Abatacept

1 INDICATIONS AND USAGE ORENCIA is a selective T cell costimulation modulator indicated for: • the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). (1.1) • the treatment of patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA). (1.2) • the treatment of patients 2 years of age and older with active psoriatic arthritis (PsA). (1.3) • the prophylaxis of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in adults and pediatric patients 2 years of age and older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor. (1.4) Limitations of Use: Concomitant use of ORENCIA with other immunosuppressives [e.g., biologic disease-modifying antirheumatic drugs (bDMARDS), Janus kinase (JAK) inhibitors] is not recommended. ( 1.5 , 5.1) 1.1 Adult Rheumatoid Arthritis ORENCIA ® is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). 1.2 Polyarticular Juvenile Idiopathic Arthritis ORENCIA is indicated for the treatment of patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA). 1.3 Psoriatic Arthritis ORENCIA is indicated for the treatment of patients 2 years of age and older with active psoriatic arthritis (PsA). 1.4 Prophylaxis for Acute Graft versus Host Disease ORENCIA is indicated for the prophylaxis of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in adults and pediatric patients 2 years of age and older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated-donor. 1.5 Limitations of Use The concomitant use of ORENCIA with other potent immunosuppressants [e.g., biologic disease-modifying antirheumatic drugs (bDMARDs), Janus kinase (JAK) inhibitors] is not recommended.

2 DOSAGE AND ADMINISTRATION Intravenous Use for Adult RA (2.1) and Adult PsA (2.3) • Administer at 0, 2, and 4 weeks, and every 4 weeks thereafter, as a 30-minute infusion Body Weight of Patient Dose Number of Vials Less than 60 kg 500 mg 2 60 to 100 kg 750 mg 3 More than 100 kg 1,000 mg 4 Subcutaneous Use for Adult RA (2.1) • Prior to the first subcutaneous dose, may administer an optional loading dose as a single intravenous infusion as per body weight categories above. • Administer 125 mg by subcutaneous injection once weekly (within a day of the intravenous infusion if infusion given). • Patients switching from intravenous use to subcutaneous use, administer first subcutaneous dose instead of next scheduled intravenous dose. Intravenous Use for pJIA in Pediatric Patients ≥6 Years Old (2.2) • Pediatric patients weighing <75 kg administer 10 mg/kg intravenously and those weighing ≥75 kg administer the adult intravenous dosing regimen (not to exceed a maximum dose of 1,000 mg), as a 30-minute infusion. • Subsequently administer infusions at 2 and 4 weeks and every 4 weeks thereafter. Subcutaneous Use for pJIA and PsA in Pediatric Patients ≥2 Years Old (2.2) • Administer subcutaneously without an intravenous loading dose Body Weight of Pediatric Patient Dose (once weekly) 10 kg to less than 25 kg 50 mg 25 kg to less than 50 kg 87.5 mg 50 kg or more 125 mg Subcutaneous Use for Adult PsA ( 2.3 ) • Administer 125 mg by subcutaneous injection once weekly without an intravenous loading dose. • Patients switching from intravenous use to subcutaneous use, administer first subcutaneous dose instead of next scheduled intravenous dose. Intravenous Use for Prophylaxis of aGVHD (2.4) • For patients 6 years and older, administer at a 10 mg/kg dose (maximum dose 1,000 mg) as a 60-minute infusion on the day before transplantation, followed by a dose on Day 5, 14, and 28 after transplant. • For patients 2 to less than 6 years old, administer a 15 mg/kg dose as a 60-minute infusion on the day before transplantation, followed by a 12 mg/kg dose as a 60-minute infusion on Day 5, 14, and 28 after transplant. Preparation and Administration Instructions ( 2.5 , 2.6 ) • Administer as a 30-minute intravenous infusion for RA, pJIA, and adult PsA. (2.5) • Administer as a 60-minute intravenous infusion for aGVHD prophylaxis. (2.5) • See the Full Prescribing Information for preparation and administration instructions for intravenous infusion and recommendations for subcutaneous use. (2.5, 2.6) Prepare ORENCIA using only the silicone-free disposable syringe. (2.5) 2.1 Dosage in Adult Rheumatoid Arthritis For adult patients with RA, administer as an intravenous infusion or as a subcutaneous injection. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than JAK inhibitors or bDMARDs (e.g., TNF antagonists). Intravenous Dosage Reconstitute ORENCIA lyophilized powder and administer after dilution [see Dosage and Administration (2.5) ] as a 30-minute intravenous infusion utilizing the weight range-based dosing recommended in Table 1. Following the initial intravenous infusion, administer as an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter. Table 1: Dose of ORENCIA for Intravenous Infusion in Adult RA Patients Body Weight of Adult Patient Dose Number of Vials a a Each vial provides 250 mg of abatacept for administration. Less than 60 kg 500 mg 2 60 to 100 kg 750 mg 3 More than 100 kg 1,000 mg 4 Subcutaneous Dosage Prior to the first subcutaneous dose, an optional loading dose may be administered as a single intravenous infusion (as per body weight categories in Table 1). If an intravenous loading dose is used, administer the first subcutaneous injection within one day of the infusion. Administer ORENCIA 125 mg in prefilled syringes or in ORENCIA ClickJect™ autoinjector by subcutaneous injection once weekly [see Dosage and Administration (2.6) ] . For patients switching from ORENCIA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. 2.2 Dosage in Polyarticular Juvenile Idiopathic Arthritis For pediatric patients with pJIA, either administer ORENCIA as an intravenous infusion (only patients 6 years of age and older) or as a subcutaneous injection (only patients 2 years of age and older) [see Use in Specific Populations (8.4) ] . ORENCIA may be used as monotherapy or concomitantly with methotrexate. Intravenous Dosage Administer ORENCIA as a 30-minute intravenous infusion based on body weight [see Dosage and Administration (2.5) ] : • For body weight less than 75 kg, administer a dose of 10 mg/kg. • For body weight of 75 kg or greater, administer as per the recommendations in Table 1 (follow the adult intravenous dosing regimen), not to exceed a maximum dose of 1,000 mg. Following the initial intravenous infusion, administer infusions at 2 and 4 weeks and every 4 weeks thereafter. Immediately discard any unused portion in the vials. Subcutaneous Dosage Administer ORENCIA for subcutaneous injection, without an intravenous loading dose, utilizing the weight range-based dosing as recommended in Table 2 [see Dosage and Administration (2.6) ] . Subsequently administer once weekly. Table 2: Dose of ORENCIA for Subcutaneous Administration in Patients 2 Years of Age and Older with pJIA Body Weight of Pediatric Patient Dose (once weekly) 10 to less than 25 kg 50 mg 25 to less than 50 kg 87.5 mg 50 kg or more 125 mg Patients with pJIA may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determine it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested. 2.3 Dosage in Psoriatic Arthritis Adult Patients For adult patients with psoriatic arthritis, administer as an intravenous infusion or a subcutaneous injection. ORENCIA may be used with or without non-biologic DMARDs. Intravenous Dosage Administer ORENCIA as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, administer an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter. Subcutaneous Dosage Administer 125 mg of ORENCIA subcutaneously once weekly (no intravenous loading dose is needed) [see Dosage and Administration (2.6) ] . For patients switching from ORENCIA intravenous infusions to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Pediatric Patients Administer ORENCIA as a subcutaneous injection in pediatric patients 2 years of age and older with psoriatic arthritis [see Use in Specific Populations (8.4) ] . ORENCIA may be used as monotherapy or concomitantly with methotrexate. Intravenous administration is not approved for pediatric patients with psoriatic arthritis. Subcutaneous Dosage Administer ORENCIA for subcutaneous injection weekly, utilizing the weight range-based dosage as recommended in Table 3 [see Dosage and Administration (2.6) ] . Table 3: Dose of ORENCIA for Subcutaneous Administration in Patients 2 Years of Age and Older with Psoriatic Arthritis Body Weight of Pediatric Patient Dose (once weekly) 10 to less than 25 kg 50 mg 25 to less than 50 kg 87.5 mg 50 kg or more 125 mg Pediatric patients with psoriatic arthritis may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determine it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested. 2.4 Dosage in Prophylaxis of Acute Graft versus Host Disease in Adults and Pediatric Patients Aged 2 Years and Older Antiviral Prophylactic Treatment Before administering ORENCIA, administer recommended antiviral prophylactic treatment for Epstein-Barr Virus (EBV) reactivation, and continue for six months following HSCT. In addition, consider prophylactic antivirals for Cytomegalovirus (CMV) infection/reactivation during treatment and for six months following HSCT [see Warnings and Precautions (5.7) ]. Intravenous Dosing Regimen For patients 6 years and older, administer ORENCIA 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation. For patients 2 to less than 6 years old, administer ORENCIA 15 mg/kg as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by 12 mg/kg as an intravenous infusion over 60 minutes on Days 5, 14, and 28 after transplantation. 