Reopro (Abciximab)

REOPRO™

Lilly

Abciximab

Chimeric Monoclonal Antiplatelet Antibody

Action And Clinical Pharmacology: General: Abciximab is the Fab fragment of the chimeric monoclonal antibody 7E3. It selectively binds to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor located on the surface of human platelets. 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.

Pharmacokinetics: Following i.v. administration of abciximab, free plasma concentrations decreased very rapidly with an initial half-life of several minutes and a second phase half-life of about 30 minutes. This disappearance from the plasma is probably related to rapid binding to the platelet GPIIb/IIIa receptors (approximately 80 000 to 100 000 GPIIb/IIIa receptors on the surface of each platelet). After a single bolus injection of abciximab, the inhibitory effects on platelet function, as measured by inhibition of platelet aggregation, were evident within 10 minutes. The antibody remains in the circulation for several days in a platelet-bound state. Its disappearance follows a monoexponential time course.

I.V. administration of a 0.25 mg/kg bolus dose of abciximab followed by continuous infusion of 5 or 10 µg/min for periods of 12 to 96 hours produced relatively constant total plasma concentrations from the first time point measured (usually 2 hours) for all infusion rates and durations. However, although the total plasma concentrations resulting from the 5 µg/min infusion were only slightly lower than those from the 10 µg/min infusion, the 5 µg/min infusion was ineffective in inhibiting platelet function over the whole infusion period. At the termination of the infusion period, plasma concentrations fell rapidly for approximately 6 hours, then declined at a much slower rate.

Pharmacodynamics: I.V. administration in humans of single bolus doses of abciximab from 0.15 to 0.30 mg/kg resulted in a dose-dependent blockade of platelet GPIIb/IIIa receptors and produced dose-dependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to ADP or by prolongation of bleeding time. At the 2 highest doses (0.25 and 0.30 mg/kg) at 2 hours postinjection, over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 µM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately 5 minutes.

I.V. administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 µg/min for periods of 12 to 96 hours produced sustained high-grade platelet inhibition (ex vivo platelet aggregation in response to 5 or 20 µM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Results in patients who received the 0.25 mg/kg bolus followed by a 5 µg/min infusion for 24 hours showed a similar initial inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. Following cessation of the infusion, platelet function typically returned to baseline values over a period of 24 to 48 hours.

Indications And Clinical Uses: As an adjunct to percutaneous transluminal coronary angioplasty or atherectomy (PTCA) for the prevention of acute cardiac ischemic complications in patients at high risk for abrupt closure of the treated coronary vessel. Patients at high risk for abrupt closure include those undergoing PTCA with at least 1 of the following conditions: unstable angina or a non-Q-wave myocardial infarction; an acute Q-wave myocardial infarction within 12 hours of the onset of symptoms; other high-risk clinical and/or morphologic characteristics (as adapted from the classification of the ACC/AHA; see Table I): 2 type B lesion characteristics in the artery to be dilated, 1 type B lesion characteristic in the artery to be dilated in a woman of at least 65 years of age, 1 type B lesion characteristic in the artery to be dilated in a patient with diabetes mellitus, 1 type C lesion characteristic in the artery to be dilated, or angioplasty of an infarct-related lesion within 7 days of myocardial infarction.

The principal data supporting the safety and efficacy of abciximab for this indication are from a full evaluation of the EPIC trial. Data included from the EPILOG and CAPTURE trials are based on interim analyses and are included because of their relevance to bleeding events. Any appropriate references to efficacy in these trials will be made in a revised Product Monograph following a full evaluation of trial data by Centocor and the Canadian Health Protection Branch.

Abciximab is intended for use with ASA and heparin and has been studied only in that setting as described in Pharmacology.

