NULOJIX

T-Cell Costimulation Blockers

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.

Reconstitution and Preparation of Infusion
Calculate the number of drug vials required to provide the total infusion dose; the prescribed dose must be evenly divisible by 12.5 mg in order for the dose to be prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. Each vial contains 250 mg of belatacept lyophilized powder.
Reconstitute the contents of each vial with 10.5 mL of sterile water for injection, 0.9% sodium chloride, or 5% dextrose in water using the silicone-free disposable syringe provided with each vial and an 18 to 21 gauge needle. Only use the silicone-free disposable syringe provided with each vial. If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. If you need additional silicone-free disposable syringes, call 1-888-685-6549. If the powder is accidentally reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes.
Using aseptic technique, inject the diluent into the vial and direct the stream of diluent to the glass wall of the vial. To minimize foaming, rotate the vial and invert with gentle swirling until the contents are completely dissolved. Avoid prolonged or vigorous agitation; do not shake. The reconstituted solution contains 25 mg/mL of belatacept and should be clear to slightly opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present.
After reconstitution in the vial, immediately prepare the infusion.
Calculate the total volume of the reconstituted 25 mg/mL solution required to provide the total infusion dose. Further dilute this volume with a suitable infusion fluid.
Use either 0.9% Sodium Chloride or 5% Dextrose if drug was reconstituted with Sterile Water for Injection.
Use 0.9% Sodium Chloride if drug was reconstituted with 0.9% Sodium Chloride.
Use 5% Dextrose if drug was reconstituted with 5% Dextrose.
From an appropriate size infusion container, first withdraw a volume of the selected infusion fluid that is equal to the volume of the reconstituted drug solution that is required to provide the prescribed dose.
With the same silicone-free disposable syringe used for reconstitution, withdraw the required amount of belatacept solution from the vial, inject it into the infusion container, and gently rotate the infusion container to ensure mixing.
The final belatacept infusion concentration should range from 2 mg/mL to 10 mg/mL. Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, but total infusion volumes ranging from 50 mL to 250 mL may be used.
Discard any unused drug solution remaining in the vials.
The drug infusion must be completed within 24 hours of drug reconstitution.
Storage: If not used immediately, the infusion solution may be stored at 2 to 8 degrees C (36 to 46 degrees F) and protected from light for up to 24 hours; a maximum of 4 hours of the total 24 hours can be at room temperature, 20 to 25 degrees C (68 to 77 degrees F) and room light.
 
Intravenous infusion
Administer the entire drug infusion over a period of 30 minutes. Administer with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter with a pore size of 0.2 to 1.2 micrometer.
Infuse in a separate line from other concomitantly infused agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of belatacept with other agents.

hyperkalemia / Delayed / 20.0-20.0
proteinuria / Delayed / 16.0-16.0
atrial fibrillation / Early / 0-10.0
wound dehiscence / Delayed / 0-10.0
renal failure (unspecified) / Delayed / 0-10.0
Guillain-Barre syndrome / Delayed / 0-10.0
renal tubular necrosis / Delayed / 9.0-9.0
post-transplant lymphoproliferative disorder (PTLD) / Delayed / 0.6-1.0
new primary malignancy / Delayed / Incidence not known
leukoencephalopathy / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
thrombosis / Delayed / Incidence not known

anemia / Delayed / 45.0-45.0
peripheral edema / Delayed / 34.0-34.0
constipation / Delayed / 33.0-33.0
hypertension / Early / 32.0-32.0
hypokalemia / Delayed / 21.0-21.0
leukopenia / Delayed / 20.0-20.0
hypophosphatemia / Delayed / 19.0-19.0
hypotension / Rapid / 18.0-18.0
hematuria / Delayed / 16.0-16.0
hyperglycemia / Delayed / 16.0-16.0
hypocalcemia / Delayed / 13.0-13.0
dyspnea / Early / 12.0-12.0
hypercholesterolemia / Delayed / 11.0-11.0
dysuria / Early / 11.0-11.0
lymphocele / Delayed / 0-10.0
neutropenia / Delayed / 0-10.0
stomatitis / Delayed / 0-10.0
urinary incontinence / Early / 0-10.0
diabetes mellitus / Delayed / 5.0-8.0
hypomagnesemia / Delayed / 7.0-7.0
hyperuricemia / Delayed / 5.0-5.0
antibody formation / Delayed / 2.0-2.0
immunosuppression / Delayed / Incidence not known
BK virus-associated nephropathy / Delayed / Incidence not known