2.5 Preparation and Administration Instructions for Intravenous Infusion Calculate the ORENCIA dose, the total volume of reconstituted solution required, and the number of ORENCIA vials needed. For a full dose, less than the full contents of one vial or more than one vial may be needed. Using aseptic technique, reconstitute, dilute, and then administer ORENCIA as follows: Reconstitution 1) Use the vial only if the vacuum is present. 2) Reconstitute each vial of supplied ORENCIA lyophilized powder (each vial supplies 250 mg of abatacept) with 10 mL of Sterile Water for Injection, USP (direct the stream toward the inside wall of the vial) to obtain a concentration of 25 mg/mL. Use only the provided silicone-free syringe with an 18- to 21-gauge needle: a. If the ORENCIA lyophilized powder is accidently reconstituted using a siliconized syringe, the solution may develop a few translucent particles (discard any solutions prepared using siliconized syringes). b. If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe. To obtain new silicone-free syringes, contact Bristol-Myers Squibb at 1-800-ORENCIA. 3) Gently swirl the vial to minimize foam formation, until the contents are completely dissolved. Do not shake. Avoid prolonged or vigorous agitation. 4) Upon complete dissolution of the lyophilized powder, vent the vial with a needle to dissipate any foam that may be present. 5) Visually inspect the reconstituted solution (the solution should be clear and colorless to pale yellow). Do not use if opaque particles, discoloration, or other foreign particles are present. 6) Repeat steps 2) through 5) if two, three, or four vials are needed for a dose (see Table 1). Dilution 7) Must further dilute the reconstituted ORENCIA solution to 100 mL as follows: a. From a 100 mL infusion bag or bottle of 0.9% Sodium Chloride Injection, USP, withdraw a volume equal to the volume of the reconstituted ORENCIA solution required for the patient’s dose. b. Slowly add the reconstituted ORENCIA solution(s) into the infusion bag or bottle using the silicone-free disposable syringe provided with each vial . c. Gently mix. Do not shake the bag or bottle . The final concentration of abatacept in the bag or bottle will depend upon the amount of abatacept added, but will be no more than 10 mg/mL. Immediately discard any unused portion in the ORENCIA vial. Administration 8) Prior to administration, visually inspect the ORENCIA diluted solution for particulate matter and discoloration. Discard the diluted solution if any particulate matter or discoloration is observed. 9) Using an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 μm to 1.2 μm), administer the entire diluted ORENCIA solution over: • 30 minutes for RA, pJIA, and adults with PsA • 60 minutes for aGVHD prophylaxis 10) Must complete the infusion of the diluted ORENCIA solution within 24 hours of reconstitution of the ORENCIA vials. Do not infuse ORENCIA concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of ORENCIA with other drugs. Storage of Diluted ORENCIA Solution May store the diluted ORENCIA solution at room temperature or refrigerate at 2ºC to 8ºC (36ºF to 46ºF) up to 24 hours before use. Discard the diluted solution if not administered within 24 hours. 2.6 Recommendations for Subcutaneous Administration ORENCIA prefilled syringes and ORENCIA ClickJect autoinjectors are intended for: • Subcutaneous use only and are not intended for intravenous infusion. • Use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient or the patient’s caregiver may administer a subcutaneous injection of ORENCIA (ClickJect autoinjector or prefilled syringe) if a healthcare practitioner determines that it is appropriate. Instruct patients and/or caregivers to follow the directions provided in the Instructions for Use for additional details on administration. Specifically instruct them to inject the full amount (which provides the proper dose of ORENCIA), rotate injection sites, and to avoid injections into areas where the skin is tender, bruised, red, or hard. Visually inspect for particulate matter and discoloration prior to administration. Do not use ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors exhibiting particulate matter or discoloration. ORENCIA should be clear to slightly opalescent and colorless to pale yellow.