DRUG DESCRIPTION
NULOJIX® (BELATACEPT), A SELECTIVE T-CELL COSTIMULATION BLOCKER, IS A SOLUBLE FUSION PROTEIN CONSISTING OF THE MODIFIED EXTRACELLULAR DOMAIN OF CTLA-4 FUSED TO A PORTION (HINGE-CH2-CH3 DOMAINS) OF THE FC DOMAIN OF A HUMAN IMMUNOGLOBULIN G1 ANTIBODY. BELATACEPT IS PRODUCED BY RECOMBINANT DNA TECHNOLOGY IN A MAMMALIAN CELL EXPRESSION SYSTEM. TWO AMINO ACID SUBSTITUTIONS (L104 TO E; A29 TO Y) WERE MADE IN THE LIGAND BINDING REGION OF CTLA-4. AS A RESULT OF THESE MODIFICATIONS, BELATACEPT BINDS CD80 AND CD86 MORE AVIDLY THAN ABATACEPT, THE PARENT CTLA4-IMMUNOGLOBULIN (CTLA4-IG) MOLECULE FROM WHICH IT IS DERIVED. THE MOLECULAR WEIGHT OF BELATACEPT IS APPROXIMATELY 90 KILODALTONS.
NULOJIX IS SUPPLIED AS A STERILE, WHITE OR OFF-WHITE LYOPHILIZED POWDER FOR INTRAVENOUS ADMINISTRATION. PRIOR TO USE, THE LYOPHILE IS RECONSTITUTED WITH A SUITABLE FLUID TO OBTAIN A CLEAR TO SLIGHTLY OPALESCENT, COLORLESS TO PALE YELLOW SOLUTION, WITH A PH IN THE RANGE OF 7.2 TO 7.8. SUITABLE FLUIDS FOR CONSTITUTION OF THE LYOPHILE INCLUDE SWFI, 0.9% NS, OR D5W [SEE DOSAGE AND ADMINISTRATION]. EACH 250 MG SINGLE-USE VIAL OF NULOJIX ALSO CONTAINS: MONOBASIC SODIUM PHOSPHATE (34.5 MG), SODIUM CHLORIDE (5.8 MG), AND SUCROSE (500 MG).
INDICATIONS
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 AND WARNINGS AND PRECAUTIONS].
USE OF NULOJIX FOR THE PROPHYLAXIS OF ORGAN REJECTION IN TRANSPLANTED ORGANS OTHER THAN KIDNEY HAS NOT BEEN ESTABLISHED [SEE WARNINGS AND PRECAUTIONS].
DOSAGE AND ADMINISTRATION
DOSAGE IN ADULT KIDNEY TRANSPLANT RECIPIENTS
NULOJIX SHOULD BE ADMINISTERED IN COMBINATION WITH BASILIXIMAB INDUCTION, MYCOPHENOLATE MOFETIL (MMF), AND CORTICOSTEROIDS. IN CLINICAL TRIALS THE MEDIAN (25TH 75TH PERCENTILE) CORTICOSTEROID DOSES WERE TAPERED TO APPROXIMATELY 15 MG (10-20 MG) PER DAY BY THE FIRST 6 WEEKS AND REMAINED AT APPROXIMATELY 10 MG (5-10 MG) PER DAY FOR THE FIRST 6 MONTHS POST-TRANSPLANT. CORTICOSTEROID UTILIZATION SHOULD BE CONSISTENT WITH THE NULOJIX CLINICAL TRIAL EXPERIENCE [SEE WARNINGS AND PRECAUTIONS AND CLINICAL STUDIES].
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 AND ADVERSE REACTIONS].
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 X10 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
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 ?M).
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.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
LYOPHILIZED POWDER FOR INJECTION: 250 MG PER VIAL.
