Belatacept

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]. 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.

Mechanism Of Action

Belatacept, a selective T-cell (lymphocyte) costimulation blocker, binds to CD80 and CD86 on antigen-presenting cells thereby blocking CD28 mediated costimulation of T lymphocytes. In vitro, belatacept inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-γ, interleukin-4, and TNF-α. Activated T lymphocytes are the predominant mediators of immunologic rejection.

In non-human primate models of renal transplantation, belatacept monotherapy prolonged graft survival and decreased the production of anti-donor antibodies, compared to vehicle.

Pharmacodynamics

Belatacept-mediated costimulation blockade results in the inhibition of cytokine production by T cells required for antigen-specific antibody production by B cells. In clinical trials, greater reductions in mean immunoglobulin (IgG, IgM, and IgA) concentrations were observed from baseline to Month 6 and Month 12 post-transplant in belatacept-treated patients compared to cyclosporine-treated patients. In an exploratory subset analysis, a trend of decreasing IgG concentrations with increasing belatacept trough concentrations was observed at Month 6. Also in this exploratory subset analysis, belatacept-treated patients with CNS PTLD, CNS infections including PML, other serious infections, and malignancies were observed to have a higher incidence of IgG concentrations below the lower limit of the normal range (<694 mg/dL) at Month 6 than those patients who did not experience these adverse events. This observation was more pronounced with the higher than recommended dose of belatacept. A similar trend was also observed for cyclosporine-treated patients with serious infections and malignancies.

However, it is unclear whether any causal relationship between an IgG concentration below the lower level of normal and these adverse events exists, as the analysis may have been confounded by other factors (e.g., age greater than 60 years, receipt of an extended criteria donor kidney, exposure to lymphocyte depleting agents) which were also associated with IgG below the lower level of normal at Month 6 in these trials.

Pharmacokinetics

Table 5 summarizes the pharmacokinetic parameters of belatacept in healthy adult subjects after a single 10 mg per kg intravenous infusion; and in kidney transplant patients after the 10 mg per kg intravenous infusion at Week 12, and after 5 mg per kg intravenous infusion every 4 weeks at Month 12 post-transplant or later.

Table 5: Pharmacokinetic Parameters (Mean±SD [Range]) of Belatacept in Healthy Subjects and Kidney Transplant Patients After 5 and 10 mg per kg Intravenous Infusions Administered Over 30 Minutes

In healthy subjects, the pharmacokinetics of belatacept was linear and the exposure to belatacept increased proportionally after a single intravenous infusion dose of 1 to 20 mg per kg. The pharmacokinetics of belatacept in de novo kidney transplant patients and healthy subjects are comparable. Following the recommended regimen, the mean belatacept serum concentration reached steady-state by Week 8 in the initial phase following transplantation and by Month 6 during the maintenance phase. Following once monthly intravenous infusion of 10 mg per kg and 5 mg per kg, there was about 20% and 10% systemic accumulation of belatacept in kidney transplant patients, respectively.

Based on population pharmacokinetic analysis of 924 kidney transplant patients up to 1 year post-transplant, the pharmacokinetics of belatacept were similar at different time periods post-transplant. In clinical trials, trough concentrations of belatacept were consistently maintained from Month 6 up to 3 years post-transplant. Population pharmacokinetic analyses in kidney transplant patients revealed that there was a trend toward higher clearance of belatacept with increasing body weight. Age, gender, race, renal function (measured by calculated glomerular filtration rate [GFR]), hepatic function (measured by albumin), diabetes, and concomitant dialysis did not affect the clearance of belatacept.

Drug Interactions

In a pharmacokinetic substudy of Studies 1 and 2, the plasma concentrations of MPA were measured in 41 patients who received fixed MMF doses of 500 to 1500 mg twice daily with either 5 mg per kg of NULOJIX or cyclosporine. The mean dose-normalized MPA Cmax and AUC0-12 were approximately 20% and 40% higher, respectively, with NULOJIX coadministration than with cyclosporine coadministration [see DRUG INTERACTIONS].

The potential of NULOJIX to alter the systemic concentrations of drugs that are CYP450 substrates was investigated in healthy subjects following administration of a cocktail of probe drugs given concomitantly with, and at 3 days and at 7 days following a single intravenous 10 mg per kg dose of NULOJIX. NULOJIX did not alter the pharmacokinetics of drugs that are substrates of CYP1A2 (caffeine), CYP2C9 (losartan), CYP2D6 (dextromethorphan), CYP3A (midazolam), and CYP2C19 (omeprazole) [see DRUG INTERACTIONS].