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Increased Risk of Infection with Concomitant Use with TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors [see Warnings and Precautions (5.1) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] • Infections [see Warnings and Precautions (5.3) ] • Increased Risk of Adverse Reactions When Used in Patients with Chronic Obstructive Pulmonary Disease (COPD) [see Warnings and Precautions (5.5) ] • Immunosuppression [see Warnings and Precautions (5.6) ] • Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Reactivation in aGVHD Prophylaxis after Hematopoietic Stem Cell Transplant (HSCT) [see Warnings and Precautions (5.7) ] • Most common adverse events (≥10%) in RA are headache, upper respiratory tract infection, nasopharyngitis, and nausea. (6.1) • Most common adverse reactions (≥10%) in prophylaxis of aGVHD are anemia, hypertension, CMV reactivation/CMV infection, pyrexia, pneumonia, epistaxis, CD4 lymphocytes decreased, hypermagnesemia, and acute kidney injury. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. Adverse Reactions in Adult Patients with RA Adverse Reactions in Adult Patients with RA Treated with Intravenous ORENCIA The data from placebo-controlled studies described herein reflect exposure to ORENCIA administered intravenously in patients with active RA (1955 patients with ORENCIA, 989 with placebo) (Studies I through VI) [see Clinical Studies (14.1) ] . The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF antagonist (204 patients with ORENCIA, 134 with placebo). The concomitant use of ORENCIA with a TNF antagonist is not recommended [see Indications and Usage (1.5) ] . The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF antagonist, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra. The most serious adverse reactions were serious infections and malignancies. The most commonly reported adverse events (occurring in ≥10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea. The adverse reactions most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%). Most Common Adverse Reactions in Adult Patients with RA Treated with Intravenous ORENCIA Adverse reactions occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients (intravenous) during placebo-controlled RA studies are summarized in Table 4. Table 4: Most Common Adverse Reactions* During Placebo-Controlled RA Studies of Intravenous ORENCIA Intravenous ORENCIA (n=1955) a Placebo (n=989) b * Occurred in ≥3% patients and >1% more frequently in ORENCIA-treated patients. a Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). b Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). Headache 18% 13% Nasopharyngitis 12% 9% Dizziness 9% 7% Cough 8% 7% Back pain 7% 6% Hypertension 7% 4% Dyspepsia 6% 4% Urinary tract infection 6% 5% Rash 4% 3% Pain in extremity 3% 2% Infections in Adult Patients with RA Treated with Intravenous ORENCIA In the placebo-controlled trials in patients with RA, infections were reported in 54% of intravenous ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia [see Warnings and Precautions (5.3) ] . Serious infections were reported in 3% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis [see Warnings and Precautions (5.3) ] . Malignancies in Adult Patients with RA Treated with Intravenous ORENCIA In the placebo-controlled portions of the clinical trials (1955 patients treated for RA with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA- and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4 cases, 0.2%) than placebo-treated patients (0 cases, 0%). In the cumulative intravenous ORENCIA clinical trials in patients with RA (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute's Surveillance, Epidemiology, and End Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers [see Warnings and Precautions (5.6) ] . The potential role of ORENCIA in the development of malignancies in humans is unknown. Infusion-Related Reactions and Hypersensitivity Reactions in Adult Patients with RA Treated with Intravenous ORENCIA Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see Clinical Studies (14.1) ] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1%-2%) were dizziness, headache, and hypertension. Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events. In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases (<0.1%) of anaphylaxis. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Warnings and Precautions (5.2) ] . Adverse Reactions in Patients with COPD Treated for RA with Intravenous ORENCIA In Study V [see Clinical Studies (14.1) ] , there were 37 and 17 patients with chronic obstructive pulmonary disease (COPD) who were treated for RA with ORENCIA and placebo, respectively. The COPD patients treated with ORENCIA for RA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37 patients (3%)] [see Warnings and Precautions (5.5) ] . Adverse Reactions in Methotrexate-Naive Patients with RA Treated with Intravenous ORENCIA Study VI was an active-controlled clinical trial in methotrexate-naive patients [see Clinical Studies (14.1) ] . The safety experience in these patients was consistent with the patients in Studies I-V. Adverse Reactions in Adult Patients with RA Treated with Subcutaneous or Intravenous ORENCIA The data described below are derived from Study SC-1. Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that compared the safety of ORENCIA administered subcutaneously or intravenously in 1457 patients with RA, who received background methotrexate, and experienced an inadequate response to methotrexate (MTX-IR) [see Clinical Studies (14.1) ] . The adverse reaction profile in patients treated with subcutaneous ORENCIA was similar to the adverse reaction profile in patients treated with intravenous ORENCIA and consistent with intravenous ORENCIA administered in Studies I-VI. Injection Site Reactions in Adult RA Patients Treated with Subcutaneous ORENCIA The overall frequency of injection site reactions in Study SC-1 was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous ORENCIA group and the subcutaneous placebo group (given intravenous ORENCIA), respectively [see Clinical Studies (14.1) ] . All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. Adverse Reactions in Adult Patients with PsA Adverse Reactions in Adult Patients with PsA Treated with Intravenous or Subcutaneous ORENCIA The safety of ORENCIA was evaluated in 594 patients with PsA (341 patients on ORENCIA and 253 patients on placebo), in two randomized, double-blind, placebo-controlled trials [see Clinical Studies (14.3) ]. Of the 341 patients who received ORENCIA, 128 patients received intravenous ORENCIA (PsA-I) and 213 patients received subcutaneous ORENCIA (PsA-II). The safety profile was comparable between ORENCIA given intravenously in Study PsA-I and ORENCIA given subcutaneously in Study PsA-II and also consistent with the safety profile of ORENCIA in patients with RA [see Warnings and Precautions (5) , Adverse Reactions (6.1 )]. Adverse Reactions in Patients with pJIA Adverse Reactions in Patients with pJIA Treated with Intravenous ORENCIA In general, the adverse events in pediatric patients with polyarticular JIA (pJIA) treated with intravenous ORENCIA were similar in frequency and type to those seen in adult patients with RA treated with intravenous ORENCIA [see Warnings and Precautions (5 ) and Adverse Reactions (6) ] . Study JIA-1 was a three-part study including an open-label extension that assessed the safety of intravenous ORENCIA in 190 pediatric patients, 6 to 17 years of age, with pJIA. Overall frequency of adverse events in the 4‑month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see Clinical Studies (14.2) ] . The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain. A total of 6 serious adverse events [acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare (2), and joint wear] were reported during the initial 4 months of treatment with intravenous ORENCIA. Of the 190 pediatric patients with pJIA treated with intravenous ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults. Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment. Adverse Reactions in Patients with pJIA Treated with Subcutaneous ORENCIA Study JIA-2 was an open-label study with a 4-month short-term period and a long-term extension period that assessed the safety of subcutaneous ORENCIA in 205 pediatric patients, 2 to 17 years of age with pJIA. The adverse reaction profile in patients with pJIA treated with ORENCIA administered subcutaneously in Study JIA-2 were consistent with the adverse reaction profile in patients with pJIA treated with intravenous Study JIA-1. There were no reported cases of hypersensitivity reactions. Local injection‑site reactions occurred at a frequency of 4.4%. Adverse Reactions in Patients Undergoing Unrelated-Donor Hematopoietic Stem Cell Transplantation (HSCT) with Intravenous ORENCIA The data described herein were from one clinical study of ORENCIA (GVHD-1) for aGVHD prophylaxis in patients 6 years and older with hematologic malignancies who were undergoing unrelated HSCT wherein all patients were receiving calcineurin inhibitor and methotrexate as the standard of care for aGVHD prophylaxis [see Clinical Studies (14.4) ] . Two cohorts were studied at 