infection / Delayed / 82.0-82.0
diarrhea / Early / 39.0-39.0
fever / Early / 28.0-28.0
nausea / Early / 24.0-24.0
cough / Delayed / 24.0-24.0
vomiting / Early / 22.0-22.0
headache / Early / 21.0-21.0
abdominal pain / Early / 9.0-19.0
arthralgia / Delayed / 17.0-17.0
insomnia / Early / 15.0-15.0
pharyngitis / Delayed / 13.0-13.0
back pain / Delayed / 13.0-13.0
influenza / Delayed / 11.0-11.0
musculoskeletal pain / Early / 0-10.0
hyperhidrosis / Delayed / 0-10.0
alopecia / Delayed / 0-10.0
anxiety / Delayed / 10.0-10.0
dizziness / Early / 9.0-9.0
acne vulgaris / Delayed / 8.0-8.0
tremor / Early / 8.0-8.0

Belatacept requires an experienced clinician; only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe belatacept. Belatacept use also requires a specialized care setting; manage patients in facilities equipped and staffed with adequate laboratory and supportive medical resources. Use only in patients who are Epstein-Barr virus (EBV) seropositive. Obtain Epstein-Barr virus (EBV) serology BEFORE belatacept administration. Belatacept is contraindicated for use by patients who are EBV seronegative or who have unknown EBV serostatus. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient.

Belatacept increases a patient's susceptibility to infection due to suppression of the immune system. Patients are at increased risk for bacterial, viral, fungal, and protozoal infections, including opportunistic infections. Use of higher than recommended doses or more frequent dosing is not recommended because of an increased risk of serious infections. Evaluate patients for tuberculosis and test for latent tuberculosis before starting belatacept. Initiate treatment of latent tuberculosis infection before belatacept receipt. Patients with a history of recurrent infections or an underlying condition that may predispose them to infections (i.e., advanced or uncontrolled diabetes mellitus, malignancy, or a history of active or chronic infections) may not be appropriate candidates for belatacept therapy. If belatacept is used, closely monitor patients.

Belatacept increases a patient's susceptibility to the development of new primary malignancy and post-transplant lymphoproliferative disorder (PTLD) and progressive multifocal leukoencephalopathy (PML) because of immunosuppression. Belatacept is contraindicated in transplant recipients who are Epstein-Barr virus (EBV) seronegative or with unknown EBV serostatus due to the risk of PTLD or PML, both of which can cause death. As the total burden of immunosuppression is a risk factor for PTLD or PML, higher than recommended doses or more frequent dosing of belatacept and higher than recommended doses of concomitant immunosuppressive agents are not recommended. Patients should be educated regarding the risks of drug use, and to report any symptoms of new, changed or worsened neurologic, cognitive or behavioral effects to their prescriber. A pre-infusion checklist is available and must be completed prior to each infusion to assess risks. To help prevent skin cancer, instruct patients to limit sunlight (UV) exposure by wearing protective clothing and by using a sunscreen with a high protection factor.

Use of belatacept in liver transplant patients is not recommended because of a higher risk of mortality and graft loss seen in these patients.

