BELATACEPT Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Mycophenolate Mofetil (MMF) Monitor for a need to adjust concomitant mycophenolate mofetil (MMF) dosage when a patient’s therapy is switched between cyclosporine and NULOJIX, as cyclosporine decreases mycophenolic acid (MPA) exposure by preventing enterohepatic recirculation of MPA while NULOJIX does not <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> :

• A higher MMF dosage may be needed after switching from NULOJIX to cyclosporine, since this may result in lower MPA concentrations and increase the risk of graft rejection.
• A lower MMF dosage may be needed after switching from cyclosporine to NULOJIX, since this may result in higher MPA concentrations and increase the risk for adverse reactions related to MPA (review the Full Prescribing Information for MMF).

7.2 Cytochrome P450 Substrates No dosage adjustments are needed for drugs metabolized via CYP1A2, CYP2C9, CYP2D6, CYP3A, and CYP2C19 when coadministered with NULOJIX <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.3 Anti-Thymocyte Globulin Coadministration (at the same or nearly the same time) of anti-thymocyte globulin (or any other cell-depleting induction treatment) and belatacept in de novo kidney transplant recipients, especially those with other predisposing risk factors for venous thrombosis of the renal allograft, may pose a risk for venous thrombosis of the renal allograft <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span> .

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 Warning and Warnings and Precautions (5.1) ] . Patients who are EBV seronegative or with unknown EBV serostatus. (4)

AND PRECAUTIONS

• Post-Transplant Lymphoproliferative Disorder (PTLD) : increased risk, predominantly involving the CNS; monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms. (Boxed Warning , 4 , 5.1 , 5.6)
• Other malignancies : increased risk with all immunosuppressants; appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight. (5.3)
• Progressive Multifocal Leukoencephalopathy (PML) : increased risk; consider in the diagnosis of patients reporting new or worsening neurological, cognitive, or behavioral signs and symptoms. Recommended doses of immunosuppressants should not be exceeded. (5.4)
• Other serious infections : increased risk of bacterial, viral, fungal, and protozoal infections, including opportunistic infections and tuberculosis. Some infections were fatal. Polyoma virus-associated nephropathy can lead to kidney graft loss; consider reduction in immunosuppression. Evaluate for tuberculosis and initiate treatment for latent infection prior to NULOJIX use. Cytomegalovirus and pneumocystis prophylaxis are recommended after transplantation. (5.1 , 5.4 , 5.5)
• Liver transplant : use is not recommended. (5.6)
• Acute Rejection and Graft Loss with Corticosteroid Minimization : corticosteroid utilization should be consistent with the NULOJIX clinical trial experience. (2.1 , 5.7 , 14.1)
• Immunizations : avoid use of live vaccines during treatment. (5.8)
• Coadministration with Anti-Thymocyte Globulin: in de novo kidney transplant recipients, especially those with other predisposing risk factors for venous thrombosis of the renal allograft, coadministration (at the same or nearly the same time) with anti-thymocyte globulin may pose a risk for venous thrombosis of the renal allograft. ( 5.9 , 6.2 , 7.3 )
• Risk of Rejection with Conversion From a CNI Based Maintenance Regimen: conversion of maintenance kidney transplant recipients from a CNI based to NULOJIX based maintenance regimen increases the risk of acute rejection. Conversion of stable kidney transplant recipients from a CNI based maintenance therapy to a belatacept based maintenance therapy is not recommended unless the patient is CNI intolerant. (5.10)

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) , Clinical Studies (14.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Warnings and Precautions (5.6) ]</span> . 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 Warning and 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.

5.2 Management of Immunosuppression Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe NULOJIX. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient <span class="opacity-50 text-xs">[see Boxed Warning ]</span> .

5.3 Other Malignancies Patients receiving immunosuppressants, including NULOJIX, are at increased risk of developing malignancies, in addition to PTLD, including the skin <span class="opacity-50 text-xs">[see Boxed Warning and Warnings and Precautions (5.1) ]</span> . Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

5.4 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an often rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma virus. In clinical trials with NULOJIX, two cases of PML were reported in patients receiving NULOJIX at higher cumulative doses and more frequently than the recommended regimen, along with mycophenolate mofetil (MMF) and corticosteroids; one case occurred in a kidney transplant recipient and the second case occurred in a liver transplant recipient <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) , Adverse Reactions (6.1) , Clinical Studies (14.2) ]</span> . As PML has been associated with high levels of overall immunosuppression, the recommended doses and frequency of NULOJIX and concomitant immunosuppressives, including MMF, should not be exceeded. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. PML is usually diagnosed by brain imaging, cerebrospinal fluid (CSF) testing for JC viral DNA by polymerase chain reaction (PCR), and/or brain biopsy. Consultation with a specialist (eg, neurologist and/or infectious disease) should be considered for any suspected or confirmed cases of PML. If PML is diagnosed, consideration should be given to reduction or withdrawal of immunosuppression taking into account the risk to the allograft.

5.5 Other Serious Infections Patients receiving immunosuppressants, including NULOJIX, are at increased risk of developing bacterial, viral (cytomegalovirus [CMV] and herpes), fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes <span class="opacity-50 text-xs">[see Boxed Warning and Adverse Reactions (6.1) ]</span> . Prophylaxis for cytomegalovirus is recommended for at least 3 months after transplantation. Prophylaxis for Pneumocystis jiroveci is recommended after transplantation.

Tuberculosis

Tuberculosis was more frequently observed in patients receiving NULOJIX than cyclosporine in clinical trials [see Adverse Reactions (6.1) ] . Patients should be evaluated for tuberculosis and tested for latent infection prior to initiating NULOJIX. Treatment of latent tuberculosis infection should be initiated prior to NULOJIX use.

Polyoma Virus

Nephropathy In addition to cases of JC virus-associated PML [see Warnings and Precautions (5.4) ] , cases of polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, have been reported. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss [see Adverse Reactions (6.1) ] . Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

5.6 Liver Transplant Use of NULOJIX in liver transplant patients is not recommended <span class="opacity-50 text-xs">[see Boxed Warning ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .

5.7 Acute Rejection and Graft Loss with Corticosteroid Minimization In postmarketing experience, use of NULOJIX in conjunction with basiliximab induction, MMF, and corticosteroid minimization to 5 mg per 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. Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience [see Dosage and Administration (2.1) and Clinical Studies (14.1) ] .

5.8 Immunizations The use of live vaccines should be avoided during treatment with NULOJIX, including but not limited to the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

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.

5.10 Risk of Rejection with Conversion From a CNI Based Maintenance Regimen Conversion of patients receiving a CNI based maintenance regimen to a NULOJIX based maintenance regimen increases the risk of acute rejection. In two randomized controlled studies, kidney transplant recipients at least six months post-transplant and stable on a CNI based regimen who were converted to a belatacept based regimen experienced higher rejection rates mostly during the first year post-conversion than patients maintained on their CNI based regimens. Conversion of stable kidney transplant recipients from a CNI based maintenance therapy to a belatacept based maintenance therapy is not recommended unless the patient is CNI intolerant.