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2. CONTENTS
EXECUTIVE SUMMARY............................................................................................................. 2
1 BACKGROUND .................................................................................................................... 2
1.1 Product Formulations and Indications ........................................................................... 2
1.2 Pediatric Filing History.................................................................................................. 2
1.3 Pediatric Malignancy Regulatory History……………………………………………...2
1.4 Pediatric Labeling .......................................................................................................... 3
2 METHODS AND MATERIALS............................................................................................ 4
2.1 Introduction.................................................................................................................... 4
2.2 AERS Search Criteria .................................................................................................... 4
3 AERS RESULTS for Adalimumab ........................................................................................ 5
3.1 Crude Counts of All AERS Reports: Table 1 ................................................................ 5
3.2 Case Characteristics From Pediatric Safety Review (Table 2) ...................................... 6
4 DISCUSSION/Summary Of PEDIATRIC Cases................................................................... 6
4.1 Pediatric Deaths (N= 4).................................................................................................. 6
4.2 Non-Fatal Serious Adverse Events (N=105).................................................................. 7
4.2.1 Serious Infections (N=24).............................................................................................. 7
4.2.2 Malignancies (N=2) ....................................................................................................... 8
4.2.3 Hypersensitivity/Injection Site Reactions (N=7) ........................................................... 8
4.2.4 Disease Flares/Drug Ineffective (N=22)........................................................................ 9
4.2.5 In Utero Exposures (N=34)............................................................................................ 9
4.2.6 Other Serious Miscellaneous Events (N=17)............................................................... 11
5 CONCLUSION..................................................................................................................... 11
6 RECOMMENDATIONS...................................................................................................... 11
APPENDICES............................................................................................................................... 16
APPENDIX I - Pediatric Labeling…………………………………………….…………12
APPENDIX II - Narrative Summary of the Pediatric Death Cases (N=4)…………..…..13
APPENDIX III - Other Serious Miscellaneous Cases (N=17) ………………………….15
APPENDIX IV - Graphical Comparision of Adult and Pediatric Reported Events …….16

3. EXECUTIVE SUMMARY
In accordance with the Pediatric Research Equity Act (PREA), the Division of
Pharmacovigilance II (DPV II) was asked to summarize post-marketing reports of adverse events
associated with the use of adalimumab in pediatric patients (0-16 years of age) from the Adverse
Event Reporting System (AERS) database.
Adalimumab is a tumor necrosis factor (TNF) blocker indicated for the treatment of juvenile
idiopathic arthritis in pediatric patients four years of age and older and for the treatment of
rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and plaque
psoriasis in adults.
The Adverse Event Reporting System (AERS) database was searched for all reports of adverse
events (serious and non-serious) up to the "data lock" date of 07/07/2009; AERS contained
42,852 reports for adalimumab. Pediatric reports represent approximately 1% of the total
(471/42,852). One hundred and nine serious pediatric adverse event cases were selected for this
case series. The reported ages ranged from 1 day to 16 years old. Adalimumab was used for JIA
(a labeled indication) in 20 cases, and it was used for off-label pediatric indications in 51 cases
(Crohn’s disease-42, ulcerative colitis-3, uveitis-2, psoriasis-2, psoriatic arthritis-1, and vasculitis-
1); the remaining cases reported in utero exposure cases (37).
Many of the events reported in pediatric patients are already included in the pediatric labeling for
adalimumab (i.e. serious infection, malignancy, hypersensitivity/injection site reactions, and
disease flares). The remaining cases that reported unlabeled events were either confounded by
concomitant medications and/or underlying disease, or provided insufficient evidence to conclude
a causal association between the events and the use of adalimumab therapy.
No new safety signals emerged from this review. No labeling changes regarding the pediatric
patients are recommended at this time.
1 BACKGROUND
PRODUCT FORMULATIONS AND INDICATIONS
Adalimumab is supplied in prefilled syringes as a preservative-free, sterile solution for
subcutaneous administration in the following configurations: 40 mg/0.8 mL in a single-use
prefilled pen, 40 mg/0.8 mL in a single-dose prefilled glass syringe, and 20 mg/0.4 mL in a
single-dose prefilled glass syringe.
Adalimumab is indicated for the treatment of juvenile idiopathic arthritis in pediatric patients four
years of age and older and for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing
spondylitis, Crohn’s disease, and plaque psoriasis in adults.
PEDIATRIC FILING HISTORY
Adalimumab received FDA approval on December 31, 2002. Pediatric approval of adalimumab
occurred on February 21, 2008. The pediatric approval of adalimumab was based on a double-
blind, multicenter, randomized, parallel-group study in 171 children (4 to 17 years old) with
polyarticular juvenile idiopathic arthritis (JIA). In the study, the patients were stratified into two
groups: MTX-treated or non-MTX-treated. All subjects had signs of active moderate or severe
disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS.
The data from the pediatric study provided statistically significant and consistent support for
efficacy of adalimumab in children with polyarticular JIA. The safety profile was similar to that
2

