ReoPro Side Effects

Generic Name: abciximab

Please note - some side effects for ReoPro may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of ReoPro - for the Consumer

ReoPro

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using ReoPro:

Back pain; dizziness; general pain; headache; indigestion; nausea; pain at injection site; slow heart rate; stomach pain; swelling; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using ReoPro:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abdominal pain or swelling; black or bloody stools; chest pain; chills; continued redness or pain after an injection; coughing up blood; excessive or unusual bleeding; fever; increased menstrual bleeding; nosebleeds; pink or red urine; severe headache; slow heartbeat; vomiting blood or material that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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ReoPro Side Effects - for the Professional

ReoPro

Bleeding- Abciximab has the potential to increase the risk of bleeding, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants or thrombolytics. Bleeding in the Phase 3 trials was classified as major, minor or insignificant by the criteria of the Thrombolysis in Myocardial Infarction study group (16). Major bleeding events were defined as either an intracranial hemorrhage or a decrease in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, observed blood loss with a hemoglobin decrease of more than 3 g/dL, or a decrease in hemoglobin of at least 4 g/dL without an identified bleeding site. Insignificant bleeding events were defined as a decrease in hemoglobin of less than 3 g/dL or a decrease in hemoglobin between 3-4 g/dL without observed bleeding. In patients who received transfusions, the number of units of blood lost was estimated through an adaptation of the method of Landefeld, et al. (17).

In the EPIC trial, in which a non-weight-adjusted, longer-duration 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 significantly increased. Major bleeding occurred in 10.6% of patients in the Abciximab bolus plus infusion arm compared with 3.3% of patients in the placebo arm. Minor bleeding was seen in 16.8% of Abciximab bolus plus infusion patients and 9.2% of placebo patients (7). 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.

Bleeding rates were reduced in the CAPTURE trial, and further reduced in the EPILOG and EPISTENT trials by use of modified dosing regimens and specific patient management techniques. In EPILOG and EPISTENT, 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 was not significantly different from that in patients receiving placebo.

Subgroup analyses in the EPIC and CAPTURE trials showed that non-CABG major bleeding was more common in Abciximab patients weighing ≤ 75 kg. In the EPILOG and EPISTENT trials, which used weight-adjusted heparin dosing, the non-CABG major bleeding rates for Abciximab-treated patients did not differ substantially by weight subgroup.

Although data are limited, Abciximab treatment was not associated with excess major bleeding in patients who underwent CABG surgery. (The range among all treatment arms was 3-5% in EPIC, and 1-2% in the CAPTURE, EPILOG, and EPISTENT trials.) Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery.

The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the CAPTURE, EPILOG, and EPISTENT trials are shown in Table 4. The rates of insignificant bleeding events are not included in Table 4.

Pulmonary alveolar hemorrhage has been rarely reported during use of Abciximab. This can present with any or all of the following in close association with ReoPro administration: hypoxemia, alveolar infiltrates on chest x-ray, hemoptysis, or an unexplained drop in hemoglobin.

Table 4 NON-CABG BLEEDING IN TRIALS OF PERCUTANEOUS CORONARY INTERVENTION (EPILOG, EPISTENT and CAPTURE) Number of Patients with Bleeds (%)

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 Patients with major non-CABG bleeding who received packed red blood cells or whole blood transfusion.
c Standard-dose heparin with or without stent (EPILOG and EPISTENT)
d Low-dose heparin with or without stent (EPILOG and EPISTENT)
e Standard-dose heparin (EPILOG)
f Standard-dose heparin (CAPTURE)
EPILOG and EPISTENT:
	Placeboc (n = 1748)	Abciximab + Low-dose Heparind (n=2525)	Abciximab + Standard-dose Heparine(n=918)
Majora	18 (1.0)	21 (0.8)	17 (1.9)
Minor	46 (2.6)	82 (3.2)	70 (7.6)
Requiring transfusionb	15 (0.9)	13 (0.5)	7 (0.8)
CAPTURE:
	Placebof (n=635)		Abciximabf (n=630)
Majora	12 (1.9)		24 (3.8)
Minor	13 (2.0)		30 (4.8)
Requiring transfusionb	9 (1.4)		15 (2.4)

Intracranial Hemorrhage and Stroke- The total incidence of intracranial hemorrhage and non-hemorrhagic stroke across all four trials was not significantly different, 9/3023 for placebo patients and 15/4680 for Abciximab-treated patients. The incidence of intracranial hemorrhage was 3/3023 for placebo patients and 7/4680 for 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.

