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Reopro (Abciximab)
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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. Abciximab also binds with similar affinity to the vitronectin (a vb 3) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The vitronectin receptor mediates pro-coagulant properties of platelets and proliferative properties of vascular endothelial cells and smooth muscle cells.
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 30minutes. This disappearance from the plasma is probably related to rapid binding to the platelet GPIIb/IIIa receptors (approximately 80000 to 100000 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 15 days or more in a platelet-bound state. Its disappearance follows a monoexponential time course.
I.V. administration of a 0.25mg/kg bolus dose of abciximab followed by continuous infusion of 5or 10µg/min for periods of 12 to 96hours produced relatively constant total plasma concentrations from the first time point measured (usually 2hours) for all infusion rates and durations. However, although the total plasma concentrations resulting from the 5µg/min infusion were only slightly lower than those from the 10µg/min infusion, the 5µg/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 6hours, then declined at a much slower rate.
Pharmacodynamics: I.V. administration in humans of single bolus doses of abciximab from 0.15to 0.30mg/kg resulted in a dose-dependent blockade of platelet GPIIb/IIIa receptors and produced dose-dependent inhibition of platelet function as measured by exvivo platelet aggregation in response to ADP or by prolongation of bleeding time. At the 2highest doses (0.25 and 0.30mg/kg) at 2hours postinjection, over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20µM ADP was almost abolished. The median bleeding time increased to over 30minutes at both doses compared with a baseline value of approximately 5 minutes.
I.V. administration in humans of a single bolus dose of 0.25mg/kg followed by a continuous infusion of 10µg/min for periods of 12 to 96hours produced sustained high-grade platelet inhibition (ex vivo platelet aggregation in response to 5or 20µM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Equivalent results were obtained when a weight adjusted infusion dose (0.125 µg/kg/min to a maximum of 10µg/min) was used in patients up to 80 kg. Results in patients who received the 0.25mg/kg bolus followed by a 5µg/min infusion for 24hours 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 24to 48hours.
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. Abciximab also binds with similar affinity to the vitronectin (a vb 3) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The vitronectin receptor mediates pro-coagulant properties of platelets and proliferative properties of vascular endothelial cells and smooth muscle cells.
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 30minutes. This disappearance from the plasma is probably related to rapid binding to the platelet GPIIb/IIIa receptors (approximately 80000 to 100000 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 15 days or more in a platelet-bound state. Its disappearance follows a monoexponential time course.
I.V. administration of a 0.25mg/kg bolus dose of abciximab followed by continuous infusion of 5or 10µg/min for periods of 12 to 96hours produced relatively constant total plasma concentrations from the first time point measured (usually 2hours) for all infusion rates and durations. However, although the total plasma concentrations resulting from the 5µg/min infusion were only slightly lower than those from the 10µg/min infusion, the 5µg/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 6hours, then declined at a much slower rate.
Pharmacodynamics: I.V. administration in humans of single bolus doses of abciximab from 0.15to 0.30mg/kg resulted in a dose-dependent blockade of platelet GPIIb/IIIa receptors and produced dose-dependent inhibition of platelet function as measured by exvivo platelet aggregation in response to ADP or by prolongation of bleeding time. At the 2highest doses (0.25 and 0.30mg/kg) at 2hours postinjection, over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20µM ADP was almost abolished. The median bleeding time increased to over 30minutes at both doses compared with a baseline value of approximately 5 minutes.
I.V. administration in humans of a single bolus dose of 0.25mg/kg followed by a continuous infusion of 10µg/min for periods of 12 to 96hours produced sustained high-grade platelet inhibition (ex vivo platelet aggregation in response to 5or 20µM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Equivalent results were obtained when a weight adjusted infusion dose (0.125 µg/kg/min to a maximum of 10µg/min) was used in patients up to 80 kg. Results in patients who received the 0.25mg/kg bolus followed by a 5µg/min infusion for 24hours 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 24to 48hours.
