INDICATIONS
INDICATION
VORAXAZE (GLUCARPIDASE) IS INDICATED FOR THE TREATMENT OF TOXIC PLASMA METHOTREXATE CONCENTRATIONS ( > 1 MICROMOLE PER LITER) IN PATIENTS WITH DELAYED METHOTREXATE CLEARANCE DUE TO IMPAIRED RENAL FUNCTION.
LIMITATION OF USE
VORAXAZE IS NOT INDICATED FOR USE IN PATIENTS WHO EXHIBIT THE EXPECTED CLEARANCE OF METHOTREXATE (PLASMA METHOTREXATE CONCENTRATIONS WITHIN 2 STANDARD DEVIATIONS OF THE MEAN METHOTREXATE EXCRETION CURVE SPECIFIC FOR THE DOSE OF METHOTREXATE ADMINISTERED) OR THOSE WITH NORMAL OR MILDLY IMPAIRED RENAL FUNCTION BECAUSE OF THE POTENTIAL RISK OF SUBTHERAPEUTIC EXPOSURE TO METHOTREXATE.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
LYOPHILIZED POWDER 1,000 UNITS PER VIAL
STORAGE AND HANDLING
VORAXAZE IS SUPPLIED AS A STERILE, PRESERVATIVE-FREE WHITE LYOPHILIZED POWDER IN AN INDIVIDUALLY PACKAGED GLASS VIAL CLOSED WITH A BROMO BUTYL ELASTOMERIC STOPPER AND BLUE FLIP-OFF SEAL.
1,000 UNITS OF GLUCARPIDASE PER VIAL (1 VIAL PER CARTON) NDC 50633-210-11
STORE VORAXAZE AT 36°F TO 46°F (2°C TO 8°C). DO NOT FREEZE. DO NOT USE VORAXAZE AFTER THE EXPIRATION DATE ON THE VIAL.
MANUFACTURED BY: BTG INTERNATIONAL INC., BRENTWOOD, TN 37027. DISTRIBUTED BY: BTG INTERNATIONAL INC., WEST CONSHOHOCKEN, PA 19428. REVISED: MARCH 2013
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSE
ADMINISTER VORAXAZE AS A SINGLE INTRAVENOUS INJECTION OF 50 UNITS PER KG.
ADMINISTRATION
ADMINISTER VORAXAZE INTRAVENOUSLY AS A BOLUS INJECTION OVER 5 MINUTES. FLUSH INTRAVENOUS LINE BEFORE AND AFTER ADMINISTRATION OF VORAXAZE.
PREPARATION
1. RECONSTITUTE THE CONTENTS OF THE VIAL WITH 1 ML OF STERILE SALINE FOR INJECTION, USP.
2. ROLL AND TILT THE VIAL GENTLY TO MIX. DO NOT SHAKE.
3. INSPECT THE VIAL AND DISCARD VORAXAZE IF THE SOLUTION IS NOT CLEAR, COLORLESS, AND FREE OF PARTICULATE MATTER.
4. USE RECONSTITUTED VORAXAZE IMMEDIATELY OR STORE UNDER REFRIGERATION AT 36° TO 46°F (2° TO 8°C) FOR UP TO 4 HOURS IF NOT USED IMMEDIATELY. VORAXAZE CONTAINS NO PRESERVATIVE AND IS SUPPLIED AS A SINGLE-USE VIAL. DISCARD ANY UNUSED PRODUCT [SEE STORAGE AND HANDLING].
SIDE EFFECTS
SERIOUS ALLERGIC REACTIONS, INCLUDING ANAPHYLACTIC REACTIONS, MAY OCCUR. THE MOST COMMON ADVERSE REACTIONS (INCIDENCE > 1%) WITH VORAXAZE ARE PARAESTHESIAS, FLUSHING, NAUSEA AND/OR VOMITING, HYPOTENSION, AND HEADACHE.
CLINICAL TRIALS EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER CONTROLLED BUT WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN CLINICAL TRIALS OF VORAXAZE CANNOT BE DIRECTLYCOMPARED TO RATES IN THE CLINICAL TRIALS OF OTHER DRUGS AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
THE EVALUATION OF ADVERSE REACTIONS IN PATIENTS TREATED WITH VORAXAZE IS CONFOUNDED BY THE POPULATION IN WHICH IT WAS STUDIED, PATIENTS WITH TOXIC PLASMA METHOTREXATE LEVELS DUE TO IMPAIRED RENAL FUNCTION. ADVERSE REACTIONS RELATED TO TOXIC METHOTREXATE LEVELS DUE TO PROLONGED METHOTREXATE CLEARANCE INCLUDE MYELOSUPPRESSION, MUCOSITIS, ACUTE HEPATITIS, AND RENAL DYSFUNCTION AND FAILURE.
