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Full Prescribing Information, Including Boxed WARNINGS

Product

INDICATION

  • NULOJIX (in combination with basiliximab induction, mycophenolate mofetil [MMF], and corticosteroids) is indicated for prophylaxis of organ rejection in adults receiving a kidney transplant
  • Use NULOJIX only in patients who are Epstein-Barr virus (EBV) seropositive
  • Use of NULOJIX for prophylaxis of organ rejection in transplanted organs other than kidney has not been established

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Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT)

 

The BENEFIT Study was a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter, 3-year trial comparing the efficacy and safety of NULOJIX to cyclosporine (CsA) in adult de novo patients receiving a living or standard criteria deceased (SCD) donor kidney transplant.1,2

Patient Population1

Adult recipients (N=666) of a kidney allograft from a living or SCD donor

  • SCD kidney defined as: deceased donor organ with anticipated cold ischemia time (CIT) of <24 hours; not meeting definition of extended-criteria deceased donor organs
    • ECD kidney defined as deceased donor organs with at least 1 of the following: donor age ≥60 years; donor age ≥50 years and other comorbidities (≥2 of the following: stroke, hypertension, serum creatinine >1.5 mg/dL); donation after cardiac death; anticipated cold ischemia time (CIT) ≥24 hours
  • Of the patients enrolled in the BENEFIT Study, the median age was 45 years, 58% received donor organs from living patients, 69% were male, 61% were white, 8% were black/African American, 31% were categorized as other races, and 27% had diabetes prior to transplant
  • Exclusion criteria: first transplant with current panel reactive antibodies (PRA) ≥50% or retransplantation with current PRA ≥30%; HIV, hepatitis C, or evidence of current hepatitis B infection; active tuberculosis; intravenous access was difficult to obtain
Dosing Regimen
  • NULOJIX patients (N=226) received a
    10 mg/kg dose on Day 1 (the day of transplantation, prior to implantation), Day 5 (approximately 96 hours after the Day 1 dose), end of Weeks 2, 4, 8, and 12. Starting at Week 16 after transplantation, NULOJIX was administered at the maintenance dose of 5 mg/kg every 4 weeks (plus or minus 3 days)1
    • Dosing was based on actual body weight at time of transplant, unless there was a >10% change
    • NULOJIX was administered as an intravenous infusion over 30 minutes
  • Cyclosporine (N=221) patients received an initial daily dose of 4-10 mg/kg. Cyclosporine dose was then adjusted to achieve serum levels of 150-300 ng/mL within the first month, and was further adjusted to achieve serum levels of 100-250 ng/mL within Months 2 through 122
  • A NULOJIX regimen with higher cumulative doses and more frequent dosing than the recommended dosing schedule was also studied (N=219). Higher than recommended doses and/or more frequent dosing of NULOJIX are not recommended due to more efficacy failures; increased risk of PTLD, predominantly involving the CNS; PML, often a rapidly progressive and fatal opportunistic infection; and serious CNS infections1
  • All treatment groups also received basiliximab induction (20 mg intravenous on the day of transplantation and 4 days post-transplantation), MMF (2 g/day orally in divided doses), and corticosteroids. Day of transplant [Day 1] preoperatively: methylprednisolone sodium succinate 500 mg intravenously; Day 2: methylprednisolone sodium succinate 250 mg intravenously; Day 3: prednisone/prednisolone 100 mg orally; Day 4 through Day 14: prednisone/prednisolone tapered to 20-30 mg/day orally; Day 15 and thereafter: prednisone/prednisolone tapered to no less than 2.5 mg/day orally1-3*
  • The protocol recommended antiviral prophylaxis for all patients for at least 3 months post-transplant, and for 3 months upon initiating T cell–depleting agents, as well as 6 months of prophylaxis against Pneumocystis jiroveci1
Endpoints1,2
  • Efficacy failure, defined as a composite of:
    • BPAR†
    • Graft loss
    • Death
    • Lost to follow-up
  • Composite patient and graft survival
  • cGFR‡
  • Cardiovascular/metabolic parameters
    • Hypertension, mean blood pressure
    • Dyslipidemia, mean change in serum lipids
    • Medication used for hypertension
    • Incidence of new-onset diabetes after transplantation (NODAT)§

*The median daily corticosteroid dosing at Week 1 was 31.7 mg; at Week 2 it was 25 mg; at Week 4 it was 20 mg; at Week 6 it was 15 mg; and at Month 6 it was 10 mg.

†Histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection.1

‡GFR was calculated using the MDRD formula.1

§NODAT: Defined as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose values ≥126 mg/dL (7.0 mmol/L) post-transplantation.1

References

  1. NULOJIX [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company.
  2. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10(3):535-546.
  3. Data on file. NULO 075. Bristol-Myers Squibb Company. Princeton, NJ.

Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial— EXTended criteria donors (BENEFIT-EXT)

The BENEFIT-EXT Study was the first large-scale trial that assessed maintenance immunosuppression with adult de novo patients who received a kidney transplant from an extended-criteria deceased (ECD) donor. The BENEFIT-EXT Study was a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter, 3-year trial comparing the efficacy and safety of NULOJIX to cyclosporine (CsA) in adults who received a de novo kidney allograft from an extended criteria deceased donor (N=543).1,2

Patient Population1

Adult recipients (N=543) of a kidney allograft from an ECD donor:

  • ECD kidney defined as deceased donor organ with at least 1 of the following: donor age ≥60 years; donor age ≥50 years and other comorbidities (≥2 of the following: stroke, hypertension, serum creatinine >1.5 mg/dL); donation after cardiac death; anticipated cold ischemia time (CIT) ≥24 hours
  • Of the patients enrolled in the BENEFIT-EXT Study, the median age was 58 years, 67% were male, 75% were white, 13% were black/African American, 12% were categorized as other races, and 29% had diabetes prior to transplant
  • Exclusion criteria: current panel reactive antibodies (PRA) ≥30%; HIV, hepatitis C, or evidence of current hepatitis B infection; active tuberculosis; intravenous access was difficult to obtain
Dosing Regimen
  • NULOJIX patients (N=175) received a 10 mg/kg dose on Day 1 (the day of transplantation, prior to implantation), Day 5 (approximately 96 hours after the Day 1 dose), end of Weeks 2, 4, 8, and 12. Starting at Week 16 after transplantation, NULOJIX was administered at the maintenance dose of 5 mg/kg every 4 weeks (plus or minus 3 days)1
    • Dosing was based on actual body weight at time of transplant, unless there was a >10% change
    • NULOJIX was administered as an intravenous infusion over 30 minutes
  • Cyclosporine (N=184) patients received an initial daily dose of 4-10 mg/kg. Cyclosporine dose was then adjusted to achieve serum levels of 150-300 ng/mL within the first month, and was further adjusted to achieve serum levels of 100-250 ng/mL within Months 2 through 122
  • A NULOJIX regimen with higher cumulative doses and more frequent dosing than the recommended dosing schedule was also studied (N=184). Higher than recommended doses and/or more frequent dosing of NULOJIX are not recommended due to more efficacy failures; increased risk of PTLD, predominantly involving the CNS; PML, often a rapidly progressive and fatal opportunistic infection; and serious CNS infections1
  • All treatment groups also received basiliximab induction (20 mg intravenous on the day of transplantation and 4 days post-transplantation), MMF (2 g/day orally in divided doses), and corticosteroids. Day of transplant [Day 1] preoperatively: methylprednisolone sodium succinate 500 mg intravenously; Day 2: methylprednisolone sodium succinate 250 mg intravenously; Day 3: prednisone/prednisolone 100 mg orally; Day 4 through Day 14: prednisone/prednisolone tapered to 20-30 mg/day orally; Day 15 and thereafter: prednisone/prednisolone tapered to no less than 2.5 mg/day orally1-3*
  • The protocol recommended antiviral prophylaxis for all patients for at least 3 months post-transplant, and for 3 months upon initiating T cell–depleting agents, as well as 6 months of prophylaxis against Pneumocystis jiroveci1
Endpoints1,2
  • Efficacy failure, defined as a composite of:
    • BPAR†
    • Graft loss
    • Death
    • Lost to follow-up
  • Composite patient and graft survival
  • cGFR‡
  • Cardiovascular/metabolic parameters
    • Hypertension, mean blood pressure
    • Dyslipidemia, mean change in serum lipids
    • Medication used for hypertension
    • Incidence of new-onset diabetes after transplantation (NODAT)§

*The median daily corticosteroid dosing at Week 1 was 30 mg; at Week 2 it was 25 mg; at Week 4 it was 20 mg; at Week 6 it was 16.7 mg; and at Month 6 it was 10 mg.

†Histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection.1

‡GFR was calculated using the MDRD formula.1

§NODAT: Defined as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose values ≥126 mg/dL (7.0 mmol/L) post-transplantation.1

References

  1. NULOJIX [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company.
  2. Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010;10(3):547-557.
  3. Data on file. NULO 059. Bristol-Myers Squibb Company. Princeton, NJ.

