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Nulojix

Generic Name: Belatacept
Class: Immunosuppressive Agents
VA Class: IM600
Chemical Name: CTLA-4 (antigen) [29-tyrosine,104-glutamic acid] (human extracellular domain-containing fragment) fusion protein with immunoglobulin G1 (human monoclonal Fc domain-containing fragment) bimol. (120→120′)-disulfide
Molecular Formula: C3508H5440N922O1096S32
CAS Number: 706808-37-9

Warning(s)

  • Posttransplant Lymphoproliferative Disorder (PTLD)
  • Increased risk of developing PTLD, predominantly involving the CNS.1 Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; use only in EBV-seropositive patients.1 Contraindicated in patients who are EBV seronegative or with unknown EBV serostatus.1 (See Cautions.)

  • Management of Immunosuppression
  • Only clinicians experienced in immunosuppressive therapy and management of renal transplant patients should prescribe belatacept.1

  • Other Malignancies and Serious Infections
  • Immunosuppression may result in increased susceptibility to infection and possible development of malignancies.1

  • Use in Liver Transplantation
  • Use in liver transplant patients is not recommended because of an increased risk of graft loss and death.1 (See Use in Liver Transplantation under Cautions.)

Introduction

Immunosuppressive agent; recombinant fusion protein and selective T-cell costimulation blocker.1 4 5 7 8 9 10 11 12 14

Uses for Nulojix

Renal Allotransplantation

Prevention of renal allograft rejection in adults1 4 5 7 8 9 10 11 12 (designated an orphan drug by FDA for this use2

Use only in EBV-seropositive patients.1 (See Boxed Warning and also see PTLD under Cautions.)

Manufacturer recommends use in conjunction with basiliximab induction, mycophenolate mofetil, and corticosteroids.1

Transplantation of Other Solid Organs

Use in preventing organ rejection in transplanted solid organs other than kidney not established.1

Has been used for prevention of rejection of liver allografts; however, manufacturer states use in liver transplant patients is not recommended because of an increased risk of graft loss and death.1 (See Use in Liver Transplantation under Cautions.)

Nulojix Dosage and Administration

General

  • Premedication not required prior to administration.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.1

Administer only by IV infusion.1

Must reconstitute and dilute belatacept lyophilized powder prior to administration.1 Complete IV infusion within 24 hours of reconstitution.1

Administer with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (pore diameter of 0.2–1.2 mcm).1

Do not infuse other drugs simultaneously in the same IV line.1

Consult manufacturer’s labeling for additional information on reconstitution, dilution, and administration.1

Reconstitution

Use only the silicone-free disposable syringe provided with each vial to reconstitute the drug.1 If accidentally reconstituted using a different syringe, translucent particles may develop in the solution; discard any solution prepared using siliconized syringes.1

Reconstitute the appropriate number of vials containing 250 mg of belatacept lyophilized powder by adding 10.5 mL of sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection to produce a solution containing 25 mg/mL.1

Direct diluent toward side of vial; rotate vial and invert with gentle swirling to minimize foaming.1 Avoid prolonged and vigorous agitation of the vial and do not shake.1

Must be diluted further before IV infusion.1

Dilution

To further dilute belatacept, use 0.9% sodium chloride injection (if reconstituted with sterile water for injection or 0.9% sodium chloride injection) or 5% dextrose injection (if reconstituted with sterile water for injection or 5% dextrose injection).1

Withdraw a volume of infusion fluid equal to the required volume of reconstituted belatacept solution from an appropriately sized infusion container.1

Using same silicone-free disposable syringe used for reconstitution, inject the required volume of reconstituted belatacept solution into the infusion container; gently rotate infusion container to ensure mixing.1

Final belatacept concentration should range from 2–10 mg/mL.1 Infusion volume of 100 mL is appropriate for most patients and doses, but infusion volumes of 50–250 mL may be used.1

