Nulojix

• •NULOJIX is a selective T cell costimulation blocker indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant.
  1.1 Adult Kidney Transplant Recipients

  NULOJIX^®(belatacept) is indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. NULOJIX is to be used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids.
• •Use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids.
  1.1 Adult Kidney Transplant Recipients

  NULOJIX^®(belatacept) is indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. NULOJIX is to be used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids.

• •Use only in patients who are EBV seropositive.
  1.2 Limitations of Use

  Use NULOJIX only in patients who are EBV seropositive

  [see Contraindications (4)and Warnings and Precautions (5.1)]

  .

  Use of NULOJIX for the prophylaxis of organ rejection in transplanted organs other than kidney has not been established

  [see Warnings and Precautions (5.6)]

  .
  ,
  4 CONTRAINDICATIONS

  NULOJIX is contraindicated in transplant recipients who are Epstein-Barr virus (EBV) seronegative or with unknown EBV serostatus due to the risk of post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS)

  [see Boxed Warningand Warnings and Precautions (5.1)]

  .

  Patients who are EBV seronegative or with unknown EBV serostatus. (4)

  ,
  5.1 Post-Transplant Lymphoproliferative Disorder

  NULOJIX-treated patients have an increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen

  [see Adverse Reactions (6.1), Clinical Studies (14.2)]

  . As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of NULOJIX and higher than recommended doses of concomitant immunosuppressive agents are not recommended

  [see Dosage and Administration (2.1)and Warnings and Precautions (5.6)]

  . Physicians should consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms.

  EBV Serostatus

  The 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 NULOJIX, and only patients who are EBV seropositive should receive NULOJIX. Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive NULOJIX

  [see Boxed Warningand Contraindications (4)]

  .

  Other Risk Factors

  Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T cell-depleting therapy. T cell-depleting therapies to treat acute rejection should be used cautiously. CMV prophylaxis is recommended for at least 3 months after transplantation

  [see Warnings and Precautions (5.5)]

  .

  Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD compared to patients who are EBV seropositive and CMV seropositive

  [see Adverse Reactions (6.1)]

  . Since CMV seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined; however, these findings should be considered when prescribing NULOJIX.
• •Use has not been established for the prophylaxis of organ rejection in transplanted organs other than the kidney.
  1.2 Limitations of Use

  Use NULOJIX only in patients who are EBV seropositive

  [see Contraindications (4)and Warnings and Precautions (5.1)]

  .

  Use of NULOJIX for the prophylaxis of organ rejection in transplanted organs other than kidney has not been established

  [see Warnings and Precautions (5.6)]

  .
  ,
  5.6 Liver Transplant

  Use of NULOJIX in liver transplant patients is not recommended

  [see Boxed Warning]

  . In a clinical trial of liver transplant patients, use of NULOJIX regimens with more frequent administration of belatacept than any of those studied in kidney transplant, along with mycophenolate mofetil (MMF) and corticosteroids, was associated with a higher rate of graft loss and death compared to the tacrolimus control arms. In addition, two cases of PTLD involving the liver allograft (one fatal) and one fatal case of PML were observed among the 147 patients randomized to NULOJIX. The two cases of PTLD were reported among the 140 EBV seropositive patients (1.4%). The fatal case of PML was reported in a patient receiving higher than recommended doses of NULOJIX and MMF

  [see Warnings and Precautions (5.4)]

  .

• 1.Calculate the number of NULOJIX vials required to provide the total infusion dose. Each vial contains 250 mg of belatacept lyophilized powder.
• 2.Reconstitute the contents of each vial of NULOJIX with 10.5 mL of a suitable diluent using the
  silicone-free disposable syringe
  provided with each vial and an 18- to 21-gauge needle. Suitable diluents include: sterile water for injection (SWFI), 0.9% sodium chloride (NS), or 5% dextrose in water (D5W).
  
  
  Note: If the NULOJIX 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.
• 3.To reconstitute the NULOJIX powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of diluent (10.5 mL of SWFI, NS, or D5W) to the glass wall of the vial.
• 4.To minimize foam formation, rotate the vial and invert with gentle swirling until the contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake.
• 5.The reconstituted solution contains a belatacept 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.
• 6.Calculate the total volume of the reconstituted 25 mg/mL NULOJIX solution required to provide the total infusion dose.
  
  Volume of 25 mg/mL NULOJIX solution (in mL) = Prescribed Dose (in mg) ÷ 25 mg/mL
• 7.Prior to intravenous infusion, the required volume of the reconstituted NULOJIX solution must be further diluted with a suitable infusion fluid (NS or D5W). NULOJIX reconstituted with:
  • •SWFI should be further diluted with either NS or D5W
  • •NS should be further diluted with NS
  • •D5W should be further diluted with D5W
• 8.From the appropriate size infusion bag or bottle, withdraw a volume of infusion fluid that is equal to the volume of the reconstituted NULOJIX solution 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 bag or bottle, and gently rotate the infusion bag or bottle to ensure mixing.
  
