Selected Pooled Safety Data at 3 Years
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
Summary of PTLD cases reported in NULOJIX kidney transplant trials through 36 months of treatment*
*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 allograft
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
- NULOJIX [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company.