Animal Toxicology And/Or Pharmacology

Abatacept, a fusion protein that differs from belatacept by 2 amino acids, binds to the same ligands (CD80/CD86) and blocks T-cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents may be predictive of adverse effects in humans treated with belatacept.

Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (observed in juvenile rats and pregnant rats) as well as autoimmunity of the thyroid and pancreas (observed in rats exposed in utero, as juveniles or as adults). Studies of abatacept in adult mice and monkeys, as well as belatacept in adult monkeys, have not demonstrated similar findings.

The increased susceptibility to opportunistic infections observed in juvenile rats is likely associated with the exposure to abatacept before the complete development of memory immune responses. In pregnant rats, the increased susceptibility to opportunistic infections may be due to the inherent lapses in immunity that occur in rats during late pregnancy/lactation. Infections related to NULOJIX have been observed in human clinical trials [see WARNINGS AND PRECAUTIONS].

Administration of abatacept to rats was associated with a significant decrease in T-regulatory cells (up to 90%). Deficiency of T-regulatory cells in humans has been associated with autoimmunity. The occurrence of autoimmune events across the core clinical trials was infrequent. However, the possibility that patients administered NULOJIX could develop autoimmunity (or that fetuses exposed to NULOJIX in utero could develop autoimmunity) cannot be excluded.

In a 6-month toxicity study with belatacept in cynomolgus monkeys administered weekly doses up to 50 mg per kg (6 times the MRHD exposure) and in a 1-year toxicity study with abatacept in adult cynomolgus monkeys administered weekly doses up to 50 mg per kg, no significant drug-related toxicities were observed. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes.

Following 5 doses (10 mg per kg or 50 mg per kg, once a week for 5 weeks) of systemic administration, belatacept was not detected in brain tissue of normal healthy cynomolgus monkeys. The number of cells expressing major histocompatibility complex (MHC) class-II antigens (potential marker of immune cell activation) in the brain were increased in monkeys administered belatacept compared to vehicle control. However, distribution of some other cells expressing CD68, CD20, CD80, and CD86, typically expressed on MHC class II-positive cells, was not altered and there were no other histological changes in the brain. The clinical relevance of the findings is unknown.

Clinical Studies

Prevention Of Organ Rejection In Kidney Transplant Recipients

The efficacy and safety of NULOJIX in de novo kidney transplantation were assessed in two open-label, randomized, multicenter, active-controlled trials (Study 1 and Study 2). These trials evaluated two dose regimens of NULOJIX, the recommended dosage regimen [see DOSAGE AND ADMINISTRATION] and a regimen with higher cumulative doses and more frequent dosing than the recommended dosage regimen, compared to a cyclosporine control regimen. All treatment groups also received basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids.

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 4 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 4 weeks (plus or minus 3 days). NULOJIX was administered as an intravenous infusion over 30 minutes [see DOSAGE AND ADMINISTRATION].

Basiliximab 20 mg was administered intravenously on the day of transplantation and 4 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).

Table 6: Actual Corticosteroid* Dosing in Studies 1 and 2

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, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS].

In Study 1, 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 Efficacy

Table 7 summarizes the results of Study 1 following one and three years of treatment with the NULOJIX recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed separately.

Table 7: Efficacy Outcomes by Years 1 and 3 for Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys

In Study 1, the rate of BPAR at one year and three years was higher in patients treated with the NULOJIX recommended regimen than the cyclosporine regimen. Of the patients who experienced BPAR with NULOJIX, 70% experienced BPAR by Month 3, and 84% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups (<3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups.

Patients treated with the NULOJIX recommended regimen experienced episodes of BPAR classified as Banff grade IIb or higher (6% [14/226] at one year and 7% [15/226] at three years) more frequently compared to patients treated with the cyclosporine regimen (2% [4/221] at one year and 2% [5/221] at three years). Also, T-cell depleting therapy was used more frequently to treat episodes of BPAR in NULOJIX-treated patients (10%; 23/226) compared to cyclosporine-treated patients (2%; 5/221). At Month 12, the difference in mean calculated glomerular filtration rate (GFR) between patients with and without history of BPAR was 19 mL/min/1.73 m2 among NULOJIXtreated patients compared to 7 mL/min/1.73 m2 among cyclosporine-treated patients. By three years, 22% (11/50) of NULOJIX-treated patients with a history of BPAR experienced graft loss and/or death compared to 10% (3/31) of cyclosporine-treated patients with a history of BPAR; at that time point, 10% (5/50) of NULOJIX-treated patients experienced graft loss and 12% (6/50) of NULOJIX-treated patients had died following an episode of BPAR, whereas 7% (2/31) of cyclosporine-treated patients experienced graft loss and 7% (2/31) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 5% and 11% for the NULOJIX recommended regimen and cyclosporine, respectively, up to 36 months post-transplant.

