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 3).
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 3: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies
Indication                           Number of      Total daily dose           Maximum patients*                                 treatment 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 ill   3,997          10 mg                      39 days patients
Treatment of deep vein thrombosis 6,790             Day 1 - 21: 30 mg          21 months (DVT), pulmonary embolism (PE)                      Day 22 and onwards: and prevention of recurrence                        20 mg
After at least 6 months:
10 mg or 20 mg
Treatment of VTE and prevention      329            Body weight-adjusted       12 months of VTE recurrence in term neonates                  dose to achieve a similar and children aged less than 18 years                exposure as that observed following initiation of standard                    in adults treated for DVT anticoagulation treatment                           with 20 mg rivaroxaban once daily
Prevention of stroke and systemic    7,750          20 mg                      41 months 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 co-administered       47 months events in patients with CAD/PAD                     with ASA or 10 mg alone 

Indication                             Number of       Total daily dose              Maximum patients*                                     treatment duration
3,256**         5 mg co-administered          42 months 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 4). The most commonly reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %).

Table 4: 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 patients       5.9% of patients thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery
Prevention of venous                         12.6% of patients      2.1% of patients thromboembolism in medically ill patients
Treatment of DVT, PE and prevention 23% of patients                 1.6% of patients of recurrence
Treatment of VTE and prevention of           39.5% of patients      4.6% of patients VTE recurrence in term neonates and children aged less than 18 years following initiation of standard anticoagulation treatment
Prevention of stroke and systemic            28 per 100 patient     2.5 per 100 patient embolism in patients with non-valvular years                        years atrial fibrillation
Prevention of atherothrombotic events 22 per 100 patient            1.4 per 100 patient in patients after an ACS                     years                  years Prevention of atherothrombotic events 6.7 per 100 patient           0.15 per 100 patient in patients with CAD/PAD                     years                  years** 8.38 per 100 patient 0.74 per 100 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 5 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 5: 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 including angioedema and                            anaphylactic shock allergic oedema
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 bilirubin, increased (with or increased blood       without alkaline              concomitant phosphataseA,         increase of ALT),
A increased GGT         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, DRESS ecchymosis,                                                   syndrome cutaneous and subcutaneous 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 failure/acute haemorrhage (incl.                                                                 renal failure haematuria and                                                                     secondary to a menorrhagiaB),                                                                     bleeding sufficient renal impairment                                                                   to cause (incl. blood                                                                       hypoperfusion, creatinine                                                                         Anticoagulant- increased, blood                                                                   related nephropathy urea increased)
General disorders and administration site conditions
FeverA, peripheral Feeling unwell           Localised oedemaA oedema, decreased (incl. malaise) general strength and energy (incl.
fatigue and asthenia)
Investigations
Increased LDHA,
increased lipaseA,
increased amylaseA
Injury, poisoning and procedural complications
Postprocedural                              Vascular haemorrhage (incl.                          pseudoaneurysmC 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.

Paediatric patients
Treatment of VTE and prevention of VTE recurrence
The safety assessment in children and adolescents is based on the safety data from two phase II and one phase III open-label active controlled studies in paediatric patients aged birth to less than 18 years.
The safety findings were generally similar between rivaroxaban and comparator in the various paediatric age groups. Overall, the safety profile in the 412 children and adolescents treated with rivaroxaban was similar to that observed in the adult population and consistent across age subgroups, although assessment is limited by the small number of patients.
In paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin (common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported more frequently as compared to adults. Consistent with adult population, menorrhagia was observed in 6.6% (common) of female adolescents after menarche. Thrombocytopenia as observed in the post-marketing experience in adult population was common (4.6%) in paediatric clinical studies. The adverse drug reactions in paediatric patients were primarily mild to moderate in severity.

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