Clinical Studies Experience
The most serious adverse reactions were:
• Serious Infections [see Warnings and Precautions]
• Malignancies [see Warnings and Precautions]
The most common adverse reaction with HUMIRA was injection site reactions.
In placebo-controlled trials, 20% of patients treated with HUMIRA developed
injection site reactions (erythema and/or itching, hemorrhage, pain or swelling),
compared to 14% of patients receiving placebo. Most injection site reactions were
described as mild and generally did not necessitate drug discontinuation.
The proportion of patients who discontinued treatment due to adverse reactions
during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III
and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated
patients. The most common adverse reactions leading to discontinuation of
HUMIRA were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).
In the controlled portions of the 32 global HUMIRA clinical trials in adult
patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4. 7
per 100 patient-years in 6694 HUMIRA-treated patients versus a rate of 2. 7
per 100 patient-years in 3749 control-treated patients. Serious infections
observed included pneumonia, septic arthritis, prosthetic and post-surgical
infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see
Warnings and Precautions].
Tuberculosis and Opportunistic Infections
In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and
Ps that included 22,026 HUMIRA-treated patients, the rate of reported active
tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD
conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and
Canadian HUMIRA-treated patients, the rate of reported active TB was 0.07 per
100 patient-years and the rate of positive PPD conversion was 0.06 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 0.07 per 100 patient-years. Some cases of serious
opportunistic infections and TB have been fatal [see Warnings and Precautions].
In the rheumatoid arthritis controlled trials, 12% of patients treated with
HUMIRA and 7% of placebo-treated patients that had negative baseline ANA
titers developed positive titers at week 24. Two patients out of 3046 treated
with HUMIRA 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 HUMIRA on the development of
autoimmune diseases is unknown.
Liver Enzyme Elevations
There have been reports of severe hepatic reactions including acute liver failure
in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA ( 40 mg
SC every other week) in patients with RA, PsA, and AS with control period
duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred
in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since
many of these patients in these trials were also taking medications that cause
liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA
and the liver enzyme elevations is not clear. In controlled Phase 3 trials of
HUMIRA (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 control period duration ranging from 4 to 52 weeks, AL T elevations
≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg
then 40 mg every other week) in patients with plaque psoriasis with 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.
Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for
antibodies to adalimumab during the 6- to 12-month period. Approximately 5%
( 58 of 1062) of adult rheumatoid arthritis patients receiving HUMIRA developed
low-titer antibodies to adalimumab at least once during treatment, which were
neutralizing in vitro. Patients treated with concomitant methotrexate had a
lower rate of antibody development than patients on HUMIRA monotherapy
(1% versus 12%). No apparent correlation of antibody development to adverse
reactions was observed. With monotherapy, patients receiving every other
week dosing may develop antibodies more frequently than those receiving
weekly dosing. In patients receiving the recommended dosage of 40 mg every
other week as monotherapy, the ACR 20 response was lo wer among antibody-positive patients than among antibody-negative patients. The long-term
immunogenicity of HUMIRA is unknown. In patients with juvenile idiopathic
arthritis, adalimumab antibodies were identified in 16% of HUMIRA-treated
patients. In patients receiving concomitant methotrexate, the incidence was
6% compared to 26% with HUMIRA monotherapy.
In patients with ankylosing spondylitis, the rate of development of antibodies
to adalimumab in HUMIRA-treated patients was comparable to patients with
rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody
development in patients receiving HUMIRA monotherapy was comparable to
patients with rheumatoid arthritis; however, in patients receiving concomitant
methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In
patients with Crohn’s disease, the rate of antibody development was 3%. In
patients with plaque psoriasis, the rate of antibody development with HUMIRA
monotherapy was 8%. However, due to the limitation of the assay conditions,
antibodies to adalimumab could be detected only when serum adalimumab
levels were < 2 ug/ml. Among the patients whose serum adalimumab
levels were < 2 ug/ml (approximately 40% of total patients studied), the
immunogenicity rate was 20.7%. In plaque psoriasis patients who were on
HUMIRA monotherapy and subsequently withdrawn from the treatment, the
rate of antibodies to adalimumab after retreatment was similar to the rate
observed prior to withdrawal.
Other Adverse Reactions
The data described below reflect exposure to HUMIRA in 2468 patients,
including 2073 exposed for 6 months, 1497 exposed for greater than
one year and 1380 in adequate and well-controlled studies (Studies
RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months
duration. The population had a mean age of 54 years, 77% were female,
91% were Caucasian and had moderately to severely active rheumatoid
arthritis. Most patients received 40 mg HUMIRA every other week.