Rate of Administration

Infuse over 30 minutes.1

Dosage

Base total infusion dose on actual body weight at the time of transplantation; do not modify during the course of therapy unless body weight changes by >10%.1

To be prepared accurately, prescribed dose must be evenly divisible by 12.5 mg.1

Adults

Renal Allotransplantation
Prevention of Allograft Rejection
IV

Initial phase: 10 mg/kg on day of transplantation (prior to implantation, day 1), day 5 (approximately 96 hours after day 1 dose), and at the end of weeks 2, 4, 8, and 12 after transplantation.1

Maintenance phase: 5 mg/kg at the end of week 16 after transplantation and then every 4 weeks (plus or minus 3 days) thereafter.1

Prescribing Limits

Adults

Renal Allotransplantation
Prevention of Allograft Rejection
IV

Higher than recommended doses or more frequent administration not recommended because of increased risk of PTLD predominantly involving the CNS, progressive multifocal leukoencephalopathy (PML), and serious CNS infections.1 (See Cautions.)

Special Populations

Manufacturer currently makes no special population dosage recommendations.1 In pharmacokinetic studies in kidney transplant recipients, age, gender, race, renal function, hemodialysis, and hepatic function did not affect clearance of belatacept.1 6 16

Cautions for Nulojix

Contraindications

  • EBV seronegative or unknown EBV serostatus. (See PTLD under Cautions.)

Warnings/Precautions

Warnings

PTLD

Increased risk of developing PTLD, predominantly CNS PTLD, compared with patients receiving a cyclosporine-based regimen.1 4 5 7 11 13 Consider possibility of PTLD in patients experiencing new or worsening neurologic, cognitive, or behavioral signs and symptoms (see Advice to Patients).1

Risk factors for PTLD include total burden of immunosuppression,1 13 EBV-seronegative status,1 4 7 cytomegalovirus (CMV) infection,1 and T-cell-depleting therapy.1

Possible increased risk of PTLD in patients who are EBV seropositive and CMV seronegative compared with those who are EBV seropositive and CMV seropositive.1 CMV-seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD); clinical importance of CMV serology for PTLD not determined.1 Consider these findings when prescribing belatacept.1

Use of higher than recommended doses or more frequent dosing of belatacept and higher than recommended doses of concomitant immunosuppressive agents not recommended.1 13

Determine EBV serology before initiating treatment; use belatacept only in EBV-seropositive patients.1 7

Use T-cell-depleting therapies (e.g., antithymocyte globulin) to treat acute rejection with caution.1 17

CMV prophylaxis is recommended for at least 3 months after transplantation.1

Management of Immunosuppression

Only clinicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe belatacept.1

Patients should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources.1

Clinician responsible for maintenance therapy should have complete information requisite for patient follow-up.1

Other Malignancies

Increased risk of developing malignancies in addition to PTLD, including skin cancer, in patients receiving immunosuppressants, including belatacept.1 Limit exposure to sunlight and UV light.1

PML

PML, an opportunistic infection of the brain caused by the polyomavirus JC (also called the JC virus) that is sometimes fatal, reported in patients treated with immunosuppressive agents, including belatacept.1 18 19 20 21 22 23 Associated with high levels of overall immunosuppression and impairment of immune function.1 18 19 20 21 22 23 24 Do not exceed recommended dose and frequency of belatacept and concomitant immunosuppressives, including mycophenolate mofetil.1

Consider PML in differential diagnosis of patients with new or worsening neurologic, cognitive, or behavioral signs or symptoms.1 Consider consultation with a specialist (e.g., neurologist and/or infectious disease) in any suspected or confirmed case of PML.1

If PML is diagnosed, consider reduction or withdrawal of immunosuppression taking into account the risk to the renal allograft.1 18 23 Optimal pharmacologic treatment not established to date; antiviral agents (e.g., cidofovir) have been successfully used in several cases of PML.18 23 Early diagnosis and rapid initiation of treatment are essential.18 23

