Adverse reactions : תופעות לוואי

4.8         Undesirable effects
Summary of the safety profile
Adalimumab 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 adalimumab 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 adalimumab 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, hemorrhage, pain or swelling), headache and musculoskeletal pain.
Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as AMGEVITA 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 leukemia, lymphoma and HSTCL) have also been reported with use of adalimumab.
Serious hematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome.
Tabulated list of adverse reactions
The following list of adverse reactions is based on experience from clinical trials and on post-marketing experience and are displayed by system organ class and frequency in table 1 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 1. Undesirable effects

System Organ Class       Frequency     Adverse Reaction
Infections and           Very common   Respiratory tract infections (including lower and upper infestations*                          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, necrotizing 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 cell malignant and                          carcinoma and squamous cell carcinoma), unspecified (including
Benign neoplasm cysts and polyps)*
Uncommon      Lymphoma**,
Solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm),
Melanoma**

Rare          Leukemia1

Not known     Hepatosplenic T-cell lymphoma1,
Merkel cell carcinoma (neuroendocrine carcinoma of the skin)1
Kaposi's sarcoma
System Organ Class      Frequency     Adverse Reaction
Blood and the           Very common   Leukopenia (including neutropenia and agranulocytosis), lymphatic system disorders*                            Anemia
Common        Leukocytosis,
Thrombocytopenia
Uncommon      Idiopathic thrombocytopenic purpura
Rare          Pancytopenia
Immune system           Common        Hypersensitivity,
disorders*
Allergies (including seasonal allergy)
Uncommon      Sarcoidosis1,
Vasculitis
Rare          Anaphylaxis1
Metabolism and          Very common   Lipids increased nutrition disorders
Common        Hypokalemia,
Uric acid increased,
Blood sodium abnormal,
Hypocalcemia,
Hyperglycemia,
Hypophosphatemia,
Dehydration
Psychiatric disorders   Common        Mood alterations (including depression), Anxiety,
Insomnia
Nervous system          Very common   Headache disorders*
Common        Paresthesias (including hypoesthesia),
Migraine,
Nerve root compression
Uncommon      Cerebrovascular accident1,
Tremor,
Neuropathy

Rare          Multiple sclerosis,
Demyelinating disorders (e.g. optic neuritis, Guillain-Barré syndrome)1

System Organ Class      Frequency   Adverse Reaction
Eye disorders           Common      Visual impairment,
Conjunctivitis,
Blepharitis,
Eye swelling

Uncommon    Diplopia

Ear and labyrinth       Common      Vertigo disorders
Uncommon    Deafness,
Tinnitus
Cardiac disorders*      Common      Tachycardia

Uncommon    Myocardial infarction1,
Arrhythmia,
Congestive heart failure
Rare        Cardiac arrest

Vascular disorders      Common      Hypertension,
Flushing,
Hematoma
Uncommon    Aortic aneurysm,
Vascular arterial occlusion,
Thrombophlebitis
Respiratory, thoracic   Common      Asthma,
and mediastinal
Dyspnea,
disorders*
Cough
Uncommon    Pulmonary embolism1,
Interstitial lung disease,
Chronic obstructive pulmonary disease,
Pneumonitis,
Pleural effusion1
Rare        Pulmonary fibrosis1



System Organ Class      Frequency     Adverse Reaction

Gastrointestinal        Very common   Abdominal pain,
disorders
Nausea and vomiting
Common        GI hemorrhage,
Dyspepsia,
Gastroesophageal reflux disease,
Sicca syndrome

Uncommon      Pancreatitis,
Dysphagia,
Face edema

Rare          Intestinal perforation1
Hepato-biliary          Very common   Elevated liver enzymes disorders*
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
Common        Worsening or new onset of psoriasis (including palmoplantar pustular psoriasis)1,
Urticaria,
Bruising (including purpura),
Dermatitis (including eczema),
Onychoclasis,
Hyperhidrosis,
Alopecia1,
Pruritus

Uncommon      Night sweats,
Scar



System Organ Class          Frequency         Adverse Reaction
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
Hematuria

Uncommon          Nocturia
Reproductive system         Uncommon          Erectile dysfunction and breast disorders

General disorders and       Very common       Injection site reaction (including injection site erythema) administration site conditions*                 Common            Chest pain,
Edema,
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

Not known         Weight increased2

Injury, poisoning and      Common             Impaired healing procedural complications
* further information is found elsewhere in sections 4.3, 4.4 and 4.8 ** including open-label extension studies
1) including spontaneous reporting data


2)
The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months.
Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures of approximately 1-2 years without control group, particularly in patients with Crohn’s disease and Ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti- inflammatory effect of adalimumab.
Hidradenitis suppurativa
The safety profile for patients with HS treated with adalimumab weekly was consistent with the known safety profile of adalimumab.
Uveitis
The safety profile for patients with uveitis treated with adalimumab every other week was consistent with the known safety profile of adalimumab.
Description of selected adverse reactions
Injection site reactions
In the pivotal controlled trials in adults and children, 12.9% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, 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 adalimumab-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 adalimumab after the infection resolved.


The incidence of serious infections was 0.04 per patient year in adalimumab-treated patients and 0.03 per patient year in placebo and active control-treated patients.
In controlled and open-label adult and pediatric studies with adalimumab, 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
During the controlled portions of pivotal adalimumab 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% CI) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 adalimumab-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 adalimumab and 3.8 months for control-treated patients).
The rate (95% CI) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% CI) of 2.7 (1.4, 5.4) per 1,000 patient- years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% CI) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.
When combining controlled portions of these trials and ongoing and completed open-label extension studies of adalimumab, 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 adalimumab 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 adalimumab 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 adalimumab in patients with rheumatoid arthritis and psoriatic arthritis with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 × ULN occurred in 3.7% of adalimumab-treated patients and 1.6% of control-treated patients.
In controlled phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis with a control period ranging from 4 to 52 weeks. ALT elevations ≥ 3 × ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of controlled-treated patients.
In controlled phase 3 trials of adalimumab in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 × ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.
In controlled trials of adalimumab (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 × ULN occurred in 0.3% of adalimumab-treated patients and 0.6% of control-treated patients.
In controlled trials of adalimumab (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 adalimumab-treated and control-treated patients, respectively, ALT elevations ≥ 3 × ULN occurred in 2.4% of adalimumab-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 adalimumab and azathioprine/6-mercaptopurine compared with adalimumab alone.
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/