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Nulojix (Belatacept) - Warnings and Precautions

 
 



WARNING: POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER, OTHER MALIGNANCIES, AND SERIOUS INFECTIONS

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. Do not use NULOJIX in transplant recipients who are EBV seronegative or with unknown EBV serostatus [see Contraindications (4) and Warnings and Precautions ].

Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients 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 maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions ].

Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5) ].

Use in liver transplant patients is not recommended due to an increased risk of graft loss and death [see Warnings and Precautions ].

 

WARNINGS AND PRECAUTIONS

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 and Table 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 and Warnings and Precautions ]. 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 ].

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 ]. 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.

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 [see Boxed Warning ].

Other Malignancies

Patients receiving immunosuppressants, including NULOJIX, are at increased risk of developing malignancies, in addition to PTLD, including the skin [see Boxed Warning and Warnings and Precautions ]. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

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 [see Warnings and Precautions ]. 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 (e.g., 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.

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 [see Boxed Warning and Adverse Reactions ].

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 ]. 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 ], 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 ]. 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.

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 ].

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.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

NULOJIX should not be used in pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. There are no studies of NULOJIX treatment in pregnant women. Belatacept is known to cross the placenta of animals. Belatacept was not teratogenic in pregnant rats and rabbits at doses approximately 16 and 19 times greater than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg per kg administered over the first month of treatment, based on area under the concentration-time curve (AUC).

Belatacept administered to female rats daily during gestation and throughout the lactation period was associated with maternal toxicity (infections) in a small percentage of dams at doses of ≥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).

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 2 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 ].

Autoimmunity was observed in one 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 ].

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

Nursing Mothers

It is not known whether belatacept is excreted in human milk or absorbed systemically after ingestion by a nursing infant. However, belatacept is excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from NULOJIX in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of NULOJIX in patients under 18 years of age have not been established. Because T cell development continues into the teenage years, the potential concern for autoimmunity in neonates applies to pediatric use as well [see Use in Specific Populations ].

Geriatric Use

Of 401 patients treated with the recommended dosage regimen of NULOJIX, 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 subjects and younger subjects, but greater sensitivity or less efficacy in older individuals cannot be ruled out.

Page last updated: 2011-06-15

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