HULIO

Adalimumab-fkjp is a tumor necrosis factor blocker. Adalimumab-fkjp is a recombinant human IgG1 monoclonal antibody. Adalimumab-fkjp is produced by recombinant DNA technology in a mammalian cell expression system (Chinese Hamster Ovary Cells) and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. HULIO (adalimumab-fkjp) injection is supplied as a sterile, preservative-free solution for subcutaneous administration. The drug product is supplied as either a single-dose, prefilled pen (HULIO Pen) or as a single-dose, 1 mL prefilled plastic syringe. Enclosed within the pen is a single- dose, 1 mL prefilled plastic syringe. The solution of HULIO is clear to slightly opalescent, colorless to pale brownish-yellow, with a pH of about 5.2. Each 40 mg/0.8 mL prefilled syringe or prefilled pen delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of HULIO contains adalimumab-fkjp (40 mg), methionine (0.60 mg), monosodium glutamate (1.50 mg), polysorbate 80 (0.80 mg), sorbitol (38.2 mg) and Water for Injection, USP. Hydrochloric acid is added as necessary to adjust pH. Each 20 mg/0.4 mL prefilled syringe delivers 0.4 mL (20 mg) of drug product. Each 0.4 mL of HULIO contains adalimumab-fkjp (20 mg), methionine (0.30 mg), monosodium glutamate (0.75 mg), polysorbate 80 (0.40 mg), sorbitol (19.1 mg) and Water for Injection, USP. Hydrochloric acid is added as necessary to adjust pH.

HULIO is a tumor necrosis factor (TNF) blocker indicated for: Rheumatoid Arthritis (RA) ( 1.1 ): 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 RA. J uvenile Idiopathic Arthritis (JIA) ( 1.2 ) : reducing signs and symptoms of moderately to severely active polyarticular JIA in patients 2 years of age and older. Psoriatic Arthritis (PsA) ( 1.3 ) : reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA. A nkylosing Spondylitis (AS) ( 1.4 ): reducing signs and symptoms in adult patients with active AS. Crohn’s Disease (CD) ( 1.5 ): treatment of moderately to severely active Crohn’s disease in adults and pediatric patients 6 years of age and older. Ulcerative Colitis (UC) ( 1.6 ): treatment of moderately to severely active ulcerative colitis in adult patients. Limitations of Use : Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Plaque Psoriasis (Ps) ( 1.7 ): 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. Hidradenitis Suppurativa (HS) ( 1.8 ): treatment of moderate to severe hidradenitis suppurativa in adult patients. Uveitis (UV) ( 1.9 ): treatment of non-infectious intermediate, posterior, and panuveitis in adult patients. 1.1 Rheumatoid Arthritis HULIO 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. HULIO can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). 1.2 Juvenile Idiopathic Arthritis HULIO is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. HULIO can be used alone or in combination with methotrexate. 1.3 Psoriatic Arthritis HULIO is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HULIO can be used alone or in combination with non-biologic DMARDs. 1.4 Ankylosing Spondylitis HULIO is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. 1.5 Crohn’s Disease HULIO 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 HULIO 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 HULIO 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. HULIO 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 HULIO is indicated for the treatment of moderate to severe hidradenitis suppurativa in adult patients. 1.9 Uveitis HULIO is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients.

• 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 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 HULIO 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 HULIO. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of HULIO to 40 mg every week or 80 mg every other week. 2.2 Juvenile Idiopathic Arthritis The recommended subcutaneous dosage of HULIO 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 HULIO. Pediatric Weight (2 Years of Age and older) Recommended Dosage 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 There is no dosage form for HULIO that allows weight-based dosing for pediatric patients below 15 kg. 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 HULIO 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 HULIO. Azathioprine, 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2) ] or MTX may be continued during treatment with HULIO if necessary. Pediatrics The recommended subcutaneous dosage of HULIO 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 2.4 Ulcerative Colitis Adults The recommended subcutaneous dosage of HULIO 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 HULIO 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 HULIO. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2) ] may be continued during treatment with HULIO if necessary. 2.5 Plaque Psoriasis or Adult Uveitis The recommended subcutaneous dosage of HULIO 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 HULIO 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 HULIO 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 HULIO is intended for use under the guidance and supervision of a physician. A patient may self-inject HULIO or a caregiver may inject HULIO using either the HULIO 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. HULIO 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 HULIO Pen or prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. HULIO does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. Instruct patients using the HULIO 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.