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day-1), followed by administration on Days 5, 14, and 28 after transplantation: 1) A single-arm cohort of ORENCIA-treated patients (n=43) who underwent 7 of 8 Human leukocyte antigen (HLA)-matched HSCT from unrelated donors (7 of 8 cohort) and 2) A randomized cohort comprised of ORENCIA-treated patients (n=73) and placebo-treated patients (n=69) who underwent 8 of 8 HLA-matched HSCT from unrelated donors (8 of 8 cohort). Of the 116 patients who received ORENCIA, 27 (23%) were 6 to less than 17 years of age [see Use in Specific Populations (8.4) ] . The safety information from the date of first dose of ORENCIA up to Day 225 post-transplantation from this study is presented below. The incidence of adverse reactions was determined based on pooled data of ORENCIA-treated patients from the 2 study cohorts (n=116). Serious adverse reactions reported in > 5% of patients who received ORENCIA in combination with a calcineurin inhibitor and methotrexate included pyrexia (20%), pneumonia (8%), acute kidney injury (7%), diarrhea (6%), hypoxia (5%), and nausea (5%). Permanent discontinuation of ORENCIA due to an adverse reaction occurred in two patients (1.7%) due to one case each of pneumonia and allergic reaction. The most common (≥10%) adverse reactions in the ORENCIA treated patients were anemia, hypertension, CMV reactivation/CMV infection, pyrexia, pneumonia, epistaxis, CD4 lymphocytes decreased, hypermagnesemia, and acute kidney injury. Table 5 summarizes the frequency of adverse reactions reported in the study of ORENCIA in GVHD-1. Table 5: Adverse Reactions (≥10%) in Patients with aGVHD Who Received ORENCIA with a Difference Between Arms of >2% Compared to Placebo in GVHD-1 7 of 8 Cohort 8 of 8 Cohort Adverse Reaction ORENCIA (+CNI and MTX) (N=43) ORENCIA (+CNI and MTX) (N=73) Placebo (+CNI and MTX) (N=69) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Blood and Lymphatic System Disorders Anemia 56 56 69 69 57 57 CD4 lymphocytes decreased 14 14 14 14 9 9 Vascular Disorders Hypertension 49 49 43 43 38 38 General Disorders and Administrative Site Conditions Pyrexia 28 9 19 10 20 4 Infections and Infestations CMV Reactivation/CMV Infection 26 26 32 32 22 22 Pneumonia 19 19 12 12 10 9 Respiratory and Mediastinal Disorders Epistaxis 12 12 16 16 10 10 Renal and Urinary Disorders Acute kidney injury 9 7 15 15 10 10 Metabolism and Nutrition Disorders Hypermagnesemia 5 5 18 18 10 10 Clinically relevant adverse reactions in <10% of patients who received ORENCIA in combination with calcineurin inhibitor and methotrexate in Study GVHD-1 included EBV reactivation. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other abatacept products may be misleading. Immunogenicity in Adult Patients with RA Treated with Intravenous ORENCIA Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with intravenous ORENCIA. Thirty-four of 1993 (2%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In the subset analysis, 9 of 154 (6%) patients that had discontinued intravenous ORENCIA treatment for over 56 days developed antibodies. Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. No correlation of anti-abatacept antibody development to clinical response or adverse events was observed. Immunogenicity in Adult RA Patients Treated with Subcutaneous or Intravenous ORENCIA Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous ORENCIA administration. The overall immunogenicity frequency to abatacept was 1% (8/725) and 2% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy. Immunogenicity in Adult RA Patients Treated with Subcutaneous ORENCIA Monotherapy Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients, who had not previously received ORENCIA or other CTLA4Ig. Patients in this study received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti-abatacept antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies. Immunogenicity in Adult RA Patients After Treatment, Withdrawal, and then Restart of Subcutaneous ORENCIA Study SC-3 was conducted to investigate the immunogenicity in adult RA patients after treatment, withdrawal (three months), and restart of ORENCIA subcutaneous treatment (patients were treated concomitantly with methotrexate). One hundred sixty-seven patients were enrolled in the first 3‑month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 (0%) patients who continued to receive subcutaneous ORENCIA developed anti-abatacept antibodies compared to 7/73 (10%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients who received subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (3%) in the group who received subcutaneous ORENCIA throughout, and 