4. seen in adults with a few exceptions; elevations in creatine phosphokinase (CPK) and higher rates
of immunogenicity and non-serious hypersensitivity reactions were observed in pediatric patients
with adalimumab use. There were no deaths in the pediatric study.1
PEDIATRIC MALIGNANCY REGULATORY HISTORY
• June 4, 2008 – An Early Communication (EC) about on ongoing safety review of the TNF
blockers and pediatric malignancies was posted on the FDA website. 2
FDA requested
additional information on the cases of pediatric malignancy from the sponsors of the TNF
blockers. In addition, FDA contacted medical experts to assess the potential association
between TNF blockers and malignancy.
• June 18, 2008 – FDA Advisory Committee meeting on the proposal for Enbrel (etanercept)
treatment for pediatric psoriasis. The committee agreed that the data presented was not
sufficient to understand the risk vs. benefit with potential for malignancy in pediatric plaque
psoriasis. The committee described that further information is needed, perhaps in the form of a
pediatric registry.3
• July 25, 2008 – The OSE review of pediatric malignancy concluded that there is an increased
risk of lymphoma and other cancers associated with the use of TNF blockers in children and
adolescents.4
• September 5, 2008 - Under provisions of FDAAA section 921, the pediatric malignancy
safety issue was posted on the FDA website as new safety information identified from the
adverse event reporting system (AERS).5
• August 4, 2009 – In the follow-up to the Early Communication on pediatric malignancies
with the TNF blockers the FDA announced that it had concluded that there is an increased risk
of lymphoma and other cancers associated with the use of the TNF blockers in children and
adolescents. The FDA is requiring that new Boxed Warnings be added to the TNF class of
drugs for the increased risk of lymphoma and other malignancies in children and adolescents. 6
• August 25, 2009 - Additional denominator and case information was released on the
FDA website to help clinicians better understand the data that was used to conclude
that there is an increased risk of malignancy in children treated with TNF blockers.7
• October 2009 – Labeling negotiations between the FDA and the sponsors of the TNF
blockers to add new Boxed Warnings for the risk of pediatric malignancies are on-going.
1
Siegel, J. Clinical review of BLA 125057; January 7, 2008.
2
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
DrugSafetyInformationforHeathcareProfessionals/ucm070725.htm
3
http://www.fda.gov/ohrms/dockets/ac/08/minutes/2008-4361m2-Final.pdf
4
Diak P, La Grenade L., Malignancy in Children - FDA Post-marketing safety review. July 2008.
5
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects
/ucm085914.htm
6
FDA: Cancer Warnings Required for TNF Blockers. Accessed September 22, 2009. URL:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm
7
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
DrugSafetyInformationforHeathcareProfessionals/ucm180694.htm
3

5. PEDIATRIC LABELING
8
Please see Appendix I for a complete listing of the relevant pediatric labeling for adalimumab.
Below is a brief summary of the pediatric labeling.
Warnings
• Immunizations should be brought up to date prior to initiating adalimumab therapy in JIA
patients.
Adverse Reactions
• Immunogenicity was identified in 16% of the JIA patients treated with adalimumab.
• Juvenile Idiopathic Arthritis Clinical Studies: In general, the adverse reactions in pediatric
patients were similar in frequency and type to those seen in adult patients
• Pregnancy Category B
METHODS AND MATERIALS
INTRODUCTION
The voluntary or spontaneous reporting of adverse events from healthcare professionals and
consumers in the U.S reflects underreporting and also duplicate reporting. For any given report,
there is no certainty that the reported suspect product(s) caused the reported adverse event(s).
The main utility of a spontaneous reporting system, such as AERS, is to provide signals of
potential drug safety issues. Therefore, crude counts from AERS cannot be used to calculate
incidence rates or estimates of drug risk for a particular product or used for comparing drug risk
between drugs.
AERS SEARCH CRITERIA
The Adverse Event Reporting System (AERS) database was searched using the drug name
adalimumab (verbatim and trade names) to obtain crude counts of adverse events associated with
the use of adalimumab from market approval (December 31, 2002) to the data lock date of July 7,
2009 (see Table 1 in Section 3.1).
A detailed (case by case) review of the serious9
reports (n=128) reported with the use of
adalimumab in pediatric patients was performed. Figure 1 below is a diagram showing the
evaluation process for selecting the eligible reports for the case series (n=109), which was used to
characterize the post-marketing adverse events associated with the pediatric use of adalimumab.
8
Humira (adalimumab) prescribing information; Abbott, Inc. August 2008.
9
Serious adverse drug experiences per regulatory definition (CFR 314.80) include outcomes of death, life-
threatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious
important medical events.
4

