Adalimumab

INDICATIONS AND USAGE Adalimumab-adaz 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 rheumatoid arthritis. (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 adult patients. ( 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 Adalimumab-adaz 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. Adalimumab-adaz can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). 1.2 Juvenile Idiopathic Arthritis Adalimumab-adaz is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. Adalimumab-adaz can be used alone or in combination with methotrexate. 1.3 Psoriatic Arthritis Adalimumab-adaz is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. Adalimumab-adaz can be used alone or in combination with non-biologic DMARDs. 1.4 Ankylosing Spondylitis Adalimumab-adaz is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. 1.5 Crohn’s Disease Adalimumab-adaz 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 Adalimumab-adaz is indicated for the treatment of moderately to severely active ulcerative colitis in adult patients. Limitations of Use: The effectiveness of adalimumab products has not been established in patients who have lost response to or were intolerant to TNF-blockers [see Clinical Studies (14.7) ] . 1.7 Plaque Psoriasis Adalimumab-adaz 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. Adalimumab-adaz 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 Adalimumab-adaz is indicated for the treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older. 1.9 Uveitis Adalimumab-adaz is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older. 1.6 Ulcerative Colitis Adalimumab-adaz is indicated for the treatment of moderately to severely active ulcerative colitis in adult patients. Limitations of Use: The effectiveness of adalimumab products has not been established in patients who have lost response to or were intolerant to TNF-blockers [see Clinical Studies (14.7) ] . 1.7 Plaque Psoriasis Adalimumab-adaz 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. Adalimumab-adaz 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) ] .

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 ( 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 • Administer by subcutaneous injection ( 2 ) Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis ( 2.1 ): • Adults: 40 mg every other week. o 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 ( 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). 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: o Day 1: 160 mg (given in one day or split over two consecutive days) o Day 15: 80 mg o Day 29 and subsequent doses: 40 mg every week or 80 mg every other week 2.1 Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis The recommended subcutaneous dosage of IDACIO for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) 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 IDACIO. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of IDACIO to 40 mg every week or 80 mg every other week. 2.2 Juvenile Idiopathic Arthritis The recommended subcutaneous dosage of IDACIO for patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with IDACIO. 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 The only dosage form for IDACIO that allows weight-based dosing for pediatric patients below 30 kg is the single-dose glass vial kit for institutional use only. Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg. 2.3 Crohn’s Disease Adults The recommended subcutaneous dosage of IDACIO for adult patients with 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 IDACIO. Azathioprine, 6-mercaptopurine (6-MP) [see Warnings and Precautions ( 5.2 )] or MTX may be continued during treatment with IDACIO if necessary. Pediatrics The recommended subcutaneous dosage of IDACIO for pediatric patients 6 years of age and older with Crohn’s disease (CD) is based on body weight as 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 The only dosage form for IDACIO that allows weight-based dosing for pediatric patients below 40 kg is the single-dose glass vial kit for institutional use only 2.4 Ulcerative Colitis Adults The recommended subcutaneous dosage of IDACIO for adult patients with 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 IDACIO 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 IDACIO. Azathioprine and 6-mercaptopurine (6-MP) [ see Warnings and Precautions (5.2) ] may be continued during treatment with IDACIO if necessary. 2.5 Plaque Psoriasis or Adult Uveitis The recommended subcutaneous dosage of IDACIO for adult patients with plaque psoriasis (Ps) or Uveitis (UV) 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 adalimumab products in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies. 2.6 Hidradenitis Suppurativa Adults The recommended subcutaneous dosage of IDACIO for adult patients with 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). 2.7 Monitoring to Assess Safety Prior to initiating IDACIO and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions ( 5.1 )] . 2.8 General Considerations for Administration IDACIO Pen or prefilled syringe is intended for use under the guidance and supervision of a physician. A patient may self-inject IDACIO or a caregiver may inject IDACIO using either the IDACIO 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. IDACIO may 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 IDACIO Pen, or prefilled syringe or single dose institutional use vial for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. IDACIO does not contain preservatives. Therefore, discard unused portions of drug remaining in the syringe. Instruct patients using the IDACIO 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 sc

