Humira

1 INDICATIONS AND USAGE HUMIRA is a tumor necrosis factor (TNF) blocker 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 r heumatoid a rthritis . ( 1.1 ) Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. ( 1.2 ) Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis . ( 1.3 ) Reducing signs and symptoms in adult patients with active ankylosing spondylitis . ( 1.4 ) Treatment of moderately to severely active Crohn’s disease in adults and pediatric patients 6 years of age and older. ( 1.5 ) Treatment of moderately to severely active ulcerative colitis in adults and pediatric patients 5 years of age and older. ( 1.6 ) Limitations of Use: Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. 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. ( 1.7 ) Treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older. ( 1.8 ) Treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older. ( 1.9 ) 1.1 Rheumatoid Arthritis 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 (DMARDs). 1.2 Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. HUMIRA can be used alone or in combination with methotrexate. 1.3 Psoriatic Arthritis 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. 1.4 Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. 1.5 Crohn’s Disease HUMIRA is indicated for the treatment of moderately to severely active Crohn’s disease in adults and pediatric patients 6 years of age and older. 1.6 Ulcerative Colitis HUMIRA is indicated for the treatment of moderately to severely active ulcerative colitis in adults and pediatric patients 5 years of age and older. Limitations of Use The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to TNF blockers [see Clinical Studies ( 14.7 , 14.8 ) ] . 1.7 Plaque Psoriasis 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 Warnings and Precautions ( 5 ) ] . 1.8 Hidradenitis Suppurativa HUMIRA is indicated for the treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older. 1.9 Uveitis HUMIRA is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older.

2 DOSAGE AND ADMINISTRATION Administer by subcutaneous injection ( 2 ) Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis ( 2.1 ): Adults: 40 mg every other week. Some patients with RA not receiving methotrexate may benefit from increasing the dosage to 40 mg every week or 80 mg every other week. Juvenile Idiopathic Arthritis or Pediatric Uveitis ( 2.2 ): Pediatric Weight 2 Years of Age and Older Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week Crohn's Disease ( 2.3 ): Adults: 160 mg on Day 1 (given in one day or split over two consecutive days); 80 mg on Day 15; and 40 mg every other week starting on Day 29. Pediatric Patients 6 Years of Age and Older : Pediatric Weight Recommended Dosage Days 1 and 15 Starting on Day 29 17 kg (37 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week Ulcerative Colitis ( 2.4 ) : Adults: 160 mg on Day 1 (given in one day or split over two consecutive days), 80 mg on Day 15 and 40 mg every other week starting on Day 29. Discontinue in patients without evidence of clinical remission by eight weeks (Day 57). Pediatric Patients 5 Years of Age and Older : Pediatric Weight Recommended Dosage Days 1 through 15 Starting on Day 29* 20 kg (44 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 8: 40 mg Day 15: 40 mg 40 mg every other week or 20 mg every week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 8: 80 mg Day 15: 80 mg 80 mg every other week or 40 mg every week * Continue the recommended pediatric dosage in patients who turn 18 years of age and who are well-controlled on their HUMIRA regimen. Plaque Psoriasis or Adult Uveitis ( 2.5 ): Adults : 80 mg initial dose, followed by 40 mg every other week starting one week after initial dose. Hidradenitis Suppurativa ( 2.6 ): Adults : ◦ Day 1: 160 mg (given in one day or split over two consecutive days) ◦ Day 15: 80 mg ◦ Day 29 and subsequent doses: 40 mg every week or 80 mg every other week Adolescents 12 years of age and older: Adolescent Weight Recommended Dosage 30 kg (66 lbs) to less than 60 kg (132 lbs) Day 1: 80 mg Day 8 and subsequent doses: 40 mg every other week 60 kg (132 lbs) and greater Day 1: 160 mg (given in one day or split over two consecutive days) Day 15: 80 mg Day 29 and subsequent doses: 40 mg every week or 80 mg every other week 2.1 Recommended Tuberculosis Evaluation Prior to initiating HUMIRA and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions ( 5.1 ) ] . 2.2 Recommended Dosage in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis The recommended subcutaneous dosage of HUMIRA for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) [see Indication and Usage ( 1.1 , 1.3 , 1.4 )] is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with HUMIRA. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of HUMIRA to 40 mg every week or 80 mg every other week. 2. 3 Recommended Dosage in Juvenile Idiopathic Arthritis or Pediatric Patients with Uveitis The recommended subcutaneous dosage of HUMIRA for pediatric patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) or pediatric uveitis [see Indications and Usage ( 1.2 , 1.9 )] , based on weight, is shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with HUMIRA. Pediatric Weight (2 Years of Age and older) Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week HUMIRA has not been studied in patients with polyarticular JIA or pediatric uveitis less than 2 years of age or in patients with a weight below 10 kg. 2. 