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Belatacept

Pronunciation

(bel AT a sept)

Index Terms

  • BMS-224818
  • LEA29Y

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Nulojix: 250 mg (1 ea)

Brand Names: U.S.

  • Nulojix

Pharmacologic Category

  • Selective T-Cell Costimulation Blocker

Pharmacology

Fusion protein which acts as a selective T-cell (lymphocyte) costimulation blocker by binding to CD80 and CD86 receptors on antigen presenting cells (APC), blocking the required CD28 mediated interaction between APCs and T cells needed to activate T lymphocytes. T-cell stimulation results in cytokine production and proliferation, mediators in immunologic rejection associated with kidney transplantation.

Distribution

Vss: 0.11 L/kg (transplant patients)

Half-Life Elimination

~10 days (healthy patients and kidney transplant patients)

Special Populations Note

Body weight: Higher clearance of belatacept may be seen with increasing body weight.

Use: Labeled Indications

Kidney transplant: Prophylaxis of organ rejection concomitantly with basiliximab induction, mycophenolate, and corticosteroids in adult Epstein-Barr virus (EBV) seropositive kidney transplant recipients

Limitations of use: Use only in EBV seropositive patients; use for prophylaxis of organ rejection in transplanted organs other than the kidney has not been established.

Contraindications

Transplant patients who are Epstein-Barr virus (EBV) seronegative or with unknown EBV serostatus

Dosing: Adult

Note: Dosing is based on actual body weight at the time of transplantation; do not modify weight-based dosing during course of therapy unless the change in body weight is >10%. The prescribed dose must be evenly divisible by 12.5 mg to allow accurate preparation of the reconstituted solution using the provided required disposable syringe for preparation. For example, the calculated dose for a 64 kg patient: 64 kg x 10 mg per kg = 640 mg. The nearest doses to 640 mg that are evenly divisible by 12.5 mg would be 637.5 mg or 650 mg; the closest dose to the calculated dose is 637.5 mg, therefore, 637.5 should be the actual prescribed dose for the patient.

Kidney transplant, prophylaxis of organ rejection: IV: Note: Use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids.

Initial phase: 10 mg/kg on Day 1 (day of transplant, prior to implantation) and on Day 5 (~96 hours after Day 1 dose), followed by 10 mg/kg at the end of Week 2, Week 4, Week 8, and Week 12 following transplantation

Maintenance phase: 5 mg/kg every 4 weeks (plus or minus 3 days) beginning at the end of Week 16 following transplantation

Dosing: Geriatric

Refer to adult dosing

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, renal function did not affect clearance in pharmacokinetic studies of kidney transplant patients.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, hepatic function did not affect clearance in pharmacokinetic studies of kidney transplant patients.

Reconstitution

Reconstitute each vial with 10.5 mL of diluent (SWFI, NS, or D5W only) using the provided silicone-free disposable syringe, and an 18- to 21-gauge needle. Reconstitute using only the silicone-free syringe provided; if the provided silicone-free syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory (contact the manufacturer on obtaining additional silicone-free disposable syringes). If powder is inadvertently mixed using a siliconized syringe, discard solution; translucent particles may develop. Inject the diluent down the side of the vial to avoid foaming. Rotate the vial and invert with gentle swirling until completely dissolved; do not shake vial. Immediately transfer the reconstituted solution using the same silicone-free syringe to an infusion bag or bottle with NS or D5W (if NS or D5W were used to reconstitute, the same fluid should be used to further dilute). Gently rotate the infusion bag or bottle; do not shake. The final concentration should range from 2 mg/mL and 10 mg/mL (typical infusion volume is 100 mL; volumes ranging from 50 mL to 250 mL may be used). Prior to adding belatacept to the infusion solution, the manufacturer recommends withdrawing a volume equal to the amount of belatacept to be added.

Administration

Administer as an IV infusion over 30 minutes using an infusion set with a 0.2 to 1.2 micron low protein-binding filter. The infusion must be completed within 24 hours of reconstitution of the lyophilized powder. Infuse in a separate line from other infused agents.