Table 1 summarizes reactions reported at a rate of at least 5% in patients
treated with HUMIRA 40 mg every other week compared to placebo and with
an incidence higher than placebo. In Study RA-III, the types and frequencies
of adverse reactions in the second year open-label extension were similar to
those observed in the one-year double-blind portion.
Table 1. Adverse Reactions Reported by ≥5% of Patients
Treated with HUMIRA During Placebo-Controlled Period of
Rheumatoid Arthritis Studies
40 mg subcutaneous
Every Other Week
Adverse Reaction (Preferred Term)
Upper respiratory infection 17% 13%
Sinusitis 11% 9%
Flu syndrome 7% 6%
Nausea 9% 8%
Abdominal pain 7% 4%
Laboratory test abnormal 8% 7%
Hypercholesterolemia 6% 4%
Hyperlipidemia 7% 5%
Hematuria 5% 4%
Alkaline phosphatase increased 5% 3%
Headache 12% 8%
Rash 12% 6%
Accidental injury 10% 8%
Injection site reaction 8% 1%
Back pain 6% 4%
Urinary tract infection 8% 5%
Hypertension 5% 3%
* Laboratory test abnormalities were reported as adverse reactions in
Does not include injection site erythema, itching, hemorrhage, pain
Juvenile Idiopathic Arthritis Clinical Studies
In general, the adverse reactions in the HUMIRA-treated pediatric patients in
the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type
to those seen in adult patients [see Warnings and Precautions, Adverse
Reactions]. Important findings and differences from adults are discussed in
the following paragraphs.
HUMIRA was studied in 171 pediatric patients, 4 to 17 years of age, with
polyarticular JIA. Severe adverse reactions reported in the study included
neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes
zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed
in 4% of patients within approximately 2 years of initiation of treatment with
HUMIRA and included cases of herpes simplex, pneumonia, urinary tract
infection, pharyngitis, and herpes zoster.
A total of 45% of children experienced an infection while receiving HUMIRA
with or without concomitant M TX in the first 16 weeks of treatment. The types
of infections reported in HUMIRA-treated patients were generally similar to
those commonly seen in JIA patients who are not treated with TNF blockers.
Upon initiation of treatment, the most common adverse reactions occurring
in the pediatric population treated with HUMIRA were injection site pain and
injection site reaction (19% and 16%, respectively). A less commonly reported
adverse event in children receiving HUMIRA was granuloma annulare which did
not lead to discontinuation of HUMIRA treatment.
In the first 48 weeks of treatment, non-serious hypersensitivity reactions were
seen in approximately 6% of children and included primarily localized allergic
hypersensitivity reactions and allergic rash.
Isolated mild to moderate elevations of liver aminotransferases (ALT more
common than AST) were observed in children with JIA exposed to HUMIRA alone;
liver enzyme test elevations were more frequent among those treated with the
combination of HUMIRA and MTX than those treated with HUMIRA alone. In
general, these elevations did not lead to discontinuation of HUMIRA treatment.
In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline
anti-dsDNA antibodies developed positive titers after 48 weeks of treatment.
No patient developed clinical signs of autoimmunity during the clinical trial.
Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5
times the upper limit of normal were observed in several patients. CPK levels
decreased or returned to normal in all patients. Most patients were able to
continue HUMIRA without interruption.
Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies
HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two
placebo-controlled trials and in an open label study and in 393 patients with
ankylosing spondylitis (AS) in t wo placebo-controlled studies. The safety profile
for patients with PsA and AS treated with HUMIRA 40 mg every other week
was similar to the safety profile seen in patients with RA, HUMIRA Studies
RA-I through IV.
Crohn’s Disease Clinical Studies
HUMIRA has been studied in 1478 patients with Crohn’s disease in four
placebo-controlled and two open-label extension studies. The safety profile for
patients with Crohn’s disease treated with HUMIRA was similar to the safety
profile seen in patients with RA.
Plaque Psoriasis Clinical Studies
HUMIRA has been studied in 1696 patients with plaque psoriasis in placebo-controlled and open-label extension studies. The safety profile for patients with
plaque psoriasis treated with HUMIRA was similar to the safety profile seen in
patients with RA with the following exceptions. In the placebo-controlled portions
of the clinical trials in plaque psoriasis patients, HUMIRA-treated patients had a
higher incidence of arthralgia when compared to controls (3% vs. 1%).
Adverse reactions have been reported during post-approval use of HUMIRA.
Because these reactions 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 HUMIRA exposure.