The EPIC Trial: The Evaluation of c7E3 to Prevent Ischemic Complications (EPIC) trial was a multicenter, double-blind, placebo-controlled trial of abciximab in patients undergoing percutaneous transluminal coronary angioplasty or atherectomy (PTCA). In the EPIC trial, 2 099 patients between 26 and 83 years of age who were at high risk for abrupt closure of the treated coronary vessel were randomly allocated to 1 of 3 treatments: 1) an abciximab bolus (0.25 mg/kg) followed by an abciximab infusion (10 µg/min) for 12 hours (bolus plus infusion group); 2) an abciximab bolus (0.25 mg/kg) followed by a placebo infusion (bolus group); or 3) a placebo bolus followed by a placebo infusion (placebo group). Patients at high risk during or following PTCA were defined as those with unstable angina or a non-Q-wave myocardial infarction (n=489), those with an acute Q-wave myocardial infarction within 12 hours of symptom onset (n=66), and those who were at high risk because of coronary morphology and/or clinical characteristics as defined in Table I (n=1 544). Treatment with study agent in each of the 3 arms was initiated 10 to 60 minutes before the onset of PTCA. All patients initially received an i.v. heparin bolus (10 000 to 12 000 units) and boluses of up to 3 000 units thereafter to a maximum of 20 000 units during PTCA. Heparin infusion was continued for 12 hours to maintain a therapeutic elevation of activated partial thromboplastin time (APTT, 1.5 to 2.5 times normal). Unless contraindicated, ASA (325 mg) was administered orally 2 hours prior to the planned procedure and then once daily.

The primary endpoint was the occurrence of any of the following events within 30 days of PTCA: death, myocardial infarction (MI), or the need for urgent intervention for recurrent ischemia (i.e., urgent PTCA, urgent coronary artery bypass graft (CABG) surgery, a coronary stent, or an intra-aortic balloon pump). The 30-day (Kaplan-Meier) primary endpoint event rates for each treatment group by intention-to-treat analysis of all randomized patients are shown in Table II. The 4.5% lower incidence of the primary endpoint in the bolus plus infusion treatment group, compared with the placebo group, was statistically significant, whereas the 1.3% lower incidence in the bolus treatment group was not. A lower incidence of the primary endpoint was observed in the bolus plus infusion treatment arm for all 3 high-risk subgroups: patients with unstable angina, patients presenting within 12 hours of the onset of symptoms of an acute myocardial infarction, and patients with other high-risk clinical and/or morphologic characteristics as defined in Table I. The treatment effect was largest in the first 2 subgroups and smallest in the third subgroup.

Mortality was uncommon and similar rates were observed in all arms. The rate of acute myocardial infarctions was significantly lower in the groups treated with abciximab. While 80% of myocardial infarctions in the study were non-Q-wave infarctions, patients in the bolus plus infusion arm experienced a lower incidence of both Q-wave and non-Q-wave infarctions. Urgent intervention rates were lower in the groups treated with abciximab, mostly because of lower rates of emergency PTCA and, to a lesser extent, emergency CABG surgery. The primary endpoint events in the bolus plus infusion treatment group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days and 6 months. At 6 months, this event rate remained lower in the bolus plus infusion arm (12.3%) than in the placebo arm (17.6%).

Abciximab should not be administered to patients with known sensitivity to the product, to any component of the product or to murine monoclonal antibodies.

The most common complication encountered in the EPIC clinical trial was bleeding, with statistically significant increases in both major and minor bleeding events and in bleeding requiring transfusions (see Adverse Effects). However, the trial results suggested that heparin administered in high, non-weight-adjusted doses might be the principal cause of the bleeding when used with abciximab. In addition, a comparison of bleeding frequencies at the various EPIC trial sites suggested that certain patient and access site management techniques, including early sheath removal, could reduce the bleeding rate.

The EPILOG Trial: A large trial (Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa Receptor Blockade or EPILOG) was initiated to formally test the hypothesis that use of a low-dose, weight-adjusted heparin regimen and early sheath removal could significantly lower the bleeding rate and while maintaining abciximab efficacy.

