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 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 Warnings and Precautions (5.9)].

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.

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.

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)].

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: 1 patient in clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and 1 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 two 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 three years, all but one NULOJIX patient lived in countries with a high prevalence of tuberculosis [see Warnings and Precautions (5.5)].

Infusion Reactions

There have been no reports of anaphylaxis or drug hypersensitivity in patients treated with NULOJIX in Studies 1 and 2 with up to three years of follow-up. However, milder 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. The most frequent reactions were hypotension and hypertension. A case of anaphylaxis was reported in the postmarketing experience [see Adverse Reactions (6.2)].

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 two 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.

Selected adverse reactions occurring in <10% from NULOJIX-treated patients in either regimen through three years in Studies 1 and 2 are listed below:

Immune System Disorders: Guillain-Barré syndrome

Infections and Infestations: see Table 3

Gastrointestinal Disorders: stomatitis, including aphthous stomatitis

Injury, Poisoning, and Procedural Complications: chronic allograft nephropathy, complications of transplanted kidney, including wound dehiscence, arteriovenous fistula thrombosis

Blood and Lymphatic System Disorders: neutropenia

Renal and Urinary Disorders: renal impairment, including acute renal failure, renal artery stenosis, urinary incontinence, hydronephrosis

Vascular Disorders: hematoma, lymphocele

Musculoskeletal and Connective Tissue Disorders: musculoskeletal pain

Skin and Subcutaneous Tissue Disorders: alopecia, hyperhidrosis

Cardiac Disorders: atrial fibrillation

Immune System Disorder: Anaphylaxis

Spontaneous reports during the postmarketing experience included a case of anaphylaxis, which was observed in a kidney transplant patient whose belatacept therapy had been interrupted for two months during treatment of a systemic varicella infection. When belatacept therapy was resumed, within five minutes after the start of the belatacept infusion the patient developed a generalized rash, pruritus, hypotension, atrial fibrillation, respiratory distress, and syncope, requiring medical treatment. Another belatacept infusion was attempted one month later, but was terminated when the patient experienced more pronounced symptoms of anaphylaxis and required medical treatment.

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

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.

Drug Interactions

Treatment Regimen

The NULOJIX recommended regimen consisted of a 10 mg per kg dose administered on Day 1 (the day of transplantation, prior to implantation), Day 5 (approximately 96 hours after the Day 1 dose), end of Weeks 2 and 4; then every four weeks through Week 12 after transplantation. Starting at Week 16 after transplantation, NULOJIX was administered at the maintenance dose of 5 mg per kg every four weeks (plus or minus three days). NULOJIX was administered as an intravenous infusion over 30 minutes [see Dosage and Administration (2.1)].

Basiliximab 20 mg was administered intravenously on the day of transplantation and four days later.

The initial dose of MMF was 1 gram twice daily and was adjusted as needed, based on clinical signs of adverse events or efficacy failure.

The protocol-specified dosing of corticosteroids in Studies 1 and 2 at Day 1 was methylprednisolone (as sodium succinate) 500 mg IV on arrival in the operating room, Day 2, methylprednisolone 250 mg IV, and Day 3, prednisone 100 mg orally. Actual median corticosteroid doses used with the NULOJIX recommended regimen from Week 1 through Month 6 are summarized in the table below (Table 6).

Study 1 enrolled recipients of living donor and standard criteria deceased donor organs and Study 2 enrolled recipients of extended criteria donor organs. Standard criteria donor organs were defined as organs from a deceased donor with anticipated cold ischemia time of <24 hours and not meeting the definition of extended criteria donor organs. Extended criteria donors were defined as deceased donors with at least one of the following: (1) donor age ≥60 years; (2) donor age ≥50 years and other donor comorbidities (≥2 of the following: stroke, hypertension, serum creatinine >1.5 mg/dL); (3) donation of organ after cardiac death; or (4) anticipated cold ischemia time of the organ of ≥24 hours. Study 1 excluded recipients undergoing a first transplant whose current Panel Reactive Antibodies (PRA) were ≥50% and recipients undergoing a retransplantation whose current PRA were ≥30%; Study 2 excluded recipients with a current PRA ≥30%. Both studies excluded recipients with HIV, hepatitis C, or evidence of current hepatitis B infection; recipients with active tuberculosis; and recipients in whom intravenous access was difficult to obtain.

