Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Janssen Biologics B.V., Einsteinweg 101, 2333 CB Leiden, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to murine monoclonal antibodies or to papain. Trace amounts of papain resulting from the production process may be present.
Because inhibition of platelet aggregation increases the risk of bleeding, ReoPro is contraindicated in the following clinical situations: active internal bleeding; history of cerebrovascular accident within two years; recent (within two months) intracranial or intraspinal surgery or trauma; recent (within two months) major surgery; intracranial neoplasm, arteriovenous malformation or aneurysm; known bleeding diathesis or severe uncontrolled hypertension; pre-existing thrombocytopenia; vasculitis; hypertensive retinopathy; severe hepatic failure.
Since there are only limited data available, use of ReoPro in severe renal failure patients requiring haemodialysis is contraindicated (see section 4.4, paragraph on Renal disease).
Careful assessment of risk:benefit should be made in individual patients before commencing therapy with ReoPro. A favourable risk:benefit has not been established in low risk patients >65 years of age.
ReoPro should be used as an adjunct to acetylsalicylic acid and heparin therapy
Acetylsalicylic acid should be administered orally at a daily dose of approximately but not less than 300 mg.
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 <150 seconds: administer 70 U/kg
ACT 150-199 seconds: administer 50 U/kg
The initial heparin bolus dose should not exceed 7,000 U.
ACT should be checked a minimum of 2 minutes after the heparin bolus. If the ACT is <200 seconds, additional heparin boluses of 20 U/kg may be administered. Should the ACT remain <200 seconds, additional 20 U/kg boluses are to be given until an ACT ≥200 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 300 seconds.
During the PTCA procedure, ACT should be checked every 30 minutes. If ACT is <200 seconds, additional heparin boluses of 20 U/kg may be administered. Should the ACT remain <200 seconds, additional 20 U/kg boluses may be given until an ACT ≥200 seconds is achieved. ACT should be checked prior to and a minimum of 2 minutes after each heparin bolus.
As an alternative to giving additional boluses as described above, a continuous heparin infusion may be initiated after the initial heparin bolus doses achieve the ACT target ≥200 seconds at a rate of 7 U/kg/hour and continued for the duration of the procedure.
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/hr is recommended (see paragraph on Bleeding Precautions – Femoral artery access site). In all circumstances, heparin should be discontinued at least 2 hours prior to arterial sheath removal.
Anticoagulation should be initiated with heparin to a target APTT of 60-85 seconds. The heparin infusion should be maintained during the ReoPro infusion. Following angioplasty, heparin management is outlined as described in the paragraph on Concomitant heparin therapy for percutaneous coronary intervention.
Administration of ReoPro may be associated with an increase in bleeding events, rarely including those with a fatal outcome.
Careful attention should be paid to all potential bleeding sites, including arterial and venous puncture sites, catheter insertion sites, cut down sites, and needle puncture sites.
ReoPro 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:
While femoral artery sheath is in place:
Femoral artery sheath removal:
After femoral artery sheath removal:
Management of femoral access site bleeding/haematoma formation:
If groin bleed continues or the haematoma expands during ReoPro infusion despite the above measures, the ReoPro infusion should be immediately discontinued and the arterial sheath removed according to the guidelines listed above. After sheath removal intravenous access should be maintained until bleeding is controlled (see paragraph on Transfusion to restore platelet function).
ReoPro is associated with an increased risk of retroperitoneal bleeding in association with femoral vascular puncture. The use of venous sheaths should be minimised and only the anterior wall of the artery or vein should be punctured when establishing vascular access (see paragraph on Bleeding Precautions – Femoral Artery Access Site).
ReoPro has rarely been associated with pulmonary (mostly alveolar) haemorrhage. This can present with any or all of the following in close association with ReoPro administration: hypoxemia, alveolar infiltrates on chest x-ray, haemoptysis, or an unexplained drop in haemoglobin. If confirmed, ReoPro and all anticoagulant and other antiplatelet medicinal products should immediately be discontinued.