View Renal Function Data

More Important Safety Information

SELECTED IMPORTANT SAFETY INFORMATION

  • NULOJIX is associated with increased risk for post-transplant lymphoproliferative disorder (PTLD), predominantly in the central nervous system (CNS)
    • NULOJIX is contraindicated in patients who are EBV seronegative or with unknown serostatus because the risk of PTLD is particularly increased in patients who are EBV seronegative
    • NULOJIX is to be used only in patients who are EBV seropositive
    • Patients should be monitored for new or worsening neurological, cognitive, or behavioral signs and symptoms
    • Higher than recommended doses or more frequent dosing of NULOJIX and concomitant immunosuppressives is not recommended
  • Immunosuppression may result in increased susceptibility to infection and development of malignancies
  • NULOJIX should be prescribed only by physicians experienced in immunosuppressive therapy and management of kidney transplant patients
  • Use in liver transplant patients is not recommended due to an increased risk of graft loss and death

Management of Immunosuppression

  • Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe NULOJIX
    • Patients should be managed in facilities 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

Progressive Multifocal Leukoencephalopathy (PML)

  • NULOJIX patients are at increased risk for PML, often a rapidly progressive and fatal opportunistic infection
    • In clinical trials, two cases were reported in patients receiving NULOJIX at higher cumulative doses and more frequently than the recommended regimen, along with MMF and corticosteroids; one occurred in a kidney transplant recipient and one occurred in a liver transplant recipient
  • As PML has been associated with high levels of immunosuppression, higher than recommended doses or more frequent dosing of NULOJIX and concomitant immunosuppressive agents, including MMF, are not recommended
  • Monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms
    • PML is usually diagnosed by brain imaging, cerebrospinal fluid testing for JC viral DNA by polymerase chain reaction, and/or brain biopsy
    • Consultation with a specialist should be considered
    • If PML is diagnosed, consider reduction or withdrawal of immunosuppression, weighing risk to the allograft

Other Malignancies and Serious Infections

  • Increased susceptibility to infection and possible development of malignancies may result from immunosuppression
  • Patients should avoid prolonged exposure to ultraviolet light and sunlight
  • Patients receiving immunosuppressants, including NULOJIX, are at increased risk for bacterial, viral, fungal, and protozoal infections, including opportunistic infections and tuberculosis. Some infections were fatal
    • Polyoma virus-associated nephropathy can lead to deteriorating renal function and graft loss; consider reduction in immunosuppression, weighing risk to the graft
    • Tuberculosis was more frequently observed in patients receiving NULOJIX. Evaluate for tuberculosis and initiate treatment for latent infection prior to NULOJIX use
    • CMV and Pneumocystis jiroveci prophylaxis is recommended after transplantation

Liver Transplant: use in liver transplant patients is not recommended due to increased risk of graft loss and death in a clinical trial with more frequent administration of NULOJIX than studied in kidney transplant, along with MMF and corticosteroids

Immunizations: avoid use of live vaccines during NULOJIX treatment

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. If anti-thymocyte globulin (or any other cell-depleting induction treatment) and NULOJIX will be administered concomitantly, a 12-hour interval between the two administrations is suggested

Acute Rejection and Graft Loss with Corticosteroid Minimization

  • In NULOJIX postmarketing experience, corticosteroid minimization to 5 mg/day between Day 3 and Week 6 post-transplant was associated with an increased rate and grade of acute rejection, particularly Grade III
    • These Grade III rejections occurred in patients with 4-6 human leukocyte antigen (HLA) mismatches
    • Graft loss was a consequence of Grade III rejection in some patients
  • Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience
    • Median (25th-75th percentile) corticosteroid doses were tapered to about 15 mg (10-20 mg)/day by the first 6 weeks and remained at about 10 mg (5-10 mg)/day for the first 6 months post-transplant

Pregnancy: the data with NULOJIX use in pregnant women are insufficient to inform on drug-associated risk. NULOJIX is known to cross the placenta of animals. 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 Transplant Pregnancy Registry International (TPR) by 1-877-955-6877 1-877-955-6877

 
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IMPORTANT SAFETY INFORMATION

Post-Transplant Lymphoproliferative Disorder (PTLD)

  • NULOJIX patients are at increased risk for developing PTLD, predominantly involving the central nervous system (CNS)
  • Recipients without immunity to EBV (ie, seronegative) are at particularly increased risk; therefore, NULOJIX is contraindicated in transplant recipients who are EBV seronegative or with unknown serostatus
  • Monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms
  • As the total burden of immunosuppression is a risk factor for PTLD, higher than recommended doses or more frequent dosing of NULOJIX or concomitant immunosuppressive agents are not recommended
  • Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T cell-depleting therapy
    • CMV prophylaxis is recommended for at least 3 months after transplantation
    • Use T cell-depleting therapy to treat acute rejection cautiously
  • Patients who are EBV seropositive and CMV seronegative may be at increased risk of PTLD
    • Since CMV seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined; however, these findings should be considered when prescribing NULOJIX

