Nulojix

belatacept

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

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 (5.1)].

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 (5.2)].

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 (5.6)].

Indications and Usage for Nulojix

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)].

Nulojix Dosage and Administration

Dosage in Adult Kidney Transplant Recipients

Due to an increased risk of post-transplant lymphoproliferative disorder (PTLD) predominantly involving the central nervous system (CNS), progressive multifocal leukoencephalopathy (PML), and serious CNS infections, administration of higher than the recommended doses or more frequent dosing of Nulojix is not recommended [see Warnings and Precautions (5.1, 5.4, 5.5) and Adverse Reactions (6.1)].

Nulojix is for intravenous infusion only. Patients do not require premedication prior to administration of Nulojix.

Dosing instructions are provided in Table 1.

• The total infusion dose of Nulojix should be based on the actual body weight of the patient at the time of transplantation, and should not be modified during the course of therapy, unless there is a change in body weight of greater than 10%.


• The prescribed dose of Nulojix must be evenly divisible by 12.5 mg in order for the dose to be prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. Evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100. For example:
  

  –

  
  

  A patient weighs 64 kg. The dose is 10 mg per kg.

  
  

  –

  
  

  Calculated Dose: 64 kg × 10 mg per kg = 640 mg

  
  

  –

  
  

  The closest doses evenly divisible by 12.5 mg below and above 640 mg are 637.5 mg and 650 mg.

  
  

  –

  
  

  The nearest dose to 640 mg is 637.5 mg.

  
  

  –

  
  

  Therefore, the actual prescribed dose for the patient should be 637.5 mg.

  
  

Table 1: Dosing*,† of Nulojix for Kidney Transplant Recipients

Dosing for Initial Phase	Dose
* [See Clinical Studies (14.1).]
† The dose prescribed for the patient must be evenly divisible by 12.5 mg (see instructions above; e.g., evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100)
Day 1 (day of transplantation, prior to implantation) and Day 5 (approximately 96 hours after Day 1 dose)	10 mg per kg
End of Week 2 and Week 4 after transplantation	10 mg per kg
End of Week 8 and Week 12 after transplantation	10 mg per kg
Dosing for Maintenance Phase	Dose
End of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter	5 mg per kg

Preparation and Administration Instructions

Nulojix is for intravenous infusion only.

Caution: Nulojix must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial.

If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb at 1-888-Nulojix.

Preparation for Administration

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 should be 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 container, 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 container, and gently rotate the infusion container to ensure mixing.

The final belatacept concentration in the infusion container 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 0.2-1.2 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°-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).


• 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.

Dosage Forms and Strengths

Lyophilized powder for injection: 250 mg per vial.

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 Warning and Warnings and Precautions (5.1)].

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 (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.

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.

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

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.

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)].

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.

Adverse Reactions

The most serious adverse reactions reported with Nulojix are:

• PTLD, predominantly CNS PTLD, and other malignancies [see Boxed Warning and Warnings and Precautions (5.1, 5.3)]


• Serious infections, including JC virus-associated PML and polyoma virus nephropathy [see Warnings and Precautions (5.4, 5.5, 5.6)]

Clinical Studies Experience

The data described below primarily derive from two randomized, active-controlled three-year trials of Nulojix in de novo kidney transplant patients. In Study 1 and Study 2, Nulojix was studied at the recommended dose and frequency [see Dosage and Administration (2.1)] in a total of 401 patients compared to a cyclosporine control regimen in a total of 405 patients. These two trials also included a total of 403 patients treated with a Nulojix regimen of higher cumulative dose and more frequent dosing than recommended [see Clinical Studies (14.1)]. All patients also received basiliximab induction, mycophenolate mofetil, and corticosteroids. Patients were treated and followed for 3 years.

CNS PTLD, PML, and other CNS infections were more frequently observed in association with a Nulojix regimen of higher cumulative dose and more frequent dosing compared to the recommended regimen; therefore, administration of higher than the recommended doses and/or more frequent dosing of Nulojix is not recommended [see Dosage and Administration (2.1)].

The average age of patients in Studies 1 and 2 in the Nulojix recommended dose and cyclosporine control regimens was 49 years, ranging from 18 to 79 years. Approximately 70% of patients were male; 67% were white, 11% were black, and 22% other races. About 25% of patients were from the United States and 75% from other countries.

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

The most commonly reported adverse reactions occurring in ≥20% of patients treated with the recommended dose and frequency of Nulojix were anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia.

The proportion of patients who discontinued treatment due to adverse reactions was 13% for the recommended Nulojix regimen and 19% for the cyclosporine control arm through three years of treatment. The most common adverse reactions leading to discontinuation in Nulojix-treated patients were cytomegalovirus infection (1.5%) and complications of transplanted kidney (1.5%).