STORAGE AND HANDLING
NULOJIX®(BELATACEPT) LYOPHILIZED POWDER FOR INTRAVENOUS INFUSION IS SUPPLIED AS A SINGLE-USE VIAL WITH A SILICONE-FREE DISPOSABLE SYRINGE IN THE FOLLOWING PACKAGING CONFIGURATION:
DESCRIPTION
NDC NUMBER
ONE 250-MG VIAL
ONE 12 ML SYRINGE
0003-0371-13
STORAGE
NULOJIX LYOPHILIZED POWDER IS STORED REFRIGERATED AT 2°-8°C (36°-46°F). PROTECT NULOJIX FROM LIGHT BY STORING IN THE ORIGINAL PACKAGE UNTIL TIME OF USE.
THE RECONSTITUTED SOLUTION SHOULD BE TRANSFERRED FROM THE VIAL TO THE INFUSION BAG OR BOTTLE IMMEDIATELY. THE NULOJIX INFUSION MUST BE COMPLETED WITHIN 24 HOURS OF CONSTITUTION OF THE NULOJIX LYOPHILIZED POWDER. IF NOT USED IMMEDIATELY, THE INFUSION SOLUTION MAY BE STORED UNDER REFRIGERATION CONDITIONS: 2°-8°C (36°-46°F) FOR UP TO 24 HOURS (A MAXIMUM OF 4 HOURS OF THE TOTAL 24 HOURS CAN BE AT ROOM TEMPERATURE: 20°-25°C [68°-77°F] AND ROOM LIGHT) [SEE DOSAGE AND ADMINISTRATION].
SIDE EFFECTS
THE MOST SERIOUS ADVERSE REACTIONS REPORTED WITH NULOJIX ARE:
PTLD, PREDOMINANTLY CNS PTLD, AND OTHER MALIGNANCIES [SEE BOXED WARNING AND WARNINGS AND PRECAUTIONS]
SERIOUS INFECTIONS, INCLUDING JC VIRUS-ASSOCIATED PML AND POLYOMA VIRUS NEPHROPATHY [SEE WARNINGS AND PRECAUTIONS]
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] 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]. 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].
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 AND WARNINGS AND PRECAUTIONS.]
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 CYCLOSPORINETREATED 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].
TABLE 2: SUMMARY OF PTLD REPORTED IN STUDIES 1, 2, AND 3 THROUGH THREE YEARS OF TREATMENT
TRIAL
NULOJIX NON-RECOMMENDED REGIMEN*
(N=477)
NULOJIX RECOMMENDED REGIMEN†
(N=472)
CYCLOSPORINE
(N=476)
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)
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
* 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.
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].
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].
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].
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].
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 (%)
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)
* 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.
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
%
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
24
HYPERGLYCEMIA
16
17
HYPOCALCEMIA
13
11
HYPERCHOLESTEROLEMIA
11
11
HYPOMAGNESEMIA
7
10
HYPERURICEMIA
5
12
PROCEDURAL COMPLICATIONS
GRAFT DYSFUNCTION
25
34
GENERAL DISORDERS
PERIPHERAL EDEMA
34
42
PYREXIA
28
26
BLOOD AND LYMPHATIC SYSTEM DISORDERS
ANEMIA
45
44
LEUKOPENIA
20
23
RENAL AND URINARY DISORDERS
HEMATURIA
16
18
PROTEINURIA
16
12
DYSURIA
11
11
RENAL TUBULAR NECROSIS
9
13
VASCULAR DISORDERS
HYPERTENSION
32
37
HYPOTENSION
18
12
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
COUGH
24
18
DYSPNEA
12
15
INVESTIGATIONS
BLOOD CREATININE INCREASED
15
20
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
ARTHRALGIA
17
13
BACK PAIN
13
13
