DailyMed Label: ORENCIA

DailyMed Label: ORENCIA

2024

DailyMed Prescription

ORENCIA

abatacept

E.R. Squibb & Sons, L.L.C.

NDC: 0003-2187

NDC: 0003-2187

NDC: 0003-2188

NDC: 0003-2188

NDC: 0003-2814

NDC: 0003-2814

NDC: 0003-2818

NDC: 0003-2818

Abatacept is a selective T-cell costimulation modulator. Abatacept is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons. ORENCIA (abatacept) for injection is a sterile, white, preservative-free lyophilized powder for reconstitution and dilution prior to intravenous infusion. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, the reconstituted solution of ORENCIA is clear, colorless to pale yellow, with a concentration of 25 mg/mL and with a pH range of 7.2 to 7.8. Each single-dose vial of ORENCIA provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg). ORENCIA (abatacept) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution with a pH range of 6.8 to 7.4 for subcutaneous administration. ORENCIA injection is supplied as a single-dose prefilled syringe or as a single-dose ClickJect autoinjector (see Table 6). Table 6:     Contents of ORENCIA Subcutaneous Injection Presentation Active Ingredient Quantity and Volume Inactive Ingredient Content ORENCIA injection 50 mg/0.4 mL prefilled syringe 50 mg of abatacept in 0.4 mL of solution dibasic sodium phosphate anhydrous (0.335 mg) monobasic sodium phosphate monohydrate (0.114 mg) poloxamer 188 (3.2 mg) sucrose (68 mg) qs to 0.4 mL Water for Injection, USP ORENCIA injection 87.5 mg/0.7 mL prefilled syringe 87.5 mg of abatacept in 0.7 mL of solution dibasic sodium phosphate anhydrous (0.587 mg) monobasic sodium phosphate monohydrate (0.200 mg) poloxamer 188 (5.6 mg) sucrose (119 mg) qs to 0.7 mL Water for Injection, USP ORENCIA injection 125 mg/mL prefilled syringe and ClickJect autoinjector 125 mg of abatacept in 1 mL of solution dibasic sodium phosphate anhydrous (0.838 mg) monobasic sodium phosphate monohydrate (0.286 mg) poloxamer 188 (8 mg) sucrose (170 mg) qs to 1 mL Water for Injection, USP Unlike the lyophilized formulation for intravenous use, the ORENCIA solutions for subcutaneous administration contain no maltose.

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) . ORENCIA ® is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). ORENCIA is indicated for the treatment of patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA). ORENCIA is indicated for the treatment of patients 2 years of age and older with active psoriatic arthritis (PsA). 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. The concomitant use of ORENCIA with other potent immunosuppressants [e.g., biologic disease-modifying antirheumatic drugs (bDMARDs), Janus kinase (JAK) inhibitors] is not recommended.

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) . 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). 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 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.

Intravenous Infusion • For injection: 250 mg lyophilized powder in a single-dose vial. (3) Subcutaneous Use • Injection: 50 mg/0.4 mL, 87.5 mg/0.7 mL, 125 mg/mL solution in single-dose prefilled syringe. (3) • Injection: 125 mg/mL solution in a single-dose prefilled ClickJect™ autoinjectors. (3) • Intravenous Infusion   For injection: 250 mg white lyophilized powder in a single-dose vial [see Dosage and Administration (2.1 , 2.2 , 2.3 , 2.5 )] . • Subcutaneous Use   Injection: 50 mg/0.4 mL, 87.5 mg/0.7 mL, and 125 mg/mL of a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose prefilled glass syringe.   Injection: 125 mg/mL of a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose prefilled ClickJect autoinjector.

None. None. (4)

• Concomitant use with a TNF antagonist can increase the risk of infections and serious infections. (5.1) • Hypersensitivity and anaphylaxis have occurred. (5.2) • Serious infections reported. Patients with a history of recurrent infections or underlying conditions predisposing to infections may experience more infections. Discontinue if a serious infection develops. (5.3) • Screen for latent TB infection prior to initiating therapy. Patients testing positive should be treated prior to initiating ORENCIA. (5.3) • Screen for viral hepatitis prior to initiating ORENCIA. (5.3) • Update vaccinations prior to initiating ORENCIA. Live vaccines should not be given concurrently or within 3 months of discontinuation. ORENCIA may blunt the effectiveness of some immunizations. (5.4) • COPD patients may develop more frequent respiratory adverse reactions. (5.5) • Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) reactivation in patients treated for aGVHD prophylaxis. (5.7) In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63% vs. 43%) and serious infections (4.4% vs. 0.8%) compared to patients treated with only TNF antagonists [see Adverse Reactions (6.1) ] . These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonists; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. Additionally, concomitant use of ORENCIA with other biologic RA/PsA therapy or JAK inhibitors is not recommended. In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases (<0.1%) of anaphylaxis reactions. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients. Of the 190 ORENCIA-treated patients in pJIA clinical trials, there was one case of a hypersensitivity reaction (0.5%) [see Adverse Reactions (6.1 )] . In postmarketing experience, fatal anaphylaxis following the first infusion of ORENCIA and life-threatening cases of angioedema have been reported. Angioedema has occurred as early as after the first dose of ORENCIA, but also has occurred with subsequent doses. Angioedema reactions have occurred within hours of administration and in some instances had a delayed onset (i.e., days). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction. If an anaphylactic or other serious allergic reaction occurs, administration of intravenous or subcutaneous ORENCIA should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA should be permanently discontinued. Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA (serious infections were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively) [see Adverse Reactions (6.1) ] . Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA compared to those treated with ORENCIA alone [see Warnings and Precautions (5.1) ] . Healthcare providers should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection. Prior to initiating ORENCIA, patients should be screened for latent tuberculosis (TB) infection according to current TB guidelines. ORENCIA has not been studied in patients with a positive TB screen, and the safety of ORENCIA in individuals with latent TB infection is unknown. Patients testing positive in TB screening should be treated by standard medical practice prior to therapy with ORENCIA. Antirheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study. Prior to initiating ORENCIA in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines. ORENCIA-treated patients may receive current non-live vaccines. Live vaccines should not be given concurrently with ORENCIA or within 3 months after discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. In addition, there are clinical considerations for administering live vaccines to infants who were exposed to ORENCIA while in utero [see Use in Specific Populations (8.1) ] . Based on its mechanism of action, ORENCIA may blunt the effectiveness of some immunizations. In Study V, adult COPD patients treated with ORENCIA for RA developed adverse reactions more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to patients treated with placebo (27% vs 6%) [see Clinical Studies (14.1) and Adverse Reactions (6.1) ] . Use of ORENCIA in patients with COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status. The possibility exists for drugs inhibiting T-cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo-treated patients [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ] . The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood [see Adverse Reactions (6.1) ] . There have been reports of malignancies, including skin cancer in patients receiving ORENCIA [see Adverse Reactions (6.3) ] . Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer. Post-Transplant Lymphoproliferative Disorder (PTLD) occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT. Of 116 patients who received ORENCIA, 4 patients (3.4%) experienced PTLD. All the PTLD events were associated with Epstein-Barr virus (EBV) infection. Three of the four patients were EBV serology positive at baseline; one patient had negative baseline EBV serology with donor EBV serology unknown. Three of the 4 patients discontinued acyclovir prophylaxis at day 30 post-transplant. The range of time to onset of the events was 49 to 89 days post-transplant. Monitor patients for EBV reactivation in accordance with institutional practices. Provide prophylaxis for EBV infection for 6 months post-transplantation to prevent EBV-associated PTLD [see Dosage and Administration (2.4) ] . Cytomegalovirus (CMV) invasive disease occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT. Of 116 patients who received ORENCIA, 7% experienced CMV invasive diseases up to day 225 post-transplant. All the patients who experienced CMV invasive disease were CMV serology positive at baseline. The median time to onset of the event was 91 days post-transplant. CMV invasive diseases predominantly involved the gastrointestinal tract [see Adverse Reactions (6.1) ] . Monitor patients for CMV infection/reactivation for 6 months post-transplant regardless of the results of donor and recipient pre-transplant CMV serology. Consider prophylaxis for CMV infection/reactivation [see Dosage and Administration (2.4) ] .

