Efient · 4.4 Special warnings and precautions for use · 1

HOS-095216 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile Safety in patients with acute coronary syndrome undergoing PCI was evaluated in one clopidogrel- controlled study (TRITON) in which 6741 patients were treated with prasugrel (60 mg loading dose and 10 mg once daily maintenance dose) for a median of 14.5 months (5802 patients were treated for over 6 months, 4136 patients were treated for more than 1 year). The rate of study drug discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these, bleeding was the most common adverse reaction for both drugs leading to study drug discontinuation (2.5% for prasugrel and 1.4% for clopidogrel). Bleeding Non-Coronary Artery Bypass Graft (CABG) related bleeding In TRITON, the frequency of patients experiencing a non-CABG related bleeding event is shown in Table 1. The incidence of Non-CABG-related TIMI major bleeding, including life-threatening and fatal, as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with prasugrel compared to clopidogrel in the UA/NSTEMI and All ACS populations. No significant difference was seen in the STEMI population. The most common site of spontaneous bleeding was the gastrointestinal tract (1.7% rate with prasugrel and 1.3% rate with clopidogrel); the most frequent site of provoked bleeding was the arterial puncture site (1.3% rate with prasugrel and 1.2% with clopidogrel). 7 Table 1: Incidence of Non-CABG related bleedinga (% Patients) Event All ACS UA/NSTEMI STEMI Prasugrelb Clopidogrelb Prasugrelb Clopidogrelb Prasugrelb Clopidogrelb +ASA +ASA +ASA +ASA +ASA +ASA (N=6741) (N=6716) (N=5001) (N=4980) (N=1740) (N=1736) TIMI major 2.2 1.7 2.2 1.6 2.2 2.0 bleedingc Life-threateningd 1.3 0.8 1.3 0.8 1.2 1.0 Fatal 0.3 0.1 0.3 0.1 0.4 0.1 Symptomatic 0.3 0.3 0.3 0.3 0.2 0.2 ICHe Requiring

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HOS-095212 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active pathological bleeding. History of stroke or transient ischaemic attack (TIA). Severe hepatic impairment (Child Pugh class C). 3

HOS-095211 · has-indication-information · PDF-Seite 2

Efient, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (i.e. unstable angina, non-ST segment elevation myocardial infarction [UA/NSTEMI] or ST segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous coronary intervention (PCI). For further information please refer to section 5.1.

HOS-095214 · has-interaction-information · PDF-Seite 5

Warfarin: Concomitant administration of Efient with coumarin derivatives other than warfarin has not been studied. Because of the potential for increased risk of bleeding, warfarin (or other coumarin derivatives) and prasugrel should be co-administered with caution (see section 4.4). Non-steroidal anti-inflammatory drugs (NSAIDs): Concomitant administration with chronic NSAIDs has not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs (including COX-2 inhibitors) and Efient should be co- administered with caution (see section 4.4). Efient can be concomitantly administered with medicinal products metabolised by cytochrome P450 enzymes (including statins), or medicinal products that are inducers or inhibitors of cytochrome P450 enzymes. Efient can also be concomitantly administered with ASA, heparin, digoxin, and medicinal products that elevate gastric pH, including proton pump inhibitors and H2 blockers. Although not studied in specific interaction studies, Efient has been co-administered in the phase 3 clinical trial with low molecular weight heparin, bivalirudin, and GP IIb/IIIa inhibitors (no information available regarding the type of GP IIb/IIIa inhibitor used) without evidence of clinically significant adverse interactions. Effects of other medicinal products on Efient Acetylsalicylic acid: Efient is to be administered concomitantly with acetylsalicylic acid (ASA). Although a pharmacodynamic interaction with ASA leading to an increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly treated with ASA. Heparin: A single intravenous bolus dose of unfractionated heparin (100 U/kg) did not significantly alter the prasugrel-mediated inhibition of platelet aggregation. Likewise, prasugrel did not significantly alter the effect of heparin on measures of coagulation. Therefore, both medicinal products can be administered concomitantly. An increased risk of bleeding is possible when Efient is co-administered with heparin. 5 Statins: Atorvastatin (80 mg daily) did not alter the pharmacokinetics of prasugrel and its inhibition of platelet aggregation. Therefore, statins that are substrates of CYP3A are not anticipated to have an effect on the pharmacokinetics of prasugrel or its inhibition of platelet aggregation. Medicinal products that elevate gastric pH: Daily co-administration of ranitidine

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HOS-095215 · has-pregnancy-information · PDF-Seite 7

No clinical study has been conducted in pregnant or breast-feeding women. Pregnancy Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Because animal reproduction studies are not always predictive of a human response, Efient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus. Breast-feeding It is unknown whether prasugrel is excreted in human breast milk. Animal studies have shown excretion of prasugrel in breast milk. The use of prasugrel during breastfeeding is not recommended. Fertility Prasugrel had no effect on fertility of male and female rats at oral doses up to an exposure 240 times the recommended daily human maintenance dose (based on mg/m2).

HOS-095213 · has-warning-information · PDF-Seite 4

Bleeding risk In the phase 3 clinical trial (TRITON) key exclusion criteria included an increased risk of bleeding; anaemia; thrombocytopaenia; a history of pathological intracranial findings. Patients with acute coronary syndromes undergoing PCI treated with Efient and ASA showed an increased risk of major and minor bleeding according to the TIMI classification system. Therefore, the use of Efient in patients at increased risk of bleeding should only be considered when the benefits in terms of prevention of ischaemic events are deemed to outweigh the risk of serious bleedings. This concern applies especially to patients: • ≥ 75 years of age (see below). • with a propensity to bleed (e.g. due to recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, or active peptic ulcer disease) • with body weight < 60 kg (see sections 4.2 and 4.8). In these patients the 10 mg maintenance dose is not recommended. A 5 mg maintenance dose should be used. • with concomitant administration of medicinal products that may increase the risk of bleeding, including oral anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics. For patients with active bleeding for whom reversal of the pharmacological effects of Efient is required, platelet transfusion may be appropriate. The use of Efient in patients ≥ 75 years of age is generally not recommended and should only be undertaken with caution after a careful individual benefit/risk evaluation by the prescribing physician indicates that benefits in terms of prevention of ischaemic events outweigh the risk of serious bleedings. In the phase 3 clinical trial these patients were at greater risk of bleeding, including fatal bleeding, compared to patients < 75 years of age. If prescribed, a lower maintenance dose of 5 mg should be used; the 10 mg maintenance dose is not recommended (see sections 4.2 and 4.8). Therapeutic experience with prasugrel is limited in patients with renal impairment (including ESRD) and in patients with moderate hepatic impairment. These patients may have an increased bleeding risk. Therefore, prasugrel should be used with caution in these patients. Patients should be told that it might take longer than usual to stop bleeding when they take prasugrel (in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician. Bleeding Risk Associated with Timing of Loading Dose in NSTEMI In a clin

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