Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), headache, allergic reactions, development of autoantibodies, itching, and fever.

Serious adverse reactions have also been reported for Enbrel. TNF-antagonists, such as Enbrel, affect the immune system and their use may affect the body’s defenses against infection and cancer. Serious infections affect fewer than 1 in 100 patients treated with Enbrel. Reports have included fatal and life-threatening infections and sepsis. Various 
malignancies have also been reported with use of Enbrel, including cancers of the breast, lung, skin and lymph glands (lymphoma).

Serious haematological, neurological and autoimmune reactions have also been reported.
These include rare reports of pancytopenia and very rare reports of aplastic anaemia. Central and peripheral demyelinating events have been seen rarely and very rarely, respectively, with Enbrel use. There have been rare reports of lupus, lupus-related conditions, and vasculitis.

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience.

Within the organ system classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: 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).

System           Very         Common         Uncommon         Rare                  Very        Not Known Organ Class      Commo        ≥ 1/100 to     ≥ 1/1,000 to     ≥ 1/10,000 to         Rare        (Cannot be n            < 1/10         < 1/100          < 1/1,000             < 1/10,00   Estimated from ≥ 1/10                                                             0           Available Data) 
Infections and   Infection                   Serious          Tuberculosis,                     Hepatitis B infestations     (includin                   infections       opportunistic                     reactivation, g upper                     (including       infection                         listeria respirator                  pneumonia,       (including invasive y tract                     cellulitis,      fungal, protozoal,
infection,                  arthritis        bacterial, atypical bronchiti                   bacterial,       mycobacterial,
s,                          sepsis and       viral infections,
cystitis,                   parasitic        and Legionella)* skin                        infection)* infection)
*
Neoplasms                                    Non-             Malignant                         Merkel cell benign,                                      melanoma         melanoma (see                     carcinoma (see malignant and                                skin cancers*    section 4.4),                     section 4.4), unspecified                                  (see section     lymphoma,                         Kaposi’s sarcoma (including                                   4.4)             leukaemia cysts and polyps)
Blood and                                    Thrombocytop     Pancytopenia*         Aplastic    Histiocytosis lymphatic                                    enia, anaemia,                         anaemia*    haematophagic system                                       leukopenia,                                        (macrophage disorders                                    neutropenia                                        activation syndrome)*
Immune                        Allergic       Vasculitis       Serious                           Worsening of system                        reactions      (including       allergic/anaphylact               symptoms of disorders                     (see Skin      anti-            ic reactions                      dermatomyositis and            neutrophilic     (including subcutaneou    cytoplasmic      angioedema,
s tissue       antibody         bronchospasm),
disorders),    positive         sarcoidosis autoantibody   vasculitis) formation*
Nervous          Headach                                      CNS system           e                                            demyelinating disorders                                                     events suggestive of multiple sclerosis or

System           Very     Common       Uncommon          Rare                  Very         Not Known Organ Class      Commo    ≥ 1/100 to   ≥ 1/1,000 to      ≥ 1/10,000 to         Rare         (Cannot be n        < 1/10       < 1/100           < 1/1,000             < 1/10,00    Estimated from ≥ 1/10                                                        0            Available Data)  localised demyelinating conditions, such as optic neuritis and transverse myelitis
(see section 4.4),
peripheral demyelinating events, including
Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy,
demyelinating polyneuropathy,
and multifocal motor neuropathy
(see section 4.4),
seizure
Eye disorders                          Uveitis,
scleritis
Cardiac                                Worsening of      New onset cardiac disorders                              cardiac failure   failure congestive congestive        (see section 4.4)
(see section
4.4)
Respiratory,                                             Interstitial lung thoracic, and                                            disease (including mediastinal                                              pneumonitis and disorders                                                pulmonary fibrosis)*
Gastrointestin                         Inflammatory al disorders                           bowel disease
Hepatobiliary                          Elevated liver    Autoimmune disorders                              enzymes*          hepatitis*
Skin and                  Pruritus,    Angioedema,       Stevens-Johnson       Toxic subcutaneous              rash         psoriasis         syndrome,             epidermal tissue                                 (including        cutaneous             necrolysis disorders                              new onset or      vasculitis worsening and     (including pustular,         hypersensitivity primarily         vasculitis),
palms and         erythema soles),           multiforme,
urticaria,        lichenoid reactions psoriasiform rash
Musculoskelet                                            Cutaneous lupus al and                                                   erythematosus, connective                                               subacute cutaneous tissue                                                   lupus disorders                                                erythematosus, lupus-like syndrome