While the difference in GFR in patients with BPAR versus those without BPAR was greater in patients treated with NULOJIX than cyclosporine, the mean GFR following BPAR was similar in NULOJIX (49 mL/min/1.73 m2) and cyclosporine treated patients (43 mL/min/1.73 m2) at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR.

Assessment of Efficacy in the EBV Seropositive Subpopulation

NULOJIX is recommended for use only in EBV seropositive patients [see INDICATIONS AND USAGE].

In Study 1, approximately 87% of patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied.

By one year, the efficacy failure rate in the EBV seropositive population was 21% (42/202) in patients treated with the NULOJIX recommended regimen and 17% (31/184) in patients treated with cyclosporine (difference=4%, 97.3% CI [−4.8, 12.8]). Patient and graft survival was 98% (198/202) in NULOJIX-treated patients and 92% (170/184) in cyclosporine-treated patients (difference=5.6%, 97.3% CI [0.8, 10.4]).

By three years, efficacy failure was 25% in both treatment groups and patient and graft survival was 94% (187/202) in NULOJIX-treated patients compared with 88% (162/184) in cyclosporine-treated patients (difference=4.6%, 97.3% CI [−2.1, 11.3]).

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 Liv ing and Standard Criteria Deceased Donor Kidneys

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

Assessment of Chronic Allograft Nephropathy (CAN)

The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff ’97 classification system, was 24% (54/226) in patients treated with the NULOJIX recommended regimen and in 32% (71/219) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown.

In Study 2, 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 Efficacy

Table 9 summarizes the results of Study 2 following one and three years of treatment with the NULOJIX recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed.

Table 9: Efficacy Outcomes by Years 1 and 3 for Study 2: Recipients of Extended Criteria Donor Kidneys

In Study 2, the rate of BPAR at one year and three years was similar in patients treated with NULOJIX and cyclosporine. Of the patients who experienced BPAR with NULOJIX, 62% experienced BPAR by Month 3, and 76% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups (<3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups.

A similar proportion of patients in the NULOJIX recommended regimen group experienced BPAR classified as Banff grade IIb or higher (5% [9/175] at one year and 6% [10/175] at three years) compared to patients treated with the cyclosporine regimen (4% [7/184] at one year and 5% [9/184] at three years). Also, T-cell depleting therapy was used with similar frequency to treat any episode of BPAR in NULOJIXtreated patients (5% or 9/175) compared to cyclosporine-treated patients (4% or 7/184). At Month 12, the difference in mean calculated GFR between patients with and without a history of BPAR was 10 mL/min/1.73 m2 among NULOJIX-treated patients compared to 14 mL/min/1.73 m2 among cyclosporine-treated patients. By three years, 24% (10/42) of NULOJIX-treated patients with a history of BPAR experienced graft loss and/or death compared to 31% (13/42) of cyclosporine-treated patients with a history of BPAR; at that time point, 17% (7/42) of NULOJIX-treated patients experienced graft loss and 14% (6/42) of NULOJIX-treated patients had died following an episode of BPAR, whereas 19% (8/42) of cyclosporine-treated patients experienced graft loss and 19% (8/42) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 6% and 15% for the NULOJIX recommended regimen and cyclosporine, respectively, up to 36 months post-transplant.

The mean GFR following BPAR was 36 mL/min/1.73 m2 in NULOJIX patients and 24 mL/min/1.73 m2 in cyclosporine-treated patients at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR.

Assessment of Efficacy in the EBV Seropositive Subpopulation

NULOJIX is recommended for use only in EBV seropositive patients [see INDICATIONS AND USAGE].

In Study 2, approximately 91% of the patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied.

