Eptifibatide Accord · 4.6 Fertility, pregnancy and lactation · 1

HOS-097667 · has-adverse-reaction-information · PDF-Seite 6

The majority of adverse reactions experienced by patients treated with eptifibatide were generally related to bleeding or to cardiovascular events that occur frequently in this patient population. Clinical Trials The data sources used to determine adverse reaction frequency descriptors included two phase III clinical studies (PURSUIT and ESPRIT). These trials are briefly described below. PURSUIT: This was a randomized, double-blind evaluation of the efficacy and safety of eptifibatide versus placebo for reducing mortality and myocardial (re)infarction in patients with unstable angina or non-Q-wave myocardial infarction. ESPRIT: This was a double-blind, multicentre, randomized, parallel-group, placebo-controlled trial evaluating the safety and efficacy of eptifibatide therapy in patients scheduled to undergo non-emergent percutaneous coronary intervention (PCI) with stent implantation. In PURSUIT, bleeding and non-bleeding events were collected from hospital discharge to the 30 day visit. In ESPRIT, bleeding events were reported at 48 hours, and non-bleeding events were reported at 30 days. While Thrombolysis in Myocardial Infarction TIMI bleeding criteria were used to categorize the incidence of major and minor bleeding in both the PURSUIT and the ESPRIT trials, PURSUIT data was collected within 30 days while ESPRIT data was limited to events within 48 hours or discharge, whichever came first. The undesirable effects are listed by system organ class and frequency. Frequencies are defined as very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). These are 6 absolute reporting frequencies without taking into account placebo rates. For a particular adverse reaction, if data was available from both PURSUIT and ESPRIT, then the highest reported incidence was used to assign adverse reaction frequency. Note that causality has not been determined for all adverse reactions. Blood and Lymphatic System Disorder Very common Bleeding (major and minor bleeding including femoral artery access, CABG- related, gastrointestinal, genitourinary, retroperitoneal, intracranial, haematemesis, haematuria, oral/oropharyngeal, haemoglobin/haematocrit decreased and other). Uncommon Thrombocytopenia. Nervous System dis

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HOS-097673 · has-adverse-reaction-information · PDF-Seite 19

The majority of adverse reactions experienced by patients treated with eptifibatide were generally related to bleeding or to cardiovascular events that occur frequently in this patient population. Clinical Trials The data sources used to determine adverse reaction frequency descriptors included two phase III clinical studies (PURSUIT and ESPRIT). These trials are briefly described below. PURSUIT: This was a randomized, double-blind evaluation of the efficacy and safety of eptifibatide versus placebo for reducing mortality and myocardial (re)infarction in patients with unstable angina or non-Q-wave myocardial infarction. ESPRIT: This was a double-blind, multicentre, randomized, parallel-group, placebo-controlled trial evaluating the safety and efficacy of eptifibatide therapy in patients scheduled to undergo non-emergent percutaneous coronary intervention (PCI) with stent implantation. In PURSUIT, bleeding and non-bleeding events were collected from hospital discharge to the 30 day visit. In ESPRIT, bleeding events were reported at 48 hours, and non-bleeding events were reported at 30 days. While Thrombolysis in Myocardial Infarction TIMI bleeding criteria were used to categorize the incidence of major and minor bleeding in both the PURSUIT and the ESPRIT trials, PURSUIT data was collected within 30 days while ESPRIT data was limited to events within 48 hours or discharge, whichever came first. The undesirable effects are listed by system organ class and frequency. Frequencies are defined as very common (≥ 1/10); common (≥ 1/100 to< 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). These are 19 absolute reporting frequencies without taking into account placebo rates. For a particular adverse reaction, if data was available from both PURSUIT and ESPRIT, then the highest reported incidence was used to assign adverse reaction frequency. Note that causality has not been determined for all adverse reactions. Blood and Lymphatic System Disorder Very common Bleeding (major and minor bleeding including femoral artery access, CABG-related, gastrointestinal, genitourinary, retroperitoneal, intracranial, haematemesis, haematuria, oral/oropharyngeal, haemoglobin/haematocrit decreased and other). Uncommon Thrombocyto

