Data from FDA - Curated by Marshall Pearce - Last updated 05 December 2017

Indication(s)

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)].

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Advisory information

contraindications
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)
Adverse reactions
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 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 3 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)]. 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. 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 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) NULOJIX regimen, there were 5 cases of PTLD: 3 in EBV seropositive patients and 2 in EBV seronegative patients. Two of the 5 cases presented with CNS involvement. Among the 477 patients in Studies 1, 2, and 3 treated with the NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended, there were 8 cases of PTLD: 2 in EBV seropositive patients and 6 in EBV seronegative or serostatus unknown patients. Six of the 8 cases presented with CNS involvement. Therefore, administration of higher than the recommended doses or more frequent dosing of NULOJIX is not recommended [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. One of the 476 patients treated with cyclosporine developed PTLD, without CNS involvement. All cases of PTLD reported up to 36 months post transplant in NULOJIX- or cyclosporine-treated patients presented within 18 months of transplantation. Overall, the rate of PTLD in 949 patients treated with any of the NULOJIX regimens was 9-fold higher in those who were EBV seronegative or EBV serostatus unknown (8/139) compared to those who were EBV seropositive (5/810 patients). Therefore NULOJIX is recommended for use only in patients who are EBV seropositive [see Boxed Warning and Contraindications (4)]. Table 2: Summary of PTLD Reported in Studies 1, 2, and 3 Through Three Years of Treatment NULOJIX Non-Recommended Regimen* (N=477) NULOJIX Recommended Regimen† (N=472) Cyclosporine (N=476) Trial EBV Positive (n=406) EBV Negative (n=43) EBV Unknown (n=28) EBV Positive (n=404) EBV Negative (n=48) EBV Unknown (n=20) EBV Positive (n=399) EBV Negative (n=57) EBV Unknown (n=20) * Regimen with higher cumulative dose and more frequent dosing than the recommended NULOJIX regimen. † In Studies 1 and 2 the NULOJIX regimen is identical to the recommended regimen, but is slightly different in Study 3. Study 1 CNS PTLD 1 1 Non-CNS PTLD 1 2 1 Study 2 CNS PTLD 1 1 1 1 Non-CNS PTLD 1 Study 3 CNS PTLD 2 Non-CNS PTLD 1 Total (%) 2 (0.5) 5 (11.6) 1 (3.6) 3 (0.7) 2 (4.1) 0 0 1 (1.8) 0 EBV Seropositive Subpopulation Among the 806 EBV seropositive patients with known CMV serostatus treated with either NULOJIX regimen in Studies 1, 2, and 3, two percent (2%; 4/210) of CMV seronegative patients developed PTLD compared to 0.2% (1/596) of CMV seropositive patients. Among the 404 EBV seropositive recipients treated with the recommended dosage regimen of NULOJIX, three PTLD cases were detected among 99 CMV seronegative patients (3%) and there was no case detected among 303 CMV seropositive patients. The clinical significance of CMV serology as a risk factor for PTLD remains to be determined; however, these findings should be considered when prescribing NULOJIX [see Warnings and Precautions (5.1)]. Other Malignancies Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in Study 1 and Study 2 in 3.5% (14/401) of patients treated with the recommended NULOJIX regimen and 3.7% (15/405) of patients treated with the cyclosporine control regimen. Non-melanoma skin cancer was reported in 1.5% (6/401) of patients treated with the recommended NULOJIX regimen and in 3.7% (15/405) of patients treated with cyclosporine [see Warnings and Precautions (5.3)]. Progressive Multifocal Leukoencephalopathy Two fatal cases of progressive multifocal leukoencephalopathy (PML) have been reported among 1096 patients treated with a NULOJIX-containing regimen: one patient in clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and one patient in a trial of liver transplant (trial of 250 patients). No cases of PML were reported in patients treated with the recommended NULOJIX regimen or the control regimen in these trials. The kidney transplant recipient was treated with the NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended, mycophenolate mofetil (MMF), and corticosteroids for 2 years. The liver transplant recipient was treated with 6 months of a NULOJIX dosage regimen that was more intensive than that studied in kidney transplant recipients, MMF at doses higher than the recommended dose, and corticosteroids [see Warnings and Precautions (5.4)]. Bacterial, Mycobacterial, Viral, and Fungal Infections Adverse reactions of infectious etiology were reported based on clinical assessment by physicians. The causative organisms for these reactions are identified when provided by the physician. The overall number of infections, serious infections, and select infections with identified etiology