, for the standard- and low-dose heparin arms) than in the placebo
`arm (25.8%) and the event rate for death, MI, or urgent intervention was substantially
`lower in the Abciximab treatment arms (8.3% and 8.4%, respectively, for the standard(cid:173)
`and low-dose heparin arms) than in tbe placebo arm (14.7%). The treatment associated
`effects continued to persist at the one-year follow up visit. The proportionate reductions
`in endpoint event rates were similar irrespective of the type of coronary intervention used
`(balloon angioplasty, atherectomy, or stent placement). Risk assessment using the
`American College of Cardiology/ American Heart Association clinical/morphological
`criteria had large inter-observer variability. Consequently, a low risk subgroup could not
`be reproducibly identified in which to evaluate efficacy.
`
`· The EPISTENT trial was a randomized, multicenter trial evaluating three different
`treatment strategies in patients undergoing PCI: conventional PTCA with Abciximab plus
`low-dose heparin, primary intracoronary stent implantation with Abciximab plus low-
`
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`dose heparin, and primary intracoronary stent implantation with placebo plus standard(cid:173)
`dose heparin (12). The heparin dose was weight-adjusted in all arms. The JJIS Palmaz(cid:173)
`Schatz stent was used in over 90% of the patients receiving stents. The two stent arms
`were blinded with respect to study agent (Abciximab or placebo) and heparin dose; the
`PCI arm with Abciximab was open-label. The Abciximab bolus plus infusion regimen
`was the same as that used in the EPILOG trial. The standard-dose and low-dose heparin
`regimens were the same as those used in the EPILOG trial. All patients were to receive
`aspirin; ticlopidine, if given, was to be started prior to study agent. Patient and access
`site management guidelines were the same as those for EPILOG, including a strong
`recommendation for early sheath removal.
`
`The results demonstrated benefit in both Abciximab arms (i.e., with and without stents)
`compared with stenting alone on the composite of death, MI, or urgent intervention
`(repeat PCI or CABG) within 30 days of PCI (12). The (Kaplan-Meier) endpoint event
`rates at 30 days are shown in Table 2.
`
`Table 2
`PRIMARY ENDPOINT EVENT RATE AT 30 DAYS - EPISTENT TRIAL
`
`Death, MI, or urgent interventiona
`p-value vs. placebo
`Components of Composite Endpointb
`Death
`Acute myocardial infarctions in surviving
`patients
`Urgent interventions in surviving patients
`without an acute myocardial infarction
`
`Placebo+ Abciximab + Abciximab +
`PTCA
`Stent
`Stent
`(n=796)
`(n=809)
`(n=794)
`Number of Patients(%)
`55 (6.9%)
`42 (5.3%)
`87 (10.8%)
`0.007
`<0.001
`
`5 (0.6%)
`
`2 (0.3%)
`
`6 (0.8%)
`
`77 (9.6%)
`
`35 (4.4%)
`
`40 (5.0%)
`
`5 (0.6%)
`
`5 (0.6%)
`
`9 (1.1%)
`
`a Patients who experienced more than one event in the first 30 days are counted only
`once.
`b Patients are counted only once under the most serious component (death > acute MI >
`urgent intervention).
`
`This benefit was maintained at 6 months: 12.1% of patients in the placebo/stent group
`experienced death, MI, or urgent revascularization compared with 6.4% of patients in the
`. Abciximab/stent group (p<O.OOI vs placebo/stent) and 9.2% in the Abciximab/PTCA
`group (p=0.051 vs placebo/stent). At 6 months, a reduction in the composite of death,
`MI, or all repeat (urgent or non-urgent) intervention was observed in the Abciximab/stent
`
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`group compared with the placebo/stent group (15.4% vs 20.4%, p=0.006); the rate of this
`composite endpoint was similar in the Abciximab/PTCA and placebo/stent groups
`(22.4% VS 20.4%, p=0.467). (13)
`
`CAPTURE was a randomized, double-blind, multicenter, placebo-controlled trial of the
`use of Abciximab in unstable angina patients not responding to conventional medical
`therapy for whom PCI was planned, but not immediately performed (14). The CAPTURE
`trial involved the administration of placebo or Abciximab starting 18 to 24 hours prior to
`PCI and continuing until one hour after completion of the intervention.
`
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`Patients were assessed as having unstable angina not responding to conventional medical
`therapy if they had at least one episode of myocardial ischemia despite bed rest and at
`least two hours of therapy with intravenous heparin and oral or intravenous nitrates.
`These patients were enrolled into the CAPTURE trial, if during a screening angiogram,
`they were determined to have a coronary lesion amenable to PCI. Patients received a
`bolus dose and intravenous infusion of placebo or Abciximab for 18 to 24 hours. At the
`end of the infusion period, the intervention was performed. The Abciximab or placebo
`infusion was discontinued one hour following the intervention. Patients were treated
`with intravenous heparin and oral or intravenous nitrates throughout the 18- to 24-hour
`Abciximab infusion period prior to the PC I.