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HOS-097663 · has-contraindication-information · PDF-Seite 3

Eptifibatide Accord must not be used to treat patients with: - hypersensitivity to the active substance or to any of the excipients listed in section 6.1: - evidence of gastrointestinal bleeding, gross genitourinary bleeding or other active abnormal bleeding within the previous 30 days of treatment; - history of stroke within 30 days or any history of haemorrhagic stroke; - known history of intracranial disease (neoplasm, arteriovenous malformation, aneurysm); - major surgery or severe trauma within past 6 weeks; - a history of bleeding diathesis; - thrombocytopenia (< 100,000 cells/mm3); - prothrombin time > 1.2 times control, or International Normalized Ratio (INR)  2.0; - severe hypertension (systolic blood pressure > 200 mm Hg or diastolic blood pressure > 110 mm Hg on antihypertensive therapy); - severe renal impairment (creatinine clearance < 30 ml/min) or dependency on renal dialysis; - clinically significant hepatic impairment; - concomitant or planned administration of another parenteral glycoprotein (GP) IIb/IIIa inhibitor.

HOS-097669 · has-contraindication-information · PDF-Seite 16

Eptifibatide Accord must not be used to treat patients with: - hypersensitivity to the active substance or to any of the excipients listed in section 6.1; - evidence of gastrointestinal bleeding, gross genitourinary bleeding or other active abnormal bleeding within the previous 30 days of treatment; - history of stroke within 30 days or any history of haemorrhagic stroke; - known history of intracranial disease (neoplasm, arteriovenous malformation, aneurysm); - major surgery or severe trauma within past 6 weeks; - a history of bleeding diathesis; - thrombocytopenia (< 100,000 cells/mm3); - prothrombin time > 1.2 times control, or International Normalized Ratio (INR) ≥ 2.0; - severe hypertension (systolic blood pressure > 200 mm Hg or diastolic blood pressure > 110 mm Hg on antihypertensive therapy); - severe renal impairment (creatinine clearance < 30 ml/min) or dependency on renal dialysis - clinically significant hepatic impairment; - concomitant or planned administration of another parenteral glycoprotein (GP) IIb/IIIa inhibitor.

HOS-097662 · has-indication-information · PDF-Seite 2

Eptifibatide Accord is intended for use with acetylsalicylic acid and unfractionated heparin. Eptifibatide Accord is indicated for the prevention of early myocardial infarction in adults presenting with unstable angina or non-Q-wave myocardial infarction, with the last episode of chest pain occurring within 24 hours and with electrocardiogram (ECG) changes and/or elevated cardiac enzymes. Patients most likely to benefit from Eptifibatide Accord treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA (Percutaneous Transluminal Coronary Angioplasty) (see section 5.1).

HOS-097668 · has-indication-information · PDF-Seite 15

Eptifibatide Accord is intended for use with acetylsalicylic acid and unfractionated heparin. Eptifibatide Accord is indicated for the prevention of early myocardial infarction in adults presenting with unstable angina or non-Q-wave myocardial infarction, with the last episode of chest pain occurring within 24 hours and with electrocardiogram (ECG) changes and/or elevated cardiac enzymes. Patients most likely to benefit from Eptifibatide Accord treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA (Percutaneous Transluminal Coronary Angioplasty) (see section 5.1).

