HULIO- adalimumab-fkjp

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.
CLINICAL PHARMACOLOGY
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 IC50 of 1-2 X 10 -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. 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. The distribution volume (Vss) ranged from 4. 0 L following intravenous administration of doses ranging from 0. 25 to 10 mg/kg in RA patients. 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. In patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations were approximately 5 mcg/mL and 8 to 9 mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA. In patients receiving 40 mg every other week, adalimumab mean steady-state trough concentrations were 6 to 10 mcg/mL and 8. 5 to 12 mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab mean steady-state trough concentration was approximately 5 to 6 mcg/mL during adalimumab 40 mg every other week treatment. Adalimumab mean steady concentration was approximately 8 to 10 mcg/mL during adalimumab 40 mg every other week treatment Adalimumab trough concentrations were approximately 7 to 8 mcg/mL at Week 2 and Week 4, respectively, after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11 mcg/mL during adalimumab 40 mg every week treatment. Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were 7 mcg/mL at Week 24 and Week 56 during adalimumab 40 mg every other week treatment. Mean steady-state trough concentrations were approximately 8 mcg/mL and 15 mcg/mL at Week 52 after receiving a dose of adalimumab 40 mg every other week and 40 mg every week, respectively. A trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies was identified. In subjects with moderate to severe HS, antibodies to adalimumab were associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum adalimumab concentrations is greater with increasing titers of antibodies to adalimumab. A lower clearance with increasing age was observed in patients with RA aged 40 to >75 years. 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: No gender-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics. No pharmacokinetic data are available in patients with hepatic or renal impairment. Minor increases in apparent clearance were predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important. Methotrexate: [see Drug Interactions (7.

INDICATIONS AND USAGE
HULIO is a tumor necrosis factor (TNF) blocker indicated for: Rheumatoid Arthritis (RA) 1. 1 J uvenile Idiopathic Arthritis (JIA) 1. 2 : Psoriatic Arthritis (PsA) 1. 3 : A nkylosing 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 HULIO is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HULIO can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). HULIO is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HULIO can be used alone or in combination with non-biologic DMARDs. HULIO is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. HULIO is indicated for the treatment of moderately to severely active ulcerative colitis in adult patients. 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. 8) HULIO is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HULIO should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Warnings and Precautions (5) HULIO is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients.
Rheumatoid Arthritis Clinical Studies
The data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). Adalimumab was studied primarily in placebo- controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week [see Clinical Studies (14.1) Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with adalimumab 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion. Table 1. Adverse Reactions Reported by >=5% of Patients Treated with Adalimumab During Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Adalimumab 40 mg subcutaneous Every Other Week Placebo (N=705) (N=690) Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection 17% 13% Sinusitis 11% 9% Flu syndrome 7% 6% Gastrointestinal Nausea 9% 8% Abdominal pain 7% 4% Laboratory Tests Laboratory test abnormalities were reported as adverse reactions in European trials Laboratory test abnormal 8% 7% Hypercholesterolemia 6% 4% Hyperlipidemia 7% 5% Hematuria 5% 4% Alkaline phosphatase increased 5% 3% Other Headache 12% 8% Rash 12% 6% Accidental injury 10% 8% Injection site reaction Does not include injection site erythema, itching, hemorrhage, pain or swelling 8% 1% Back pain 6% 4% Urinary tract infection 8% 5% Hypertension 5% 3%
Rheumatoid Arthritis and Ankylosing Spondylitis
In patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations were approximately 5 mcg/mL and 8 to 9 mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.
Psoriatic Arthritis
In patients receiving 40 mg every other week, adalimumab mean steady-state trough concentrations were 6 to 10 mcg/mL and 8.5 to 12 mcg/mL, without and with MTX concomitant treatment, respectively.
Plaque Psoriasis
Adalimumab mean steady-state trough concentration was approximately 5 to 6 mcg/mL during adalimumab 40 mg every other week treatment.
Adult Ulcerative Colitis
Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were approximately 8 mcg/mL and 15 mcg/mL at Week 52 after receiving a dose of adalimumab 40 mg every other week and 40 mg every week, respectively.
Rheumatoid Arthritis
A trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies was identified.

