NULOJIX

1 INDICATIONS AND USAGE • NULOJIX is a selective T cell costimulation blocker indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. (1.1) • Use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. (1.1) Limitations of Use : • Use only in patients who are EBV seropositive. (1.2 , 4 , 5.1) • Use has not been established for the prophylaxis of organ rejection in transplanted organs other than the kidney. (1.2 , 5.6) 1.1 Adult Kidney Transplant Recipients NULOJIX ® (belatacept) is indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. NULOJIX is to be used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. 1.2 Limitations of Use Use NULOJIX only in patients who are EBV seropositive [see Contraindications (4) and Warnings and Precautions (5.1) ] . Use of NULOJIX for the prophylaxis of organ rejection in transplanted organs other than kidney has not been established [see Warnings and Precautions (5.6) ] .

2 DOSAGE AND ADMINISTRATION • Use of higher than recommended or more frequent dosing is not recommended due to increased risk of serious infections and malignancy. (5.1 , 5.4 , 6.1) • For complete dosing instructions, see full prescribing information. (2.1) Dosing of NULOJIX for Kidney Transplant Recipients (2.1) Dosing for Initial Phase Dose Day 1 (day of transplantation, prior to implantation) and Day 5 (approximately 96 hours after Day 1 dose) 10 mg per kg End of Week 2 and Week 4 after transplantation 10 mg per kg End of Week 8 and Week 12 after transplantation 10 mg per kg Dosing for Maintenance Phase Dose End of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter 5 mg per kg • For intravenous infusion only; administer over 30 minutes. (2.1 , 2.2) • Only use the enclosed silicone-free disposable syringe to prepare for administration. (2.2) 2.1 Dosage in Adult Kidney Transplant Recipients NULOJIX should be administered in combination with basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids. In clinical trials the median (25 th to 75 th percentile) corticosteroid doses were tapered to approximately 15 mg (10 to 20 mg) per day by the first 6 weeks and remained at approximately 10 mg (5 to 10 mg) per day for the first 6 months post-transplant. Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience [see Warnings and Precautions (5.7) and Clinical Studies (14.1) ] . Due to an increased risk of post-transplant lymphoproliferative disorder (PTLD) predominantly involving the central nervous system (CNS), progressive multifocal leukoencephalopathy (PML), and serious CNS infections, administration of higher than the recommended doses or more frequent dosing of NULOJIX is not recommended [see Warnings and Precautions (5.1 , 5.4 , 5.5) and Adverse Reactions (6.1) ] . NULOJIX is for intravenous infusion only. Patients do not require premedication prior to administration of NULOJIX. Dosing instructions are provided in Table 1. • The total infusion dose of NULOJIX should be based on the actual body weight of the patient at the time of transplantation, and should not be modified during the course of therapy, unless there is a change in body weight of greater than 10%. • The prescribed dose of NULOJIX must be evenly divisible by 12.5 mg in order for the dose to be prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. Evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100. For example: - A patient weighs 64 kg. The dose is 10 mg per kg. - Calculated Dose: 64 kg × 10 mg per kg = 640 mg - The closest doses evenly divisible by 12.5 mg below and above 640 mg are 637.5 mg and 650 mg. - The nearest dose to 640 mg is 637.5 mg. - Therefore, the actual prescribed dose for the patient should be 637.5 mg. Table 1: Dosing a,b of NULOJIX for Kidney Transplant Recipients a [See Clinical Studies (14.1) ] b The dose prescribed for the patient must be evenly divisible by 12.5 mg (see instructions above; eg, evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100). Dosing for Initial Phase Dose Day 1 (day of transplantation, prior to implantation) and Day 5 (approximately 96 hours after Day 1 dose) 10 mg per kg End of Week 2 and Week 4 after transplantation 10 mg per kg End of Week 8 and Week 12 after transplantation 10 mg per kg Dosing for Maintenance Phase Dose End of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter 5 mg per kg 2.2 Preparation and Administration Instructions NULOJIX is for intravenous infusion only. Caution: NULOJIX must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial. If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. Preparation for Administration 1. Calculate the number of NULOJIX vials requir…