EPILOG was a 3-treatment arm trial of abciximab+standard dose, weight-adjusted heparin (bolus of 100 U/kg heparin to achieve an ACT of 300 seconds; maximum initial bolus 10 000 units), Abciximab+low dose, weight-adjusted heparin (bolus of 70 U/kg heparin to achieve an ACT of 200 seconds; maximum initial bolus 7,000 units) and placebo+standard dose, weight-adjusted heparin in a broad population of PTCA patients (but excluding patients with myocardial infarction, unstable angina and obvious contraindications). The abciximab dose regimen was the same as that used in the EPIC trial, except that the continuous infusion dose was weight-adjusted (0.125 µg/kg/min). Improved patient and access site management as well as a strong recommendation for early sheath removal were also incorporated into the trial which was designed to enroll 4 800 patients with an interim safety analysis at 1 500.

At the 1 500 patient interim analysis, 2 major and positive findings led to the termination of the trial. These findings were: 1) the bleeding rate of abciximab+low dose, weight-adjusted heparin was reduced to the same order as placebo. Bleeding rates in both arms were lower than that seen in the EPIC trial with a standard, non-weight-adjusted heparin dose regimen (see Table IV). 2) In spite of the modification of the heparin regimen, efficacy in the abciximab+low dose and the abciximab+standard dose, weight-adjusted heparin arms was maintained. There was no significant difference between the 2 abciximab treatment arms.

The CAPTURE Trial: The Chimeric Anti-Platelet Therapy in Unstable Angina Refractory to Standard Medical Therapy (CAPTURE) trial was designed to determine if potent antiplatelet therapy would reduce ischemic complications in patients with refractory unstable angina scheduled for PTCA. Enrollment was planned for 1 400 patients who were randomly allocated to abciximab or placebo treatment for approximately 24 hours preceding PTCA and continued until 1 hour afterwards. This dose regimen differs from that used in the EPIC trial and included in the current prescribing information. The CAPTURE trial incorporated weight adjustment of the heparin dose, but did not investigate the effect of a low heparin dose on bleeding and efficacy, and arterial sheaths were left in place for approximately 30 hours.

An important and positive finding that was apparent at an interim analysis at 1 050 patients, leading to termination of the trial, dealt with safety. The rate of major bleeding not associated with CABG was 1.7% in the placebo group and 2.9% in the abciximab group (p=0.21, 2-tailed) and transfusions were 3.6% and 7.8%, respectively (p=0.006, 2-tailed).

The bleeding rates in the CAPTURE trial are moderately higher than in the EPILOG trial, probably due to higher heparin dosing in CAPTURE and the extended time until sheath removal. Major bleeding not related to CABG was markedly lower in the ReoPro treated patients in the EPILOG low dose, weight adjusted heparin arm (1.4%), the EPILOG standard dose, weight adjusted heparin arm (1.8%) and the CAPTURE trial (2.9%) than in the original EPIC trial (10.6%). In contrast to the EPIC trial, no statistically significant differences in the major non-CABG bleeding rates were observed in the EPILOG and CAPTURE trials between abciximab and placebo treatment arms.

Contra-Indications: Abciximab should not be administered to patients with known sensitivity to abciximab, to any component of the product or to murine monoclonal antibodies.

Because inhibition of platelet aggregation increases the risk of bleeding, abciximab is contraindicated in the following clinical situations: active internal bleeding; recent (within 6 weeks) gastrointestinal or genitourinary bleeding of clinical significance; history of cerebrovascular accident (CVA) within 2 years or a CVA with a significant residual neurological deficit; recent (within 6 weeks) major surgery or trauma; intracranial neoplasm, arteriovenous malformation or aneurysm; known bleeding diathesis or severe uncontrolled hypertension; pre-existing thrombocytopenia; vasculitis; use of i.v. dextran before PTCA, or intent to use it during PTCA; administration of oral anticoagulants within 7 days unless prothrombin time is £1.2 times control.

Manufacturers’ Warnings In Clinical States: Abciximab has been shown to be of benefit in patients who have high risk of ischemic complications in relation to PTCA. However, due to the increased risk of bleeding, careful assessment of risk:benefit should be made in individual patients before commencing therapy with abciximab.

