1958/ELI LILLY
`
`Nebcin-Cont.
`
`REDUCED DOSAGE NOMOGRAM*
`Creatinine Clearance (ml/min/1. 73 m 2 )
`
`70
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`11
`
`" :;;
`"' ...
`E
`_g
`" "' "' "' 0 c
`
`;;;
`E
`0 z
`0
`E
`" ~
`" c..
`
`53 3 3 2.4 1.9 1 6 1.4 1.3
`
`Serum Creatinine
`(mg/100 ml)
`*Scales have been adjusted to
`facilitate dosage calculations.
`
`Use of ADD-Vantage Nebcin Vials -ADD· Vantage Nebcin
`vials are not intended for multiple Use and should ilot be
`used with a syringe in the conventional way. These products
`are intended for use only with Abbott ADD-Vantage diluent
`containers and in those instances in which the physician's
`order specified 60-mg or 80-mg doses. Use within 24 hours
`after activation.
`Nebcin should not be physically premixed with other drugs
`but should be administered separately according to the rec(cid:173)
`ommended dose and route.
`Prior to administration, parenteral drug products should be
`inspected visually for particulate matter and discoloration
`whenever solution and container permit.
`INSTRUCTIONS FOR USE·ADD· Vantage® Vial
`To Open:
`Peel overwrap from the comer and remove container. Some
`opacity of the plastic due to moisture absorption during the
`sterilization process may be observed. This is normal and
`does not affect the solution quality or safety. The opacity
`will diminish gradually.
`To Assemble Vial and Flexible Diluent Container: USE
`ASEPTIC TECHNIQUE
`1. Remove the protective covers from the top of the vial and
`the vial port on the diluent container as follows:
`a. To remove the breakaway vial cap, swing the pull ring
`over the top of the vial and pull down far enough to start
`the opening (SEE FIGURE 1.), then pull straight up ta
`remove the cap. (SEE FIGURE 2.) NOTE: Do not access
`vial with syringe.
`
`Fig.1~
`
`Lri''
`
`b. To remove the vial port cover, grasp the tab on the pull
`ring, pull up to break the three tie strings, then pull back
`to remove the cover. (SEE FIGURE 3.)
`
`Fig.3
`
`2. Screw the vial into the viaJ port until it will go no further.
`THE VIAL MUST BE SCREWED IN TIGHTLY TO AS(cid:173)
`SURE A SEAL. This occurs approximately 1/2 turn (180')
`after the first audible click. (SEE FIGURE 4.} The click·
`ing sound does not assure a seal; the vial must be turned
`
`as fAr as it will go. NOTE: Once vial is seated, do not at(cid:173)
`tempt to remove. (SEE FIGURE 4.)
`
`ADD-Vantage® (vials and diluent containers} is a registered
`trademark of Abbott·Laboratories.
`Literature revised March 25, 1999
`PA 2012 AMP
`
`[032599]
`
`PHYSICIANS' DESK REFERENCE®
`
`Fig.4
`
`3. Recheck the vial to assure that it is tight by trying to turn
`it further in the direction of assembly.
`4. Label appropriately.
`To Mix the Drug:
`1. Squeeze the bottom of the diluent container gently to in(cid:173)
`flate the portion of the container surrounding the end of
`the drug vial.
`2. With the other hand, push the drug vial down into the
`container telescoping the walls of the container. Grasp
`the inner cap of the vial through the walls of the con(cid:173)
`tainer. (SEE FIGURE 5.)
`
`Fig. 5
`
`3. Pull the inner cap from the drug vial (SEE FIGURE 6.)
`VerifY that the rubber stapper has been pulled out, allow(cid:173)
`ing the drug and diluent to mix.
`
`Fig. 6
`
`4. Mix container contents thoroughly and use within the
`specified time.
`5. Immediately prior to administration, confirm that the
`contents of the vial have been mixed by observing the in(cid:173)
`ner cap/stopper in the flexible container.