The following clinically significant adverse reactions are described elsewhere in the labeling:

Concomitant administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended [see Warnings and Precautions (5.1) ]. There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, or other biologic PsA therapy, and JAK inhibitors and therefore such use is not recommended. [see Warnings and Precautions (5.1) ] . Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving intravenous ORENCIA, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods. ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. However, there are clinical considerations for administering live vaccines to infants who were exposed to ORENCIA while in utero (see Clinical Considerations) . In reproductive toxicology studies in rats and rabbits, no fetal malformations were observed with intravenous administration of ORENCIA during organogenesis at doses that produced exposures approximately 29 times the exposure at the maximum recommended human dose (MRHD) of 10 mg/kg/month on an AUC basis. However, in a pre- and postnatal development study in rats, ORENCIA altered immune function in female rats at 11 times the MRHD on an AUC basis. Infants and Administration of Live Vaccines It is unknown if abatacept can cross the placenta into the fetus when a woman is treated with ORENCIA during pregnancy. Abatacept is an immunomodulatory agent. It is unknown if the immune response of an infant who was exposed in utero to abatacept and subsequently administered a live vaccine is impacted. Risks and benefits should be considered prior to vaccinating such infants [see Warnings and Precautions (5.4) ] . There are no adequate and well-controlled studies of ORENCIA use in pregnant women. The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. Intravenous administration of abatacept during organogenesis to mice (10, 55, or 300 mg/kg/day), rats (10, 45, or 200 mg/kg/day), and rabbits (10, 45, or 200 mg/kg every 3 days) produced exposures in rats and rabbits that were approximately 29 times the MRHD on an AUC basis (at maternal doses of 200 mg/kg/day in rats and rabbits), and no embryotoxicity or fetal malformations were observed in any species. In a study of pre- and postnatal development in rats (10, 45, or 200 mg/kg every 3 days from gestation day 6 through lactation day 21), alterations in immune function in female offspring, consisting of a 9-fold increase in T-cell-dependent antibody response relative to controls on postnatal day (PND) 56 and thyroiditis in a single female pup on PND 112, occurred at approximately 11 times the MRHD on an AUC basis (at a maternal dose of 200 mg/kg). No adverse effects were observed at approximately 3 times the MRHD (a maternal dose of 45 mg/kg). It is not known if immunologic perturbations in rats are relevant indicators of a risk for development of autoimmune diseases in humans exposed in utero to abatacept. Exposure to abatacept in the juvenile rat, which may be more representative of the fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas  [see Nonclinical Toxicology (13.2) ] . There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept. Polyarticular Juvenile Idiopathic Arthritis The safety and effectiveness of ORENCIA for reducing signs and symptoms in patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) have been established (ORENCIA may be used as monotherapy or concomitantly with methotrexate). Use of ORENCIA for this indication is supported by evidence from the following studies:   Intravenous Use : A randomized withdrawal efficacy, safety, and pharmacokinetic study of intravenous ORENCIA in 190 pediatric patients 6 to 17 years of age with pJIA [see Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] . Given that population pharmacokinetic (PK) analyses (after intravenous ORENCIA administration) showed that clearance of abatacept increased with baseline body weight, intravenous ORENCIA is administered either weight-based or weight ranged based [see Dosage and Administration (2.2) ] . Intravenous ORENCIA administration has not been studied in patients younger than 6 years of age.   Subcutaneous Use : An open-label PK and safety study of subcutaneous ORENCIA in 205 pediatric patients aged 2 to 17 years old with pJIA, extrapolation of effectiveness of intravenous ORENCIA in patients with pJIA and subcutaneous ORENCIA in patients with RA [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)] . Given that population PK analyses (after subcutaneous ORENCIA injection) in pJIA patients showed that there was a trend toward higher clearance of abatacept with increasing body weight, subcutaneous ORENCIA dosage is weight range-based [see Dosage and Administration (2.2) ] . The safety and effectiveness of ORENCIA use in pJIA in pediatric patients less than two years of age have not been established. Acute Graft Versus Host Disease Prophylaxis The safety and effectiveness of ORENCIA for the prophylaxis of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in pediatric patients aged 2 years of age and older undergoing HSCT from a matched or 1 allele-mismatched unrelated donor have been established. Use of ORENCIA for this indication is supported by evidence from: • adequate and well-controlled studies in adults and pediatric patients aged 6 years and older administered a dose of 10 mg/kg intravenously on the day before transplantation followed by a dose of 10 mg/kg intravenously on Days 5, 14, and 28 after transplantation and • pharmacokinetic modeling and simulations of abatacept exposure in pediatric patients aged 2 to less than 6 years administered a dose of 15 mg/kg intravenously on the day before transplantation followed by a dose of 12 mg/kg intravenously on Days 5, 14, and 28 after transplantation. Furthermore, the course of disease is sufficiently similar in pediatric patients aged 2 years to less than 6 years to that of patients aged 6 years and older to allow extrapolation of data to younger pediatric patients [see Clinical Pharmacology (12.3) and Clinical Studies (14.4) ] . No new safety signals were observed in pediatric patients aged 6 years and older in Study GVHD-1. The safety and effectiveness of ORENCIA for this indication have not been established in pediatric patients less than 2 years of age. Psoriatic Arthritis Subcutaneous Administration The safety and effectiveness of subcutaneous ORENCIA have been established for treatment of psoriatic arthritis in pediatric patients 2 to 17 years old. Use of ORENCIA in this age group is supported by evidence from adequate and well-controlled studies of ORENCIA in adults with PsA, pharmacokinetic data from adult patients with RA, adult patients with PsA, and pediatric patients with pJIA, and safety data from clinical studies in pediatric patients 2 to 17 years old with pJIA using the subcutaneous formulation. The observed pre-dose (trough) concentrations are generally comparable between adults with RA and PsA and pediatric patients with JIA with active polyarthritis, and the PK exposure is expected to be comparable between adult PsA and pediatric patients with PsA. [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1 , 14.2 , 14.3 )]. The safety and effectiveness of subcutaneous ORENCIA have not been established in pediatric patients less than 2 years old with psoriatic arthritis. Intravenous Administration The safety and effectiveness of intravenous ORENCIA in pediatric patients with psoriatic arthritis have not been established. A juvenile animal study conducted in rats dosed with abatacept from 4 to 94 days of age (prior to immune system maturity) showed an increase in the incidence of infections leading to death at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, lymphocytic inflammation of the thyroid and pancreatic islets was observed. In contrast, studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans is unknown. Rheumatoid Arthritis A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between geriatric patients (patients aged 65 years of age and older) and younger adults, and other reported clinical experience has not identified differences in responses between geriatric patients and younger adults, but greater sensitivity of some geriatric patients cannot be ruled out. The frequency of serious infection and malignancy among ORENCIA-treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the geriatric population in general, caution should be used when treating geriatric patients. Acute Graft Versus Host Disease Prophylaxis Of the 116 patients in Study GVHD-1 who received ORENCIA at a dose of 10 mg/kg for the prophylaxis of aGVHD, 12 (10%) were 65 years of age and older, and 2 (2%) patients were 75 years of age and older [see Clinical Studies (14.4) ]. Clinical studies of ORENCIA for aGVHD did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

