WARNINGS: SERIOUS INFECTIONS AND MALIGNANCY
SERIOUS INFEC TIONS
Patients treated with HUMIRA are at increased risk for developing
serious infections that may lead to hospitalization or death [see
Warnings and Precautions]. Most patients who developed these
infections were taking concomitant immunosuppressants such as
methotrexate or corticosteroids.
HUMIRA should be discontinued if a patient develops a serious
infection or sepsis.
Reported infections include:
• Active tuberculosis (TB), including reactivation of latent TB.
Patients with TB have frequently presented with disseminated or
extrapulmonary disease. Patients should be tested for latent TB
before HUMIRA use and during therapy. Treatment for latent TB
should be initiated prior to HUMIRA use.
• Invasive fungal infections, including histoplasmosis,
coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and
pneumocystosis. Patients with histoplasmosis or other invasive
fungal infections may present with disseminated, rather than
localized, disease. Antigen and antibody testing for histoplasmosis
may be negative in some patients with active infection. Empiric
anti-fungal therapy should be considered in patients at risk for
invasive fungal infections who develop severe systemic illness.
• Bacterial, viral and other infections due to opportunistic pathogens,
including Legionella and Listeria.
The risks and benefits of treatment with HUMIRA should be carefully
considered prior to initiating therapy in patients with chronic or
Patients should be closely monitored for the development of signs
and symptoms of infection during and after treatment with HUMIRA,
including the possible development of TB in patients who tested
negative for latent TB infection prior to initiating therapy. [See
Warnings and Precautions and Adverse Reactions]
Lymphoma and other malignancies, some fatal, have been reported in
children and adolescent patients treated with TNF blockers, of which
HUMIRA is a member. [See Warnings and Precautions] Post-marketing
cases of hepatosplenic T-cell lymphoma (HS TCL), a rare type of T-cell
lymphoma, have been reported in patients treated with TNF blockers
including HUMIRA. These cases have had a very aggressive disease
course and have been fatal. The majority of reported TNF blocker
cases has occurred in patients with Crohn’s disease or ulcerative
colitis and the majority were in adolescent and young adult males.
Almost all these patients had received treatment with azathioprine
or 6-mercaptopurine concomitantly with a TNF blocker at or prior to
diagnosis. It is uncertain whether the occurrence of HSTCL is related
to use of a TNF blocker or a TNF blocker in combination with these
INDICATIONS AND USAGE
HUMIRA is indicated for reducing signs and symptoms, inducing major
clinical response, inhibiting the progression of structural damage, and
improving physical function in adult patients with moderately to severely
active rheumatoid arthritis. HUMIRA can be used alone or in combination with
methotrexate or other non-biologic disease-modifying anti-rheumatic drugs
Juvenile Idiopathic Arthritis
HUMIRA is indicated for reducing signs and symptoms of moderately to severely
active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age
and older. HUMIRA can be used alone or in combination with methotrexate.
HUMIRA is indicated for reducing signs and symptoms, inhibiting the
progression of structural damage, and improving physical function in adult
patients with active psoriatic arthritis. HUMIRA can be used alone or in
combination with non-biologic DMARDs.
HUMIRA is indicated for reducing signs and symptoms in adult patients with
active ankylosing spondylitis.
HUMIRA is indicated for reducing signs and symptoms and inducing and
maintaining clinical remission in adult patients with moderately to severely
active Crohn’s disease who have had an inadequate response to conventional
therapy. HUMIRA is indicated for reducing signs and symptoms and inducing
clinical remission in these patients if they have also lost response to or are
intolerant to infliximab.
HUMIRA is indicated for the treatment of adult patients with moderate to
severe chronic plaque psoriasis who are candidates for systemic therapy
or phototherapy, and when other systemic therapies are medically less
appropriate. HUMIRA should only be administered to patients who will be
closely monitored and have regular follow-up visits with a physician [see Boxed
Warnings and Warnings and Precautions].
WARNINGS AND PRECAUTIONS
(see also Boxed WARNINGS)
Patients treated with HUMIRA are at increased risk for developing
serious infections involving various organ systems and sites that may
lead to hospitalization or death. Opportunistic infections due to bacterial,
mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens
including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis,
histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis
have been reported with TNF blockers. Patients have frequently presented with
disseminated rather than localized disease.
The concomitant use of a TNF blocker and abatacept or anakinra was
associated with a higher risk of serious infections in patients with rheumatoid
arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic
products is not recommended in the treatment of patients with RA [see
Warnings and Precautions and Drug Interactions].
Treatment with HUMIRA should not be initiated in patients with an active
infection, including localized infections. Patients greater than 65 years of
age, patients with co-morbid conditions and/or patients taking concomitant
immunosuppressants (such as corticosteroids or methotrexate), may be
at greater risk of infection. The risks and benefits of treatment should be
considered prior to initiating therapy in patients:
• with chronic or recurrent infection;
• who have been exposed to tuberculosis;
• with a history of an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic
mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
• with underlying conditions that may predispose them to infection.