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 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 Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week Ulcerative Colitis ( 2. 4 Adults: Plaque Psoriasis or Adult Uveitis ( 2. 5 Adults: Hidradenitis Suppurativa ( 2. 6 Adults: o o o The recommended subcutaneous dosage of HULIO for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with HULIO. Pediatric Weight (2 Years of Age and older) 40 mg every other week There is no dosage form for HULIO that allows weight-based dosing for pediatric patients below 15 kg. Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg. [see Warnings and Precautions (5. 2) Pediatric Weight Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week The recommended subcutaneous dosage of HULIO for adult patients with ulcerative colitis is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) continue with a dosage of 40 mg every other week. Discontinue HULIO in adult patients without evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with HULIO. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5. 2) The recommended subcutaneous dosage of HULIO for adult patients with plaque psoriasis (Ps) is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of adalimumab products in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies. Prior to initiating HULIO and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5. 1) HULIO is intended for use under the guidance and supervision of a physician. A patient may self-inject HULIO or a caregiver may inject HULIO using either the HULIO Pen or prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. HULIO can be taken out of the refrigerator for 15 to 30 minutes before injecting to allow the liquid to come to room temperature. Do not remove the cap or cover while allowing it to reach room temperature. Carefully inspect the solution in the HULIO Pen or prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. HULIO does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. Instruct patients using the HULIO Pen or prefilled syringe to inject the full amount in the syringe, according to the directions provided in the Instructions for Use [see Instructions for Use Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
Adults
The safety profile of adalimumab in 1478 adult patients with Crohn’s disease from four placebo-controlled and two open-label extension studies [see Clinical Studies (14.5)
INSTRUCTIONS FOR USE - Pen
HULIO registered (adalimumab-fkjp) injection 40 mg/0.8 mL Single-Dose Pen Important Information: Do not If your healthcare provider decides that you or a caregiver may be able to give your injections of HULIO at home, you should receive training on the right way to prepare and inject HULIO. There will be a “click” during your injections. You should practice injecting HULIO with your healthcare provider so that you are not startled by this “click” when you start giving yourself injections at home. It is important that you read, understand, and follow these instructions so that you inject HULIO the right way. It is also important to talk to your healthcare provider to be sure you understand your HULIO dosing instructions. To help you remember when to inject HULIO, 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 HULIO. Each HULIO Pen can only be used one time. Throw the used Pen away (See How should I throw away (dispose of) the used HULIO Pen) For Questions or Assistance, Call Biocon Biologics at 1-833-986-1468 The figure below shows what the HULIO Pen looks like. See Figure A. Step 1. Gather the Supplies for Your Injection Take your HULIO Pen out of the refrigerator 15 to 30 minutes Do not do not Do not use HULIO if it has been frozen, even if it has been thawed. Do not Do not You will need the following supplies for each injection of HULIO. 1 HULIO Pen (See Figure A) 1 alcohol swab 1 cotton ball or gauze pad (not included in your HULIO carton) Puncture-resistant sharps disposal container for HULIO Pen disposal (not included in your HULIO carton). See the “ How should I throw away (dispose of) the used HULIO PEN If you do not have all the supplies you need to give yourself an injection, go to a pharmacy or call your pharmacist. Find a clean, flat surface to place the supplies on. Step 2. Check the Carton, Dose Tray and HULIO Pen Make sure the name HULIO appears on the carton, dose tray, and HULIO Pen label. Check the seals on the top or bottom of the carton to make sure they are not broken or missing. Check the expiration date on the carton, dose tray, and HULIO Pen. Do not use call you drop or crush your HULIO Pen. the seals on the top or bottom of the carton are broken or missing. the expiration date on the carton, dose tray, and Pen has passed. The HULIO PEN has been frozen or left in direct sunlight. HULIO has been kept at room temperature for longer than 14 the liquid in the HULIO Pen is cloudy, discolored or has flakes or particles in it. See the “ How should I store HULIO Check the fluid level in the Pen: Hold the Pen with the protective clear cap covering the orange activator pointed down. (See Figure B). Make sure the amount of liquid in the Pen is at the fill line or close to the fill line seen through the window. You may need to shake gently to see the liquid. This is the full dose of HULIO that you will inject. (See Figure B). If the Pen does not have the full amount of liquid, do not use that Pen Turn the Pen and hold with the protective clear cap covering the orange activator pointed sideways. (See Figure C). Check the solution Do not use It is normal to see one or more bubbles in the window. Step 3. Choose the Injection Site Wash your hands with soap and water and dry well. Choose an injection site on: the front of your thighs or your lower abdomen (belly). If you choose your abdomen, do not use the area 2 inches around your belly button (navel). (See Figure D). Choose a different site (rotate) each time you