Adverse reactions : תופעות לוואי

4.8 Undesirable effects

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.
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).
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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 Respiratory, thoracic and mediastinal disorders
Epistaxis                                                                      Common Haemoptysis                                                                    Uncommon Gastrointestinal disorders
Abdominal pain                                                                 Common Lower GI haemorrhage                                                           Common Upper GI haemorrhage                                                           Common Oral/pharyngeal haemorrhage                                                    Common Nausea                                                                         Common Retroperitoneal haemorrhage                                                    Rare Hepatobiliary disorders
Blood bilirubin increased                                                      Common Gammaglutamyltransferase increased                                             Common Blood alkaline phosphatase increased                                           Uncommon Transaminases increased                                                        Uncommon Skin and subcutaneous tissue disorders
Cutaneous soft tissue haemorrhage                                              Common Rash                                                                           Common System organ class                                                                Frequency Pruritus                                                                          Common Urticaria                                                                         Uncommon Musculoskeletal and connective tissue disorders
Intramuscular haemorrhage (no compartment syndrome)                                Rare Intra-articular haemorrhage                                                        Rare Renal and urinary disorders
Macroscopic haematuria/urethral haemorrhage                                       Common Anticoagulant-related nephropathy                                                 Not known Reproductive system and breast disorders
Vaginal haemorrhage1                                                               Common General disorders and administration site conditions
Puncture site haemorrhage                                                          Common Investigations
Liver function test abnormal                                                       Common Injury, poisoning and procedural complications
Surgical site haemorrhage                                                          Uncommon Subdural haemorrhage                                                               Rare Procedural haemorrhage                                                            Rare 
1
Reporting rates are based on the female population in clinical studies. Vaginal bleeds were reported commonly in women under the age of 50 years, while it was uncommon in women over the age of 50 years.

Description of selected adverse reactions

Haemorrhagic anaemia
Due to the pharmacological mode of action, the use of edoxaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 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. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see section 4.4). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion , or anticoagulant-related nephropathy have been reported for edoxaban.
Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Paediatric population

The safety of edoxaban was evaluated in two Phase 3 studies (Hokusai VTE PEDIATRICS and ENNOBLE-ATE) in paediatric patients from birth to less than 18 years of age with VTE (286 patients, 145 patients treated with edoxaban) and cardiac diseases at risk of thrombotic events (167 patients, 109 patients treated with edoxaban). Overall, the safety profile in children was similar as in the adult patient population (see Table 3). In total, 16.6% of paediatric patients treated with edoxaban for VTE experienced adverse reactions.
Reporting of suspected adverse reactions
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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il