None. None. ( 4 )

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 Biocon Biologics at 1-833-986-1468 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, 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 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week [see Clinical Studies (14.1) ] . Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with adalimumab 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 Adalimumab During Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Adalimumab 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 abnormalities were reported as adverse reactions in European trials 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 Does not include injection site erythema, itching, hemorrhage, pain or swelling 8% 1% Back pain 6% 4% Urinary tract infection 8% 5% Hypertension 5% 3% 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 adalimumab-treated patients in RA studies 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 adalimumab-treated patients 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 patients [see Warnings and Precautions (5) , Adverse Reactions (6) ] . Important findings and differences from adults are discussed in the following paragraphs. In Study JIA-I, adalimumab 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 adalimumab 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 adalimumab with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in adalimumab-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 adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in patients receiving adalimumab was granuloma annulare which did not lead to discontinuation of adalimumab 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 adalimumab 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 adalimumab 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 concentrations decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption. In Study JIA-II, adalimumab 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 adalimumab. 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 adalimumab 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 Adalimumab has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies [see Clinical Studies (14.3 , 14.4) ] . The safety profile for patients with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in patients with RA, adalimumab Studies RA-I through IV. Crohn’s Disease Clinical Studies Adults The safety profile of adalimumab in 1478 adult patients 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 patients with RA. Pediatric Patients 6 Years to 17 Years The safety profile of adalimumab in 192 pediatric patients 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 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 adalimumab were injection site pain and injection site reaction (6% and 5%, respectively). A total of 67% of children experienced an infection while receiving adalimumab in Study PCD-I. These included upper respiratory tract infection and nasopharyngitis. A total of 5% of children experienced a serious infection while receiving adalimumab 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 adalimumab in 1010 adult patients 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 patients with RA. Plaque Psoriasis Clinical Studies Adalimumab 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 adalimumab 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, adalimumab-treated subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%). Hidradenitis Suppurativa Clinical Studies Adalimumab 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 adalimumab weekly was consistent with the known safety profile of adalimumab. 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 adalimumab treatment following the primary efficacy timepoint in two studies. Uveitis Clinical Studies Adalimumab has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-label extension studies [see Clinical Studies (14.11) ] . The safety profile for patients with UV treated with adalimumab was similar to the safety profile seen in patients with RA. 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of adalimumab or of other adalimumab products. 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 adalimumab are presented in Table 2. Table 2: Anti-Adalimumab Antibody Development Determined by ELISA and ECL Assay in Patients Treated with Adalimumab n: number of patients with anti-adalimumab antibody; NR: not reported; NA: Not applicable (not performed) 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 In patients receiving concomitant methotrexate (MTX), the incidence of anti-adalimumab antibody was 1% compared to 12% with adalimumab monotherapy 6 to 12 months 5% (58/1062) NR NA Juvenile Idiopathic Arthritis (JIA) 4 to 17 years of age In patients receiving concomitant MTX, the incidence of anti-adalimumab antibody was 6% compared to 26% with adalimumab monotherapy 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) This patient received concomitant MTX NR NA Psoriatic Arthritis In patients receiving concomitant MTX, the incidence of antibody development was 7% compared to 1% in RA 48 weeks Subjects enrolled after completing 2 previous studies of 24 weeks or 12 weeks of treatments. 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 Plaque Psoriasis In plaque psoriasis patients who were on adalimumab monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal Up to 52 weeks One 12-week Phase 2 study and one 52-week Phase 3 study 8% (77/920) 21% (77/372) NA Hidradenitis Suppurativa 36 weeks 7% (30/461) 28% (58/207) Among subjects in the 2 Phase 3 studies who stopped adalimumab treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to <2 mcg/mL (approximately 22% of total subjects studied) 61% (272/445) No apparent association between antibody development and safety was observed Non-infectious Uveitis 52 weeks 5% (12/249) 21% (12/57) 40% (99/249) No correlation of antibody development to safety or efficacy outcomes was observed Rheumatoid Arthritis and Psoriatic Arthritis Patients 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, 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 adalimumab products is unknown. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of adalimumab products. 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 adalimumab products 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, lichenoid skin reaction Vascular disorders: Systemic vasculitis, deep vein thrombosis

• 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 HULIO. ( 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 HULIO 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 adalimumab clearance, the data do not suggest the need for dose adjustment of either HULIO 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 HULIO 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 HULIO and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of HULIO 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 HULIO [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 HULIO 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.