Compatibility

Stable in SWFI, NS, D5W

Storage

Prior to use, store refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. After dilution, the reconstituted solution should be transferred from the vial to infusion bag or bottle immediately; infusion solution may be stored refrigerated for up to 24 hours, with a maximum of 4 hours of the 24 hours at room temperature, 20°C to 25°C (68°F to 77°F), and room light. Infusion must be completed within 24 hours of reconstitution. Discard unused solution in vials.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Belatacept may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Incidences reported occurred during clinical trials using belatacept compared to a cyclosporine control regimen. All patients also received basiliximab induction, mycophenolate mofetil, and corticosteroids, and were followed up to 3 years.

>10%:

Cardiovascular: Peripheral edema (34%), hypertension (32%), hypotension (18%)

Central nervous system: Fever (28%), headache (21%), insomnia (15%)

Endocrine & metabolic: Hypokalemia (21%), hyperkalemia (20%), hypophosphatemia (19%), lipid metabolism disorder (19%), hyperglycemia (16%), hypocalcemia (13%), hypercholesterolemia (11%)

Gastrointestinal: Diarrhea (39%), constipation (33%), nausea (24%), vomiting (22%), abdominal pain (19%)

Genitourinary: Urinary tract infection (37%), dysuria (11%)

Hematologic & oncologic: Anemia (45%), leukopenia (20%)

Infection: Increased susceptibility to infection (72% to 82%, serious infection 24% to 36%), herpes (7% to 14%), cytomegalovirus disease (11% to 13%), influenza (11%)

Neuromuscular & skeletal: Arthralgia (17%), back pain (13%)

Renal: Proteinuria (16%; up to 33% 2+ proteinuria at 1 month post-transplant), renal graft dysfunction (25%), hematuria (16%), increased serum creatinine (15%)

Respiratory: Cough (24%), upper respiratory tract infection (15%), nasopharyngitis (13%), dyspnea (12%)

1% to 10%:

Cardiovascular: Arteriovenous fistula site complication (thrombosis, <10%), atrial fibrillation (<10%)

Central nervous system: Anxiety (10%), Guillain-Barré syndrome (<10%), dizziness (9%)

Dermatologic: Alopecia (<10%), hyperhidrosis (<10%), acne vulgaris (8%)

Endocrine & metabolic: Diabetes mellitus (new onset, 5% to 8%), hypomagnesemia (7%), hyperuricemia (5%)

Gastrointestinal: Stomatitis (<10%), upper abdominal pain (9%)

Genitourinary: Urinary incontinence (<10%)

Hematologic & oncologic: Hematoma (<10%), lymphocele (<10%), neutropenia (<10%), malignant neoplasm (4%), malignant neoplasm of skin (nonmelanoma, 2%)

Immunologic: Antibody development (2%)

Infection: Polyoma virus (3% to 4%)

Neuromuscular & skeletal: Musculoskeletal pain (<10%), tremor (8%)

Renal: Acute renal failure (<10%), chronic allograft nephropathy (<10%), hydronephrosis (<10%), renal insufficiency (<10%), renal artery stenosis (<10%), renal tubular necrosis (9%), renal disease (BK virus-associated, 1%)

Respiratory: Bronchitis (10%), tuberculosis (1% to 2%)

Miscellaneous: Infusion related reaction (5%)

<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Aspergillosis (cerebral; higher dosing regimen), encephalitis (Chagas, West Nile; higher dosing regimen), lymphoproliferative disorder (post-transplant; incidence is 9-fold higher in non-EBV seropositive patients), meningitis (cryptococcal), progressive multifocal leukoencephalopathy (higher dosing regimen), renal graft rejection

ALERT: U.S. Boxed Warning

Posttransplant lymphoproliferative disorder, other malignancies, and serious infections:

Increased risk for developing posttransplant lymphoproliferative disorder, predominantly involving the CNS. Recipients without immunity to Epstein-Barr virus are at a particularly increased risk; therefore, use in Epstein-Barr virus–seropositive patients only. Do not use belatacept in transplant recipients who are Epstein-Barr virus seronegative or with unknown Epstein-Barr virus serostatus.

Only health care providers experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe belatacept. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider 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.

Use in liver transplant patients is not recommended because of an increased risk of graft loss and death.

