Belatacept

Dosage Forms

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

Solution Reconstituted, Intravenous:

Nulojix: 250 mg (1 ea)

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss: 0.11 L/kg (transplant patients)

Half-Life Elimination

~10 days (healthy patients and kidney transplant patients)

Use in Specific Populations

Special Populations Note

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

Use: Labeled Indications

Kidney transplant (de novo use): 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.

Use: Off Label

Lung transplant, prophylaxis of organ rejectionc

Data from a limited number of patients studied (case study of 8 lung transplant recipients) with renal dysfunction post-transplant suggest that belatacept for maintenance immunosuppression may be beneficial to reduce calcineurin inhibitor dose and prevent rejection while preserving renal function after lung transplantation. Additional data may be necessary to further define the role of belatacept in lung transplant recipients. Timofte 2016.

Contraindications

Transplant patients who are Epstein-Barr virus (EBV) seronegative or with unknown EBV serostatus due to increased risk for posttransplant lymphoproliferative disorder (PTLD).

Dosage and Administration

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

Conversion from calcineurin inhibitor (off-label dosing) (Grinyo 2012; Grinyo 2016; Rostaing 2011): IV:

Initial phase: 5 mg/kg on transition days 1, 15, 29, 43, and 57

Maintenance phase: 5 mg/kg every 4 weeks beginning 4 weeks after completion of the initial phase. Note: Taper calcineurin inhibitor dose slowly over 1 month (no reduction on day 1, 40% to 60% reduction on day 15, 70% to 80% reduction on day 23; discontinue on day 29 and beyond).

Lung transplant, prophylaxis of organ rejection (off-label use): IV:

Initial phase: 10 mg/kg on days 0 and 4, and again at weeks 2 and 4 (Timofte 2016)

Maintenance phase (for chronic treatment patients only): 10 mg/kg every month beginning 4 weeks after completion of the initial phase (Timofte 2016)

Dosing: Geriatric

Refer to adult dosing.

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

IV: 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.

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 in NS or D5W 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

Antithymocyte Globulin (Equine): May enhance the adverse/toxic effect of Belatacept. Specifically, the risk for venous thrombosis of the renal allograft may be increased. Management: A 12-hour interval between administration of these 2 agents is suggested if these agents are to be used concomitantly. Consider therapy modification

Antithymocyte Globulin (Rabbit): May enhance the adverse/toxic effect of Belatacept. Specifically, the risk for venous thrombosis of the renal allograft may be increased. Management: A 12-hour interval between administration of these 2 agents is suggested if these agents are to be used concomitantly. Consider therapy modification

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. 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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Incidences reported as part of a combination therapy regimen.

>10%:

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

Central nervous system: 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: Infection (72% to 82%, serious infection 24% to 36%), fungal infection (18%), herpes virus infection (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), graft complications (renal: 25%), hematuria (16%), increased serum creatinine (15%)

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

Miscellaneous: Fever (28%)

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%; including aphthous stomatitis), 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 infection (3% to 4%)

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

Renal: Acute renal failure (<10%), hydronephrosis (<10%), kidney transplant dysfunction (chronic allograft nephropathy: <10%), renal disease (renal artery stenosis: <10%), renal insufficiency (<10%), renal tubular necrosis (9%)

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

Miscellaneous: Infusion related reaction (5%)

<1%, postmarketing, and/or case reports: Anaphylaxis, aspergillosis (cerebral; higher dosing regimen), encephalitis (Chagas, West Nile; higher dosing regimen), graft rejection (renal), lymphoproliferative disorder (post transplant; incidence is 9-fold higher in non-EBV seropositive patients), meningitis (cryptococcal), nephropathy (polyoma virus-associated mainly BK), progressive multifocal leukoencephalopathy (higher dosing regimen)

Warnings/Precautions

Concerns related to adverse effects:

• Infections: [US 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 jirovecii 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: [US 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: [US 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:

• Coadministration with anti-thymocyte globulin: In postmarketing reports, venous thrombosis of the renal allograft has occurred in de novo kidney transplant patients, some with other predisposing venous thrombosis risk factors, when the initial anti-thymocyte globulin dose was coadministered (at the same or nearly the same time) with belatacept; if administering anti-thymocyte globulin or any other cell-depleting induction therapy concomitantly with belatacept, separate the dosing by 12 hours. Use with caution in these patients as concurrent administration may increase renal allograft venous thrombosis risk.
• 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: [US 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: [US 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

Monitor for new-onset or worsening neurological, cognitive, or behavioral signs/symptoms; signs/symptoms of infection or malignancy; gastrointestinal side effects (eg, nausea, vomiting, diarrhea); TB screening prior to therapy initiation; EBV serostatus verification prior to therapy initiation (only use belatacept in seropositive patients); potassium, magnesium.

Pregnancy

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

The Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or www.transplantpregnancyregistry.org.

Patient Education

What is this drug used for?

• It is used after a kidney transplant to keep the body from rejecting the kidney.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Constipation
• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Joint pain
• Anxiety
• Tremors
• Back pain
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Infection
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Mood changes
• Behavioral changes
• Severe loss of strength and energy
• Shortness of breath
• Swelling of arms or legs
• Excessive weight loss
• Night sweats
• Persistent fever
• Swollen glands
• Mole changes
• Skin growths
• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, mood changes, behavioral changes, change in strength on one side is greater than the other, trouble speaking, change in balance, or vision changes.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.