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The controlled pivotal studies involved 6089 patients receiving adalimumab and 3801 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.
Approximately 13% of patients can be expected to experience injection site reactions, based on one of the most common adverse events with adalimumab in controlled clinical studies.
Adverse events at least possibly causally-related to adalimumab, both clinical and laboratory, are displayed by system organ class and frequency (very common ≥1/10; common ≥1/100 to <1/10; uncommon ≥1/1000 to <1/100; rare ≥ 1/10,000 to <1/1000) in Table 10 as follows. 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 CONTRAINDICATIONS, PRECAUTIONS and as follows. (See Table 10.)
Click on icon to see table/diagram/imageHidradenitis Suppurativa: The safety profile for patients with hidradenitis suppurativa treated with Adalimumab weekly was consistent with the known safety profile of Adalimumab.
Uveitis: The safety profile for patients with non-infectious uveitis treated with adalimumab was consistent with the known safety profile of adalimumab.
Pediatric Population: In general, the adverse reactions in pediatric patients were similar in frequency and type to those seen in adult patients.
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 control treatment. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.
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 control-treated patients. The incidence of serious infections was 0.04 per patient year in Adalimumab treated patients and 0.03 per patient year in control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infections and sinusitis. Most patients continued on Adalimumab after the infection resolved.
In the 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 extrapulmonary locations) and invasive opportunistic infections (e.g., disseminated histoplasmosis, pneumocystis carinii pneumonia, aspergillosis and listeriosis).
Malignancies and Lymphoproliferative Disorders: No malignancies were observed in 249 pediatric patients with an exposure of 655.6 patient-years during Adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis).
In addition, no malignancies were observed in 192 pediatric patients with an exposure of 498.1 patient years during a Adalimumab trial in pediatric patients with Crohn's disease.
During the controlled portions of pivotal Adalimumab trials in adults at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), Crohn's disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, 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 1000 patient-years among 5291 Adalimumab treated patients versus a rate of 6.3 (3.4, 11.8) per 1000 patient-years among 3444 control patients (median duration of treatment was 4.0 months for Adalimumab 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 1000 patient-years among Adalimumab-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 1000 patient-years among Adalimumab-treated patients and 0.6 (0.1, 4.5) per 1000 patient-years among control patients.
The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1000 patient-years among Adalimumab-treated patients and 0.6 (0.1, 4.5) per 1000 patient-years among control patients.
The observed rate of malignancies, other than lymphoma and non-melanoma skin cancers, is approximately 8.5 per 1000 patient years in the controlled portion of clinical trials and in ongoing and completed open label extension studies. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1000 patient years. The median duration of these studies is approximately 3.3 years and included 6427 patients who were on Adalimumab for at least 1 year or who developed a malignancy within a year of starting therapy, representing over 26439.6 patient years of therapy.
Autoantibodies: Patients had serum samples tested for autoantibodies at multiple time points in RA Studies I-V. In these adequate and well-controlled 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 titers reported positive titers at week 24.
Two patients out of 3989 treated with Adalimumab in all RA, PsA and AS 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. The impact of long-term treatment with Adalimumab on the development of autoimmune diseases is unknown.
Psoriasis: New onset and Worsening: Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, and cases of worsening of pre-existing psoriasis have been reported with the use of TNF-blockers, including Adalimumab. Many of these patients were taking concomitant immunosuppressants (e.g. MTX, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of Adalimumab should be considered for severe cases and those that do not improve or that worsen despite topical treatments.
Liver Enzyme Elevations: In controlled Phase 3 trials of Adalimumab (40 mg SC every other week), in patients with RA and PsA with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.7% of Adalimumab-treated patients and 1.6% of control-treated patients. Since many of the patients in these trials were also taking medications that cause liver enzyme elevations (e.g. NSAIDS, MTX), the relationship between Adalimumab and the liver enzyme elevations is not clear. In controlled Phase 3 trials of Adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week), in patients with Crohn's disease with a control period duration ranging from 4 to 52 weeks. ALT elevations ≥ 3 x ULN occurred in 0.9% of Adalimumab-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of Adalimumab (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week), patients with ulcerative colitis with a control period duration ranging from 1 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 1.5% of Adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase 3 trials of Adalimumab (initial dose of 80 mg then 40 mg every other week), in patients treated with plaque psoriasis with a control period duration ranging from 12 to 24 weeks. ALT elevations ≥ 3 x 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 x ULN occurred in 0.3% of Adalimumab-treated patients and 0.6% of control-treated patients.
In controlled Phase 3 trials of Adalimumab (40 mg every other week), in patients with axial spondyloarthriris (ankylosing spondylitis and non-radiographic axial spondyloarthritis) with a control period of 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 2.1% of Adalimumab-treated patients and 0.8% of control-treated patients.
In controlled Phase 3 trials of Adalimumab 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 Adalimumab-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 Adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 2 to <4 years.
In the Phase 3 trial of Adalimumab in patients with pediatric 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 trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs 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.
No ALT elevations ≥ 3 X ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaque psoriasis.
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 been very rare postmarketing reports of severe hepatic reactions including liver failure in patients receiving TNF-blockers, including adalimumab. The causal relationship to adalimumab treatment remains unclear.
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.
Additional Adverse Reactions from Postmarketing Surveillance or Phase IV Clinical Trials: Adverse events have been reported during post-approval use of Adalimumab. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Adalimumab exposure. (See Table 11.)
Click on icon to see table/diagram/imageComparability of AMGEVITA with HUMIRA: Both the AMGEVITA Rheumatoid Arthritis (RA) and Psoriasis (Ps) Studies showed clinical equivalence between AMGEVITA and HUMIRA (see Pharmacology: Clinical Trials under Actions).
Table 12 and Table 13 as follows show comparative data for adverse events between AMGEVITA and HUMIRA from the RA and Ps studies, respectively.
The data in Table 12 reflect exposure to AMGEVITA in 264 subjects and HUMIRA in 262 subjects in the RA Study treated at the recommended dose and schedule for a median of 480 mg doses (see Pharmacology: Clinical Trials under Actions). 52.3% of all subjects had at least 1 treatment-emergent adverse event during the study, and similar proportions were reported in each treatment group (50.0% in ABP 501 group and 54.6% in Adalimumab group). The overall safety profile of AMGEVITA is similar to that of HUMIRA. (See Table 12.)
Click on icon to see table/diagram/imageThe data in Table 13 reflect exposure to AMGEVITA/AMGEVITA in 152 subjects, HUMIRA/HUMIRA in 79 subjects, and HUMIRA/AMGEVITA in 77 subjects in the Ps study treated at the recommended dose and schedule for a median of 1040 mg doses [see Pharmacology: Clinical Trials under Actions]. 82.1% of subjects, from baseline to end of study, had at least 1 treatment emergent adverse event and similar proportions were reported across treatment groups (86.2% of subjects in Treatment Group A (AMGEVITA/AMGEVITA), 78.5% of subjects in Treatment Group B1 (HUMIRA/HUMIRA), and 85.7% of subjects in Treatment Group B2 (HUMIRA/AMGEVITA). The overall safety profiles of the AMGEVITA/AMGEVITA, HUMIRA/HUMIRA and HUMIRA/AMGEVITA groups were similar. (See Table 13.)
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