Indications
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. Abciximab Also Binds With Similar Affinity To The Vitronectin (a Vb 3) Receptor Found On Platelets And Vessel Wall Endothelial And Smooth Muscle Cells. The Vitronectin Receptor Mediates Pro-coagulant Properties Of Platelets And Proliferative Properties Of Vascular Endothelial Cells And Smooth Muscle Cells.
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 30minutes. This Disappearance From The Plasma Is Probably Related To Rapid Binding To The Platelet GPIIb/IIIa Receptors (approximately 80000 To 100000 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 15 Days Or More In A Platelet-bound State. Its Disappearance Follows A Monoexponential Time Course.
I.V. Administration Of A 0.25mg/kg Bolus Dose Of Abciximab Followed By Continuous Infusion Of 5or 10µg/min For Periods Of 12 To 96hours Produced Relatively Constant Total Plasma Concentrations From The First Time Point Measured (usually 2hours) For All Infusion Rates And Durations. However, Although The Total Plasma Concentrations Resulting From The 5µg/min Infusion Were Only Slightly Lower Than Those From The 10µg/min Infusion, The 5µg/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 6hours, Then Declined At A Much Slower Rate.
Pharmacodynamics: I.V. Administration In Humans Of Single Bolus Doses Of Abciximab From 0.15to 0.30mg/kg Resulted In A Dose-dependent Blockade Of Platelet GPIIb/IIIa Receptors And Produced Dose-dependent Inhibition Of Platelet Function As Measured By Exvivo Platelet Aggregation In Response To ADP Or By Prolongation Of Bleeding Time. At The 2highest Doses (0.25 And 0.30mg/kg) At 2hours Postinjection, Over 80% Of The GPIIb/IIIa Receptors Were Blocked And Platelet Aggregation In Response To 20µM ADP Was Almost Abolished. The Median Bleeding Time Increased To Over 30minutes At Both Doses Compared With A Baseline Value Of Approximately 5 Minutes.
I.V. Administration In Humans Of A Single Bolus Dose Of 0.25mg/kg Followed By A Continuous Infusion Of 10µg/min For Periods Of 12 To 96hours Produced Sustained High-grade Platelet Inhibition (ex Vivo Platelet Aggregation In Response To 5or 20µM ADP Less Than 20% Of Baseline And Bleeding Time Greater Than 30 Minutes) For The Duration Of The Infusion In Most Patients. Equivalent Results Were Obtained When A Weight Adjusted Infusion Dose (0.125 µg/kg/min To A Maximum Of 10µg/min) Was Used In Patients Up To 80 Kg. Results In Patients Who Received The 0.25mg/kg Bolus Followed By A 5µg/min Infusion For 24hours 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 24to 48hours.
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. Abciximab Also Binds With Similar Affinity To The Vitronectin (a Vb 3) Receptor Found On Platelets And Vessel Wall Endothelial And Smooth Muscle Cells. The Vitronectin Receptor Mediates Pro-coagulant Properties Of Platelets And Proliferative Properties Of Vascular Endothelial Cells And Smooth Muscle Cells.
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 30minutes. This Disappearance From The Plasma Is Probably Related To Rapid Binding To The Platelet GPIIb/IIIa Receptors (approximately 80000 To 100000 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 15 Days Or More In A Platelet-bound State. Its Disappearance Follows A Monoexponential Time Course.
I.V. Administration Of A 0.25mg/kg Bolus Dose Of Abciximab Followed By Continuous Infusion Of 5or 10µg/min For Periods Of 12 To 96hours Produced Relatively Constant Total Plasma Concentrations From The First Time Point Measured (usually 2hours) For All Infusion Rates And Durations. However, Although The Total Plasma Concentrations Resulting From The 5µg/min Infusion Were Only Slightly Lower Than Those From The 10µg/min Infusion, The 5µg/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 6hours, Then Declined At A Much Slower Rate.