Other Serious Infections

Increased risk of developing bacterial, viral (e.g., CMV, herpes), fungal, and protozoal infections, including opportunistic infections,1 25 with potentially serious or fatal outcomes.1 25 Prophylaxis for CMV recommended for at least 3 months after transplantation.1 Prophylaxis for Pneumocystis jiroveci also recommended after transplantation.1

Tuberculosis observed more frequently in belatacept-treated patients than in those receiving cyclosporine in clinical trials.1 13 Evaluate patients for tuberculosis and test for latent infection prior to initiating therapy.1 Initiate treatment for latent tuberculosis infection prior to belatacept administration.1

Cases of polyoma virus-associated nephropathy (PVAN), mainly due to BK virus infection, reported.1 8 13 PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss.1 Patient monitoring may help detect patients at risk for PVAN.1 Decreasing total immunosuppression may improve outcome, but also may increase the risk of graft rejection.1

Use in Liver Transplantation

Use of belatacept in combination with mycophenolate mofetil and corticosteroids associated with a higher rate of mortality and graft loss in liver transplant patients compared with the tacrolimus control arms.1 In addition, 2 cases (one fatal) of PTLD involving the liver allograft and one fatal case of PML reported in the 147 patients randomized to belatacept.1

Use of belatacept in liver transplant patients is not recommended by manufacturer.1 (See PTLD and also see PML under Cautions.)

General Precautions

Immunizations

Avoid live vaccines (e.g., influenza virus vaccine live intranasal, measles virus vaccine live, mumps virus vaccine live, rubella virus vaccine live, poliovirus vaccine live oral [OPV; no longer commercially available in the US], BCG vaccine, yellow fever vaccine, varicella virus vaccine live, typhoid vaccine live oral) during belatacept therapy.1 (See Vaccines under Interactions.)

Specific Populations

Pregnancy

Category C.1

National Transplantation Pregnancy Registry (NTPR) at 877-955-6877 or .1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No overall differences in safety or efficacy relative to younger adults, but increased sensitivity or reduced efficacy cannot be ruled out.1

In population pharmacokinetic analyses, patient age did not affect belatacept clearance.1 16

Hepatic Impairment

In population pharmacokinetic analyses, hepatic function (measured by albumin concentrations) did not affect belatacept clearance.1 16

Renal Impairment

In population pharmacokinetic analyses, renal function (measured by calculated GFR) and concurrent hemodialysis did not affect belatacept clearance.1 6 16

Common Adverse Effects

Anemia,1 4 5 diarrhea,1 4 5 8 urinary tract infection,1 4 8 peripheral edema,1 4 constipation,1 4 5 hypertension,1 4 pyrexia,1 graft dysfunction,1 5 cough,1 nausea,1 vomiting,1 headache,1 hypokalemia,1 hyperkalemia,1 leukopenia.1

Interactions for Nulojix

No formal drug interaction studies to date.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibits production of certain cytokines during an autoimmune response in vitro.1 Other biologic therapies (e.g., cytokines, cytokine modulators) affect the expression and/or functional activities of CYP enzymes in vitro and/or in vivo.1

Consider potentially altered CYP metabolism in patients exhibiting signs and symptoms of altered efficacy or adverse events associated with concurrently administered CYP-substrate drugs.1

Immunosuppressive Agents

Increased susceptibility to infection, increased risk of malignancies, and some other adverse effects (e.g., PTLD, PML).1 (See Cautions.)

T-cell-depleting agents used in the treatment of acute rejection: Use concomitantly with caution.1 17 (See Cautions.)