In order to prevent spontaneous GI 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.
Unnecessary arterial and venous punctures, intramuscular injections, routine use of urinary catheters, nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be avoided. When obtaining intravenous access, non-compressible sites (e.g. subclavian or jugular veins) should be avoided. Sodium chloride solution 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.
Before administration of ReoPro, platelet count, ACT, prothrombin time (PT) and APTT should be measured to identify pre-existing coagulation abnormalities. Additional platelet counts should be taken 2-4 hours following the bolus dose and at 24 hours. Haemoglobin and haematocrit measurements should be obtained prior to the ReoPro administration, at 12 hours following the ReoPro bolus injection, and again at 24 hours following the bolus injection. Twelve lead electrocardiograms (ECG) should be obtained prior to the bolus injection of ReoPro, and repeated once the patient has returned to the hospital ward from the catheterization laboratory, and at 24 hours after the bolus injection of ReoPro. Vital signs (including blood pressure and pulse) should be obtained hourly for the first 4 hours following the ReoPro bolus injection, and then at 6, 12, 18 and 24 hours following the ReoPro bolus injection.
Thrombocytopenia, including severe thrombocytopenia, has been observed with ReoPro administration (See section 4.8). In clinical studies, most cases of severe thrombocytopenia (<50,000 cells/μL) occurred within the first 24 hours of ReoPro administration.
To evaluate the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2 to 4 hours following the bolus dose of ReoPro 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 three separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively, to exclude pseudothrombocytopenia, due to in vitro anticoagulant interaction. If true thrombocytopenia is verified, ReoPro 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 acetylsalicylic acid should be discontinued. If a patient’s platelet count drops below 50,000 cells/µL, transfusion of platelets should be considered, especially if the patient is bleeding and/or invasive procedures are planned or ongoing. If the patient’s platelet count drops below 20,000 cells/µL, platelets should be transfused. The decision to use platelet transfusion should be based upon clinical judgment on an individual basis. Thrombocytopenia has been observed at higher rates following readministration (see paragraph on Readministration).
In the event of serious uncontrolled bleeding or the need for emergency surgery, ReoPro should be discontinued.
In the majority of patients, bleeding time returns to normal within 12 hours. If bleeding time remains prolonged and/or there is a marked inhibition of platelet function and/or if rapid haemostasis is required and/or in case(s) where haemostasis is not adequately restored, consideration should be given to seeking advice of a haematologist experienced in the diagnosis and management of bleeding disorders. Transfusion of donor platelets has been shown to restore platelet function following ReoPro administration in animal studies and transfusions of fresh random donor platelets have been given empirically to restore platelet function in humans.
When considering the need to transfuse patients, the patient’s intravascular volume should be assessed. If hypovolaemic, then the intravascular volume should be adequately restored with crystalloids. In asymptomatic patients, normovolaemic anaemia (haemoglobin 7-10 g/dL) can be well tolerated; transfusion is not indicated unless a deterioration in vital signs is seen or unless the patient develops signs and symptoms. In symptomatic patients (e.g., syncope, dyspnoea, postural hypotension, tachycardia), crystalloids should be used to replace intravascular volume. If symptoms persist, the patient should receive transfusions with packed red blood cells or whole blood on a unit-by-unit basis to relieve symptoms; one unit may be sufficient.
If rapid haemostasis is required, therapeutic doses of platelets may be administered (at least 5.5 × 10 11 platelets). Redistribution of ReoPro from endogenous platelet receptors to platelets, which have been transfused, may take place. 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 haemostasis.
Specific guidelines for access site bleeding are given above under the paragraph on Bleeding precautions – Femoral artery access site.
Because ReoPro inhibits platelet aggregation, caution should be employed when used with other medicinal products affecting haemostasis such as heparin or low molecular weight dextrans, oral anticoagulants such as warfarin, thrombolytics and antiplatelet agents other than acetylsalicylic acid, such as P2Y12 inhibitors (e.g., ticlopidine, clopidogrel, prasugrel, and ticagrelor) and dipyridamole (see section 4.5).