Pharmacodynamics: I.V. Administration In Humans Of Single Bolus Doses Of Abciximab From 0.15to 0.30mg/kg Resulted In A Dose-dependent Blockade Of Platelet GPIIb/IIIa Receptors And Produced Dose-dependent Inhibition Of Platelet Function As Measured By Exvivo Platelet Aggregation In Response To ADP Or By Prolongation Of Bleeding Time. At The 2highest Doses (0.25 And 0.30mg/kg) At 2hours Postinjection, Over 80% Of The GPIIb/IIIa Receptors Were Blocked And Platelet Aggregation In Response To 20µM ADP Was Almost Abolished. The Median Bleeding Time Increased To Over 30minutes At Both Doses Compared With A Baseline Value Of Approximately 5 Minutes.
I.V. Administration In Humans Of A Single Bolus Dose Of 0.25mg/kg Followed By A Continuous Infusion Of 10µg/min For Periods Of 12 To 96hours Produced Sustained High-grade Platelet Inhibition (ex Vivo Platelet Aggregation In Response To 5or 20µM ADP Less Than 20% Of Baseline And Bleeding Time Greater Than 30 Minutes) For The Duration Of The Infusion In Most Patients. Equivalent Results Were Obtained When A Weight Adjusted Infusion Dose (0.125 µg/kg/min To A Maximum Of 10µg/min) Was Used In Patients Up To 80 Kg. Results In Patients Who Received The 0.25mg/kg Bolus Followed By A 5µg/min Infusion For 24hours 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 24to 48hours.
Contraindications
Abciximab should not be administered to patients with known sensitivity to abciximab, to any component of the product or to murine monoclonal antibodies.
Abciximab is contraindicated in the following clinical situations: active internal bleeding; recent (within 6weeks) gastrointestinal or genitourinary bleeding of clinical significance; history of cerebrovascular accident (CVA) within 2years or a CVA with a significant residual neurological deficit; recent (within 6weeks) 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 7days unless prothrombin time is £1.2times control.
Abciximab should not be administered to patients with known sensitivity to abciximab, to any component of the product or to murine monoclonal antibodies.
Abciximab is contraindicated in the following clinical situations: active internal bleeding; recent (within 6weeks) gastrointestinal or genitourinary bleeding of clinical significance; history of cerebrovascular accident (CVA) within 2years or a CVA with a significant residual neurological deficit; recent (within 6weeks) 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 7days unless prothrombin time is £1.2times control.
Safety Information / Warning
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.
Abciximab has the potential to increase the risk of bleeding, particularly in the presence of excessive anticoagulation, e.g., from heparin or thrombolytics (see Adverse Effects, Bleeding).
The risks of major bleeds due to abciximab therapy may be increased in patients receiving thrombolytics and should be weighed against the anticipated benefits (see Precautions, Use of Thrombolytics, Anticoagulants and Other Antiplatelet Agents).
Should serious bleeding occur that is not controllable with pressure, the infusion of abciximab and any concomitant heparin should be stopped.
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.
Abciximab has the potential to increase the risk of bleeding, particularly in the presence of excessive anticoagulation, e.g., from heparin or thrombolytics (see Adverse Effects, Bleeding).
The risks of major bleeds due to abciximab therapy may be increased in patients receiving thrombolytics and should be weighed against the anticipated benefits (see Precautions, Use of Thrombolytics, Anticoagulants and Other Antiplatelet Agents).
Should serious bleeding occur that is not controllable with pressure, the infusion of abciximab and any concomitant heparin should be stopped.
Precautions
Bleeding Precautions: Results of the EPILOG clinical trial show that bleeding can be reduced to the level of placebo by the use of low-dose, weight-adjusted heparin regimens, early sheath removal, careful patient and access site management and weight-adjustment of the abciximab infusion dose.
Before infusion of abciximab, platelet count, prothrombin time, ACT and APTT should be measured to identify pre-existing hemostatic abnormalities.