WARNINGS AND PRECAUTIONS • Serious infections: Do not start IDACIO during an active infection. If an infection develops, monitor carefully, and stop IDACIO if infection becomes serious. ( 5.1 ) • Invasive fungal infections: For patients who develop a systemic illness on IDACIO, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic. ( 5.1 ) • Malignancies: Incidence of malignancies was greater in adalimumab-treated patients than in controls ( 5.2 ) • Anaphylaxis or serious hypersensitivity reactions may occur ( 5.3 ) • Hepatitis B virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop IDACIO and begin anti‑ viral therapy. ( 5.4 ) • Demyelinating disease: Exacerbation or new onset, may occur. ( 5.5 ) • Cytopenias, pancytopenia: Advise patients to seek immediate medical attention if symptoms develop and consider stopping IDACIO. ( 5.6 ) • Heart failure: Worsening or new onset, may occur. ( 5.8 ) • Lupus-like syndrome: Stop IDACIO if syndrome develops. ( 5.9 ) 5.1 Serious Infections Patients treated with adalimumab products including IDACIO are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of IDACIO and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions ( 5.7 , 5.11 ) and Drug Interactions ( 7.2 )] . Treatment with IDACIO should not be initiated in patients with an active infection, including localized infections. Patients 65 years of age and older, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection. Tuberculosis Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving adalimumab products, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating IDACIO and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating IDACIO, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Consider anti-tuberculosis therapy prior to initiation of IDACIO in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab products. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti- tuberculosis therapy is appropriate for an individual patient. Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during IDACIO treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with IDACIO, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with IDACIO. Discontinue IDACIO if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with IDACIO, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy. Invasive Fungal Infections If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections. 5.2 Malignancies Consider the risks and benefits of TNF-blocker treatment including IDACIO prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy. Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including adalimumab products, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 39 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS) and uveitis (UV), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973 adalimumab-treated patients versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated patients (median duration of treatment of 4 months for adalimumab-treated patients and 4 months for control-treated patients). In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). 1 In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulom

CONTRAINDICATIONS None. None. ( 4 )

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 Adalimumab-adaz ( 5.10 , 7.3 ) * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Adalimumab-adaz has been demonstrated for the condition(s) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. 7.1 Methotrexate Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent clearance of adalimumab, the data do not suggest the need for dose adjustment of either Adalimumab-adaz 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 Adalimumab-adaz 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 Adalimumab-adaz and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of Adalimumab-adaz 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 Adalimumab-adaz [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 products that antagonize cytokine activity, such as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of Adalimumab-adaz 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.

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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 adalimumab was injection site reactions. In placebo- controlled trials, 20% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA‑ II, RA-III and RA-IV) was 7% for patients taking adalimumab and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of adalimumab 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 adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973 adalimumab-treated patients versus a rate of 2.9 per 100 patient-years in 4848 control-treated patients. 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 adalimumab-treated patients, 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 adalimumab-treated patients, 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 patients treated with adalimumab and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with adalimumab developed clinical signs suggestive of new- onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab products on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of adalimumab (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of adalimumab-treated patients and 1.5% of control- treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear. In a controlled Phase 3 trial of adalimumab in patients with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% of adalimumab-treated patients and 1.5% of control-treated patients (ALT more common than AST); liver enzyme test elevations were more frequent among those treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In general, these elevations did not lead to discontinuation of adalimumab treatment. No ALT elevations ≥ 3 x ULN occurred in the open-label study of adalimumab in patients with polyarticular JIA who were 2 to <4 years. In controlled Phase 3 trials of adalimumab (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 Crohn’s Disease with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of control-treated patients. In the Phase 3 trial of adalimumab 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 adalimumab (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in adult patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase 3 trials of adalimumab (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 adalimumab-treated patients and 1.8% of control-treated patients. In controlled trials of adalimumab (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 adalimumab-treated subjects and 0.6% of control-treated subjects. In controlled trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in adalimumab-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients. Other Adverse Reactions Rheumatoid Arthritis Clinical Studies The data described below reflect exposure to adalimumab 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). Adalimumab 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

Mechanism of Action Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated concentrations of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with Adalimumab-adbm may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown. Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC 50 of 1-2 × 10 -10 M).