By one year, the efficacy failure rate in the EBV seropositive population was 29% (45/156) in patients treated with the NULOJIX recommended regimen and 28% (47/168) in patients treated with cyclosporine (difference=0.8%, 97.3% CI [−10.3, 11.9]). Patient and graft survival rate in the EBV seropositive population was 89% (139/156) in the NULOJIX-treated patients and 86% (144/168) in cyclosporine-treated patients (difference=3.4%, 97.3% CI [−4.7, 11.5]).

By three years, efficacy failure was 35% (54/156) in NULOJIX-treated patients and 36% (61/168) in cyclosporine-treated patients. Patient and graft survival was 83% (130/156) in NULOJIX-treated patients compared with 77% (130/168) in cyclosporinetreated patients (difference=5.9%, 97.3% CI [−3.8, 15.6]).

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

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

Assessment of Chronic Allograft Nephropathy (CAN)

The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff ’97 classification system, was 46% (80/174) in patients treated with the NULOJIX recommended regimen and 52% (95/184) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown.

Mechanism of Action

Monoclonal antibody; inhibits T-cell CD28 activation and proliferation by binding costimulatory ligands (CD80, CD86) of antigen presenting cells

Inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-alpha, interleukin-4, and TNF-alpha

Activated T lymphocytes are the predominant mediators of immunologic rejection

Pharmacokinetics

After single and multiple doses

Peak Plasma Concentration: 139-300 mcg/mL

AUC: 14.1-26.4 mg•h/mL

Vd: 0.09-0.12 L/kg

Half-life: 8.2-9.8 days

Total body clearance: 0.39-0.51 mL/hr/kg

Belatacept lowers your body's immune system. The immune system helps your body fight infections. The immune system can also fight or "reject" a transplanted organ such as a kidney. This is because the immune system treats the new organ as an invader.

Belatacept is used in combination with other medicines to prevent organ rejection after a kidney transplant.

Belatacept may also be used for purposes not listed in this medication guide.

You should not receive belatacept if you are allergic to it, or:

• if you have never been exposed to Epstein-Barr virus (your doctor will perform a test to confirm this); or

• if you have ever received a liver transplant.

Talk with your doctor about the risks and benefits of using this medicine. Belatacept can lower blood cells that help fight infection, and may cause you to produce too much of a certain type of white blood cell. This can lead to serious conditions including cancer, severe brain infection causing disability or death, or a viral infection causing kidney transplant failure.

To make sure belatacept is safe for you, tell your doctor if you have:

• cytomegalovirus (CMV); or

• if you are scheduled to receive any vaccine.

It is not known whether belatacept will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

If you are pregnant, or you are a man and your sexual partner is pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of belatacept on the baby.

It is not known whether belatacept passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using belatacept.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Serious and sometimes fatal infections may occur. Call your doctor right away if you have signs of infection such as:

• fever, swollen glands, flu symptoms, night sweats, stomach pain, vomiting, diarrhea, weight loss;

• any change in your mental state, weakness on one side of your body, decreased vision, problems with speech or walking;

• blood in your urine, painful or difficult urination, little or no urinating;

• pain on the side where you received the transplanted kidney; or

• a new skin lesion, or a mole that has changed in size or color.

Also call your doctor at once if you have:

• low potassium--constipation, numbness or tingling, tiredness, muscle weakness, slow heart rate, fainting;

• high potassium--nausea, slow or unusual heart rate, weakness, loss of movement; or

• low red blood cells (anemia)--pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating.

Common side effects may include:

• nausea, diarrhea, constipation;

• headache;

• cough;

• fever; or

• swelling in your hands or feet.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other drugs may interact with belatacept, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Renal Allotransplantation

Prevention of renal allograft rejection in adults1 4 5 7 8 9 10 11 12 (designated an orphan drug by FDA for this use2

Use only in EBV-seropositive patients.1 (See Boxed Warning and also see PTLD under Cautions.)

Manufacturer recommends use in conjunction with basiliximab induction, mycophenolate mofetil, and corticosteroids.1

Transplantation of Other Solid Organs

Use in preventing organ rejection in transplanted solid organs other than kidney not established.1

Has been used for prevention of rejection of liver allografts†; however, manufacturer states use in liver transplant patients is not recommended because of an increased risk of graft loss and death.1 (See Use in Liver Transplantation under Cautions.)