6. Figure 1. Diagram of AERS Case Selection for Adalimumab Pediatric Use
(12/31/2002-7/7/2009)
Serious Reports Meeting AERS
Search Criteria (n= 128)
Non-duplicated Serious Reports
(n=114)
Duplicate Reports
(n=14)
Eligible Serious Reports for
Case Series (n=109)
Excluded Reports-- adverse event
reported prior to initial
adalimumab use (n=2)
Excluded Reports-- miscoded and
no adverse event reported with
adalimumab use (n=3)
AERS RESULTS FOR ADALIMUMAB
CRUDE COUNTS OF ALL AERS REPORTS: TABLE 1
Table 1: Crude counts1
of AERS Reports from All Sources
From Approval Date 12/31/2002 to 07/07/2009
All reports (US)2
Serious3
(US) Death (US)
Adults (≥ 17 yrs.) 34,240 (27,759) 10,627 (4,410) 1,331 (539)
Pediatrics (0-16 yrs.) 471 (412) 128 (79) 4 (2)
Age unknown (Null values) 8,141 (6,718) 1,938 (659) 283 (117)
Total 42,852 (34,889) 12,693 (5,148) 1,618 (658)
1
May include duplicates
2
US counts in parentheses
3
Serious adverse drug experiences per regulatory definition (CFR 314.80) include outcomes of death, life-
threatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious important
medical events.
5

7. Figure 1: Number of pediatric AERS reports by year from US approval date (12/31/2002)
10 21 28
3
45
213
151
0
50
100
150
200
250
2003 2004 2005 2006 2007 2008 2009
# Peds Reports
CASE CHARACTERISTICS FROM PEDIATRIC SAFETY REVIEW (TABLE 2)
Table 2 : Characteristics of Serious Pediatric Cases (December 31, 2002 through July 7, 2009) n=109
Gender [ n= 98] Male: (52)
Female: (46)
Age [n=109] 0- <1 month (34)
1 month <2 yrs (4)
2-5 yrs (4)
6-11 yrs (13)
12-16 yrs (54)
Mean (9 years); Median (12 years); Range (0-16 years)
Origin [n=109] US (66), Foreign (43)
Report Year [n=109] 2003(1), 2004 (3), 2005 (4), 2006 (3), 2007 (15), 2008 (50), 2009 (33)
Report Type [n=109] Expedited 15-day (94), Periodic (13), Direct (2)
Time to onset from start of adalimumab
therapy [n=55]
Mean (5 months) , Median (2 months)
Range: (1 day – 3.75 years)
Reason for Use [n=108] Crohn’s disease (42), JIA (20), Ulcerative colitis (3)Uveitis (2),
Psoriasis (2), Psoriatic arthritis (1), Vasculitis (1)
In utero exposure (37)
Outcomes10
[n=109]
Death (4), Hospitalization (60), Congenital Anomaly (17), Life-
Threatening (2), Disability (2), Other Medically Serious (53)
DISCUSSION/SUMMARY OF PEDIATRIC CASES
PEDIATRIC DEATHS (N= 4)
Four pediatric cases reported an outcome of death with exposure to adalimumab. Three of the
four cases involved neonates following in utero adalimumab exposure. Respiratory disorders
were reported as the cause of death in the three newborn infants. The remaining death case
10
Cases may have more than one outcome reported
6

8. involved a 16 year old who developed respiratory failure secondary to pneumonia. The causality
assessments of the pediatric death cases were confounded by the use of concomitant the
(i.e. alcohol, tobacco, corticosteroids, cyclosporine, penicillin, and sedation/anesthetic
medications drug delivery) and/or underlying disease (i.e. Crohn’s disease, RA), or provi
insufficient evidence t
rapies
ded
o conclude a causal association between the events and the use of
summary and a causality assessment for each pediatric death case are located in
Appendix II.
ty
2.1,
cy
reported
s associated with adalimumab use in pediatric patients in the
AERS database as of July 7, 2009.
.
patients
to
.
nd
for adalimumab adequately warns of
e potential risk of serious infections in pediatric patients.
adalimumab therapy.
**A narrative
NON-FATAL SERIOUS ADVERSE EVENTS (N=105)
OPT requested that we specifically address serious infections, malignancies, and hypersensitivi
reactions in our review of non-fatal AERS cases. These events are reviewed in sections 4.
4.2.2, and 4.2.3, respectively. For completeness, we have also provided a synopsis of the
remaining reported non-fatal serious adverse events including, disease flares, adverse pregnan
outcomes, and other miscellaneous events in sections 4.2.4, 4.2.5, and 4.2.6, respectively. A
graphical comparison by system organ class (SOC) and the top 25 preferred terms (PT)
with adalimumab use in adults and pediatric patients can be found in the Appendix IV.
Of note, DPV II was also requested to highlight cases of CPK elevation as approximately 15% of
the children in the JIA clinical trial developed mild-to-moderate elevations of CPK.11
However,
there were no cases of CPK elevation
1.1.1 SERIOUS INFECTIONS (N=24)
Twenty four cases reported serious infections (TB – 3, Staph – 2, Cellulitis – 2, Viral – 2, H
Zoster – 1, CMV – 1, C. difficile – 1, pneumonia – 1, Candida – 1, keratitis – 1, Unknown
etiology – 9). Of the 24 cases, 15 cases were of U.S. origin and 9 cases were foreign. Serious
infections were reported more in males (15) than females (9). The median age of the
was 11 years old with an age range of 2 to 16 years. Eleven cases reported the use of
concomitant immunosuppressants (methotrexate, 6-MP, azathioprine, mycophenolate, and
corticosteroids), which are labeled for infections. Time to onset of infection ranged from 1 day
19 months after initiating adalimumab with a median of 60 days. The reported indications for
adalimumab use included Crohn’s disease (11), JIA (8), ulcerative colitis (3), and uveitis (2).
Hospitalization was the outcome in 21 cases, 1 case reported life threatening outcomes, and 11
cases reported other serious medically significant events.12
Thirteen patients recovered, 4
patients had not recovered, and in the remaining 7 cases, the patient’s recovery was not reported
The contributory role of adalimumab in these 24 serious infection cases could not be excluded
given the plausible temporal association and the immunosuppressive pharmacologic mechanism
of adalimumab. The risk of serious infections is found in the Boxed Warnings, the Warnings a
Precautions, and the Adverse Reactions sections of the adalimumab label. Also included are
recommendations for not starting adalimumab during active infection and to stop therapy if the
patient develops a serious infection. The pediatric labeling
th
11
Humira (adalimumab) package insert, Abbott; February 2008.
12
Cases may have more than one outcome listed.
7