5 WARNINGS AND PRECAUTIONS • Post-Transplant Lymphoproliferative Disorder (PTLD) : increased risk, predominantly involving the CNS; monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms. (Boxed Warning , 4 , 5.1 , 5.6) • Other malignancies : increased risk with all immunosuppressants; appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight. (5.3) • Progressive Multifocal Leukoencephalopathy (PML) : increased risk; consider in the diagnosis of patients reporting new or worsening neurological, cognitive, or behavioral signs and symptoms. Recommended doses of immunosuppressants should not be exceeded. (5.4) • Other serious infections : increased risk of bacterial, viral, fungal, and protozoal infections, including opportunistic infections and tuberculosis. Some infections were fatal. Polyoma virus-associated nephropathy can lead to kidney graft loss; consider reduction in immunosuppression. Evaluate for tuberculosis and initiate treatment for latent infection prior to NULOJIX use. Cytomegalovirus and pneumocystis prophylaxis are recommended after transplantation. (5.1 , 5.4 , 5.5) • Liver transplant : use is not recommended. (5.6) • Acute Rejection and Graft Loss with Corticosteroid Minimization : corticosteroid utilization should be consistent with the NULOJIX clinical trial experience. (2.1 , 5.7 , 14.1) • Immunizations : avoid use of live vaccines during treatment. (5.8) • Coadministration with Anti-Thymocyte Globulin: in de novo kidney transplant recipients, especially those with other predisposing risk factors for venous thrombosis of the renal allograft, coadministration (at the same or nearly the same time) with anti-thymocyte globulin may pose a risk for venous thrombosis of the renal allograft. ( 5.9 , 6.2 , 7.3 ) • Risk of Rejection with Conversion From a CNI Based Maintenance Regimen: conversion of maintenance kidney transplant recipients from a CNI based to NULOJIX based maintenance regimen increases the risk of acute rejection. Conversion of stable kidney transplant recipients from a CNI based maintenance therapy to a belatacept based maintenance therapy is not recommended unless the patient is CNI intolerant. (5.10) 5.1 Post-Transplant Lymphoproliferative Disorder NULOJIX-treated patients have an increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen [see Adverse Reactions (6.1) , Clinical Studies (14.2) ] . As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of NULOJIX and higher than recommended doses of concomitant immunosuppressive agents are not recommended [see Dosage and Administration (2.1) and Warnings and Precautions (5.6) ] . Physicians should consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms. EBV Serostatus The risk of PTLD was higher in EBV seronegative patients compared to EBV seropositive patients. EBV seropositive patients are defined as having evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA). Epstein-Barr virus serology should be ascertained before starting administration of NULOJIX, and only patients who are EBV seropositive should receive NULOJIX. Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive NULOJIX [see Boxed Warning and Contraindications (4) ] . Other Risk Factors Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T cell-depleting therapy. T cell-depleting therapies to treat acute rejection should be used cautiously. CMV prophylaxis is recommended for at least 3 months after transplantation [see Warnings and Precautions (5.5) ] . Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD com…

4 CONTRAINDICATIONS NULOJIX is contraindicated in transplant recipients who are Epstein-Barr virus (EBV) seronegative or with unknown EBV serostatus due to the risk of post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS) [see Boxed Warning and Warnings and Precautions (5.1) ] . Patients who are EBV seronegative or with unknown EBV serostatus. (4)

7 DRUG INTERACTIONS 7.1 Mycophenolate Mofetil (MMF) Monitor for a need to adjust concomitant mycophenolate mofetil (MMF) dosage when a patient’s therapy is switched between cyclosporine and NULOJIX, as cyclosporine decreases mycophenolic acid (MPA) exposure by preventing enterohepatic recirculation of MPA while NULOJIX does not [see Clinical Pharmacology (12.3) ] : • A higher MMF dosage may be needed after switching from NULOJIX to cyclosporine, since this may result in lower MPA concentrations and increase the risk of graft rejection. • A lower MMF dosage may be needed after switching from cyclosporine to NULOJIX, since this may result in higher MPA concentrations and increase the risk for adverse reactions related to MPA (review the Full Prescribing Information for MMF). 7.2 Cytochrome P450 Substrates No dosage adjustments are needed for drugs metabolized via CYP1A2, CYP2C9, CYP2D6, CYP3A, and CYP2C19 when coadministered with NULOJIX [see Clinical Pharmacology (12.3) ] . 7.3 Anti-Thymocyte Globulin Coadministration (at the same or nearly the same time) of anti-thymocyte globulin (or any other cell-depleting induction treatment) and belatacept in de novo kidney transplant recipients, especially those with other predisposing risk factors for venous thrombosis of the renal allograft, may pose a risk for venous thrombosis of the renal allograft [see Warnings and Precautions (5.9) ] .

