1 ML abatacept 125 MG/ML Prefilled Syringe [Orencia]

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

DOSAGE AND ADMINISTRATION Intravenous Use for Adult RA (2.1) and Adult PsA (2.3) • Administer at 0, 2, and 4 weeks, and every 4 weeks thereafter, as a 30-minute infusion Body Weight of Patient Dose Number of Vials Less than 60 kg 500 mg 2 60 to 100 kg 750 mg 3 More than 100 kg 1,000 mg 4 Subcutaneous Use for Adult RA (2.1) • Prior to the first subcutaneous dose, may administer an optional loading dose as a single intravenous infusion as per body weight categories above. • Administer 125 mg by subcutaneous injection once weekly (within a day of the intravenous infusion if infusion given). • Patients switching from intravenous use to subcutaneous use, administer first subcutaneous dose instead of next scheduled intravenous dose. Intravenous Use for pJIA in Pediatric Patients ≥6 Years Old (2.2) • Pediatric patients weighing <75 kg administer 10 mg/kg intravenously and those weighing ≥75 kg administer the adult intravenous dosing regimen (not to exceed a maximum dose of 1,000 mg), as a 30-minute infusion. • Subsequently administer infusions at 2 and 4 weeks and every 4 weeks thereafter. Subcutaneous Use for pJIA and PsA in Pediatric Patients ≥2 Years Old (2.2) • Administer subcutaneously without an intravenous loading dose Body Weight of Pediatric Patient Dose (once weekly) 10 kg to less than 25 kg 50 mg 25 kg to less than 50 kg 87.5 mg 50 kg or more 125 mg Subcutaneous Use for Adult PsA ( 2.3 ) • Administer 125 mg by subcutaneous injection once weekly without an intravenous loading dose. • Patients switching from intravenous use to subcutaneous use, administer first subcutaneous dose instead of next scheduled intravenous dose. Intravenous Use for Prophylaxis of aGVHD (2.4) • For patients 6 years and older, administer at a 10 mg/kg dose (maximum dose 1,000 mg) as a 60-minute infusion on the day before transplantation, followed by a dose on Day 5, 14, and 28 after transplant. • For patients 2 to less than 6 years old, administer a 15 mg/kg dose as a 60-minute infusion on the day before transplantation, followed by a 12 mg/kg dose as a 60-minute infusion on Day 5, 14, and 28 after transplant. Preparation and Administration Instructions ( 2.5 , 2.6 ) • Administer as a 30-minute intravenous infusion for RA, pJIA, and adult PsA. (2.5) • Administer as a 60-minute intravenous infusion for aGVHD prophylaxis. (2.5) • See the Full Prescribing Information for preparation and administration instructions for intravenous infusion and recommendations for subcutaneous use. (2.5, 2.6) Prepare ORENCIA using only the silicone-free disposable syringe. (2.5) 2.1 Dosage in Adult Rheumatoid Arthritis For adult patients with RA, administer as an intravenous infusion or as a subcutaneous injection. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than JAK inhibitors or bDMARDs (e.g., TNF antagonists). Intravenous Dosage Reconstitute ORENCIA lyophilized powder and administer after dilution [see Dosage and Administration (2.5) ] as a 30-minute intravenous infusion utilizing the weight range-based dosing recommended in Table 1. Following the initial intravenous infusion, administer as an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter. Table 1: Dose of ORENCIA for Intravenous Infusion in Adult RA Patients Body Weight of Adult Patient Dose Number of Vials a a Each vial provides 250 mg of abatacept for administration. Less than 60 kg 500 mg 2 60 to 100 kg 750 mg 3 More than 100 kg 1,000 mg 4 Subcutaneous Dosage Prior to the first subcutaneous dose, an optional loading dose may be administered as a single intravenous infusion (as per body weight categories in Table 1). If an intravenous loading dose is used, administer the first subcutaneous injection within one day of the infusion. Administer ORENCIA 125 mg in prefilled syringes or in ORENCIA ClickJect™ autoinjector by subcutaneous injection once weekly [see Dosage and Administration (2.6) ] . For patients switching from ORENCIA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. 