THE SAFETY OF VORAXAZE IS BASED ON DATA FROM 290 PATIENTS WHO WERE TREATED IN 2 SINGLE-ARM, OPEN-LABEL, MULTICENTER TRIALS ENROLLING PATIENTS WHO HAD MARKEDLY DELAYED METHOTREXATE CLEARANCE SECONDARY TO RENAL DYSFUNCTION. PATIENTS WITH OSTEOSARCOMA WERE ELIGIBLE FOR THESE STUDIES IF THE PLASMA METHOTREXATE CONCENTRATION WAS GREATER THAN 50 ?MOL/L AT 24 HOURS, GREATER THAT 5 ?MOL/L AT 48 HOURS, OR GREATER THAN 2 STANDARD DEVIATIONS ABOVE THE MEAN METHOTREXATE ELIMINATION CURVE AT LEAST 12 HOURS AFTER METHOTREXATE ADMINISTRATION AND THERE WAS A 2-FOLD OR GREATER INCREASE IN SERUM CREATININE ABOVE BASELINE. ALL OTHER PATIENTS WERE ELIGIBLE FOR THESE STUDIES IF THE PLASMA METHOTREXATE LEVEL WAS GREATER THAN 10 ?MOL/L MORE THAN 42 HOURS AFTER THE START OF THE METHOTREXATE OR THE PLASMA LEVEL WAS GREATER THAN 2 STANDARD DEVIATIONS ABOVE THE MEAN METHOTREXATE EXCRETION CURVE AT LEAST 12 HOURS FOLLOWING METHOTREXATE AND THE SERUM CREATININE WAS GREATER THAN 1.5 TIMES THE UPPER LIMIT OF NORMAL OR THE CREATININE CLEARANCE WAS LESS THAN 60 ML/MIN AT LEAST 12 HOURS FOLLOWING METHOTREXATE ADMINISTRATION.
STUDY 1, CONDUCTED BY THE NATIONAL CANCER INSTITUTE (NCI), ENROLLED 184 PATIENTS; SAFETY INFORMATION IS AVAILABLE FOR 149 PATIENTS. VORAXAZE WAS GIVEN AT A DOSE OF 50 UNITS/KG AS AN INTRAVENOUS INJECTION OVER 5 MINUTES. PATIENTS WITH PRE-VORAXAZE METHOTREXATE CONCENTRATIONS > 100 ?MOL/L WERE TO RECEIVE A SECOND DOSE OF VORAXAZE 48 HOURS AFTER THE FIRST DOSE. THE PROTOCOL SPECIFIED THAT PATIENTS CONTINUE RECEIVING INTRAVENOUS HYDRATION, URINARY ALKALINIZATION AND LEUCOVORIN, AND THAT LEUCOVORIN ADMINISTRATION BE ADJUSTED TO ENSURE THAT IT WAS NOT ADMINISTERED WITHIN TWO HOURS BEFORE OR AFTER VORAXAZE.
IN STUDY 1, VORAXAZE-RELATED ADVERSE REACTIONS WERE COLLECTED ON A FLOW SHEET WITH A DAILY LOG OF ADVERSE REACTIONS CHARACTERIZED AS "GLUCARPIDASE TOXICITY." ADDITIONAL SAFETY INFORMATION WAS COLLECTED FROM CLINICAL RECORDS SUBMITTED BY TREATING PHYSICIANS. THIS INFORMATION WAS ABSTRACTED AND CATEGORIZED USING THE NATIONAL CANCER INSTITUTE (NCI) "COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS" (CTCAE) VERSION 3 SCALE.
THE STUDY 1 POPULATION ENROLLED PATIENTS WITH A MEDIAN AGE OF 18 YEARS (1 MONTH TO 85 YEARS); 63% WERE MALE, AND THE UNDERLYING MALIGNANCIES WERE OSTEOSARCOMA/SARCOMAS IN 32%, AND LEUKEMIA OR LYMPHOMA IN 63% OF PATIENTS. ONE (N=106) OR 2 (N= 30) DOSES OF VORAXAZE WERE ADMINISTERED INTRAVENOUSLY; THE NUMBER OF DOSES WAS NOT SPECIFIED IN 13 PATIENTS. DOSES RANGED FROM 18 TO 98 UNITS/KG, WITH A MEDIAN DOSE OF 49 UNITS/KG.
