belatacept (Rx)

Brand and Other Names:Nulojix
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 250mg/vial

Kidney Transplant Rejection Prophylaxis

Indicated for use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids to prevent kidney transplant rejection

Due to an increased risk of post-transplant lymphoproliferative disorder predominantly involving the central nervous system, progressive multifocal leukoencephalopathy, and serious CNS infections, administration of higher than the recommended doses or more frequent dosing is NOT recommended

Dose calculation and schedule

  • Total infusion dose based on actual body weight of patient at time of transplantation; modify dose if weight changes by >10%
  • Prescribed dose must be divisible by 12.5 mg in order to accurately prepare dose from the reconstituted solution
  • Initial phase: 10 mg/kg IV on day of transplant (prior to implantation); repeat this dose on Day 5 and at end of Weeks 2, 4, 8, and 12 after transplantation  
  • Maintenance phase: 5 mg/kg IV at end of Week 16 after transplantation and then q4Weeks (within +/- 3 days) thereafter

Dosage Modifications

Renal impairment

  • Dose adjustments may not be necessary per pharmacokinetic studies showing clearance of belatacept not affected in kidney transplant patients; not described in manufacturer's label

Hepatic impairment

  • Dose adjustments may not be necessary per pharmacokinetic studies showing clearance of belatacept not affected in kidney transplant patients; not described in manufacturer's label

Dosing Considerations

Corticosteroid utilization

  • In clinical trials the median corticosteroid doses were tapered to ~15 mg/day (10-20 mg/day) by the first 6 weeks and remained at ~10 mg/day (5-10 mg/day) for the first 6 months post-transplant
  • Corticosteroid utilization should be consistent with the clinical trial experience

Limitations of use

  • Use only in patients who are EBV seropositive
  • Use for the prophylaxis of organ rejection in transplanted organs other than kidney not been established

<18 years: Safety and efficacy not established

Because T cell development continues into the teenage years, the potential concern for autoimmunity in neonates applies to pediatric use as well

Of 401 patients treated with belatacept, 15% were 65 years of age and older, while 3% were 75 and older

No overall differences in safety or effectiveness were observed between these recipients and younger recipients, but cannot rule out greater sensitivity or less efficacy in older individuals

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Interactions

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            Adverse Effects

            ≥ 10%

            Anemia (45%)

            Diarrhea (39%)

            Urinary tract infection (37%)

            Peripheral edema (34%)

            Constipation (33%)

            Hypertension (32%)

            Pyrexia (28%)

            Graft dysfunction (25%)

            Cough (24%)

            Nausea (24%)

            Vomiting (22%)

            Headache (21%)

            Hypokalemia (21%)

            Hyperkalemia (20%)

            Leukopenia (20%)

            Dyslipidemia (19%)

            Abdominal pain (19%)

            Hypophosphatemia (19%)

            Hypotension (18%)

            Arthralgia (17%)

            Hyperglycemia (16%)

            Hematuria (16%)

            Proteinuria (16%)

            Blood creatinine increased (15%)

            Insomnia (15%)

            Upper respiratory infection (15%)

            Nasopharyngitis (13%)

            Back pain (13%)

            Hypocalcemia (13%)

            CMV infection (12%)

            Dyspnea (12%)

            Influenza (11%)

            Dysuria (11%)

            Hypercholesterolemia (11%)

            1-10%

            Anxiety (10%)

            Bronchitis (10%)

            Renal tubular necrosis (9%)

            New onset diabetes (8%)

            Acne (8%)

            Hypomagnesemia (7%)

            Hyperuricemia (5%)

            Postmarketing Reports

            Venous thrombosis of the renal allograft when belatacept and antithymocyte coadministered at the same or nearly the same time

            Anaphylaxis

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            Warnings

            Black Box Warnings

            Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS)

            Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only

            Contraindicated in transplant recipients who are EBV seronegative or with unknown EBV serostatus

            Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe

            Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources

            The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient

            Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression

            Not recommended for use in liver transplant patients because of increased risk of graft loss and death