8.1 Pregnancy Pregnancy Exposure Registry To monitor maternal-fetal outcomes of pregnant women who have received immunosuppressants including NULOJIX or whose partners have received NULOJIX, healthcare providers are strongly encouraged to register pregnant patients in the Transplant Pregnancy Registry International (TPR) by calling 1-877-955-6877. Risk Summary The data with NULOJIX use in pregnant women are insufficient to inform on drug-associated risk. Belatacept is known to cross the placenta of animals. Administration of belatacept to pregnant rats and rabbits during the period of organogenesis was not teratogenic at exposures approximately 16 and 19 times greater than that observed at the maximum recommended human dose (MRHD) of 10 mg per kg body weight administered over the first month of treatment, based on area under the concentration-time curve (AUC). In a pre- and postnatal development study in rats, treatment-related infections in dams were associated with increased pup mortality, presumably secondary to deteriorating maternal health, at exposures 3 times higher than that observed at MRHD [see Animal Data ] . The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data In embryo-fetal development studies, daily intravenous administration of belatacept to pregnant rats and rabbits throughout the period of organogenesis did not produce adverse fetal effects at doses up to 200 mg per kg and 100 mg per kg, respectively (16 and 19 times the MRHD exposure, based on AUC). In a pre- and postnatal development study, daily intravenous administration of belatacept to rats from Day 6 of gestation through Day 20 of the lactation period was associated with maternal toxicity (infections) in a small percentage of dams at doses ≥20 mg per kg (3 times the MRHD exposure, based on AUC) resulting in increased pup mortality (up to 100% pup mortality in some dams). In pups that survived, there were no abnormalities or malformations at doses up to 200 mg per kg (19 times the MRHD exposure, based on AUC). In vitro data indicate that belatacept has lower binding affinity to CD80/CD86 and lower potency in rodents than in humans. Although the rat toxicity studies with belatacept were done at pharmacologically saturating doses, the in vivo difference in potency between rats and humans is unknown. Therefore, the relevance of the rat toxicities to humans and the significance of the magnitude of the relative exposures (rats:humans) are unknown. Abatacept, a fusion protein that differs from belatacept by two amino acids, binds to the same ligands (CD80/CD86) and blocks T cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents, including infections and autoimmunity, may be predictive of adverse effects in humans treated with belatacept [see Nonclinical Toxicology (13.2) ] . Autoimmunity was observed in 1 rat offspring exposed to abatacept in utero and/or during lactation and in juvenile rats after treatment with abatacept. However, the clinical relevance of autoimmunity in rats to patients or a fetus exposed in utero is unknown [see Nonclinical Toxicology (13.2) ] .

6 ADVERSE REACTIONS The most serious adverse reactions reported with NULOJIX are: • PTLD, predominantly CNS PTLD, and other malignancies [see Boxed Warning and Warnings and Precautions (5.1 , 5.3) ] • Serious infections, including JC virus-associated PML and polyoma virus nephropathy [see Warnings and Precautions (5.4 , 5.5 , 5.6) ] Most common adverse reactions (≥20% on NULOJIX treatment) are anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The data described below primarily derive from two randomized, active-controlled three-year trials of NULOJIX in de novo kidney transplant patients. In Study 1 and Study 2, NULOJIX was studied at the recommended dose and frequency [see Dosage and Administration (2.1) ] in a total of 401 patients compared to a cyclosporine control regimen in a total of 405 patients. These two trials also included a total of 403 patients treated with a NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended [see Clinical Studies (14.1) ] . All patients also received basiliximab induction, mycophenolate mofetil, and corticosteroids. Patients were treated and followed for three years. CNS PTLD, PML, and other CNS infections were more frequently observed in association with a NULOJIX regimen of higher cumulative dose and more frequent dosing compared to the recommended regimen; therefore, administration of higher than the recommended doses and/or more frequent dosing of NULOJIX is not recommended [see Dosage and Administration (2.1) , Clinical Studies (14.2) ] . The average age of patients in Studies 1 and 2 in the NULOJIX recommended dose and cyclosporine control regimens was 49 years, ranging from 18 to 79 years. Approximately 70% of patients were male; 67% were white, 11% were black, and 22% other races. About 25% of patients were from the United States and 75% from other countries. The most commonly reported adverse reactions occurring in ≥20% of patients treated with the recommended dose and frequency of NULOJIX were anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia. The proportion of patients who discontinued treatment due to adverse reactions was 13% for the recommended NULOJIX regimen and 19% for the cyclosporine control arm through three years of treatment. The most common adverse reactions leading to discontinuation in NULOJIX-treated patients were cytomegalovirus infection (1.5%) and complications of transplanted kidney (1.5%). Information on selected significant adverse reactions observed during clinical trials is summarized below. Post-Transplant Lymphoproliferative Disorder Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months post-transplant were obtained for NULOJIX by pooling both dosage regimens of NULOJIX in Studies 1 and 2 (804 patients) with data from a third study in kidney transplantation (Study 3, 145 patients) which evaluated two NULOJIX dosage regimens similar, but slightly different, from those of Studies 1 and 2 (see Table 2). The total number of NULOJIX patients from these three studies (949) was compared to the pooled cyclosporine control groups from all three studies (476 patients). Among 401 patients in Studies 1 and 2 treated with the recommended regimen of NULOJIX and the 71 patients in Study 3 treated with a very similar (but non-identical) NULO…