9. 1.1.2 MALIGNANCIES (N=2)
Lymphoma was reported in two female pediatric patients. Prior to the diagnosis of malignanc
both cases reported an approximately 10 year history of immunosuppressant use (infliximab,
etanercept, abatacept, rituximab, anakinra, cyclophosphamide, rituximab, prednisone, and
methotrexate), which are labeled for malignancy (non-age specific). In the first case, a 10 year-
old developed Hodgkin’s lymphoma stage IIA while receiving adalimumab for 2.4 years and
methotrexate for 3.7 years for JIA. Systemic JIA was diagnosed when the patient was 1 year old.
The patient received chemotherapy for this newly diagnosed lymphoma but the outcome was n
reported. In the second case, the diagnosis of malignancy did not occur while the patient was
receiving adalimumab. While receiving abatacept therapy for vasculitis, a 16 year old was
diagnosed with lymphomatoid papulosis and lymphoma. Previously, the patient had received 1
months of adalimumab therapy with the last dose of adalimumab given 19 months prior to the
diagnosis of lymphoma. Prior use of methotrexate, rituximab, etanercept, infliximab,
azathioprine, cyclophosphamide, and prednisolone was also reported. The type of lymphoma
not reported
y,
ot
4
was
. The patient received chemotherapy for the lymphoma but the outcome was not
e since the medications were given over a 10 year
3 for
e TNF blockers).
vents.16
reported.
In these two cases, it is possible that the lymphomas were associated with any or all of the
reported immunosuppressive medications. It is not possible to determine which medication was
more likely to be associated with the outcom
period, and are all labeled for malignancy.
Based on a separate drug class review of the TNF blockers, the FDA has concluded that there is
an increased risk of lymphoma and other cancers associated with the use of TNF blockers in
children and adolescents.13,14
The Warnings section of the current adalimumab label describes
the increased observance of malignancies found in the adult clinical trials of the TNF blockers.
The Division of Anesthesia, Analgesia, and Rheumatology Products is currently working with the
sponsors to update all the TNF blocker labels to include a Boxed Warning for an increased risk of
malignancy in children. The pending changes to the adalimumab label will adequately warn of an
increased risk of malignancy in pediatric patients treated with TNF blockers (see Section 1.
the regulatory history of the pediatric malignancy safety concern with th
1.1.3 HYPERSENSITIVITY/INJECTION SITE REACTIONS (N=7)
Seven cases reported hypersensitivity or injection site reactions. All the reported events occurred
within one month of initiating adalimumab therapy and provided a plausible temporal association
with adalimumab. The reported events included injection site pain (3), diffuse swelling (2),
pyrexia (2), neck swelling (1), head to toe rash (1), difficulty opening mouth (1), weight gain (1),
injection site bruising (1), dizziness (1), and nausea (1).15
None of the cases reported events of
anaphylaxis or the formation of autoantibodies. Five cases were of U.S. origin and 2 cases were
foreign. The cases were reported more often in males (4) than females (3). The median age of
the patients was 13 years old with an age range of 5 to 16 years. The reported indications for
adalimumab use included Crohn’s disease (5) and JIA (2). Hospitalization was the outcome in 4
cases, 1 case reported disability, and 4 cases reported other serious medically significant e
13
Diak P, La Grenade L., Malignancy in Children - FDA Post-marketing safety review. July 2008.
14
FDA: Cancer Warnings Required for TNF Blockers. Accessed September 22, 2009. URL:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm
15
Cases may have more than one event reported
16
Cases may have more than one outcome listed.
8