give yourself an injection. Each new injection should be given at least 1 inch from a site you used before. Do not sore (tender) bruised red hard Scarred or where you have stretch marks If you have psoriasis, do not Do not Figure D Step 4: Prepare the Injection Site Wipe the injection site with an alcohol prep (swab) using a circular motion. Do not Allow the skin to dry before injecting. Do not Step 5. Prepare the HULIO PEN Do not remove the protective clear cap until right before your injection. Hold the middle of the Pen (white body) with one hand so that you are not touching the protective clear cap. Turn the Pen so that the orange activator end is pointing down. See (Figure E). With your other hand, pull the protective clear cap straight off (do not twist the cap). Make sure the small needle cover of the syringe has come off with the protective clear cap. (See Figure F). Important: Do not Throw away the protective clear cap. The orange activator which covers the needle is where the needle comes out. The needle can now be seen. Caution: Never put your thumb, fingers, or hand over the orange activator after the protective clear cap is removed. Never press or push the orange activator with your thumb, fingers, or hand. If accidental injection to your fingers or hands happens, apply first-aid and either call your healthcare provider or go to the nearest hospital emergency room if needed. Do not You may see a few drops of liquid come out of the needle. This is normal. Turn the Pen so the white end is pointed up. (See Figure G). Hold the Pen so that you can see the window. (See Figure H). It is normal to see one or more bubbles in the window. Step 6. Position the Pen Squeeze Place the orange activator end of the Pen straight ( at a 90º angle Place the Pen so that it will not inject the needle into your fingers that are holding the raised skin. (See Figure J). Step 7. Inject HULIO It is important that you firmly push the Pen down Do not move, twist, or rotate the Pen during the injection. Keep pushing down You will hear a loud ‘click’ when the orange activator is pressed down against the injection site. The loud click means the start of the injection. Continue to push the Pen against your squeezed, raised skin until all the medicine is injected. This can take up to 10 seconds, so count slowly to ten. Keep pushing the Pen against the squeezed, raised skin of your injection site for the whole time so you get the full dose of medicine. You will know that the injection has finished when: A 2nd ‘Click’ was heard, and Orange indicator has stopped moving and completely blocked the viewing window (See Figure L) 10 seconds has passed. Make sure all 3 of these have happened to make certain all the medicine was delivered. If the needle did not retract or you do not think you received the full dose, contact your healthcare provider for help. When the injection is finished, slowly pull the Pen from your skin. The white needle sleeve will move to cover the needle tip. (See Figure M). Do not touch the needle. The white needle sleeve is there to prevent you from touching the needle. If the needle did not retract or you do not think you received the full dose, contact your healthcare provider for help. There may be a small amount of liquid on the injection site. This is normal. Press a cotton ball or gauze pad over the injection site and hold it for 10 seconds. Do not Step 8. “How should I throw away (dispose of) the used Pen?” How should I throw away (dispose of) the used HULIO PEN? Put your Pen in an FDA-cleared sharps disposal container right away after use. (See Figure N). Do not throw away the Pen in your household trash. Do not If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, Can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal For the safety and health of you and others, never re-use your HULIO Pens. The used alcohol pads, cotton balls, dose trays and packaging may be placed in your household trash. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Always keep the sharps container out of the reach of children. Keep a record of the dates and location of your injection sites. To help you remember when to take HULIO, you can mark your calendar ahead of time. How should I Store HULIO? Store HULIO in the refrigerator between 36ºF to 46ºF (2ºC to 8ºC). Store HULIO in the original carton until use to protect it from light. Do not If needed, for example when you are traveling, you may also store HULIO at room temperature up to 77°F (25°C) for up to 14 Throw away HULIO if it has been kept at room temperature and not been used within 14 Do not Keep HULIO, injection supplies, and all other medicines out of the reach of children. Manufactured by and for: Biocon Biologics Inc. 245 Main St, 2nd Floor, Cambridge, MA 02142, U.S.A. U.S. License No. 2324 Product of Japan This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 02/2025
INSTRUCTIONS FOR USE - Syringe
HULIO registered (adalimumab-fkjp) injection 40 mg/0. 8 mL and 20 mg/0. 4 mL Single-Dose Prefilled Syringe Important Information: Do not If your healthcare provider decides that you or a caregiver may be able to give your injections of HULIO at home, you should receive training on the right way to prepare and inject HULIO. It is important that you read, understand, and follow these instructions so that you inject HULIO the right way. It is also important to talk to your healthcare provider to be sure you understand your HULIO dosing instructions. To help you remember when to inject HULIO, 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 HULIO. Each HULIO Prefilled Syringe can only be used one time. Throw the used Prefilled Syringe away (See How should I throw away (dispose of) the used Prefilled Syringe?) For Questions or Assistance, Call Biocon Biologics at 1-833-986-1468 The figure shows what a prefilled syringe looks like. See Figure A. Gather the Supplies for Your Injection Take your HULIO prefilled syringe out of the refrigerator 15 to 30 minutes Do not do not Do not use HULIO if it has been frozen, even if it has been thawed. Do not put HULIO back in the refrigerator after reaching room temperature. Do not You will need the following supplies for each injection of HULIO. 