Increased Risk of Bleeding (see Adverse Effects): The most common complication encountered during abciximab therapy is bleeding. The types of bleeding associated with abciximab therapy fall into two broad categories: bleeding observed at the arterial access site for cardiac catheterization and internal bleeding involving the gastrointestinal tract, genitourinary tract, or retroperitoneal sites.

In the following conditions, clinical data suggest that the risks of major bleeds due to abciximab therapy may be increased and should be weighed against the anticipated benefits: patients who weigh less than 75 kg, patients >65 years old, patients with a history of prior gastrointestinal disease and patients receiving thrombolytics.

The following conditions are also associated with an increased risk of bleeding in the angioplasty setting which may be additive to that of abciximab: PTCA within 12 hours of the onset of symptoms for acute myocardial infarction, prolonged PTCA (lasting more than 70 minutes) and failed PTCA .

Heparin anticoagulation may contribute to the risk of bleeding. See Bleeding, Precautions: Patient Monitoring.

Should serious bleeding occur that is not controllable with pressure, the infusion of abciximab and any concomitant heparin should be stopped (see Restoration of Platelet Function).

Bleeding Precautions: Requirement for Specialist Facilities: Abciximab should only be administered in conjunction with extensive specialist medical and nursing care. In addition, there must be availability of laboratory tests of hematology function and facilities for administration of blood products.

Concomitant ASA and Heparin Therapy: Abciximab should be used as an adjunct to ASA and heparin therapy.

ASA: ASA should be administered orally at a daily dose of approximately but not less than 300 mg.

Heparin: Heparin Bolus Pre-PTCA: If a patient’s activated clotting time (ACT) is less than 200 seconds prior to the start of the PTCA procedure, an initial bolus of heparin should be given upon gaining arterial access according to the following algorithm: ACT.

The initial heparin bolus dose should not exceed 7 000 U.

Should a situation arise where higher doses of heparin are considered clinically necessary in spite of the possibility of a greater bleeding risk, it is recommended that heparin be carefully titrated using weight-adjusted boluses and that the target ACT not exceed 300 seconds.

Heparin Infusion after PTCA: Discontinuation of heparin immediately following completion of the procedure, with removal of the arterial sheath within 6 hours, is strongly recommended . In individual patients, if prolonged heparin therapy after PTCA or later sheath removal is used, then an initial infusion rate of 7 U/kg/h is recommended (see Bleeding Precautions: Femoral Artery Sheath Removal).

Femoral Artery Access Site: Abciximab is associated with an increase in bleeding rate particularly at the site of arterial access for femoral artery sheath placement. The following are specific recommendations for access site care: Femoral Artery Sheath Insertion: when appropriate, place only an arterial sheath for vascular access (avoid venous sheath placement); puncture only the anterior wall of the artery or vein when establishing vascular access; the use of a through and through technique to identify the vascular structure is strongly discouraged.

While Femoral Artery Sheath Is In Place: Check sheath insertion site and distal pulses of affected leg(s) every 15 minutes for 1 hour, then hourly for 6 hours; maintain complete bed rest with head of bed £30°; maintain affected leg(s) straight via sheet tuck method or soft restraint; medicate for back/groin pain as necessary; educate patient on post-PTCA care via verbal instructions.

Femoral Artery Sheath Removal: heparin should be discontinued at least 4 hours prior to arterial sheath removal; check APTT or ACT prior to arterial sheath removal: do not remove sheath unless APTT £50 seconds or ACT £175 seconds; apply pressure to access site for at least 30 minutes following sheath removal, using either manual compression or a mechanical device; apply pressure dressing after hemostasis has been achieved.

After Femoral Artery Sheath Removal: check groin for bleeding/hematoma and distal pulses every 15 minutes for the first hour or until stable, then hourly; continue complete bed rest with head of bed £30° and affected leg(s) straight for 6 to 8 hours following femoral artery sheath removal, 6 to 8 hours following discontinuation of abciximab or 4 hours following discontinuation of heparin, whichever is later; remove pressure dressing prior to ambulation; continue to medicate for discomfort.