10. Three cases reported discontinuation of adalimumab therapy, 3 cases reported continued
treatment, and the remaining case did not provide information regarding the continuation of
are
unexpected with the use of adalimumab and is adequately labeled for the pediatric population.
f
reports of
treated
s that the AERS cases of disease flare and drug ineffectiveness were possibly
d
h
ing 4 cases did not
t use of
provided
that
immunogenicity could have played a role in the reports of drug ineffectiveness.
adalimumab therapy.
In these seven cases, it is possible that the adverse events were associated with adalimumab based
on the plausible temporal associations reported. Hypersensitivity and injection site reactions
included in the pediatric labeling for adalimumab. The risk of these types of reactions is not
1.1.4 DISEASE FLARES/DRUG INEFFECTIVE (N=22)
Occurrences of disease flares and reports of drug ineffectiveness are expected in patients with
autoimmune diseases such as Crohn’s disease, JIA, and psoriasis. In the JIA clinical trial, 43% o
the pediatric patients who received adalimumab without methotrexate experienced disease flare
and 37% experienced flares with concomitant methotrexate.17
Disease flare and immunogenicity
are included in the pediatric labeling for adalimumab. A possible explanation for the
drug ineffectiveness is that the pediatric patients treated with adalimumab developed
immunogenicity. Another possibility for the reports of drug ineffectiveness is that the
patient did not respond to adalimumab therapy. It is difficult to assess efficacy from
postmarketing reports; the main utility of AERS is to provide signals of potential drug safety
issues. It appear
disease related.
Twenty two AERS cases reported disease flares or drug ineffectiveness. Crohn’s disease (18)
was the listed indication for adalimumab use in the majority of the cases followed by JIA (2) an
psoriasis (2). Crohn’s disease and psoriasis are off-label uses for adalimumab in the pediatric
population. Fifteen cases were of U.S. origin and 7 cases were foreign. The cases were reported
more often in females (15) than males (7). The median age of the patients was 15 years old wit
an age range of 13 years to 16 years. Hospitalization was the outcome in 16 cases and 7 cases
reported other serious medically significant events.18
Nine cases reported discontinuation of
adalimumab therapy, 9 cases reported continued treatment, and the remain
provide information regarding the continuation of adalimumab therapy.
Nine cases reported the use of concomitant immunosuppressants (methotrexate, azathioprine,
tacrolimus, and corticosteroids). The remaining 13 cases did not report the concomitan
immunosuppressants, which can potentially increase the rate of immunogenicity with
adalimumab. Immunogenicity has been shown to be higher in JIA patients treated with
adalimumab monotherapy (26%) compared to patients receiving concomitant methotrexate
(6%).13
In addition, adalimumab patients with antibodies to adalimumab had lower efficacy
results than in patients without antibodies.19
Although none of these 22 pediatric cases
information regarding the development of antibodies to adalimumab, it is possible
1.1.5 IN UTERO EXPOSURE/ADVERSE PREGNANCY OUTCOMES (N=34)
Thirty four cases reported non-fatal adverse pregnancy outcomes with in utero exposure to
adalimumab.20
Seventeen cases reported congenital anomalies, which included reports of
17
Humira (adalimumab) package insert, Abbott; February 2008.
18
Cases may have more than one outcome listed.
19
Humira (adalimumab) package insert, Abbott; February 2008.
20
Three additional in utero exposure cases were reported with an outcome of pediatric death (Section 4.1)
9

11. Down’s syndrome (2), hip dysplasia (2), cleft lip (1), ectopic testicle (1), hypospadias (1),
inguinal hernia (1), microcephaly (1), cyanosis (1), craniosynostosis (1), hexadactyly (1), sacral
dimple (1), atrial septal defect (1), ventricular septal defect (1), bicuspid aortic valve (1), and
cardiomegaly (1). Of the remaining 17 cases, the reported adverse pregnancy outcomes included
premature baby (8), neonatal infections {herpes encephalitis-1, meningitis-1, RSV-1}(3),
in
s not
,
e in 5 cases, gestational diabetes in
ablishing
as
vious OSE
dy
s due to adalimumab. However, there have been no well-controlled
e
mab
a
f non-adalimumab pregnancies) and within the expected range in the general
neonatal aspiration (2), neonatal lupus (1), hypoxia (1), apnea (1), and jaundice (1).
In utero exposure to adalimumab was reported during preconception in 16 cases, 1st
trimester
19 cases, 2nd
trimester in 11 cases, 3rd
trimester in 8 cases, and the time of exposure wa
provided in 8 cases.21
Nine of the 34 cases reported the maternal use of concomitant
immunosuppressants (i.e. corticosteroids-6, methotrexate-2, azathioprine-1, and leflunomide-1).
The reported indications for maternal use of adalimumab included Crohn’s disease (15), RA (12)
ulcerative colitis (2), psoriasis (1), psoriatic arthritis (1), and ankylosing spondylitis (1); 2 cases
did not report this information. Twenty six cases were of U.S. origin and 8 cases were foreign.
Pertinent maternal medical history reports included tobacco us
2 cases, marijuana use in 2 cases, and alcohol use in 1 case.
These cases are difficult to assess due to the confounding factors such as the maternal medical
history (i.e. tobacco and alcohol use), underlying autoimmune diseases (i.e. Crohn’s disease and
RA), and the use of concomitant immunosuppressants. A significant limitation of AERS data is
that the number of pregnant women exposed to adalimumab is unknown. Therefore, est
an increased risk compared to the background rate is not attainable due to the lack of a
denominator. Overall, no consistent pattern of adverse pregnancy outcomes was observed.
Given the confounding factors and the lack of information in many of these cases, there w
insufficient evidence to conclude a causal association between the events and the use of
adalimumab therapy during pregnancy. A similar conclusion was made in a pre
review from February 2005 on pregnancy outcomes with the TNF blockers.22
Adalimumab is Pregnancy Category B. An embryo-fetal perinatal developmental toxicity stu
was performed in cynomolgus monkeys at supratherapeutic human dosages and revealed no
evidence of harm to the fetuse
studies in pregnant women.
A disease based pregnancy registry has been established by the Organization of Teratology
Information Specialists (OTIS) for medications, including adalimumab, used to treat autoimmune
diseases. The conclusions that will be generated, once a sufficient sample size is enrolled in th
OTIS registry, may provide meaningful information regarding the reproductive risks of these
drugs. As of December 8, 2008, preliminary results from the OTIS registry for the adalimu
cohort (n=34) have not shown an increased reproductive risk for spontaneous abortion (5),
stillbirth (0), congenital defect (2), and preterm delivery (4). Pregnancy outcomes for the
adalimumab cohort were similar to two comparison groups (i.e. a disease-matched group and
healthy group o
population.23
21
The use of adalimumab may have been reported during multiple trimesters.
22
Kwon H. FDA Outcomes of Pregnancy with infliximab, etanercept, and adalimumab. OSE Post-
marketing safety review. February 2005.
23
Johnson D., Jones K., Chambers C. Pregnancy Outcomes in Women Exposed to Adalimumab: OTIS
Autoimmune Diseases in Pregnancy Project. Accessed September 22, 2009. http://www.otispregnancy.org
10