`HOW SUPPLIED
`Multiple-Dose Vials:
`80 mg*/2 mL, 2 mL (No. 781)-('rraypakt of 25) NDC
`0002-1499-25
`Pediatric, 20 mg*/2 mL, 2 mL (No. 782)-(1s) NDC 0002·
`0501-01
`40 mg*/mL, 1.2 g/30 mL (No. 7090H1'raypak of 6) NDC
`0002-7090·16
`ADD-Vantage Vials:
`60 mg*/6 mL, 6 mL (No. 7293)-('rraypak of 25) NDC
`0002· 7293·25
`80 mg*/8 mL, 8 mL (No. 7294H1'raypak of 25) NDC
`0002-7294-25
`'fhe above ADD-Vantage vials are to be used only with Ab(cid:173)
`ti'ott Laboratories' diluent containers.
`Instructions for the use of ADD-Vantage vials are described
`above. (See DOSAGE AND ADMINISTRATION.)
`Also Available:
`Phannacy Bulk Vial:
`1.2 g* (Dry Powder) (40-mL size) (No. 7040H1'raypak of6)
`NDC 0002-7040-16
`Store at controlled room temperature 59o to 86°F (15° ·to
`30"C).
`
`* Equivalent to tobramycin.
`t TraypakTM (multivial carton, Lilly).
`REFERENCES
`1. National Committee for Clinical Laboratory Standards,
`Performance Standards for Antimicrobial Disk Suscepti(cid:173)
`bility Tests-Sixth Edition. Approved Standard NCCLS
`Document M2-A6, Vol. 17, No 1, NCCLS, Wayne, PA,
`1997.
`2. National Committee for Clinical Laboratory Standards,
`Methods for Dilution Antimicrobial Susceptibility Tests
`for Bacteria that Grow Aerobically-Fourth F.dition: Ap(cid:173)
`proved Standard NCCLS DocumentM7-A4, Vol. 17, No 2,
`NCCLS, Wayne, PA, 1997.
`
`OTC
`NPH ILETIN® II
`(isophane insulin suspension, Lilly} See Under lletin®
`(insulin)
`
`REGULAR ILETIN® II
`(insulin injection. Lilly) See under lletin® (insulin)
`
`OTC
`
`REOPRO®
`[re·ll·pro]
`Abciximab
`For intravenous administration
`
`DESCRIPTION
`Abciximab, ReoPro®~ is the Fab fragment of the chimeri('
`human-murine monoclonal antibody 7E3. Abciximab binds
`to the glycoprotein (GP) Ilb/Illa receptor of human platelets
`and inhibits platelet aggregation. Abciximab also binds to
`the vitronectin (avl3.,) receptor found on platelets and vessel
`wall endothelial and smooth muscle cells.
`The chimeric 7E3 antibody is produced by continuous per(cid:173)
`fusion in mammalian cell culture. The 4 7,615 dalton Fab
`fragment \s purified from cell culture supernatant by a se(cid:173)
`ries of steps involving specific viral inactivation and re(cid:173)
`moval procedures, digestion with papain and column
`chromatography.
`·
`ReoPro® is a clear, colorless, sterile, non-pyrogenic solution
`for iDtravenous (IV) use. Each single use v~al contains 2
`mg/mL of Abciximab in a buffered solution (pH 7 .2) of 0.01
`M sodium phosphate, 0.15 M sodiuin chloride and 0.001%
`polysorbate 80 in Water for Injection. No preservatives are
`added.
`CLThnCALPHARMACOLOGY
`General: Abciximab binds ta the intact platelet GPI!blllla
`receptor, which is a member- of the integrin family of adhe(cid:173)
`sion receptors and the major platelet surface receptor in(cid:173)
`volved in platelet aggregation. Abciximab inhibits platelet
`aggregation by preventing the binding of fibrinogen, von
`Willebrand factor, and other adhesive molecules to GPIIb/
`lila receptor sites on activated platelets. The mechanism of
`action is thought to involve steric hindrance and/or confor(cid:173)
`mational effects tO block access of large molecules to there(cid:173)
`ceptor rather than direct interaction with the RGD (argi(cid:173)
`nine-glycine-aspartic acid) binding site of GPI!blllla.