4 Recommended Dosage in Crohn’s Disease Subcutaneous Adult Dosage Regimen The recommended subcutaneous dosage of HUMIRA for adult patients with moderately to severely active Crohn’s disease (CD) is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) begin a dosage of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with HUMIRA. Azathioprine, 6-mercaptopurine (6-MP) [see Warnings and Precautions ( 5.2 ) ] or MTX may be continued during treatment with HUMIRA if necessary. Subcutaneous Pediatric Dosage Regimen The recommended subcutaneous dosage of HUMIRA for pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease (CD), based on body weight, is shown below: Pediatric Weight Recommended Dosage Days 1 through 15 Starting on Day 29 17 kg (37 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week 2. 5 Recommended Dosage in Ulcerative Colitis Subcutaneous Adult Dosage Regimen The recommended subcutaneous dosage of HUMIRA for adult patients with moderately to severely active ulcerative colitis is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) continue with a dosage of 40 mg every other week. Discontinue HUMIRA in adult patients without evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with HUMIRA. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions ( 5.2 ) ] may be continued during treatment with HUMIRA if necessary. Subcutaneous Pediatric Dosage Regimen The recommended subcutaneous dosage of HUMIRA for pediatric patients 5 years of age and older with moderately to severely active ulcerative colitis, based on body weight, is shown below: Pediatric Weight Recommended Dosage Days 1 through 15 Starting on Day 29* 20 kg (44 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 8: 40 mg Day 15: 40 mg 40 mg every other week or 20 mg every week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 8: 80 mg Day 15: 80 mg 80 mg every other week or 40 mg every week * Continue the recommended pediatric dosage in patients who turn 18 years of age and who are well-controlled on their HUMIRA regimen. 2. 6 Recommended Dosage in Plaque Psoriasis or Adult s with Uveitis The recommended subcutaneous dosage of HUMIRA for adult patients with plaque psoriasis (Ps) or uveitis (UV) [see Indications and Usage ( 1.7 , 1.9 )] is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of HUMIRA in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies. 2.7 Recommended Dosage in Hidradenitis Suppurativa Subcutaneous Adult Dosage Regimen The recommended subcutaneous dosage of HUMIRA for adult patients with moderate to severe hidradenitis suppurativa (HS) is an initial dose of 160 mg (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Begin 40 mg weekly or 80 mg every other week dosing two weeks later (Day 29). Subcutaneous Pediatric Dosage Regimen The recommended subcutaneous dosage of HUMIRA for pediatric patients 12 years of age and older weighing at least 30 kg with moderate to severe hidradenitis suppurativa (HS), based on body weight, is shown below [see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 ) ] : Body Weight of Pediatric Patients (12 years of age and older) Recommended Dosage 30 kg (66 lbs) to less than 60 kg (132 lbs) Day 1: 80 mg Day 8 and subsequent doses: 40 mg every other week 60 kg (132 lbs) and greater Day 1: 160 mg (given in one day or split over two consecutive days); Day 15: 80 mg Day 29 and subsequent doses: 40 mg every week or 80 mg every other week 2.8 General Considerations for Administration HUMIRA is intended for use under the guidance and supervision of a physician. A patient may self-inject HUMIRA or a caregiver may inject HUMIRA using either the HUMIRA Pen or prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. HUMIRA can be taken out of the refrigerator for 15 to 30 minutes before injecting to allow the liquid to come to room temperature. Do not remove the cap or cover while allowing it to reach room temperature. Carefully inspect the solution in the HUMIRA Pen or prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. HUMIRA does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. NOTE: Instruct patients sensitive to latex not to handle the needle cover of the HUMIRA 40 mg/0.8 mL Pen and 40 mg/0.8 mL prefilled syringe because it may contain natural rubber latex [see How Supplied/Storage and Handling ( 16 ) ] . Instruct patients using the HUMIRA Pen or prefilled syringe to inject the full amount in the syringe, according to the directions provided in the Instructions for Use [see Instructions for Use ] . Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions ( 5.1 ) ] Malignancies [see Warnings and Precautions ( 5.2 ) ] Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 ) ] Hepatitis B Virus Reactivation [see Warnings and Precautions ( 5.4 ) ] Neurologic Reactions [see Warnings and Precautions ( 5.5 ) ] Hematological Reactions [see Warnings and Precautions ( 5.6 ) ] Heart Failure [see Warnings and Precautions ( 5.8 ) ] Autoimmunity [see Warnings and Precautions ( 5.9 ) ] Most common adverse reactions (>10%) are: infections (e.g. upper respiratory, sinusitis), injection site reactions, headache and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of subjects treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of subjects receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of subjects who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in subjects with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for subjects taking HUMIRA and 4% for placebo-treated subjects. The most common adverse reactions leading to discontinuation of HUMIRA in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). Infections In the controlled portions of the 39 global HUMIRA clinical trials in adult subjects with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973 HUMIRA-treated subjects versus a rate of 2.9 per 100 patient-years in 4848 control-treated subjects. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions ( 5.1 ) ] . Tuberculosis and Opportunistic Infections In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV that included 24,605 HUMIRA-treated subjects, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113 U.S. and Canadian HUMIRA-treated subjects, the rate of reported active TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions ( 5.1 ) ] . Autoantibodies In the rheumatoid arthritis controlled trials, 12% of subjects treated with HUMIRA and 7% of placebo-treated subjects that had negative baseline ANA titers developed positive titers at week 24. Two subjects out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The subjects improved following discontinuation of therapy. No subjects 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 subjects receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in subjects 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 subjects and 1.5% of control-treated subjects. Since many of these subjects 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 a controlled Phase 3 trial of HUMIRA in subjects with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% of HUMIRA-treated subjects and 1.5% of control-treated subjects (ALT more common than AST); 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. No ALT elevations ≥ 3 x ULN occurred in the open-label study of HUMIRA in subjects with polyarticular JIA who were 2 to <4 years. 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 subjects with Crohn’s Disease with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated subjects and 0.9% of control-treated subjects. In the Phase 3 trial of HUMIRA in pediatric subjects 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 subjects, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these subjects 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 adult subjects with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of HUMIRA-treated subjects and 1.0% of control-treated subjects. In the controlled Phase 3 trial of HUMIRA in subjects with pediatric ulcerative colitis (N=93), which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every week (N=32), following body weight based induction doses of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=30), ALT elevations ≥ 3 X ULN occurred in 1.1% (1/93) of subjects. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in subjects with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated subjects and 1.8% of control-treated subjects. 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 adult subjects with uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and control-treated subjects, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of HUMIRA-treated subjects and 2.4% of control-treated subjects. Other Adverse Reactions Rheumatoid Arthritis Clinical Studies The data described below reflect exposure to HUMIRA in 2468 subjects, 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 subjects received 40 mg HUMIRA every other week [see Clinical Studies ( 14.1 ) ]. Table 1 summarizes reactions reported at a rate of at least 5% in subjects 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 Subjects 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 Placebo (N=705) (N=690) Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection 17% 13% Sinusitis 11% 9% Flu syndrome 7% 6% Gastrointestinal Nausea 9% 8% Abdominal pain 7% 4% Laboratory Tests* Laboratory test abnormal 8% 7% Hypercholesterolemia 6% 4% Hyperlipidemia 7% 5% 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 Less Common Adverse Reactions in Rheumatoid Arthritis Clinical Studies Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in HUMIRA-treated subjects in RA studies (RA-I, RA-II, RA-III, and RA-IV) were: Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomiting Endocrine System: Parathyroid disorder Hemic And Lymphatic System: Agranulocytosis, polycythemia Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema Musculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorder Neoplasia: Adenoma Nervous System: Confusion, paresthesia, subdural hematoma, tremor Respiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion Special Senses: Cataract Thrombosis: Thrombosis leg