Low-dose, Weight-adjusted Heparin: Percutaneous Coronary Intervention: Heparin Bolus Pre-PTCA: If a patient's activated clotting time (ACT) is less than 200seconds 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 <150seconds: administer 70U/kg; ACT 150-199 seconds: administer 50U/kg.
The initial heparin bolus dose should not exceed 7000U.
ACT should be checked a minimum of 2 minutes after the heparin bolus. If the ACT is <200 seconds, additional heparin boluses of 20U/kg may be administered. Should the ACT remain <200 seconds, additional 20U/kg boluses are to be given until an ACT ³200 seconds is achieved.
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 300seconds.
Heparin Bolus during PTCA: During the PTCA procedure, ACT should be checked every 30 minutes. If ACT is <200 seconds, additional heparin boluses of 20U/kg may be administered. Should the ACT remain <200 seconds, additional 20U/kg boluses may be given until an ACT ³200 seconds is achieved. ACT should be checked prior to and a minimum of 2 minutes after each heparin bolus.
Heparin Infusion after PTCA: Discontinuation of heparin immediately following completion of the procedure, with removal of the arterial sheath within 6hours, is strongly recommended . In individual patients, if prolonged heparin therapy after PTCA or later sheath removal is used, then an initial infusion rate of 7U/kg/h is recommended (see Bleeding Precautions: Femoral Artery Sheath Removal). In all circumstances, heparin should be discontinued at least 2hours prior to arterial sheath removal.
Stabilization of Unstable Angina: Anticoagulation should be initiated with heparin to a target APTT of 60 to 85 seconds. The heparin infusion should be maintained during the abciximab infusion. Following angioplasty, heparin management is outlined above under Percutaneous Coronary Intervention.
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 15minutes for 1hour, then hourly for 6hours; 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 2hours prior to arterial sheath removal; check APTT or ACT prior to arterial sheath removal: do not remove sheath unless APTT £50 seconds or ACT £175seconds; apply pressure to access site for at least 30min 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 15minutes for the first hour or until stable, then hourly; continue complete bed rest with head of bed £30° and affected leg(s) straight for 6to 8hours following femoral artery sheath removal, 6to 8hours following discontinuation of abciximab or 4hours 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 H 2-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 12hours following the abciximab bolus injection, and again at 24hours 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 24hours after the bolus injection of abciximab. Vital signs (including blood pressure and pulse) should be obtained hourly for the first 4hours following the abciximab bolus injection, and then at 6, 12, 18 and 24hours 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, it is recommended that PTCA using abciximab be attempted first to salvage the situation. 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. Prior to surgical interventions, the bleeding time should be determined by the Ivy method (see above) and should be 12minutes or less (see Precautions, Restoration of Platelet Function).
Thrombocytopenia: To reduce the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2to 4hours following the bolus dose of abciximab and at 24hours. If a patient experiences an acute platelet decrease, additional platelet counts should be determined. These platelet counts should be drawn in 3separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively, 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 60000 cells/µL, heparin and ASA should bediscontinued. If a patient's platelet count drops below 50000cells/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 12minutes, 10units 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 60to 70% at which level platelet function is restored. Repeat platelet transfusions may be required to maintain the bleeding time at or below 12minutes.
Readministration: There are limited data concerning readministration of abciximab. Administration of abciximab may result in human anti-chimeric antibody (HACA) formation (see Adverse Effects) that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration of abciximab. Readministration of abciximab to 29 patients known to be HACA-negative has not led to any change in abciximab pharmacokinetics or to any reduction in antiplatelet potency.
Allergic Reactions: Anaphylaxis has not been reported for abciximab-treated patients in any of the pivotal clinical trials (EPIC, EPILOG, CAPTURE). However, anaphylaxis may occur. 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 titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
Carcinogenesis and Mutagenesis: In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Children: Safety and effectiveness of abciximab in children below the age of 18 have not been established.
Pregnancy: Animal reproduction studies have not been conducted with abciximab and the effects on fertility in male or female animals are unknown. 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.
