ABRILADA- adalimumab-afzb

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 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 -10 After treatment with adalimumab, a decrease in concentrations of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP concentrations was also observed in patients with Crohn's disease, ulcerative colitis, and hidradenitis suppurativa. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration. The pharmacokinetics of adalimumab were linear over the dose range of 0. 5 to 10 mg/kg following administration of a single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics. Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week. Absorption The average absolute bioavailability of adalimumab following a single 40 mg subcutaneous dose was 64%. The mean time to reach the maximum concentration was 5. 5 days (131 +/- 56 hours) and the maximum serum concentration was 4. 6 mcg/mL in healthy subjects following a single 40 mg subcutaneous administration of adalimumab. Distribution The distribution volume (V ss Elimination The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0. 25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. Patient Population Rheumatoid Arthritis and Ankylosing Spondylitis: Psoriatic Arthritis: Plaque Psoriasis: Adult Uveitis: Adult Hidradenitis Suppurativa: Adult Crohn's Disease: Adult Ulcerative Colitis: Anti-Drug Antibody Effects on Pharmacokinetics Rheumatoid Arthritis: Hidradenitis Suppurativa: Specific Populations Geriatric Patients: Pediatric Patients: Juvenile Idiopathic Arthritis 4 years to 17 years of age: 2 years to <4 years of age or 4 years of age and older weighing <15 kg: Pediatric Crohn's Disease: Male and Female Patients: Patients with Renal or Hepatic Impairment: Rheumatoid Factor or CRP Concentrations: Drug Interaction Studies: Methotrexate: [see Drug Interactions (7.

INDICATIONS AND USAGE
ABRILADA is a tumor necrosis factor (TNF) blocker indicated for: Rheumatoid Arthritis (RA) ( 1. 1 Juvenile Idiopathic Arthritis (JIA) ( 1. 2 Psoriatic Arthritis (PsA) ( 1. 3 Ankylosing Spondylitis (AS) ( 1. 4 Crohn''s Disease (CD) ( 1. 5 Ulcerative Colitis (UC) ( 1. 6 Limitations of Use: Plaque Psoriasis (Ps) ( 1. 7 Hidradenitis Suppurativa (HS) ( 1. 8 Uveitis (UV) ( 1. 9 ABRILADA 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. ABRILADA can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). ABRILADA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. ABRILADA can be used alone or in combination with methotrexate. ABRILADA is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. ABRILADA can be used alone or in combination with non-biologic DMARDs. ABRILADA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. ABRILADA is indicated for the treatment of moderately to severely active Crohn''s disease in adults and pediatric patients 6 years of age and older. ABRILADA 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) ABRILADA 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. ABRILADA 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) ABRILADA is indicated for the treatment of moderate to severe hidradenitis suppurativa in adult patients. ABRILADA is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients.
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 (14.10)

DOSAGE AND ADMINISTRATION
2 Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis ( 2. 1 Adults: 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: 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 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) 40 mg every other week Ulcerative Colitis ( 2. 4 Adults: Plaque Psoriasis or Adult Uveitis ( 2. 5 Adults: Hidradenitis Suppurativa ( 2. 6 Adults: The recommended subcutaneous dosage of ABRILADA 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 ABRILADA. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of ABRILADA to 40 mg every week or 80 mg every other week. The recommended subcutaneous dosage of ABRILADA 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 ABRILADA. 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 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. Adults The recommended subcutaneous dosage of ABRILADA 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 ABRILADA. Azathioprine, 6-mercaptopurine (6-MP) [see Warnings and Precautions (5. 2) Pediatrics The recommended subcutaneous dosage of ABRILADA 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 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) 40 mg every other week Adults The recommended subcutaneous dosage of ABRILADA 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 ABRILADA in adult patients without evidence of clinical remission by eight weeks (Day 57) of therapy. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5. 2) The recommended subcutaneous dosage of ABRILADA for adult patients with plaque psoriasis (Ps) or uveitis (UV) Adults The recommended subcutaneous dosage of ABRILADA 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). Prior to initiating ABRILADA and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5. 1) ABRILADA is intended for use under the guidance and supervision of a physician. A patient may self-inject ABRILADA or a caregiver may inject ABRILADA using either the ABRILADA 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. ABRILADA 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 ABRILADA pen, prefilled syringe, or single-dose institutional use vial for particulate matter and discoloration prior to subcutaneous administration. If particulates or discolorations are noted, do not use the product. ABRILADA does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe [see How Supplied/Storage and Handling (16) Instruct patients using the ABRILADA 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. The ABRILADA single-dose institutional use vial is for administration within an institutional setting only, such as a hospital, physician''s office or clinic. Withdraw the dose using a sterile needle and syringe and administer promptly by a healthcare provider within an institutional setting. Only administer one dose per vial. The vial does not contain preservatives; therefore, discard unused portions.
