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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

Close 

Selected Pooled Safety Data at 3 Years

Post-Transplant Lymphoproliferative Disorder (PTLD)

  • NULOJIX® (belatacept) 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

Summary of PTLD cases reported in NULOJIX kidney transplant trials through 36 months of treatment*

PTLD Chart A

PTLD chart A mobile

*Empty boxes indicate 0.

In the BENEFIT and BENEFIT-EXT studies, the NULOJIX regimen is identical to the recommended regimen, but slightly different in the phase 2 study.

2 of the 5 cases presented with CNS involvement.

§Regimen with higher cumulative dose and more frequent dosing than recommended NULOJIX regimen.

||6 of the 8 cases presented with CNS involvement.

  • NULOJIX regimen-treated patients who were EBV seronegative or whose EBV serostatus was unknown had a 9-fold higher rate of PTLD (8/139) compared to those who were EBV seropositive (5/810)
  • Therefore, NULOJIX is recommended for use only in patients who are EBV seropositive

Other Malignancies and Serious Infections

  • Increased susceptibility to infection and possible development of malignancies may result from immunosuppression
  • Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in the BENEFIT Study and the BENEFIT-EXT Study 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
  • 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

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

Infections Data

Pooled analysis using data from the BENEFIT and BENEFIT-EXT studies1, *

 

*The BENEFIT and BENEFIT-EXT studies 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, and 1163 for cyclosporine in BENEFIT and BENEFIT-EXT studies.

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 Month 36.

Most herpes infections were nonserious and 1 led to treatment discontinuation.

  • Following 3 years of treatment in the BENEFIT and BENEFIT-EXT Studies, cryptoccocal meningitis was reported in 1/401 patients treated with NULOJIX (belatacept) recommended dosing (0.2%) and 1/405 treated with the cyclosporine control (0.2%)
  • 6/403 who were treated with the NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended in the BENEFIT and BENEFIT-EXT Studies (1.5%) were reported to have developed CNS infections: 2 cryptococcal meningitis, 1 Chagas encephalitis with cryptococcal meningitis, 1 cerebral aspergillosis, 1 West Nile encephalitis, and 1 PML

Common Adverse Reactions ≥20%

  • The most commonly reported adverse reactions (≥20%) by Month 36 with NULOJIX were 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%)
  • The proportion of patients who discontinued treatment due to adverse reactions was 13% for NULOJIX and 19% for cyclosporine through 36 months of treatment
  • The most common adverse reactions leading to discontinuation in NULOJIX regimen-treated patients were cytomegalovirus infection (1.5%) and complications of transplanted kidney (1.5%)

Blood Pressure Profile

  • Hypertension was reported as an adverse reaction in 32% of NULOJIX regimen-treated patients and 37% of cyclosporine regimen-treated patients

Difference in mean systolic and diastolic blood pressure in a pooled analysis of the BENEFIT and BENEFIT-EXT studies1

*SBP=systolic blood pressure.

DBP=diastolic blood pressure.

  • At Month 36, 1 or more antihypertensive medications were used in 85% of NULOJIX regimen-treated patients and 92% of cyclosporine regimen-treated patients

Lipid Profile

Pooled analysis using data from the BENEFIT and BENEFIT-EXT studies1

*HDL-C=high-density lipoprotein cholesterol.

LDL-C=low-density lipoprotein cholesterol.

  • The clinical significance of the lower mean triglyceride values in NULOJIX regimen-treated patients at Month 12 and Month 36 is unknown

NODAT

The effects of immunosuppression regimens on new onset diabetes after transplantation (NODAT)

Incidence of NODAT from a pooled analysis of the BENEFIT and BENEFIT-EXT studies1

  • 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.

References

  1. NULOJIX [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company.
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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