Bleeding Precautions: Results of the EPILOG clinical trial show that bleeding can be reduced to the level of placebo by the use of low-dose, weight-adjusted heparin regimens, early sheath removal, careful patient and access site management and weight-adjustment of the abciximab infusion dose.
Before infusion of abciximab, platelet count, prothrombin time, ACT and APTT should be measured to identify pre-existing hemostatic abnormalities.
Low-dose, Weight-adjusted Heparin: Percutaneous Coronary Intervention: Heparin Bolus Pre-PTCA: If a patient's activated clotting time (ACT) is less than 200seconds 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 <150seconds: administer 70U/kg; ACT 150-199 seconds: administer 50U/kg.
The initial heparin bolus dose should not exceed 7000U.
ACT should be checked a minimum of 2 minutes after the heparin bolus. If the ACT is <200 seconds, additional heparin boluses of 20U/kg may be administered. Should the ACT remain <200 seconds, additional 20U/kg boluses are to be given until an ACT ³200 seconds is achieved.
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 300seconds.
Heparin Bolus during PTCA: During the PTCA procedure, ACT should be checked every 30 minutes. If ACT is <200 seconds, additional heparin boluses of 20U/kg may be administered. Should the ACT remain <200 seconds, additional 20U/kg boluses may be given until an ACT ³200 seconds is achieved. ACT should be checked prior to and a minimum of 2 minutes after each heparin bolus.
Heparin Infusion after PTCA: Discontinuation of heparin immediately following completion of the procedure, with removal of the arterial sheath within 6hours, is strongly recommended . In individual patients, if prolonged heparin therapy after PTCA or later sheath removal is used, then an initial infusion rate of 7U/kg/h is recommended (see Bleeding Precautions: Femoral Artery Sheath Removal). In all circumstances, heparin should be discontinued at least 2hours prior to arterial sheath removal.
Stabilization of Unstable Angina: Anticoagulation should be initiated with heparin to a target APTT of 60 to 85 seconds. The heparin infusion should be maintained during the abciximab infusion. Following angioplasty, heparin management is outlined above under Percutaneous Coronary Intervention.
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 15minutes for 1hour, then hourly for 6hours; 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 2hours prior to arterial sheath removal; check APTT or ACT prior to arterial sheath removal: do not remove sheath unless APTT £50 seconds or ACT £175seconds; apply pressure to access site for at least 30min 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 15minutes for the first hour or until stable, then hourly; continue complete bed rest with head of bed £30° and affected leg(s) straight for 6to 8hours following femoral artery sheath removal, 6to 8hours following discontinuation of abciximab or 4hours 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 H 2-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 12hours following the abciximab bolus injection, and again at 24hours 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 24hours after the bolus injection of abciximab. Vital signs (including blood pressure and pulse) should be obtained hourly for the first 4hours following the abciximab bolus injection, and then at 6, 12, 18 and 24hours 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, it is recommended that PTCA using abciximab be attempted first to salvage the situation. 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. Prior to surgical interventions, the bleeding time should be determined by the Ivy method (see above) and should be 12minutes or less (see Precautions, Restoration of Platelet Function).
Thrombocytopenia: To reduce the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2to 4hours following the bolus dose of abciximab and at 24hours. If a patient experiences an acute platelet decrease, additional platelet counts should be determined. These platelet counts should be drawn in 3separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively, 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 60000 cells/µL, heparin and ASA should bediscontinued. If a patient's platelet count drops below 50000cells/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 12minutes, 10units 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 60to 70% at which level platelet function is restored. Repeat platelet transfusions may be required to maintain the bleeding time at or below 12minutes.
Readministration: There are limited data concerning readministration of abciximab. Administration of abciximab may result in human anti-chimeric antibody (HACA) formation (see Adverse Effects) that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration of abciximab. Readministration of abciximab to 29 patients known to be HACA-negative has not led to any change in abciximab pharmacokinetics or to any reduction in antiplatelet potency.