STUDY 2 IS AN ONGOING EXPANDED ACCESS PROGRAM. AT THE TIME OF DATA CUT-OFF, 243 PATIENTS WERE ENROLLED AND SAFETY DATA WAS AVAILABLE FOR 141 PATIENTS. VORAXAZE WAS GIVEN AT A DOSE OF 50 UNITS/KG AS AN INTRAVENOUS INJECTION OVER 5 MINUTES. THE CRITERION FOR ALLOWING PATIENTS TO RECEIVE A SECOND GLUCARPIDASE DOSE WAS NOT SPECIFIED IN THE PROTOCOL. THE PROTOCOL SPECIFIED THAT PATIENTS CONTINUE RECEIVING INTRAVENOUS HYDRATION, URINARY ALKALINIZATION AND LEUCOVORIN, AND THAT LEUCOVORIN ADMINISTRATION BE ADJUSTED TO ENSURE THAT IT WAS NOT ADMINISTERED WITHIN TWO HOURS BEFORE OR AFTER VORAXAZE.
STUDY 2 ENROLLED PATIENTS WITH A MEDIAN AGE OF 17 YEARS (6 MONTHS TO 85 YEARS); 64% WERE MALE, AND THE UNDERLYING MALIGNANCIES WERE OSTEOGENICSARCOMA IN 32%, AND LEUKEMIA OR LYMPHOMA IN 62% OF PATIENTS. ONE (N=122) OR 2 (N= 18) DOSES OF VORAXAZE WERE ADMINISTERED INTRAVENOUSLY; THE NUMBER OF DOSES WAS NOT SPECIFIED FOR 1 PATIENT. DOSES RANGED FROM 6 TO 189 UNITS/KG, WITH A MEDIAN DOSE OF 50 UNITS/KG.
IN STUDY 2 ONLY VORAXAZE-RELATED ADVERSE REACTIONS WERE COLLECTED AND SEVERITY WAS GRADED ACCORDING TO NCI CTCAE VERSION 3.
AMONG THE 290 PATIENTS INCLUDED IN THE SAFETY EVALUATION OF VORAXAZE, THERE WERE 8 DEATHS WITHIN 30 DAYS OF VORAXAZE EXPOSURE THAT WERE NOT RELATED TO PROGRESSIVE DISEASE. TWENTY-ONE OF 290 PATIENTS (7%) EXPERIENCED ADVERSE REACTIONS THAT WERE ASSESSED AS RELATED TO VORAXAZE. MOST WERE GRADE 1 OR 2 EVENTS. ONE PATIENT EXPERIENCED RELATED GRADE 3 FLUSHING. THE MOST COMMON RELATED ADVERSE REACTIONS THAT WERE NOT HEMATOLOGIC, HEPATIC OR RENAL EVENTS WERE PARESTHESIA, FLUSHING, AND NAUSEA AND/OR VOMITING, WHICH EACH OCCURRED IN 2% OF PATIENTS (TABLE 1).
TABLE 1: PER PATIENT INCIDENCE OF GRADE 1 AND 2 ADVERSE REACTIONS ASSESSED AS POSSIBLY, PROBABLY, OR DEFINITELY RELATED TO VORAXAZE EXCLUDING HEMATOLOGIC, HEPATIC, OR RENAL ADVERSE REACTIONS
ADVERSE REACTION N= 290
N (%)
PARESTHESIAS 7 (2%)
FLUSHING1,2 5 (2%)
NAUSEA/V OMITING 5 (2%)
HEADACHE 2 (1%)
HYPOTENSION 2 (1%)
BLURRED VISION 1 ( < 1%)
DIARRHEA 1 ( < 1%)
HYPERSENSITIVITY 1 ( < 1%)
HYPERTENSION 1 ( < 1%)
RASH 1 ( < 1%)
THROAT IRRITATION/THROAT TIGHTNESS 1 ( < 1%)
TREMOR 1 ( < 1%)
1THIS INCIDENCE INCLUDES THE FOLLOWING TERMS: FLUSHING, FEELING HOT, BURNING SENSATION.
2ONE OF THESE REACTIONS WAS CLASSIFIED AS GRADE 3 IN SEVERITY.
IMMUNOGENICITY
AS WITH ALL THERAPEUTIC PROTEINS, THERE IS POTENTIAL FOR IMMUNOGENICITY. IN CLINICAL TRIALS, 121 PATIENTS WHO RECEIVED ONE (N=99), TWO (N=21), OR THREE (N=1) DOSES OF VORAXAZE WERE EVALUATED FOR ANTI-GLUCARPIDASE ANTIBODIES. TWENTY-FIVE OF THESE 121 PATIENTS (21%) HAD DETECTABLE ANTI-GLUCARPIDASE ANTIBODIES FOLLOWING VORAXAZE ADMINISTRATION, OF WHICH 19 RECEIVED A SINGLE DOSE OF VORAXAZE AND 6 RECEIVED TWO DOSES OF VORAXAZE. ANTIBODY TITERS WERE DETERMINED USING A BRIDGING ENZYME-LINKED IMMUNOSORBENT ASSAY(ELISA) FOR ANTIGLUCARPIDASE ANTIBODIES.