Among patients in the EPILOG and EPISTENT trials who were treated with Abciximab plus low-dose heparin, the proportion of patients with any thrombocytopenia (platelets less than 100,000 cells/μL) ranged from 2.5 to 3.0%. The incidence of severe thrombocytopenia (platelets less than 50,000 cells/μL) ranged from 0.4 to 1.0% and platelet transfusions were required in 0.9 to 1.1%, respectively. Modestly lower rates were observed among patients treated with placebo plus standard-dose heparin. Overall higher rates were observed among patients in the EPIC and CAPTURE trials treated with Abciximab plus longer duration heparin: 2.6 to 5.2% were found to have any thrombocytopenia, 0.9 to 1.7% had severe thrombocytopenia, and 2.1 to 5.5% required platelet transfusion, respectively.

In a readministration registry study of patients receiving a second or subsequent exposure to Abciximab the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% (<20,000 cell/μL). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous Abciximab exposure, readministration within 30 days, and a positive HACA assay prior to the readministration.

Among 14 patients who had thrombocytopenia associated with a prior exposure to Abciximab, 7 (50%) had recurrent thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe.

Allergic Reactions- There have been rare reports of allergic reactions, some of which were anaphylaxis.

Other Adverse Reactions- Table 5 shows adverse events other than bleeding and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in patients in the bolus plus infusion arm at an incidence of more than 0.5% higher than in those treated with placebo.

Table 5 ADVERSE EVENTS AMONG TREATED PATIENTS IN THE EPIC, EPILOG, AND CAPTURE TRIALS

Event	Placebo (n=2226)	Bolus + Infusion (n=3111)
	Number of Patients (%)
Cardiovascular system
Hypotension	230 (10.3)	447 (14.4)
Bradycardia	79 (3.5)	140 (4.5)
Gastrointestinal system
Nausea	255 (11.5)	423 (13.6)
Vomiting	152 ( 6.8)	226 (7.3)
Abdominal pain	49 ( 2.2)	97 (3.1)
Miscellaneous
Back pain	304 (13.7)	546 (17.6)
Chest pain	208 (9.3)	356 (11.4)
Headache	122 (5.5)	200 (6.4)
Puncture site pain	58 (2.6)	113 (3.6)
Peripheral edema	25 (1.1)	49 (1.6)

The following additional adverse events from the EPIC, EPILOG and CAPTURE trials were reported by investigators for patients treated with a bolus plus infusion of Abciximab at incidences which were less than 0.5% higher than for patients in the placebo arm.

Cardiovascular System: ventricular tachycardia (1.4%), pseudoaneurysm (0.8%), palpitation (0.5%), arteriovenous fistula (0.4%), incomplete AV block (0.3%), nodal arrhythmia (0.2%), complete AV block (0.1%), embolism (limb)(0.1%); thrombophlebitis (0.1%);

Gastrointestinal System: dyspepsia (2.1%), diarrhea (1.1%), ileus (0.1%), gastroesophogeal reflux (0.1%);

Hemic and Lymphatic System: anemia (1.3%), leukocytosis (0.5%), petechiae (0.2%);

Nervous System: dizziness (2.9%), anxiety (1.7%), abnormal thinking (1.3%), agitation (0.7%), hypesthesia (0.6%), confusion (0.5%) muscle contractions (0.4%), coma (0.2%), hypertonia (0.2%), diplopia (0.1%);

Respiratory System: pneumonia (0.4%), rales (0.4%), pleural effusion (0.3%), bronchitis (0.3%) bronchospasm (0.3%), pleurisy (0.2%), pulmonary embolism (0.2%), rhonchi (0.1%);