Efficacy data are presented for the NULOJIX recommended regimen and cyclosporine regimen in Studies 1 and 2.

The NULOJIX regimen with higher cumulative doses and more frequent dosing of belatacept was associated with more efficacy failures. Higher doses and/or more frequent dosing of NULOJIX are not recommended [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys

In Study 1 (NCT00256750), 666 patients were enrolled, randomized, and transplanted: 226 to the NULOJIX recommended regimen, 219 to the NULOJIX regimen with higher cumulative doses and more frequent dosing than recommended, and 221 to cyclosporine control regimen. The median age was 45 years; 58% of organs were from living donors; 3% were re-transplanted; 69% of the study population was male; 61% of patients were white, 8% were black/African-American, 31% were categorized as of other races; 16% had PRA ≥10%; 41% had 4 to 6 HLA mismatches; and 27% had diabetes prior to transplant. The incidence of delayed graft function was similar in all treatment arms (14% to 18%).

Premature discontinuation from treatment at the end of the first year occurred in 19% of patients receiving the NULOJIX recommended regimen and 19% of patients on the cyclosporine regimen. Among the patients who received the NULOJIX recommended regimen, 10% discontinued due to lack of efficacy, 5% due to adverse events, and 4% for other reasons. Among the patients who received the cyclosporine regimen, 9% discontinued due to adverse events, 5% due to lack of efficacy, and 5% for other reasons.

At the end of three years, 25% of patients receiving the NULOJIX recommended regimen and 34% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the NULOJIX recommended regimen, 12% discontinued due to lack of efficacy, 7% due to adverse events, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 15% discontinued due to adverse events, 8% due to lack of efficacy, and 11% for other reasons.

Assessment of Glomerular Filtration Rate (GFR)

Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 8, both measured and calculated GFR was higher in patients treated with the NULOJIX recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 1, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between three and 36 months demonstrated an increase of 0.8 mL/min/year (95% CI [−0.2, 1.8]) for NULOJIX-treated patients and a decrease of 2.2 mL/min/year (95% CI [−3.2, −1.2]) for cyclosporine-treated patients.

Table 8: Measured and Calculated GFR for Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys

Parameter	NULOJIX Recommended Regimen N=226	Cyclosporine (CSA) N=221	NULOJIX-CSA (97.3% CI)
a  GFR was measured using the cold-iothalamate method. b  Measured GFR was not assessed at Year 3. c  GFR was calculated using the MDRD formula.
Measured GFRa mL/min/1.73 m2 mean (SD)
Year 1	63.4 (27.7)	50.4 (18.7)	13.0 (7.3, 18.7)
	(n=206)	(n=199)
Year 2b	67.9 (29.9)	50.5 (20.5)	17.4 (11.5, 23.4)
	(n=199)	(n=185)
Calculated GFRc mL/min/1.73 m2 mean (SD)
Year 1	65.4 (22.9)	50.1 (21.1)	15.3 (10.3, 20.3)
	(n=200)	(n=199)
Year 2	65.4 (25.2)	47.9 (23)	17.5 (12, 23.1)
	(n=201)	(n=182)
Year 3	65.8 (27)	44.4 (23.6)	21.4 (15.4, 27.4)
	(n=190)	(n=171)

Figure 1: Calculated (MDRD) GFR Through Month 36; Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys

Study 2: Recipients of Extended Criteria Donor Kidneys

In Study 2 (NCT00114777), 543 patients were enrolled, randomized, and transplanted: 175 to the NULOJIX recommended regimen, 184 to the NULOJIX regimen with higher cumulative doses and more frequent dosing than recommended, and 184 to the cyclosporine control regimen. The median age was 58 years; 67% of the study population was male; 75% of patients were white, 13% were black/African-American, 12% were categorized as of other races; 3% had PRA ≥10%; 53% had 4 to 6 HLA mismatches; and 29% had diabetes prior to transplantation. The incidence of delayed graft function was similar in all treatment arms (47% to 49%).

