Nulojix

NULOJIX®
(noo-LOJ-jiks)
(belatacept) For Injection, For Intravenous Use

Read this Medication Guide before you start receiving NULOJIX and before each treatment. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about NULOJIX?

NULOJIX increases your risk of serious side effects, including:

• Post-transplant lymphoproliferative disorder (PTLD). PTLD is a condition that can happen if certain white blood cells grow out of control after an organ transplant because your immune system is weak. PTLD can get worse and become a type of cancer. PTLD can lead to death. People treated with NULOJIX have a higher risk of getting PTLD. If you get PTLD with NULOJIX you are at especially high risk of getting it in your brain. Your risk for PTLD is also higher if you:
  • have never been exposed to the Epstein-Barr virus (EBV). Your doctor should test you for EBV. Do not receive NULOJIX unless you are EBV positive (you have been exposed to EBV).
  • get an infection with a virus called cytomegalovirus (CMV).
  • receive treatment for transplant rejection that lowers certain white blood cells called T lymphocytes.
• Increased risk of getting cancers other than PTLD. People who take medicines that weaken the immune system, including NULOJIX, have a higher risk of getting other cancers, including skin cancer. Talk to your doctor about your risk for cancer. See “What should I avoid while receiving NULOJIX?”
• Progressive multifocal leukoencephalopathy (PML). PML is a rare, serious brain infection caused by JC virus. People with weakened immune systems are at risk for getting PML. PML can result in death or severe disability. There is no known prevention, treatment, or cure for PML.
• Increased risk of getting other serious infections, including tuberculosis (TB) and other infections caused by bacteria, viruses, or fungi. These serious infections may lead to death. Also, a virus called BK virus can affect how your kidney works and cause your transplanted kidney to fail.

Tell your doctor right away if you get any of the following symptoms during treatment with NULOJIX:

• change in mood or your usual behavior
• confusion or problems thinking or with memory
• change in the way you walk or talk
• decreased strength or weakness on one side of your body
• change in vision
• fever, night sweats, or tiredness that does not go away
• weight loss
• swollen glands
• flu, cold symptoms, or cough
• stomach-area pain
• vomiting or diarrhea
• tenderness over your transplanted kidney
• change in the amount of urine that you make, blood in your urine, pain or burning on urination
• a new skin lesion or bump, or change in size or color of a mole

See “What are the possible side effects of NULOJIX?” for more information about side effects. Liver transplant patients should not receive NULOJIX because of an increased risk of losing the transplanted liver (graft loss) and death. Talk to your doctor if you would like more information about this risk.

What is NULOJIX?

NULOJIX is a prescription medicine used in adults to prevent transplant rejection in people who have received a kidney transplant. Transplant rejection happens when the body’s immune system senses that the new transplanted kidney is different or foreign, and attacks it. NULOJIX is used with corticosteroids and certain other medicines to help prevent rejection of your new kidney.

It is not known if NULOJIX is safe and effective in children under 18 years of age.

NULOJIX is only used in people who have been exposed to the EBV virus.

It is not known if NULOJIX is safe and effective in people who receive an organ transplant other than a kidney transplant.

Who should not receive NULOJIX?

Do not receive treatment with NULOJIX if you are EBV negative. Your doctor will do a test to see if you were exposed to EBV in the past.

What should I tell my doctor before receiving NULOJIX?

Before receiving NULOJIX, tell your doctor if you:

• plan to receive any vaccines. Talk to your doctor about which vaccines are safe for you to receive during your treatment with NULOJIX. See “What should I avoid while receiving NULOJIX?”
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if NULOJIX will harm your unborn baby. If you become pregnant while taking NULOJIX:
  • Tell your doctor right away. You and your doctor should decide if you will keep receiving NULOJIX while you are pregnant.
  • Talk with your doctor about enrolling in the National Transplant Pregnancy Registry (NTPR). This Registry collects information about pregnancies in women who have received NULOJIX or if their partner has received NULOJIX, and had a transplant. You can also enroll by calling 1-877-955-6877.
• are breast-feeding or plan to breast-feed. It is not known if NULOJIX passes into your breast milk. You and your doctor should decide if you will receive NULOJIX or breast-feed. You should not do both.

Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. Do not take any new medicine without talking with your transplant doctor first.

How will I receive NULOJIX?