General

• Premedication not required prior to administration.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.1

Administer only by IV infusion.1

Must reconstitute and dilute belatacept lyophilized powder prior to administration.1 Complete IV infusion within 24 hours of reconstitution.1

Administer with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (pore diameter of 0.2–1.2 mcm).1

Do not infuse other drugs simultaneously in the same IV line.1

Consult manufacturer’s labeling for additional information on reconstitution, dilution, and administration.1

Use only the silicone-free disposable syringe provided with each vial to reconstitute the drug.1 If accidentally reconstituted using a different syringe, translucent particles may develop in the solution; discard any solution prepared using siliconized syringes.1

Reconstitute the appropriate number of vials containing 250 mg of belatacept lyophilized powder by adding 10.5 mL of sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection to produce a solution containing 25 mg/mL.1

Direct diluent toward side of vial; rotate vial and invert with gentle swirling to minimize foaming.1 Avoid prolonged and vigorous agitation of the vial and do not shake.1

Must be diluted further before IV infusion.1

To further dilute belatacept, use 0.9% sodium chloride injection (if reconstituted with sterile water for injection or 0.9% sodium chloride injection) or 5% dextrose injection (if reconstituted with sterile water for injection or 5% dextrose injection).1

Withdraw a volume of infusion fluid equal to the required volume of reconstituted belatacept solution from an appropriately sized infusion container.1

Using same silicone-free disposable syringe used for reconstitution, inject the required volume of reconstituted belatacept solution into the infusion container; gently rotate infusion container to ensure mixing.1

Final belatacept concentration should range from 2–10 mg/mL.1 Infusion volume of 100 mL is appropriate for most patients and doses, but infusion volumes of 50–250 mL may be used.1

Infuse over 30 minutes.1

Dosage

Base total infusion dose on actual body weight at the time of transplantation; do not modify during the course of therapy unless body weight changes by >10%.1

To be prepared accurately, prescribed dose must be evenly divisible by 12.5 mg.1

Adults

Initial phase: 10 mg/kg on day of transplantation (prior to implantation, day 1), day 5 (approximately 96 hours after day 1 dose), and at the end of weeks 2, 4, 8, and 12 after transplantation.1

Maintenance phase: 5 mg/kg at the end of week 16 after transplantation and then every 4 weeks (plus or minus 3 days) thereafter.1

Prescribing Limits

Adults

Higher than recommended doses or more frequent administration not recommended because of increased risk of PTLD predominantly involving the CNS, progressive multifocal leukoencephalopathy (PML), and serious CNS infections.1 (See Cautions.)

Special Populations

Manufacturer currently makes no special population dosage recommendations.1 In pharmacokinetic studies in kidney transplant recipients, age, gender, race, renal function, hemodialysis, and hepatic function did not affect clearance of belatacept.1 6 16

• Selective T-Cell Costimulation Blocker

Increased risk for developing posttransplant lymphoproliferative disorder, predominantly involving the CNS. Recipients without immunity to Epstein-Barr virus are at a particularly increased risk; therefore, use in Epstein-Barr virus–seropositive patients only. Do not use belatacept in transplant recipients who are Epstein-Barr virus seronegative or with unknown Epstein-Barr virus serostatus.

Only health care providers experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe belatacept. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression.

Use in liver transplant patients is not recommended because of an increased risk of graft loss and death.

Initial phase dose: 10 mg/kg IV on Day 1 (day of transplant, prior to implantation) and Day 5 (approximately 96 hours after Day 1 dose), and at the end of Weeks 2, 4, 8, and 12 after transplantation

Maintenance phase dose: 5 mg/kg IV at the end of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter

Comments:
-This drug should be administered in combination with basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids.
-Dosing is based on actual body weight at the time of transplantation. The dose should not be modified during therapy unless body weight changes by more than 10%.
-The prescribed dose should be evenly divisible by 12.5 mg to allow accurate preparation of the solution (i.e., the calculated dose for a 64 kg patient: 64 kg x 10 mg per kg = 640 mg; the nearest doses to 640 mg that are evenly divisible by 12.5 mg would be 637.5 mg or 650 mg; the closest dose to the calculated dose is 637.5 mg; therefore, 637.5 should be the actual prescribed dose).

Use: In combination with basiliximab induction, mycophenolate mofetil, and corticosteroids for prophylaxis of organ rejection in EBV seropositive adult patients receiving a kidney transplant

Administration advice:
-This drug is for IV administration only. Therapeutic monitoring is not necessary.
-Therapy should be initiated under the supervision of a specialist clinician experienced in the management of immunosuppressive therapy and renal transplant patients.
-The total infusion dose 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 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.
-Patients do not need premedication prior to administration of this drug