Premature discontinuation from treatment at the end of the first year occurred in 25% of patients receiving the NULOJIX recommended regimen and 30% of patients receiving the cyclosporine control regimen. Among the patients who received the NULOJIX recommended regimen, 14% discontinued due to adverse events, 9% due to lack of efficacy, and 2% for other reasons. Among the patients who received the cyclosporine regimen, 17% discontinued due to adverse events, 7% due to lack of efficacy, and 6% for other reasons.

At the end of three years, 35% of patients receiving the NULOJIX recommended regimen and 44% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the NULOJIX recommended regimen, 20% discontinued due to adverse events, 9% due to lack of efficacy, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 25% discontinued due to adverse events, 10% due to lack of efficacy, and 10% for other reasons.

Assessment of Glomerular Filtration Rate (GFR)

Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 10, both measured and calculated GFR was higher in patients treated with the NULOJIX recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 2, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between Month 3 and Month 36 demonstrated a decrease of 0.8 mL/min/year (95% CI [−1.9, 0.3]) for NULOJIX-treated patients and a decrease of 2.0 mL/min/year (95% CI [−3.1, −0.8]) for cyclosporine-treated patients.

Table 10: Measured and Calculated GFR for Study 2: Recipients of Extended Criteria Donor Kidneys

Parameter	NULOJIX Recommended Regimen N=175	Cyclosporine (CSA) N=184	NULOJIX-CSA (97.3% CI)
a  GFR was measured using the cold-iothalamate method. b  Measured GFR was not assessed at Year 3. c  GFR was calculated using the MDRD formula.
Measured GFRa mL/min/1.73 m2 mean (SD)
Year 1	49.6 (25.8)	45.2 (21.1)	4.3 (−1.5, 10.2)
	(n=151)	(n=154)
Year 2b	49.7 (23.7)	45.0 (27.2)	4.7 (−1.8, 11.3)
	(n=139)	(n=136)
Calculated GFRc mL/min/1.73 m2 mean (SD)
Year 1	44.5 (21.8)	36.5 (21.1)	8.0 (2.5, 13.4)
	(n=158)	(n=159)
Year 2	42.8 (24.1)	34.9 (21.6)	8.0 (1.9, 14)
	(n=158)	(n=154)
Year 3	42.2 (25.2)	31.5 (22.1)	10.7 (4.3, 17.2)
	(n=154)	(n=143)

Figure 2: Calculated (MDRD) GFR Through Month 36; Study 2: Recipients of Extended Criteria Donor Kidneys

Long-Term Extension of Study 1

In the LTE of Study 1, of the 666 originally randomized and transplanted patients, 457 (69%) patients enrolled into the LTE study: 73% (166/226) in the NULOJIX recommended regimen group, 71% (155/219) in the NULOJIX nonrecommended regimen group, and 62% (136/221) in the cyclosporine group. Fourteen (2%) patients who completed the assigned treatment at the end of Year 3 did not enroll into the LTE study: 4 in the NULOJIX recommended regimen group, 3 in the NULOJIX nonrecommended regimen group, and 7 in the cyclosporine group.

Of the 457 patients enrolled in the LTE study, 356 (79%) patients completed the assigned treatment at the end of Year 7: 82% (136/166) in the NULOJIX recommended regimen group, 83% (128/155) in the NULOJIX nonrecommended regimen group, and 68% (92/136) in the cyclosporine group. The most common reasons for discontinuation from the LTE study included adverse events and death.

Seven (4.2%) deaths and 2 (1.2%) graft losses were reported in the NULOJIX recommended regimen group while 7 (4.5%) deaths and no graft loss were reported in the NULOJIX nonrecommended regimen group, and 10 (7.4%) deaths and 6 (4.4%) graft losses were reported in the cyclosporine group.

No PTLD was reported in the NULOJIX groups while 1 case of non-CNS PTLD was reported in the cyclosporine group, in a patient who was EBV seropositive at the time of transplant.

