Belatacept is a selective T-cell costimulation blocker indicated for rejection prophylaxis in adults receiving a kidney transplant. Belatacept is used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids and is only indicated for use in Epstein-Barr virus (EBV) seropositive patients. Belatacept is contraindicated for use by patients who are EBV seronegative or with unknown serostatus because of the risk of post-transplant lymphoproliferative disorder. Belatacept was FDA approved in June 2011.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
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.
Intravenous Administration
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.
Patients receiving belatacept are at increased risk of developing a new primary malignancy due to immunosuppression. Instruct patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and by using a sunscreen with a high protection factor. Of 401 patients treated with the recommended belatacept regimen, 3.5% had malignancies excluding non-melanoma skin cancer and post-transplant lymphoproliferative disorder (PTLD), and 1.5% had non-melanoma skin cancer. Belatacept is associated with an increased risk of PTLD, predominantly involving the central nervous system. Among 472 patients who received the recommended regimen or a very similar regimen of belatacept, there were 5 cases of PTLD: 3 in Epstein-Barr virus (EBV) seropositive patients and 2 in EBV seronegative patients. Two of the 5 cases presented with CNS involvement. All cases of PTLD reported up to 36 months after transplantation presented within 18 months of transplantation. Consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms. Overall, the rate of PTLD in 949 patients treated with any of the belatacept regimens studied 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, belatacept is recommended for use only in patients who are EBV seropositive. Ascertain EBV serology before starting belatacept. Epstein-Barr virus seropositive patients are defined as having evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen and EBV nuclear antigen. In addition to EBV seronegativity, the total burden of immunosuppression is a risk factor for PTLD. Administration of higher than the recommended doses or more frequent dosing of belatacept is not recommended. Also, higher than recommended doses of concomitant immunosuppressive agents is not recommended. Cautiously use T-cell-depleting therapies to treat acute rejection, as T-cell-depleting therapy is a risk factor for PTLD. Also, cytomegalovirus (CMV) infection is a risk factor for PTLD; CMV prophylaxis is recommended for at least 3 months after transplantation. The clinical significance of CMV serology for PTLD remains to be determined; however, consider CMV serology results when prescribing belatacept. CMV seronegative patients are at increased risk for CMV disease, which is a known risk factor for PTLD. Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD as compared with patients who are EBV seropositive and CMV seropositive.
Patients receiving immunosuppressants such as belatacept are at increased risk of developing a bacterial, viral (e.g., cytomegalovirus and herpes), fungal, or protozoal infection, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. After transplantation, prophylaxis for Pneumocystis jiroveci is advised. Also, prophylaxis for cytomegalovirus is recommended for at least 3 months after transplantation. Consider progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by reactivated latent JC virus, 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 testing for JC viral DNA by polymerase chain reaction, and/or brain biopsy. Consider consultation with a neurologist and/or infectious disease specialist for any suspected or confirmed cases of PML. If PML is diagnosed, consider reducing or withdrawing immunosuppression; take into account the risk to the allograft. Unfortunately, PML is usually fatal or leads to severe disability, and there are no known effective treatments. As PML has been associated with high levels of overall immunosuppression, do not exceed the recommended doses and frequency of belatacept and of concomitant immunosuppressives including MMF. In addition to PML, cases of BK virus-associated nephropathy have been reported, consider reductions in immunosuppression for patients who develop evidence of polyoma virus-associated nephropathy (PVAN); take into account the risk to the allograft. Patient monitoring may help detect patients at risk for PVAN, which is associated with serious outcomes including deteriorating renal function and kidney graft loss. Most cases of PVAN were due to BK virus infection. Among 401 belatacept recipients who received the recommended dose, 28% had fever, less than 10% had neutropenia, 20% had leukopenia, less than 10% had lymphocele, and 82% had an infection of any severity due to bacterial, viral, fungal, or other organisms during a 3 year period. Serious infections such as those that resulted in death or hospitalization, prolonged hospitalization, or were life-threatening were noted in 36% of patients. Specific infections included urinary tract infection (37%), upper respiratory tract infection (15%), naso-pharyngitis (13%), cytomegalovirus infection (12%), influenza (11%), and bronchitis (10%). In clinical trials, tuberculosis and herpes infections were more frequently observed in patients receiving belatacept (2% and 14%, respectively) than cyclosporine (less than 1% and 11%, respectively). Fungal infections primarily of the skin and of mucocutaneous areas were noted in 18% of belatacept recipients as compared with 22% of cyclosporine recipients. One patient had cryptococcal meningitis (0.2%). In clinical trials, 2 cases of progressive multifocal leukoencephalopathy (PML) were reported in patients receiving belatacept at higher cumulative doses and more frequently than the recommended regimen along with mycophenolate mofetil and corticosteroids; 1 case occurred in a kidney transplant recipient and the other case occurred in a liver transplant recipient.