System            Very         Common             Uncommon       Rare                 Very        Not Known Organ Class       Commo        ≥ 1/100 to         ≥ 1/1,000 to   ≥ 1/10,000 to        Rare        (Cannot be n            < 1/10             < 1/100        < 1/1,000            < 1/10,00   Estimated from ≥ 1/10                                                              0           Available Data) 
Renal and                                                        Glomerulonephritis urinary disorders
General          Injection     Pyrexia disorders and    site administration   reactions site conditions  (includin g bleeding,
bruising,
erythema
, itching,
pain,
swelling)
*
*see Description of selected adverse reactions,
below.

Description of selected adverse reactions

Malignancies and lymphoproliferative disorders
One hundred and twenty-nine (129) new malignancies of various types were observed in 4,114 rheumatoid arthritis patients treated in clinical trials with Enbrel for up to approximately 6 years, including 231 patients treated with Enbrel in combination with methotrexate in the 2-year active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. A total of 2 malignancies were reported in clinical studies of approximately 2 years duration involving 240 Enbrel-treated psoriatic arthritis patients. In clinical studies conducted for more than
2 years with 351 ankylosing spondylitis patients, 6 malignancies were reported in Enbrel- treated patients. In a group of 2,711 plaque psoriasis patients treated with Enbrel in double- blind and open-label studies of up to 2.5 years, 30 malignancies and 43 nonmelanoma skin cancers were reported.

In a group of 7,416 patients treated with Enbrel in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis clinical trials, 18 lymphomas were reported.

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have also been received in the postmarketing period (see section 4.4).

Injection site reactions
Compared to placebo, patients with rheumatic diseases treated with Enbrel had a significantly higher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the first month. Mean duration was approximately 3 to 5 days. No treatment was given for the majority of injection site reactions in the Enbrel treatment groups, and the majority of patients who were given treatment received topical preparations, such as corticosteroids, or oral antihistamines. Additionally, some patients developed recall injection site reactions characterised by a skin reaction at the most recent site of injection, along with the simultaneous appearance of injection site reactions at previous injection sites. These reactions were generally transient and did not recur with treatment.

In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with Enbrel developed injection site reactions compared with 3.4% of placebo-treated patients during the first 12 weeks of treatment.


Serious infections
In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, or requiring hospitalisation or intravenous antibiotics) was observed. Serious infections occurred in 6.3% of rheumatoid arthritis patients treated with Enbrel for up to 48 months. These included abscess (at various sites), bacteraemia, bronchitis, bursitis,
cellulitis, cholecystitis, diarrhoea, diverticulitis, endocarditis (suspected), gastroenteritis, hepatitis B, herpes zoster, leg ulcer, mouth infection, osteomyelitis, otitis, peritonitis, pneumonia, pyelonephritis, sepsis, septic arthritis, sinusitis, skin infection, skin ulcer, urinary tract infection, vasculitis, and wound infection. In the 2-year active-controlled study where patients were treated with either Enbrel alone, methotrexate alone or Enbrel in combination with methotrexate, the rates of serious infections were similar among the treatment groups.
However, it cannot be excluded that the combination of Enbrel with methotrexate could be associated with an increase in the rate of infections.

There were no differences in rates of infection among patients treated with Enbrel and those treated with placebo for plaque psoriasis in placebo-controlled trials of up to 24 weeks duration. Serious infections experienced by Enbrel-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis, gastritis, appendicitis, Streptococcal fasciitis, myositis, septic shock, diverticulitis and abscess. In the double-blind and open-label psoriatic arthritis trials, 1 patient reported a serious infection (pneumonia).