• To help prevent rejection of your new kidney, you will receive NULOJIX regularly as prescribed by your doctor. It is important for you to keep all your appointments for NULOJIX treatment and follow up.
• You will receive NULOJIX as an intravenous (IV) infusion in your arm. Each IV infusion takes about 30 minutes.
• During treatment with NULOJIX, your doctor will test your blood and urine to check how your kidney is working.
• Take all the medicines prescribed by your doctor to prevent infection or transplant rejection. Take them exactly as your doctor tells you. Talk to your doctor or pharmacist if you have any questions about how to take your medicines.

What should I avoid while receiving NULOJIX?

• Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. People who take medicines that weaken the immune system, including NULOJIX, have a higher risk of getting cancer, including skin cancer. Wear protective clothing and use sunscreen with a high protection factor (SPF) when you have to be in the sun.
• Avoid receiving live vaccines during treatment with NULOJIX. Talk to your doctor to find out which vaccines are safe for you during this time. Some vaccines may not work as well while you are receiving NULOJIX. See “What should I tell my doctor before receiving NULOJIX?”

What are the possible side effects of NULOJIX?

NULOJIX increases your risk of serious side effects that can cause death. See “What is the most important information I should know about NULOJIX?”

Common side effects of NULOJIX include:

• low red blood count (anemia)
• diarrhea
• kidney or bladder infection
• swollen legs, feet, or ankles
• constipation
• high blood pressure
• fever
• new kidney not working well
• cough
• nausea or vomiting
• headache
• low potassium or high potassium in your blood
• low white blood cell count

Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects of NULOJIX. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to BMS at 1-800-321-1335.

General information about NULOJIX

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide summarizes the most important information about NULOJIX. If you would like more information about NULOJIX, talk with your doctor. You can ask your pharmacist or doctor for information about NULOJIX that is written for healthcare professionals.

For more information, go to www.NULOJIX.com or call 1-800-321-1335.

What are the ingredients in NULOJIX?

Active ingredient: belatacept

Inactive ingredients: monobasic sodium phosphate, sodium chloride, and sucrose

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Avoid exposure to sunlight or tanning beds. Belatacept can increase your risk of skin cancer. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Do not receive a "live" vaccine while using belatacept. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

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

• 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

Belatacept injection belongs to a group of medicines known as immunosuppressive agents. It is used together with other medicines to prevent the body from rejecting a transplanted kidney.

When a patient receives a kidney transplant, the body's white blood cells will try to get rid of (reject) the transplanted kidney. Belatacept works by suppressing the immune system and prevents the white blood cells from trying to get rid of the transplanted organ.

This medicine is to be given only by or under the direct supervision of a doctor.

Use Nulojix as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Nulojix is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Nulojix (belatacept) or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Nulojix. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

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.

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)].

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) 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 (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.

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 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.

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 (5.1)]. 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 (5.6)]. 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 (6.1)].

Prophylaxis for cytomegalovirus is recommended for at least 3 months after transplantation. Prophylaxis for Pneumocystis jiroveci is recommended after transplantation.

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.

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.

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)].

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)].

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 patients 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.

Single doses up to 20 mg per kg of Nulojix have been administered to healthy subjects without apparent toxic effect. The administration of Nulojix of higher cumulative dose and more frequent dosing than recommended in kidney transplant patients resulted in a higher frequency of CNS-related adverse reactions [see Adverse Reactions (6.1)]. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

Nulojix® (belatacept) lyophilized powder for intravenous infusion is supplied as a single-use vial with a silicone-free disposable syringe in the following packaging configuration:

Storage

Nulojix lyophilized powder is stored refrigerated at 2°-8°C (36°-46°F). Protect Nulojix from light by storing in the original package until time of use.

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 constitution of the Nulojix lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-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°-25°C [68°-77°F] and room light) [see Dosage and Administration (2.2)].

Usual Adult Dose for Rejection Prophylaxis:

Initial dose: 10 mg/kg, intravenously, once daily, on day 1 (day of transplant, prior to implantation) and day 5, and at the end of weeks 2, 4, 8, and 12.

Maintenance dose: 5 mg/kg, intravenously, at the end of week 16 and every 4 weeks (plus or minus 3 days) thereafter.

Nulojix should be administered in combination with basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids. In clinical trials the median corticosteroid doses were tapered to approximately 15 mg per day by the first 6 weeks and remained at approximately 10 mg per day for the first 6 months post-transplant. Corticosteroid utilization should be consistent with the clinical trial experience.

Common side effects of Nulojix include: cytomegalovirus disease. See below for a comprehensive list of adverse effects.