Vaccines

Potential for decreased response to vaccination.1

Avoid concomitant use of live vaccines (see Immunizations under Cautions).1

Specific Drugs

Drug

Interaction

Comments

Antithymocyte globulin

Increased risk of serious adverse effects (e.g., PTLD, PML), infections, and malignancies1 15

Use concomitantly with caution1 17

Mycophenolate mofetil

Increased peak plasma concentrations and exposure of mycophenolic acid (MPA)

Consider potential change in MPA exposure when switching from cyclosporine to belatacept and vice versa

Nulojix Pharmacokinetics

Absorption

Following the recommended dosage regimen consisting of multiple IV infusions, steady-state serum concentrations reached by 8 weeks in the initial phase following transplantation and by 6 months during the maintenance phase.1

Following once-monthly IV infusion of 10 and 5 mg/kg, systemic accumulation of approximately 20 and 10%, respectively, observed in kidney transplant recipients.1

Distribution

Extent

Crosses the placenta in animals.1

Distributed into milk in animals; not known whether belatacept distributes into human milk.1

Elimination

Half-life

Terminal half-life averages 9.8 days following single-dose administration in healthy individuals.1

Terminal half-life averages 8.2 and 9.8 days following multiple-dose administration of 5 and 10 mg/kg, respectively, in renal transplant recipients.1

Special Populations

In population pharmacokinetic analyses, trend toward higher clearance with increasing body weight; age, gender, race, renal function, hemodialysis, hepatic function, and diabetes did not affect clearance.1 6 16

Stability

Storage

Parenteral

Powder for Injection

2–8°C in the original package; protect from light.1

Store fully diluted solution at 2–8°C; protect from light.1 Infusion of diluted solution must be completed within 24 hours of reconstitution; a maximum of 4 hours of the total 24 hours may be at 20–25°C and room light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water1

Sodium chloride 0.9%1

Actions

  • Consists of the modified extracellular domain of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 fused to a portion of the Fc domain of human IgG1.1

  • Structurally and pharmacologically related to abatacept, but binds CD80 and CD86 more avidly than does abatacept.1 12

  • Binds to CD80 and CD86 on antigen-presenting cells thereby blocking CD28-mediated costimulation of T lymphocytes.1 6

  • In vitro, inhibits T-lymphocyte proliferation and production of interleukin-2, interferon-γ, interleukin-4, and tumor necrosis factor-α (TNF-α).1 6 Activated T lymphocytes are the principal mediators of immunologic rejection.1

  • In nonhuman primate models of renal transplantation, belatacept monotherapy prolonged graft survival and decreased production of antidonor antibodies.1

Advice to Patients

  • Importance of providing copy of manufacturer's patient information (medication guide) each time belatacept is dispensed, and importance of reading this information before beginning therapy with the drug and before each treatment.1 (See REMS.)

  • Increased risk of PTLD, especially CNS PTLD, and PML.1 Instruct patients to immediately report any neurologic, cognitive, or behavioral signs and symptoms (e.g., changes in mood or usual behavior; confusion, problems thinking, loss of memory; changes in walking or talking; decreased strength or weakness on one side of the body; changes in vision) occurring during or after belatacept therapy.1

  • Increased risk of malignancies in addition to PTLD (e.g., skin cancer) in patients receiving immunosuppressive therapy.1 Importance of limiting exposure to sunlight and other UV light by wearing protective clothing and using sunscreens with a high protection factor.1 Instruct patients to watch for any signs or symptoms of skin cancer (e.g., suspicious moles or lesions).1

  • Increased risk of infection in patients receiving immunosuppressive therapy; importance of taking antimicrobial prophylaxis regimens as prescribed.1 Instruct patients to immediately report any signs and symptoms of infection.1

  • Importance of informing patients that vaccinations may be less effective while receiving belatacept.1 Importance of avoiding live vaccines during therapy.1

  • Importance of informing patients that belatacept has not been studied in pregnant or nursing women, and that the effects of the drug on pregnant women or nursing infants are not known.1 Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 Importance of encouraging enrollment of pregnant women in the National Transplantation Pregnancy Registry (see Pregnancy under Cautions).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., immunizations) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Belatacept

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion only

250 mg

Nulojix (available in single-use vials with a silicone-free disposable syringe)

Bristol-Myers Squibb

AHFS DI Essentials. © Copyright 2016, Selected Revisions January 7, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb Company. Nulojix (belatacept) for injection prescribing information. Princeton, NJ; 2011 Jun.