`Abciximab binds with similar affinity to the vitronectin re(cid:173)
`ceptor, also known as the cxv~a integrin. The vitronectin re(cid:173)
`ceptor 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~a­
`mediated effects including cell adhesion (!C50=0.34 11g/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 p~atelet activation than select com(cid:173)
`parator antibodies which inhibit GPI!blllla alone(l). The
`relationship of these 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 lgG blocked Mac-1 receptor function as
`evidenced by inhibition of monocyte adhesion (3). In addi(cid:173)
`tion, 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 compared to control patients (4).
`The relationship of these in vitro data to clinical efficacy is
`uncertain.
`Pre-clinical experience Maximal inhibition of platelet ag(cid:173)
`gregation was observed when ~ 80% of GPIIb/JIIa receptors
`were blocked by Abciximab. In non-human primates, Abcix(cid:173)
`imab bolus doses of 0.25 mg/kg generally achieved a block(cid:173)
`ade 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 in(cid:173)
`fusion. The inhibitory effects of Abciximab were substan(cid:173)
`tially reversed by the transfusion of platelets in monkeys.
`The anti thrombotic efficacy of prototype antibodies {murine
`7E3 Fab and F(ab'),] and Abciximab was evaluated in dog,
`monkey and baboon models of coronary, carotid, and femo(cid:173)
`ral artery thrombosis. Doses of the murine version of7E3 or
`Abciximab sufficient to produce high-grade(;, 80%) GPI!b/
`Ilia receptor blockade pievented acute thrombosis and
`yielded lower rates of thrombosis compared with aspirin
`and/or heparin.
`Pharmacokinetics. Following intravenous bolus adminis(cid:173)
`tration, free plasma 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 re(cid:173)
`lated to rapid binding ta the platelet GPI!blllla receptors.
`
`Information will be superseded by supplements and subsequent editions
`
`Ex. 2025-0001
`
`

`
`PRODUCT INFORMATION
`
`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 mglkg bolus dose of Abciximab fol(cid:173)
`lowed by continuous infusion of 10 pg/n:'.in (or a weight(cid:173)
`adjusted infusion of 0.125 )lg/kg/min to a maximum of 10
`pg/min) produces approximately constant free plasma con(cid:173)
`centrations 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 hu(cid:173)
`mans 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 aggrega(cid:173)
`tion in response to adenosine diphosphate (ADP) or by pro(cid:173)
`longation 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 GPIIblllla receptors were
`blocked and platelet aggregation in response to 20 )1M 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
`).lg/min for periods of 12 to 96 hours produced sustained
`high·grade GPIIb!llla receptor blockade (;, 80%) and inhi(cid:173)
`bition of platelet function (ex vivo platelet aggregation in re(cid:173)
`sponse to 5 ).1M or 20 p.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 pg/kg/min to a
`maximum of 10 p.g/min) was used in patients weighing up t.o
`80 kg. Results in patients who received the 0.25 mg/kg bolus
`followed by a 5 pg/min infusion for 24 hours showed a sim(cid:173)
`ilar initial receptor blockade and inhibition of platelet ag(cid:173)
`gregation, but the response was not maintained throughout
`the infusion period. The onset of Abciximab-mediated plate(cid:173)
`let
`inhibition
`following a 0.25 mg/kg bolus and
`0.125 )lg/kg/min infusion vias rapid and platelet aggrega(cid:173)
`tion was reduced to less than 20% of baseline in 8 of 10 pa(cid:173)
`tients 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 re(cid:173)
`turns gradually to normal. Bleeding time returned to :$ 12
`minutes within 12 hours following the end of infusion in 15
`of 20 patients (75%), and within 24 hours in 18 of 20 pa(cid:173)
`tient.q (90%). Ex vivo platelet aggregation in response to 5
`)1M ADP returned to ;, 50% of baseline within 24 hours fol·
`lowing the end of infusion in 11 of 32 patients (34%) and
`within 48 hours in 23 of 32 patients (72%). In response to
`20 pM 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%).