INSTRUCTIONS FOR USE
ABRILADA (AH brill-ah-dah) (adalimumab-afzb) 40 mg/0. 8 mL Single-dose Prefilled Pen Injection, for subcutaneous (under the skin) use Keep this leaflet. These instructions show step by step directions on how to prepare and give an injection. Storage Information: Do not freeze ABRILADA. Note: The ABRILADA prefilled pen is not made with natural rubber latex. Keep ABRILADA, injection supplies, and all other medicines out of the reach of children. ABRILADA for injection comes in a disposable (throw away) single-use pen that contains a single dose of medicine. ABRILADA for injection can be given by a patient, caregiver or healthcare provider. Do not try to inject ABRILADA yourself until you are shown the right way to give the injections and read and understand the Instructions for Use. If your healthcare provider decides that you or a caregiver may be able to give your injections of ABRILADA at home, you should receive training on the right way to prepare and inject ABRILADA. It is important that you read, understand, and follow these instructions so that you inject ABRILADA the right way. It is important to talk to your healthcare provider to be sure you understand your ABRILADA dosing instructions. To help you remember when to inject ABRILADA, you can mark your calendar ahead of time. Call your healthcare provider if you or your caregiver have any questions about the right way to inject ABRILADA. Supplies you need o o o o See Step 10 Step 2. Getting ready Do not o o o o o o o o Do not Do not Do not Do not o o Do not o Do not Do not Do not Important: Note: Push Note: Keep your pen pushed against the skin until Step 9. Press Keep holding nd Wait nd Note Do not remove your pen until you have waited at least 5 seconds after the 2 nd Remove Note: Do not inject another dose. Do not o o o o o http://www. gov/safesharpsdisposal Do not Do not Do not Note: Questions and Answers What should I do with my pen if it has been dropped? Do not use it, even if it looks undamaged. Dispose of your pen in the same way as a used pen. You will need to use a new pen to give your injection. Can I use my pen straight from the refrigerator? Yes, however you may find that using the pen at room temperature reduces stinging or discomfort. If you allow your pen to reach room temperature before use, you must keep it away from direct sunlight as this can damage your medicine. What should I do if I need to travel? When you are traveling, you may store your pen in its carton at room temperature up to 86°F (30°C) for up to 30 days. Is it okay to shake my pen before I use it? No, do not shake your pen. Shaking can damage your medicine. When you check your medicine, gently tilt your pen back and forth while looking carefully into the window. It is normal to see one or more air bubbles. Do I need to remove any air bubbles before using my pen? No, do not attempt to remove air bubbles. Drops of medicine have appeared at the needle tip. Is this okay? Yes, it is normal to see a few drops of medicine at the needle tip when you remove the cap. Can I re-insert the needle if I change my mind where I want to inject? No, you should not I pushed my pen against the skin but could not press the button down. What should I do? Take your finger off the injection button and push your pen down more firmly against the skin. Then try pushing the button again. If this does not work, stretching the skin may make the injection site firmer, making pressing the injection button easier. Can I pinch or stretch the skin at the injection area? Yes, pinching or stretching the skin before injection may make the injection site firmer, making it easier to press the injection button. Do I need to keep my finger pressed on the injection button for the whole injection? No, you can stop pressing the button when the injection has started. However, make sure you keep holding the pen firmly against the skin. The pen will continue to deliver your medicine. How long will the injection take? From the time the dose begins until you hear the 2 nd nd What should I do if I see more than a small drop of medicine on the skin after giving my injection? Nothing this time, but for your next injection wait a little longer before removing the pen from the skin to make sure all of the medicine went into your skin. What should I do if I have any questions about my ABRILADA pen or medicine? Contact your healthcare provider or pharmacist. This Instructions for Use has been approved by the U. Food and Drug Administration. Manufactured by Pfizer Inc. Distributed by Pfizer Labs US License No. 2001 LAB-1352-4. 0 Revised: 4/2024 Step 3 Image Step 4 Step 5 C:\Temp\Pfizer Oct 4\Attached file _1664891496641_2578536_2022_09_20_81a33cfa-262f_11027\abrilada-09. jpg Step 7 Step 8 Step 9 Step 10 Step 11 Image Pfizer.
INSTRUCTIONS FOR USE
ABRILADA (AH brill-ah-dah) (adalimumab-afzb) 10 mg/0. 2 mL, 20 mg/0. 4 mL, 40 mg/0. 8 mL Single-dose Prefilled Syringe Injection, for subcutaneous (under the skin) use only Keep this leaflet. These instructions show step by step directions on how to prepare and give an injection. Storage Information: Do not freeze ABRILADA. Note: The ABRILADA prefilled syringe is not made with natural rubber latex. Keep ABRILADA, injection supplies, and all other medicines out of the reach of children. ABRILADA for injection comes in a disposable (throw away) single use prefilled syringe that contains a single dose of medicine. ABRILADA for injection can be given by a patient, caregiver or healthcare provider. Do not try to inject ABRILADA yourself until you are shown the right way to give the injections and read and understand the Instructions for Use. If your healthcare provider decides that you or a caregiver may be able to give your injections of ABRILADA at home, you should receive training on the right way to prepare and inject ABRILADA. It is important that you read, understand, and follow these instructions so that you inject ABRILADA the right way. It is important to talk to your healthcare provider to be sure you understand your ABRILADA dosing instructions. To help you remember when to inject ABRILADA, you can mark your calendar ahead of time. Call your healthcare provider if you or your caregiver have any questions about the right way to inject ABRILADA. Supplies you need o o o o See Step 10 Step 2. Getting ready Do not o o o o o o Wash your hands with soap and water, and dry completely. Do not o o o Do not Always hold the prefilled syringe by the barrel to prevent damage. o o Do not o Do not Do not Do not Note: a 45 degree angle Note: Never re-insert the needle. Never put the cap back on the needle. Do not o o o o o http://www. gov/safesharpsdisposal Do not Do not Do not Note: Questions and Answers What should I do with my prefilled syringe if it has been dropped? Do not use it if it has been dropped or the carton containing your prefilled syringe has been dropped even if it looks undamaged. Dispose of your prefilled syringe in the same way as a used prefilled syringe. You will need to use a new prefilled syringe to give your injection. Can I use my prefilled syringe straight from the refrigerator? Yes, however you may find that using the prefilled syringe at room temperature reduces stinging or discomfort. If you allow your prefilled syringe to reach room temperature before use, you must keep it away from direct sunlight as this can damage your medicine. What should I do if I need to travel? When you are traveling, you may store your prefilled syringe in its carton at room temperature up to 86°F (30°C) for up to 30 days. Is it okay to shake my prefilled syringe before I use it? No, do not shake your prefilled syringe. Shaking can damage your medicine. When you check your medicine, gently tilt your syringe back and forth while looking carefully into the window. It is normal to see one or more bubbles. Do I need to remove any air bubbles before using my prefilled syringe? No, do not attempt to remove air bubbles. Drops of medicine have appeared at the needle tip. Is this okay? Yes, it is normal to see a few drops of medicine at the needle tip when you remove the needle cover. Can I re-insert the needle into my skin? No, you should not re-insert the needle into the skin. You will need a replacement prefilled syringe if the needle has already been inserted into the skin. How long will the injection take? Dose delivery will take approximately 2 to 5 seconds. Remember to hold your prefilled syringe in place for at least 5 seconds after the plunger has been pushed down all the way. What should I do if I have any questions about my prefilled syringe or medicine? Contact your healthcare provider or pharmacist. This Instructions for Use has been approved by the U. Food and Drug Administration. Manufactured by Pfizer Inc. Distributed by Pfizer Labs US License No. 2001 LAB-1353-4. 0 Revised: 4/2024 Image Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 9 Step 10 Step 11 Pfizer.

The following clinically significant adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 9) Most common adverse reactions (>10%) are: infections (e. upper respiratory, sinusitis), injection site reactions, headache, and rash. 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. , 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. 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. 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 × 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. , 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 × 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 × 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 × 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 × 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 × ULN occurred in 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 × 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. 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) Adverse Reaction (Preferred Term) Adalimumab 40 mg Subcutaneous Every Other Week (N=705) Placebo (N=690) 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: 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) [see Warnings and Precautions (5) Adverse Reactions (6) 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. 4) Crohn's Disease Clinical Studies Adults: [see Clinical Studies (14. 5) Pediatric Patients 6 Years to 17 Years: [see Clinical Studies (14. 6) 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 [see Clinical Studies (14. 7) 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. 8) 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. 9) 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. Adalimumab has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-label extension studies [see Clinical Studies (14. 10) 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 adalimumab are presented in 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 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: 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. .