1 HULIO Prefilled Syringe (See Figure A) 1 alcohol swab 1 cotton ball or gauze pad (not included in your HULIO carton) Puncture-resistant sharps disposal container for HULIO prefilled syringe disposal (not included in your HULIO carton). See “How should I throw away (dispose of) the used prefilled syringes and needles?” If you do not have all the supplies you need to give yourself an injection, go to a pharmacy or call your pharmacist. Find a clean, flat surface to place the supplies on. Check the carton, dose tray, and prefilled Syringe Make sure the name HULIO appears on the dose tray and prefilled syringe label. Check the seals on the top or bottom of the carton to make sure they are not broken or missing. Check the expiration date on the carton, dose tray, and HULIO Prefilled Syringe. Do not use call o you drop or crush your HULIO Prefilled Syringe. o the seals on the top or bottom of the carton are broken or missing. o the expiration date on the carton, dose tray, and HULIO Prefilled Syringe have passed. o the prefilled syringe has been frozen or left in direct sunlight. o HULIO has been kept at room temperature for longer than 14 days or HULIO has been stored above 77°F (25°C). o the liquid in the prefilled syringe is cloudy, discolored or has flakes or particles in it. See the “How should I store HULIO?” Check the fluid level in the syringe: Hold the syringe with the covered needle pointing down. (See Figure B). Hold the syringe at eye level. Look closely to make sure that the amount of liquid in the syringe is the same or close to the: 0. 8 mL line for the 40 mg prefilled syringe. (See Figure C). 4 mL line for the 20 mg prefilled syringe. You may need to shake gently to see liquid. The top of the liquid may be curved. If the syringe does not have the correct amount of liquid, do not use that syringe. Choose the Injection Site Wash your hands with soap and water and dry well. Choose an injection site on: the front of your thighs or your lower abdomen (belly). If you choose your abdomen, do not use the area 2 inches around your belly button (navel). (See Figure D). Choose a different site (rotate) each time you give yourself an injection. Each new injection should be given at least 1 inch from a site you used before. Do not sore (tender) bruised red hard scarred or where you have stretch marks If you have psoriasis, do not Do not Step 4. Prepare the Injection Site Wipe the injection site with an alcohol prep (swab) using a circular motion. Do not Allow the skin to dry before injecting. Do not fan or blow on the clean area. Prepare the HULIO Prefilled Syringe and Needle Do not remove the needle cover until right before your injection. Hold the syringe in one hand. With the other hand gently remove the needle cover. (See Figure E). Throw away the needle cover. Important: Do not Do not Do not Do not You may see a drop of liquid at the end of the needle. This is normal. Position the Syringe Hold the body of the prefilled syringe in one hand between the thumb and index finger. Hold the syringe in your hand like a pencil. (See Figure F). Do not With your other hand, gently squeeze the area of the cleaned skin and hold it firmly. (See Figure G). Inject HULIO Using a quick, dart-like motion, insert the needle into the squeezed skin at about a 45-degree angle After the needle is in, let go of the skin. Do not move, twist, or rotate the Syringe during the injection. Slowly push the plunger all the way in until all the liquid is injected and the syringe is empty. If the plunger is not pressed all the way down the Needle Safety Feature will not activate afterwards to cover the needle Do not Pull the needle out of the skin while keeping the syringe at the same angle, then release your thumb from the plunger. The needle will retract and the Needle Safety Feature will cover the needle. (See Figure I). Caution: Press a cotton ball or gauze pad over the injection site and hold it for 10 seconds. Do not Step 8. How should I throw away (dispose of) used prefilled syringes and needles?” How should I throw away (dispose of) used prefilled syringes and needles? Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. (See Figure J). Do not throw away (dispose of) loose needles and syringes in your household trash. Do not If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www. gov/safesharpsdisposal For the safety and health of you and others, needles and used syringes must never The used alcohol pads, cotton balls, dose trays and packaging may be placed in your household trash. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Always keep the sharps container out of the reach of children. Keep a record of the dates and location of your injection sites in the injection diary. To help you remember when to take HULIO, you can mark your calendar ahead of time. How should I store HULIO? Store HULIO in the refrigerator between 36ºF to 46ºF (2ºC to 8ºC). Store HULIO in the original carton until use to protect it from light. Do not If needed, for example when you are traveling, you may also store HULIO at room temperature up to 77°F (25°C) for up to 14 days. Throw away HULIO if it has been kept at room temperature and not been used within 14 days. Do not Keep HULIO, injection supplies, and all other medicines out of the reach of children. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor, Cambridge, MA 02142, U. 2324 Product of Japan Revised: 02/2025 This Instructions for Use has been approved by the U. Food and Drug Administration. Instructions for Use Figure A Instructions for Use Figure E Instructions for Use Figure F Instructions for Use Figure G Instructions for Use Figure H Instructions for Use Figure I.