Information on selected significant adverse reactions observed during clinical trials is summarized below.

Post-Transplant Lymphoproliferative Disorder

Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months post transplant were obtained for Nulojix by pooling both dosage regimens of Nulojix in Studies 1 and 2 (804 patients) with data from a third study in kidney transplantation (Study 3, 145 patients) which evaluated two Nulojix dosage regimens similar, but slightly different, from those of Studies 1 and 2 (see Table 2). The total number of Nulojix patients from these three studies (949) was compared to the pooled cyclosporine control groups from all three studies (476 patients).

Among 401 patients in Studies 1 and 2 treated with the recommended regimen of Nulojix and the 71 patients in Study 3 treated with a very similar (but non-identical) Nulojix regimen, there were 5 cases of PTLD: 3 in EBV seropositive patients and 2 in EBV seronegative patients. Two of the 5 cases presented with CNS involvement.

Among the 477 patients in Studies 1, 2, and 3 treated with the Nulojix regimen of higher cumulative dose and more frequent dosing than recommended, there were 8 cases of PTLD: 2 in EBV seropositive patients and 6 in EBV seronegative or serostatus unknown patients. Six of the 8 cases presented with CNS involvement. Therefore, administration of higher than the recommended doses or more frequent dosing of Nulojix is not recommended. [See Dosage and Administration (2.1) and Warnings and Precautions (5.1).]

One of the 476 patients treated with cyclosporine developed PTLD, without CNS involvement.

All cases of PTLD reported up to 36 months post transplant in Nulojix- or cyclosporine-treated patients presented within 18 months of transplantation.

Overall, the rate of PTLD in 949 patients treated with any of the Nulojix regimens was 9-fold higher in those who were EBV seronegative or EBV serostatus unknown (8/139) compared to those who were EBV seropositive (5/810 patients). Therefore Nulojix is recommended for use only in patients who are EBV seropositive [see Boxed Warning and Contraindications (4)].

Table 2: Summary of PTLD Reported in Studies 1, 2, and 3 Through Three Years of Treatment

	Nulojix Non-Recommended Regimen* (N=477)			Nulojix Recommended Regimen† (N=472)			Cyclosporine (N=476)
Trial	EBV Positive (n=406)	EBV Negative (n=43)	EBV Unknown (n=28)	EBV Positive (n=404)	EBV Negative (n=48)	EBV Unknown (n=20)	EBV Positive (n=399)	EBV Negative (n=57)	EBV Unknown (n=20)
*  Regimen with higher cumulative dose and more frequent dosing than the recommended Nulojix regimen.
†  In Studies 1 and 2 the Nulojix regimen is identical to the recommended regimen, but is slightly different in Study 3.
Study 1
CNS PTLD	1	1
Non-CNS PTLD		1		2				1
Study 2
CNS PTLD	1	1		1	1
Non-CNS PTLD					1
Study 3
CNS PTLD		2
Non-CNS PTLD			1
Total (%)	2 (0.5)	5 (11.6)	1 (3.6)	3 (0.7)	2 (4.1)	0	0	1 (1.8)	0

EBV Seropositive Subpopulation

Among the 806 EBV seropositive patients with known CMV serostatus treated with either Nulojix regimen in Studies 1, 2, and 3, two percent (2%; 4/210) of CMV seronegative patients developed PTLD compared to 0.2% (1/596) of CMV seropositive patients. Among the 404 EBV seropositive recipients treated with the recommended dosage regimen of Nulojix, three PTLD cases were detected among 99 CMV seronegative patients (3%) and there was no case detected among 303 CMV seropositive patients. The clinical significance of CMV serology as a risk factor for PTLD remains to be determined; however, these findings should be considered when prescribing Nulojix [see Warnings and Precautions (5.1)].

Other Malignancies

Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in Study 1 and Study 2 in 3.5% (14/401) of patients treated with the recommended Nulojix regimen and 3.7% (15/405) of patients treated with the cyclosporine control regimen. Non-melanoma skin cancer was reported in 1.5% (6/401) of patients treated with the recommended Nulojix regimen and in 3.7% (15/405) of patients treated with cyclosporine [see Warnings and Precautions (5.3)].

Progressive Multifocal Leukoencephalopathy

Two fatal cases of progressive multifocal leukoencephalopathy (PML) have been reported among 1096 patients treated with a Nulojix-containing regimen: one patient in clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and one patient in a trial of liver transplant (trial of 250 patients). No cases of PML were reported in patients treated with the recommended Nulojix regimen or the control regimen in these trials.