NERVOUS SYSTEM DISORDERS
HEADACHE
21
18
DIZZINESS
9
10
TREMOR
8
17
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
ACNE
8
11
PSYCHIATRIC DISORDERS
INSOMNIA
15
18
ANXIETY
10
11
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
READ THE NULOJIX (BELATACEPT) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS »
DRUG INTERACTIONS
CYTOCHROME P450 SUBSTRATES
NO FORMAL DRUG INTERACTION STUDIES HAVE BEEN CONDUCTED WITH NULOJIX. OTHER BIOLOGIC THERAPIES THAT ARE CYTOKINES OR CYTOKINE MODULATORS HAVE BEEN SHOWN TO AFFECT THE EXPRESSION AND/OR FUNCTIONAL ACTIVITIES OF CYTOCHROME P450 (CYP450) ENZYMES IN VITRO AND/OR IN VIVO. IN VITRO STUDIES HAVE SHOWN THAT NULOJIX INHIBITS THE PRODUCTION OF CERTAIN CYTOKINES DURING AN ALLOIMMUNE RESPONSE. NO STUDIES IN KIDNEY TRANSPLANT PATIENTS HAVE BEEN CONDUCTED TO ASSESS IF NULOJIX INHIBITS CYTOKINE PRODUCTION IN VIVO. THE POTENTIAL FOR NULOJIX TO ALTER THE SYSTEMIC CONCENTRATIONS OF DRUGS THAT ARE CYP450 SUBSTRATES HAS NOT BEEN STUDIED; HOWEVER, IN THE EVENT THAT KIDNEY TRANSPLANT PATIENTS RECEIVING NULOJIX EXHIBIT SIGNS AND SYMPTOMS OF ALTERED EFFICACY OR ADVERSE EVENTS ASSOCIATED WITH COADMINISTERED DRUGS WHICH ARE KNOWN TO BE METABOLIZED BY CYP450, THE CLINICIAN SHOULD BE AWARE OF POTENTIALLY ALTERED CYP450 METABOLISM OF THESE DRUGS.
USE WITH MYCOPHENOLATE MOFETIL
IN A PHARMACOKINETIC SUBSTUDY OF STUDIES 1 AND 2, THE PLASMA CONCENTRATIONS OF MYCOPHENOLIC ACID (MPA) WERE MEASURED IN 41 PATIENTS WHO RECEIVED FIXED MYCOPHENOLATE MOFETIL (MMF) DOSES OF 500 MG 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.
CLINICIANS SHOULD BE AWARE THAT THERE IS ALSO A POTENTIAL CHANGE OF MPA EXPOSURE AFTER CROSSOVER FROM CYCLOSPORINE TO NULOJIX OR FROM NULOJIX TO CYCLOSPORINE IN PATIENTS CONCOMITANTLY RECEIVING MMF.
PRECAUTIONS
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
NULOJIX-TREATED PATIENTS HAVE AN INCREASED RISK FOR DEVELOPING POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD), PREDOMINANTLY INVOLVING THE CNS, COMPARED TO PATIENTS ON A CYCLOSPORINE-BASED REGIMEN [SEE ADVERSE REACTIONS AND TABLE 2]. AS THE TOTAL BURDEN OF IMMUNOSUPPRESSION IS A RISK FACTOR FOR PTLD, HIGHER THAN THE RECOMMENDED DOSES OR MORE FREQUENT DOSING OF NULOJIX AND HIGHER THAN RECOMMENDED DOSES OF CONCOMITANT IMMUNOSUPPRESSIVE AGENTS ARE NOT RECOMMENDED [SEE DOSAGE AND ADMINISTRATION]. 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].
OTHER RISK FACTORS
OTHER KNOWN RISK FACTORS FOR PTLD INCLUDE CYTOMEGALOVIRUS (CMV) INFECTION AND T-CELLDEPLETING THERAPY. T-CELL-DEPLETING THERAPIES TO TREAT ACUTE REJECTION SHOULD BE USED CAUTIOUSLY. CMV PROPHYLAXIS IS RECOMMENDED FOR AT LEAST 3 MONTHS AFTER TRANSPLANTATION.
PATIENTS WHO ARE EBV SEROPOSITIVE AND CMV SERONEGATIVE MAY BE AT INCREASED RISK FOR PTLD COMPARED TO PATIENTS WHO ARE EBV SEROPOSITIVE AND CMV SEROPOSITIVE [SEE ADVERSE REACTIONS]. SINCE CMV SERONEGATIVE PATIENTS ARE AT INCREASED RISK FOR CMV DISEASE (A KNOWN RISK FACTOR FOR PTLD), THE CLINICAL SIGNIFICANCE OF CMV SEROLOGY FOR PTLD REMAINS TO BE DETERMINED; HOWEVER, THESE FINDINGS SHOULD BE CONSIDERED WHEN PRESCRIBING NULOJIX.