Risk Summary Available studies with use of adalimumab during pregnancy do not reliably establish an association between adalimumab and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohn's disease (CD) treated with adalimumab. Registry results showed a rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or CD and a rate of 7. 5% for major birth defects in the disease-matched comparison cohort. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects (see Data Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero (see Clinical Considerations (see Data The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2en dash4% and 15en dash20%, respectively. Clinical Considerations Disease-Associated Maternal and Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester (see Data in utero [see Use in Specific Populations (8. 4) Data Human Data A prospective cohort pregnancy exposure registry conducted by OTIS/MotherToBaby in the U. and Canada between 2004 and 2016 compared the risk of major birth defects in live-born infants of 221 women (69 RA, 152 CD) treated with adalimumab during the first trimester and 106 women (74 RA, 32 CD) not treated with adalimumab. The proportion of major birth defects among live-born infants in the adalimumab-treated and untreated cohorts was 10% (8. 5% CD) and 7. 4% CD), respectively. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects. This study cannot reliably establish whether there is an association between adalimumab and major birth defects because of methodological limitations of the registry, including small sample size, the voluntary nature of the study, and the non-randomized design. In an independent clinical study conducted in ten pregnant women with IBD treated with adalimumab, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth. The last dose of adalimumab was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0. 16en dash19. 7 mcg/mL in cord blood, 4. 28en dash17. 7 mcg/mL in infant serum, and 0en dash16. 1 mcg/mL in maternal serum. In all but one case, the cord blood concentration of adalimumab was higher than the maternal serum concentration, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum concentrations at each of the following: 6 weeks (1. 94 mcg/mL), 7 weeks (1. 31 mcg/mL), 8 weeks (0. 93 mcg/mL), and 11 weeks (0. 53 mcg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero Animal Data In an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week). Adalimumab did not elicit harm to the fetuses or malformations. Risk Summary Limited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0. 1% to 1% of the maternal serum concentration. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because adalimumab is a large molecule and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal tract are unknown. There are no reports of adverse effects of adalimumab products on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ABRILADA and any potential adverse effects on the breastfed child from ABRILADA or from the underlying maternal condition. The safety and effectiveness of ABRILADA have been established for: Pediatric assessments for ABRILADA demonstrate that ABRILADA is safe and effective for pediatric patients in indications for which Humira (adalimumab) is approved. However, ABRILADA is not approved for such indications due to marketing exclusivity for Humira (adalimumab). Due to their inhibition of TNFalpha, adalimumab products administered during pregnancy could affect immune response in the in utero in utero [see Use in Specific Populations (8. 1) Postmarketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab products [see Warnings and Precautions (5. 2) Juvenile Idiopathic Arthritis In Study JIA-I, adalimumab was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age [see Clinical Studies (14. 2) [see Adverse Reactions (6. 1) The safety of adalimumab in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions (6. 1) The safety and effectiveness of adalimumab products have not been established in pediatric patients with JIA less than 2 years of age. Pediatric Crohn's Disease The safety and effectiveness of adalimumab products for the treatment of moderately to severely active Crohn's disease have been established in pediatric patients 6 years of age and older. Use of adalimumab products for this indication is supported by evidence from adequate and well-controlled studies in adults with additional data from a randomized, double-blind, 52-week clinical study of two dose concentrations of adalimumab in 192 pediatric patients (6 years to 17 years of age) [see Adverse Reactions (6. 1) Clinical Pharmacology (12. 3) Clinical Studies (14. 6) The safety and effectiveness of adalimumab products have not been established in pediatric patients with Crohn's disease less than 6 years of age. A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab-treated patients 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of ABRILADA in patients 65 years of age and older. In patients treated with ABRILADA, closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.

Abatacept: 5. 2 Anakinra: 5. 2 Live vaccines: 5. 3 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 ABRILADA or MTX [see Clinical Pharmacology (12. 3) 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 ABRILADA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5. 11) Avoid the use of live vaccines with ABRILADA [see Warnings and Precautions (5. 10) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e. , TNFalpha, 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 ABRILADA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e. , warfarin) or drug concentration (e. , cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

=10% BSA involvement and PASI >=12. Subjects received placebo, or an initial dose of 80 mg adalimumab at Week 0 followed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from "moderate" (41%) to "severe" (51%) to "very severe" (8%). Studies Ps-I and II evaluated the proportion of subjects who achieved "clear" or "minimal" disease on the 6-point PGA scale and the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Tables 16 17 Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of "clear" or "minimal" disease or a PASI 75 response after Week 33 and on or before Week 52. Efficacy Results at 16 Weeks in Study Ps-I Number of Subjects (%) Adalimumab 40 mg Every Other Week N=814 Placebo N=398 PGA: Clear minimal Clear=no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration. 506 (62%) 17 (4%) PASI 75 578 (71%) 26 (7%) Table 17. Efficacy Results at 16 Weeks in Study Ps-II Number of Subjects (%) Adalimumab 40 mg Every Other Week N=99 Placebo N=48 PGA: Clear minimal Clear=no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration. 