Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile

Humira was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving Humira and 3,801 patients receiving placebo or active comparator during the controlled period.

The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking Humira and 5.4% for control treated patients.


The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.

Serious adverse reactions have been reported for Humira. TNF-antagonists, such as Humira affect the immune system and their use may affect the body’s defence against infection and cancer.

Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV reactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been reported with use of Humira.

Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome.


Paediatric population

In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 3 below: 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); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.


Table 3
Undesirable Effects


System Organ Class                  Frequency                   Adverse Reaction Infections and                  Very common        respiratory tract infections (including lower and infestations*                                      upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)

Common             systemic infections (including sepsis, candidiasis and influenza),
intestinal infections (including gastroenteritis viral),
skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster),
ear infections,
oral infections (including herpes simplex, oral herpes and tooth infections),
reproductive tract infections (including vulvovaginal mycotic infection),
urinary tract infections (including pyelonephritis),
fungal infections joint infections
Uncommon           neurological infections (including viral meningitis),
opportunistic infections and tuberculosis
(including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection),
bacterial infections,
eye infections,
diverticulitis1)
Neoplasms benign,               Common             skin cancer excluding melanoma (including basal malignant and unspecified                          cell carcinoma and squamous cell carcinoma), (including cysts and                               benign neoplasm polyps)*
Uncommon           lymphoma**,
solid organ neoplasm (including breast cancer,
lung neoplasm and thyroid neoplasm),
melanoma**
Rare               leukaemia1)

Not Known          hepatosplenic T-cell lymphoma1),
Merkel cell carcinoma (neuroendocrine carcinoma of the skin) 1)

Blood and the lymphatic         Very common        leucopaenia (including neutropaenia and system disorders*                                  agranulocytosis),
anaemia

Common             leucocytosis,
thrombocytopaenia,

Uncommon           idiopathic thrombocytopaenic purpura
Rare               pancytopaenia

System Organ Class                  Frequency                   Adverse Reaction Immune system disorders*        Common             hypersensitivity,
allergies (including seasonal allergy)


Uncommon           sarcoidosis1) vasculitis


Rare              anaphylaxis1)
Metabolism and nutrition        Very common        lipids increased disorders
Common             hypokalaemia,
uric acid increased,
blood sodium abnormal,
hypocalcaemia,
hyperglycaemia,
hypophosphataemia,
dehydration
Psychiatric disorders           Common             mood alterations (including depression), anxiety,
insomnia

Nervous system disorders* Very common              headache

Common             paraesthesias (including hypoaesthesia),
migraine,
nerve root compression
Uncommon           cerebrovascular accident1),
tremor,
neuropathy
Rare               multiple sclerosis,
demyelinating disorders (e.g. optic neuritis,
Guillain-Barré syndrome) 1)

Eye disorders                   Common             visual impairment, conjunctivitis,
blepharitis,
eye swelling
Uncommon           diplopia

Ear and labyrinth               Common             vertigo disorders
Uncommon           deafness,
tinnitus
Cardiac disorders*              Common             tachycardia

System Organ Class                  Frequency                     Adverse Reaction Uncommon           myocardial infarction1),
arrhythmia,
congestive heart failure
Rare               cardiac arrest

Vascular disorders              Common             hypertension,
flushing,
haematoma
Uncommon           aortic aneurysm,
vascular arterial occlusion,
thrombophlebitis

Respiratory, thoracic and       Common             asthma,
mediastinal disorders*                             dyspnoea,
cough
Uncommon           pulmonary embolism1),
interstitial lung disease,
chronic obstructive pulmonary disease,
pneumonitis,
pleural effusion1)
Rare pulmonary fibrosis1)

Gastrointestinal disorders      Very common        abdominal pain,
nausea and vomiting
Common             GI haemorrhage,
dyspepsia,
gastroesophageal reflux disease,
sicca syndrome

Uncommon           pancreatitis,
dysphagia,
face oedema
Rare               intestinal perforation1)
Hepato-biliary disorders*       Very Common        elevated liver enzymes Uncommon           cholecystitis and cholelithiasis,
hepatic steatosis bilirubin increased

Rare               hepatitis reactivation of hepatitis B1) autoimmune hepatitis1)

Not known          liver failure1)
Skin and subcutaneous           Very Common        rash (including exfoliative rash), tissue disorders