Cases of reactivation of tuberculosis or new tuberculosis infections have
been observed in patients receiving HUMIRA, including patients who have
previously received treatment for latent or active tuberculosis. Patients should
be evaluated for tuberculosis risk factors and tested for latent infection prior to
initiating HUMIRA and periodically during therapy.
Treatment of latent tuberculosis infection prior to therapy with TNF blocking
agents has been shown to reduce the risk of tuberculosis reactivation during
Anti-tuberculosis therapy should also be considered prior to initiation of
HUMIRA in patients with a past history of latent or active tuberculosis in whom
an adequate course of treatment cannot be confirmed, and for patients with
a negative test for latent tuberculosis but having risk factors for tuberculosis
infection. Consultation with a physician with expertise in the treatment of
tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Tuberculosis should be strongly considered in patients who develop a new
infection during HUMIRA treatment, especially in patients who have previously
or recently traveled to countries with a high prevalence of tuberculosis, or who
have had close contact with a person with active tuberculosis.
Patients should be closely monitored for the development of signs and
symptoms of infection during and after treatment with HUMIRA, including
the development of tuberculosis in patients who tested negative for latent
tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis
infection may also be falsely negative while on therapy with HUMIRA.
HUMIRA should be discontinued if a patient develops a serious infection or
sepsis. A patient who develops a new infection during treatment with HUMIRA
should be closely monitored, undergo a prompt and complete diagnostic
workup appropriate for an immunocompromised patient, and appropriate
antimicrobial therapy should be initiated.
Invasive Fungal Infections
For patients who reside or travel in regions where mycoses are endemic,
invasive fungal infection should be suspected if they develop a serious
systemic illness. Appropriate empiric antifungal therapy should be considered
while a diagnostic workup is being performed. Antigen and antibody testing for
histoplasmosis may be negative in some patients with active infection. When
feasible, the decision to administer empiric antifungal therapy in these patients
should be made in consultation with a physician with expertise in the diagnosis
and treatment of invasive fungal infections and should take into account both
the risk for severe fungal infection and the risks of antifungal therapy.
The risks and benefits of TNF-blocker treatment including HUMIRA should
be considered prior to initiating therapy in patients with a known malignancy
other than a successfully treated non-melanoma skin cancer (NMSC) or when
considering continuing a TNF blocker in patients who develop a malignancy.
Malignancies in Adults
In the controlled portions of clinical trials of some TNF-blockers, including
HUMIRA, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients.
During the controlled portions of 32 global HUMIRA clinical trials in adult
patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing
spondylitis (AS), Crohn’s disease (CD), and plaque psoriasis (Ps), malignancies,
other than non-melanoma (basal cell and squamous cell) skin cancer, were
observed at a rate (95% confidence interval) of 0.6 (0.38, 0.93) per 100 patient-years among 6694 HUMIRA-treated patients versus a rate of 0.5 (0.28, 1.05)
per 100 patient-years among 3749 control-treated patients (median duration
of treatment of 4 months for HUMIRA-treated patients and 4 months for
control-treated patients). In 45 global controlled and uncontrolled clinical trials
of HUMIRA in adult patients with RA, PsA, AS, CD and Ps, the most frequently
observed malignancies, other than lymphoma and NMSC, were breast, colon,
prostate, lung, and melanoma. The malignancies in HUMIRA-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).
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
Non-Melanoma Skin Cancer
During the controlled portions of 32 global HUMIRA clinical trials in adult
patients with RA, PsA, AS, CD, and Ps, the rate (95% confidence interval) of
NMSC was 0.7 (0.50, 1. 11) per 100 patient-years among HUMIRA-treated
patients and 0.2 (0.06, 0.56) per 100 patient-years among control-treated
patients. All patients, and in particular patients with a medical history of prior
prolonged immunosuppressant therapy or psoriasis patients with a history of
PUVA treatment should be examined for the presence of NMSC prior to and
during treatment with HUMIRA.
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 32
global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, 3
lymphomas occurred among 6694 HUMIRA-treated patients versus 1 among
3749 control-treated patients. In 45 global controlled and uncontrolled clinical
trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps with a median
duration of approximately 0.6 years, including 22,026 patients and over 32,000
patient-years of HUMIRA, 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). Rates of lymphoma in clinical trials of HUMIRA 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.