Management of Immunosuppression

  • Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe NULOJIX
    • Patients should be managed in facilities 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

Progressive Multifocal Leukoencephalopathy (PML)

  • NULOJIX patients are at increased risk for PML, often a rapidly progressive and fatal opportunistic infection
    • In clinical trials, two cases were reported in patients receiving NULOJIX at higher cumulative doses and more frequently than the recommended regimen, along with MMF and corticosteroids; one occurred in a kidney transplant recipient and one occurred in a liver transplant recipient
  • As PML has been associated with high levels of immunosuppression, higher than recommended doses or more frequent dosing of NULOJIX and concomitant immunosuppressive agents, including MMF, are not recommended
  • Monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms
    • PML is usually diagnosed by brain imaging, cerebrospinal fluid testing for JC viral DNA by polymerase chain reaction, and/or brain biopsy
    • Consultation with a specialist should be considered
    • If PML is diagnosed, consider reduction or withdrawal of immunosuppression, weighing risk to the allograft

Other Malignancies and Serious Infections

  • Increased susceptibility to infection and possible development of malignancies may result from immunosuppression
  • Patients should avoid prolonged exposure to ultraviolet light and sunlight
  • Patients receiving immunosuppressants, including NULOJIX, are at increased risk for bacterial, viral, fungal, and protozoal infections, including opportunistic infections and tuberculosis. Some infections were fatal
    • Polyoma virus-associated nephropathy can lead to deteriorating renal function and graft loss; consider reduction in immunosuppression, weighing risk to the graft
    • Tuberculosis was more frequently observed in patients receiving NULOJIX. Evaluate for tuberculosis and initiate treatment for latent infection prior to NULOJIX use
    • CMV and Pneumocystis jiroveci prophylaxis is recommended after transplantation

Liver Transplant: use in liver transplant patients is not recommended due to increased risk of graft loss and death in a clinical trial with more frequent administration of NULOJIX than studied in kidney transplant, along with MMF and corticosteroids

Acute Rejection and Graft Loss with Corticosteroid Minimization

  • In NULOJIX postmarketing experience, corticosteroid minimization to 5 mg/day between Day 3 and Week 6 post-transplant was associated with an increased rate and grade of acute rejection, particularly Grade III
    • These Grade III rejections occurred in patients with 4-6 human leukocyte antigen (HLA) mismatches
    • Graft loss was a consequence of Grade III rejection in some patients
  • Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience
    • Median (25th-75th percentile) corticosteroid doses were tapered to about 15 mg (10-20 mg)/day by the first 6 weeks and remained at about 10 mg (5-10 mg)/day for the first 6 months post-transplant

Immunizations: avoid use of live vaccines during NULOJIX treatment

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. If anti-thymocyte globulin (or any other cell-depleting induction treatment) and NULOJIX will be administered concomitantly, a 12-hour interval between the two administrations is suggested

Risk of Rejection with Conversion From a Calcineurin Inhibitor (CNI) Based Maintenance Regimen: conversion of patients from a CNI based maintenance regimen increases the risk of acute rejection. Conversion of stable kidney transplant recipients from a CNI based maintenance regimen to a NULOJIX based maintenance regimen is not recommended unless the patient is CNI intolerant

Pregnancy: the data with NULOJIX use in pregnant women are insufficient to inform on drug-associated risk. NULOJIX is known to cross the placenta of animals. 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 Transplant Pregnancy Registry International (TPR) by calling 1-877-955-6877

Lactation: there are no data on the presence of NULOJIX in human milk or the effects on breastfed infants or human milk production to inform risk of NULOJIX to an infant during lactation. NULOJIX is excreted in rat milk and it is possible that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NULOJIX, and any potential adverse effects on the breastfed child from NULOJIX or from the underlying maternal conditions

Most Common Adverse Reactions (≥20%) through 3 years: anemia (45%), diarrhea (39%), urinary tract infection (37%), peripheral edema (34%), constipation (33%), hypertension (32%), pyrexia (28%), graft dysfunction (25%), cough (24%), nausea (24%), vomiting (22%), headache (21%), hypokalemia (21%), hyperkalemia (20%), and leukopenia (20%). No new adverse reactions were observed in the long-term extension (years 4-7) studies

Please see Full Prescribing Information, including Boxed WARNINGS.

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