Allergic Reactions: Anaphylaxis has not been reported for abciximab-treated patients in any of the pivotal clinical trials (EPIC, EPILOG, CAPTURE). However, anaphylaxis may occur. 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 titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
Carcinogenesis and Mutagenesis: In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Children: Safety and effectiveness of abciximab in children below the age of 18 have not been established.
Pregnancy: Animal reproduction studies have not been conducted with abciximab and the effects on fertility in male or female animals are unknown. 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.
Side Effects / Adverse Effects
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 (1:1000 dilution), corticosteroids, respiratory assistance and other resuscitative measures are essential.
Bleeding: Bleeding was classified as major or minor by the criteria of the Thrombolysis in Myocardial Infarction (TIMI) study group. Major bleeding events were defined as either an intracranial hemorrhage or decrease in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria or hematemesis or observed blood loss with a hemoglobin decreasing more than 3 g/dL or with a decrease in hemoglobin of at least 4 g/dL with no observed blood loss.
In the EPIC trial, in which a non-weight-adjusted, standard heparin dose regimen was used, the most common complication during abciximab therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and transfusion of blood products were approximately doubled. Approximately 70% of abciximab-treated patients with major bleeding had bleeding at the arterial access site in the groin. Abciximab-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites.
In a subsequent clinical trial, EPILOG, using the heparin and abciximab dosing, sheath removal and arterial access site guidelines described under Precautions, the incidence of major bleeding in patients treated with abciximab and low-dose, weight-adjusted heparin (1.8%) was not significantly different from patients receiving placebo (3.1%) and there was no significant increase in the incidence of intracranial hemorrhage. The reduction in bleeding observed in the EPILOG trial was achieved without loss of efficacy.
a. Patients who had bleeding in more than one classification are counted only once according to the most severe classification. Patients with multiple bleeding events of the same classification are also counted once within that classification.
b. Packed red blood cells or whole blood.
Although data are limited, abciximab treatment was not associated with excess major bleeding in patients who underwent CABG surgery. Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery (See Precautions, Restoration of Platelet Function).
The total incidence of intracranial hemorrhage and nonhemorrhagic stroke across all 3 trials was similar, 7/2225 (0.31%) for placebo patients and 10/3112 (0.32%) for abciximab-treated patients. The incidence of intracranial hemorrhage was 0.13% in placebo patients and 0.19% in abciximab patients.
Thrombocytopenia: In the clinical trials, patients treated with abciximab were more likely than patients treated with placebo to experience decreases in platelet counts. The overall rates of thrombocytopenia (platelet counts <100000 cells/µL) in the EPIC, EPILOG and CAPTURE trials were 0.5% for placebo-treated patients and 2.9% for patients receiving abciximab bolus plus infusion. The incidence of thrombocytopenia was lowest in the EPILOG trial (placebo: 1.5%; abciximab and standard-dose, weight-adjusted heparin: 2.6%; abciximab and low-dose, weight-adjusted heparin: 2.5%). The lowest rates of platelet transfusions in abciximab-treated patients were also observed in the EPILOG trial, (placebo: 1.1%; abciximab and standard-dose, weight-adjusted heparin: 1.6%; abciximab and low-dose, weight-adjusted heparin: 0.9%).
Human Antichimeric Antibody (HACA): Human antichimeric antibody (HACA) may appear in response to the administration of abciximab. In the EPIC, EPILOG, and CAPTURE trials, positive responses occurred in approximately 5.8% of the abciximab-treated patients. There was no excess of hypersensitivity or allergic reactions related to abciximab treatment compared with placebo treatment. See also Precautions, Allergic Reactions.
Other Adverse Events: Clinical toxicity has been infrequent with the administration of abciximab. Adverse events reasonably related to study agent that were reported by investigators with at least a 0.2% greater incidence for abciximab bolus plus infusion compared with placebo for the 2038 treated patients in the 3pivotal clinical trials.