Data in patients receiving thrombolytics suggest an increase in the risk of bleeding when ReoPro is administered to patients treated with thrombolytics at doses sufficient to produce a systemic fibrinolytic state. Therefore, the use of ReoPro therapy for rescue angioplasty in those patients that have received systemic thrombolytic therapy should only be considered after careful consideration of the risks and benefits for each patient. The risk of bleeding and ICH appears higher the sooner ReoPro is administered after the application of the thrombolytic (see section 4.8, paragraph on Other vascular disorders).
If urgent intervention is required for refractory symptoms in a patient receiving ReoPro (or who has received the medicinal product 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 and should be 12 minutes or less. Should PTCA and any other appropriate procedures fail, and should the angiographic appearance suggest that the aetiology 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 if at all possible.
Hypersensitivity reactions should be anticipated whenever protein solutions such as ReoPro are administered. Adrenaline, 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 immediately. Subcutaneous administration of 0.3 to 0.5 mL of aqueous adrenaline (1:1000 dilution), and use of corticosteroids, respiratory assistance and other resuscitative measures are essential.
Hypersensitivity or allergic reactions have been observed rarely following treatment with ReoPro. Anaphylactic reactions (sometimes fatal) have been reported very rarely and may potentially occur at any time during administration.
Administration of ReoPro may result in the formation of human anti-chimeric antibody (HACA) that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration (see section 4.8, paragraph on Readministration).
Available evidence suggests that human antibodies to other monoclonal antibodies do not cross-react with ReoPro.
Thrombocytopenia was observed at higher rates in a readministration study than in the phase III studies of first-time administration, suggesting that readministration may be associated with an increased incidence and severity of thrombocytopenia (see section 4.8, paragraph on Readministration).
Benefits may be reduced in patients with renal disease. The use of ReoPro in patients with severe renal failure should only be considered after careful appraisal of the risks and benefits. Because the potential risk of bleeding is increased in patients with severe renal disease, patients should be more frequently monitored for bleeding. In the event serious bleeding occurs platelet transfusion should be considered (see paragraph on Bleeding precautions – Transfusion to restore platelet function). In addition the bleeding precautions as described above should be taken into consideration.
Use of ReoPro in patients receiving dialysis is contraindicated (see section 4.3).
ReoPro has been formally studied as an adjunct to heparin and acetylsalicylic acid treatment. In the presence of ReoPro, heparin is associated with an increase in the incidence of bleeding. Limited experience with ReoPro in patients who have received thrombolytics suggests an increase in the risk of bleeding. Although there have been no formal studies of ReoPro with other commonly used cardiovascular medicinal products, in clinical studies there have been no adverse reactions associated with concomitant use of other medicinal products used in the treatment of angina, myocardial infarction or hypertension nor with common intravenous infusion fluids. These medicinal products have included warfarin (before and following but not during PTCA), beta-adrenergic receptor blockers, calcium channel antagonists, angiotensin converting enzyme (ACE) inhibitors, and intravenous and oral nitrates.
It is also not known whether abciximab can cause foetal harm when administered to a pregnant woman. ReoPro should not be used during pregnancy unless clearly necessary.
Breastfeeding of infants should be discontinued in breastfeeding mothers since the secretion of abciximab in animal or human breast milk has not been studied.
Animal reproduction studies have not been conducted with ReoPro. It is also not known whether abciximab can affect reproduction capacity.
Not relevant.
The most frequent adverse reactions are bleeding, back pain, hypotension, nausea, chest pain, vomiting, headache, bradycardia, fever (pyrexia), puncture site pain and thrombocytopenia. Cardiac tamponade, pulmonary (mostly alveolar) haemorrhage and adult respiratory distress syndrome have been reported rarely.
The adverse reactions listed in Table 1 are based on experience from clinical studies and from world-wide post-marketing use of abciximab. Within the organ system classes, adverse reactions are listed under headings of frequency using the following convention: Very common ((≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).