70 (71%) 5 (10%) PASI 75 77 (78%) 9 (19%) Additionally, in Study Ps-I, subjects on adalimumab who maintained a PASI 75 were re-randomized to adalimumab (N=250) or placebo (N=240) at Week 33. After 52 weeks of treatment with adalimumab, more subjects on adalimumab maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of "clear" or "minimal" disease (68% vs. 28%) or a PASI 75 (79% vs. A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA "moderate" or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of adalimumab, then 40 mg every other week beginning at Week 1. At Week 16, 69% (123/178) of subjects had a response of PGA "clear" or "minimal". A randomized, double-blind study (Study Ps-III) compared the efficacy and safety of adalimumab versus placebo in 217 adult subjects. Subjects in the study had to have chronic plaque psoriasis of at least moderate severity on the PGA scale, fingernail involvement of at least moderate severity on a 5-point Physician''s Global Assessment of Fingernail Psoriasis (PGA-F) scale, a Modified Nail Psoriasis Severity Index (mNAPSI) score for the target-fingernail of >=8, and either a BSA involvement of at least 10% or a BSA involvement of at least 5% with a total mNAPSI score for all fingernails of >=20. Subjects received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks. This study evaluated the proportion of subjects who achieved "clear" or "minimal" assessment with at least a 2-grade improvement on the PGA-F scale and the proportion of subjects who achieved at least a 75% improvement from baseline in the mNAPSI score (mNAPSI 75) at Week 26. At Week 26, a higher proportion of subjects in the adalimumab group than in the placebo group achieved the PGA-F endpoint. Furthermore, a higher proportion of subjects in the adalimumab group than in the placebo group achieved mNAPSI 75 at Week 26 (see Table 18 Table 18. Efficacy Results at 26 Weeks Endpoint Adalimumab 40 mg Every Other Week Subjects received 80 mg of adalimumab at Week 0, followed by 40 mg every other week starting at Week 1. N=109 Placebo N=108 PGA-F: >=2-grade improvement and clear minimal 49% 7% mNAPSI 75 47% 3% Nail pain was also evaluated and improvement in nail pain was observed in Study Ps-III. Two randomized, double-blind, placebo-controlled studies (Studies HS-I and II) evaluated the safety and efficacy of adalimumab in a total of 633 adult subjects with moderate to severe hidradenitis suppurativa (HS) with Hurley Stage II or III disease and with at least 3 abscesses or inflammatory nodules. In both studies, subjects received placebo or adalimumab at an initial dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every week starting at Week 4 and continued through Week 11. Subjects used topical antiseptic wash daily. Concomitant oral antibiotic use was allowed in Study HS-II. Both studies evaluated Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12. HiSCR was defined as at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to baseline (see Table 19 In both studies, a higher proportion of adalimumab- than placebo-treated subjects achieved HiSCR (see Table 19 Table 19. Efficacy Results at 12 Weeks in Subjects with Moderate to Severe Hidradenitis Suppurativa HS Study I HS Study II 19. 3% of subjects in Study HS-II continued baseline oral antibiotic therapy during the study. Placebo Adalimumab 40 mg Weekly Placebo Adalimumab 40 mg Weekly Hidradenitis Suppurativa Clinical Response (HiSCR) N=154 40 (26%) N=153 64 (42%) N=163 45 (28%) N=163 96 (59%) In both studies, from Week 12 to Week 35 (Period B), subjects who had received adalimumab were re-randomized to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo). Subjects who had been randomized to placebo were assigned to receive adalimumab 40 mg every week (Study HS-I) or placebo (Study HS-II). During Period B, 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. The safety and efficacy of adalimumab were assessed in adult patients with non-infectious intermediate, posterior and panuveitis excluding patients with isolated anterior uveitis, in two randomized, double-masked, placebo-controlled studies (UV I and II). Patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. The primary efficacy endpoint in both studies was ´time to treatment failure´. Treatment failure was a multi-component outcome defined as the development of new inflammatory chorioretinal and/or inflammatory retinal vascular lesions, an increase in anterior chamber (AC) cell grade or vitreous haze (VH) grade or a decrease in best corrected visual acuity (BCVA). Study UV I evaluated 217 patients with active uveitis while being treated with corticosteroids (oral prednisone at a dose of 10 to 60 mg/day). All patients received a standardized dose of prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by Week 15. Study UV II evaluated 226 patients with inactive uveitis while being treated with corticosteroids (oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequently underwent a mandatory taper schedule, with complete corticosteroid discontinuation by Week 19. Clinical Response Results from both studies demonstrated statistically significant reduction of the risk of treatment failure in patients treated with adalimumab versus patients receiving placebo. In both studies, all components of the primary endpoint contributed cumulatively to the overall difference between adalimumab and placebo groups (Table 20). Time to Treatment Failure in Studies UV I and UV II UV I UV II Placebo (N=107) Adalimumab (N=110) HR [95% CI] HR of adalimumab versus placebo from proportional hazards regression with treatment as factor. Placebo (N=111) Adalimumab (N=115) HR [95% CI] Failure Treatment failure at or after Week 6 in Study UV I, or at or after Week 2 in Study UV II, was counted as event. Subjects who discontinued the study were censored at the time of dropping out. 84] Median Time to Failure (Months) [95% CI] 3. 0] NE NE=not estimable. Fewer than half of at-risk subjects had an event. N/A Figure 3. Kaplan-Meier Curves Summarizing Time to Treatment Failure on or after Week 6 (Study UV I) or Week 2 (Study UV II) Study UV I Study UV II Note: P#=Placebo (Number of Events/Number at Risk); A#=Adalimumab (Number of Events/Number at Risk). Study UV I Study UV II.
REFERENCES
1.">Hidradenitis Suppurativa Clinical Studies
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. 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) Adverse Reaction (Preferred Term) Adalimumab 40 mg Subcutaneous Every Other Week (N=705) Placebo (N=690) 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: 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) [see Warnings and Precautions (5) Adverse Reactions (6) 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. 4) Crohn''s Disease Clinical Studies Adults: [see Clinical Studies (14. 5) Pediatric Patients 6 Years to 17 Years: [see Clinical Studies (14. 6) 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 [see Clinical Studies (14. 7) 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. 8) 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. 9) 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. Adalimumab has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-label extension studies [see Clinical Studies (14.
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 (14.9) 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.
OVERDOSAGE
Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.
NONCLINICAL TOXICOLOGY
Long-term animal studies of adalimumab products have not been conducted to evaluate the carcinogenic potential or its effect on fertility.
