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 of                                    treatment patients*                             duration
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 medically        3,997     10 mg                       39 days ill patients
Treatment of deep vein                 6,790    Day 1 - 21: 30 mg           21 months thrombosis (DVT), pulmonary                     Day 22 and onwards: embolism (PE) and prevention                    20 mg of recurrence                                   After at least 6 months: 10 mg or 20 mg
Treatment of VTE and                  329       Body weight-adjusted dose 12 months prevention of VTE recurrence in                 to achieve a similar term neonates and children                      exposure as that observed aged less than 18 years                         in adults treated for DVT following initiation of standard                with 20 mg rivaroxaban anticoagulation treatment                       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 acute               respectively, co- coronary syndrome (ACS)                         administered with either ASA or ASA plus clopidogrel or ticlopidine
Prevention of atherothrombotic        18,244    5 mg co-administered with   47 months events in patients with                         ASA or 10 mg alone
CAD/PAD
3,256**   5 mg co-administered with   42 months
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              23% of          1.6% of patients prevention 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 embolism in patients with             patient years   years non-valvular atrial fibrillation
Prevention of atherothrombotic        22 per 100       1.4 per 100 patient events in patients after an ACS       patient years years
Prevention of atherothrombotic        6.7 per 100      0.15 per 100 events in patients with CAD/PAD       patient years patient 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,
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,
diarrhoea,
vomitingA
Hepatobiliary disorders
Increase in         Hepatic         Jaundice, Bilirubin transaminases       impairment,     conjugated
Increased       increased (with or bilirubin,      without increased blood concomitant alkaline        increase of ALT),
phosphataseA,   Cholestasis,
increased GGTA Hepatitis (incl.
hepatocellular injury)

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



(incl.
postoperative anaemia, and wound haemorrhage),
contusion,
wound secretionA
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.. The 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