NEUTRALIZING ANTIBODIES WERE DETECTED IN 11 OF THE 25 PATIENTS WHO TESTED POSITIVE FOR ANTIGLUCARPIDASE BINDING ANTIBODIES. EIGHT OF THESE 11 PATIENTS HAD RECEIVED A SINGLE DOSE OF VORAXAZE. HOWEVER, THE DEVELOPMENT OF NEUTRALIZING ANTIBODIES MAY BE UNDERREPORTED DUE TO LACK OF ASSAY SENSITIVITY.
THE DETECTION OF ANTIBODY FORMATION IS HIGHLY DEPENDENT ON THE SENSITIVITY AND SPECIFICITY OF THE ASSAY. ADDITIONALLY, THE OBSERVED INCIDENCE OF ANTIBODY (INCLUDING NEUTRALIZING ANTIBODY) POSITIVITY IN AN ASSAY MAY BE INFLUENCED BY SEVERAL FACTORS , INCLUDING ASSAY METHODOLOGY, SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, CONCOMITANT MEDICATIONS, AND UNDERLYING DISEASE. FOR THESE REASONS, COMPARISON OF INCIDENCE OF ANTIBODIES TO VORAXAZE WITH THE INCIDENCE OF ANTIBODIES TO OTHER PRODUCTS MAY BE MISLEADING.
READ THE VORAXAZE (GLUCARPIDASE FOR INJECTION, FOR INTRAVENOUS USE) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
VORAXAZE (GLUCARPIDASE) IS A RECOMBINANT BACTERIAL ENZYME THAT HYDROLYZES THE CARBOXYLTERMINAL GLUTAMATE RESIDUE FROM FOLIC ACID AND CLASSICAL ANTIFOLATES SUCH AS METHOTREXATE. VORAXAZE CONVERTS METHOTREXATE TO ITS INACTIVE METABOLITES 4-DEOXY-4-AMINO-N10- METHYLPTEROIC ACID (DAMPA) AND GLUTAMATE. VORAXAZE PROVIDES AN ALTERNATE NON-RENAL PATHWAY FOR METHOTREXATE ELIMINATION IN PATIENTS WITH RENAL DYSFUNCTION DURING HIGH-DOSE METHOTREXATE TREATMENT.
PHARMACODYNAMICS
PLASMA METHOTREXATE CONCENTRATIONS WITHIN 48 HOURS FOLLOWING ADMINISTRATION OF VORAXAZE CAN ONLY BE RELIABLY MEASURED BY A CHROMATOGRAPHIC METHOD BECAUSE DAMPA INTERFERES WITH THE IMMUNOASSAYS [SEE WARNINGS ANDPRECAUTIONS]. FOLLOWING ADMINISTRATION OF VORAXAZE 50 UNITS/KG TO PATIENTS IN STUDY 1, METHOTREXATE CONCENTRATION MEASURED BY A CHROMATOGRAPHIC METHOD WAS REDUCED BY ? 97% WITHIN 15 MINUTES IN ALL 22 TREATMENT-EVALUABLE PATIENTS, AND WAS MAINTAINED AT A > 95% REDUCTION UP TO 8 DAYS IN 20 OF THE 22 PATIENTS [SEE CLINICAL STUDIES].
PHARMACOKINETICS
THE PHARMACOKINETICS OF GLUCARPIDASE IN THE ABSENCE OF METHOTREXATE WERE STUDIED IN EIGHT HEALTHY SUBJECTS FOLLOWING AN INTRAVENOUS INJECTION OF VORAXAZE 50 UNITS/KG OVER 5 MINUTES. SERUM GLUCARPIDASE ACTIVITY LEVELS WERE MEASURED BY AN ENZYMATIC ASSAY AND SERUM TOTAL GLUCARPIDASE CONCENTRATIONS WERE MEASURED BY ELISA.