System Organ Class                  Frequency                   Adverse Reaction Common             worsening or new onset of psoriasis (including palmoplantar pustular psoriasis)1),
urticaria,
bruising (including purpura),
dermatitis (including eczema),
onychoclasis,
hyperhydrosis alopecia1),
pruritus
Uncommon           night sweats,
scar
Rare               erythema multiforme1),
Stevens-Johnson syndrome1),
angioedema1),
cutaneous vasculitis1) lichenoid skin reaction1)

Not known          worsening of symptoms of dermatomyositis1)

Musculoskeletal and             Very common        musculoskeletal pain connective tissue disorders
Common             muscle spasms (including blood creatine phosphokinase increased)

Uncommon           rhabdomyolysis systemic lupus erythematosus

Rare               lupus-like syndrome1)
Renal and urinary               Common             renal impairment,
disorders                                          haematuria
Uncommon           nocturia

Reproductive system and         Uncommon           erectile dysfunction breast disorders
General disorders and           Very Common        injection site reaction (including injection site administration site                                erythema) conditions*
Common             chest pain,
oedema,
pyrexia1)
Uncommon           inflammation

Investigations*                 Common             coagulation and bleeding disorders (including activated partial thromboplastin time prolonged),
autoantibody test positive (including double stranded DNA antibody),
blood lactate dehydrogenase increased
Injury, poisoning and           Common procedural complications                           impaired healing

* further information is found elsewhere in sections 4.3, 4.4 and 4.8 ** including open label extension studies
1) including spontaneous reporting data

Hidradenitis suppurativa

The safety profile for patients with HS treated with Humira weekly was consistent with the known safety profile of Humira.


Uveitis
The safety profile for patients with uveitis treated with Humira every other week was consistent with the known safety profile of Humira.

Description of selected adverse reactions

Injection site reactions
In the pivotal controlled trials in adults and children, 12.9% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.

Infections

In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the Humira treated patients and 1.46 per patient year in the placebo and active control-treated patients.
The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis.
Most patients continued on Humira after the infection resolved.

The incidence of serious infections was 0.04 per patient year in Humira treated patients and 0.03 per patient year in placebo and active control − treated patients.

In controlled and open label adult and paediatric studies with Humira, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g.
disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystis candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.

Malignancies and lymphoproliferative disorders

No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during Humira trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with an exposure of 498.1 patient years during Humira trials in paediatric patients with Crohn’s disease. . No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a Humira trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a Humira trial in paediatric patients with uveitis.


During the controlled portions of pivotal Humira trials in adults of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291Humira treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for Humira and 3.8 months for control-treated patients).

The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among Humira-treated patients and 3.2 (1.3, 7.6) per 1000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1000 patient-years among control patients.

When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.

In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively (see section 4.4).

Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4).

Autoantibodies

Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies I − V. In these trials, 11.9% of patients treated with Humira and 8.1% of placebo and active control − treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at Week 24. Two patients out of 3,441 treated with Humira in all rheumatoid arthritis and psoriatic arthritis studies developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.

Hepato-biliary events

In controlled Phase 3 trials of Humira in patients with rheumatoid arthritis and psoriatic arthritis with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.7% of Humira-treated patients and 1.6% of control-treated patients.

In controlled Phase 3 trials of Humira in patients with polyarticular juvenile idiopathic arthritis who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥ 3 x ULN occurred in 6.1% of Humira-treated patients and 1.3% of control-treated patients. Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of Humira in patients with polyarticular juvenile idiopathic arthritis who were 2 to <4 years.

In controlled Phase 3 trials of Humira in patients with Crohn’s disease and ulcerative colitis with a control period ranging from 4 to 52 weeks. ALT elevations ≥ 3 x ULN occurred in 0.9% of Humira- treated patients and 0.9% of controlled-treated patients.

In the Phase 3 trial of Humira in patients with paediatric Crohn’s disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients, of whom 4 were receiving concomitant immunosuppressants at baseline.

In controlled Phase 3 trials of Humira in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of Humira-treated patients and 1.8% of control-treated patients.

No ALT elevations ≥3 X ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaque psoriasis.

In controlled trials of Humira (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of Humira-treated patients and 0.6% of control-treated patients.

In controlled trials of Humira (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in Humira-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of Humira-treated patients and 2.4% of control-treated patients.

Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have also been post- marketing reports of liver failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis in patients receiving adalimumab.

Concurrent treatment with azathioprine/6-mercaptopurine

In adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of Humira and azathioprine/6-mercaptopurine compared with Humira alone.

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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il