ORENCIA ® (abatacept) for injection is a white lyophilized powder for intravenous infusion after reconstitution and dilution. It is supplied as an individually packaged, single-dose vial (one may use less than the full contents of the vial or use more than one vial) with a silicone-free disposable syringe, providing 250 mg of abatacept:                     NDC 0003-2187-10: in a clamshell presentation                     NDC 0003-2187-13: in a carton presentation ORENCIA ® (abatacept) injection and ORENCIA ® ClickJect (abatacept) injection are clear to slightly opalescent, colorless to pale yellow solutions for subcutaneous administration. ORENCIA (abatacept) injection, 50 mg/0.4 mL, 87.5 mg/0.7 mL, and 125 mg/mL, is supplied as single-dose disposable prefilled glass syringes with BD UltraSafe Passive™ needle guard and flange extenders. The Type I glass syringe has a coated stopper and fixed stainless steel needle (5 bevel, 29-gauge thin wall, ½-inch needle) covered with a rigid needle shield. The prefilled syringe provides ORENCIA in the following packages:                     NDC 0003-2814-11 (50 mg/0.4 mL): pack of 4 syringes with a passive needle safety guard                     NDC 0003-2818-11 (87.5 mg/0.7 mL): pack of 4 syringes with a passive needle safety guard                     NDC 0003-2188-11 (125 mg/mL): pack of 4 syringes with a passive needle safety guard ORENCIA (abatacept) ClickJect, 125 mg/mL, is supplied as a single-dose disposable prefilled autoinjector. The Type I glass syringe contained in the autoinjector has a coated stopper and fixed stainless steel needle (5 bevel, 27-gauge special thin wall, ½-inch needle) covered with a rigid needle shield. The autoinjector provides 125 mg of abatacept in 1 mL and is provided in the following package:                     NDC 0003-2188-51: pack of 4 autoinjectors Storage Refrigerate ORENCIA lyophilized powder supplied in a vial at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use. Refrigerate ORENCIA solution supplied in a prefilled syringe or ClickJect autoinjector at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the prefilled syringe or autoinjector. Protect from light by storing in the original package until time of use. Do not allow the prefilled syringe or autoinjector to freeze.

Abatacept, a selective costimulation modulator, inhibits T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of RA, pJIA and PsA and are found in the synovium of patients with RA, pJIA and PsA. In vitro , abatacept decreases T-cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown. In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNFα. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown. No formal pharmacodynamic analyses of biologic response markers have been performed in patients exposed to ORENCIA as prophylaxis for aGVHD. 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. 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. 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. 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. 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. 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.