reported in patients treated with the NULOJIX recommended regimen or the cyclosporine control in Studies 1 and 2 are shown in Table 3. Fungal infections were reported in 18% of patients receiving NULOJIX compared to 22% receiving cyclosporine, primarily due to skin and mucocutaneous fungal infections. Tuberculosis and herpes infections were reported more frequently in patients receiving NULOJIX than cyclosporine. Of the patients who developed tuberculosis through 3 years, all but one NULOJIX patient lived in countries with a high prevalence of tuberculosis [see Warnings and Precautions (5.5)]. Table 3: Overall Infections and Select Infections with Identified Etiology by Treatment Group following One and Three Years of Treatment in Studies 1 and 2* Up to Year 1 Up to Year 3† NULOJIX Recommended Regimen N=401 n (%) Cyclosporine N=405 n (%) NULOJIX Recommended Regimen N=401 n (%) Cyclosporine N=405 n (%) * Studies 1 and 2 were not designed to support comparative claims for NULOJIX for the adverse reactions reported in this table. † Median exposure in days for pooled studies: 1203 for NULOJIX recommended regimen and 1163 for cyclosporine in Studies 1 and 2. ‡ All infections include bacterial, viral, fungal, and other organisms. For infectious adverse reactions, the causative organism is reported if specified by the physician in the clinical trials. § A medically important event that may be life-threatening or result in death or hospitalization or prolongation of existing hospitalization. Infections not meeting these criteria are considered non-serious. ¶ BK virus-associated nephropathy was reported in 6 NULOJIX patients (4 of which resulted in graft loss) and 6 cyclosporine patients (none of which resulted in graft loss) by Year 3. # Most herpes infections were non-serious and 1 led to treatment discontinuation. All infections‡ 287 (72) 299 (74) 329 (82) 327 (81) Serious infections§ 98 (24) 113 (28) 144 (36) 157 (39) CMV 44 (11) 52 (13) 53 (13) 56 (14) Polyoma virus¶ 10 (3) 23 (6) 17 (4) 27 (7) Herpes# 27 (7) 26 (6) 55 (14) 46 (11) Tuberculosis 2 (1) 1 (<1) 6 (2) 1 (<1) Infections Reported in the CNS Following three years of treatment in Studies 1 and 2, cryptococcal meningitis was reported in one patient out of 401 patients treated with the NULOJIX recommended regimen (0.2%) and one patient out of the 405 treated with the cyclosporine control (0.2%). Six patients out of the 403 who were treated with the NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended in Studies 1 and 2 (1.5%) were reported to have developed CNS infections, including 2 cases of cryptococcal meningitis, one case of Chagas encephalitis with cryptococcal meningitis, one case of cerebral aspergillosis, one case of West Nile encephalitis, and one case of PML (discussed above). Infusion Reactions There have been no reports of anaphylaxis or drug hypersensitivity in patients treated with NULOJIX in Studies 1 and 2 up to three years of follow-up. However, milder infusion-related reactions within one hour of infusion were reported in 5% of patients treated with the recommended dose of NULOJIX, similar to the placebo rate. The most frequent reactions were hypotension and hypertension. A case of anaphylaxis was reported in the postmarketing experience [see Adverse Reactions (6.2) ]. Proteinuria At Month 1 after transplantation in Studies 1 and 2, the frequency of 2+ proteinuria on urine dipstick in patients treated with the NULOJIX recommended regimen was 33% (130/390) and 28% (107/384) in patients treated with the cyclosporine control regimen. The frequency of 2+ proteinuria was similar between the two treatment groups between one and three years after transplantation (<10% in both studies). There were no differences in the occurrence of 3+ proteinuria (<4% in both studies) at any time point, and no patients experienced 4+ proteinuria. The clinical significance of this increase in early proteinuria is unknown. Immunogenicity Antibodies directed against the belatacept molecule were assessed in 398 patients treated with the NULOJIX recommended regimen in Studies 1 and 2 (212 of these patients were treated for at least 2 years). Of the 372 patients with immunogenicity assessment at baseline (prior to receiving belatacept treatment), 29 patients tested positive for anti-belatacept antibodies; 13 of these patients had antibodies to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Anti-belatacept antibody titers did not increase during treatment in these 29 patients. Eight (2%) patients developed antibodies during treatment with the NULOJIX recommended regimen. In the patients who developed antibodies during treatment, the median titer (by dilution method) was 8, with a range of 5 to 80. Of 56 patients who tested negative for antibodies during treatment and reassessed approximately 7 half-lives after discontinuation of NULOJIX, 1 tested antibody positive. Anti-belatacept antibody development was not associated with altered clearance of belatacept. Samples from 6 patients with confirmed binding activity