NULOJIX

Rx

Selective T-cell costimulation blocker
For rejection prophylaxis in adults receiving a kidney transplant
May increase risk for developing post-transplant lymphoproliferative disorder; ONLY use in Epstein-Barr virus seropositive patients

10 mg/kg to nearest 12.5 mg increment IV over 30 minutes on day 1 before transplantation, on day 5 approximately 96 hours after the first dose, and at the end of weeks 2, 4, 8, and 12. Then, 5 mg/kg to nearest 12.5 mg-increment IV over 30 minutes at the end of week 16 and every 4 weeks +/- 3 days thereafter. Base all doses on the patient's actual body weight on the transplantation day unless the patient's weight varies by more than 10%. Higher belatacept doses or more frequent dosing are not recommended because of an increased risk of serious infections and post-transplant lymphoproliferative disorder. Corticosteroid utilization needs to be consistent with the clinical trial experience, which was methylprednisolone 500 mg IV on arrival in the operating room, methylprednisolone 250 mg IV on day 2, prednisone 100 mg PO on day 3, and a prednisone or prednisolone dose taper to a median dose of approximately 15 mg/day (10 to 20 mg/day, 25th to 75th percentile) by the first 6 weeks and a median dose of approximately 10 mg/day (5 to 10 mg/day, 25th to 75th percentile) for the first 6 months after transplantation. An increased rate and grade of acute rejection were noted postmarketing among patients with corticosteroid minimization to 5 mg/day between day 3 and week 6 after transplantation. Grade III rejections, which led to graft loss in some, occurred in patients with 4 to 6 HLA mismatches.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Antithymocyte Globulin: (Moderate) Coadministration at the same time or nearly the same time of belatacept and anti-thymocyte immune globulin in patients with other predisposing risk factors for venous thrombosis of the renal allograft may pose a risk for venous thrombosis of the renal allograft.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Intranasal Influenza Vaccine: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Live Vaccines: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Rotavirus Vaccine: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Typhoid Vaccine: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.
Yellow Fever Vaccine, Live: (Contraindicated) Avoid the use of live vaccines such as the intranasal influenza vaccine; measles/mumps/rubella vaccines, MMR; Bacillus Calmette-Guerin Live, BCG; yellow fever vaccine; oral polio vaccine; varicella virus vaccine live; and TY21a typhoid vaccine during belatacept treatment. Further, inactive vaccine receipt may not illicit an acceptable response; belatacept may blunt the effectiveness of some immunizations. Consult the most current CDC guidances for vaccination recommendations.

NULOJIX Intravenous Inj Pwd F/Sol: 250mg

10 mg/kg/dose IV for first 6 doses then 5 mg/kg/dose IV.

10 mg/kg/dose IV for first 6 doses then 5 mg/kg/dose IV.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Activated T lymphocytes are the predominant mediators of immunologic rejection, and belatacept is a selective T-cell costimulation blocker. Specifically, belatacept blocks the CD28 mediated costimulation of T lymphocytes by binding to CD80 and CD86 on antigen-presenting cells. In vitro, belatacept inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-gamma, interleukin-4, and TNF-alpha. The inhibition of cytokine production by T cells required for antigen-specific antibody production by B cells leads to reduced antibody concentrations.

Belatacept is administered by intravenous infusion. The mean terminal half life among kidney transplant patients was 9.8 +/- 3.2 days (range, 6.1—15.1 days) during receipt of 10 mg/kg IV doses. During receipt of 5 mg/kg IV doses, the mean terminal half life was 8.2 +/- 2.4 days (range, 3.1—11.9 days). The mean clearance after receipt of multiple 10 mg/kg doses was 0.49 +/- 0.13 mL/kg/hour. A similar value was obtained with the maintenance dose of 5 mg/kg. A trend toward higher clearance with increasing body weight was noted among kidney transplant patients; all doses are based on the patient's actual body weight on the transplantation day unless the patient's weight varies by more than 10%. Age, gender, race, renal function measured by calculated glomerular filtration rate, hepatic function measured by albumin, diabetes, and concomitant dialysis did not affect the clearance.
 