Gastrointestinal adverse effects noted among 401 belatacept recipients include diarrhea (39%), constipation (33%), nausea (24%), vomiting (22%), abdominal pain (9-19%), and stomatitis including aphthous stomatitis (< 10%).
Among 401 belatacept recipients enrolled in 2 clinical studies for 3 years, hypertension occurred in 32% of recipients compared to 37% of cyclosporine recipients (n = 405). Other reported adverse cardiac reactions to belatacept include hypotension (18%) and atrial fibrillation (< 10%). Dyslipidemia occurred in 19% of belatacept recipients compared to 24% of cyclosporine recipients, and 11% of patients from each treatment arm experienced hypercholesterolemia. Peripheral edema was observed in 34% of belatacept recipients vs. 42% of cyclosporine recipients.
There were no reports of anaphylaxis or drug hypersensitivity in patients treated with belatacept in clinical pre-approval studies for up to 3 years. Mild infusion-related reactions within 1 hour of belatacept infusion were reported in 5% of patients during clinical studies. The most frequent reactions were hypotension and hypertension. Anaphylactoid reactions are possible with the drug. An anaphylactoid reaction was observed with belatacept infusion during postmarketing use in a kidney transplant recipient whose belatacept therapy had been interrupted for 2 months due to a systemic varicella infection. When belatacept therapy was resumed, within 5 minutes after the start of the first belatacept infusion, the patient experienced generalized rash, pruritus, hypotension, atrial fibrillation, respiratory distress, and syncope requiring medical treatment. After belatacept infusion was attempted again 1 month later, the patient experienced more pronounced symptoms of anaphylaxis and required medical treatment.
Cough was noted in 24% and dyspnea in 12% of 401 belatacept recipients.
Among 401 belatacept recipients, 17% had arthralgia, 13% had back pain, and < 10% had musculoskeletal pain.
Adverse events noted among 401 belatacept recipients include acne vulgaris (8%), alopecia (< 10%), and hyperhidrosis (< 10%).
Adverse renal or urinary disorders noted among 401 belatacept recipients include anemia (45%), hematuria (16%), proteinuria (16%), increased blood creatinine (15%), dysuria (11%), renal tubular necrosis (9%), renal impairment including renal failure (unspecified) (less than 10%), renal artery stenosis (less than 10%), urinary incontinence (less than 10%), chronic allograft nephropathy (less than 10%), graft dysfunction (25%), and hydronephrosis (less than 10%). Complications of the transplanted kidney including wound dehiscence and arteriovenous fistula thrombosis were noted in less than 10% of patients. In postmarketing experience, venous thrombosis of the renal allograft has occurred in patients with other predisposing risk factors for venous thrombosis of the renal allograft when the initial doses of antithymocyte immune globulin and belatacept were coadministered (at the same or nearly the same time) as immunosuppressive induction. Electrolyte abnormalities included hyperkalemia (20%), hypokalemia (21%), hypophosphatemia (19%), hypocalcemia (13%), hypomagnesemia (7%), and hyperuricemia (5%).
Nervous system disorders noted among 401 belatacept recipients included headache (21%), insomnia (15%), anxiety (10%), dizziness (9%), tremor (8%), and Guillain-Barre syndrome (< 10%). Consider post-transplant lymphoproliferative disorder (PTLD) in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms. Also, a serious, rare brain infection such as progressive multifocal leukoencephalopathy (PML) may cause similar symptoms.
