Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The safety of apixaban has been investigated in 7 Phase III clinical studies including more than 21,000 patients: more than 5,000 patients in VTEp studies, more than 11,000 patients in NVAF studies and more than 4,000 patients in the VTE treatment (VTEt) studies, for an average total exposure of 20 days, 1.7 years and 221 days respectively (see section 5.1).


Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 2 for adverse event profile and frequencies by indication).

In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. The overall incidence of adverse reactions related to bleeding with apixaban was 10% in the apixaban vs enoxaparin studies.

In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was 24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid study. In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18%/year.

In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was 15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study (see section 5.1).


Tabulated list of adverse reactions
Table 2 shows the adverse reactions ranked under headings of System Organ Class 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); not known (cannot be estimated from the available data) for VTEp, NVAF, and VTEt respectively.

Table 2: Tabulated adverse reactions

System organ class                          Prevention of VTE        Prevention of       Treatment of in adult patients         stroke and        DVT and PE,
who have               systemic             and undergone elective        embolism in       prevention of hip or knee          adult patients     recurrent DVT replacement            with NVAF,        and PE (VTEt) surgery (VTEp)          with one or more risk factors (NVAF)
Blood and lymphatic system disorders
Anaemia                                           Common               Common              Common Thrombocytopenia                                 Uncommon             Uncommon             Common Immune system disorders
Hypersensitivity, allergic oedema and                Rare             Uncommon           Uncommon Anaphylaxis
Pruritus                                         Uncommon             Uncommon           Uncommon* 
Angioedema                                       Not known             Not known          Not known Nervous system disorders
Brain haemorrhage†                               Not known            Uncommon               Rare Eye disorders
Eye haemorrhage (including conjunctival              Rare               Common           Uncommon haemorrhage)


System organ class                         Prevention of VTE     Prevention of     Treatment of in adult patients      stroke and      DVT and PE,
who have            systemic           and undergone elective     embolism in     prevention of hip or knee       adult patients   recurrent DVT replacement         with NVAF,      and PE (VTEt) surgery (VTEp)       with one or more risk factors (NVAF)
Vascular disorders


Haemorrhage, haematoma                           Common            Common           Common Hypotension (including procedural               Uncommon           Common          Uncommon hypotension)
Intra-abdominal haemorrhage                     Not known         Uncommon         Not known Respiratory, thoracic and mediastinal disorders
Epistaxis                                         Uncommon         Common           Common Haemoptysis                                         Rare          Uncommon         Uncommon Respiratory tract haemorrhage                     Not known         Rare             Rare Gastrointestinal disorders
Nausea                                             Common          Common           Common Gastrointestinal haemorrhage                      Uncommon         Common           Common Haemorrhoidal haemorrhage,                        Not known       Uncommon         Uncommon mouth haemorrhage                                 Not known       Uncommon          Common Haematochezia                                     Uncommon        Uncommon         Uncommon Rectal haemorrhage, gingival bleeding               Rare           Common           Common Retroperitoneal haemorrhage                       Not known         Rare           Not known Hepatobiliary disorders
Liver function test abnormal, aspartate           Uncommon        Uncommon         Uncommon aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased gamma-glutamyltransferase increased               Uncommon         Common           Common Alanine aminotransferase incresed                 Uncommon        Uncommon          Common Skin and subcutaneous tissue disorders
Skin rash                                         Not known       Uncommon          Common Alopecia                                            Rare          Uncommon         Uncommon Erythema multiforme                               Not known       Very rare        Not known Cutaneous vasculitis                              Not known       Not known        Not known Musculoskeletal and connective tissue disorders
Muscle haemorrhage                                  Rare             Rare          Uncommon Renal and urinary disorders
Haematuria                                        Uncommon         Common           Common Reproductive system and breast disorders
Abnormal vaginal haemorrhage,                       Uncommon      Uncommon          Common urogenital haemorrhage
General disorders and administration site conditions
Application site bleeding                           Not known     Uncommon         Uncommon 

System organ class                           Prevention of VTE         Prevention of       Treatment of in adult patients          stroke and        DVT and PE,
who have                systemic             and undergone elective         embolism in       prevention of hip or knee           adult patients     recurrent DVT replacement             with NVAF,        and PE (VTEt) surgery (VTEp)           with one or more risk factors (NVAF)
Investigations
Occult blood positive                                  Not known        Uncommon            Uncommon Injury, poisoning and procedural complications
Contusion                                          Common                Common              Common 
Post procedural haemorrhage (including         Uncommon              Uncommon          Uncommon post procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage) wound secretion, incision site haemorrhage (including incision site haematoma), operative haemorrhage
Traumatic haemorrhage,                             Not known         Uncommon          Uncommon * There were no occurrences of generalised pruritus in CV185057 (long term prevention of VTE) † The term “Brain haemorrhage” encompasses all intracranial or intraspinal haemorrhages (i.e.,  haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).

The use of apixaban 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 will vary according to the location and degree or extent of the bleeding (see sections 4.4 and 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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/