MANAGEMENT OF IMMUNOSUPPRESSION
ONLY PHYSICIANS EXPERIENCED IN MANAGEMENT OF SYSTEMIC IMMUNOSUPPRESSANT THERAPY IN TRANSPLANTATION SHOULD PRESCRIBE NULOJIX. PATIENTS RECEIVING THE DRUG SHOULD BE MANAGED IN FACILITIES EQUIPPED AND STAFFED WITH ADEQUATE LABORATORY AND SUPPORTIVE MEDICAL RESOURCES. THE PHYSICIAN RESPONSIBLE FOR THE MAINTENANCE THERAPY SHOULD HAVE COMPLETE INFORMATION REQUISITE FOR THE FOLLOW-UP OF THE PATIENT [SEE BOXED WARNING].
OTHER MALIGNANCIES
PATIENTS RECEIVING IMMUNOSUPPRESSANTS, INCLUDING NULOJIX, ARE AT INCREASED RISK OF DEVELOPING MALIGNANCIES, IN ADDITION TO PTLD, INCLUDING THE SKIN [SEE BOXED WARNING]. 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. AS PML HAS BEEN ASSOCIATED WITH HIGH LEVELS OF OVERALL IMMUNOSUPPRESSION, THE RECOMMENDED DOSES AND FREQUENCY OF NULOJIX AND CONCOMITANT IMMUNOSUPPRESSIVES, INCLUDING MMF, SHOULD NOT BE EXCEEDED.
PHYSICIANS SHOULD CONSIDER PML IN THE DIFFERENTIAL DIAGNOSIS IN PATIENTS WITH NEW OR WORSENING NEUROLOGICAL, COGNITIVE, OR BEHAVIORAL SIGNS OR SYMPTOMS. PML IS USUALLY DIAGNOSED BY BRAIN IMAGING, CEREBROSPINAL FLUID (CSF) TESTING FOR JC VIRAL DNA BY POLYMERASE CHAIN REACTION (PCR), AND/OR BRAIN BIOPSY. CONSULTATION WITH A SPECIALIST (E.G., NEUROLOGIST AND/OR INFECTIOUS DISEASE) SHOULD BE CONSIDERED FOR ANY SUSPECTED OR CONFIRMED CASES OF PML.
IF PML IS DIAGNOSED, CONSIDERATION SHOULD BE GIVEN TO REDUCTION OR WITHDRAWAL OF IMMUNOSUPPRESSION TAKING INTO ACCOUNT THE RISK TO THE ALLOGRAFT.
OTHER SERIOUS INFECTIONS
PATIENTS RECEIVING IMMUNOSUPPRESSANTS, INCLUDING NULOJIX, ARE AT INCREASED RISK OF DEVELOPING BACTERIAL, VIRAL (CYTOMEGALOVIRUS [CMV] AND HERPES), FUNGAL, AND PROTOZOAL INFECTIONS, INCLUDING OPPORTUNISTIC INFECTIONS. THESE INFECTIONS MAY LEAD TO SERIOUS, INCLUDING FATAL, OUTCOMES [SEE BOXED WARNING AND ADVERSE REACTIONS].
PROPHYLAXIS FOR CYTOMEGALOVIRUS IS RECOMMENDED FOR AT LEAST 3 MONTHS AFTER TRANSPLANTATION. PROPHYLAXIS FOR PNEUMOCYSTIS JIROVECI IS RECOMMENDED AFTER TRANSPLANTATION.
TUBERCULOSIS
TUBERCULOSIS WAS MORE FREQUENTLY OBSERVED IN PATIENTS RECEIVING NULOJIX THAN CYCLOSPORINE IN CLINICAL TRIALS [SEE ADVERSE REACTIONS]. PATIENTS SHOULD BE EVALUATED FOR TUBERCULOSIS AND TESTED FOR LATENT INFECTION PRIOR TO INITIATING NULOJIX. TREATMENT OF LATENT TUBERCULOSIS INFECTION SHOULD BE INITIATED PRIOR TO NULOJIX USE.