to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) region of the belatacept molecule were assessed by an in vitro bioassay for the presence of neutralizing antibodies. Three of these 6 patients tested positive for neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. The clinical impact of anti-belatacept antibodies (including neutralizing anti-belatacept antibodies) could not be determined in the studies. The data reflect the percentage of patients whose test results were positive for antibodies to belatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belatacept with the incidence of antibodies to other products may be misleading. New-Onset Diabetes After Transplantation The incidence of new-onset diabetes after transplantation (NODAT) was defined in Studies 1 and 2 as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose values ≥126 mg/dL (7.0 mmol/L) post-transplantation. Of the patients treated with the NULOJIX recommended regimen, 5% (14/304) developed NODAT by the end of one year compared to 10% (27/280) of patients on the cyclosporine control regimen. However, by the end of the third year, the cumulative incidence of NODAT was 8% (24/304) in patients treated with the NULOJIX recommended regimen and 10% (29/280) in patients treated with the cyclosporine regimen. Hypertension Blood pressure and use of antihypertensive medications were reported in Studies 1 and 2. By Year 3, one or more antihypertensive medications were used in 85% of NULOJIX-treated patients and 92% of cyclosporine-treated patients. At one year after transplantation, systolic blood pressures were 8 mmHg lower and diastolic blood pressures were 3 mmHg lower in patients treated with the NULOJIX recommended regimen compared to the cyclosporine control regimen. At three years after transplantation, systolic blood pressures were 6 mmHg lower and diastolic blood pressures were 3 mmHg lower in NULOJIX-treated patients compared to cyclosporine-treated patients. Hypertension was reported as an adverse reaction in 32% of NULOJIX-treated patients and 37% of cyclosporine-treated patients (see Table 4). Dyslipidemia Mean values of total cholesterol, HDL, LDL, and triglycerides were reported in Studies 1 and 2. At one year after transplantation these values were 183 mg/dL, 50 mg/dL, 102 mg/dL, and 151 mg/dL, respectively, in 401 patients treated with the NULOJIX recommended regimen and 196 mg/dL, 48 mg/dL, 108 mg/dL, and 195 mg/dL, respectively, in 405 patients treated with the cyclosporine control regimen. At three years after transplantation, the total cholesterol, HDL, LDL, and triglycerides were 176 mg/dL, 49 mg/dL, 100 mg/dL, and 141 mg/dL, respectively, in NULOJIX-treated patients compared to 193 mg/dL, 48 mg/dL, 106 mg/dL, and 180 mg/dL in cyclosporine-treated patients. The clinical significance of the lower mean triglyceride values in NULOJIX-treated patients at one and three years is unknown. Other Adverse Reactions Adverse reactions that occurred at a frequency of ≥10% in patients treated with the NULOJIX recommended regimen or cyclosporine control regimen in Studies 1 and 2 through three years are summarized by preferred term in decreasing order of frequency within Table 4. Table 4: Adverse Reactions Reported by ≥10% of Patients Treated with Either the NULOJIX Recommended Regimen or Control in Studies 1 and 2 Through Three Years*,† Adverse Reaction NULOJIX Recommended Regimen N=401 % Cyclosporine N=405 % * All randomized and transplanted patients in Studies 1 and 2. † Studies 1 and 2 were not designed to support comparative claims for NULOJIX for the adverse reactions reported in this table. Infections and Infestations Urinary tract infection 37 36 Upper respiratory infection 15 16 Nasopharyngitis 13 16 Cytomegalovirus infection 12 12 Influenza 11 8 Bronchitis 10 7 Gastrointestinal Disorders Diarrhea 39 36 Constipation 33 35 Nausea 24 27 Vomiting 22 20 Abdominal pain 19 16 Abdominal pain upper 9 10 Metabolism and Nutrition Disorders Hyperkalemia 20 20 Hypokalemia 21 14 Hypophosphatemia 19 13 Dyslipidemia 19 24 Hyperglycemia 16 17 Hypocalcemia 13 11 Hypercholesterolemia 11 11 Hypomagnesemia 7 10 Hyperuricemia 5 12 Procedural Complications Graft dysfunction 25 34 General Disorders Peripheral edema 34 42 Pyrexia 28 26 Blood and Lymphatic System Disorders Anemia 45 44 Leukopenia 20 23 Renal and Urinary Disorders Hematuria 16 18 Proteinuria 16 12 Dysuria 11 11 Renal tubular necrosis 9 13 Vascular Disorders Hypertension 32 37 Hypotension 18 12 Respiratory, Thoracic, and Mediastinal Disorders Cough 24 18 Dyspnea 12 15 Investigations Blood creatinine increased 15 20 Musculoskeletal and Connective Tissue Disorders Arthralgia 17 13 Back pain 13 13 Nervous System Disorders Headache 21 18 Dizziness 9 10 Tremor 8 17 Skin and Subcutaneous Tissue Disorders Acne 8 11 Psychiatric Disorders Insomnia 15 18 Anxiety 10 11 Selected adverse reactions occurring in <10% from NULOJIX-treated patients in either regimen through three years in Studies 1 and 2 are listed below: Immune System Disorders: Guillain-Barré syndrome