2/73 (3%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months compared to those who remained on subcutaneous therapy (these results occurred in those who received or did not receive an intravenous loading dose). The safety observed in this study was consistent with that observed in the other studies. Immunogenicity in Patients with pJIA Treated with Intravenous ORENCIA Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with pJIA following repeated treatment with intravenous ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies. The presence of antibodies was generally transient, and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy. Immunogenicity in Patients Treated for Prophylaxis of aGVHD with Intravenous ORENCIA Immunogenicity was assessed in patients undergoing HSCT. Overall, immunogenicity incidence and associated antibody titers were low from the 4-dose intravenous ORENCIA regimen used in this study. Of the 114 immunogenicity evaluable subjects in the ORENCIA groups, none were positive during the ORENCIA treatment period (Day -1 to Day 28 following transplant). During the off-treatment period (Day 29 and up to Day 180 following transplant); 6 of 91 immunogenicity evaluable subjects (6.6%) were positive for CTLA4 and possibly Ig; 4 of the 6 positive subjects were found to have at least one positive sample with neutralization activity. In this study, immunogenicity positive subjects only had ADA positive samples on Day 180 (off-treatment period) and thus due to the timing of the response, the impact on PK, safety, or efficacy could not be determined. 6.3 Postmarketing Experience Adverse reactions have been reported during the postapproval use of ORENCIA. 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 ORENCIA. Based on the postmarketing experience with ORENCIA, the following adverse reactions have been identified: • Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis) • New or worsening psoriasis • Non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) • Angioedema reactions [see Warnings and Precautions (5.2) ] During postmarketing experience with intravenous ORENCIA, systemic infusion reactions were similar to that seen in the clinical trial experience with intravenous ORENCIA with the exception of one case of fatal anaphylaxis [see Warnings and Precautions (5.2) ] . Postmarketing reports of systemic injection reactions (e.g., pruritus, throat tightness, dyspnea) have occurred following the use of subcutaneous ORENCIA.

12.3 Pharmacokinetics Healthy Adults and Adult RA - Intravenous Administration The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions of ORENCIA (see Table 7). Table 7: Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg ORENCIA Intravenous Infusion(s) PK Parameter Healthy Subjects (After 10 mg/kg Single Dose) n=13 RA Patients (After 10 mg/kg Multiple Doses a ) n=14 a Multiple intravenous infusions of ORENCIA were administered at days 1, 15, 30, and monthly thereafter. Peak Concentration (C max ) [mcg/mL] 292 (175-427) 295 (171-398) Terminal half-life (t 1/2 ) [days] 16.7 (12-23) 13.1 (8-25) Systemic clearance (CL) [mL/h/kg] 0.23 (0.16-0.30) 0.22 (0.13-0.47) Volume of distribution (Vss) [L/kg] 0.09 (0.06-0.13) 0.07 (0.02-0.13) The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of C max and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients. Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF antagonists did not influence abatacept clearance. No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept. Adult RA - Subcutaneous Administration Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for C min and C max at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration was 79%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration. Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients [see Adverse Reactions (6.3) ] . In this study, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing. Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous ORENCIA in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight [see Dosage and Administration (2.1) ] . Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance. Polyarticular Juvenile Idiopathic Arthritis - Intravenous Administration In Study JIA-1 among patients 6 to 17 years of age, the mean (range) steady state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL) [see Clinical Studies (14.2)] . Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight [see Dosage and Administration (2.2) ] . The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance. Polyarticular Juvenile Idiopathic Arthritis - Subcutaneous Administration In Study JIA-2 among patients 2 to 17 years of age, steady state of abatacept was achieved by Day 85 following the weekly body-weight–tiered subcutaneous ORENCIA dosing [see Clinical Studies (14.2) ] . Comparable trough concentrations across weight tiers and age groups were achieved by the body-weight–tiered subcutaneous dosing regimen. The mean (range) trough concentration of abatacept at Day 113 was 44.4 mcg/mL (13.4 to 88.1 mcg/mL), 46.6 mcg/mL (22.4 to 97.0 mcg/mL), and 38.5 mcg/mL (9.3 to 73.2 mcg/mL) in pediatric JIA patients weighing 10 to <25 kg, 25 to <50 kg, and ≥50 kg, respectively. Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous ORENCIA in JIA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight [see Dosage and Administration (2.2) ] . Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance. Adult Psoriatic Arthritis - Intravenous and Subcutaneous Administration In Study PsA-I, a dose ranging study, intravenous ORENCIA was administered at 3 mg/kg, weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg, or doses of 30 mg/kg on Days 1 and 15 followed by weight-range-based dosing [see Clinical Studies (14.3) ] . Following monthly intravenous ORENCIA administration, abatacept showed linear PK over the dose range in this study. At the weight-range-based dosing (see above), the steady state of abatacept was reached by Day 57 and the geometric mean (CV%) trough concentration (C min ) was 24.3 mcg/mL (40.8%) at Day 169. In Study PsA-II following weekly subcutaneous administration of ORENCIA at 125 mg, the steady state of abatacept was reached at Day 57 and the geometric mean (CV%) C min was 25.6 mcg/mL (47.7%) at Day 169. Consistent with the RA results, population pharmacokinetic analyses for abatacept in PsA patients revealed that there was a trend toward higher clearance (L/h) of abatacept with increasing body weight [see Dosage and Administration (2.3) ] . In addition, relative to the RA patients with the same body weight, abatacept clearance in PsA patients was approximately 8% lower, resulting in higher abatacept exposures in patients with PsA. This slight difference in exposures, however, is not considered to be clinically meaningful. Prophylaxis of Acute Graft versus Host Disease – Intravenous Administration Table 8: Pharmacokinetic Parameters (Mean, Range) in Subjects Undergoing HSCT from a Matched or 1 Allele-Mismatched Unrelated Donor in Study GVHD-1 a C min observed on Day 5 of the treatment period; n = 18 for the 7/8 Cohort; n = 32 for the 8/8 Cohort. C max , t 1/2 , CL, and Vss are model predicted after first 10 mg/kg ORENCIA intravenous infusion. PK Parameter 7 of 8 Cohort n=42 8 of 8 Cohort n=73 Minimum Concentration (C min ) a [mcg/mL] 59 (26-112) 43 (25-73) Peak Concentration (C max ) [mcg/mL] 221 (163-292) 172 (107-254) Terminal half-life (t 1/2 ) [days] 20.6 (6-43) 20.8 (12-38) Systemic clearance (CL) [mL/h/kg] 0.26 (0.15-0.65) 0.32 (0.18-0.56) Volume of distribution (Vss) [L/kg] 0.13 (0.08-0.27) 0.17 (0.11-0.26) In a study of patients who received ORENCIA for prophylaxis of acute Graft Versus Host Disease (aGVHD) aged 6 years and older, the geometric mean (%CV) trough concentrations (C min ) of abatacept on Day 63 after transplant after 4 doses utilizing weight-based dosing of 10 mg/kg (maximum dose of 1,000 mg) administered on the day before transplantation (Day -1), followed by a dose on Day 5, 14, and 28 after transplant, were 22.5 mcg/mL (243.9 %CV) for recipients of 8 of 8 Human leukocyte antigen (HLA)-matched HSCTs from unrelated donors (URD), and 31.1 mcg/mL (114.4 %CV) for recipients of 7 of 8 HLA-matched HSCTs from unrelated donors (URD), respectively. Population pharmacokinetic analyses in patients with aGVHD demonstrated that 7 of 8 HLA-matched HSCT recipients had 29% lower clearance compared to 8 of 8 HLA-matched HSCT recipients. Consistent with previous data, increasing body weight was associated with higher clearance of abatacept, while age (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate and calcineurin inhibitors (e.g., cyclosporine and tacrolimus), did not influence abatacept clearance. Based on population PK modeling and simulation with data from patients aged 6 and older, simulated exposures of abatacept following the first and last dose in pediatric subjects 2 to less than 6 years of age who received 15 mg/kg of ORENCIA via 60-minute intravenous infusion on Day -1, followed by 12 mg/kg via 60-minute intravenous infusion on Day 5, 14, and 28 are comparable to those in pediatric patients 6 to less than 17 years of age and adults patients who received 10 mg/kg via 60-minute intravenous infusion on Day -1, 5, 14, and 28.