Leitlinien & Arzneimittelsicherheit

HOS-096478 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The safety profile of edoxaban is based on two Phase 3 studies (21,105 patients with NVAF and 8,292 patients with VTE (DVT and PE)), and from post-authorisation experience. 12 The most commonly reported adverse reactions associated with edoxaban treatment are epistaxis (7.7%), haematuria (6.9%) and anaemia (5.3%). Bleeding can occur at any site and may be severe and even fatal (see section 4.4). Tabulated list of adverse reactions Table 3 provides the list of adverse reactions from the two pivotal Phase 3 studies in patients with VTE and NVAF combined for both indications and adverse drug reactions identified in the post- marketing setting. The adverse reactions are classified according to the MedDRA system organ class (SOC) and 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) and not known (cannot be estimated from the available data). Table 3: List of adverse reactions for NVAF and VTE System organ class Frequency Blood and lymphatic system disorders Anaemia Common Thrombocytopenia Uncommon Immune system disorders Hypersensitivity Uncommon Anaphylactic reaction Rare Allergic oedema Rare Nervous system disorders Dizziness Common Headache Common Intracranial haemorrhage (ICH) Uncommon Subarachnoid haemorrhage Rare Eye disorders Conjunctival/scleral haemorrhage Uncommon Intraocular haemorrhage Uncommon Cardiac disorders Pericardial haemorrhage Rare Vascular disorders Other haemorrhage Uncommon Respirator

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HOS-096474 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Clinically significant active bleeding. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent 7 brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Uncontrolled severe hypertension. Concomitant treatment with any other anticoagulants e.g. UFH, LMWH (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, rivaroxaban, apixaban etc.) except under specific circumstances of switching oral anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5). Pregnancy and breast-feeding (see section 4.6).

HOS-096473 · has-indication-information · PDF-Seite 2

Lixiana is indicated in prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA). Lixiana is indicated in treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and PE in adults (see section 4.4 for haemodynamically unstable PE patients). 2

HOS-096476 · has-interaction-information · PDF-Seite 10

Edoxaban is predominantly absorbed in the upper gastrointestinal (GI) tract. Thus, medicinal products or disease conditions that increase gastric emptying and gut motility have the possibility of reducing edoxaban dissolution and absorption. P-gp inhibitors Edoxaban is a substrate for the efflux transporter P-gp. In pharmacokinetic (PK) studies, concomitant administration of edoxaban with the P-gp inhibitors ciclosporin, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil resulted in increased plasma concentrations of edoxaban. Concomitant use of edoxaban with ciclosporin, dronedarone, erythromycin, or ketoconazole requires dose reduction to 30 mg once daily. Concomitant use of edoxaban with quinidine, verapamil, or amiodarone does not require dose reduction based on clinical data (see section 4.2). The use of edoxaban with other P-gp inhibitors including human immunodeficiency virus (HIV) protease inhibitors has not been studied. Edoxaban 30 mg once daily must be administered during concomitant use with the following P-gp inhibitors: • Ciclosporin: Concurrent administration of a single dose of ciclosporin 500 mg with a single dose of edoxaban 60 mg increased edoxaban AUC and maximum serum concentration (Cmax) by 73% and 74%, respectively. • Dronedarone: Dronedarone 400 mg twice daily for 7 days with a single concomitant dose of edoxaban 60 mg on day 5 increased edoxaban AUC and Cmax by 85% and 46%, respectively. • Erythromycin: Erythromycin 500 mg four times daily for 8 days with a single concomitant dose of edoxaban 60 mg on day 7 increased the edoxaban AUC and Cmax by 85% and 68%, respectively. • Ketoconazole: Ketoconazole 400 mg once daily for 7 days with a single concomitant dose of edoxaban 60 mg on day 4, increased edoxaban AUC and Cmax by 87% and 89%, respectively. 10 Edoxaban 60 mg once daily is recommended during concomitant use with the following P-gp inhibitors: • Quinidine: Quinidine 300 mg once daily on days 1 and 4 and three times daily on days 2 and 3, with a single concomitant dose of edoxaban 60 mg on day 3, increased edoxaban AUC over 24 hours by 77% and Cmax by 85%, respectively. • Verapamil: Verapamil 240 mg once daily for 11 days with a single concomitant dose of edoxaban 60 mg on day 10 increased the edoxaban AUC and Cmax by approximately 53%. • Amiodarone: Co-admin

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HOS-096477 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential Women of childbearing potential should avoid becoming pregnant during treatment with edoxaban. Pregnancy Safety and efficacy of edoxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that edoxaban passes the placenta, Lixiana is contraindicated during pregnancy (see section 4.3). Breast-feeding Safety and efficacy of edoxaban have not been established in breast-feeding women. Data from animals indicate that edoxaban is secreted into breast milk. Therefore Lixiana is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast- feeding or to discontinue/abstain from therapy. Fertility No specific studies with edoxaban in human beings have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

HOS-096475 · has-warning-information · PDF-Seite 8

Edoxaban 15 mg is not indicated as monotherapy, as it may result in decreased efficacy. It is only indicated in the process of switching from edoxaban 30 mg (patients with one or more clinical factors for increased exposure; see table 1) to VKA, together with an appropriate VKA dose (see table 2, section 4.2). Haemorrhagic risk Edoxaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. Edoxaban, like other anticoagulants, is recommended to be used with caution in patients with increased risk of bleeding. Edoxaban administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 4.9). In the clinical studies mucosal bleedings (e.g. epistaxis, gastrointestinal, genitourinary) and anaemia were seen more frequently during long term edoxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory testing. A specific anticoagulant reversal agent for edoxaban is not available (see section 4.9). Haemodialysis does not significantly contribute to edoxaban clearance (see section 5.2). Elderly The co-administration of edoxaban with acetylsalicylic acid (ASA) in elderly patients should be used cautiously because of a potentially higher bleeding risk (see section 4.5). Renal impairment The plasma area under the curve (AUC) for subjects with mild (CrCl > 50 - 80 mL/min), moderate (CrCl 30 - 50 mL/min) and severe (CrCl < 30 mL/min but not undergoing dialysis) renal impairment was increased by 32%, 74%, and 72%, respectively, relative to subjects with normal renal function (see section 4.2 for dose reduction). In patients with end stage renal disease or on dialysis, Lixiana is not recommended (see sections 4.2 and 5.2). 8 Renal function in NVAF A trend towards decreasing efficacy with increasing CrCl was observed for edoxaban compared to well-managed warfarin (see section 5.1 for

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