            Contraindications

            Hypersensitivity

            Patients who are EBV seronegative or with unknown EBV serostatus (see Black Box Warnings)

            Cautions

            See Black Box Warnings

            In postmarketing experience, use in conjunction with basiliximab induction, MMF, and corticosteroid minimization to 5 mg/day between Day 3 and Week 6 post-transplant was associated with an increased rate and grade of acute rejection, particularly Grade III rejection; these Grade III rejections occurred in patients with 4 to 6 HLA mismatches; graft loss was a consequence of Grade III rejection in some patients.

            Serious infection may occur including bacterial, viral (cytomegalovirus [CMV], herpes, polyoma virus nephropathy), fungal, and protozoal infections, including opportunistic infections (eg, tuberculosis); these infections may lead to serious, including fatal, outcomes

            Tuberculosis was more frequently observed

            Cases of polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, reported

            Patients receiving immunosuppressants, including belatacept, are in increased risk for developing malignancies; advised added precautions including limiting UV exposure and wearing sunscreen

            Post-transplant lymphoproliferative disorder

            • Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen
            • As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of belatacept and higher than recommended doses of concomitant immunosuppressive agents are not recommended
            • Consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms
            • Risk of PTLD was higher in EBV seronegative patients compared to EBV seropositive patients
            • EBV seropositive patients are defined as having evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA)
            • Epstein-Barr virus serology should be ascertained before starting administration of belatacept, and only patients who are EBV seropositive should receive belatacept
            • Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive belatacept (see Black Box Warnings and Contraindications)
            • Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell depleting therapy

            Progressive multifocal leukoencephalopathy (PML)

            • PML is a rare occurrence but is a rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma virus
            • In clinical trials, 2 cases of PML were reported in patients receiving belatacept at higher cumulative doses and administered more frequently than the recommended regimen

            Drug interaction overview

            • Avoid use of live vaccines during treatment with belatacept, including but not limited to the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines
            • In postmarketing experience in de novo kidney transplant recipients, venous thrombosis of the renal allograft reported when the initial dose of antithymocyte globulin (ATG), as immunosuppressive induction, was coadministered (at the same or nearly the same time) with the first dose of belatacept; coadministration of ATG and belatacept may pose a risk for venous thrombosis of the renal allograft; if ATG (or any other cell-depleting induction treatment) and belatacept will be administered concomitantly, consider a 12-hr interval between the 2 administrations
            • Monitor mycophenolate mofetil (MMF) dosage when a patient’s therapy is switched between cyclosporine and belatacept; cyclosporine decreases mycophenolic acid (MPA) exposure by preventing enterohepatic recirculation of MPA while belatacept does not
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            Pregnancy & Lactation

            Pregnancy

            To monitor maternal-fetal outcomes of pregnant women who have received immunosuppressants, healthcare providers are strongly encouraged to register pregnant patients in the Transplant Pregnancy Registry International (TPR) by calling 1-877-955-687

            There is insufficient data with belatacept use in pregnant women to inform on drug-associated risk

            Animal data

            • Belatacept is known to cross the placenta of animals
            • Administration of belatacept to pregnant rats and rabbits during the period of organogenesis was not teratogenic at exposures approximately 16 and 19 times greater than that observed at the maximum recommended human dose (MRHD) of 10 mg/kg body weight administered over the first month of treatment, based on area under the concentration-time curve (AUC)
            • In a pre- and postnatal development study in rats, treatment-related infections in dams were associated with increased pup mortality, presumably secondary to deteriorating maternal health, at exposures 3 times higher than that observed at MRHD

            Lactation

            There are no data on the presence of belatacept in human milk or the effects of belatacept on breastfed infants or human milk production to inform risk of belatacept to an infant during lactation

            Belatacept is excreted in rat milk after IV administration, and it is possible that the drug will be present in human milk