CLINICAL STUDIES
The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in patients >=18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. Adalimumab was administered subcutaneously in combination with methotrexate (MTX) (12. 5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV). Study RA-I evaluated 271 patients who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks. Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks. Study RA-III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week for up to 5 years. Study RA-IV assessed safety in 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks. Study RA-V evaluated 799 patients with moderately to severely active RA of less than 3 years duration who were >=18 years old and MTX naïve. Patients were randomized to receive either MTX (optimized to 20 mg/week by Week 8), adalimumab 40 mg every other week or adalimumab/MTX combination therapy for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among patients enrolled in the study was 5 months. The median MTX dose achieved was 20 mg. Clinical Response The percent of adalimumab-treated patients achieving ACR 20, 50, and 70 responses in Studies RA-II and III are shown in Table 3. ACR Responses in Studies RA-II and RA-III (Percent of Patients) Response Study RA-II Monotherapy (26 weeks) Study RA-III Methotrexate Combination (24 and 52 weeks) Placebo N=110 Adalimumab 40 mg Every Other Week N=113 Adalimumab 40 mg Weekly N=103 Placebo/MTX N=200 Adalimumab/MTX 40 mg Every Other Week N=207 ACR20 Month 6 19% 46% p<0. 01, adalimumab vs. 53% 30% 63% Month 12 NA NA NA 24% 59% ACR50 Month 6 8% 22% 35% 10% 39% Month 12 NA NA NA 10% 42% ACR70 Month 6 2% 12% 18% 3% 21% Month 12 NA NA NA 5% 23% The results of Study RA-I were similar to Study RA-III; patients receiving adalimumab 40 mg every other week in Study RA-I also achieved ACR 20, 50, and 70 response rates of 65%, 52%, and 24%, respectively, compared to placebo responses of 13%, 7%, and 3% respectively, at 6 months (p<0. The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in Table 4. ACR response rates and improvement in all components of ACR response were maintained to Week 104. Over the 2 years in Study RA-III, 20% of adalimumab patients receiving 40 mg every other week achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. ACR responses were maintained in similar proportions of patients for up to 5 years with continuous adalimumab treatment in the open-label portion of Study RA-III. Components of ACR Response in Studies RA-II and RA-III Parameter (median) Study RA-II Study RA-III Placebo N=110 Adalimumab 40 mg adalimumab administered every other week. N=113 Placebo/MTX N=200 Adalimumab /MTX N=207 Baseline Wk 26 Baseline Wk 26 Baseline Wk 24 Baseline Wk 24 Number of tender joints (0en dash68) 35 26 31 16 p<0. 001, adalimumab vs. placebo, based on mean change from baseline. 26 15 24 8 Number of swollen joints (0en dash66) 19 16 18 10 17 11 18 5 Physician global assessment Visual analogue scale; 0=best, 10=worst. 0 Patient global assessment 7. 1 Disability index (HAQ) Disability Index of the Health Assessment Questionnaire; 0=best, 3=worst, measures the patient''s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. 8 CRP (mg/dL) 3. 4 The time course of ACR 20 response for Study RA-III is shown in Figure 1. In Study RA-III, 85% of patients with ACR 20 responses at Week 24 maintained the response at 52 weeks. The time course of ACR 20 response for Study RA-I and Study RA-II were similar. Study RA-III ACR 20 Responses Over 52 Weeks In Study RA-IV, 53% of patients treated with adalimumab 40 mg every other week plus standard of care had an ACR 20 response at Week 24 compared to 35% on placebo plus standard of care (p<0. No unique adverse reactions related to the combination of adalimumab and other DMARDs were observed. In Study RA-V with MTX naïve patients with recent onset RA, the combination treatment with adalimumab plus MTX led to greater percentages of patients achieving ACR responses than either MTX monotherapy or adalimumab monotherapy at Week 52 and responses were sustained at Week 104 (see Table 5 Table 5. ACR Response in Study RA-V (Percent of Patients) Response MTX p<0. 05, adalimumab/MTX vs. MTX for ACR 20; p<0. 001, adalimumab/MTX vs. MTX for ACR 50 and 70, and Major Clinical Response. N=257 Adalimumab p<0. N=274 Adalimumab/MTX N=268 ACR20 Week 52 63% 54% 73% Week 104 56% 49% 69% ACR50 Week 52 46% 41% 62% Week 104 43% 37% 59% ACR70 Week 52 27% 26% 46% Week 104 28% 28% 47% Major Clinical Response Major clinical response is defined as achieving an ACR70 response for a continuous six month period. 28% 25% 49% At Week 52, all individual components of the ACR response criteria for Study RA-V improved in the adalimumab/MTX group and improvements were maintained to Week 104. Figure 1 Radiographic Response In Study RA-III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The results are shown in Table 6. Adalimumab/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks. Radiographic Mean Changes Over 12 Months in Study RA-III Placebo/MTX Adalimumab/MTX 40 mg Every Other Week Placebo/MTX Adalimumab/MTX (95% Confidence Interval 95% confidence intervals for the differences in change scores between MTX and adalimumab. ) P-value Based on rank analysis. Total Sharp score 2. 001 Erosion score 1. 001 JSN score 1. 002 In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of adalimumab were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined by a change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg adalimumab every other week have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with 50% showing no progression of structural damage defined by a change in the TSS of zero or less. In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the adalimumab/MTX combination group as compared to either the MTX or adalimumab monotherapy group at Week 52 as well as at Week 104 (see Table 7 Table 7. Radiographic Mean Change mean (95% confidence interval). MTX at 52 and 104 weeks and for adalimumab/MTX vs. adalimumab at 104 weeks. N=257 Adalimumab , p<0. 01, for adalimumab/MTX vs. adalimumab at 52 weeks. N=274 Adalimumab/MTX N=268 52 Weeks Total Sharp score 5. 1) Erosion score 3. 2) JSN score 2. 0) 104 Weeks Total Sharp score 10. 9) Erosion score 6. 6) JSN score 4. 5) Physical Function Response In Studies RA-I through IV, adalimumab showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ-DI) from baseline to the end of study, and significantly greater improvement than placebo in the health-outcomes as assessed by the Short Form Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS). In Study RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at Week 52 was 0. 65) for the adalimumab patients and 0. 33) for placebo/MTX (p<0. 001) patients. Sixty-three percent of adalimumab-treated patients achieved a 0. 5 or greater improvement in HAQ-DI at Week 52 in the double-blind portion of the study. Eighty-two percent of these patients maintained that improvement through Week 104 and a similar proportion of patients maintained this response through Week 260 (5 years) of open-label treatment. Mean improvement in the SF-36 was maintained through the end of measurement at Week 156 (3 years). In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement (p<0. 