Malignancies in Pediatric Patients and Young Adults
Malignancies, some fatal, have been reported among children, adolescents, and
young adults who received treatment with TNF-blockers (initiation of therapy ≤
18 years of age), of which HUMIRA is a member. Approximately half the cases
were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The
other cases represented a variety of different malignancies and included rare
malignancies usually associated with immunosuppression and malignancies
that are not usually observed in children and adolescents. The malignancies
occurred after a median of 30 months of therapy (range 1 to 84 months).
Most of the patients were receiving concomitant immunosuppressants. These
cases were reported post-marketing and are derived from a variety of sources
including registries and spontaneous postmarketing reports.
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type
of T-cell lymphoma, have been reported in patients treated with TNF blockers
including HUMIRA. These cases have had a very aggressive disease course
and have been fatal. The majority of reported TNF blocker cases has occurred
in patients with Crohn’s disease or ulcerative colitis and the majority were in
adolescent and young adult males. Almost all of these patients had received
treatment with the immunosuppressants azathioprine or 6-mercaptopurine
concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain
whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF
blocker in combination with these other immunosuppressants.
In postmarketing experience, anaphylaxis and angioneurotic edema have
been reported rarely following HUMIRA administration. If an anaphylactic or
other serious allergic reaction occurs, administration of HUMIRA should be
discontinued immediately and appropriate therapy instituted. In clinical trials
of HUMIRA in adults, allergic reactions overall (e.g., allergic rash, anaphylactoid
reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been
observed in approximately 1% of patients.
Hepatitis B Virus Reactivation
Use of TNF blockers, including HUMIRA, may increase the risk of reactivation
of hepatitis B virus (HBV) in patients who are chronic carriers of this virus.
In some instances, HBV reactivation occurring in conjunction with TNF
blocker therapy has been fatal. The majority of these reports have occurred
in patients concomitantly receiving other medications that suppress the
immune system, which may also contribute to HBV reactivation. Patients at
risk for HBV infection should be evaluated for prior evidence of HBV infection
before initiating TNF blocker therapy. Prescribers should exercise caution in
prescribing TNF blockers for patients identified as carriers of HBV. Adequate
data are not available on the safety or efficacy of treating patients who are
carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy
to prevent HBV reactivation. In patients who develop HBV reactivation, HUMIRA
should be stopped and effective anti-viral therapy with appropriate supportive
treatment should be initiated. The safety of resuming TNF blocker therapy after
HBV reactivation is controlled is not known.
Use of TNF blocking agents, including HUMIRA, 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. Prescribers should exercise caution in
considering the use of HUMIRA in patients with preexisting or recent-onset
central or peripheral nervous system demyelinating disorders.
Rare reports of pancytopenia including aplastic anemia have been reported
with TNF blocking agents. Adverse reactions of the hematologic system,
including medically significant cytopenia (e.g., thrombocytopenia, leukopenia)
have been infrequently reported with HUMIRA. The causal relationship of these
reports to HUMIRA remains unclear. All patients should be advised to seek
immediate medical attention if they develop signs and symptoms suggestive of
blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor)
while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in
patients with confirmed significant hematologic abnormalities.
Use with Anakinra
Concurrent use of anakinra (an interleukin- 1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and
neutropenia and no added benefit compared with the TNF-blocker alone in
patients with RA. Therefore, the combination of HUMIRA and anakinra is not
recommended [see Drug Interactions].
Cases of worsening congestive heart failure (CHF) and new onset CHF have
been reported with TNF blockers. Cases of worsening CHF have also been
observed with HUMIRA. Physicians should exercise caution when using
HUMIRA in patients who have heart failure and monitor them carefully.
Treatment with HUMIRA may result in the formation of autoantibodies and,
rarely, in the development of a lupus-like syndrome. If a patient develops
symptoms suggestive of a lupus-like syndrome following treatment with
HUMIRA, treatment should be discontinued [see Adverse Reactions].
In a placebo-controlled clinical trial of patients with rheumatoid arthritis,
no difference was detected in anti-pneumococcal antibody response
between HUMIRA and placebo treatment groups when the pneumococcal
polysaccharide vaccine and influenza vaccine were administered concurrently
with HUMIRA. Patients on HUMIRA may receive concurrent vaccinations,
except for live vaccines. No data are available on the secondary transmission
of infection by live vaccines in patients receiving HUMIRA.
It is recommended that juvenile idiopathic arthritis patients, if possible,
be brought up to date with all immunizations in agreement with current
immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA
may receive concurrent vaccinations, except for live vaccines.
Use with Abatacept
In controlled trials, the concurrent administration of TNF-blockers and
abatacept was associated with a greater proportion of serious infections than
the use of a TNF-blocker alone; the combination therapy, compared to the use
of a TNF-blocker alone, has not demonstrated improved clinical benefit in the
treatment of RA. Therefore, the combination of abatacept with TNF-blockers
including HUMIRA is not recommended [see Drug Interactions].
PROFESSIONAL BRIEF SUMMARY