Lymphoma and Leukemia
In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, 2 lymphomas occurred among 7973 adalimumab-treated patients versus 1 among 4848 control-treated patients. In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV with a median duration of approximately 0.7 years, including 24,605 patients and over 40,215 patient-years of adalimumab, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). 1
ADVERSE REACTIONS
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 Biocon Biologics at 1-833-986-1468 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. In the controlled portions of the 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS, UV, the rate of serious infections was 4. 3 per 100 patient years in 7973 adalimumab treated patients versus a rate of 2. 9 per 100 patient years in 4848 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions (5. 1) In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS, UV, and another indication 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) 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. There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of adalimumab (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations >= 3 x ULN occurred in 3. 5% of adalimumab-treated patients and 1. 5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e. , NSAIDS, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear. In a controlled Phase 3 trial of adalimumab in patients with polyarticular JIA who were 4 to 17 years, ALT elevations >= 3 x ULN occurred in 4. 4% of adalimumab-treated patients and 1. 5% of control-treated patients (ALT more common than AST); liver enzyme test elevations were more frequent among those treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In general, these elevations did not lead to discontinuation of adalimumab treatment. No ALT elevations >= 3 x ULN occurred in the open-label study of adalimumab in patients with polyarticular JIA who were 2 to < 4 years. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in adult patients with Crohn’s Disease with a control period duration ranging from 4 to 52 weeks, ALT elevations >= 3 x ULN occurred in 0. 9% of adalimumab-treated patients and 0. 9% of control-treated patients. In the Phase 3 trial of adalimumab in pediatric patients with Crohn’s disease which evaluated efficacy and safety of two body weight based maintenance dose regimens following body weight based induction therapy up to 52 weeks of treatment, ALT elevations >= 3 x ULN occurred in 2. 6% (5/192) of patients, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these patients discontinued due to abnormalities in ALT tests. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in adult patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations >=3 x ULN occurred in 1. 0% of control-treated patients. In controlled Phase 3 trials of adalimumab (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations >= 3 x ULN occurred in 1. 8% of adalimumab-treated patients and 1. 8% of control-treated patients. In controlled trials of adalimumab (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in subjects with HS with a control period duration ranging from 12 to 16 weeks, ALT elevations >= 3 x ULN occurred in 0. 3% of adalimumab-treated subjects and 0. 6% of control-treated subjects. In controlled trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis with an exposure of 165. 4 PYs and 119. 8 PYs in adalimumab-treated and control-treated patients, respectively, ALT elevations >= 3 x ULN occurred in 2. 4% of adalimumab-treated patients and 2. 4% of control-treated patients. 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) Adalimumab 40 mg subcutaneous Every Other Week Placebo (N=705) (N=690) Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection 17% 13% Sinusitis 11% 9% Flu syndrome 7% 6% Gastrointestinal Nausea 9% 8% Abdominal pain 7% 4% Laboratory Tests Laboratory test abnormalities were reported as adverse reactions in European trials Laboratory test abnormal 8% 7% Hypercholesterolemia 6% 4% Hyperlipidemia 7% 5% Hematuria 5% 4% Alkaline phosphatase increased 5% 3% Other Headache 12% 8% Rash 12% 6% Accidental injury 10% 8% Injection site reaction Does not include injection site erythema, itching, hemorrhage, pain or swelling 8% 1% Back pain 6% 4% Urinary tract infection 8% 5% Hypertension 5% 3% Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in adalimumab-treated patients in RA studies were: Body As A Whole: Cardiovascular System: Digestive System: Endocrine System: Hemic And Lymphatic System: Metabolic And Nutritional Disorders: Musculo-Skeletal System: Neoplasia: Nervous System: Respiratory System: Special Senses: Thrombosis: Urogenital System: 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. 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) The safety profile of adalimumab in 1478 adult patients with Crohn’s disease from four placebo-controlled and two open-label extension studies [see Clinical Studies (14. 5) The safety profile of adalimumab in 192 pediatric patients from one double-blind study (Study PCD-I) and one open-label extension study [see Clinical Studies (14. 6) 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. Adults: [see Clinical Studies (14. 