Table 1. Tabulated list of ADRs*:
Common: Thrombocytopenia
Rare: Anaphylactic reaction, hypersensitivity/allergic reactions
Common: Headache
Common: Bradycardia
Rare: Cardiac tamponade
Common: Bleeding, hypotension, peripheral oedema
Uncommon: Intracranial haemorrhage
Rare: Fatal bleeding
Rare: Adult respiratory distress syndrome, pulmonary haemorrhage
Common: Gastrointestinal haemorrhage, nausea, vomiting
Common: Back pain
Common: Chest pain, pyrexia, puncture site pain, abdominal pain
* See section 4.4
In the EPIC study, in which a non-weight-adjusted, standard heparin dose regimen was used, the most common complication during ReoPro therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and transfusion of blood products were approximately doubled. In patients who had major bleeding, 67% had bleeding associated with the arterial access site in the groin.
Major and minor bleeding are defined as follows:
Major bleeding: Decrease in haemoglobin >5 g/dL
Minor bleeding: Spontaneous gross haematuria or haematemesis, or observed blood loss with a haemoglobin decrease >3 g/dL, or a decrease in haemoglobin ≥4 g/dL with no observed blood loss.
In a subsequent clinical study, EPILOG, using the heparin regimen, sheath removal and femoral access care guidelines outlined in section 4.4, paragraph on Bleeding precautions, the incidence of major bleeding not associated with CABG surgery in patients treated with ReoPro (1.1%) was not different from patients receiving placebo (1.1%) and there was no significant increase in the incidence of intracranial haemorrhage. The reduction in major bleeding observed in the EPILOG study was achieved without loss of efficacy. Likewise, in the EPISTENT study, the incidence of major bleeding not associated with CABG surgery in patients receiving ReoPro plus balloon angioplasty (0.6%) or ReoPro with stent placement (0.8%) was not significantly different from patients receiving placebo with stent placement (1.0%). In the CAPTURE study, which did not use the low-dose heparin regimen, the incidence of major bleeding not associated with CABG surgery was higher in patients receiving ReoPro (3.8%) than in patients receiving placebo (1.9%).
Although data are limited, ReoPro 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 section 4.4, paragraph on Transfusion to restore platelet function).
Clinical studies suggest that adherence to the currently recommended, weight adjusted heparin regimen is associated with a lower risk of intracranial haemorrhage than previous (higher dose, non-weight-adjusted) protocols. The total incidence of intracranial haemorrhage and non-haemorrhagic stroke in all 4 pivotal studies was similar, 9/3023 (0.30%) for placebo patients and 15/4680 (0.32%) for ReoPro treated patients. The incidence of intracranial haemorrhage was 0.10% in placebo patients and 0.15% in ReoPro patients.
The GUSTO V study randomised 16,588 patients with acute myocardial infarction to treatment with combined ReoPro and half-dose reteplase or full dose reteplase alone. The incidence of moderate or severe non-intracranial bleeding was increased in those patients receiving ReoPro and half-dose reteplase versus those receiving reteplase alone (4.6% versus 2.3% respectively).
Patients treated with ReoPro were more likely to experience thrombocytopenia (platelet counts less than 100,000 cells/μL) than placebo patients. The incidence in the EPILOG and EPISTENT studies using ReoPro with the recommended low-dose, weight-adjusted heparin regimen was 2.8% and 1.1% in placebo-treated patients. Thrombocytopenia has been observed at higher rates following readministration (see paragraph below on Readministration).
Human antichimeric antibody (HACA) formation appeared, generally as a low titre, in approximately 5% to 6% of patients 2 to 4 weeks after receiving a first exposure to ReoPro in the Phase III clinical studies.
Readministration of ReoPro to patients undergoing PTCA was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second ReoPro exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the readministration was 6% and increased to 27% postreadministration.
In a readministration registry study of patients receiving a second or subsequent exposure to ReoPro, 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 ReoPro exposure, readministration within 30 days, and a positive HACA assay prior to the readministration.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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