Warnings/Precautions

Concerns related to adverse effects:

• Infections: [U.S. Boxed Warning]: Risk for infection is increased. Immunosuppressive therapy may lead to bacterial, viral (cytomegalovirus [CMV] and herpes), fungal, and protozoal infections, including opportunistic infections (may be fatal). Tuberculosis (TB) is increased; test patients for latent TB prior to initiation, and treat latent TB infection prior to use. Prophylaxis for cytomegalovirus (CMV) is recommended for at least 3 months after transplantation; prophylaxis for Pneumocystis jiroveci is recommended after transplantation.

• Latent viral infections: Patients receiving immunosuppressive therapy are at an increased risk of activation of latent viral infections, including John Cunningham virus (JCV) and BK virus infection. Activation of JCV may result in progressive multifocal leukoencephalopathy (PML), a rare and potentially-fatal condition affecting the CNS. Symptoms of PML include apathy, ataxia, cognitive deficiencies, confusion, and hemiparesis. Polyoma virus-associated nephropathy (PVAN), primarily from activation of BK virus, may also occur and lead to the deterioration of renal function and/or renal graft loss. Risk factors for the development of PML and PVAN include immunosuppression and treatment with immunosuppressant therapy. The onset of PML or PVAN may warrant a reduction in immunosuppressive therapy; however, in transplant recipients, the risk of reduced immunosuppression and graft rejection should be considered.

• Lymphoproliferative disorders: [U.S. Boxed Warning]: Risk of post-transplant lymphoproliferative disorder (PTLD) is increased, primarily involving the CNS, in patients receiving belatacept compared to patients receiving cyclosporine-based regimens. Degree of immunosuppression is a risk factor for PTLD developing; do not exceed recommended dosing. Patients who are Epstein-Barr virus (EBV) seronegative are at an even higher risk; use is contraindicated in patients without evidence of immunity to EBV. Cytomegalovirus (CMV) infection and T-cell depleting therapy also increases the risk for PTLD; T-cell depleting therapies to treat acute rejection should be used with caution. CMV prophylaxis is recommended for a minimum of 3 months following transplantation. Although CMV disease is a risk for PTLD and CMV seronegative patients are at an increased risk for CMV disease, the clinical role, if any, of determining CMV serology to determine risk of PTLD development has not been determined.

• Malignancy: [U.S. Boxed Warning]: Risk for malignancy is increased. Malignancy, including skin malignancy and PTLD, is associated with the use of belatacept; patients should be advised to limit their exposure to sunlight/UV light.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: [U.S. Boxed Warning]: Therapy is not recommended in liver transplant patients due to increased risk of graft loss and death.

• Corticosteroid minimization: Increased rate and grade of acute rejection, particularly grade 3 rejection, and graft loss has been observed with belatacept when corticosteroids were minimized to 5 mg daily between day 3 and week 6 post-transplant; corticosteroid dosing should be consistent with clinical trial experience (ie, tapered to ~15 mg [10 to 20 mg] daily by the first 6 weeks post-transplant and remain at ~10 mg [5 to 10 mg] daily for the first 6 months post-transplant).

• EBV serostatus: Therapy is only appropriate in patients who are EBV seropositive via evidence of acquired immunity, such as presence of IgG antibodies to viral capsid antigen [VCA] and EBV nuclear antigen [EBNA].

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of a physician experienced in immunosuppressive therapy.

• Immunizations: Immunization with live vaccines should be avoided during treatment.

Monitoring Parameters

New-onset or worsening neurological, cognitive, or behavioral signs/symptoms; signs/symptoms of infection or malignancy; TB screening prior to therapy initiation; EBV seropositive verification prior to therapy initiation

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. According to the manufacturer, do not use belatacept in pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. A pregnancy registry has been established to monitor outcomes of women exposed to belatacept during pregnancy (1-877-955-6877).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, dizziness, constipation, diarrhea, nausea, vomiting, abdominal pain, joint pain, anxiety, back pain, or insomnia. Have patient report immediately to prescriber signs of infection, signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), loss of strength and energy, shortness of breath, swelling of arm or leg, excessive weight loss, night sweats, enlarged lymph nodes, mole changes, skin growths, signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, vision changes), or signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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