HOS-097665 · has-interaction-information · PDF-Seite 5

Warfarin and dipyridamole Eptifibatide did not appear to increase the risk of major and minor bleeding associated with concomitant use of warfarin and dipyridamole. Eptifibatide -treated patients who had a prothrombin time (PT) > 14.5 seconds and received warfarin concomitantly did not appear to be at an increased risk of bleeding. Eptifibatide and thrombolytic agents Data are limited on the use of eptifibatide in patients receiving thrombolytic agents. There was no consistent evidence that eptifibatide increased the risk of major or minor bleeding associated with tissue plasminogen activator in either a PCI or an acute myocardial infarction study. Eptifibatide appeared to increase the risk of bleeding when administered with streptokinase in an acute myocardial infarction study. The combination of reduced dose tenecteplase and eptifibatide compared to placebo and 5 eptifibatide significantly increased the risk of both major and minor bleeding when administered concomitantly in an acute ST-elevation myocardial infarction study. In an acute myocardial infarction study involving 181 patients, eptifibatide (in regimens up to a bolus injection of 180 microgram/kg, followed by an infusion up to 2 microgram/kg/min for up to 72 hours) was administered concomitantly with streptokinase (1.5 million units over 60 minutes). At the highest infusion rates (1.3 microgram/kg/min and 2.0 microgram/kg/min) studied, eptifibatide was associated with an increased incidence of bleeding and transfusions compared to the incidence seen when streptokinase was given alone.

HOS-097671 · has-interaction-information · PDF-Seite 18

Warfarin and dipyridamole Eptifibatide did not appear to increase the risk of major and minor bleeding associated with concomitant use of warfarin and dipyridamole. Eptifibatide -treated patients who had a prothrombin time (PT) > 14.5 seconds and received warfarin concomitantly did not appear to be at an increased risk of bleeding. Eptifibatide and thrombolytic agents Data are limited on the use of eptifibatide in patients receiving thrombolytic agents. There was no consistent evidence that eptifibatide increased the risk of major or minor bleeding associated with tissue plasminogen activator in either a PCI or an acute myocardial infarction study. Eptifibatide appeared to increase the risk of bleeding when administered with streptokinase in an acute myocardial infarction study. The combination of reduced dose tenecteplase and eptifibatide compared to placebo and 18 eptifibatide significantly increased the risk of both major and minor bleeding when administered concomitantly in an acute ST-elevation myocardial infarction study. In an acute myocardial infarction study involving 181 patients, eptifibatide (in regimens up to a bolus injection of 180 microgram/kg, followed by an infusion up to 2 microgram/kg/min for up to 72 hours) was administered concomitantly with streptokinase (1.5 million units over 60 minutes). At the highest infusion rates (1.3 microgram/kg/min and 2.0 microgram/kg/min) studied, eptifibatide was associated with an increased incidence of bleeding and transfusions compared to the incidence seen when streptokinase was given alone.

HOS-097672 · has-pregnancy-information · PDF-Seite 19

Pregnancy There are no adequate data from the use of eptifibatide in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential risk for humans is unknown. Eptifibatide Accord should not be used during pregnancy unless clearly necessary. Breast-feeding It is not known whether eptifibatide is excreted in human milk. Interruption of breast-feeding during the treatment period is recommended. Fertility No human data on the effect of drug substance eptifibatide on fertility are available.

HOS-097666 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no adequate data from the use of eptifibatide in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential risk for humans is unknown. Eptifibatide Accord should not be used during pregnancy unless clearly necessary. Breast-feeding It is not known whether eptifibatide is excreted in human milk. Interruption of breast-feeding during the treatment period is recommended. Fertility No human data on the effect of drug substance eptifibatide on fertility are available.