12. Given the uncertainty of an association between adalimumab and adverse pregnancy outcomes,
the adalimumab label adequately provides caution that adalimumab “should be used during
e
a
ediatric risk for these events with abatacept use. Chest pain, which
s unlabeled adverse events in this section that suggested an
association to adalimumab.
individual miscellaneous cases are displayed along with the labeling status of
r
maining cases that reported unlabeled events were either
d the use of adalimumab therapy
(i.e. adverse pregnancy outcomes).
g labeling changes for pediatric malignancies, the adalimumab
RECOMMENDATIONS
No labeling changes regarding the pediatric patients are recommended at this time.
pregnancy only if clearly needed.”
1.1.6 OTHER SERIOUS MISCELLANEOUS EVENTS (N=16)
There were 16 cases of other serious miscellaneous events (chest pain-3, hypertension-1,
dizziness-1, seizure-1, syncope-1, psoriasis-1, purpura-1, increased hepatic enzymes-1,
hemoglobin decreased-1, muscle spasms-1, back pain-1, uveitis-1, diabetes mellitus-1, lupus-lik
syndrome-1). The miscellaneous events were predominately single case reports precluding
meaningful evaluation of the p
is already included in the label (non-age specific), was the only event reported more than once.
There was no pattern of seriou
In Appendix III, the
the reported adverse events.
CONCLUSION
No new safety signals emerged as part of this review. The reported adverse events in AERS fo
the pediatric patients appear to be similar to those seen in the JIA clinical trial and in the adult
population. Many of the events reported in pediatric patients are already included in the pediatric
labeling for adalimumab (i.e. serious infection, malignancy, hypersensitivity/injection site
reactions, and disease flares). The re
confounded by concomitant medications and/or underlying disease, or provided insufficient
evidence to conclude a causal association between the events an
With the addition of the pendin
label addresses all of the safety issues discussed in this review.
11

13. APPENDIX I Adalimumab Pediatric Labeling24
Warnings: Immunizations - 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.
Adverse Reactions: Immunogenicity - In patients with juvenile idiopathic arthritis, adalimumab antibodies
were identified in16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the
incidence was 6% compared to 26% with HUMIRA monotherapy.
Juvenile Idiopathic Arthritis Clinical Studies: In general, the adverse reactions in pediatric patients were
similar in frequency and type to those seen in adult patients [see Warnings and Precautions (5) and other
sections under Adverse Reactions (6)]. Important findings and differences from adults are discussed in the
following paragraphs.
HUMIRA has been studied in 171 pediatric patients, aged 4 to 17 years of age, with polyarticular juvenile
idiopathic arthritis. 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
MTX in the first 16 weeks of treatment. The types of infections reported in juvenile idiopathic arthritis
patients were generally similar to those commonly seen in outpatient JIA populations. 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 juvenile idiopathic arthritis exposed to HUMIRA alone; liver function tests
(LFT) elevations were more frequent among those treated with the combination of HUMIRA and MTX. In
general, these elevations did not lead to discontinuation of HUMIRA treatment.
In the juvenile idiopathic arthritis 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.
Pregnancy: Pregnancy Category B - An embryo-fetal perinatal developmental toxicity study has been
performed in cynomolgus monkeys at dosages up to 100 mg/kg (266 times human AUC when given 40 mg
subcutaneously with methotrexate every week or 373 times human AUC when given 40 mg subcutaneously
without methotrexate) and has revealed no evidence of harm to the fetuses due to adalimumab. There are,
however, 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.
24
Humira (adalimumab) prescribing information; Abbott, Inc. August 2008.
12