Musculoskeletal System: myalgia (0.2%);

Urogenital System: urinary retention (0.7%), dysuria (0.4%), abnormal renal function (0.4%), frequent micturition (0.1%), cystalgia (0.1%), urinary incontinence (0.1%), prostatitis (0.1%);

Miscellaneous: pain (5.4%), sweating increased (1.0%), asthenia (0.7%), incisional pain (0.6%), pruritus (0.5%), abnormal vision (0.3%), edema (0.3%), wound (0.2%), abscess (0.2%), cellulitis (0.2%), peripheral coldness (0.2%), injection site pain (0.1%), dry mouth (0.1%), pallor (0.1%), diabetes mellitus (0.1%), hyperkalemia (0.1%), enlarged abdomen (0.1%), bullous eruption (0.1%), inflammation (0.1%), drug toxicity (0.1%).

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. In the EPIC, EPILOG, and CAPTURE trials, positive HACA responses occurred in approximately 5.8% of these patients receiving a first exposure to Abciximab. No increase in hypersensitivity or allergic reactions was observed with Abciximab treatment.

In a study of readministration of Abciximab to patients the overall rate of HACA positivity prior to the readministration was 6% and increased post-readministration to 27%. Among the 36 subjects receiving a fourth or greater Abciximab exposure, HACA positive assays were observed post-readministration in 16 subjects (44%). There were no reports of serious allergic reactions or anaphylaxis. HACA positive status was associated with an increased risk of thrombocytopenia.

The data reflect the percentage of patients whose test results were considered positive for antibodies to Abciximab using an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Abciximab with the incidence of antibodies to other products may be misleading.

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Side Effects by Body System - for Healthcare Professionals

Hematologic

There was no significant increase in bleeding between patients who received abciximab and those who received aspirin, heparin, or placebo among the 58 patients from the EPIC trial who underwent emergency coronary artery bypass grafting (CABG) after PTCA. The authors concluded that surgery can be performed after treatment with abciximab with acceptable mortality and bleeding complications. These data are supported by data from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study.

In the EPILOG trial, use of weight-adjusted abciximab infusion and low-dose weight-adjusted heparin, early removal of the femoral sheath, and arterial access guidelines reduced the incidence of major bleeding in patients receiving abciximab and heparin to rates similar to patients receiving placebo.

Immediate discontinuation of abciximab (and heparin) is recommended in the event of serious bleeding that cannot be controlled by compression.

The first and second most common sites of bleeding are the femoral artery access site and the gastrointestinal (GI) tract, respectively. Great care should be exercised when placing the femoral artery introducer. Indwelling arterial and venous lines should be in place prior to administration of abciximab, and recent puncture sites should be monitored closely.

In clinical trials, the incidence of intracranial hemorrhage in treated patients was similar to placebo, but the incidence of major bleeding events from GI, genitourinary, retroperitoneal, and other sites was higher in treated patients.

The incidence of hematologic side effects such as bleeding increases when abciximab is given following full dose thrombolytic therapy. In a Canadian study involving 147 acute myocardial infarction (AMI) patients, the researchers reported a 2-fold increase in bleeding risk in patients who had received full dose thrombolytics followed by adjunctive abciximab (plus low dose heparin) therapy during rescue or urgent PTCA. The patients were treated with full dose thrombolytics within the first 12 hours following the onset of AMI symptoms. Abciximab was given to 57 patients as adjunctive therapy during rescue (PTCA within 12 hours of AMI) or urgent (PTCA within 48 hours of AMI) angioplasty. The remaining 90 patients did not receive abciximab, and served as the control group. The authors reported that the risk of intracranial or fatal bleeding events was the same for both treated and non-treated groups, however, the risk for minor bleeding was doubled for the abciximab-treated group.

Major bleeding events were increased in patients receiving abciximab within 24 hours of full dose thrombolytic therapy according to a study conducted between July 1995 and March 1999. Of the 214 total patients studied, 50 (23%) experienced major bleeding episodes. A total of 34 patients required transfusions. Intracranial bleeding occurred in 3 (1.4%) patients. The authors concluded that major bleeding occurs in about 20% to 25% of patients when abciximab is used within 24 hours of full-dose thrombolytic therapy.