`CLINICAL STUDIES
`Abciximab has been studied in four Phase 3 clinical trials,
`all of which evaluated the effect of Abcixirnab in patients
`undergoing percutaneous coronary intervention (PCI): in
`patients at high risk for abrupt closure of the treated coro(cid:173)
`nary vessel (EPIC), in a broader group of patients (EPI(cid:173)
`LOG), and 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; EPISTENTJ.
`Percutaneous interventjon 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 (PI'CA)
`who were at high risk for abrupt closure of the treated cor(cid:173)
`onary 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 infu(cid:173)
`sion. 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, myocar(cid:173)
`dial infarction (MD, or urgent intervention for recurrent is~
`chemia within 30 days of randomization. The primary end(cid:173)
`point 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 pa(cid:173)
`tients with myocardial infarction and unstable angina
`meeting the EPIC high risk criteria) (10). Study procedures
`emphasized discontinuation of heparin after the procedure
`with early femoral arterial sheath removal and careful ac(cid:173)
`cess 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 Abcix.imab bolus plus
`infusion regimen was: 0.25 mg/kg bolus followed by a
`0.125 llg/kg/min infusion (to a maximum of 10 p.g/min) for
`12 hours. The heparin regimen was either a standard-dose
`regimen (initial 100 U/kg bolus, target ACT " 300 seconds)
`or a low--dose regimen (initial 70 Ulkg bolus, target ACT
`?. 200 seconds).
`
`Table 1
`ENDPOINT EVENT RATES AT 30 DAYS - EPILOG TRIAL
`Abciximab +
`Placebo+
`Standard Dose
`Standard Dose
`Heparin
`Heparin
`(n=939)
`(n=918)
`
`Death or MI11
`p-value vs. placebo
`Death, MI, or urgent interventionR
`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
`
`85 (9.1)
`
`109 (11.7)
`
`7 (0.8)
`78 (84)
`
`24 (2.6)
`
`Number of Patients(%)
`38 (4.2)
`<0.001
`49 (5.4)
`<0.001
`
`4 (0,4)
`34 (3.7)
`
`11 (1.2)
`
`Ell LILL Y/1959
`
`Abciximab +
`Low Dose
`Heparin
`(n=935)
`
`35 (3.8)
`<0.001
`48 (5.2)
`<0.001
`
`3 (0.3)
`32 (3.4)
`
`13 (1.4)
`
`8 Patients who experienced more than one event in the first 30 days are counted only once.
`bPatients are counted only once under the most serious component (death > acute MI > urgent intervention).
`
`Table 2
`PRIMARY ENDPOINT EVENT RATE AT 30 DAYS - EPISTENT TRIAL
`Placebo+
`Abciximab+
`Stent
`Stent
`(n=809)
`(n=794)
`
`Death, MI, or urgent intervention11
`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
`
`87 (10.8%)
`
`5 (0.6%)
`77 (9.6%)
`
`5 (0.6%)
`
`~~mber...2fRatients (%)
`42 (5.3%)
`<0.001
`
`2 (0.3%)
`35 (4.4%)
`
`5 (0.6%)
`
`Abciximab+
`PTCA
`(n=796)
`
`55 (6.9%)
`0.007
`
`6 (0.8%)
`40 (5.0%)
`
`9 (1.1%)
`
`11Patients who experienced more than one event in the first 30 days are counted only once.
`hPatients are counted only once under the most seri~ms component (death > acute MI > urgent intervention).
`
`Table 3
`PRIMARY ENDPOINT EVENT RATE AT 30 DAYS • CAPTURE TRIAL
`Placebo
`(n=635)
`
`Abciximab
`(n=630)
`
`Death, MI, or urgent intervention8
`p-value vs. placebo
`Components of Primary Endpointb
`Death
`· MI in surviving patients
`Urgent intervention in surviving patients
`without an acute myocardial infarctions
`
`Number of Patients(%)
`101 (15.9)
`71 (11.3)
`0.012
`
`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 un(cid:173)
`planned CABG or use of an intra-aortic balloon pump.