In clinical trials, greater reductions in mean immunoglobulin (IgG, IgM, and IgA) concentrations were observed from baseline to month 6 and month 12 after transplant in belatacept-treated patients as compared with cyclosporine-treated patients. Administration of higher than recommended belatacept doses or more frequent dosing is not recommended: a trend of decreasing IgG concentrations with increasing belatacept trough concentrations was observed. Also, belatacept-treated patients with CNS PTLD, CNS infections including PML, other serious infections, and malignancies were observed to have a higher incidence of IgG concentrations below the lower limit of the normal range (< 694 mg/dL) as compared with patients who did not experience these adverse events. Of note, any causal relationship between an IgG concentration below the lower level of normal and these adverse events is uncertain, as the analysis may have been confounded by other factors such as age greater than 60 years, receipt of an extended criteria donor kidney, and exposure to lymphocyte depleting agents. These other factors were also associated with an IgG concentration below the lower level of normal.
 
Affected cytochrome P450 isoenzymes: none
Biologic therapies that are cytokines or cytokine modulators have been shown to affect the expression and/or functional activities of cytochrome P450 enzymes. In vitro studies have shown that belatacept inhibits the production of certain cytokines during an alloimmune response, but in vivo data were unavailable at the time of FDA approval. Further, the potential to alter the systemic concentrations of drugs that are CYP450 substrates has not been studied. Belatacept may alter the metabolism of drugs that go through the CYP450 system; consider this possibility if a patient exhibits signs and symptoms of altered efficacy or adverse events associated with coadministered drugs that are known to be metabolized by CYP450.

In healthy patients, the pharmacokinetic parameters of belatacept were linear, and the exposure to belatacept increased proportionally after a single intravenous infusion dose of 1 to 20 mg per kg. The pharmacokinetic parameters of belatacept in de novo kidney transplant patients and healthy patients are comparable. After the recommended regimen, the mean belatacept serum concentration reached steady-state by week 8 after transplantation and by month 6 during the maintenance phase. In kidney transplant patients, about a 20% systemic accumulation of belatacept occurred after once monthly intravenous infusion of 10 mg/kg, and about a 10% systemic accumulation of belatacept occurred after once monthly intravenous infusion of 5 mg/kg. At steady state, the mean peak belatacept concentration was 247 +/- 68 mcg/mL after multiple 10 mg/kg IV doses and was 139 +/- 28 mcg/mL after multiple 5 mg/kg IV doses. As expected, the mean systemic exposure was higher with the 10 mg/kg dosing (22,252 +/- 7868 mcg x hour/mL) as compared with the 5 mg/kg dosing (14,090 +/- 3860 mcg x hour/mL). The pharmacokinetic parameters of belatacept were similar at different time periods up to 1 year after transplant receipt, and belatacept trough concentrations were consistently maintained from month 6 up to 3 years after transplant receipt.

The data with belatacept use in human pregnancy are insufficient to inform a drug-associated risk. Belatacept is known to cross the placenta of animals. Administration of belatacept to pregnant rats and rabbits during organogenesis was not teratogenic at exposures approximately 16 and 19 times more than that observed at the maximum recommended human dose (MRHD) of 10 mg/kg administered over the first month of treatment, based on area under the concentration-time curve (AUC). Maternal infections resulting in increased pup mortality occurred at exposures 3 times the MRHD. In vitro data indicate that belatacept has a lower binding affinity to CD80/CD 86 and lower potency in rodents than in humans; therefore, the true relevance of rat toxicities to humans is unclear. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to belatacept; information about the registry can be obtained at www.transplantpregnancyregistry.com or by calling 1-877-955-6877.

There are no data on the presence of belatacept in human milk or the effects of belatacept on breast-fed infants or human milk production. Belatacept is excreted in rat milk. Absorption of intact belatacept from the breast-fed infant's gastrointestinal tract has not been studied. Due to belatacept having a half-life of 8 to 10 days, it may be more than a month after administration before the drug is not present in breast milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for belatacept and any potential adverse effects on the breast-fed infant from belatacept or the underlying maternal condition.