Serious and fatal infections have been reported during use of Enbrel; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks after initiating treatment with Enbrel in patients who have underlying conditions (e.g., diabetes, congestive heart failure, history of active or chronic infections) in addition to their rheumatoid arthritis (see section 4.4). Enbrel treatment may increase mortality in patients with established sepsis.

Opportunistic infections have been reported in association with Enbrel, including invasive fungal, parasitic (including protozoal), viral (including herpes zoster), bacterial (including Listeria and Legionella), and atypical mycobacterial infections. In a pooled data set of clinical trials, the overall incidence of opportunistic infections was 0.09% for the 15,402 subjects who received Enbrel. The exposure-adjusted rate was 0.06 events per 100 patient-years. In postmarketing experience, approximately half of all of the case reports of opportunistic infections worldwide were invasive fungal infections. The most commonly reported invasive fungal infections included Candida, Pneumocystis, Aspergillus, and Histoplasma. Invasive fungal infections accounted for more than half of the fatalities amongst patients who developed opportunistic infections. The majority of the reports with a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, and aspergillosis (see section 4.4).

Autoantibodies
Adult patients had serum samples tested for autoantibodies at multiple timepoints. Of the rheumatoid arthritis patients evaluated for antinuclear antibodies (ANA), the percentage of patients who developed new positive ANA (1:40) was higher in patients treated with Enbrel (11%) than in placebo-treated patients (5%). The percentage of patients who developed new positive anti-double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Enbrel compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with Enbrel compared to none of placebo-treated patients). The proportion of patients treated with Enbrel who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with Enbrel on the development of autoimmune diseases is unknown.


There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a lupus-like syndrome or rashes that are compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.

Pancytopenia and aplastic anaemia
There have been postmarketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes (see section 4.4).

Interstitial lung disease
In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of interstitial lung disease in patients receiving etanercept without concomitant methotrexate was 0.06% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of interstitial lung disease was 0.47% (frequency uncommon). There have been postmarketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.

Concurrent treatment with anakinra
In studies when adult patients received concurrent treatment with Enbrel plus anakinra, a higher rate of serious infections compared to Enbrel alone was observed and 2% of patients (3/139) developed neutropenia (absolute neutrophil count  1000/mm3). While neutropenic, one patient developed cellulitis that resolved after hospitalisation (see sections 4.4 and 4.5).

Elevated liver enzymes
In the double-blind periods of controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of adverse events of elevated liver enzymes in patients receiving etanercept without concomitant methotrexate was 0.54% (frequency uncommon). In the double-blind periods of controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of adverse events of elevated liver enzymes was 4.18% (frequency common).

Autoimmune hepatitis
In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of autoimmune hepatitis in patients receiving etanercept without concomitant methotrexate was 0.02% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0.24% (frequency uncommon).

Paediatric population

Undesirable effects in paediatric patients with juvenile idiopathic arthritis In general, the adverse events in paediatric patients with juvenile idiopathic arthritis were similar in frequency and type to those seen in adult patients. Differences from adults and other special considerations are discussed in the following paragraphs.

The types of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years were generally mild to moderate and consistent with those commonly seen in outpatient paediatric populations. Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae (see also section 4.4), appendicitis, gastroenteritis, depression/personality disorder, cutaneous ulcer, oesophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection.


In one study in children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 (62%) children experienced an infection while receiving Enbrel during 3 months of the study (part 1, open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of Enbrel in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile idiopathic arthritis patients receiving 3 months of Enbrel compared to the 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 event per patient year), abdominal pain (19%, 0.74 events per patient year), and vomiting (13%, 0.74 events per patient year).

There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.

Undesirable effects in paediatric patients with plaque psoriasis
In a 48-week study in 211 children aged 4 to 17 years with paediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.

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/.