`b Patients are counted only once under the most serious component (death>acute Mhurgent intervention).
`
`The primary endpoint of the EPILOG trial was the compos·
`ite of death or MI occurring within 30 days of PC!. The com·
`posite of death, MI, or urgent intervention was an impor(cid:173)
`tant 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 (10).and one year (11). The (Kaplan-Meier)
`endpoint event rates at 30 days are shown in Table 1.
`[See table 1 at top of page I
`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 Abcix.imab treatment arms (8.3% and 8.4%, respectively,
`for the standard~ and low-dose heparin arms) than in the
`plicebo arm (14.7%). The treatment associated effects con~
`tinued to persist at the one~ year follow up visit. The propor(cid:173)
`tionate reductions in endpoint event rates were similar ir(cid:173)
`respective of the type of coronary intervention used (balloon
`angioplasty, atherectomy, or stent placement). Risk assess(cid:173)
`ment using the American College of Cardiology/American
`Heart Association clinical/morphological criteria had large
`inter-observer variability. Consequently, a low risk sub(cid:173)
`group could not be reproducibly identified in which to eval(cid:173)
`uate 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-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 bo(cid:173)
`lus 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.
`Al1 patients were to receive aspinn; 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 (re(cid:173)
`peat PC! or CABG) within 30 days ofPCI (12). The (Kaplan(cid:173)
`Meier) endpoint event rates at 30 days are shown in Table 2.
`ISee table 2 above)
`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<0.001 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) intenrention was observed in
`the Abciximablstent group compared with the placebo/stent
`group (15.4% vs 20.4%, p=0.006); the rate of this composite
`endpbint 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 adminis(cid:173)
`tration of placebo or Abciximab starting 18 to 24 hours prior
`to PCI and continuing until one hour after completion of the
`intervention.
`Patients were assessed as having unstable angina not re(cid:173)
`sponding to conventional medical therapy if they had at
`
`Continued on next page
`
`* ldenti-Code® symbol. This product information was
`prepared in June 2001. Current information on these and other
`products of Eli Lilly and Company may be obtained by direct
`inquiry to Lilly Research Laboratories, lilly Corporate Center,
`Indianapolis, Indiana 46285, (800) 545-5979.
`
`Consult 2002 PDR® supplements and future editions for revisions
`
`Ex. 2025-0002
`
`

`
`I:JOU/CLI LILL T
`
`Reo Pro-Cont.
`
`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 en(cid:173)
`rolled into the CAPrURE trial if, during a screening angi(cid:173)
`ogram, they were determined to have a coronary lesion ame(cid:173)
`nable to PCI. Patients received a bolus dose and intrave(cid:173)
`nous infusion of placebo or Abciximab for 18 to 24 hours. At
`the end of the infusion period, the intervention was per(cid:173)
`formed. The Abciximab or placebo infusion was discontin(cid:173)
`ued 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!.
`The Abciximab dose was a 0.25 mglkg bolus followed by a
`continuous infusion at a rate of 10 pg/min. The CAPTURE
`trial incorporated weight adjustment of the standard hepa(cid:173)
`rin 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
`PC!: death, MI, or urgent intervention. The 30-day (Kaplan(cid:173)
`Meier) primary endpoint event rates are shown in Table 3.