Management of Femoral Access Site Bleeding/Hematoma Formation: In the event of groin bleeding with or without hematoma formation, the following procedures are recommended: Lower head of bed to 0°; apply manual pressure/compression device until hemostasis has been achieved; any hematoma should be measured and monitored for enlargement; change pressure dressing as needed; if heparin is being given, obtain APTT and adjust heparin as needed; maintain i.v. access if sheath has been removed.

If groin bleed continues or the hematoma expands during abciximab infusion despite the above measures, the abciximab infusion should be immediately discontinued and the arterial sheath removed according to the guidelines listed above. After sheath removal i.v. access should be maintained until bleeding is controlled.

Potential Bleeding Sites: Careful attention should be paid to all potential bleeding sites, including arterial and venous puncture sites, catheter insertion sites, cutdown sites, and needle puncture sites.

Retroperitoneal Bleeding: Abciximab is associated with an increased risk of retroperitoneal bleeding in association with femoral vascular puncture. The use of venous sheaths should be minimized and only the anterior wall of the artery or vein should be punctured when establishing vascular access.

Gastrointestinal Bleeding Prophylaxis: In order to prevent spontaneous gastrointestinal bleeding it is recommended that patients are pretreated with H2-histamine receptor antagonists or liquid antacids. Antiemetics should be given as needed to prevent vomiting.

General Nursing Care: Unnecessary arterial and venous punctures, i.m. injections, routine use of urinary catheters, nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be avoided. When obtaining i.v. access, noncompressible 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.

Patient Monitoring: Before administration of abciximab, platelet count, ACT, prothrombin time (PT) and APTT should be measured to identify pre-existing coagulation abnormalities. Hemoglobin and hematocrit measurements should be obtained prior to the abciximab administration, at 12 hours following the abciximab bolus injection, and again at 24 hours following the bolus injection. Twelve lead electrocardiograms (ECG) should be obtained prior to the bolus injection of abciximab, and repeated once the patient has returned to the hospital ward from the catheterization laboratory, and at 24 hours after the bolus injection of abciximab. Vital signs (including blood pressure and pulse) should be obtained hourly for the first 4 hours following the abciximab bolus injection, and then at 6, 12, 18 and 24 hours following the abciximab bolus injection.

Thrombolytics, Anticoagulants and Other Antiplatelet Agents: Because abciximab inhibits platelet aggregation, caution should be employed when used with other drugs affecting hemostasis such as heparin, oral anticoagulants such as warfarin, thrombolytics and antiplatelet agents other than ASA, such as dipyridamole, ticlopidine or low molecular weight dextrans.

There are limited data on the use of abciximab in patients receiving thrombolytic agents. However these data suggest an increase in the risk of bleeding when abciximab is administered to patients treated with thrombolytics at doses sufficient to produce a systemic fibrinolytic state. If urgent intervention is required for refractory symptoms in a patient receiving abciximab (or who has received the drug in the previous 48 hours), it is recommended that PTCA be attempted first to salvage the situation. Prior to further surgical interventions, the bleeding time should be determined by the Ivy method and should be 12 minutes or less. Should PTCA and any other appropriate procedures fail, and should the angiographic appearance suggest that the etiology is due to thrombosis, consideration may be given to the administration of adjunctive thrombolytic therapy via the intracoronary route. A systemic fibrinolytic state should be avoided.

Thrombocytopenia: To reduce the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2 to 4 hours following the bolus dose of abciximab and at 24 hours. If a patient experiences an acute platelet decrease, additional platelet counts should be determined. These platelet counts should be drawn in separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin to exclude pseudothrombocytopenia due to in vitro anticoagulant interaction. If true thrombocytopenia is verified, abciximab should be immediately discontinued and the condition appropriately monitored and treated. A daily platelet count should be obtained until it returns to normal. If a patient’s platelet count drops to 60 000 cells/µL, heparin and ASA should be discontinued. If a patient’s platelet count drops below 50 000 cells/µL, platelets should be transfused.