POLYOMA VIRUS NEPHROPATHY
IN ADDITION TO CASES OF JC VIRUS-ASSOCIATED PML, CASES OF POLYOMA VIRUS-ASSOCIATED NEPHROPATHY (PVAN), MOSTLY DUE TO BK VIRUS INFECTION, HAVE BEEN REPORTED. PVAN IS ASSOCIATED WITH SERIOUS OUTCOMES; INCLUDING DETERIORATING RENAL FUNCTION AND KIDNEY GRAFT LOSS [SEE ADVERSE REACTIONS]. PATIENT MONITORING MAY HELP DETECT PATIENTS AT RISK FOR PVAN. REDUCTIONS IN IMMUNOSUPPRESSION SHOULD BE CONSIDERED FOR PATIENTS WHO DEVELOP EVIDENCE OF PVAN. PHYSICIANS SHOULD ALSO CONSIDER THE RISK THAT REDUCED IMMUNOSUPPRESSION REPRESENTS TO THE FUNCTIONING ALLOGRAFT.
LIVER TRANSPLANT
USE OF NULOJIX IN LIVER TRANSPLANT PATIENTS IS NOT RECOMMENDED [SEE BOXED WARNING]. IN A CLINICAL TRIAL OF LIVER TRANSPLANT PATIENTS, USE OF NULOJIX REGIMENS WITH MORE FREQUENT ADMINISTRATION OF BELATACEPT THAN ANY OF THOSE STUDIED IN KIDNEY TRANSPLANT, ALONG WITH MYCOPHENOLATE MOFETIL (MMF) AND CORTICOSTEROIDS, WAS ASSOCIATED WITH A HIGHER RATE OF GRAFT LOSS AND DEATH COMPARED TO THE TACROLIMUS CONTROL ARMS. IN ADDITION, TWO CASES OF PTLD INVOLVING THE LIVER ALLOGRAFT (ONE FATAL) AND ONE FATAL CASE OF PML WERE OBSERVED AMONG THE 147 PATIENTS RANDOMIZED TO NULOJIX. THE TWO CASES OF PTLD WERE REPORTED AMONG THE 140 EBV SEROPOSITIVE PATIENTS (1.4%). THE FATAL CASE OF PML WAS REPORTED IN A PATIENT RECEIVING HIGHER THAN RECOMMENDED DOSES OF NULOJIX AND MMF.
ACUTE REJECTION AND GRAFT LOSS WITH CORTICOSTEROID MINIMIZATION
IN POSTMARKETING EXPERIENCE, USE OF NULOJIX IN CONJUNCTION WITH BASILIXIMAB INDUCTION, MMF, AND CORTICOSTEROID MINIMIZATION TO 5 MG PER DAY BETWEEN DAY 3 AND WEEK 6 POST-TRANSPLANT WAS ASSOCIATED WITH AN INCREASED RATE AND GRADE OF ACUTE REJECTION, PARTICULARLY GRADE III REJECTION. THESE GRADE III REJECTIONS OCCURRED IN PATIENTS WITH 4 TO 6 HLA MISMATCHES. GRAFT LOSS WAS A CONSEQUENCE OF GRADE III REJECTION IN SOME PATIENTS.
CORTICOSTEROID UTILIZATION SHOULD BE CONSISTENT WITH THE NULOJIX CLINICAL TRIAL EXPERIENCE [SEE DOSAGE AND ADMINISTRATION AND CLINICAL STUDIES].
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.
PATIENT COUNSELING INFORMATION
SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE).
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]:
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 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].
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]:
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].
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].
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]. INSTRUCT PATIENTS TO TELL THEIR HEALTHCARE PROVIDER IF THEY PLAN TO BREAST-FEED THEIR INFANT [SEE USE IN SPECIFIC POPULATIONS].