Among 401 belatacept recipients, 16% had hyperglycemia. Of 304 belatacept recipients, 5% had new-onset diabetes mellitus 1 year after transplantation, and 8% had new-onset diabetes by the end of the third year after transplantation; new-onset diabetes was defined as use of an antidiabetic agent for >= 30 days or >= 2 fasting plasma glucose values >= 126 mg/dL after transplantation. As a comparison, 10% of patients on the cyclosporine control regimen had the event at the end of 1 year and 3 years.
Of the 372 patients with immunogenicity assessment before receiving belatacept, 29 tested positive for anti-belatacept antibodies; 13 of these patients had antibodies to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Anti-belatacept antibody titers did not increase during treatment in these 29 patients. Samples from 6 patients with confirmed binding activity to the modified CTLA-4 region of the belatacept molecule were assessed by an in vitro bioassay for the presence of neutralizing antibodies. Three of these 6 patients tested positive for neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. The clinical impact of anti-belatacept antibodies including neutralizing anti-belatacept antibodies could not be determined in the studies. During treatment with the belatacept recommended regimen, 2% of the 401 patients had antibody formation, and the median titer by dilution method was 8 (range, 5 to 80). Anti-belatacept antibody development was not associated with altered clearance of belatacept. One of 56 patients who tested negative for antibodies during treatment tested antibody positive when checked approximately 7 half-lives after belatacept discontinuation.
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.
The safety and efficacy of belatacept in neonates, infants, children, or adolescents have not been established. The potential concern for autoimmunity in neonates also applies to pediatric use, as T cell development continues into the teenage years.
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.
Use of belatacept in liver transplant patients is not recommended because of a higher risk of mortality and graft loss seen in these patients.
Coadministration (at the same time or nearly the same time) of belatacept and antithymocyte immune globulin in patients with thromboembolic disease or other predisposing risk factors for venous thrombosis of the renal allograft may pose a risk for venous thrombosis of the renal allograft. In postmarketing experience, venous thrombosis of the renal allograft has occurred in patients with other predisposing risk factors for venous thrombosis of the renal allograft when the initial doses of antithymocyte immune globulin and belatacept were coadministered as immunosuppressive induction.
Vaccination with live vaccines should be avoided due to immunosuppression during belatacept therapy.
Conversion of stable kidney transplant recipients from a calcineurin inhibitor-based maintenance therapy to a belatacept-based maintenance therapy is not recommended unless the patient is calcineurin inhibitor intolerant due to increased risk of acute rejection. There is an increased risk of acute organ rejection in kidney transplant patients converted from a calcineurin inhibitor-based maintenance regimen to a belatacept-based regimen. In 2 clinical studies, higher rates of rejection were observed among kidney transplant recipients at least 6 months post-transplant and stable on a calcineurin inhibitor-based regimen who were converted to a belatacept-based regimen compared to patients who continued their calcineurin inhibitor-based regimen. Acute organ rejection occurred mainly during the first year post-conversion.
For kidney transplant rejection prophylaxis in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids:
NOTE: 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.
Intravenous dosage:
Adults who are Epstein-Barr virus seropositive: 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.
Maximum Dosage Limits:
-Adults
10 mg/kg/dose IV for first 6 doses then 5 mg/kg/dose IV.
-Geriatric
10 mg/kg/dose IV for first 6 doses then 5 mg/kg/dose IV.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
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.
Chikungunya 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.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure 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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
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.
-Route-Specific Pharmacokinetics
Intravenous Route
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.
-Special Populations
Hepatic Impairment
Hepatic function measured by albumin did not affect the clearance of belatacept.
Renal Impairment
Renal function as measured by calculated glomerular filtration rate (GFR) did not affect the clearance of belatacept. Also, concomitant dialysis did not affect the clearance of belatacept.
Geriatric
Age did not affect the clearance of belatacept.
Gender Differences
Gender did not affect the clearance of belatacept.
Ethnic Differences
Race did not affect the clearance of belatacept.
Obesity
A trend toward higher clearance of belatacept with increasing body weight was noted among kidney transplant patients; all belatacept doses are based on the patient's actual body weight on the transplantation day unless the patient's weight varies by more than 10%.