`[See table 3 on previous page]
`The 30-day results are consistent with the results of the
`other three trials, with the greatest effects on the myocar(cid:173)
`dial infarction and urgent intervention components of the
`composite endpoint. As secondary endpoints, the campo·
`nents of the composite endpoint were analyzed separately
`for the period prior to the PC! and the period from the be(cid:173)
`ginning 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 com(cid:173)
`pared with placebo (Abciximab 3.6%, placebo 6.1%). There
`was also a reduction in MI occurring prior to the PCI (Ab(cid:173)
`cixiroab 0.6%, placebo 2.0%). An Abciximab-associated re(cid:173)
`duction in the incidence of urgent intervention occurred in
`the post-intervention period. No effect on mortality was ob(cid:173)
`served in either period. At six months of follow up, the com(cid:173)
`posite endpoint of death, MI, or 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 ali four trials. Similar mortal(cid:173)
`ity rates were observed in all arms within each trial. Pa(cid:173)
`tient follow-up through one year of the EPISTENT trial sug(cid:173)
`gested decreased mortality among patients treated with
`Abciximab and stent placement compared to patients
`treated with stent alone (8/794 vs. 19/809, p=0.037). Data
`from earlier studies with balloon angioplasty were not sug(cid:173)
`gestive 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 in(cid:173)
`tervention rates were also lower in Abciximab-treated
`groups in these trials.
`Anticoagulation:
`EPILOG and EPISTENT: Weight-adjusted low dose hepa(cid:173)
`rin. weight-adjusted Abciximab, careful vascular access site
`management and discontinuation of heparin after the pro(cid:173)
`cedure 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 Ulkg heparin
`ACT ~ 200 seconds: administer no heparin
`Additional 20 U/kg heparin boluses were given to achieve
`and maintain an ACT of :=:200 seconds during the
`procedure.
`Discontinuation of heparin immediately after the proce(cid:173)
`dure and removal of the arterial sheath within six hours
`were strongly recommended in the trial. If prolonged hep(cid:173)
`arin therapy or delayed sheath removal was clinically in(cid:173)
`dicated, heparin was adjusted to keep the APTT at a tar(cid:173)
`get of 60 to 85 seconds (EPILOG) or 55 to 75 seconds
`(EPISTENTJ.
`CAPTURE trial: Anticoagulation was initiated prior to
`the administration of Abciximab. Anticoagulation was
`initiated with an intravenous heparin infusion to achieve
`a target APT'l' of 60 to 85 seconds. The heparin infusion
`was not uniformly weight adjusted in this trial. The hep(cid:173)
`arin infusion was maintained during the Abciximab ~nfu­
`sion 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
`Abcixim.ab is indicated as an adjunct to percutaneous Coro(cid:173)
`nary intervention for the prevention of cardiac ischemic
`complications.
`• in patients undergoing percutaneous coronary
`intervention
`• in patients with unstable angina not responding to con(cid:173)
`ventional medical therapy when percutaneous coronary
`intervention is planned within 24 hours
`·
`Abciximab use in patients not undergoing percutaneous cor·
`onary 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 CLIN(cid:173)
`ICAL 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 genito(cid:173)
`urinary (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/pL)
`• 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 mu(cid:173)
`rine 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 AD(cid:173)
`VERSE REACTIONS: Bleeding).
`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(cid:173)
`adjusted heparin regimen, a weight-adjusted Abciximab bo(cid:173)
`lus and infusion, strict anticoagulation guidelines, careful
`vascular access site management, discontinuation of hepa~
`rin after the procedure and early femoral arterial sheath
`remOval.
`Therapy with Abciximab requires careful attention to all po(cid:173)
`tential bleeding sites (including catheter insertion sites, ar(cid:173)
`terial and venous puncture sites, cutdown sites, needle
`puncture sites, and gastrointestinal, genitourinary, and ret(cid:173)
`roperitoneal sites).
`Arterial and venous punctures, intramuscular injections,
`and use of urinary catheters, nasotracheal intubation, na(cid:173)
`sogastric tubes and automatic blood pressure cuffs should
`be minimized. When obtaining intravenous access, non(cid:173)
`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 docu(cid:173)
`mented 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 s30" 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
`s 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 pres(cid:173)
`sure dressing should be applied following hemostasis. The
`patient should be maintained on bed rest for six to eight
`hotirs following sheath removal or discontinuation of Abcix(cid:173)
`iiri3.b, or four hours following discontinuation of heparin,
`whichever is later. The pressure dressing should be re(cid:173)
`moved 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