The kidney transplant recipient was treated with the Nulojix regimen of higher cumulative dose and more frequent dosing than recommended, mycophenolate mofetil (MMF), and corticosteroids for 2 years. The liver transplant recipient was treated with 6 months of a Nulojix dosage regimen that was more intensive than that studied in kidney transplant recipients, MMF at doses higher than the recommended dose, and corticosteroids [see Warnings and Precautions (5.4)].

Bacterial, Mycobacterial, Viral, and Fungal Infections

Adverse reactions of infectious etiology were reported based on clinical assessment by physicians. The causative organisms for these reactions are identified when provided by the physician. The overall number of infections, serious infections, and select infections with identified etiology reported in patients treated with the Nulojix recommended regimen or the cyclosporine control in Studies 1 and 2 are shown in Table 3. Fungal infections were reported in 18% of patients receiving Nulojix compared to 22% receiving cyclosporine, primarily due to skin and mucocutaneous fungal infections. Tuberculosis and herpes infections were reported more frequently in patients receiving Nulojix than cyclosporine. Of the patients who developed tuberculosis through 3 years, all but one Nulojix patient lived in countries with a high prevalence of tuberculosis [see Warnings and Precautions (5.5)].

Table 3: Overall Infections and Select Infections with Identified Etiology by Treatment Group following One and Three Years of Treatment in Studies 1 and 2*

	Up to Year 1		Up to Year 3†
	Nulojix Recommended Regimen N=401 n (%)	Cyclosporine N=405 n (%)	Nulojix Recommended Regimen N=401 n (%)	Cyclosporine N=405 n (%)
*  Studies 1 and 2 were not designed to support comparative claims for Nulojix for the adverse reactions reported in this table.
†  Median exposure in days for pooled studies: 1203 for Nulojix recommended regimen and 1163 for cyclosporine in Studies 1 and 2.
‡  All infections include bacterial, viral, fungal, and other organisms. For infectious adverse reactions, the causative organism is reported if specified by the physician in the clinical trials.
§  A medically important event that may be life-threatening or result in death or hospitalization or prolongation of existing hospitalization. Infections not meeting these criteria are considered non-serious.
¶  BK virus-associated nephropathy was reported in 6 Nulojix patients (4 of which resulted in graft loss) and 6 cyclosporine patients (none of which resulted in graft loss) by Year 3.
#  Most herpes infections were non-serious and 1 led to treatment discontinuation.
All infections‡	287 (72)	299 (74)	329 (82)	327 (81)
Serious infections§	98 (24)	113 (28)	144 (36)	157 (39)
CMV	44 (11)	52 (13)	53 (13)	56 (14)
Polyoma virus¶	10 (3)	23 (6)	17 (4)	27 (7)
Herpes#	27 (7)	26 (6)	55 (14)	46 (11)
Tuberculosis	2 (1)	1 (<1)	6 (2)	1 (<1)

Infections Reported in the CNS

Following three years of treatment in Studies 1 and 2, cryptococcal meningitis was reported in one patient out of 401 patients treated with the Nulojix recommended regimen (0.2%) and one patient out of the 405 treated with the cyclosporine control (0.2%).

Six patients out of the 403 who were treated with the Nulojix regimen of higher cumulative dose and more frequent dosing than recommended in Studies 1 and 2 (1.5%) were reported to have developed CNS infections, including 2 cases of cryptococcal meningitis, one case of Chagas encephalitis with cryptococcal meningitis, one case of cerebral aspergillosis, one case of West Nile encephalitis, and one case of PML (discussed above).

Infusion Reactions

There were no reports of anaphylaxis or drug hypersensitivity in patients treated with Nulojix in Studies 1 and 2 through three years.

Infusion-related reactions within one hour of infusion were reported in 5% of patients treated with the recommended dose of Nulojix, similar to the placebo rate. No serious events were reported through Year 3. The most frequent reactions were hypotension and hypertension.

Proteinuria

At Month 1 after transplantation in Studies 1 and 2, the frequency of 2+ proteinuria on urine dipstick in patients treated with the Nulojix recommended regimen was 33% (130/390) and 28% (107/384) in patients treated with the cyclosporine control regimen. The frequency of 2+ proteinuria was similar between the two treatment groups between one and three years after transplantation (<10% in both studies). There were no differences in the occurrence of 3+ proteinuria (<4% in both studies) at any time point, and no patients experienced 4+ proteinuria. The clinical significance of this increase in early proteinuria is unknown.

