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Indications
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)
1.1Adult 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.
1.2Limitations 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) ] .
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)
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Post-Transplant Lymphoproliferative Disorder (PTLD) : increased risk, predominantly involving the CNS; monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms. (Boxed Warning , 4 , 5.1 , 5.6)
Other malignancies : increased risk with all immunosuppressants; appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight. (5.3)
Progressive Multifocal Leukoencephalopathy (PML) : increased risk; consider in the diagnosis of patients reporting new or worsening neurological, cognitive, or behavioral signs and symptoms. Recommended doses of immunosuppressants should not be exceeded. (5.4)
Other serious infections : increased risk of bacterial, viral, fungal, and protozoal infections, including opportunistic infections and tuberculosis. Some infections were fatal. Polyoma virus-associated nephropathy can lead to kidney graft loss; consider reduction in immunosuppression. Evaluate for tuberculosis and initiate treatment for latent infection prior to NULOJIX use. Cytomegalovirus and pneumocystis prophylaxis are recommended after transplantation. (5.1 , 5.4 , 5.5)
Liver transplant : use is not recommended. (5.6)
Acute Rejection and Graft Loss with Corticosteroid Minimization : corticosteroid utilization should be consistent with the NULOJIX clinical trial experience. (2.1 , 5.7 , 14.1)
Immunizations : avoid use of live vaccines during treatment. (5.8)
Coadministration with Anti-Thymocyte Globulin: in de novo kidney transplant recipients, especially those with other predisposing risk factors for venous thrombosis of the renal allograft, coadministration (at the same or nearly the same time) with anti-thymocyte globulin may pose a risk for venous thrombosis of the renal allograft. ( 5.9 , 6.2 , 7.3 )
Risk of Rejection with Conversion From a CNI Based Maintenance Regimen: conversion of maintenance kidney transplant recipients from a CNI based to NULOJIX based maintenance regimen increases the risk of acute rejection. Conversion of stable kidney transplant recipients from a CNI based maintenance therapy to a belatacept based maintenance therapy is not recommended unless the patient is CNI intolerant. (5.10)
5.1Post-Transplant Lymphoproliferative Disorder
NULOJIX-treated patients have an increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen [see Adverse Reactions (6.1) , Clinical Studies (14.2) ] . As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of NULOJIX and higher than recommended doses of concomitant immunosuppressive agents are not recommended [see Dosage and Administration (2.1) and Warnings and Precautions (5.6) ] .
Physicians should consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms. EBV Serostatus The risk of PTLD was higher in EBV seronegative patients compared to EBV seropositive patients. EBV seropositive patients are defined as having evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA). Epstein-Barr virus serology should be ascertained before starting administration of NULOJIX, and only patients who are EBV seropositive should receive NULOJIX.
Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive NULOJIX [see Boxed Warning and Contraindications (4) ] . Other Risk Factors Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T cell-depleting therapy. T cell-depleting therapies to treat acute rejection should be used cautiously. CMV prophylaxis is recommended for at least 3 months after transplantation [see Warnings and Precautions (5.5) ] .
Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD compared to patients who are EBV seropositive and CMV seropositive [see Adverse Reactions (6.1) ] . 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.
5.2Management of Immunosuppression
Only physicians experienced in management of systemic immunosuppressant therapy in transplantation 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 the maintenance therapy should have complete information requisite for the follow-up of the patient [see Boxed Warning ] .
5.3Other Malignancies
Patients receiving immunosuppressants, including NULOJIX, are at increased risk of developing malignancies, in addition to PTLD, including the skin [see Boxed Warning and Warnings and Precautions (5.1) ] . Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
5.4Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is an often rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma virus. In clinical trials with NULOJIX, two cases of PML were reported in patients receiving NULOJIX at higher cumulative doses and more frequently than the recommended regimen, along with mycophenolate mofetil (MMF) and corticosteroids; one case occurred in a kidney transplant recipient and the second case occurred in a liver transplant recipient [see Warnings and Precautions (5.6) , Adverse Reactions (6.1) , Clinical Studies (14.2) ] .