2.2 Dosage in Polyarticular Juvenile Idiopathic Arthritis For pediatric patients with pJIA, either administer ORENCIA as an intravenous infusion (only patients 6 years of age and older) or as a subcutaneous injection (only patients 2 years of age and older) [see Use in Specific Populations (8.4) ] . ORENCIA may be used as monotherapy or concomitantly with methotrexate. Intravenous Dosage Administer ORENCIA as a 30-minute intravenous infusion based on body weight [see Dosage and Administration (2.5) ] : • For body weight less than 75 kg, administer a dose of 10 mg/kg. • For body weight of 75 kg or greater, administer as per the recommendations in Table 1 (follow the adult intravenous dosing regimen), not to exceed a maximum dose of 1,000 mg. Following the initial intravenous infusion, administer infusions at 2 and 4 weeks and every 4 weeks thereafter. Immediately discard any unused portion in the vials. Subcutaneous Dosage Administer ORENCIA for subcutaneous injection, without an intravenous loading dose, utilizing the weight range-based dosing as recommended in Table 2 [see Dosage and Administration (2.6) ] . Subsequently administer once weekly. Table 2: Dose of ORENCIA for Subcutaneous Administration in Patients 2 Years of Age and Older with pJIA Body Weight of Pediatric Patient Dose (once weekly) 10 to less than 25 kg 50 mg 25 to less than 50 kg 87.5 mg 50 kg or more 125 mg Patients with pJIA may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determine it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested. 2.3 Dosage in Psoriatic Arthritis Adult Patients For adult patients with psoriatic arthritis, administer as an intravenous infusion or a subcutaneous injection. ORENCIA may be used with or without non-biologic DMARDs. Intravenous Dosage Administer ORENCIA as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, administer an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter. Subcutaneous Dosage Administer 125 mg of ORENCIA subcutaneously once weekly (no intravenous loading dose is needed) [see Dosage and Administration (2.6) ] . For patients switching from ORENCIA intravenous infusions to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Pediatric Patients Administer ORENCIA as a subcutaneous injection in pediatric patients 2 years of age and older with psoriatic arthritis [see Use in Specific Populations (8.4) ] . ORENCIA may be used as monotherapy or concomitantly with methotrexate. Intravenous administration is not approved for pediatric patients with psoriatic arthritis. Subcutaneous Dosage Administer ORENCIA for subcutaneous injection weekly, utilizing the weight range-based dosage as recommended in Table 3 [see Dosage and Administration (2.6) ] . Table 3: Dose of ORENCIA for Subcutaneous Administration in Patients 2 Years of Age and Older with Psoriatic Arthritis Body Weight of Pediatric Patient Dose (once weekly) 10 to less than 25 kg 50 mg 25 to less than 50 kg 87.5 mg 50 kg or more 125 mg Pediatric patients with psoriatic arthritis may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determine it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested. 2.4 Dosage in Prophylaxis of Acute Graft versus Host Disease in Adults and Pediatric Patients Aged 2 Years and Older Antiviral Prophylactic Treatment Before administering ORENCIA, administer recommended antiviral prophylactic treatment for Epstein-Barr Virus (EBV) reactivat

WARNINGS AND PRECAUTIONS • 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) 5.1 Increased Risk of Infection with Concomitant Use of TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors 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. 5.2 Hypersensitivity Reactions 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. 5.3 Infections 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. 5.4 Immunizations 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. 5.5 Increased Risk of Adverse Reactions When Used in Patients with Chronic Obstructive Pulmonary Disease (COPD) 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. 5.6 Immunosuppression 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. 5.7 Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Reactivation in aGVHD Prophylaxis after Hematopoietic Stem Cell Transplant (HSCT) 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 reactivat

CONTRAINDICATIONS None. None. (4)

Mechanism of Action 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.