NONCLINICAL TOXICOLOGY
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
A CARCINOGENICITY STUDY WAS NOT CONDUCTED WITH BELATACEPT. HOWEVER, A MURINE CARCINOGENICITY STUDY WAS CONDUCTED WITH ABATACEPT (A MORE ACTIVE ANALOG IN RODENTS) TO DETERMINE THE CARCINOGENIC POTENTIAL OF CD28 BLOCKADE. WEEKLY SUBCUTANEOUS INJECTIONS OF 20, 65, OR 200 MG PER KG OF ABATACEPT WERE ASSOCIATED WITH INCREASES IN THE INCIDENCE OF MALIGNANT LYMPHOMAS (ALL DOSES) AND MAMMARY GLAND TUMORS (INTERMEDIATE- AND HIGH-DOSE IN FEMALES) AT CLINICALLY RELEVANT EXPOSURES. THE MICE IN THIS STUDY WERE INFECTED WITH ENDOGENOUS MURINE LEUKEMIA AND MOUSE MAMMARY TUMOR VIRUSES WHICH ARE ASSOCIATED WITH AN INCREASED INCIDENCE OF LYMPHOMAS AND MAMMARY GLAND TUMORS, RESPECTIVELY, IN IMMUNOSUPPRESSED MICE. ALTHOUGH THE PRECISE RELEVANCE OF THESE FINDINGS TO THE CLINICAL USE OF NULOJIX IS UNKNOWN, CASES OF PTLD (A PREMALIGNANT OR MALIGNANT PROLIFERATION OF B LYMPHOCYTES) WERE REPORTED IN CLINICAL TRIALS.
GENOTOXICITY TESTING IS NOT REQUIRED FOR PROTEIN THERAPEUTICS; THEREFORE, NO GENOTOXICITY STUDIES WERE CONDUCTED WITH BELATACEPT.
BELATACEPT HAD NO ADVERSE EFFECTS ON MALE OR FEMALE FERTILITY IN RATS AT DOSES UP TO 200 MG PER KG DAILY (25 TIMES THE MRHD EXPOSURE).
USE IN SPECIFIC POPULATIONS
PREGNANCY
PREGNANCY CATEGORY C
NULOJIX SHOULD NOT BE USED IN PREGNANCY UNLESS THE POTENTIAL BENEFIT TO THE MOTHER OUTWEIGHS THE POTENTIAL RISK TO THE FETUS. THERE ARE NO STUDIES OF NULOJIX TREATMENT IN PREGNANT WOMEN. BELATACEPT IS KNOWN TO CROSS THE PLACENTA OF ANIMALS. BELATACEPT WAS NOT TERATOGENIC IN PREGNANT RATS AND RABBITS AT DOSES APPROXIMATELY 16 AND 19 TIMES GREATER THAN THE EXPOSURE ASSOCIATED WITH THE MAXIMUM RECOMMENDED HUMAN DOSE (MRHD) OF 10 MG PER KG ADMINISTERED OVER THE FIRST MONTH OF TREATMENT, BASED ON AREA UNDER THE CONCENTRATION-TIME CURVE (AUC).
BELATACEPT ADMINISTERED TO FEMALE RATS DAILY DURING GESTATION AND THROUGHOUT THE LACTATION PERIOD WAS ASSOCIATED WITH MATERNAL TOXICITY (INFECTIONS) IN A SMALL PERCENTAGE OF DAMS AT DOSES OF = 20 MG PER KG ( = 3 TIMES THE MRHD EXPOSURE BASED ON AUC) RESULTING IN INCREASED PUP MORTALITY (UP TO 100% PUP MORTALITY IN SOME DAMS). IN PUPS THAT SURVIVED, THERE WERE NO ABNORMALITIES OR MALFORMATIONS AT DOSES UP TO 200 MG PER KG (19 TIMES THE MRHD EXPOSURE).