2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA web site. Accessed 2012 Oct 9.

3. Nulojix (belatacept) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2011 Sept 8.

4. Vincenti F, Charpentier B, Vanrenterghem Y et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010; 10:535-46. [PubMed 20415897]

5. Durrbach A, Pestana JM, Pearson T et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010; 10:547-57. [PubMed 20415898]

6. Martin ST, Tichy EM, Gabardi S. Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. Pharmacotherapy. 2011; 31:394-407. [PubMed 21449628]

7. Larsen CP, Grinyó J, Medina-Pestana J et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation. 2010; 90:1528-35. [PubMed 21076381]

8. Vincenti F, Blancho G, Durrbach A et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol. 2010; 21:1587-96. [PubMed 20634298]

9. Rostaing L, Massari P, Garcia VD et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol. 2011; 6:430-9. [PubMed 21051752]

10. Ferguson R, Grinyó J, Vincenti F et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. 2011; 11:66-76. [PubMed 21114656]

11. Vincenti F, Larsen C, Durrbach A et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005; 353:770-81. [PubMed 16120857]

12. Larsen CP, Pearson TC, Adams AB et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005; 5:443-53. [PubMed 15707398]

13. Grinyó J, Charpentier B, Pestana JM et al. An integrated safety profile analysis of belatacept in kidney transplant recipients. Transplantation. 2010; 90:1521-7. [PubMed 21088650]

14. Anon. Belatacept (Nulojix) for prevention of renal transplant rejection. Med Lett Drugs Ther. 2011; 53:98-9.

15. Bremer S, Vethe NT, Rootwelt H et al. Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. j Transl Med. 2009; 7:64. [PubMed 19635156]

16. Zhou Z, Shen J, Hong Y et al. Time-varying belatacept exposure and its relationship to efficacy/safety responses in kidney-transplant recipients. Clin Pharmacol Ther. 2012; 92:251-7. [PubMed 22760001]

17. Simpson D. T-cell depleting antibodies: new hope for induction of allograft tolerance in bone marrow transplantation?. BioDrugs. 2003; 17:147-54. [PubMed 12749751]

18. McCalmont V, Bennett K. Progressive multifocal leukoencephalopathy: a case study. Prog Transplant. 2007; 17:157-60. [PubMed 17624139]

19. Waggoner J, Martinu T, Palmer SM. Progressive multifocal leukoencephalopathy following heightened immunosuppression after lung transplant. J Heart Lung Transplant. 2009; 28:395-8. [PubMed 19332268]

20. Crowder CD, Gyure KA, Drachenberg CB et al. Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant. 2005; 5:1151-8. [PubMed 15816900]

21. Boulton-Jones JR, Fraser-Moodie C, Ryder SD. Long term survival from progressive multifocal leucoencephalopathy after liver transplantation. J Hepatol. 2001; 35:828-9. [PubMed 11738115]

22. Kharfan-Dabaja MA, Ayala E, Greene J et al. Two cases of progressive multifocal leukoencephalopathy after allogenic hematopoietic cell transplantation and a review of the literature. Bone Marrow Transplant. 2007; 39:101-7. [PubMed 17143300]

23. Shitrit D, Lev N, Bar-Gil-Shitrit A et al. Progressive multifocal leukoencephalopathy in transplant recipients. Transpl Int. 2005; 17:658-65. [PubMed 15616809]

24. Manfro RC, Vedolin L, Cantarelli M et al. Progressive multifocal leukoencephalopathy in a kidney transplant recipient after conversion to mycophenolic acid therapy. Transpl Infect Dis. 2009; 11:189-90. [PubMed 19210690]

25. Haidinger M, Hecking M, Memarsadeghi M et al. Late onset Pneumocystis pneumonia in renal transplantation after long-term immunosuppression with belatacept. Transpl Infect Dis. 2009; 11:171-4. [PubMed 19210692]

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