Risk factors for bleeding events in patients treated with glycoprotein (GP) IIb/IIIa inhibitors undergoing percutaneous coronary intervention (PCI) have been identified and include advanced age, renal dysfunction, female gender, peripheral vascular disease, lower body weight, duration of GP IIb/IIIa inhibitor infusion, baseline platelet count, lower baseline hemoglobin, diabetes, and elevated peak activated clotting time. According to one study (CRUSADE trial) involving patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) treated with a GP IIb/IIIa inhibitor, women are at a greater risk of bleeding than men, primarily because of excessive dosing. Results of another study indicate that among patients with NSTEACS undergoing a PCI, compared with men, women experienced a greater incidence of major and minor bleeding complications and required more transfusions of blood products.

Hematologic complications are the most common and potentially life-threatening side effects of abciximab. Thrombocytopenia (less than 100,000 cells/mcL) associated with abciximab and standard dose heparin occurred at a rate of 2.5% to 6% (1% to 2% had platelet counts less than 50,000 cells/mcL.). Thrombocytopenia (less than 100,000 cells/mcL) associated with abciximab and low-dose weight-adjusted heparin (EPILOG) occurred at a rate of 2.5% (less than 0.5% had platelet counts less than 50,000 cells/mcL).

Pseudothrombocytopenia, which is considered a benign laboratory condition that does not increase bleeding, stroke, need for transfusion or repeat revascularization, has been reported as the cause of more than one third of low platelet counts in patients undergoing coronary interventions treated with abciximab. Compared with placebo, the incidence of pseudothrombocytopenia in four trials using abciximab was 0.6% vs 2.1%, respectively.

Major bleeding, defined as either an intracranial hemorrhage or a decrease in hemoglobin greater than 5 g/dL, has been reported in 2% to 11% of patients receiving abciximab and standard-dose heparin. Major bleeding was reported in 1% of patients receiving abciximab and low-dose heparin (EPILOG). Minor bleeding, including spontaneous gross hematuria, spontaneous hematemesis, observed blood loss with a hemoglobin decrease of greater than 3g/dL, or a decrease in hemoglobin of at least 4g/dL without an identified bleeding site, has been reported in 4% to 17% of patients receiving abciximab and standard-dose heparin. Minor bleeding was reported in 4% of patients receiving abciximab and low-dose heparin (EPILOG).

Excess spontaneous major organ bleeding has occurred primarily in abciximab treated patients weighing 75 kg or less. In addition, patients who experienced a greater incidence of major bleeding episodes have included: patients greater than 65 years old; those who had a prior history of GI disease; those who had received thrombolytics; those who were administered heparin; those who received PTCA within 12 hours of the onset of AMI symptoms; those whose PTCA procedure was greater than 70 minutes in length; and those who failed PTCA.

Anemia, leukocytosis, and petechiae have been reported in 1.3%, 0.5%, and 0.2% of patients, respectively.

Hypersensitivity

Abciximab can induce the formation of human anti-chimeric antibodies (HACA) and can produce allergic reactions, including anaphylaxis and thrombocytopenia. These antibodies may diminish the potential benefit of readministration of abciximab (not recommended by manufacturer). Human anti-chimeric antibodies to abciximab may appear at approximately 14 days after initiating therapy and peak at 4 to 6 weeks.

Hypersensitivity reactions (which may be anticipated whenever protein solutions such as abciximab are administered) may present as anaphylaxis, and may require epinephrine, dopamine, theophylline, antihistamine, and corticosteroid therapy. To date, anaphylaxis has not been reported with abciximab therapy.