`
`The Abciximab dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate
`of 10 j.lg/min. The CAPTURE trial incorporated weight adjustment of the standard
`heparin dose only during the performance of the intervention, but did not investigate the
`effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40
`hours. The primary endpoint of the CAPTURE trial was the occurrence of any of the
`following events within 30 days of PCI: death, Ml, or urgent intervention. The 30-day
`(Kaplan-Meier) primary endpoint event rates are shown in Table 3.
`
`Table 3
`PRIMARY ENDPOINT EVENT RATE AT 30 DAYS- CAPTURE TRIAL
`
`Death, MI, or urgent intervention a
`p-value vs. placebo
`Components of Primary Endpointb
`
`Abciximab
`Placebo
`(n=630)
`(n=635)
`Number of Patients(%)
`71 (11.3)
`101 (15.9)
`0.012
`
`Death
`MI in surviving patients
`Urgent intervention in surviving patients
`without an acute MI
`
`8 (1.3)
`49 (7.7)
`
`44 (6.9)
`
`6 (1.0)
`24 (3.8)
`
`41 (6.6)
`
`a Patients who experienced more than one event in the first 30 days are counted only
`once. Urgent interventions included any unplanned PCI after the· planned intervention,
`as well as any stent placement for immediate patency and any unplanned CABO or use
`of an intra-aortic balloon pump.
`b Patients are counted only once under the most serious component (death> acute MI >
`urgent intervention).
`
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`The 30-day results are consistent with the results of the other three trials, with the greatest
`effects on the myocardial infarction and urgent intervention components of the composite
`endpoint. As secondary endpoints, the components of the composite endpoint were
`analyzed separately for the period prior to the PCI and the period from the beginning of
`the intervention through Day 30. The greatest difference in MI occurred in the
`post-intervention period: the rates of MI were lower in the Abciximab group compared
`with placebo (Abciximab 3.6%, placebo 6.1%). There was also a reduction in MI
`occurring prior to the PCI (Abciximab 0.6%, placebo 2.0%). An Abciximab-associated
`reduction in the incidence of urgent intervention occurred in the post-intervention period.
`No effect on mortality was observed in either period. At six months of follow up, the
`composite endpoint of death, MI, or all repeat intervention (urgent or non-urgent) was not
`different between the Abciximab and placebo groups (Abciximab 31.0%, placebo 30.8%,
`p=0.77).
`
`Mortality was uncommon in all four trials. Similar mortality rates were observed in all
`arms within each trial. Patient follow-up through one year of the EPISTENT trial
`suggested decreased mortality among patients treated with Abciximab and stent
`placement compared to patients treated with stent alone (8/794 vs. 19/809, p=0.03 7).
`Data from earlier studies with balloon angioplasty were not suggestive of the same
`benefit. In all four trials, the rates of acute MI were significantly lower in the groups
`treated with Abciximab. Most of the Abciximab treatment effect was seen in reduction in
`the rate of acute non-Q-wave MI. Urgent intervention rates were also lower in
`Abciximab-treated groups in these trials.
`
`Anticoagulation:
`low dose heparin, weight-adjusted
`EPILOG and EPISTENT: Weight-adjusted
`Abciximab, careful vascular access site management and discontinuation of heparin after
`the procedure with early femoral arterial sheath removal were used.
`
`The initial heparin bolus was based upon the results of the baseline ACT, according to the
`following regimen:
`
`ACT< 150 seconds: administer 70 U/kg heparin
`ACT 150- 199 seconds: administer 50 U/kg heparin
`ACT;?;: 200 seconds: administer no heparin
`
`Additional20 U/kg heparin boluses were given to achieve and maintain an ACT of2: 200
`seconds during the procedure.
`
`Discontinuation of heparin immediately after the procedure and removal of the arterial
`sheath within six hours were strongly recommended in the trials. If prolonged heparin
`therapy or delayed sheath removal was clinically indicated, heparin was adjusted to keep
`the APTT at a target of 60 to 85 seconds (EPILOG) or 55 to 75 seconds (EPISTENT).
`
`CAPTURE trial: Anticoagulation was initiated prior to the administration of Abciximab.
`Anticoagulation was initiated with an intravenous heparin infusion to achieve a target
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`APTT of 60 to 85 seconds. The heparin infusion was not uniformly weight adjusted in
`this trial. The heparin infusion was maintained during the Abciximab infusion and was
`adjusted to achieve an ACT of 300 seconds or an APTT of 70 seconds during the PCI.
`Following the intervention, heparin management was as outlined above for the EPILOG
`trial.