14. APPENDIX II
Narrative Summary of the Pediatric Death Cases through 7/7/09 (n=4)
1) Fetal Distress Syndrome (ISR # 6220490, Foreign): A newborn infant with in utero exposure
to adalimumab during the first, second, and third trimesters experienced acute fetal distress and
died. The infant was born via Cesarean section at 39 weeks and six days gestation. No
congenital malformation or neonatal pathology was found. Ultrasonographies performed at 12
weeks, 25 weeks, 31 weeks, and 36 weeks were unremarkable. Neonatal birth weight was 3700
g, length was 50 cm, sex was female, cranial perimeter was 38 cm, Apgar score at one minute
was 0 and at five minutes was 0. The infant was transferred to the NICU. On an unreported date,
the infant died of acute fetal distress. The infant's mother received sedation and anesthetic
medications during delivery (drug names not reported). The infant’s mother was 25 years old.
No maternal medical problems or complications during delivery or postpartum were noted. The
infant’s mother had a medical history of smoking 20 cigarettes per day and received adalimumab
and corticosteroids for the treatment of Crohn’s disease; both medications were started during the
first trimester. Corticosteroids are Pregnancy Category D when used during the first trimester.25
Reviewer’s comment: The mother’s concomitant use of corticosteroids, sedation and anesthetic
medications during delivery, and smoking history confounded the causality assessment of this
case.
2) Hypoxia (ISR # 4741573, Domestic): A newborn infant with in utero exposure to adalimumab
during preconception experienced hypoxia and died. The infant’s mother was 39 years old when
she became pregnant. She had discontinued adalimumab therapy for rheumatoid arthritis four
months prior to conception. During delivery, the infant’s mother received penicillin to treat a
Group B Streptococcal infection. Consequently, the infant’s mother experienced a severe
anaphylactic reaction to penicillin and required treatment with epinephrine. Upon delivery the
newborn was hypoxic and died. No other case details were reported.
Reviewer’s comment: The adverse event in this case was unlikely related to adalimumab given
that adalimumab was discontinued four months prior to conception and has a mean terminal
half-life of 2 weeks.26
The adverse events reported in this case were likely related to the mother’s
anaphylactic reaction to penicillin.
3) Pulmonary Malformation (ISR 5135851, Domestic – OTIS Pregnancy Registry): A newborn
infant with in utero exposure to adalimumab during preconception through the first trimester
experienced underdeveloped lungs and died. The infant was prematurely born via emergency
Cesarean section at 28 weeks gestation. The infant had to be resuscitated and died 8.5 hours after
birth. The underdeveloped lungs were reported as a congenital anomaly. The infant’s mother
was 22 years old while pregnant and received sedation and anesthetic medications during delivery
(drug names not provided). The infant’s mother had a history of tobacco and alcohol use and
received adalimumab and calcipotriene solution therapies during the first trimester of the
pregnancy for psoriasis.
Reviewer’s comment: The concomitant use of alcohol, tobacco, and calcipotriene while pregnant
confounded the causality assessment of this case. The patient’s premature birth at 28 weeks
provides a plausible explanation for the origin of the underdeveloped lungs and death.
25
Briggs GB, Freeman RK, Summer JY. Drugs in Pregnancy and Lactation. 8th ed. Philadelphia PA:
Lippincott Williams & Wilkins; 2008.
26
Humira (adalimumab) package insert, Abbott; February 2008.
13

15. 4) Pneumonia (ISR # 5968876, Foreign): A 16 year old male was diagnosed with interstitial
pneumonia, pyrexia, productive cough, and worsening dyspnea after he received approximately
11 months of adalimumab therapy for JIA. The patient was treated with antibiotics while
hospitalized; however, his symptoms worsened and he died nine days after being admitted. The
patient died from respiratory failure. The etiology of the infection was not determined; cultures
were negative with no evidence of fungal infections or tuberculosis. During the hospitalization,
the patient experienced laboratory abnormalities associated with macrophage activation
syndrome, including increased ferritin, increased liver enzymes, hyperlipidemia, and
pancytopenia. The reporting physician felt that the development of macrophage activation
syndrome might have served as a contributing factor in the patient’s death. An autopsy was not
performed. Concomitant medication included cyclosporine (indication not provided), which is
labeled for serious infections.
Reviewer’s comment: The causality assessment of the patient’s death in this case was
confounded by the use of concomitant medication labeled for infections and the development of
macrophage activation syndrome, which is associated with JIA.27
The events of fever and
pneumonia were possibly related to adalimumab and cyclosporine. Adalimumab is labeled for
the risk of serious infection in the boxed warnings.
27
Villanueva J, Lee S, Giannini EH, Graham T, Passo M, Filipovich A; Grom A. Natural killer cell
dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage
activation syndrome. Arthritis Res Ther. 2005;7(1):R30-37.
14

