5.2 Malignancies
Additions and/or
revisions underlined:
…
Malignancies in Adults
In
the controlled portions of clinical trials of some TNF-blockers, including
adalimumab products, more cases of malignancies have been observed among
TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 39 global
adalimumab clinical trials in adult patients with rheumatoid arthritis (RA),
psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD),
ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS)
and uveitis (UV), malignancies, other than non- melanoma (basal
cell and squamous
cell) skin cancer,
were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03)
per 100 patient-years among 7973 adalimumab-treated patients versus
a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated
patients (median duration of treatment of 4 months for adalimumab-treated
patients and 4 months for control-treated patients). In 52 global controlled and uncontrolled clinical
trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV,
the most frequently observed malignancies, other than lymphoma and NMSC, were
breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated
patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general
U.S. population according to the SEER database (adjusted for age, gender, and race).1
In controlled
trials of other TNF blockers in adult patients at higher risk for malignancies
(i.e., patients with COPD with a significant smoking history and
cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion
of malignancies occurred
in the TNF blocker group
compared to the control group.
Non-Melanoma Skin Cancer
During
the controlled portions of 39 global adalimumab clinical trials in adult
patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate (95%
confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among
adalimumab-treated patients and 0.2 (0.10, 0.59) per 100 patient-years among control-treated patients.
Examine all patients, and in particular patients with a
medical history of prior prolonged immunosuppressant therapy or psoriasis
patients with a history of PUVA treatment for the presence of NMSC prior to and
during treatment with HULIO.
Lymphoma and Leukemia
In
the controlled portions of clinical trials of all the TNF-blockers in adults,
more cases of lymphoma have been observed among TNF-blocker-treated patients
compared to control-treated patients. In the controlled portions of 39 global
adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, 2 lymphomas occurred
among 7973 adalimumab-treated patients versus 1
among 4848 control-treated patients. In 52 global controlled and uncontrolled
clinical trials of adalimumab in adult patients
with RA, PsA, AS, CD, UC, Ps, HS and UV with a
median duration of approximately 0.7 years, including 24,605 patients and over
40,215 patient- years of adalimumab, the observed rate of lymphomas was
approximately 0.11 per 100 patient- years. This is approximately 3-fold higher
than expected in the general U.S. population according to the SEER database
(adjusted for age, gender, and race).1 Rates
of lymphoma in clinical trials of adalimumab cannot be compared to rates of
lymphoma in clinical trials of other TNF blockers and may not predict the rates
observed in a broader patient population. Patients with RA and other chronic
inflammatory diseases, particularly those with highly active disease and/or
chronic exposure to immunosuppressant therapies, may be at a higher risk (up to
several fold) than the general population for the development of lymphoma, even
in the absence of TNF blockers. Post-marketing cases of acute and chronic
leukemia have been reported in association with TNF-blocker use in
RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher
risk (approximately 2-fold)
than the general
population for the
development of leukemia.
…
5.5 Neurologic
Reactions
Additions and/or
revisions underlined:
Use
of TNF blocking agents, including adalimumab products, has been associated with
rare cases of new onset or
exacerbation of clinical symptoms and/or radiographic evidence of central
nervous system demyelinating disease, including multiple sclerosis (MS) and
optic neuritis, and peripheral demyelinating disease, including Guillain-Barré
syndrome. Exercise caution in considering the use of HULIO in patients with
preexisting or recent-onset central or peripheral nervous system demyelinating
disorders; discontinuation of HULIO should be considered if any of these
disorders develop. There
is a known association between
intermediate uveitis and central
demyelinating disorders.
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
…
Infections
In
the controlled portions of the 39 global adalimumab clinical trials in adult
patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient
years in 7973 adalimumab
treated patients versus a rate of 2.9 per 100 patient years in 4848 control-
treated patients. Serious infections observed included pneumonia, septic
arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis,
diverticulitis, and pyelonephritis [see
Warnings and Precautions (5.1)].
Tuberculosis and
Opportunistic Infections
In 52 global controlled and uncontrolled clinical
trials in RA, PsA, AS, CD, UC, Ps, HS and UV that included 24,605 adalimumab
treated patients, the rate of reported active tuberculosis was
0.20
per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100
patient- years. In a subgroup of 10,113 U.S. and Canadian adalimumab treated
patients, the rate of reported active
TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was
0.07 per 100 patient-years. These trials included reports of miliary,
lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within
the first eight months after initiation of therapy and may reflect
recrudescence of latent disease. In these global clinical trials, cases of
serious opportunistic infections have been reported at an overall rate of 0.05
per 100 patient- years. Some cases
of serious opportunistic infections and TB have been fatal [see Warnings
and Precautions (5.1)].
…
Liver Enzyme Elevations
…
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 adult 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 the Phase 3 trial of adalimumab in pediatric
patients with Crohn’s disease which evaluated efficacy and safety of two body
weight based maintenance dose
regimens following body weight based 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; none of these
patients discontinued due to abnormalities in ALT tests. 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) in adult patients with UC
with 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 with Ps with 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 subjects with HS
with a control period duration ranging from 12 to 16 weeks, ALT elevations ? 3
x ULN occurred in 0.3% of adalimumab-treated subjects and 0.6% of control-
treated subjects. 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 with an exposure of 165.4 PYs and 119.8 PYs in adalimumab-treated and control-treated patients,
respectively, ALT elevations ?
3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-
treated patients.
…
Uveitis Clinical Studies
Adalimumab has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-label extension studies [see Clinical Studies (14.11)]. The safety profile for patients
with UV treated with adalimumab was similar to the safety profile seen in
patients with RA.
6.2 Immunogenicity
Change to Table 2; please refer to label
Get Email Alerts |
Guide