Infections and Infestations: see Table 3 Gastrointestinal Disorders: stomatitis, including aphthous stomatitis Injury, Poisoning, and Procedural Complications: chronic allograft nephropathy, complications of transplanted kidney, including wound dehiscence, arteriovenous fistula thrombosis Blood and Lymphatic System Disorders: neutropenia Renal and Urinary Disorders: renal impairment, including acute renal failure, renal artery stenosis, urinary incontinence, hydronephrosis Vascular Disorders: hematoma, lymphocele Musculoskeletal and Connective Tissue Disorders: musculoskeletal pain Skin and Subcutaneous Tissue Disorders: alopecia, hyperhidrosis Cardiac Disorders: atrial fibrillation 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorder: Anaphylaxis Spontaneous reports during the postmarketing experience included a case of anaphylaxis, which was observed in a kidney transplant patient whose belatacept therapy had been interrupted for two months during treatment of a systemic varicella infection. When belatacept therapy was resumed, within five minutes after the start of the belatacept infusion the patient developed a generalized rash, pruritus, hypotension, atrial fibrillation, respiratory distress and syncope, requiring medical treatment. Another belatacept infusion was attempted one month later, but was terminated when the patient experienced more pronounced symptoms of anaphylaxis and required medical treatment. Vascular Disorder: Venous Thrombosis of the Renal Allograft In postmarketing experience in de novo kidney transplant recipients, some with other predisposing risk factors for venous thrombosis of the renal allograft, venous thrombosis of the renal allograft has occurred when the initial dose of anti-thymocyte globulin, as immunosuppressive induction, was coadministered (at the same or nearly the same time) with the first dose of belatacept [see Warnings and Precautions (5.9)].

Usage information

Dosing and administration
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 (25th-75th percentile) corticosteroid doses were tapered to approximately 15 mg (10-20 mg) per day by the first 6 weeks and remained at approximately 10 mg (5-10 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*,† of NULOJIX for Kidney Transplant Recipients * [See Clinical Studies (14.1).] † The dose prescribed for the patient must be evenly divisible by 12.5 mg (see instructions above; e.g., 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 required to provide the total infusion dose. Each vial contains 250 mg of belatacept lyophilized powder. 2.Reconstitute the contents of each vial of NULOJIX with 10.5 mL of a suitable diluent using the silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. Suitable diluents include: sterile water for injection (SWFI), 0.9% sodium chloride (NS), or 5% dextrose in water (D5W). Note: If the NULOJIX powder is accidentally reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes. 3.To reconstitute the NULOJIX powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of diluent (10.5 mL of SWFI, NS, or D5W) to the glass wall of the vial. 4.To minimize foam formation, rotate the vial and invert with gentle swirling until the contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake. 5.The reconstituted solution contains a belatacept concentration of 25 mg/mL and should be clear to slightly opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. 6.Calculate the total volume of the reconstituted 25 mg/mL NULOJIX solution required to provide the total infusion dose. Volume of 25 mg/mL NULOJIX solution (in mL) = Prescribed Dose (in mg) ÷ 25 mg/mL 7.Prior to intravenous infusion, the required volume of the reconstituted NULOJIX solution must be further diluted with a suitable infusion fluid (NS or D5W). NULOJIX reconstituted with: •SWFI should be further diluted with either NS or D5W •NS should be further diluted with NS •D5W should be further diluted with D5W 8.From the appropriate size infusion bag or bottle, withdraw a volume of infusion fluid that is equal to the volume of the reconstituted NULOJIX solution required to provide the prescribed dose. With the same silicone-free disposable syringe used for reconstitution, withdraw the required amount of belatacept solution from the vial, inject it into the infusion bag or bottle, and gently rotate the infusion bag or bottle to ensure mixing. The final belatacept concentration in the infusion bag or bottle should range from 2 mg/mL to 10 mg/mL. Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, but total infusion volumes ranging from 50 mL to 250 mL may be used. Any unused solution remaining in the vials must be discarded. 9.Prior to administration, the NULOJIX infusion should be inspected visually for particulate matter and discoloration. Discard the infusion if any particulate matter or discoloration is observed. 