16. 15
APPENDIX III
Table 3. Summary of Other Serious Miscellaneous Cases in AERS through 7/7/09 (n=16)
ISRNUM
Age
(yrs)
Gender Indication Adverse Event Labeled Term
Cardiac Disorders (4)
6061322 15 Female Crohn’s disease Hypertension Yes
6092504 13 Female Crohn’s disease Chest pain Yes
5754242 12 Female Crohn’s disease Chest pain Yes
6230242 14 Female JIA Chest pain Yes
Nervous System Disorders (3)
6078221 12 Male Crohn’s disease Dizziness Yes
6120880 16 Female JIA Seizure28
none
6106232 15 Male JIA Syncope Yes
Skin Disorders (2)
5389744 13 Male Crohn’s disease Psoriasis (new-onset) Pending29
5963134 12 Male Not reported Purpura Bruising
Investigations (2)
6223731 16 Male Psoriasis
Increased hepatic
enzymes
Yes
5731570 7 Male Crohn’s disease Hemoglobin decreased Pancytopenia
Musculoskeletal Disorders (2)
5175238 11 Male JIA Muscle spasms Yes
5994403 16 Male Crohn’s disease Back pain Yes
Eye Disorders (1)
4684902 16 Female JIA Uveitis Cataract
Metabolism Disorders (1)
5653658 12 Female JIA Diabetes mellitus none
Immune System Disorders (1)
5901735 10 Female Crohn’s disease Lupus-like syndrome Yes
28
The patient had uncontrolled diabetes that was reported to be the suspected root cause of the event.
29
Psoriasis will be added to the Adverse Reactions section per FDA’s public communication. Accessed
September 22, 2009. URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety
InformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174474.htm

17. APPENDIX IV30
Top 25 Serious Preferred Terms in Pediatrics from approval through July 7, 2009
2
2
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
5
8
9
10
14
16
26
0 5 10 15 20 25 30
Anaemia
Cellulitis
CRP Increased
Chest Discomfort
Diarrhoea
Dizziness
Headache
Hodgkin's stage II
RBC Sed Rate Increased
Sepsis
Abdominal Pain
Anaphylactic Reaction
Chest Pain
Convulsion
Dyspnoea
Neonatal Aspiration
Rash
Small For Dates Baby
Psoriasis
Pyrexia
Hodgkin's Disease
Drug Ineffective
Premature Baby
Crohn's Disease
Exposure in Pregnancy
PreferredTerms(PT)
Number of events in AERS
30
Graphs in the Appendix IV are based on AERS crude counts, duplicates have not been reconciled; more than one event may be reported in a case
16

18. Serious adverse events by MedDRA SOC reported in Pediatrics
from approval through July 7, 2009
1
3
4
4
4
4
5
5
6
7
7
10
14
14
15
16
18
18
19
26
34
35
40
0 5 10 15 20 25 30 35 40
Psychiatric
Social Circumstances
Blood
Eye
Hepatobiliary
Immune System
Renal
Vascular
Cardiac
Metabolism
Surgical
Musculoskeletal
Nervous System
Skin
Neoplasms
Investigations
Congenital, familial & genetic
Pregnancy
Respiratory
Infections
Gastrointestinal
Injury
General Disorders
SystemOrganClass(SOC)
Number of events in AERS
17

19. 18
Top 25 serious Preferred Terms in Adults from approval through July 7, 2009
218
221
222
224
232
239
240
247
252
253
272
272
280
288
326
333
353
353
367
400
418
446
457
541
614
0 100 200 300 400 500 600 700
Anaemia
Urinary Tract Infection
Cough
Chest Pain
Myocardial Infarction
Fatigue
Malaise
Sepsis
Crohn'S Disease
Weight Decreased
Headache
Oedema Peripheral
Asthenia
Abdominal Pain
Drug Ineffective
Nausea
Rheumatoid Arthritis
Vomiting
Pain
Diarrhoea
Fall
Arthralgia
Dyspnoea
Pyrexia
Pneumonia
PreferredTerms(PT)
Number of events in AERS

20. 19
Serious adverse events by MedDRA SOC reported in Adults
from approval through July 7, 2009
22
64
69
110
122
245
246
381
439
465
539
566
620
763
840
1073
1321
1341
1403
1526
1820
1852
2194
2224
3402
3543
0 500 1000 1500 2000 2500 3000 3500 4000
Congenital, Familial & Genetic
Endocrine
Social Circumstances
Pregnancy
Ear
Reproductive System
Immune System
Hepatobiliary
Eye
Psychiatric
Metabolism
Renal
Blood
Surgical
Vascular
Cardiac
Neoplasms
Skin
Injury
Investigations
Respiratory
Nervous System
Musculoskeletal
Gastrointestinal
General Disorders
Infections
SystemOrganClass
Number of events in AERS