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 (1:1000 dilution), corticosteroids, respiratory assistance and other resuscitative measures are essential.
Overdose
Symptoms and Treatment: There has been no experience of overdosage with abciximab in human clinical trials. However, refer to Precautions, Restoration of Platelet Function.
Symptoms and Treatment: There has been no experience of overdosage with abciximab in human clinical trials. However, refer to Precautions, Restoration of Platelet Function.
Recommended Dosage
The safety and efficacy of abciximab have only been investigated with concomitant administration of heparin and ASA.
ASA should be administered orally at a daily dose of 300 to 325 mg.
For heparin anticoagulation guidelines see Precautions, Bleeding Precautions: Heparin.
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 Precautions, Restoration of Platelet Function).
Adults: The recommended dose of abciximab is a 0.25 mg/kg i.v. bolus followed by a 0.125µg/kg/min (to a maximum of 10µg/min) continuous i.v. infusion.
For the stabilization of unstable angina patients, the bolus dose followed by the infusion should be started up to 24 hours prior to the possible intervention.
For the prevention of ischemic cardiac complications in patients undergoing percutaneous coronary intervention, and who are not currently receiving an abciximab infusion, the bolus should be administered 10 to 60 minutes prior to the intervention, followed by the 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 into a syringe. Filter the bolus injection using a sterile, nonpyrogenic, low protein-binding 0.2 or 0.22µm filter (Millipore SLGV025LS or equivalent).
Withdraw the necessary amount of abciximab for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% saline or 5% dextrose and infuse at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, nonpyrogenic, low protein-binding 0.2 or 0.22 µm syringe filter (Millipore SLGV025LS or equivalent) or upon administration using an in-line, sterile, nonpyrogenic, low protein-binding 0.2 or 0.22 µm filter (Abbott #4524 or equivalent).
Discard the unused portion at the end of the 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.
The safety and efficacy of abciximab have only been investigated with concomitant administration of heparin and ASA.
ASA should be administered orally at a daily dose of 300 to 325 mg.
For heparin anticoagulation guidelines see Precautions, Bleeding Precautions: Heparin.
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 Precautions, Restoration of Platelet Function).
Adults: The recommended dose of abciximab is a 0.25 mg/kg i.v. bolus followed by a 0.125µg/kg/min (to a maximum of 10µg/min) continuous i.v. infusion.
For the stabilization of unstable angina patients, the bolus dose followed by the infusion should be started up to 24 hours prior to the possible intervention.
For the prevention of ischemic cardiac complications in patients undergoing percutaneous coronary intervention, and who are not currently receiving an abciximab infusion, the bolus should be administered 10 to 60 minutes prior to the intervention, followed by the 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 into a syringe. Filter the bolus injection using a sterile, nonpyrogenic, low protein-binding 0.2 or 0.22µm filter (Millipore SLGV025LS or equivalent).
Withdraw the necessary amount of abciximab for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% saline or 5% dextrose and infuse at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, nonpyrogenic, low protein-binding 0.2 or 0.22 µm syringe filter (Millipore SLGV025LS or equivalent) or upon administration using an in-line, sterile, nonpyrogenic, low protein-binding 0.2 or 0.22 µm filter (Abbott #4524 or equivalent).
Discard the unused portion at the end of the 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.
Supplied / Packaging
Each mL of clear, colorless, sterile, nonpyrogenic solution for i.v. use contains: abciximab 2mg. Nonmedicinal ingredients: polysorbate 80, sodium chloride and sodium phosphate. Preservative-free. Vials of 5mL, packages of 1. Store at 2to 8°C. Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial.
Each mL of clear, colorless, sterile, nonpyrogenic solution for i.v. use contains: abciximab 2mg. Nonmedicinal ingredients: polysorbate 80, sodium chloride and sodium phosphate. Preservative-free. Vials of 5mL, packages of 1. Store at 2to 8°C. Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial.