10.The entire NULOJIX infusion should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 µm). •The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The NULOJIX infusion must be completed within 24 hours of reconstitution of the NULOJIX lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C [68°-77°F] and room light). •Infuse NULOJIX in a separate line from other concomitantly infused agents. NULOJIX should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of NULOJIX with other agents [see Warnings and Precautions (5.9)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm; pregnancy registry available. (8.1) • Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3) 8.1 Pregnancy Pregnancy Category C NULOJIX should not be used in pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. There are no studies of NULOJIX treatment in pregnant women. Belatacept is known to cross the placenta of animals. Belatacept was not teratogenic in pregnant rats and rabbits at doses approximately 16 and 19 times greater than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg per kg administered over the first month of treatment, based on area under the concentration-time curve (AUC). Belatacept administered to female rats daily during gestation and throughout the lactation period was associated with maternal toxicity (infections) in a small percentage of dams at doses of ≥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). 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 2 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 one 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)]. Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women who have received NULOJIX or whose partners have received NULOJIX, healthcare providers are strongly encouraged to register pregnant patients in the National Transplant Pregnancy Registry (NTPR) by calling 1-877-955-6877. 8.3 Nursing Mothers It is not known whether belatacept is excreted in human milk or absorbed systemically after ingestion by a nursing infant. However, belatacept is excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from NULOJIX in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of NULOJIX in patients under 18 years of age have not been established. Because T cell development continues into the teenage years, the potential concern for autoimmunity in neonates applies to pediatric use as well [see Use in Specific Populations (8.1)]. 8.5 Geriatric Use Of 401 patients treated with the recommended dosage regimen of NULOJIX, 15% were 65 years of age and older, while 3% were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity or less efficacy in older individuals cannot be ruled out.
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether belatacept is excreted in human milk or absorbed systemically after ingestion by a nursing infant. However, belatacept is excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from NULOJIX in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS 7.1 Mycophenolate Mofetil (MMF) Monitor for a need to adjust concomitant mycophenolate mofetil (MMF) dosage when 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)].

More information

Category Value
Authorisation number BLA125288
Agency product number E3B2GI648A
Orphan designation No
Product NDC 0003-0371
Date Last Revised 09-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1112976
Storage and handling 16.1 Storage NULOJIX lyophilized powder is stored refrigerated at 2°-8°C (36°-46°F). Protect NULOJIX from light by storing in the original package until time of use. The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The NULOJIX infusion must be completed within 24 hours of constitution of the NULOJIX lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C [68°-77°F] and room light) [see Dosage and Administration (2.2)].
Marketing authorisation holder E.R. Squibb & Sons, L.L.C.
Warnings WARNING: POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER, OTHER MALIGNANCIES, AND SERIOUS INFECTIONS Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS). Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only. Do not use NULOJIX in transplant recipients who are EBV seronegative or with unknown EBV serostatus [see Contraindications (4) and Warnings and Precautions (5.1)]. Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe NULOJIX. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions (5.2)]. Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5)]. Use in liver transplant patients is not recommended due to an increased risk of graft loss and death [see Warnings and Precautions (5.6)]. WARNING: POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER, OTHER MALIGNANCIES, AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning. • Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS). Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only. Do not use NULOJIX in transplant recipients who are EBV seronegative or with unknown serostatus. (4, 5.1) • Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe NULOJIX. (5.2) • Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression. (5.1, 5.3, 5.4, 5.5) • Use in liver transplant patients is not recommended due to an increased risk of graft loss and death. (5.6)