001) for the adalimumab/MTX combination therapy group versus either the MTX monotherapy or the adalimumab monotherapy group at Week 52, which was maintained through Week 104. The safety and efficacy of adalimumab were assessed in two studies (Studies JIA-I and JIA-II) in patients with active polyarticular juvenile idiopathic arthritis (JIA). Study JIA-I The safety and efficacy of adalimumab were assessed in a multicenter, randomized, withdrawal, double-blind, parallel-group study in 171 patients who were 4 to 17 years of age with polyarticular JIA. In the study, the patients were stratified into two groups: MTX-treated or non MTX-treated. All patients had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. Patients who received prior treatment with any biologic DMARDS were excluded from the study. The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, adalimumab was administered based on body surface area at a dose of 24 mg/m 2 Patients demonstrating a Pediatric ACR 30 response at the end of OL-LI phase were randomized into the double-blind (DB) phase of the study and received either adalimumab or placebo every other week for 32 weeks or until disease flare. Disease flare was defined as a worsening of >=30% from baseline in >=3 of 6 Pediatric ACR core criteria, >=2 active joints, and improvement of >30% in no more than 1 of the 6 criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE-BSA), before converting to a fixed dose regimen based on body weight (OLE-FD phase). Study JIA-I Clinical Response At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients who received adalimumab experienced disease flare compared to placebo, both without MTX (43% vs. 71%) and with MTX (37% vs. More patients treated with adalimumab continued to show Pediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses were maintained for up to two years in the OLE phase in patients who received adalimumab throughout the study. Study JIA-II Adalimumab was assessed in an open-label, multicenter study in 32 patients who were 2 to <4 years of age or 4 years of age and older weighing <15 kg with moderately to severely active polyarticular JIA. Most patients (97%) received at least 24 weeks of adalimumab treatment dosed 24 mg/m 2 [see Adverse Reactions (6. 1) The safety and efficacy of adalimumab were assessed in two randomized, double-blind, placebo-controlled studies in 413 patients with psoriatic arthritis (PsA). Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week. Study PsA-I enrolled 313 adult patients with moderately to severely active PsA (>3 swollen and >3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose of <=30 mg/week for >1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or placebo every other week were administered during the 24-week double-blind period of the study. Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease activity (see Tables 8 9 Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p<0. PASI responses were apparent in some patients at the time of the first visit (two weeks). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. ACR Response in Study PsA-I (Percent of Patients) Placebo N=162 Adalimumab p<0. 001 for all comparisons between adalimumab and placebo. N=151 ACR20 Week 12 Week 24 14% 15% 58% 57% ACR50 Week 12 Week 24 4% 6% 36% 39% ACR70 Week 12 Week 24 1% 1% 20% 23% Table 9. Components of Disease Activity in Study PsA-I Placebo N=162 Adalimumab p<0. 001 for adalimumab vs. placebo comparisons based on median changes. N=151 Parameter: median Baseline 24 weeks Baseline 24 weeks Number of tender joints Scale 0en dash78. 0 Number of swollen joints Scale 0en dash76. 0 Physician global assessment Visual analog scale; 0=best, 100=worst. 0 Patient global assessment 49. 0 Disability index (HAQ) Disability Index of the Health Assessment Questionnaire; 0=best, 3=worst; measures the patient''s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. 4 CRP (mg/dL) Normal range: 0en dash0. 2 Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by >=3 tender joints and >=3 swollen joints at enrollment. Radiographic Response Radiographic changes were assessed in the PsA studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on adalimumab or placebo and at Week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i. , not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs. Adalimumab-treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 weeks (see Table 10 Table 10. Change in Modified Total Sharp Score in Psoriatic Arthritis Placebo N=141 Adalimumab N=133 Week 24 Week 24 Week 48 Baseline mean 22. 4 Mean change +/- SD 0. 001 for the difference between adalimumab, Week 48 and Placebo, Week 24 (primary analysis). Physical Function Response In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of adalimumab every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24, respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24, respectively). At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study. The safety and efficacy of adalimumab 40 mg every other week were assessed in 315 adult patients in a randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score >=4 cm, (2) a visual analog score (VAS) for total back pain >=40 mm, and (3) morning stiffness >=1 hour. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks. Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 11. Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis. ASAS 20 Response By Visit, Study AS-I At 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of patients receiving adalimumab, compared to 21%, 10%, and 5% respectively, of patients receiving placebo (p<0. Similar responses were seen at Week 24 and were sustained in patients receiving open-label adalimumab for up to 52 weeks. A greater proportion of patients treated with adalimumab (22%) achieved a low level of disease activity at 24 weeks (defined as a value <20 [on a scale of 0 to 100 mm] in each of the four ASAS response parameters) compared to patients treated with placebo (6%). Components of Ankylosing Spondylitis Disease Activity Placebo N=107 Adalimumab N=208 Baseline mean Week 24 mean Baseline mean Week 24 mean ASAS 20 Response Criteria Statistically significant for comparisons between adalimumab and placebo at Week 24. Patient''s Global Assessment of Disease Activity Percent of subjects with at least a 20% and 10-unit improvement measured on a Visual Analog Scale (VAS) with 0=none and 100=severe. , 65 60 63 38 Total back pain 67 58 65 37 Inflammation Mean of questions 5 and 6 of BASDAI (defined in ''d''). 6 BASFI Bath Ankylosing Spondylitis Functional Index. , 56 51 52 34 BASDAI Bath Ankylosing Spondylitis Disease Activity Index. 7 BASMI Bath Ankylosing Spondylitis Metrology Index. 3 Tragus to wall (cm) 15. 4 Lumbar flexion (cm) 4. 4 Cervical rotation (degrees) 42. 6 Lumbar side flexion (cm) 8. 7 Intermalleolar distance (cm) 92. 8 CRP C-Reactive Protein (mg/dL). 6 A second randomized, multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis showed similar results. Patients treated with adalimumab achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3. 1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7. 9) compared to placebo-treated patients at Week 24. Figure 2 The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with moderately to severely active Crohn''s disease, CD, (Crohn''s Disease Activity Index (CDAI) >=220 and <=450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of patients continued to receive at least one of these medications. Induction of clinical remission (defined as CDAI <150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker naïve patients were randomized to one of four treatment groups: the placebo group received placebo at Weeks 0 and 2, the 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2. Clinical results were assessed at Week 4. In the second induction study, Study CD-II, 325 patients who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg adalimumab at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 patients with active disease received open-label adalimumab, 80 mg at Week 0 and 40 mg at Week 2. Patients were then randomized at Week 4 to 40 mg adalimumab every other week, 40 mg adalimumab every week, or placebo. The total study duration was 56 weeks. Patients in clinical response (decrease in CDAI >=70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4. Induction of Clinical Remission A greater percentage of the patients treated with 160/80 mg adalimumab achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF blocker naïve (CD-I), or had lost response to or were intolerant to infliximab (CD-II) (see Table 12 Table 12. Induction of Clinical Remission in Studies CD-I and CD-II (Percent of Patients) Clinical remission is CDAI score <150; clinical response is decrease in CDAI of at least 70 points. CD-I CD-II Placebo N=74 Adalimumab 160/80 mg N=76 Placebo N=166 Adalimumab 160/80 mg N=159 Week 4 Clinical remission 12% 36% p<0. placebo pairwise comparison of proportions. 7% 21% Clinical response 34% 58% p<0. 