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INDICATION

  • NULOJIX® (belatacept) (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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 Study Design Overview

The clinical data for NULOJIX® (belatacept) are based on 2 trials: the BENEFIT study and BENEFIT-EXT study. The studies were phase 3, randomized, open-label, active-controlled, parallel-group, multicenter, 3-year trials comparing the efficacy and safety of NULOJIX to cyclosporine (CsA) in adults.1-3

BENEFIT STUDY
Participants received a de novo kidney allograft from a living donor or a deceased standard criteria donor (SCD) with an anticipated cold ischemic time (CIT) of <24 hours (N=666).1,2

BENEFIT-EXT STUDY
Participants received a de novo kidney allograft from a deceased extended criteria donor (ECD*) (N=543).1,3

Dosing regimen1-3

  • All treatment groups also received basiliximab induction, MMF, and corticosteroids
  • NULOJIX (BENEFIT study, n=226; BENEFIT-EXT study, n=175): 10 mg/kg on Day 1 (day of transplantation prior to implantation), Day 5 (~96 hours after Day 1 dose), and end of Weeks 2, 4, 8, and 12. Starting at end of
    Week 16, 5 mg/kg every 4 weeks (plus or minus 3 days). 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; progressive multifocal leukoencephalopathy (PML), often a rapidly progressive and fatal opportunistic infection; and serious CNS infections
  • Cyclosporine (BENEFIT study, n=221; BENEFIT-EXT study, n=184): 4-10 mg/kg then adjusted to serum levels 150-300 ng/mL within the first month, then 100-250 ng/mL within Months 2-12

Endpoints1-3

Study endpoints are the same for BENEFIT and BENEFIT-EXT studies:

  • Efficacy failure, defined as a composite of
    • Biopsy-proven acute rejection (BPAR)§
    • Graft loss
    • Death
    • Lost to follow-up
  • Composite patient and graft survival
  • Renal function assessed as mean calculated glomerular filtration rate (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)

*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.

Dose based on actual body weight at time of transplant unless there was >10% change.

A NULOJIX regimen with higher cumulative doses and more frequent dosing than the recommended dosage regimen was also studied (N=219). Study results for this arm are not reported here.

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

||GFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula.

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.

Selected 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 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

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. 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.
Expand

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 graft

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

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 Category C: based on animal data, NULOJIX may cause fetal harm. NULOJIX should not be used in pregnancy unless potential benefit to the mother outweighs potential risk to the fetus. 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

 
Expand

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

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 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 graft

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

Pregnancy Category C: based on animal data, NULOJIX may cause fetal harm. NULOJIX should not be used in pregnancy unless potential benefit to the mother outweighs potential risk to the fetus. 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

Nursing Mothers: discontinue NULOJIX or nursing, considering importance of NULOJIX to the mother

Most Common Adverse Reactions (≥20%): 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%)

Please see Full Prescribing Information, including Boxed WARNINGS.

721US1604879-02-01 02/17

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