7) Adalimumab has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies [see Clinical Studies (14. Adalimumab has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo-controlled studies and one open-label extension study [see Clinical Studies (14. 10) 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. 11) The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of adalimumab or of other adalimumab products. There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of anti-adalimumab antibody (AAA) development in patients treated with adalimumab are presented in Table 2. Table 2: Anti-Adalimumab Antibody Development Determined by ELISA and ECL Assay in Patients Treated with Adalimumab n: number of patients with anti-adalimumab antibody; NR: not reported; NA: Not applicable (not performed) Indications Study Duration Anti-Adalimumab Antibody Incidence by ELISA (n/N) Anti-Adalimumab Antibody Incidence by ECL Assay (n/N) In all patients who received adalimumab In patients with serum adalimumab concentrations < 2 mcg/mL Rheumatoid Arthritis In patients receiving concomitant methotrexate (MTX), the incidence of anti-adalimumab antibody was 1% compared to 12% with adalimumab monotherapy 6 to 12 months 5% (58/1062) NR NA Juvenile Idiopathic Arthritis (JIA) 4 to 17 years of age In patients receiving concomitant MTX, the incidence of anti-adalimumab antibody was 6% compared to 26% with adalimumab monotherapy 48 weeks 16% (27/171) NR NA 2 to 4 years of age or >= 4 years of age and weighing < 15 kg 24 weeks 7% (1/15) This patient received concomitant MTX NR NA Psoriatic Arthritis In patients receiving concomitant MTX, the incidence of antibody development was 7% compared to 1% in RA 48 weeks Subjects enrolled after completing 2 previous studies of 24 weeks or 12 weeks of treatments. 13% (24/178) NR NA Ankylosing Spondylitis 24 weeks 9% (16/185) NR NA Adult Crohn’s Disease 56 weeks 3% (7/269) 8% (7/86) NA Pediatric Crohn’s Disease 52 weeks 3% (6/182) 10% (6/58) NA Adult Ulcerative Colitis 52 weeks 5% (19/360) 21% (19/92) NA Plaque Psoriasis In plaque psoriasis patients who were on adalimumab monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal Up to 52 weeks One 12-week Phase 2 study and one 52-week Phase 3 study 8% (77/920) 21% (77/372) NA Hidradenitis Suppurativa 36 weeks 7% (30/461) 28% (58/207) Among subjects in the 2 Phase 3 studies who stopped adalimumab treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to <2 mcg/mL (approximately 22% of total subjects studied) 61% (272/445) No apparent association between antibody development and safety was observed Non-infectious Uveitis 52 weeks 5% (12/249) 21% (12/57) 40% (99/249) No correlation of antibody development to safety or efficacy outcomes was observed Rheumatoid Arthritis and Psoriatic Arthritis Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12- month period. No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab products is unknown. The following adverse reactions have been identified during post-approval use of adalimumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to adalimumab products exposure. Gastrointestinal disorders: General disorders and administration site conditions: Hepato-biliary disorders: Immune system disorders: Neoplasms benign, malignant and unspecified (including cysts and polyps): Nervous system disorders: Respiratory disorders: Skin reactions: Vascular disorders:.
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)

Pediatric Patients 6 Years to 17 Years
The safety profile of adalimumab in 192 pediatric patients from one double-blind study (Study PCD-I) and one open-label extension study [see Clinical Studies (14.6) 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.
USE IN SPECIFIC POPULATIONS
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 2-4% and 15-20%, respectively. 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. 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) 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. 7 mcg/mL in cord blood, 4. 7 mcg/mL in infant serum, and 0-16. 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 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. 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 HULIO and any potential adverse effects on the breastfed child from HULIO or from the underlying maternal condition. The safety and effectiveness of HULIO have been established for: Pediatric assessments for HULIO demonstrate that HULIO is safe and effective for additional indications in pediatric patients for which Humira (adalimumab) is approved. However, HULIO 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-exposed newborn and infant. Data from eight infants exposed to adalimumab in utero suggest adalimumab crosses the placenta [see Use in Specific Populations (8. 1) Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab products [see Warnings and Precautions (5. 2) 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 HULIO have not been established in pediatric patients with JIA less than 2 years of age. The safety and effectiveness of HULIO 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 HULIO 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 HULIO 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 HULIO in patients 65 years of age and older. In patients treated with HULIO, closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.