01 for adalimumab vs. 34% 52% Maintenance of Clinical Remission In Study CD-III at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. At Weeks 26 and 56, greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the adalimumab 40 mg every other week maintenance group compared to patients in the placebo maintenance group (see Table 13 Table 13. Maintenance of Clinical Remission in CD-III (Percent of Patients) Clinical remission is CDAI score <150; clinical response is decrease in CDAI of at least 70 points. Placebo N=170 40 mg Adalimumab Every Other Week N=172 Week 26 Clinical remission 17% 40% p<0. placebo pairwise comparisons of proportions Clinical response 28% 54% Week 56 Clinical remission 12% 36% Clinical response 18% 43% Of those in response at Week 4 who attained remission during the study, patients in the adalimumab every other week group maintained remission for a longer time than patients in the placebo maintenance group. Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses. A randomized, double-blind, 52-week clinical study of 2 dose concentrations of adalimumab (Study PCD-I) was conducted in 192 pediatric patients (6 to 17 years of age) with moderately to severely active Crohn''s disease (defined as Pediatric Crohn''s Disease Activity Index (PCDAI) score >30). Enrolled patients had over the previous two year period an inadequate response to corticosteroids or an immunomodulator (i. , azathioprine, 6-mercaptopurine, or methotrexate). Patients who had previously received a TNF blocker were allowed to enroll if they had previously had loss of response or intolerance to that TNF blocker. Patients received open-label induction therapy at a dose based on their body weight (>=40 kg and <40 kg). Patients weighing >=40 kg received 160 mg (at Week 0) and 80 mg (at Week 2). Patients weighing <40 kg received 80 mg (at Week 0) and 40 mg (at Week 2). At Week 4, patients within each body weight category (>=40 kg and <40 kg) were randomized 1:1 to one of two maintenance dose regimens (high dose and low dose). The high dose was 40 mg every other week for patients weighing >=40 kg and 20 mg every other week for patients weighing <40 kg. The low dose was 20 mg every other week for patients weighing >=40 kg and 10 mg every other week for patients weighing <40 kg. Concomitant stable dosages of corticosteroids (prednisone dosage <=40 mg/day or equivalent) and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted throughout the study. At Week 12, patients who experienced a disease flare (increase in PCDAI of >=15 from Week 4 and absolute PCDAI >30) or who were non-responders (did not achieve a decrease in the PCDAI of >=15 from baseline for 2 consecutive visits at least 2 weeks apart) were allowed to dose-escalate (i. , switch from blinded every other week dosing to blinded every week dosing); patients who dose-escalated were considered treatment failures. At baseline, 38% of patients were receiving corticosteroids, and 62% of patients were receiving an immunomodulator. Forty-four percent (44%) of patients had previously lost response or were intolerant to a TNF blocker. The median baseline PCDAI score was 40. Of the 192 patients total, 188 patients completed the 4 week induction period, 152 patients completed 26 weeks of treatment, and 124 patients completed 52 weeks of treatment. Fifty-one percent (51%) (48/95) of patients in the low maintenance dose group dose-escalated, and 38% (35/93) of patients in the high maintenance dose group dose-escalated. At Week 4, 28% (52/188) of patients were in clinical remission (defined as PCDAI <=10). The proportions of patients in clinical remission (defined as PCDAI <=10) and clinical response (defined as reduction in PCDAI of at least 15 points from baseline) were assessed at Weeks 26 and 52. At both Weeks 26 and 52, the proportion of patients in clinical remission and clinical response was numerically higher in the high dose group compared to the low dose group (Table 14). The recommended maintenance regimen is 20 mg every other week for patients weighing <40 kg and 40 mg every other week for patients weighing >=40 kg. Every week dosing is not the recommended maintenance dosing regimen [see Dosage and Administration (2. 3) Table 14. Clinical Remission and Clinical Response in Study PCD-I Low Maintenance Dose The low maintenance dose was 20 mg every other week for patients weighing >=40 kg and 10 mg every other week for patients weighing <40 kg. (20 or 10 mg Every Other Week) N=95 High Maintenance Dose The high maintenance dose was 40 mg every other week for patients weighing >= 40 kg and 20 mg every other week for patients weighing <40 kg. (40 or 20 mg Every Other Week) N=93 Week 26 Clinical Remission Clinical remission defined as PCDAI <=10. 28% 39% Clinical Response Clinical response defined as reduction in PCDAI of at least 15 points from baseline. 48% 59% Week 52 Clinical Remission 23% 33% Clinical Response 28% 42% The safety and efficacy of adalimumab were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 on a 12 point scale, with an endoscopy subscore of 2 to 3 on a scale of 0 to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP in two randomized, double-blind, placebo-controlled clinical studies (Studies UC-I and UC-II). Both studies enrolled TNF-blocker naïve patients, but Study UC-II also allowed entry of patients who lost response to or were intolerant to TNF-blockers. Forty percent (40%) of patients enrolled in Study UC-II had previously used another TNF-blocker. Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I and II, patients were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of patients received at least one of these medications. Induction of clinical remission (defined as Mayo score <=2 with no individual subscores >1) at Week 8 was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks 8 and 52) were evaluated in Study UC-II. In Study UC-I, 390 TNF-blocker naïve patients were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Weeks 0, 2, 4 and 6. The 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, and the 80/40 group received 80 mg adalimumab at Week 0 and 40 mg at Week 2. After Week 2, patients in both adalimumab treatment groups received 40 mg every other week. In Study UC-II, 518 patients were randomized to receive either adalimumab 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week starting at Week 4 through Week 50, or placebo starting at Week 0 and every other week through Week 50. Corticosteroid taper was permitted starting at Week 8. In both Studies UC-I and UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved induction of clinical remission. In Study UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved sustained clinical remission (clinical remission at both Weeks 8 and 52) (Table 15). Induction of Clinical Remission in Studies UC-I and UC-II and Sustained Clinical Remission in Study UC-II (Percent of Patients) Clinical remission is defined as Mayo score <=2 with no individual subscores >1. CI=Confidence interval. Study UC-I Study UC-II Placebo N=130 Adalimumab 160/80 mg N=130 Treatment Difference (95% CI) Placebo N=246 Adalimumab 160/80 mg N=248 Treatment Difference (95% CI) Induction of Clinical Remission (Clinical Remission at Week 8) 9. 05 for adalimumab vs. 2% Sustained Clinical Remission (Clinical Remission at both Weeks 8 and 52) N/A N/A N/A 4. 4% In Study UC-I, there was no statistically significant difference in clinical remission observed between the adalimumab 80/40 mg group and the placebo group at Week 8. In Study UC-II, 17. 3% (43/248) in the adalimumab group were in clinical remission at Week 52 compared to 8. 5% (21/246) in the placebo group (treatment difference: 8. 