IN VITRO DATA INDICATE THAT BELATACEPT HAS LOWER BINDING AFFINITY TO CD80/CD86 AND LOWER POTENCY IN RODENTS THAN IN HUMANS. ALTHOUGH THE RAT TOXICITY STUDIES WITH BELATACEPT WERE DONE AT PHARMACOLOGICALLY SATURATING DOSES, THE IN VIVO DIFFERENCE IN POTENCY BETWEEN RATS AND HUMANS IS UNKNOWN. THEREFORE, THE RELEVANCE OF THE RAT TOXICITIES TO HUMANS AND THE SIGNIFICANCE OF THE MAGNITUDE OF THE RELATIVE EXPOSURES (RATS: HUMANS) ARE UNKNOWN.
ABATACEPT, A FUSION PROTEIN THAT DIFFERS FROM BELATACEPT BY 2 AMINO ACIDS, BINDS TO THE SAME LIGANDS (CD80/CD86) AND BLOCKS T-CELL COSTIMULATION LIKE BELATACEPT, BUT IS MORE ACTIVE THAN BELATACEPT IN RODENTS. THEREFORE, TOXICITIES IDENTIFIED WITH ABATACEPT IN RODENTS, INCLUDING INFECTIONS AND AUTOIMMUNITY, MAY BE PREDICTIVE OF ADVERSE EFFECTS IN HUMANS TREATED WITH BELATACEPT [SEE NONCLINICAL TOXICOLOGY].
AUTOIMMUNITY WAS OBSERVED IN ONE RAT OFFSPRING EXPOSED TO ABATACEPT IN UTERO AND/OR DURING LACTATION AND IN JUVENILE RATS AFTER TREATMENT WITH ABATACEPT. HOWEVER, THE CLINICAL RELEVANCE OF AUTOIMMUNITY IN RATS TO PATIENTS OR A FETUS EXPOSED IN UTERO IS UNKNOWN [SEE NONCLINICAL TOXICOLOGY].
PREGNANCY REGISTRY
TO MONITOR MATERNAL-FETAL OUTCOMES OF PREGNANT WOMEN WHO HAVE RECEIVED NULOJIX OR WHOSE PARTNERS HAVE RECEIVED NULOJIX, HEALTHCARE PROVIDERS ARE STRONGLY ENCOURAGED TO REGISTER PREGNANT PATIENTS IN THE NATIONAL TRANSPLANT PREGNANCY REGISTRY (NTPR) BY CALLING 1-877-955-6877.
NURSING MOTHERS
IT IS NOT KNOWN WHETHER BELATACEPT IS EXCRETED IN HUMAN MILK OR ABSORBED SYSTEMICALLY AFTER INGESTION BY A NURSING INFANT. HOWEVER, BELATACEPT IS EXCRETED IN RAT MILK. BECAUSE MANY DRUGS ARE EXCRETED IN HUMAN MILK AND BECAUSE OF THE POTENTIAL FOR SERIOUS ADVERSE REACTIONS FROM NULOJIX IN NURSING INFANTS, A DECISION SHOULD BE MADE WHETHER TO DISCONTINUE NURSING OR TO DISCONTINUE THE DRUG, TAKING INTO ACCOUNT THE IMPORTANCE OF THE DRUG TO THE MOTHER.
PEDIATRIC USE
THE SAFETY AND EFFICACY OF NULOJIX IN PATIENTS UNDER 18 YEARS OF AGE HAVE NOT BEEN ESTABLISHED. BECAUSE T CELL DEVELOPMENT CONTINUES INTO THE TEENAGE YEARS, THE POTENTIAL CONCERN FOR AUTOIMMUNITY IN NEONATES APPLIES TO PEDIATRIC USE AS WELL.
GERIATRIC USE
OF 401 PATIENTS TREATED WITH THE RECOMMENDED DOSAGE REGIMEN OF NULOJIX, 15% WERE 65 YEARS OF AGE AND OLDER, WHILE 3% WERE 75 AND OLDER. NO OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN THESE SUBJECTS AND YOUNGER SUBJECTS, BUT GREATER SENSITIVITY OR LESS EFFICACY IN OLDER INDIVIDUALS CANNOT BE RULED OUT.
OVERDOSE
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.
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].
CLINICAL PHARMACOLOGY
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-G, INTERLEUKIN-4, AND TNF-?. 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.
TRANSPLANTATION. AS SHOWN IN TABLE 8, BOTH MEASU