Urogenital System: Cystitis, kidney calculus, menstrual disorder Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated subjects in the polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) [see Clinical Studies ( 14.2 ) ] were similar in frequency and type to those seen in adult subjects [see Warnings and Precautions ( 5 ) , Adverse Reactions ( 6 ) ] . Important findings and differences from adults are discussed in the following paragraphs. In Study JIA-I, HUMIRA was studied in 171 subjects 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 subjects 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 subjects 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 subjects were generally similar to those commonly seen in polyarticular JIA subjects who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in subjects 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 subjects and included primarily localized allergic hypersensitivity reactions and allergic rash. In Study JIA-I, 10% of subjects treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No subject developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of subjects 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 subjects. CPK concentrations decreased or returned to normal in all subjects. Most subjects were able to continue HUMIRA without interruption. In Study JIA-II, HUMIRA was studied in 32 subjects 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 population was similar to the safety profile seen in subjects 4 to 17 years of age with polyarticular JIA. In Study JIA-II, 78% of subjects 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 subjects 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 subjects 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 subjects with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 subjects with ankylosing spondylitis (AS) in two placebo-controlled studies [see Clinical Studies ( 14.3 , 14.4 )] . The safety profile for subjects with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in subjects with RA, HUMIRA Studies RA-I through IV. Crohn’s Disease Clinical Studies Adults: The safety profile of HUMIRA in 1478 adult subjects with Crohn’s disease from four placebo-controlled and two open-label extension studies [see Clinical Studies ( 14.5 ) ] was similar to the safety profile seen in subjects with RA. Pediatric Patient s 6 Years to 17 Years : The safety profile of HUMIRA in 192 pediatric subjects from one double-blind study (Study PCD-I) and one open-label extension study [see Clinical Studies ( 14.6 ) ] was similar to the safety profile seen in adult subjects 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 non-serious and were primarily localized reactions. Ulcerative Colitis Clinical Studies Adults: The safety profile of HUMIRA in 1010 adult subjects with ulcerative colitis (UC) from two placebo-controlled studies and one open-label extension study [see Clinical Studies ( 14.7 ) ] was similar to the safety profile seen in subjects with RA. Pediatric Patient s 5 Years to 17 Years: The safety profile of HUMIRA in 93 pediatric subjects with ulcerative colitis from one double-blind study and one open-label extension study [see Clinical Studies ( 14.8 ) ] was similar to the safety profile seen in adult subjects with ulcerative colitis. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies [see Clinical Studies ( 14.9 ) ] . 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 [see Clinical Studies ( 14.10 ) ] . 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 adult subjects with uveitis (UV) in placebo-controlled and open-label extension studies and in 90 pediatric subjects with uveitis (Study PUV-I) [see Clinical Studies ( 14.11 , 14.12 )] . The safety profile for subjects with UV treated with HUMIRA was similar to the safety profile seen in subjects with RA. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other adalimumab products may be misleading. There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of anti-adalimumab antibody (AAA) development in patients treated with HUMIRA are presented in Table 2. Table 2: Anti-Adalimumab Antibody Development Determined by ELISA and ECL Assay in Patients Treated with HUMIRA Indications Study Duration Anti-Adalimumab Antibody Incidence by ELISA (n/N) Anti-Adalimumab Antibody Incidence by ECL Assay (n/N) In all patients who received adalimumab In patients with serum adalimumab concentrations < 2 mcg/mL Rheumatoid Arthritis a 6 to 12 months 5% (58/1062) NR NA Juvenile Idiopathic Arthritis (JIA) 4 to 17 years of age b 48 weeks 16% (27/171) NR NA 2 to 4 years of age or ≥ 4 years of age and weighing < 15 kg 24 weeks 7% (1/15) c NR NA Psoriatic Arthritis d 48 weeks e 13% (24/178) NR NA Ankylosing Spondylitis 24 weeks 9% (16/185) NR NA Adult Crohn’s Disease 56 weeks 3% (7/269) 8% (7/86) NA Pediatric Crohn’s Disease 52 weeks 3% (6/182) 10% (6/58) NA Adult Ulcerative Colitis 52 weeks 5% (19/360) 21% (19/92) NA Pediatric Ulcerative Colitis 52 weeks 3% (3/100) 13% (3/23) 33% (33/100) i Plaque Psoriasis f Up to 52 weeks g 8% (77/920) 21% (77/372) NA Hidradenitis Suppurativa 36 weeks 7% (30/461) 28% (58/207) h 61% (272/445) j Non-infectious Uveitis 52 weeks 