In a mouse carcinogenicity study, weekly subcutaneous injections of 20, 65, or 200 mg/kg of abatacept administered for up to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females). The mice from this study were infected with murine leukemia virus and mouse mammary tumor virus. These viruses are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. The doses used in these studies produced exposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). The relevance of these findings to the clinical use of ORENCIA is unknown. In a one-year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure based on AUC). Abatacept was not associated with any significant drug-related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of ORENCIA is unknown. No mutagenic potential of abatacept was observed in the in vitro bacterial reverse mutation (Ames) or Chinese hamster ovary/hypoxanthine guanine phosphoribosyl-transferase (CHO/HGPRT) forward point mutation assays with or without metabolic activation, and no chromosomal aberrations were observed in human lymphocytes treated with abatacept with or without metabolic activation. Abatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg/kg every three days (11 times the MRHD exposure based on AUC). In studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed.

The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization, and Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in Studies I, II, III, IV, and VI. • Study I (NCT00279760) evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept. • In Study II (NCT00162266) and Study III (NCT00048568), the efficacy of ORENCIA were assessed in patients with an inadequate response to MTX and who were continued on their stable dose of MTX. • In Study IV (NCT00048581), the efficacy of ORENCIA was assessed in patients with an inadequate response to a TNF antagonist, with the TNF antagonist discontinued prior to randomization; other DMARDs were permitted. • Study V (NCT00048932) primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions. • In Study VI (NCT00122382), the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo. Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 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. The efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1 (NCT00559585), which was a randomized, double-blind, double-dummy, non-inferiority study that compared ORENCIA administered subcutaneously to ORENCIA administered intravenously in 1457 patients with moderate to severely active RA, receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR). In Study SC-1, patients were randomized with stratification by body weight (<60 kg, 60 to 100 kg, >100 kg) to receive (1) ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or (2) ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of MTX from the day of randomization. The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 9. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III. In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus MTX in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness. In Study VI, a greater proportion of patients treated with ORENCIA plus MTX achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with MTX plus placebo (Table 9). Of patients treated with ORENCIA plus MTX who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both. In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified non-inferiority margin was a treatment difference of −7.5%. As shown in Table 10, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 9. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown). Table 9:       Clinical Responses in Controlled Trials in Patients with RA Percent of Patients Intravenous Administration Subcutaneous or Intravenous Administration   Inadequate Response to DMARDs Inadequate Response to Methotrexate (MTX) Inadequate Response to TNF Antagonists MTX-Naive Inadequate Response to MTX   Study I Study III Study IV Study VI Study SC-1 *      p<0.05, ORENCIA (ORN) vs placebo (PBO) or MTX. †       p<0.01, ORENCIA vs placebo or MTX. ‡       p<0.001, ORENCIA vs placebo or MTX. §       95% CI: −4.2, 4.8 (based on prespecified margin for non-inferiority of −7.5%). a       10 mg/kg. b       Dosing based on weight range [ see Dosage and Administration (2.1) ] . c       Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period. d       Refer to text for additional description of remaining joint activity. e       Per protocol data is presented in table. For ITT; n=736, 721 for SC and IV ORENCIA, respectively. Response Rate ORN a n=32 PBO n=32 ORN b +MTX n=424 PBO +MTX n=214 ORN b + DMARDs n=256 PBO + DMARDs n=133 ORN b +MTX n=256 PBO +MTX n=253 ORN e SC +MTX n=693 ORN e IV +MTX n=678 ACR 20         Month 3 53% 31% 62% ‡ 37% 46% ‡ 18% 64%* 53% 68% 69% Month 6 NA NA 68% ‡ 40% 50% ‡ 20% 75% † 62% 76% § 76% Month 12 NA NA 73% ‡ 40% NA NA 76% ‡ 62% NA NA ACR 50           Month 3 16% 6% 32% ‡ 8% 18% † 6% 40% ‡ 23% 33% 39% Month 6 NA NA 40% ‡ 17% 20% ‡ 4% 53% ‡ 38% 52% 50% Month 12 NA NA 48% ‡ 18% NA NA 57% ‡ 42% NA NA ACR 70           Month 3 6% 0 13% ‡ 3% 6%* 1% 19% † 10% 13% 16% Month 6 NA NA 20% ‡ 7% 10% † 2% 32% † 20% 26% 25% Month 12 NA NA 29% ‡ 6% NA NA 43% ‡ 27% NA NA Major Clinical Response c NA NA 14% ‡ 2% NA NA 27% ‡ 12% NA NA DAS28-CRP <2.6 d           Month 12 NA NA NA NA NA NA 41% ‡ 23% NA NA The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 10 (results at Baseline [BL] and 6 months [6 M]). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients. Table 10:     Components of ACR Responses at 6 Months in Adult Patients with RA   Intravenous Administration Subcutaneous or Intravenous Administration   Inadequate Response to MTX Inadequate Response to TNF Antagonists Inadequate Response to MTX Study III Study IV Study SC-1 c †      p<0.01, ORENCIA (ORN) vs placebo (PBO), based on mean percent change from baseline. ‡      p<0.001, ORENCIA vs placebo, based on mean percent change from baseline. a      Visual analog scale: 0 = best, 100 = worst. b      Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating,        walking, hygiene, reach, grip, and activities. c      SC-1 is a non-inferiority study. Per protocol data is presented in table.   ORN +MTX n=424 PBO +MTX n=214 ORN +DMARDs n=256 PBO +DMARDs n=133 ORN SC +MTX n=693 ORN IV +MTX n=678 Component (median) BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M Number of tender joints (0-68) 28 7 ‡ 31 14 30 13 ‡ 31 24 27 5 27 6 Number of swollen joints (0-66) 19 5 ‡ 20 11 21 10 ‡ 20 14 18 4 18 3 Pain a 67 27 ‡ 70 50 73 43 † 74 64 71 25 70 28 Patient global assessment a 66 29 ‡ 64 48 71 44 ‡ 73 63 70 26 68 27 Disability index b 1.75 1.13 ‡ 1.75 1.38 1.88 1.38 ‡ 2.00 1.75 1.88 1.00 1.75 1.00 Physician global assessment a 69 21 ‡ 68 40 71 32 ‡ 69 54 65 16 65 15 CRP (mg/dL) 2.2 0.9 ‡ 2.1 1.8 3.4 1.3 ‡ 2.8 2.3 1.6 0.7 1.8 0.7 The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III. Figure 1:     Percent of Patients Achieving ACR 50 Response by Visit* (Study III) *The same patients may not have responded at each time point. The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15—SC 3%, IV 5%; Day 29—SC 11%, IV 14%; Day 57—SC 24%, IV 30%; Day 85—SC 33%, IV 38%; Day 113—SC 39%, IV 41%; Day 141—SC 46%, IV 47%; Day 169—SC 51%, IV 50%. Figure 1 ACR50 Response Study III In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/MTX slowed the progression of structural damage compared to placebo/MTX after 12 months of treatment as shown in Table 11. Table 11:     Mean Radiographic Changes in Study III a and Study VI b Parameter ORENCIA/MTX Placebo/MTX Differences P-value d a      Patients with an inadequate response to MTX. b      MTX-naive patients. c      Patients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX. d      Based on a nonparametric ANCOVA model. Study III         First Year      TSS 1.07 2.43 1.36 <0.01      ES 0.61 1.47 0.86 <0.01      JSN score 0.46 0.97 0.51 <0.01 Second Year      TSS 0.48 0.74 c - -      ES 0.23 0.22 c - -      JSN score 0.25 0.51 c - - Study VI         First Year              TSS 0.6 1.1 0.5 0.04 In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/MTX and 65% of patients initially randomized to placebo/MTX were evaluated radiographically at Year 2. As shown in Table 11, progression of structural damage in ORENCIA/MTX-treated patients was further reduced in the second year of treatment. Following 2 years of treatment with ORENCIA/MTX, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/MTX-treated patients had no progression during the first year compared to 45% of placebo/MTX-treated patients. In their second year of treatment with ORENCIA/MTX, more patients had no progression than in the first year (65% vs 56%). Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus MTX in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous ORENCIA administration. The results from Studies II and III are shown in Table 12. Similar results were observed in Study V compared to placebo and in Study VI compared to MTX. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years. Table 12:     Mean Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) in Adult Patients with RA   Inadequate Response to Methotrexate   Study II Study III ***  p<0.001, ORENCIA vs placebo. a       10 mg/kg. b       Dosing based on weight range [ see Dosage and Administration (2.1) ] . c       Modified Health Assessment Questionnaire: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. d       Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. HAQ Disability Index ORENCIA a +MTX (n=115) Placebo +MTX (n=119) ORENCIA b +MTX (n=422) Placebo +MTX (n=212) Baseline (Mean) 0.98 c 0.97 c 1.69 d 1.69 d Mean Improvement      Year 1 0.40 c, *** 0.15 c 0.66 d, *** 0.37 d Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The safety and efficacy of ORENCIA with intravenous administration were assessed in Study JIA-1 (NCT00095173), a three-part study including an open-label extension in pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). Patients 6 to 17 years of age (n=190) with moderately to severely active pJIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had JIA subtypes that at disease onset included oligoarticular (16%), polyarticular (64%; 20% were rheumatoid factor positive), and systemic JIA without systemic manifestations (20%). At study entry, 74% of patients were receiving MTX (mean dose, 13.2 mg/m 2 per week) and remained on a stable dose of MTX (those not receiving MTX did not initiate MTX treatment during the study). In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1,000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare. At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied. During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients (intravenous) experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on intravenous ORENCIA was less than one-third than that for patients withdrawn from intravenous ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received intravenous ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year. ORENCIA for subcutaneous administration without an intravenous loading dose was assessed in Study JIA-2 (NCT01844518), a 2-period, open-label study that included pediatric patients 2 to 17 years of age (n=205). Patients had active polyarticular disease at the time of the study and had inadequate response to at least one nonbiologic or biologic DMARD. The JIA patient subtypes at study entry included polyarticular (79%; 22% were rheumatoid factor positive), extended and persistent oligoarticular (14%), enthesitis-related arthritis (1%), and systemic JIA without systemic manifestations (2%). Patients had a mean disease duration of 2.5 years with active joints (mean, 11.9), joints with loss of motion (mean, 10.4), and elevated C-reactive protein (CRP) levels (mean, 1.2 mg/dL). At study entry, 80% of patients were receiving MTX and remained on a stable dose of MTX. Patients received weekly open-label ORENCIA subcutaneously by a weight-tiered dosing regimen. The primary objective of the study was evaluation of PK in order to support the extrapolation of efficacy based on exposure to ORENCIA supported by descriptive efficacy [see Clinical Pharmacology (12.3) ] . JIA ACR 30/50/70 responses assessed at 4 months in the 2- to 17-year-old patients treated with subcutaneous ORENCIA were consistent with the results from intravenous ORENCIA in Study JIA-1. The efficacy of ORENCIA was assessed in 594 adult patients (18 years and older) with psoriatic arthritis (PsA), in two randomized, double-blind, placebo-controlled studies (Studies PsA-I [NCT00534313] and PsA-II [NCT01860976]). Patients had active PsA (≥3 swollen joints and ≥3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNF antagonists previously. During the initial 24-week, double-blind period of Study PsA-I, 170 patients were randomized to receive one of four intravenous treatments on Days 1, 15, 29, and then every 28 days (there was no escape during the 24-week period): • Placebo • ORENCIA 3 mg/kg • ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg (weight-range-based dosing), or • ORENCIA 30 mg/kg on Days 1 and 15 followed by weight range-based ORENCIA dosing (i.e., 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). After the 24-week double blind period in Study PsA-I, patients received open-label intravenous ORENCIA every 28 days. Patients were allowed to receive stable doses of concomitant MTX, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. At enrollment, approximately 60% of patients were receiving MTX. At baseline, the mean (SD) CRP for ORENCIA IV was 17 mg/L (33.0) and mean number (SD) of tender joints and swollen joints was 22.2 (14.3) and 10.9 (7.6), respectively. In PsA-II, 424 patients were randomized 1:1 to receive weekly doses of subcutaneous placebo or ORENCIA 125 mg without a loading dose for 24 weeks-in a double-blind manner, followed by open-label subcutaneous ORENCIA 125 mg weekly. Patients were allowed to receive stable doses of concomitant MTX, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. At randomization, 60% of patients were receiving MTX. The baseline disease characteristics included presence of joint erosion on X-rays in 84% (341/407) with a mean (SD) PsA-modified Sharp van der Heijde erosion score (SHS) of 10.8 (24.2), elevated serum C reactive protein (CRP) in 66% [277/421]) with a mean (SD) of 14.1 mg/L (25.9), and polyarticular disease in 98% (416/424) of patients with a mean number (SD) of tender joints and swollen joints of 20.2 (13.3) and 11.6 (7.5), respectively. Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by Week 16 escaped to open-label subcutaneous ORENCIA 125 mg weekly. The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169). A greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with intravenous ORENCIA (weight-range-based dosing as described above) compared to placebo in Study PsA-I and a greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with subcutaneous 125 mg compared to placebo in Study PsA-II at Week 24. Responses were seen regardless of prior TNF antagonist treatment and regardless of concomitant non-biologic DMARD treatment. The percent of patients achieving ACR 20, 50, or 70 responses in Studies PsA‑I and PsA-II are presented in Table 13 below. Table 13:     Proportion of Patients With ACR Responses at Week 24 in Studies PsA-I and PsA-II a   PsA-I PsA-II *      p<0.05 versus placebo. a       Patients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders. b       Weight range-based intravenous dosing: ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg. ORENCIA Weight-Range-Based Intravenous Dosing b N=40 Placebo N=42 ORENCIA 125 mg Subcutaneous N=213 Placebo N=211 ACR 20 47.5%* 19.0% 39.4%* 22.3% ACR 50 25.0% 2.4% 19.2% 12.3% ACR 70 12.5% 0% 10.3% 6.6% The percentage of patients in PsA-II achieving ACR 20 response through Week 24 is shown below in Figure 2. Figure 2:     Percent of Patients Achieving ACR 20 Response a in PsA-II Study Through Week 24 (Day 169) Results were generally consistent across the ACR components in Study PsA-I and PsA-II. Improvements in enthesitis and dactylitis were seen with ORENCIA treatment at Week 24 in both PsA-I and PsA-II. Orencia Figure 2 % of Patients achieving ACR 20 In study PsA-I, there was a higher proportion of patients with at least a 0.30 decrease from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24, with an estimated difference for ORENCIA weight range-based dosing as described above (45%) vs. placebo (19%) of 26.1 (95% confidence interval: 6.8, 45.5). In study PsA-II, the proportion of patients with at least a 0.35 decrease from baseline in HAQ-DI on ORENCIA was 31%, as compared to 24% on placebo (estimated difference: 7%; 95% confidence interval: -1%, 16%). There was a higher adjusted mean change from baseline in HAQ-DI on ORENCIA (-0.33) vs. placebo (-0.20) at Week 24, with an estimated difference of -0.13 (95% confidence interval: -0.25, -0.01). Study GVHD-1 The efficacy of ORENCIA, in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), for the prophylaxis of acute graft versus host disease (aGVHD), was evaluated in a multicenter, two cohort clinical study (GVHD-1, NCT01743131) in patients age 6 years and older who underwent hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor (URD). The two cohorts in GVHD-1 included: 1) an open-label, single-arm study of 43 patients who underwent a 7 of 8 Human Leukocyte Antigen (HLA)-matched HSCT (7 of 8 cohort); and 2) a randomized (1:1), double-blind, placebo-controlled study of patients who underwent an 8 of 8 HLA-matched HSCT who received ORENCIA or placebo in combination with a CNI and MTX (8 of 8 cohort). In both the 7/8 and 8/8 cohorts, ORENCIA was administered at a dose of 10 mg/kg (1,000 mg maximum dose) as an intravenous infusion over 60 minutes, beginning on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation. Baseline demographic and clinical characteristics of both the 7 of 8 and 8 of 8 cohorts are outlined below in Table 14. Table 14:     Baseline Demographic and Clinical Characteristics: 7 of 8 and 8 of 8 Cohort Treated Analysis Population in Study GVHD-1 7 of 8 Cohort 8 of 8 Cohort ORENCIA (+ CNI and MTX) N=43 ORENCIA (+ CNI and MTX) N=73 Placebo (+CNI and MTX) N=69 Age - Median 38 44 40 Age - Range 6-76 6-71 7-74 Gender - Male 27 (63) 41 (56) 37 (54) White 31 (72) 63 (86) 61 (88) Black or African American 7 (16) 3 (4.1) 2 (2.9) Asian 2 (4.7) 4 (6) 2 (2.9) Hispanic 7 (16) 4 (6) 2 (2.9) Malignancy type    Acute Myeloid Leukemia (AML) 15 (35) 30 (41) 22 (32)    Myelodysplastic Syndrome (MDS) 11 (26) 15 (21) 12 (17)    Acute Lymphoblastic Leukemia (ALL) 8 (19) 20 (27) 22 (32)    Acute leukemia or ambiguous lineage 1 (2.3) 0 1 (1.4)    Hodgkin and Non-Hodgkin lymphoma 1 (2.3) 1 (1.4) 1 (1.4)    Acute Lymphoblastic Lymphoma in 2nd or Greater Complete Remission 1 (2.3) 4 (6) 1 (1.4)    Chronic Myelomonocytic leukemia 1 (2.3) 1 (1.4) 4 (6)    Chronic Myelogenous leukemia 4 (9) 1 (1.4) 5 (7)    Not reported 1 (2.3) 1 (1.4) 1 (1.4) GVHD Prophylaxis    Cyclosporine 16 (37) 11 (15) 11 (16)    Tacrolimus 27 (63) 62 (85) 58 (84) Type of Graft    Bone Marrow 21 (49) 33 (45) 26 (38)    Cytokine Mobilized Peripheral Blood (PBSC) 22 (51) 40 (55) 43 (62) Conditioning Regimen    TBI and Chemotherapy 11 (26) 20 (27) 26 (38)    Busulfan and Cyclophosphamide 13 (30) 28 (38) 21 (30)    Busulfan and Fludarabine 8 (19) 7 (10) 2 (2.9)    Melphalan and Fludarabine 11 (26) 18 (25) 20 (29) Efficacy was established based on overall survival (OS) and grade II-IV aGVHD free survival (GFS) results assessed at Day 180 post-transplantation. ORENCIA + CNI and MTX did not significantly improve grade III-IV GFS versus placebo + CNI and MTX at Day 180 post-transplantation. The efficacy results of the GVHD-1 8 of 8 cohort are shown in Table 15. Table 15:     Efficacy Results in 8 of 8 Cohort in Study GVHD-1 at Day 180 Post-Transplantation a Gr III-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade III-IV aGVHD, or death by any cause up to Day 180 post-transplantation. b Gr II-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade II-IV aGVHD, or death by any cause up to Day 180 post-transplantation. Endpoint ORENCIA (+CNI and MTX) n=73 Placebo (+CNI and MTX) n=69 Gr III-IV aGVHD Free Survival a Rate (95% CI) 87% (77%, 93%) 75% (63%, 84%) Hazard Ratio (95% CI) 0.55 (0.26, 1.18) Gr II-IV aGVHD Free Survival b Rate (95% CI) 50% (38%, 61%) 32% (21%, 43%) Hazard Ratio (95% CI) 0.54 (0.35, 0.83) Overall Survival Rate (95% CI) 97% (89%, 99%) 84% (73%, 91%) Hazard Ratio (95% CI) 0.33 (0.12, 0.93) In an exploratory analysis of the 7 of 8 cohort of ORENCIA-treated patients (n=43), the rates of Grade III-IV GVHD-free survival, Grade II-IV GVHD-free survival, and overall survival at day 180 post-transplantation were 95% (95% CI 83%, 99%), 53% (95% CI 38%, 67%), and 98% (95% CI 85%, 100%), respectively. Study GVHD-2 GVHD-2 (NCT05421299) was a clinical study that used data from the Center for International Blood and Marrow Transplant Research (CIBMTR). The study analyzed outcomes of ORENCIA in combination with a CNI and MTX, versus a CNI and MTX alone, for the prophylaxis of aGVHD, in patients 6 years of age or older who underwent HSCT from a 1 allele-mismatched URD between 2011 and 2018. The ORENCIA + CNI and MTX-treated group (n=54) included 42 patients from GVHD-1, in addition to 12 patients treated with ORENCIA outside of GVHD-1. The comparator group (n=162) was randomly selected in a 3:1 ratio to the ORENCIA-treated group from the CIBMTR registry from patients who had not received ORENCIA during the study period. Analyses used propensity score matching and inverse probability of treatment weighting to help address the impact of selection bias. Efficacy was based on Overall Survival (OS) at Day 180 post-HSCT. The OS rate at Day 180 in the ORENCIA in combination with CNI and MTX group was 98% (95% CI: 78, 100) and the OS rate at Day 180 in the CNI and MTX group was 75% (95% CI: 67, 82).