`
`INDICATIONS AND USAGE:
`Abciximab is indicated as an adjunct to percutaneous coronary intervention for the
`prevention of cardiac ischemic complications
`•
`in patients undergoing percutaneous coronary intervention
`•
`in patients with unstable angina not responding to conventional medical therapy
`when percutaneous coronary intervention is planned within 24 hours
`
`Abciximab use in patients not undergoing percutaneous coronary intervention has not
`been studied.
`
`Abciximab is intended for use with aspirin and heparin and has been studied only in that
`setting, as described in CLINICAL STUDIES.
`
`CONTRAINDICATIONS:
`Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in
`the following clinical situations:
`• Active internal bleeding
`• Recent (within six weeks) gastrointestinal (GI) or genitourinary (GU) bleeding of
`clinical significance.
`• History of cerebrovascular accident (CVA) within two years, or CVA with a
`significant residual neurological deficit
`• Bleeding diathesis
`• Administration of oral anticoagulants within seven days unless prothrombin time is
`~ 1.2 times control
`• Thrombocytopenia(< 100,000 cells/f.!L)
`• Recent (within six weeks) major surgery or trauma
`•
`Intracranial neoplasm, arteriovenous malformation, or aneurysm
`• Severe uncontrolled hypertension
`• Presumed or documented history of vasculitis
`• Use of intravenous dextran before PCI, or intent to use it during an intervention
`
`Abciximab is also contraindicated in patients with known hypersensitivity to any
`component of this product or to murine proteins.
`
`WARNINGS:
`Abciximab has the potential to increase the risk of bleeding, particularly in the presence
`. of anticoagulation, e.g., from heparin, other anticoagulants, or thrombolytics (see
`ADVERSE REACTIONS: Bleeding).
`
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`The risk of major bleeds due to Abciximab therapy may be increased in patients receiving
`thrombolytics and should be weighed against the anticipated benefits.
`
`Should serious bleeding occur that is not controllable with pressure, the infusion of
`Abciximab and any concomitant heparin should be stopped.
`
`PRECAUTIONS:
`Bleeding Precautions- To minimize the risk of bleeding with Abciximab, it is important
`to use a low-dose, weight-adjusted heparin regimen, a weight-adjusted Abciximab bolus
`and infusion, strict anticoagulation guidelines, careful vascular access site management,
`discontinuation of heparin after the procedure and early femoral arterial sheath removal.
`
`Therapy with Abciximab requires careful attention to all potential bleeding sites
`(including catheter insertion sites, arterial and venous puncture sites, cutdown sites,
`needle puncture sites, and gastrointestinal, genitourinary, and retroperitoneal sites).
`
`Arterial and venous punctures, intramuscular injections, and use of urinary catheters,
`nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be
`minimized. When obtaining intravenous access, non-compressible sites (e.g., subclavian
`or jugular veins) should be avoided. Saline or heparin locks should be considered for
`blood drawing. Vascular puncture sites should be documented and monitored. Gentle
`care should be provided when removing dressings.
`
`Femoral artery access site: Arterial access site care is important to prevent bleeding.
`Care should be taken when attempting vascular access that only the anterior wall of the
`femoral artery is punctured, avoiding a Seldinger (through and through) technique for
`obtaining sheath access. Femoral vein sheath placement should be avoided unless
`needed. While the vascular sheath is in place, patients should be maintained on complete
`bed rest with the head of the bed ~ 30° and the affected limb restrained in a straight
`position. Patients may be medicated for back/groin pain as necessary.
`
`Discontinuation of heparin immediately upon completion of the procedure and removal
`of the arterial sheath within six hours is strongly recommended if APTT ~ 50 sec or
`ACT::;; 175 sec (See PRECAUTIONS: Laboratory Tests). In all circumstances, heparin
`should be discontinued at least two hours prior to arterial sheath removal.
`
`Following sheath removal, pressure should be applied to the femoral artery for at least 30
`minutes using either manual compression or a mechanical device for hemostasis. A
`pressure dressing should be applied following hemostasis. The patient should be
`maintained on bed rest for six to eight hours following sheath removal or discontinuation
`of Abciximab, or four hours following discontinuation of heparin, whichever is later.
`The pressure dressing should be removed prior to ambulation. The sheath insertion site
`and distal pulses of affected leg(s) should be frequently checked while the femoral artery
`· sheath is in place and for six hours after femoral artery sheath removal. Any hematoma
`should be measured and monitored for enlargement.
`
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`The following conditions have been associated with an increased risk of bleeding and
`may be additive with the effect of Abciximab in the angioplasty setting: PCI within 12
`hours of the onset of symptoms for acute myocardial infarction, prolonged PCI (lasting
`more than 70 minutes) and failed PCI.
