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 adult patients with CD with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In the Phase 3 trial of HUMIRA 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 HUMIRA (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of HUMIRA-treated patients and 1.0% 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 Ps 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. In controlled trials of HUMIRA (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 HUMIRA-treated subjects and 0.6% of control-treated subjects. In controlled trials of HUMIRA (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of HUMIRA-treated patients and 2.4% of control-treated patients. Immunogenicity 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 RA patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) 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 lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown. In patients with polyarticular JIA who were 4 to 17 years of age, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with HUMIRA monotherapy. In patients with polyarticular JIA who were 2 to <4 years of age or 4 years of age and older weighing <15 kg, adalimumab antibodies were identified in 7% (1 of 15) of HUMIRA-treated patients, and the one patient was receiving concomitant MTX. In patients with AS, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with RA. In patients with PsA, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA. In adult patients with CD, the rate of antibody development was 3%. In pediatric patients with Crohn’s disease, the rate of antibody development in patients receiving HUMIRA was 3%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 32% of total patients studied), the immunogenicity rate was 10%. In patients with moderately to severely active UC, the rate of antibody development in patients receiving HUMIRA was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 25% of total patients studied), the immunogenicity rate was 20.7%. In patients with Ps, 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 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps 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. In subjects with moderate to severe HS, the rate of anti-adalimumab antibody development in subjects treated with HUMIRA was 6.5%. However, because of the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among subjects who stopped HUMIRA treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to < 2 mcg/mL (approximately 22% of total subjects studied), the immunogenicity rate was 28%. In patients with non-infectious uveitis, anti-adalimumab antibodies were identified in 4.8% (12/249) of patients treated with adalimumab. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 23% of total patients studied), the immunogenicity rate was 21.1%. Using an assay which could measure an anti-adalimumab antibody titer in all patients, titers were measured in 39.8% (99/249) of non-infectious uveitis patients treated with adalimumab. No correlation of antibody development to safety or efficacy outcomes was observed. The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab or titers, and are highly dependent on the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading. Other Adverse Reactions Rheumatoid Arthritis Clinical Studies 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 Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) HUMIRA 40 mg subcutaneous Every Other Week (N=705) (N=690) 17% 11% 7% 13% 9% 6% 9% 7% 8% 4% 8% 6% 7% 7% 4% 5% Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection Sinusitis Flu syndrome Gastrointestinal Nausea Abdominal pain Laboratory Tests* Laboratory test abnormal Hypercholesterolemia Hyperlipidemia (continued) Placebo Table 1. continued HUMIRA 40 mg subcutaneous Every Other Week (N=705) Placebo (N=690) Laboratory Tests* (continued) Hematuria 5% 4% Alkaline phosphatase increased 5% 3% Other 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 European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated patients in the polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) were similar in frequency and type to those seen in adult patients [see Warnings and Precautions and Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs. In Study JIA-I, HUMIRA was studied in 171 patients who were 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, and 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. In Study JIA-I, 45% of patients experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in polyarticular JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in patients receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment. In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in approximately 6% of patients and included primarily localized allergic hypersensitivity reactions and allergic rash. In Study JIA-I, 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 patients treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. 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. In Study JIA-II, HUMIRA was studied in 32 patients who were 2 to <4 years of age or 4 years of age and older weighing <15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in patients 4 to 17 years of age with polyarticular JIA. In Study JIA-II, 78% of patients experienced an infection while receiving HUMIRA. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of patients receiving HUMIRA in the study and included dental caries, rotavirus gastroenteritis, and varicella. In Study JIA-II, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity. Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebocontrolled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two 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. Adult Crohn’s Disease Clinical Studies HUMIRA has been studied in 1478 adult patients with Crohn’s disease (CD) in four placebocontrolled and two open-label extension studies. The safety profile for adult patients with CD treated with HUMIRA was similar to the safety profile seen in patients with RA. Pediatric Crohn’s Disease Clinical Studies HUMIRA has been studied in 192 pediatric patients with Crohn’s disease in one double-blind study (Study PCD-I) and one open-label extension study. The safety profile for pediatric patients with Crohn’s disease treated with HUMIRA was similar to the safety profile seen in adult patients with Crohn’s disease. During the 4 week open label induction phase of Study PCD-I, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (6% and 5%, respectively). A total of 67% of children experienced an infection while receiving HUMIRA in Study PCD-I. These included upper respiratory tract infection and nasopharyngitis. A total of 5% of children experienced a serious infection while receiving HUMIRA in Study PCD-I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis. In Study PCD-I, allergic reactions were observed in 5% of children which were all nonserious and were primarily localized reactions. Ulcerative Colitis Clinical Studies HUMIRA has been studied in 1010 patients with ulcerative colitis (UC) in two placebocontrolled studies and one open-label extension study. The safety profile for patients with UC treated with HUMIRA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies. The safety profile for subjects with Ps treated with HUMIRA was similar to the safety profile seen in subjects with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps subjects, HUMIRA-treated subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%). Hidradenitis Suppurativa Clinical Studies HUMIRA has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo-controlled studies and one open-label extension study. The safety profile for subjects with HS treated with HUMIRA weekly was consistent with the known safety profile of HUMIRA. Flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from HUMIRA treatment following the primary efficacy timepoint in two studies. Uveitis Clinical Studies HUMIRA has been studied in 464 patients with uveitis (UV) in placebo-controlled and openlabel extension studies. The safety profile for patients with UV treated with HUMIRA was similar to the safety profile seen in patients with RA. Postmarketing Experience The following adverse reactions have been identified 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 General disorders and administration site conditions: Pyrexia Hepato-biliary disorders: Liver failure, hepatitis Immune system disorders: Sarcoidosis Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia Vascular disorders: Systemic vasculitis, deep vein thrombosis DRUG INTERACTIONS Methotrexate HUMIRA has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX. Biological Products 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 regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of HUMIRA with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions. Live Vaccines Avoid the use of live vaccines with HUMIRA [see Warnings and Precautions]. Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for a molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of HUMIRA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. USE IN SPECIFIC POPULATIONS Pregnancy Limited clinical data are available from the Humira Pregnancy Registry. Excluding lost-to-follow-up, data from the registry reports a rate of 5.6% for major birth defects with first trimester use of adalimumab in pregnant women with rheumatoid arthritis (RA), and a rate of 7.8% and 5.5% for major birth defects in the disease-matched and non-diseased comparison groups [see Data]. Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant [see Clinical Considerations]. In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and miscarriage is 15-20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester [see Data]. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to HUMIRA in utero [see Use in Specific Populations]. Data Human Data In a prospective cohort pregnancy exposure registry conducted in the U.S. and Canada between 2004 and 2013, 74 women with RA treated with adalimumab at least during the first trimester, 80 women with RA not treated with adalimumab and 218 women without RA (non-diseased) were enrolled. Excluding lost-to-follow-up, the rate of major defects in the adalimumab-exposed pregnancies (N=72), disease-matched (N=77), and non-diseased comparison groups (N=201) was 5.6%, 7.8% and 5.5%, respectively. However, this study cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Data from the Crohn’s disease portion of the study is in the follow-up phase and the analysis is ongoing. In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease treated with HUMIRA, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth. The last dose of HUMIRA was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 µg/mL in cord blood, 4.28-17.7 µg/mL in infant serum, and 0-16.1 µg/mL in maternal serum. In all but one case, the cord blood level of adalimumab was higher than the maternal serum level, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum levels at each of the following: 6 weeks (1.94 µg/mL), 7 weeks (1.31 µg/mL), 8 weeks (0.93 µg/mL), and 11 weeks (0.53 µg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth. Lactation Risk Summary Limited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum level. There are no reports of adverse effects of adalimumab on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMIRA and any potential adverse effects on the breastfed child from HUMIRA or from the underlying maternal condition. Pediatric Use Safety and efficacy of HUMIRA in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohn’s disease have not been established. Due to its inhibition of TNFα, HUMIRA administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to HUMIRA in utero suggest adalimumab crosses the placenta [see Use in Specific Populations]. The clinical significance of elevated adalimumab levels in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants. Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Boxed Warning and Warnings and Precautions]. Juvenile Idiopathic Arthritis In Study JIA-I, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age [see Clinical Studies]. In Study JIA-II, the safety profile for patients 2 to <4 years of age was similar to the safety profile for patients 4 to 17 years of age with polyarticular JIA [see Adverse Reactions]. HUMIRA has not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg. The safety of HUMIRA in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions]. Pediatric Crohn’s Disease The safety and effectiveness of HUMIRA for reducing signs and symptoms and inducing and maintaining clinical remission have been established in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate. Use of HUMIRA in this age group is supported by evidence from adequate and well-controlled studies of HUMIRA in adults with additional data from a randomized,