As PML has been associated with high levels of overall immunosuppression, the recommended doses and frequency of NULOJIX and concomitant immunosuppressives, including MMF, should not be exceeded. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. PML is usually diagnosed by brain imaging, cerebrospinal fluid (CSF) testing for JC viral DNA by polymerase chain reaction (PCR), and/or brain biopsy.
Consultation with a specialist (eg, neurologist and/or infectious disease) should be considered for any suspected or confirmed cases of PML. If PML is diagnosed, consideration should be given to reduction or withdrawal of immunosuppression taking into account the risk to the allograft.
5.5Other Serious Infections
Patients receiving immunosuppressants, including NULOJIX, are at increased risk of developing bacterial, viral (cytomegalovirus [CMV] and herpes), fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes [see Boxed Warning and Adverse Reactions (6.1) ] . Prophylaxis for cytomegalovirus is recommended for at least 3 months after transplantation.
Prophylaxis for Pneumocystis jiroveci is recommended after transplantation. Tuberculosis Tuberculosis was more frequently observed in patients receiving NULOJIX than cyclosporine in clinical trials [see Adverse Reactions (6.1) ] . Patients should be evaluated for tuberculosis and tested for latent infection prior to initiating NULOJIX. Treatment of latent tuberculosis infection should be initiated prior to NULOJIX use.
Polyoma Virus Nephropathy In addition to cases of JC virus-associated PML [see Warnings and Precautions (5.4) ] , cases of polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, have been reported. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss [see Adverse Reactions (6.1) ] . Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who deve
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Interactions
7.1 Mycophenolate Mofetil (MMF) Monitor for a need to adjust concomitant mycophenolate mofetil (MMF) dosage when a patient’s therapy is switched between cyclosporine and NULOJIX, as cyclosporine decreases mycophenolic acid (MPA) exposure by preventing enterohepatic recirculation of MPA while NULOJIX does not [see Clinical Pharmacology (12.3) ] :
A higher MMF dosage may be needed after switching from NULOJIX to cyclosporine, since this may result in lower MPA concentrations and increase the risk of graft rejection.
A lower MMF dosage may be needed after switching from cyclosporine to NULOJIX, since this may result in higher MPA concentrations and increase the risk for adverse reactions related to MPA (review the Full Prescribing Information for MMF).
7.2Cytochrome 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) ] .
7.3Anti-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) ] .
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
To monitor maternal-fetal outcomes of pregnant women who have received immunosuppressants including NULOJIX or whose partners have received NULOJIX, healthcare providers are strongly encouraged to register pregnant patients in the Transplant Pregnancy Registry International (TPR) by calling 1-877-955-6877. Risk Summary The data with NULOJIX use in pregnant women are insufficient to inform on drug-associated risk. Belatacept is known to cross the placenta of animals.
Administration of belatacept to pregnant rats and rabbits during the period of organogenesis was not teratogenic at exposures approximately 16 and 19 times greater than that observed at the maximum recommended human dose (MRHD) of 10 mg per kg body weight administered over the first month of treatment, based on area under the concentration-time curve (AUC). In a pre- and postnatal development study in rats, treatment-related infections in dams were associated with increased pup mortality, presumably secondary to deteriorating maternal health, at exposures 3 times higher than that observed at MRHD [see Animal Data ] .
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data In embryo-fetal development studies, daily intravenous administration of belatacept to pregnant rats and rabbits throughout the period of organogenesis did not produce adverse fetal effects at doses up to 200 mg per kg and 100 mg per kg, respectively (16 and 19 times the MRHD exposure, based on AUC).
In a pre- and postnatal development study, daily intravenous administration of belatacept to rats from Day 6 of gestation through Day 20 of the lactation period was associated with maternal toxicity (infections) in a small percentage of dams at doses ≥20 mg per kg (3 times the MRHD exposure, based on AUC) resulting in increased pup mortality (up to 100% pup mortality in some dams). In pups that survived, there were no abnormalities or malformations at doses up to 200 mg per kg (19 times the MRHD exposure, based on AUC).