No PML was reported in the NULOJIX groups while 1 case of PML was reported in the cyclosporine group at 82 months post-transplant (56 days after discontinuing therapy).

The higher calculated GFR observed in NULOJIX-treated patients compared to cyclosporine-treated patients during the first three years was maintained during the LTE period.

Long-Term Extension of Study 2

In the LTE of Study 2, of the 543 originally randomized and transplanted patients, 304 (56%) patients enrolled into the LTE study: 65% (113/175) in the NULOJIX recommended regimen group, 57% (104/184) in the NULOJIX nonrecommended regimen group, and 47% (87/184) in the cyclosporine group. Nineteen (3.5%) patients who completed the assigned treatment at the end of Year 3 did not enroll into the LTE study: 1 in the NULOJIX recommended regimen group, 5 in the NULOJIX nonrecommended regimen group, and 13 in the cyclosporine group.

Of the 304 patients enrolled in the LTE study, 215 (71%) patients completed the assigned treatment at the end of Year 7: 74% (84/113) in the NULOJIX recommended regimen group, 71% (74/104) in the NULOJIX nonrecommended regimen group, and 66% (57/87) in the cyclosporine group. The most common reasons for discontinuation from the LTE study included adverse events and death.

Twenty-one (18.6%) deaths and 1 (0.9%) graft loss were reported in the NULOJIX recommended regimen group while 14 (13.5%) deaths and 2 (1.9%) graft losses were reported in the NULOJIX nonrecommended regimen group, and 9 (10.3%) deaths and 6 (6.9%) graft losses were reported in the cyclosporine group.

Six cases of PTLD were reported among the three treatment groups: 4 in the NULOJIX recommended regimen group, 1 in the NULOJIX nonrecommended regimen group, and 1 in the cyclosporine group. Three of these cases (1 in each treatment group) occurred in patients who were EBV seropositive at the time of transplant and the other 3 cases (in NULOJIX recommended regimen) occurred in patients who were EBV seronegative. No case of PML was reported among the three treatment groups.

The higher mean calculated GFR observed in NULOJIX-treated patients compared to cyclosporine-treated patients during the first three years was maintained during the LTE period.

Post-Transplant Lymphoproliferative Disorder

The overall risk of PTLD, especially CNS PTLD, was elevated in NULOJIX-treated patients. Instruct patients to immediately report any of the following neurological, cognitive, or behavioral signs and symptoms during and after therapy with NULOJIX [see Boxed Warning and Warnings and Precautions (5.1)]:

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changes in mood or usual behavior

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confusion, problems thinking, loss of memory

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changes in walking or talking

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decreased strength or weakness on one side of the body

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changes in vision

Other Malignancies

Inform patients about the increased risk of malignancies, in addition to PTLD, while taking immunosuppressive therapy, especially skin cancer. Instruct patients to limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor. Instruct patients to look for any signs and symptoms of skin cancer, such as suspicious moles or lesions [see Warnings and Precautions (5.3)].

Progressive Multifocal Leukoencephalopathy

Cases of PML have been reported in NULOJIX-treated patients. Instruct patients to immediately report any of the following neurological, cognitive, or behavioral signs and symptoms during and after therapy with NULOJIX [see Warnings and Precautions (5.4)]:

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changes in mood or usual behavior

•

confusion, problems thinking, loss of memory

•

changes in walking or talking

•

decreased strength or weakness on one side of the body

•

changes in vision

Other Serious Infections

Inform patients about the increased risk of infection while taking immunosuppressive therapy. Instruct patients to adhere to antimicrobial prophylaxis regimens as prescribed. Tell patients to immediately report any signs and symptoms of infection during therapy with NULOJIX [see Warnings and Precautions (5.5)].

Immunizations

Inform patients that vaccinations may be less effective while they are being treated with NULOJIX. Advise patients that live vaccines should be avoided [see Warnings and Precautions (5.8)].

Pregnant Women and Nursing Mothers

Inform patients that NULOJIX has not been studied in pregnant women or nursing mothers so the effects of NULOJIX on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations (8.1)]. Instruct patients to tell their healthcare provider if they plan to breast-feed their infant [see Use in Specific Populations (8.2)].