Restoration of Platelet Function: Transfusion of donor platelets has been shown to restore platelet function following abciximab administration in animal studies and transfusions of fresh random donor platelets have been given empirically to restore platelet function in humans. In the event of serious uncontrolled bleeding or the need for surgery, a bleeding time should be determined. If the bleeding time is greater than 12 minutes, 10 units of platelets may be given. Abciximab may be displaced from endogenous platelet receptors and subsequently bind to platelets which have been transfused. Nevertheless, a single transfusion may be sufficient to reduce receptor blockade to 60 to 70% at which level platelet function is restored. Repeat platelet transfusions may be required to maintain the bleeding time at or below 12 minutes.

Precautions: Children: Safety and effectiveness of abciximab in children below the age of 18 have not been established.

Obstetrics: In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate the carcinogenic potential or effects on fertility in male or female animals.

Animal reproduction studies have not been conducted with abciximab. It is also not known whether abciximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Abciximab should be given to a pregnant woman only if clearly needed.

Lactation: It is not known if this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when abciximab is administered to a nursing woman.

Readministration: There are no data concerning readministration of abciximab. Administration of abciximab may result in human antichimeric antibody (HACA) formation (see Adverse Effects) that can cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration of abciximab.

Allergic Reactions: Anaphylaxis may occur at any time during administration. If it does, 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, angiotensin converting enzyme inhibitors, i.v. and oral nitrates, and ASA. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents may be associated with an increase in bleeding. Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.

Adverse Reactions: Clinical toxicity has been infrequent with the administration of abciximab. Adverse events reasonably related to study agent that were reported by investigators for more than 0.5% of the 2 038 treated patients in the pivotal trial are shown in Table V. Although extremely unlikely, anaphylaxis may potentially occur at any time during administration. If it does, immediate cessation of infusion, s.c. administration of 0.3 to 0.5 mL of aqueous epinephrine (1:1 000 dilution), corticosteroids, respiratory assistance and other resuscitative measures are essential.

Major bleeding events occurred in 14% (99/708) of patients treated with the bolus plus infusion regimen, 11.1% (77/695) of patients treated with the bolus regimen and 6.6% (46/696) of the patients treated with placebo. If bleeding associated with CABG is excluded, these major bleeding rates become 10.6% (75/708), 8.6% (60/695) and 3.3% (23/696), respectively. The rates for major and minor bleeding observed in the EPILOG and CAPTURE trials are described in Indications.

The principal site of bleeding in the majority of the abciximab-treated patients was the femoral artery access site. The incidence of intracranial hemorrhage was the same in all 3 groups (3 in the bolus plus infusion group, 1 of which was in a patient who did not receive abciximab but is included in the intent to treat analysis; 1 in the bolus group; and 2 in the placebo group). The incidence of CABG-related blood loss was also the same in all 3 groups (24 or 3.4% in the bolus plus infusion group, 21 or 3% in the bolus group, and 26 or 3.7% in the placebo group). There was no increase in the need for surgical intervention as a consequence of bleeding in either of the abciximab-treated groups. The incidence and site of major bleeding events not associated with CABG and the frequencies of transfusions and surgical interventions for bleeding in patients with these bleeding events are listed in Table VII.

If patients undergoing CABG and other patients are also included, transfusions of blood products were given to 16.8% of the bolus plus infusion patients, 14% of the bolus patients and 7.5% of the placebo patients. Similarly, including all patients in the analysis, surgical intervention for bleeding remained infrequent in all 3 treatment groups, being 1.7% (12/708) in the bolus plus infusion group, 2.6% (18/695) in the bolus group and 1.4% (10/696) in the placebo group.

Taken together, these data show that administration of abciximab in combination with ASA and heparin may cause bleeding complications, usually at the arterial puncture site. Women over 65 years of age and low weight patients had the highest risk of bleeding events. The relationship of bleeding to lower weight suggests that heparin may play a role. While the abciximab bolus was weight adjusted, heparin administration was not. The most frequent actions taken in response to major bleeding events following abciximab bolus plus infusion were application of pressure or a change of dressing (72%), discontinuation or reduction of heparin administration (46.7%) and discontinuation or reduction of abciximab administration (28%).