Cardiovascular

Cardiovascular side effects have included hypotension in 14 % of patients (often related to hemorrhagic complications) and bradycardia in 5% of patients. Chest pain has been reported in 11% of patients and peripheral edema has been reported in 2% of patients. The following cardiovascular side effects have occurred at incidences less than 0.5% higher for patients who received abciximab than for patients who received placebo: ventricular tachycardia (1.4%), pseudoaneurysm (0.8%) , palpitation (0.5%), arteriovenous fistula (0.4%), incomplete AV block (0.3%), nodal arrhythmia (0.2%), peripheral coldness (0.2%), complete AV block (0.1%), embolism (limb) (0.1%), and thromboembolism (0.1%).

Analysis of one study (TARGET trial) indicates that patients with renal dysfunction undergoing PCI and receiving a GP IIb/IIIa inhibitor (i.e., tirofiban, abciximab) are at a higher risk of developing ischemic complications (30-day death, myocardial infarction,urgent revascularization) than patients with normal creatinine clearance.

Gastrointestinal

Gastrointestinal side effects have included nausea and vomiting in 14% and 7% of patients, respectively and abdominal pain in 3% of patients. The following GI system side effects have occurred at incidences less than 0.5% higher for patients who received abciximab than for patients who received placebo: dyspepsia (2.1%), diarrhea (1.1%), ileus or gastroesophageal reflux or enlarged abdomen or dry mouth (0.1%).

Nervous system

Nervous system side effects are unusual, but have included headache in 6.4%, hyperesthesia or increased sweating in 1% and confusion in 0.6% of patients. The following nervous system side effects have occurred at incidences less than 0.5% higher for patients who received abciximab than for patients who received placebo: abnormal vision (0.3%), dizziness (2.9%), anxiety (1.7%), abnormal thinking (1.3%), agitation (0.7%), hypesthesia (0.6%), confusion (0.5%), muscle contractions (0.4%), coma (0.2%), hypertonia (0.2%), and diplopia (0.1%).

Respiratory

Respiratory side effects have rarely included pulmonary hemorrhage (0.19%), with fatalities reported in 6 cases. All patients presented with acute myocardial infarction and abnormal chest X-ray at baseline. Five patients presented with a history of COPD. The following respiratory side effects have occurred at incidences less than 0.5% higher for patients who received abciximab than for patients who received placebo: pneumonia or rales (0.4%), pleural effusions or bronchitis or bronchospasm (0.3%), pleurisy or pulmonary embolism (0.2%), and rhonchi (0.1%).

Musculoskeletal

Musculoskeletal pain, primarily back pain, has been reported in up to 18% of patients. Asthenia has been report in 0.7% and myalgias in less than 0.2% of patients.

Genitourinary

Genitourinary side effects that have occurred at incidences less than 1% higher for patients who received abciximab than for patients who received placebo include: urinary retention (0.7%), dysuria or abnormal renal function (0.4%), frequent micturition or cystalgia or urinary incontinence or prostatitis (0.1%).

Dermatologic

Dermatologic side effects that have occurred at incidences equal to or less than 0.5% in patients who received abciximab include: pruritus (0.5%), wound or cellulitis (0.2%), injection site pain or bullous eruption or inflammation or pallor (0.1%). These side effects occurred at an equal or greater frequency in patients receiving a placebo.

Endocrine

Endocrine side effects are unusual and have included diabetes mellitus and hyperkalemia (0.1%).

Local

Pain at the puncture site or incision pain has occurred in 3.6% and 0.6% of patients, respectively.

Other

Drug toxicity has occurred in 0.1% of patients receiving abciximab.

Immunologic

Readministration of abciximab to 29 healthy volunteers who did not develop a human anti-chimeric antibody (HACA) response following the initial dose did not alter the pharmacokinetic disposition of abciximab or reduce its antiplatelet activity. However, results in this group indicate that the incidence of HACA formation may be increased after readministration. The clinical significance of a positive HACA titer remains to be determined.

Abciximab can induce the formation of human anti-chimeric antibodies (HACA). Most patients develop IgG rather than IgE immune globulins (associated with anaphylaxis) that do not appear to interfere with abciximab binding to GP IIb/IIIa receptors. Human anti-chimeric antibodies to abciximab may appear at approximately 14 days after initiating therapy and peak at 4 to 6 weeks.

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