8%; 95% confidence interval (CI): [2. In the subgroup of patients in Study UC-II with prior TNF-blocker use, the treatment difference for induction of clinical remission appeared to be lower than that seen in the whole study population, and the treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be similar to those seen in the whole study population. The subgroup of patients with prior TNF-blocker use achieved induction of clinical remission at 9% (9/98) in the adalimumab group versus 7% (7/101) in the placebo group, and sustained clinical remission at 5% (5/98) in the adalimumab group versus 1% (1/101) in the placebo group. In the subgroup of patients with prior TNF-blocker use, 10% (10/98) were in clinical remission at Week 52 in the adalimumab group versus 3% (3/101) in the placebo group. The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo-controlled studies in 1696 adult subjects with moderate to severe chronic plaque psoriasis (Ps) who were candidates for systemic therapy or phototherapy. Study Ps-I evaluated 1212 subjects with chronic Ps with >=10% body surface area (BSA) involvement, Physician''s Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) >=12 within three treatment periods. In period A, subjects received placebo or adalimumab at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, subjects who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open-label 40 mg adalimumab every other week. After 17 weeks of open-label therapy, subjects who maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician''s Global Assessment score ranged from "moderate" (53%) to "severe" (41%) to "very severe" (6%). Study Ps-II evaluated 99 subjects randomized to adalimumab and 48 subjects randomized to placebo with chronic plaque psoriasis with >=10% BSA involvement and PASI >=12. Subjects received placebo, or an initial dose of 80 mg adalimumab at Week 0 followed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from "moderate" (41%) to "severe" (51%) to "very severe" (8%). Studies Ps-I and II evaluated the proportion of subjects who achieved "clear" or "minimal" disease on the 6-point PGA scale and the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Tables 16 17 Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of "clear" or "minimal" disease or a PASI 75 response after Week 33 and on or before Week 52. Efficacy Results at 16 Weeks in Study Ps-I Number of Subjects (%) Adalimumab 40 mg Every Other Week N=814 Placebo N=398 PGA: Clear minimal Clear=no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration. 506 (62%) 17 (4%) PASI 75 578 (71%) 26 (7%) Table 17. Efficacy Results at 16 Weeks in Study Ps-II Number of Subjects (%) Adalimumab 40 mg Every Other Week N=99 Placebo N=48 PGA: Clear minimal Clear=no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration. 70 (71%) 5 (10%) PASI 75 77 (78%) 9 (19%) Additionally, in Study Ps-I, subjects on adalimumab who maintained a PASI 75 were re-randomized to adalimumab (N=250) or placebo (N=240) at Week 33. After 52 weeks of treatment with adalimumab, more subjects on adalimumab maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of "clear" or "minimal" disease (68% vs. 28%) or a PASI 75 (79% vs. A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA "moderate" or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of adalimumab, then 40 mg every other week beginning at Week 1. At Week 16, 69% (123/178) of subjects had a response of PGA "clear" or "minimal". A randomized, double-blind study (Study Ps-III) compared the efficacy and safety of adalimumab versus placebo in 217 adult subjects. Subjects in the study had to have chronic plaque psoriasis of at least moderate severity on the PGA scale, fingernail involvement of at least moderate severity on a 5-point Physician''s Global Assessment of Fingernail Psoriasis (PGA-F) scale, a Modified Nail Psoriasis Severity Index (mNAPSI) score for the target-fingernail of >=8, and either a BSA involvement of at least 10% or a BSA involvement of at least 5% with a total mNAPSI score for all fingernails of >=20. Subjects received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks. This study evaluated the proportion of subjects who achieved "clear" or "minimal" assessment with at least a 2-grade improvement on the PGA-F scale and the proportion of subjects who achieved at least a 75% improvement from baseline in the mNAPSI score (mNAPSI 75) at Week 26. At Week 26, a higher proportion of subjects in the adalimumab group than in the placebo group achieved the PGA-F endpoint. Furthermore, a higher proportion of subjects in the adalimumab group than in the placebo group achieved mNAPSI 75 at Week 26 (see Table 18 Table 18. Efficacy Results at 26 Weeks Endpoint Adalimumab 40 mg Every Other Week Subjects received 80 mg of adalimumab at Week 0, followed by 40 mg every other week starting at Week 1. N=109 Placebo N=108 PGA-F: >=2-grade improvement and clear minimal 49% 7% mNAPSI 75 47% 3% Nail pain was also evaluated and improvement in nail pain was observed in Study Ps-III. Two randomized, double-blind, placebo-controlled studies (Studies HS-I and II) evaluated the safety and efficacy of adalimumab in a total of 633 adult subjects with moderate to severe hidradenitis suppurativa (HS) with Hurley Stage II or III disease and with at least 3 abscesses or inflammatory nodules. In both studies, subjects received placebo or adalimumab at an initial dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every week starting at Week 4 and continued through Week 11. Subjects used topical antiseptic wash daily. Concomitant oral antibiotic use was allowed in Study HS-II. Both studies evaluated Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12. HiSCR was defined as at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to baseline (see Table 19 In both studies, a higher proportion of adalimumab- than placebo-treated subjects achieved HiSCR (see Table 19 Table 19. Efficacy Results at 12 Weeks in Subjects with Moderate to Severe Hidradenitis Suppurativa HS Study I HS Study II 19. 3% of subjects in Study HS-II continued baseline oral antibiotic therapy during the study. Placebo Adalimumab 40 mg Weekly Placebo Adalimumab 40 mg Weekly Hidradenitis Suppurativa Clinical Response (HiSCR) N=154 40 (26%) N=153 64 (42%) N=163 45 (28%) N=163 96 (59%) In both studies, from Week 12 to Week 35 (Period B), subjects who had received adalimumab were re-randomized to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo). Subjects who had been randomized to placebo were assigned to receive adalimumab 40 mg every week (Study HS-I) or placebo (Study HS-II). During Period B, 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. The safety and efficacy of adalimumab were assessed in adult patients with non-infectious intermediate, posterior and panuveitis excluding patients with isolated anterior uveitis, in two randomized, double-masked, placebo-controlled studies (UV I and II). Patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. The primary efficacy endpoint in both studies was ´time to treatment failure´. Treatment failure was a multi-component outcome defined as the development of new inflammatory chorioretinal and/or inflammatory retinal vascular lesions, an increase in anterior chamber (AC) cell grade or vitreous haze (VH) grade or a decrease in best corrected visual acuity (BCVA). Study UV I evaluated 217 patients with active uveitis while being treated with corticosteroids (oral prednisone at a dose of 10 to 60 mg/day). All patients received a standardized dose of prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by Week 15. Study UV II evaluated 226 patients with inactive uveitis while being treated with corticosteroids (oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequently underwent a mandatory taper schedule, with complete corticosteroid discontinuation by Week 19. Clinical Response Results from both studies demonstrated statistically significant reduction of the risk of treatment failure in patients treated with adalimumab versus patients receiving placebo. In both studies, all components of the primary endpoint contributed cumulatively to the overall difference between adalimumab and placebo groups (Table 20). Time to Treatment Failure in Studies UV I and UV II UV I UV II Placebo (N=107) Adalimumab (N=110) HR [95% CI] HR of adalimumab versus placebo from proportional hazards regression with treatment as factor. Placebo (N=111) Adalimumab (N=115) HR [95% CI] Failure Treatment failure at or after Week 6 in Study UV I, or at or after Week 2 in Study UV II, was counted as event. Subjects who discontinued the study were censored at the time of dropping out. 84] Median Time to Failure (Months) [95% CI] 3. 0] NE NE=not estimable. Fewer than half of at-risk subjects had an event. N/A Figure 3. Kaplan-Meier Curves Summarizing Time to Treatment Failure on or after Week 6 (Study UV I) or Week 2 (Study UV II) Study UV I Study UV II Note: P#=Placebo (Number of Events/Number at Risk); A#=Adalimumab (Number of Events/Number at Risk). Study UV I Study UV II.
REFERENCES
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