Dosing and uses of Nulojix (belatacept)
Adult dosage forms and strengths
lyophilized powder for injection
- 250mg/vial
Kidney Transplant Rejection Prophylaxis
Indicated for use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids to prevent kidney transplant rejection
Use limitations include: Patients who are EBV seropositive; efficacy not established for use in other solid organ transplants besides kidney
Due to an increased risk of post-transplant lymphoproliferative disorder predominantly involving the central nervous system, progressive multifocal leukoencephalopathy, and serious CNS infections, administration of higher than the recommended doses or more frequent dosing is NOT recommended
Dose calculation and schedule
- Total infusion dose based on actual body weight of patient at time of transplantation; modify dose if weight changes by >10%
- Prescribed dose must be divisible by 12.5 in order to accurately prepare dose from the reconstituted solution
- Initial phase dosing: 10 mg/kg IV on day of transplant (prior to implantation); repeat this dose on Day 5 and at end of Weeks 2, 4, 8, and 12 after transplantation
- Maintenance phase dosing: 5 mg/kg IV at end of Week 16 after transplantation and then q4Weeks (within +/- 3 days) thereafter
Dosing Considerations
Corticosteroid utilization
- In clinical trials the median corticosteroid doses were tapered to ~15 mg/day (10-20 mg/day) by the first 6 weeks and remained at ~10 mg/day (5-10 mg/day) for the first 6 months post-transplant
- Corticosteroid utilization should be consistent with the clinical trial experience
Renal Impairment
Dose adjustments may not be necessary per pharmacokinetic studies showing clearance of belatacept not affected in kidney transplant patients; not described in manufacturer's labeL
Hepatic Impairment
Dose adjustments may not be necessary per pharmacokinetic studies showing clearance of belatacept not affected in kidney transplant patients; not described in manufacturer's labeL
Administration
For IV use only
Administer over 30 minutes
Only use enclosed silicone-free disposable syringe when preparing IV infusion
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Because T cell development continues into the teenage years, the potential concern for autoimmunity in neonates applies to pediatric use as welL
Geriatric dosage forms and strengths
Of 401 patients treated with belatacept, 15% were 65 years of age and older, while 3% were 75 and older
No overall differences in safety or effectiveness were observed between these recipients and younger recipients, but cannot rule out greater sensitivity or less efficacy in older individuals
Nulojix (belatacept) adverse (side) effects
≥ 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%)
Leukopenia (20%)
11-19%
Dyslipidemia (19%)
Abdominal pain (19%)
Hypophosphatemia (19%)
Hypotension (18%)
Arthralgia (17%)
Hyperglycemia (16%)
Hematuria (16%)
Proteinuria (16%)
Blood creatinine increased (15%)
Insomnia (15%)
Upper respiratory infection (15%)
Nasopharyngitis (13%)
Back pain (13%)
Hypocalcemia (13%)
CMV infection (12%)
Dyspnea (12%)
Influenza (11%)
Dysuria (11%)
Hypercholesterolemia (11%)
1-10%
Anxiety (10%)
Bronchitis (10%)
Renal tubular necrosis (9%)
New onset diabetes (8%)
Acne (8%)
Hypomagnesemia (7%)
Hyperuricemia (5%)
Warnings
Black box warnings
Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS)
Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only
Contraindicated in transplant recipients who are EBV seronegative or with unknown EBV serostatus
Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe
Patients receiving the drug should be managed in facilities equipped and staffed 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
Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression
Not recommended for use in liver transplant patients because of increased risk of graft loss and death
Contraindications
Hypersensitivity
Patients who are EBV seronegative or with unknown EBV serostatus
Cautions
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 rejection; these Grade III rejections occurred in patients with 4-6 HLA mismatches; graft loss was a consequence of Grade III rejection in some patients (see Dosing Considerations)
Serious infection may occur including bacterial, viral (cytomegalovirus [CMV], herpes, polyoma virus nephropathy), fungal, and protozoal infections, including opportunistic infections (eg, tuberculosis); these infections may lead to serious, including fatal, outcomes
Prophylaxis for CMV is recommended for at least 3 months after transplantation
Prophylaxis for P jiroveci is recommend after transplantation
Patients receiving immunosuppressants, including belatacept, are in increased risk for developing malignancies; advised added precautions including limiting UV exposure and wearing sunscreen
DO NOT USE to prevent rejection of liver transplantation; in clinical trials for liver transplantation, belatacept was associated with a higher rate of graft loss and death compared to the tacrolimus control arms
Monitor for a need to adjust concomitant mycophenolate mofetil (MMF) dosage when patient’s therapy is switched between cyclosporine and belatacept, as cyclosporine decreases mycophenolic acid (MPA) exposure by preventing enterohepatic recirculation of MPA while belatacept does not
A lower MMF dosage may be needed after switching from cyclosporine to belatacept, since this may result in higher MPA concentrations and increase the risk for adverse reactions related to MPA
A higher MMF dosage may be needed after switching from belatacept to cyclosporine, since this may result in lower MPA concentrations and increase the risk of graft rejection.
