Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1).
Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban.



Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies
Indication                        Number Total daily dose          Maximum treatment duration of patients*
Prevention of venous              6,097        10 mg               39 days thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery
Prevention of VTE in              3,997        10 mg               39 days medically ill patients
Treatment of deep vein                         Day 1 - 21: 30 mg   21 months thrombosis (DVT), pulmonary 6,790              Day 22 and embolism (PE) and prevention                   onwards: 20 mg of recurrence                                  After at least 6 months: 10 mg or
20 mg
Treatment of VTE and              329          Body weight-         12 months prevention of VTE recurrence                   adjusted dose to in term neonates and children                  achieve a similar aged less than 18 years                        exposure as that following initiation of standard               observed in adults anticoagulation treatment                      treated for DVT with 20 mg rivaroxaban once daily
Prevention of stroke and          7,750        20 mg               41 months systemic embolism in patients with non-valvular atrial fibrillation
Prevention of atherothrombotic 10,225          5 mg or 10 mg       31 months events in patients after an ACS                respectively, co- administered with either ASA or ASA plus clopidogrel or ticlopidine
Prevention of atherothrombotic 18,244          5 mg                47 months events in patients with                        co-administered
CAD/PAD                                        with ASA or 10 mg alone
3,256**        5 mg co-           42 months administered with
ASA
*Patients exposed to at least one dose of rivaroxaban
**      From the VOYAGER PAD study

The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see section 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonly reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %).



Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the completed adult and paediatric phase III studies

Indication                               Any bleeding      Anaemia
Prevention of venous                     6.8% of           5.9% of patients thromboembolism (VTE) in adult           patients patients undergoing elective hip or knee replacement surgery
Prevention of venous                     12.6% of          2.1% of patients thromboembolism in medically ill         patients patients
Treatment of DVT, PE and prevention      23% of            1.6% of patients of recurrence                            patients
Treatment of VTE and prevention of       39.5% of          4.6% of patients VTE recurrence in term neonates and      patients children aged less than 18 years following initiation of standard anticoagulation treatment
Prevention of stroke and systemic        28 per 100        2.5 per 100 patient years embolism in patients with                patient years non-valvular atrial fibrillation
Prevention of atherothrombotic events     22 per 100        1.4 per 100 patient years in patients after an ACS                  patient years
Prevention of atherothrombotic events     6.7 per 100       0.15 per 100 patient in patients with CAD/PAD                  patient years     years**
8.38 per 100      0.74 per 100 patient patient years # years*** #
*     For all rivaroxaban studies all bleeding events are collected, reported and adjudicated.
**    In the COMPASS study, there is a low anaemia incidence as a selective approach to adverse event collection was applied
*** A selective approach to adverse event collection was applied
#     From the VOYAGER PAD study

Tabulated list of adverse reactions
The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are summarised in Table 3 below by system organ class (in MedDRA) and by 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 < 1/1,000) very rare (< 1/10,000) not known (cannot be estimated from the available data)

Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through post-marketing use* and in two phase II and two phase III studies in paediatric patients 


Common               Uncommon             Rare              Very rare       Not known 
Blood and lymphatic system disorders
Anaemia (incl.    Thrombocytosis respective        (incl. platelet count laboratory        increased)A, P


 parameters)       Thrombocytopenia
Immune system disorders
Allergic reaction,                        Anaphylactic dermatitis allergic,                      reactions
Angioedema and                            including allergic oedema                           anaphylactic shock
Nervous system disorders
Dizziness,             Cerebral and headache               intracranial haemorrhage,
syncope
Eye disorders
Eye haemorrhage
(incl. conjunctival haemorrhage)
Cardiac disorders
Tachycardia
Vascular disorders
Hypotension,
haematoma
Respiratory, thoracic and mediastinal disorders
Epistaxis,                                                   Eosinophilic haemoptysis                                                  pneumonia Gastrointestinal disorders
Gingival bleeding, Dry mouth gastrointestinal tract haemorrhage (incl.
rectal haemorrhage),
gastrointestinal and abdominal pains,
dyspepsia, nausea,
constipationA,
P   P


 diarrhoea,
vomitingAP



Hepatobiliary disorders
Increase in            Hepatic              Jaundice,
transaminases          impairment,          Bilirubin
Increased bilirubin, conjugated increased blood      increased (with alkaline             or without phosphataseA,        concomitant
A increased GGT        increase of
ALT),
Cholestasis,
Hepatitis (incl.
hepatocellular injury)

Common                            Uncommon                           Rare        Very rare         Not known 
Skin and subcutaneous tissue disorders
Pruritus (incl.    Urticaria                                                     Stevens-Johnson uncommon cases of                                                                syndrome/ Toxic generalised                                                                      Epidermal pruritus), rash,                                                                 Necrolysis, ecchymosis,                                                                      DRESS cutaneous and                                                                    syndrome subcutaneous haemorrhage
Musculoskeletal and connective tissue disorders
Pain in extremityA Haemarthrosis
P        Muscle                                                      Compartment haemorrhage                                                 syndrome secondary to a bleeding
Renal and urinary disorders
Urogenital tract                                                                                   Renal haemorrhage (incl.                                                                                 failure/acute haematuria and                                                                                     renal failure menorrhagiaB),    P   P                                                                            secondary to a renal impairment                                                                                   bleeding (incl. blood                                                                                       sufficient to creatinine                                                                                         cause increased, blood                                                                                   hypoperfusion urea increased)           P                                                                        Anticoagulant- related nephropathy
General disorders and administration site conditions
FeverA, peripheral Feeling unwell
P   P                                  Localised oedema, decreased (incl. malaise)           oedemaA                        P 

 general strength and energy (incl. fatigue and asthenia)
Investigations
Increased LDHA,
P          P       P


 increased lipaseA,        P       P

 increased amylaseA                    P   P



Injury, poisoning and procedural complications
Postprocedural                              Vascular haemorrhage (incl.                          pseudoaneurys postoperative                               mC                       P 

 anaemia, and wound haemorrhage),
contusion, wound secretionA   P



A: observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery
B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years
C: observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous coronary intervention)
* A pre-specified selective approach to adverse event collection was applied in selected phase III studies. As incidence of adverse reactions did not increase and no new adverse drug reaction was identified after analysis of these studies..

Description of selected adverse reactions
Due to the pharmacological mode of action, the use of Xarelto 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 “Management of bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban 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 and quantify the clinical relevance of overt 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 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged.
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion, or anticoagulant-related nephropathy have been reported for Xarelto.
Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

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