In vitro data indicate that belatacept has lower binding affinity to CD80/CD86 and lower potency in rodents than in humans. Although the rat toxicity studies with belatacept were done at pharmacologically saturating doses, the in vivo difference in potency between rats and humans is unknown. Therefore, the relevance of the rat toxicities to humans and the significance of the magnitude of the relative exposures (rats:humans) are unknown.
Abatacept, a fusion protein that differs from belatacept by two amino acids, binds to the same ligands (CD80/CD86) and blocks T cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents, including infections and autoimmunity, may be predictive of adverse effects in humans treated with belatacept [see Nonclinical Toxicology (13.2) ] . Autoimmunity was observed in 1 rat offspring exposed to abatacept in utero and/or during lactation and in juvenile rats after treatment with abatacept.
However, the clinical relevance of autoimmunity in rats to patients or a fetus exposed in utero is unknown [see Nonclinical Toxicology (13.2) ] .
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 .
6.1Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The data described below primarily derive from two randomized, active-controlled three-year trials of NULOJIX in de novo kidney transplant patients. In Study 1 and Study 2, NULOJIX was studied at the recommended dose and frequency [see Dosage and Administration (2.1) ] in a total of 401 patients compared to a cyclosporine control regimen in a total of 405 patients.
These two trials also included a total of 403 patients treated with a NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended [see Clinical Studies (14.1) ] . All patients also received basiliximab induction, mycophenolate mofetil, and corticosteroids. Patients were treated and followed for three years. CNS PTLD, PML, and other CNS infections were more frequently observed in association with a NULOJIX regimen of higher cumulative dose and more frequent dosing compared to the recommended regimen; therefore, administration of higher than the recommended doses and/or more frequent dosing of NULOJIX is not recommended [see Dosage and Administration (2.1) , Clinical Studies (14.2) ] .
The average age of patients in Studies 1 and 2 in the NULOJIX recommended dose and cyclosporine control regimens was 49 years, ranging from 18 to 79 years. Approximately 70% of patients were male; 67% were white, 11% were black, and 22% other races. About 25% of patients were from the United States and 75% from other countries. The most commonly reported adverse reactions occurring in ≥20% of patients treated with the recommended dose and frequency of NULOJIX were anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia.
The proportion of patients who discontinued treatment due to adverse reactions was 13% for the recommended NULOJIX regimen and 19% for the cyclosporine control arm through three years of treatment. The most common adverse reactions leading to discontinuation in NULOJIX-treated patients were cytomegalovirus infection (1.5%) and complications of transplanted kidney (1.5%). Information on selected significant adverse reactions observed during clinical trials is summarized below.
Post-Transplant Lymphoproliferative Disorder Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months post-transplant were obtained for NULOJIX by pooling both dosage regimens of NULOJIX in Studies 1 and 2 (804 patients) with data from a third study in kidney transplantation (Study 3, 145 patients) which evaluated two NULOJIX dosage regimens similar, but slightly different, from those of Studies 1 and 2 (see Table 2).
The total number of NULOJIX patients from these three studies (949) was compared to the pooled cyclosporine control groups from all three studies (476 patients). Among 401 patients in Studies 1 and 2 treated with the recommended regimen of NULOJIX and the 71 patients in Study 3 treated with a very similar (but non-identical) 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 Nonrecommended Regimen a (N=477) NULOJIX Recommended Regimen b (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) a Regimen with higher cumulative dose and more frequent dosing than the recommended NULOJIX regimen. b 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 PTLD in EBV Seropositive Subpopulation Among the 806 EBV seropositive patients with known CMV serostatus treated with either NULOJIX regimen in Studies 1, 2, and 3, 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, 3 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: 1 patient in clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and 1 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 two years. The liver transplant recipient was treated with 6 months of a NULOJIX dosage regim
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
BELATACEPT 250MG
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA125288.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