HOS-097664 · has-warning-information · PDF-Seite 3

Bleeding 3 Eptifibatide Accord is an antithrombotic agent that acts by inhibition of platelet aggregation; therefore, the patient must be observed carefully for indications of bleeding during treatment (see section 4.8). Women, the elderly, patients with low body weight or with moderate renal impairment (creatinine clearance > 30 - < 50 ml/min) may have an increased risk of bleeding. Monitor these patients closely with regard to bleeding. An increased risk of bleeding may also be observed in patients who receive early administration of eptifibatide (e.g. upon diagnosis) compared to receiving it immediately prior to PCI, as seen in the Early ACS trial. Unlike the approved posology in the EU, all patients in this trial were administered a double bolus before the infusion (see section 5.1). Bleeding is most common at the arterial access site in patients undergoing percutaneous arterial procedures. All potential bleeding sites, (e.g., catheter insertion sites; arterial, venous, or needle puncture sites; cutdown sites; gastrointestinal and genitourinary tracts) must be observed carefully. Other potential bleeding sites such as central and peripheral nervous system and retroperitoneal sites, must be carefully considered too. Because Eptifibatide Accord inhibits platelet aggregation, caution must be employed when it is used with other medicinal products that affect haemostasis, including ticlopidine, clopidogrel, thrombolytics, oral anticoagulants, dextran solutions, adenosine, sulfinpyrazone, prostacyclin, non-steroidal anti- inflammatory agents, or dypyridamole (see section 4.5). There is no experience with eptifibatide and low molecular weight heparins. There is limited therapeutic experience with eptifibatide in patients for whom thrombolytic therapy is generally indicated (e.g. acute transmural myocardial infarction with new pathological Q-waves or elevated ST-segments or left bundle branch block in the ECG). Consequently, the use of Eptifibatide Accord is not recommended in these circumstances (see section 4.5). Eptifibatide Accord infusion should be stopped immediately if circumstances arise that necessitate thrombolytic therapy or if the patient must undergo an emergency CABG surgery or requires an intraortic balloon pump. If serious bleeding occurs that is not controllable with pressure, the Eptifibatide Accord infusion should be stopped immediately and any unfractionated heparin that is given

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HOS-097670 · has-warning-information · PDF-Seite 16

Bleeding 16 Eptifibatide Accord is an antithrombotic agent that acts by inhibition of platelet aggregation; therefore the patient must be observed carefully for indications of bleeding during treatment (see section 4.8). Women, the elderly, patients with low body weight or with moderate renal impairment (creatinine clearance > 30 - < 50 ml/min) may have an increased risk of bleeding. Monitor these patients closely with regard to bleeding. An increased risk of bleeding may also be observed in patients who receive early administration of eptifibatide (e.g. upon diagnosis) compared to receiving it immediately prior to PCI, as seen in the Early ACS trial. Unlike the approved posology in the EU, all patients in this trial were administered a double bolus before the infusion (see section 5.1). Bleeding is most common at the arterial access site in patients undergoing percutaneous arterial procedures. All potential bleeding sites, (e.g., catheter insertion sites; arterial, venous, or needle puncture sites; cutdown sites; gastrointestinal and genitourinary tracts) must be observed carefully. Other potential bleeding sites such as central and peripheral nervous system and retroperitoneal sites, must be carefully considered too. Because Eptifibatide Accord inhibits platelet aggregation, caution must be employed when it is used with other medicinal products that affect haemostasis, including ticlopidine, clopidogrel, thrombolytics, oral anticoagulants, dextran solutions, adenosine, sulfinpyrazone, prostacyclin, non-steroidal anti- inflammatory agents, or dypyridamole (see section 4.5). There is no experience with eptifibatide and low molecular weight heparins. There is limited therapeutic experience with eptifibatide in patients for whom thrombolytic therapy is generally indicated (e.g. acute transmural myocardial infarction with new pathological Q-waves or elevated ST-segments or left bundle branch block in the ECG). Consequently, the use of Eptifibatide Accord is not recommended in these circumstances (see section 4.5). Eptifibatide Accord infusion should be stopped immediately if circumstances arise that necessitate thrombolytic therapy or if the patient must undergo an emergency CABG surgery or requires an intraortic balloon pump. If serious bleeding occurs that is not controllable with pressure, the Eptifibatide Accord infusion should be stopped immediately and any unfractionated heparin that is given co

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