Immunogenicity

Antibodies directed against the belatacept molecule were assessed in 398 patients treated with the Nulojix recommended regimen in Studies 1 and 2 (212 of these patients were treated for at least 2 years). Of the 372 patients with immunogenicity assessment at baseline (prior to receiving belatacept treatment), 29 patients tested positive for anti-belatacept antibodies; 13 of these patients had antibodies to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Anti-belatacept antibody titers did not increase during treatment in these 29 patients.

Eight (2%) patients developed antibodies during treatment with the Nulojix recommended regimen. In the patients who developed antibodies during treatment, the median titer (by dilution method) was 8, with a range of 5 to 80. Of 56 patients who tested negative for antibodies during treatment and reassessed approximately 7 half-lives after discontinuation of Nulojix, 1 tested antibody positive. Anti-belatacept antibody development was not associated with altered clearance of belatacept.

Samples from 6 patients with confirmed binding activity to the modified cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) region of the belatacept molecule were assessed by an in vitro bioassay for the presence of neutralizing antibodies. Three of these 6 patients tested positive for neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.

The clinical impact of anti-belatacept antibodies (including neutralizing anti-belatacept antibodies) could not be determined in the studies.

The data reflect the percentage of patients whose test results were positive for antibodies to belatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belatacept with the incidence of antibodies to other products may be misleading.

New-Onset Diabetes After Transplantation

The incidence of new-onset diabetes after transplantation (NODAT) was defined in Studies 1 and 2 as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose values ≥126 mg/dL (7.0 mmol/L) post-transplantation. Of the patients treated with the Nulojix recommended regimen, 5% (14/304) developed NODAT by the end of one year compared to 10% (27/280) of patients on the cyclosporine control regimen. However, by the end of the third year, the cumulative incidence of NODAT was 8% (24/304) in patients treated with the Nulojix recommended regimen and 10% (29/280) in patients treated with the cyclosporine regimen.

Hypertension

Blood pressure and use of antihypertensive medications were reported in Studies 1 and 2. By Year 3, one or more antihypertensive medications were used in 85% of Nulojix-treated patients and 92% of cyclosporine-treated patients. At one year after transplantation, systolic blood pressures were 8 mmHg lower and diastolic blood pressures were 3 mmHg lower in patients treated with the Nulojix recommended regimen compared to the cyclosporine control regimen. At three years after transplantation, systolic blood pressures were 6 mmHg lower and diastolic blood pressures were 3 mmHg lower in Nulojix-treated patients compared to cyclosporine-treated patients. Hypertension was reported as an adverse reaction in 32% of Nulojix-treated patients and 37% of cyclosporine-treated patients (see Table 4).

Dyslipidemia

Mean values of total cholesterol, HDL, LDL, and triglycerides were reported in Studies 1 and 2. At one year after transplantation these values were 183 mg/dL, 50 mg/dL, 102 mg/dL, and 151 mg/dL, respectively, in 401 patients treated with the Nulojix recommended regimen and 196 mg/dL, 48 mg/dL, 108 mg/dL, and 195 mg/dL, respectively, in 405 patients treated with the cyclosporine control regimen. At three years after transplantation, the total cholesterol, HDL, LDL, and triglycerides were 176 mg/dL, 49 mg/dL, 100 mg/dL, and 141 mg/dL, respectively, in Nulojix-treated patients compared to 193 mg/dL, 48 mg/dL, 106 mg/dL, and 180 mg/dL in cyclosporine-treated patients.

The clinical significance of the lower mean triglyceride values in Nulojix-treated patients at one and three years is unknown.

Other Adverse Reactions

Adverse reactions that occurred at a frequency of ≥10% in patients treated with the Nulojix recommended regimen or cyclosporine control regimen in Studies 1 and 2 through three years are summarized by preferred term in decreasing order of frequency within Table 4.

Table 4: Adverse Reactions Reported by ≥10% of Patients Treated with Either the Nulojix Recommended Regimen or Control in Studies 1 and 2 Through Three Years*,†

Adverse Reaction	Nulojix Recommended Regimen N=401 %	Cyclosporine N=405 %
* All randomized and transplanted patients in Studies 1 and 2.
† Studies 1 and 2 were not designed to support comparative claims for Nulojix for the adverse reactions reported in this table.
Infections and Infestations
Urinary tract infection	37	36
Upper respiratory infection	15	16
Nasopharyngitis	13	16
Cytomegalovirus infection	12	12
Influenza	11	8
Bronchitis	10	7
Gastrointestinal Disorders
Diarrhea	39	36
Constipation	33	35
Nausea	24	27
Vomiting	22	20
Abdominal pain	19	16
Abdominal pain upper	9	10
Metabolism and Nutrition Disorders
Hyperkalemia	20	20
Hypokalemia	21	14
Hypophosphatemia	19	13
Dyslipidemia	19