PATIENT INFORMATION ORENCIA ® (oh-REN-see-ah) (abatacept) injection, for intravenous or subcutaneous use What is ORENCIA? ORENCIA is a prescription medicine that reduces signs and symptoms in: • adults with moderate to severe rheumatoid arthritis (RA), including those who have not been helped enough by other medicines for RA. ORENCIA may prevent further damage to your bones and joints and may help your ability to perform daily activities. In adults, ORENCIA may be used alone or with other RA treatments other than tumor necrosis factor (TNF) antagonists. • people 2 years of age and older with moderate to severe polyarticular juvenile idiopathic arthritis (pJIA). ORENCIA may be used alone or with methotrexate. • people 2 years of age and older with active psoriatic arthritis (PsA). In adults, ORENCIA can be used alone or with other PsA treatments. In children, ORENCIA can be used alone or with methotrexate. ORENCIA is also used for the preventative treatment of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in: • people 2 years of age and older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated-donor. It is not known if ORENCIA is safe and effective in children less than two years of age for the treatment of pJIA. It is not known if ORENCIA is safe and effective in children less than two years of age for the treatment of PsA. It is not known if ORENCIA is safe and effective in children less than two years of age for the preventative treatment of aGVHD. Before you receive or use ORENCIA, tell your healthcare provider about all of your medical conditions, including if you: • have any kind of infection even if it is small (such as an open cut or sore), or an infection that is in your whole body (such as the flu). If you have an infection during treatment with ORENCIA, you may have a higher chance for getting serious side effects. • have an infection that will not go away or an infection that keeps coming back. • are allergic to abatacept or any of the ingredients in ORENCIA. See the end of this Patient Information leaflet for a complete list of ingredients in ORENCIA. • have or have had inflammation of your liver due to an infection (viral hepatitis). Your healthcare provider may examine you for hepatitis before treatment with ORENCIA. • have had a lung infection called tuberculosis (TB), a positive skin test for TB, or you recently have been in close contact with someone who has had TB. Your healthcare provider may examine you for TB or perform a skin test before treatment with ORENCIA. Symptoms of TB may include: o a cough that does not go away o weight loss o fever o night sweats • have a history of Epstein-Barr Virus (EBV) or Cytomegalovirus (CMV) in people receiving ORENCIA for preventative treatment of aGVHD during HSCT from an unrelated donor. • are scheduled to have surgery. • recently received a vaccination or are scheduled for a vaccination. • have a history of a breathing problem called chronic obstructive pulmonary disease (COPD). • have diabetes and use a blood glucose monitor to check your blood sugar (blood glucose) levels. o ORENCIA for intravenous infusion (given through a needle placed in a vein) contains maltose, a type of sugar, that can give false high blood sugar readings with certain types of blood glucose monitors on the day of ORENCIA infusion. Your healthcare provider may tell you to use a different way to monitor your blood sugar levels. o ORENCIA for subcutaneous injection (injected under the skin) does not contain maltose. You do not need to change your blood sugar monitoring if you are using ORENCIA subcutaneously. • are pregnant or plan to become pregnant. It is not known if ORENCIA can harm your unborn baby. If you took ORENCIA during pregnancy, talk to your healthcare provider before your baby receives any vaccines. • are breastfeeding or plan to breastfeed. It is not known if ORENCIA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use ORENCIA. • Some people treated with ORENCIA have developed skin cancer. Tell your healthcare provider if you have a family or personal history of skin cancer, and if you see any growths or changes in the appearance of your skin during or after your treatment with ORENCIA. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. ORENCIA may affect the way other medicines work, and other medicines may affect the way ORENCIA works causing serious side effects. Especially tell your healthcare provider if you take other biologic medicines that may affect your immune system, such as: • Enbrel ® (etanercept) • Humira ® (adalimumab) • Remicade ® (infliximab) • Kineret ® (anakinra) • Rituxan ® (rituximab) • Simponi ® (golimumab) • Cimzia ® (certolizumab pegol) • Actemra ® (tocilizumab) You may have a higher chance of getting a serious infection if you take ORENCIA with other biologic medicines that may affect your immune system. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new prescription. How will I receive or use ORENCIA? For treatment of RA, pJIA or PsA: • You may receive ORENCIA given by a healthcare provider through a vein in your arm (intravenous infusion). It takes about 30 minutes to give you the full dose of medicine. You will then receive ORENCIA 2 weeks and 4 weeks after the first dose and then every 4 weeks. Intravenous administration of ORENCIA is not approved for pediatric patients with psoriatic arthritis. • You may also receive ORENCIA as an injection under your skin (subcutaneous). For home use, ORENCIA comes in a prefilled syringe or prefilled ClickJect autoinjector. Your healthcare provider will prescribe the type that is best for you. If your healthcare provider decides that you or a caregiver can give your injections of ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors at home, you or your caregiver should receive training on the right way to prepare and inject ORENCIA. Do not try to inject ORENCIA until you have been shown the right way to give the injections by your healthcare provider. • Your healthcare provider will tell you how much ORENCIA to use and when to use it. See the Instructions for Use at the end of this Patient Information leaflet for instructions about the right way to prepare and give your ORENCIA injections at home. For preventative treatment of aGVHD: • You will receive ORENCIA by a healthcare provider through a vein in your arm (intravenous infusion) over 60 minutes on the day before transplantation (Day -1). You will then receive ORENCIA on Days 5, 14, and 28 after transplantation. • Your healthcare provider may give you antiviral medicines before, during, and after your transplantation to help prevent Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) infections. What are the possible side effects of ORENCIA? ORENCIA may cause serious side effects, including: • infections . ORENCIA can make you more likely to get infections or make the infection that you have get worse. Some people have died from these infections. Call your healthcare provider right away if you have any symptoms of an infection. Symptoms of an infection may include: o fever o feel very tired o have a cough o have flu-like symptoms o warm, red, or painful skin • allergic reactions . Allergic reactions can happen to people who are treated with ORENCIA. Call your healthcare provider or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include: o hives o swollen face, eyelids, lips, or tongue o trouble breathing • hepatitis B infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus can become active during treatment with ORENCIA. Your healthcare provider may do a blood test before you start treatment with ORENCIA. • vaccinations. You should not receive ORENCIA with certain types of vaccines (live vaccines). You can receive non-live vaccines, such as pneumococcal and inactivated influenza (flu) vaccines. ORENCIA may also cause some vaccinations to be less effective. Talk with your healthcare provider about your vaccination plans. • breathing problems in people with Chronic Obstructive Pulmonary Disease (COPD). You may get certain respiratory problems more often if you receive ORENCIA and have COPD. Symptoms of respiratory problems include: o COPD that becomes worse o cough o trouble breathing • cancer (malignancies). Certain kinds of cancer have been reported in people using ORENCIA. It is not known if ORENCIA increases your chance of getting certain kinds of cancer. • Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) infections. CMV and EBV infections and return of CMV and EBV (reactivation) have happened in people receiving ORENCIA for preventative treatment of aGVHD during unrelated HSCT. Your healthcare provider will monitor you for 6 months after transplantation and may treat you with medicines to help prevent CMV and EBV infection if needed. The most common side effects of ORENCIA in people with RA include: • headache • upper respiratory tract infection • sore throat • nausea In children and adolescents, other side effects may include: • diarrhea • cough • fever • abdominal pain The most common side effects of ORENCIA in prevention of aGVHD include: • low red blood cell count • high blood pressure • CMV infection • fever • pneumonia • nosebleed • decreased CD4 lymphocytes • increased levels of magnesium in the blood • kidney problems These are not all the possible side effects of ORENCIA. 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 ORENCIA? • Store ORENCIA in the refrigerator at 36°F to 46°F (2°C to 8°C). • Keep ORENCIA in the original package and out of the light. • Do not freeze ORENCIA. • Safely throw away medicine that is out of date or no longer needed. Keep ORENCIA and all medicines out of the reach of children. General information about the safe and effective use of ORENCIA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ORENCIA for a condition for which it was not prescribed. Do not give ORENCIA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ORENCIA that is written for health professionals. What are the ingredients in ORENCIA? Active ingredient: abatacept Intravenous inactive ingredients: maltose, monobasic sodium phosphate, sodium chloride for administration Subcutaneous inactive ingredients: sucrose, poloxamer 188, monobasic sodium phosphate monohydrate, dibasic sodium phosphate anhydrous, water for injection. Bristol-Myers Squibb Company Princeton, NJ 08543 USA, U.S. License Number 1713 All other trademarks are property of their respective owners. For more information, go to www.ORENCIA.com or call 1-800-ORENCIA. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 5/2024

See How Supplied section for a complete list of available packages of ORENCIA. Rx only NDC 0003-2187-13 ORENCIA ® (abatacept) Lyophilized Powder for IV Infusion 250 mg/vial ONLY USE THE SILICONE-FREE DISPOSABLE SYRINGE INCLUDED IN THE PACKAGE FOR RECONSTITUTION Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA US License No. 1713 orencia-250mgvial