Gastrointestinal disorders: Diverticulitis, large bowel perforations including
perforations associated with diverticulitis and appendiceal perforations
associated with appendicitis, pancreatitis
Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis
Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema
multiforme, new or worsening psoriasis (all sub-types including pustular and
Vascular disorders: Systemic vasculitis
Although methotrexate (M TX) reduces the apparent adalimumab clearance, the
data do not suggest the need for dose adjustment of either HUMIRA or M TX.
In clinical studies in patients with RA, an increased risk of serious infections has
been seen with the combination of TNF blockers with anakinra or abatacept,
with no added benefit; therefore, use of HUMIRA with abatacept or anakinra
is not recommended in patients with RA [see Warnings and Precautions]. A
higher rate of serious infections has also been observed in patients with RA
treated with rituximab who received subsequent treatment with a TNF blocker.
There is insufficient information to provide recommendations regarding the
concomitant use of HUMIRA and other biologic products for the treatment of
RA, PsA, AS, Crohn’s Disease, and plaque psoriasis.
Live vaccines should not be given concurrently with HUMIRA [see Warnings
USE IN SPECIFIC POPULA TIONS
Pregnancy Category B - There are no adequate and well-controlled studies
in pregnant women. Because animal reproduction and developmental studies
are not always predictive of human response, HUMIRA should be used during
pregnancy only if clearly needed.
Pregnancy Registry: To monitor outcomes of pregnant women exposed
to HUMIRA, a pregnancy registry has been established. Physicians are
encouraged to register patients by calling 1-877-311-8972.
It is not known whether adalimumab is excreted in human milk or absorbed
systemically after ingestion. Because many drugs and immunoglobulins are
excreted in human milk, and because of the potential for serious adverse
reactions in nursing infants from HUMIRA, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Safety and efficacy of HUMIRA in pediatric patients for uses other than juvenile
idiopathic arthritis (JIA) have not been established.
Juvenile Idiopathic Arthritis In the JIA trial, HUMIRA was shown to reduce
signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age.
HUMIRA has not been studied in children less than 4 years of age, and there are
limited data on HUMIRA treatment in children with weight < 15 kg.
The safety of HUMIRA in pediatric patients in the JIA trial was generally similar
to that observed in adults with certain exceptions [see Adverse Reactions].
Post-marketing cases of malignancies, some fatal, have been reported among
children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Warnings and Precautions].
A total of 519 rheumatoid arthritis patients 65 years of age and older, including
107 patients 75 years of age and older, received HUMIRA in clinical studies
RA-I through IV. No overall difference in effectiveness was observed between
these subjects and younger subjects. The frequency of serious infection and
malignancy among HUMIRA treated subjects over 65 years of age was higher
than for those under 65 years of age. Because there is a higher incidence of
infections and malignancies in the elderly population in general, caution should
be used when treating the elderly.
Doses up to 10 mg/kg have been administered to patients in clinical trials
without evidence of dose-limiting toxicities. In case of overdosage, it is
recommended that the patient be monitored for any signs or symptoms of
adverse reactions or effects and appropriate symptomatic treatment instituted
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies of HUMIRA have not been conducted to evaluate
the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic
effects of HUMIRA were observed in the in vivo mouse micronucleus test or the
Salmonella-Escherichia coli (Ames) assay, respectively.
PA TIENT COUNSELING INFORMA TION
Patients or their caregivers should be provided the HUMIRA “Medication Guide”
and provided an opportunity to read it and ask questions prior to initiation of
therapy. The healthcare provider should ask the patient questions to determine
any risk factors for treatment. Patients developing signs and symptoms of
infection should seek medical evaluation immediately.
Patients should be advised of the potential benefits and risks of HUMIRA.
Physicians should instruct their patients to read the Medication Guide before
starting HUMIRA therapy and to reread each time the prescription is renewed.
Inform patients that HUMIRA may lo wer the ability of their immune system to
fight infections. Instruct patients of the importance of contacting their doctor
if they develop any symptoms of infection, including tuberculosis, invasive
fungal infections, and reactivation of hepatitis B virus infections.
Patients should be counseled about the risk of malignancies while receiving
• Allergic Reactions
Patients should be advised to seek immediate medical attention if they
experience any symptoms of severe allergic reactions. Advise latex-sensitive
patients that the needle cap of the prefilled syringe contains latex.
• Other Medical Conditions
Advise patients to report any signs of new or worsening medical conditions
such as congestive heart failure, neurological disease, autoimmune
disorders, or cytopenias. Advise patients to report any symptoms suggestive
of a cytopenia such as bruising, bleeding, or persistent fever.
Revised: December, 2011
North Chicago, IL 60064, U. S.A.