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Monoclonal antibody; inhibits T-cell CD28 activation and proliferation by binding costimulatory ligands (CD80, CD86) of antigen presenting cells

            Inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-alpha, interleukin-4, and TNF-alpha

            Activated T lymphocytes are the predominant mediators of immunologic rejection

            Absorption

            Peak plasma concentration: 300 mcg/mL (healthy subjects [after 10mg/kg single dose); 247 mcg/mL (kidney transplant pts [after 10 mg/kg multiple doses]); 139 mcg/mL (kidney transplant pts [after 5 mg/kg multiple doses])

            AUC: 26,398 mcg•hr/mL (healthy subjects [after 10mg/kg single dose); 22,252 mcg•hr/mL(kidney transplant pts [after 10 mg/kg multiple doses]); 14,090 mcg•hr/mL (kidney transplant pts [after 5 mg/kg multiple doses])

            Distribution

            Vd: 0.09 L/kg (healthy subjects [after 10mg/kg single dose); 0.11 L/kg (kidney transplant pts [after 10 mg/kg multiple doses]); 0.12 L/kg (kidney transplant pts [after 5 mg/kg multiple doses])

            Excretion

            Half-life: 9.8 days (healthy subjects [after 10mg/kg single dose); 9.8 days (kidney transplant pts [after 10 mg/kg multiple doses]); 8.2 days (kidney transplant pts [after 5 mg/kg multiple doses])

            Clearance: 0.39 mL/hr/kg (healthy subjects [after 10mg/kg single dose); 0.49 mL/hr/kg (kidney transplant pts [after 10 mg/kg multiple doses]); 0.51 mL/hr/kg (kidney transplant pts [after 5 mg/kg multiple doses])

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            Administration

            IV Compatibilities

            D5W or NS

            IV Preparation

            Reconstitution

            • Reconstitute each vial with 10.5 mL of diluent (ie, sterile water for injection [SWFI], 0.9% NaCl, D5W)
            • Use a silicone-free syringe only during preparation; if siliconized syringe is used, solution may develop a few translucent particles and therefore should be discarded
            • Direct the stream of diluent to the wall of vial to minimize foam formation
            • To minimize foam formation, rotate vial and invert with gentle swirling until the contents are completely dissolved
            • DO NOT SHAKE vial and avoid prolonged or vigorous agitation
            • Reconstituted solution contains concentration of 25 mg/mL and should be clear to slightly opalescent and colorless to pale yellow; do not use if opaque particles, discoloration, or other foreign particles are present

            Dilution

            • Transfer reconstituted vials to an infusion bag or bottle immediately
            • Calculate total volume required (refer to prescribing information) for injection
            • Using the same silicone-free disposable syringe used for reconstitution, withdraw required amount of belatacept solution from the vial
            • Infusion bag
              • Reconstituted with SWFI: Further dilute with either 0.9% NaCl or D5W
              • Reconstituted with 0.9% NaCl or D5W: Further dilute with the same diluent used to reconstitute the vial with
              • Inject reconstituted drug into appropriate infusion container, and gently rotate infusion container to ensure mixing (final concentration: 2-10 mg/mL)
              • Discard any unused solution remaining in the vials

            IV Administration

            Visually inspect for particulate matter and discoloration prior to administration

            Discard the infusion if any particulate matter or discoloration is observed

            Administer over 30 minutes and must be administered with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 microns)

            Infuse in a separate IV line from other concomitantly infused agents and should not be infused concomitantly in the same intravenous line with other agents

            Storage

            Unused vials: Refrigerate at 2-8ºC (36-46ºF) and protected from light

            Reconstituted vials: Refrigerate at 2-8ºC (36-46ºF) and protected from light for up to 24 hr

            Infusion must be completed within 24 hr of reconstitution of the lyophilized powder

            Reconstituted solutions: Refrigerate at 2-8ºC (36-46ºF) and protected from light for up to 24 hr or may be stored at room temperature (20-25ºC [68-77ºF]) and room light for up to 4 hr of the total 24 hr

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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