5% (12/249) 21% (12/57) 40% (99/249) k n: number of patients with anti-adalimumab antibody; NR: not reported; NA: Not applicable (not performed) a In patients receiving concomitant methotrexate (MTX), the incidence of anti-adalimumab antibody was 1% compared to 12% with HUMIRA monotherapy b In patients receiving concomitant MTX, the incidence of anti-adalimumab antibody was 6% compared to 26% with HUMIRA monotherapy c This patient received concomitant MTX d In patients receiving concomitant MTX, the incidence of antibody development was 7% compared to 1% in RA e Subjects enrolled after completing 2 previous studies of 24 weeks or 12 weeks of treatments. f 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 g One 12-week Phase 2 study and one 52-week Phase 3 study h Among subjects in the 2 Phase 3 studies 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) i No apparent association between antibody development and safety was observed. The association of antibody development and efficacy outcome was not assessed due to limited number of subjects in each treatment group stratified by anti-adalimumab antibody titer. j No apparent association between antibody development and safety was observed k No correlation of antibody development to safety or efficacy outcomes was observed Rheumatoid Arthritis and Psoriatic Arthritis: Subjects in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12-month period. No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, subjects receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In subjects receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive subjects than among antibody-negative subjects. The long-term immunogenicity of HUMIRA is unknown. 6.3 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, autoimmune 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, lichenoid skin reaction Vascular disorders: Systemic vasculitis, deep vein thrombosis

7 DRUG INTERACTIONS Abatacept: Increased risk of serious infection. ( 5.1 , 5.11 , 7.2 ) Anakinra: Increased risk of serious infection. ( 5.1 , 5.7 , 7.2 ) Live vaccines: Avoid use with HUMIRA. ( 5.10, 7.3 ) 7.1 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 [see Clinical Pharmacology ( 12.3 ) ] . 7.2 Biological Products In clinical studies in patients with RA, an increased risk of serious infections has been observed 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 ( 5.7 , 5.11 )] . 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. 7.3 Live Vaccines Avoid the use of live vaccines with HUMIRA [see Warnings and Precautions ( 5.10 ) ] . 7.4 Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased concentrations 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.

16 HOW SUPPLIED/STORAGE AND HANDLING HUMIRA ® (adalimumab) is supplied as a preservative-free, sterile, clear and colorless solution for subcutaneous administration. The following packaging configurations are available. HUMIRA Pen Carton - 40 mg/0.4 mL HUMIRA is supplied in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-dose pen, containing a 1 mL prefilled glass syringe with a fixed thin wall, ½ inch needle, providing 40 mg/0.4 mL of HUMIRA. The black needle cover is not made with natural rubber latex. The NDC number is 83457-554-02 HUMIRA Pen Carton – 80 mg/0.8 mL HUMIRA is supplied in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-dose pen, containing a 1 mL prefilled glass syringe with a fixed thin wall, ½ inch needle, providing 80 mg/0.8 mL of HUMIRA. The black needle cover is not made with natural rubber latex. The NDC number is 83457-124-02. Prefilled Syringe Carton - 40 mg/0.4 mL HUMIRA is supplied in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-dose, 1 mL prefilled glass syringe with a fixed thin wall, ½ inch needle, providing 40 mg/0.4 mL of HUMIRA. The black needle cover is not made with natural rubber latex. The NDC number is 83457-243-02. Prefilled Syringe Carton - 20 mg/0.2 mL HUMIRA is supplied in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-dose, 1 mL prefilled glass syringe with a fixed thin wall, ½ inch needle, providing 20 mg/0.2 mL of HUMIRA. The black needle cover is not made with natural rubber latex. The NDC number is 83457-616-02. Prefilled Syringe Carton - 10 mg/0.1 mL HUMIRA is supplied in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-dose, 1 mL prefilled glass syringe with a fixed thin wall, ½ inch needle, providing 10 mg/0.1 mL of HUMIRA. The black needle cover is not made with natural rubber latex. The NDC number is 83457-817-02. Storage and Stability Do not use beyond the expiration date on the container. HUMIRA must be refrigerated at 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. Do not use if frozen even if it has been thawed. Store in original carton until time of administration to protect from light. If needed, for example when traveling, HUMIRA may be stored at room temperature up to a maximum of 77°F (25°C) for a period of up to 14 days, with protection from light. HUMIRA should be discarded if not used within the 14-day period. Record the date when HUMIRA is first removed from the refrigerator in the spaces provided on the carton and dose tray. Do not store HUMIRA in extreme heat or cold.