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.
Geriatric Patients
A lower clearance with increasing age was observed in patients with RA aged 40 to >75 years.
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
No gender-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.
Patients with Renal or Hepatic Impairment
No pharmacokinetic data are available in patients with hepatic or renal impairment.

Abatacept: 5. 2 Anakinra: 5. 2 Live vaccines: 5. 3 *Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of HULIO has been demonstrated for the condition(s) of use (e. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HULIO or MTX [see Clinical Pharmacology (12. 3) In clinical studies in patients with RA, an increased risk of serious infections has been observed with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HULIO with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5. 11) Avoid the use of live vaccines with HULIO [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 HULIO 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.

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. 7 mcg/mL in cord blood, 4. 7 mcg/mL in infant serum, and 0-16. 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 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.
Human Data
A prospective cohort pregnancy exposure registry conducted by OTIS/MotherToBaby in the U.S. 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% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% 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 0.16-19.7 mcg/mL in cord blood, 4.28-17.7 mcg/mL in infant serum, and 0-16.1 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
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.
Adult Hidradenitis Suppurativa
Adalimumab trough concentrations were approximately 7 to 8 mcg/mL at Week 2 and Week 4, respectively, after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11 mcg/mL during adalimumab 40 mg every week treatment.
Hidradenitis Suppurativa
In subjects with moderate to severe HS, antibodies to adalimumab were associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum adalimumab concentrations is greater with increasing titers of antibodies to adalimumab.
Rheumatoid factor or CRP concentrations
Minor increases in apparent clearance were predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.
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. 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) Study RA-II Monotherapy (26 weeks) Study RA-III Methotrexate Combination (24 and 52 weeks) Response Placebo Adalimumab Adalimumab Placebo/MTX Adalimumab/MTX 40 mg every 40 mg weekly 40 mg every other week other week N=110 N=113 N=103 N=200 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 Study RA-II Study RA-III Parameter (median) 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 (0-68) 35 26 31 16 p<0. 001, adalimumab vs. 26 15 24 8 Number of swollen joints (0-66) 19 16 18 10 17 11 18 5 Physician global assessment Visual analogue scale; 0 = best, 10 = worst 7. 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 2. 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). ACR Response in Study RA-V (Percent of Patients) Response MTX p<0. 05, adalimumab/MTX vs. N=257 Adalimumab p<0. 001, adalimumab/MTX vs. N=274 Adalimumab/MTX N=268 ACR20 Week 52 Week 104 63% 56% 54% 49% 73% 69% ACR50 Week 52 Week 104 46% 43% 41% 37% 62% 59% ACR70 Week 52 Week 104 27% 28% 26% 28% 46% 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. Study RA-III ACR 20 Responses over 52 Weeks 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). Radiographic Mean Change mean (95% confidence interval) MTX p<0. 01, for adalimumab/MTX vs. 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) 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 was assessed in two studies (JIA-I and JIA-II) in patients with active polyarticular juvenile idiopathic arthritis (JIA). 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). 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. 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 was 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 and 9). Among patients with PsA who received adalimumab, the clinical responses were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. 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). 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. N=151 Parameter: median Baseline 24 weeks Baseline 24 weeks Number of tender joints Scale 0-78 23. 0 Number of swollen joints Scale 0-76 11. 0 Physician global assessment Visual analog scale; 0=best, 100=worst 53. 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: 0-0. 287 mg/dL 0. 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 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). 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) 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 was 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. 6 BASFI Bath Ankylosing Spondylitis Functional Index 56 51 52 34 BASDAI Bath Ankylosing Spondylitis Disease Activity Index 6. 7 BASMI Bath Ankylosing Spondylitis Metrology Index 4. 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) 2. 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. ASAS 20 Response By Visit, Study AS-I 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. 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). 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. 7% 21% Clinical response 34% 58% p<0. 01 for adalimumab vs. 34% 52% 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). The group that received adalimumab therapy every week did not demonstrate significantly higher remission rates compared to the group that received adalimumab every other week. 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 40 mg Adalimumab every other week N=170 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. 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. 9%) Sustained Clinical Remission (Clinical Remission at both Weeks 8 and 52) N/A N/A N/A 4. 6%) 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 Table 17 and 18). 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 (%) Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration Adalimumab 40 mg every other week Placebo N = 814 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 18. Efficacy Results at 16 Weeks in Study Ps-II Number of Subjects (%) Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration Adalimumab 40 mg every other week Placebo N = 99 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. 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 19). 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 18). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale in patients who entered the study with an initial baseline score of 3 or greater on a 11 point scale. In both studies, a higher proportion of adalimumab- than placebo-treated subjects achieved HiSCR (see Table 20). Efficacy Results at 12 Weeks in Subjects with Moderate to Severe Hidradenitis Suppurativa HS Study 1 HS Study 2 19. 3% of subjects in Study HS-II continued baseline oral antibiotic therapy during the study. Placebo Adalimumab Weekly Placebo Adalimumab 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. 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 21). 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) [A1] To Applicant: Note: P# = Placebo (Number of Events/Number at Risk); A# = Adalimumab (Number of Events/Number at Risk).