Avoid use of live vaccines during treatment with belatacept, including but not limited to the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines
Post-transplant lymphoproliferative disorder
- Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen
- As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of belatacept and higher than recommended doses of concomitant immunosuppressive agents are not recommended
- Consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms
- 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 belatacept, and only patients who are EBV seropositive should receive belatacept
- Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive belatacept (see Black box warnings and Contraindications)
- Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell depleting therapy
- Patients are encouraged to participate in ENLIST registry to further determine safety of belatacept (1-800-321-1335)
Progressive multifocal leukoencephalopathy (PML)
- PML is a rare occurrence but is a rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma virus
- In clinical trials, 2 cases of PML were reported in patients receiving belatacept at higher cumulative doses and administered more frequently than the recommended regimen
Pregnancy and lactation
Pregnancy category: C; National Transplant Pregnancy Registry (NTPR): 1-877-955-6877
Should not be used in pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus
There are no studies of treatment in pregnant women
Known to cross the placenta of animals
Lactation: Unknown whether distributed in breast milk; a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Nulojix (belatacept)
Mechanism of action
Monoclonal antibody; inhibits T-cell CD28 activation and proliferation by binding costimulatory ligands (CD80, CD86) of antigen presenting cells
Inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-alpha, interleukin-4, and TNF-alpha
Activated T lymphocytes are the predominant mediators of immunologic rejection
Pharmacokinetics
After single and multiple doses
Peak Plasma Concentration: 139-300 mcg/mL
AUC: 14.1-26.4 mg•h/mL
Vd: 0.09-0.12 L/kg
Half-life: 8.2-9.8 days
Total body clearance: 0.39-0.51 mL/hr/kg
Administration
IV Incompatibilities & Compatibilities
No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of belatacept with other agents
IV Preparation Initial Reconstitution
Calculate the number of vials required to provide the total infusion dose; each vial contains 250 mg of belatacept lyophilized powder
Reconstitute the contents of each vial with 10.5 mL of a suitable diluent (ie, sterile water for injection, 0.9% NaCl, D5W) using the silicone-free disposable syringe provided with each vial and an 18-21-gauge needle
Silicone-free syringe: If 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
To reconstitute the lyophilized powder, remove the flip-top from the vial and wipe the top with an alcohol swab; insert syringe needle into vial through the center of the rubber stopper and direct the stream of diluent to the glass wall of vial to minimize foam formation
To minimize foam formation, rotate vial and invert with gentle swirling until the contents are completely dissolved
DO NOT SHAKE vial and avoid prolonged or vigorous agitation
Reconstituted solution contains concentration of 25 mg/mL 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
IV Preparation Further dilution
The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately
Calculate the total volume of the reconstituted 25 mg/mL solution required to provide the total infusion dose
Volume of 25 mg/mL solution (in mL) = Prescribed Dose (in mg) divided by 25 mg/mL
Prior to IV infusion, the required volume of the reconstituted solution must be further diluted with a suitable infusion fluid (NS or D5W)
If initially reconstituted with sterile water for injection, further dilute with either NS or D5W
If initially reconstituted with NS, further diluted with Ns
If initially reconstituted with D5W, further diluted with D5W
From the appropriate size infusion container, withdraw a volume of infusion fluid that is equal to the volume of the reconstituted solution required for 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 concentration in the infusion container should range from 2-10 mg/mL
Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, but total infusion volumes ranging from 50-250 mL may be used
Any unused solution remaining in the vials must be discarded
IV Administration
Visually inspect for particulate matter and discoloration prior to administration
Discard the infusion if any particulate matter or discoloration is observed
The entire infusion should be administered over 30 minutes and must be administered with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 microns)
Infuse in a separate IV line from other concomitantly infused agents and should not be infused concomitantly in the same intravenous line with other agents
Storage
Infusion must be completed within 24 hours of reconstitution of the lyophilized powder
If not used immediately, the infusion solution may be stored under refrigeration conditions: 2-8ºC (36-46ºF) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20-25ºC [68-77ºF] and room light)