`
`In the EPIC,
`Use of Thrombolytics, Anticoagulants and Other Antiplatelet Agents-
`EPILOG, CAPTURE, and EPISTENT trials, Abciximab was used concomitantly with
`heparin and aspirin. For details of the anticoagulation algorithms used in these clinical
`trials, see CLINICAL STUDIES: Anticoagulation. Because Abciximab inhibits platelet
`aggregation, caution should be employed when it is used with other drugs that affect
`hemostasis, including thrombolytics, oral anticoagulants, non-steroidal anti-inflammatory
`drugs, dipyridamole, and ticlopidine.
`
`In the EPIC trial, there was limited experience with the administration of Abciximab with
`low molecular weight dextran. Low molecular weight dextran was usually given for the
`deployment of a coronary stent, for which oral anticoagulants were also given. In the 11
`patients who received low molecular weight dextran with Abciximab, five had major
`bleeding events and four had minor bleeding events. None of the five placebo patients
`treated with low molecular weight dextran had a major or minor bleeding event (see
`CONTRAINDICA TIONS).
`
`There are limited data on the use of Abciximab in patients receiving thrombolytic agents.
`Because of concern about synergistic effects on bleeding, systemic thrombolytic therapy
`should be used judiciously.
`
`Thrombocytopenia- Platelet counts should be monitored prior to treatment, two to four
`hours following the bolus dose of Abciximab and at 24 hours or prior to discharge,
`whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet
`decrease to less than 100,000 cells/J.!L and a decrease of at least 25% from pre-treatment
`value), additional platelet counts should be determined. These platelet counts should be
`drawn in three separate tubes containing ethylenediaminetetraacetic acid (EDT A), citrate
`in vitro
`and heparin, respectively,
`to exclude pseudothrombocytopenia due
`to
`anticoagulant interaction.
`If true thrombocytopenia is verified, Abciximab should be
`immediately discontinued and the condition appropriately monitored and treated. For
`patients with thrombocytopenia in the clinical trials, a daily platelet count was obtained
`until it returned to normal.
`If a patient's platelet count dropped to 60,000 cells/).!L,
`heparin and aspirin were discontinued. If a patient's platelet count dropped below 50,000
`cells/J.!L, platelets were transfused. Most cases of severe thrombocytopenia (< 50,000
`cells/J.!L) occurred within the first 24 hours of Abciximab administration.
`
`In the event of serious uncontrolled bleeding or the
`Restoration of Platelet Function-
`need for emergency surgery, Abciximab should be discontinued. If platelet function does
`not return to normal, it may be restored, at least in part, with platelet transfusions.
`
`Laboratory Tests- Before infusion of Abciximab, platelet count, prothrombin time,
`ACT and APTT should be measured to identify pre-existing hemostatic abnormalities.
`
`12
`
`Sanofi/Regeneron Ex. 1 044, pg 1 089
`
`Merck Ex. 1044, pg 1115
`
`

`
`Based on an integrated analysis of data from all studies, the following guidelines may be
`utilized to minimize the risk for bleeding:
`
`When Abciximab is initiated 18 to 24 hours before PCI, the APTT should be maintained
`between 60 and 85 seconds during the Abciximab and heparin infusion period.
`
`During PCI the ACT.should be maintained between 200 and 300 seconds.
`
`If anticoagulation is continued in these patients following PCI, the APTT should be
`maintained between 55 and 75 seconds.
`
`The APTT or ACT should be checked prior to arterial sheath removal. The sheath should
`not be removed unless APTT :5 50 seconds or ACT :5 175 seconds.
`
`Readministration- Administration of Abciximab may result in human anti-chimeric
`antibody (HACA) formation that could potentially cause allergic or hypersensitivity
`reactions (including anaphylaxis),
`thrombocytopenia or diminished benefit upon
`readministration of Abciximab. In the EPIC, EPILOG, and CAPTURE trials, positive
`HACA responses occurred in approximately 5.8% of the Abciximab-treated patients.
`There was no excess of hypersensitivity or allergic reactions related to Abciximab
`treatment.
`
`Readministration of Abciximab to 29 healthy volunteers who had not developed a HACA
`to any change
`in Abciximab
`response after first administration has not
`led
`pharmacokinetics or to any reduction in antiplatelet potency. However, results in this
`small group of patients suggest that the incidence of HACA response may be increased
`after readministration. Readministration to patients who have developed a positive
`HACA response after initial administration has not been evaluated in clinical trials.
`
`Allergic Reactions- Anaphylaxis has not been reported for Abciximab-treated patients
`If it does,
`in any of the Phase 3 clinical trials. However, anaphylaxis may occur.
`administration of Abciximab should be immediately stopped and standard appropriate
`resuscitative measures should be initiated.
`
`Drug Interactions- Although drug interactions with Abciximab have not been studied
`systematically, Abciximab has been administered to patients with ischemic heart disease
`treated concomitantly with a broad range of medications used in the treatment of angina,
`myocardial infarction and hypertension. These medications have included heparin,
`warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, angiot