  The final belatacept concentration in the infusion bag or bottle 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. Any unused solution remaining in the vials must be discarded.
• 9.Prior to administration, the NULOJIX infusion should be inspected visually for particulate matter and discoloration. Discard the infusion if any particulate matter or discoloration is observed.
• 10.The entire NULOJIX infusion should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2 to 1.2 µm).
  • •The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The NULOJIX infusion must be completed within 24 hours of reconstitution of the NULOJIX lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°C to 8°C (36°F to 46°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°C to 25°C [68°F to 77°F] and room light).
  • •Infuse NULOJIX in a separate line from other concomitantly infused agents. NULOJIX should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of NULOJIX with other agents
    [see

    5.9 Coadministration with Anti-Thymocyte Globulin

    In postmarketing experience in de novo kidney transplant recipients, some with other predisposing risk factors for venous thrombosis of the renal allograft, venous thrombosis of the renal allograft has occurred when the initial dose of anti-thymocyte globulin, as immunosuppressive induction, was coadministered (at the same or nearly the same time) with the first dose of belatacept. In such patients, the coadministration (at the same or nearly the same time) of anti-thymocyte globulin and belatacept may pose a risk for venous thrombosis of the renal allograft. If anti-thymocyte globulin (or any other cell-depleting induction treatment) and belatacept will be administered concomitantly, a twelve-hour interval between the two administrations is suggested.

    ]
    .

Lyophilized powder for injection: 250 mg per vial.

• •
  Pregnancy
  : Based on animal data, may cause fetal harm; pregnancy registry available.
  8.1 Pregnancy

  Pregnancy Exposure Registry

  To monitor maternal-fetal outcomes of pregnant women who have received immunosuppressants including NULOJIX or whose partners have received NULOJIX, healthcare providers are strongly encouraged to register pregnant patients in the Transplant Pregnancy Registry International (TPR) by calling 1-877-955-6877.

  Risk Summary

  The data with NULOJIX use in pregnant women are insufficient to inform on drug-associated risk. 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 per 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

  [see Animal Data]

  .

  The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

  Data

  Animal Data

  In embryo-fetal development studies, daily intravenous administration of belatacept to pregnant rats and rabbits throughout the period of organogenesis did not produce adverse fetal effects at doses up to 200 mg per kg and 100 mg per kg, respectively (16 and 19 times the MRHD exposure, based on AUC). In a pre- and postnatal development study, daily intravenous administration of belatacept to rats from Day 6 of gestation through Day 20 of the lactation period was associated with maternal toxicity (infections) in a small percentage of dams at doses ≥20 mg per kg (3 times the MRHD exposure, based on AUC) resulting in increased pup mortality (up to 100% pup mortality in some dams). In pups that survived, there were no abnormalities or malformations at doses up to 200 mg per kg (19 times the MRHD exposure, based on AUC).

  In vitro data indicate that belatacept has lower binding affinity to CD80/CD86 and lower potency in rodents than in humans. Although the rat toxicity studies with belatacept were done at pharmacologically saturating doses, the in vivo difference in potency between rats and humans is unknown. Therefore, the relevance of the rat toxicities to humans and the significance of the magnitude of the relative exposures (rats:humans) are unknown.

  Abatacept, a fusion protein that differs from belatacept by two amino acids, binds to the same ligands (CD80/CD86) and blocks T cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents, including infections and autoimmunity, may be predictive of adverse effects in humans treated with belatacept

  [see Nonclinical Toxicology (13.2)]

  .

  Autoimmunity was observed in 1 rat offspring exposed to abatacept in utero and/or during lactation and in juvenile rats after treatment with abatacept. However, the clinical relevance of autoimmunity in rats to patients or a fetus exposed in utero is unknown

  [see Nonclinical Toxicology (13.2)]

  .
• •
  Lactation
  : Discontinue drug or nursing, taking into consideration importance of drug to mother.
  8.2 Lactation

  Risk Summary

  There are no data on the presence of NULOJIX in human milk or the effects of NULOJIX on breastfed infants or human milk production to inform risk of NULOJIX to an infant during lactation. Belatacept is excreted in rat milk after intravenous administration, and it is possible that the drug will be present in human milk. However, absorption of intact belatacept from the nursing infant’s gastrointestinal tract has not been studied. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NULOJIX and any potential adverse effects on the breastfed child from NULOJIX or from the underlying maternal conditions.