REFERENCES
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MEDICATION GUIDE
HULIO registered Read the Medication Guide that comes with HULIO before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information I should know about HULIO? HULIO is a medicine that affects your immune system. HULIO can lower the ability of your immune system to fight infections. Serious infections have happened in people taking adalimumab products. These serious infections include tuberculosis (TB) and infections caused by viruses, fungi or bacteria that have spread throughout the body. Some people have died from these infections. You should not start taking HULIO if you have any kind of infection unless your healthcare provider says it is okay. Before starting HULIO, tell your healthcare provider if you: o o o o o o o o o o After starting HULIO, call your healthcare provider right away HULIO can make you more likely to get infections or make any infection that you may have worse. Cancer What is HULIO? HULIO is a medicine called a Tumor Necrosis Factor (TNF) blocker. HULIO is used: o moderate to severe RA in adults. o moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children o psoriatic arthritis (PsA) in adults. o ankylosing spondylitis (AS) in adults. o moderate to severe hidradenitis suppurativa (HS) in adults. To treat moderate to severe Crohn’s disease (CD) in adults and children 6 years of age and older. To treat moderate to severe ulcerative colitis (UC) in adults. It is not known if adalimumab products are effective in people who stopped responding to or could not tolerate TNF-blocker medicines. To treat moderate to severe chronic (lasting a long time) plaque psoriasis (Ps) in adults To treat non-infectious intermediate, posterior, and panuveitis in adults. What should I tell my healthcare provider before taking HULIO? HULIO may not be right for you. Before starting HULIO, tell your healthcare provider about all of your medical conditions, including if you: “What is the most important information I should know about HULIO?” Tell your healthcare provider about all the medicines you take, Especially tell your healthcare provider if you use: Keep a list of your medicines with you to show your healthcare provider and pharmacist each time you get a new medicine. How should I take HULIO? Do not inject HULIO more often than you were prescribed. Instructions for Use Do not Do not What are the possible side effects of HULIO? HULIO can cause serious side effects, including: See “What is the most important information I should know about HULIO?” Serious Infections. o o o o Hepatitis B infection in people who carry the virus in their blood. o o o o o o o o o o o Allergic reactions. o o o Nervous system problems. Blood problems. New heart failure or worsening of heart failure you already have. Call your healthcare provider right away o o o Immune reactions including a lupus-like syndrome. Liver problems. o o o o Psoriasis. Call your healthcare provider or get medical care right away if you develop any of the above symptoms. Your treatment with HULIO may be stopped. The most common side effects of HULIO include: These are not all the possible side effects with HULIO. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store HULIO? Do not freeze HULIO. Keep HULIO, injection supplies, and all other medicines out of the reach of children. General information about the safe and effective use of HULIO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use HULIO for a condition for which it was not prescribed. Do not give HULIO to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about HULIO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about HULIO that is written for health professionals. What are the ingredients in HULIO? Active ingredient: HULIO Pen 40 mg/0.8 mL, HULIO 40 mg/0.8 mL prefilled syringe, HULIO 20 mg/0.4 mL prefilled syringe. Inactive ingredients: Manufactured by: Biocon Biologics Inc, 245 Main St, 2nd Floor, Cambridge, MA 02142, U.S.A. Product of Japan U.S. License Number 2324 For more information, call Biocon Biologics at 1-833-986-1468 or you can enroll in a patient support program by calling 1-833-44-HULIO (1-833-444-8546). This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 02/2025 Manufactured by: Biocon Biologics Inc.

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