Human antichimeric antibody (HACA) may appear in response to the administration of abciximab. Positive responses occurred in 5.2% (32/616) of the bolus patients and 6.5% (40/616) of the bolus plus infusion patients who could be evaluated. None of the 605 placebo patients who could be evaluated had a positive HACA response. Most of the patients with a positive HACA result had a low-titer response. All of the 32 patients who had a positive HACA result in the bolus group and 34 of the 40 patients who had a positive HACA result in the bolus plus infusion group had a titer 1:1 600. There were 6 patients in the bolus group who had HACA titers ranging between 1:6 400 and 1:51 200. However, there was no excess of hypersensitivity or allergic reactions related to abciximab treatment compared with placebo treatment.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There has been no experience of overdosage with abciximab in human clinical trials. However, refer to Reversal of Antiplatelet Effects in the Warnings section. It is recommended that infusion be discontinued after 12 hours to avoid effects of prolonged platelet receptor blockade.

Dosage And Administration: Abciximab is intended for use in patients undergoing PTCA. The safety and efficacy of ReoPro have only been investigated with concomitant administration of heparin and ASA as described in Pharmacology.

In patients with failed PTCAs, the continuous infusion of abciximab should be stopped because there is no evidence for abciximab efficacy in that setting.

In the event of serious bleeding that cannot be controlled by compression, abciximab and heparin should be discontinued immediately (see Warnings, Restoration of Platelet Function).

Adults: The recommended dose is a 0.25 mg/kg i.v. bolus administered over 1 minute, 10 to 60 minutes prior to PTCA, followed by a 10 µg/min continuous i.v. infusion for 12 hours.

Children: There is no experience on the use of abciximab in children.

Administration Instructions: Parenteral drug products should be inspected visually for particulate matter prior to administration. Preparations of abciximab containing visibly opaque particles should not be used.

Hypersensitivity reactions should be anticipated whenever protein solutions such as abciximab are administered. Epinephrine, dopamine, theophylline, antihistamines and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or anaphylaxis appear, the infusion should be stopped and appropriate treatment given.

As with all parenteral drug products, aseptic procedures should be used during the administration of abciximab.

Withdraw the necessary amount of abciximab for bolus injection through a sterile, nonpyrogenic, low protein-binding 0.2 or 0.22 µm filter (Millipore SLGV025LS or equivalent) into a syringe. Ten to 60 minutes prior to PTCA, the bolus injection should be administered over 1 minute.

Withdraw the necessary amount of abciximab for the continuous infusion through a sterile, nonpyrogenic, low protein-binding 0.2 or 0.22 µm filter (Millipore SLGV025LS or equivalent) into a syringe. Inject into sterile 0.9% saline or 5% dextrose and infuse at a rate of 10 µg/min for 12 hours via a continuous infusion pump equipped with an in-line sterile, nonpyrogenic, low protein-binding 0.2 or 0.22 µm filter (Abbott #4524 or equivalent). For example, withdraw 4.5 mL abciximab and inject into 250 mL of 0.9% saline or 5% dextrose and infuse at 17 mL/hr for 12 hours.

Once mixed, the solution can be stored up to 12 hours at 2 to 8°C. Discard the unused portion at the end of the 12-hour infusion.

Although incompatibilities have not been observed with i.v. infusion fluids or commonly used cardiovascular drugs, it is recommended that abciximab be administered in a separate i.v. line whenever possible and not mixed with other medications.

No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.

Availability And Storage: Each mL of clear, colorless, sterile, nonpyrogenic solution for i.v. use contains: abciximab 2 mg. Nonmedicinal ingredients: polysorbate 80, sodium chloride and sodium phosphate. Preservative-free. Vials of 5 mL, packages of 1. Store at 2 to 8°C. Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial.

REOPRO™ Lilly Abciximab Chimeric Monoclonal Antiplatelet Antibody

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