SERUM GLUCARPIDASE ACTIVITY LEVELS DECLINED WITH A MEAN ELIMINATION HALF-LIFE (T½) OF 5.6 HOURS. THE MEAN CMAX WAS 3.3 ?G/ML AND THE MEAN AREA UNDER THE CURVE (AUC0-INF) WAS 23.3 ?G·H/ML. THE MEAN SYSTEMIC CLEARANCE (CL) WAS 7.5 ML/MIN. THE MEAN VOLUME OF DISTRIBUTION (VD) WAS 3.6 L, SUGGESTING THAT GLUCARPIDASE DISTRIBUTION IS RESTRICTED TO PLASMA VOLUME. THE PHARMACOKINETIC PARAMETERS DERIVED FROM THE SERUM TOTAL GLUCARPIDASE CONCENTRATIONS WERE SIMILAR TO THOSE GENERATED BY SERUM GLUCARPIDASE ACTIVITY LEVELS EXCEPT FOR A LONGER T½ OF 9 HOURS.
RENAL IMPAIRMENT
THE PHARMACOKINETICS OF GLUCARPIDASE IN THE ABSENCE OF METHOTREXATE WERE STUDIED IN FOUR SUBJECTS WITH SEVERE RENAL IMPAIRMENT (CREATININE CLEARANCE < 30 ML/MIN). FOLLOWING AN INTRAVENOUS DOSE OF 50 UNITS/KG OF VORAXAZE, THE MEAN PHARMACOKINETIC PARAMETERS WERE SIMILAR TO THOSE OBSERVED IN HEALTHY SUBJECTS EXCEPT FOR A LONGER T½ OF 8.2 HOURS ASCOMPARED TO 5.6 HOURS IN HEALTHY SUBJECTS BY THE ENZYMATIC ASSAY.
DRUG INTERACTIONS
IN A STUDY OF CANCER PATIENTS RECEIVING A HIGH-DOSE METHOTREXATE ( ? 1 G/M²) AND LEUCOVORIN RESCUE REGIMEN, INTRAVENOUS ADMINISTRATION OF 50 UNITS/KG VORAXAZE 2 HOURS BEFORE LEUCOVORIN REDUCED (6S)-LEUCOVORIN AUC0-3H BY 33% AND CMAX BY 52%, AND ALSO REDUCED ITS ACTIVE METABOLITE, (6S)-5-METHYLTETRAHYDROFOLATE, AUC0-3H BY 92% AND CMAX BY 93% [SEE DRUG INTERACTIONS].
CLINICAL STUDIES
THE EFFICACY OF VORAXAZE WAS EVALUATED IN A SUBSET CONSISTING OF 22 TREATMENT-EVALUABLE PATIENTS ENROLLED IN STUDY 1. STUDY 1 WAS A SINGLE-ARM, OPEN-LABEL STUDY IN PATIENTS WHO HAD MARKEDLY DELAYED METHOTREXATE CLEARANCE (DEFINED AS MORE THAN 2 STANDARD DEVIATIONS GREATER THAN THE MEAN EXCRETION CURVE FOR METHOTREXATE) SECONDARY TO RENAL DYSFUNCTION. ALL PATIENTS RECEIVED VORAXAZE 50 UNITS/KG AS AN INTRAVENOUS INJECTION OVER 5 MINUTES; THOSE PATIENTS WITH PRE-VORAXAZE METHOTREXATE CONCENTRATIONS > 100 ?MOL/L WERE TO RECEIVE A SECOND DOSE OF VORAXAZE 48 HOURS AFTER THE FIRST DOSE. THE PROTOCOL SPECIFIED THAT PATIENTS CONTINUE RECEIVING INTRAVENOUS HYDRATION, URINARY ALKALINIZATION AND LEUCOVORIN, AND THAT LEUCOVORIN ADMINISTRATION BE ADJUSTED TO ENSURE THAT IT WAS NOT ADMINISTERED WITHIN TWO HOURS BEFORE OR AFTER VORAXAZE.
EFFICACY WAS EVALUATED IN A SUBSET OF PATIENTS ENROLLED IN STUDY 1 WHO MET THE INCLUSION CRITERIA FOR THE STUDY, HAD A PRE-VORAXAZE METHOTREXATE CONCENTRATION > 1 ?MOL/L, AND HAD BOTH PREAND POST-TREATMENT PLASMA SAMPLES AVAILABLE FOR DETERMINATION OF METHOTREXATE CONCENTRATION BY A CHROMATOGRAPHIC METHOD ANALYSIS. THE MAIN OUTCOME MEASURE WAS THE PROPORTION OF PATIENTS WHO ACHIEVED A RAPID AND SUSTAINED CLINICALLY IMPORTANT REDUCTION (RSCIR) IN PLASMA METHOTREXATE CONCENTRATION, DEFINED AS AN ATTAINMENT OF PLASMA METHOTREXATE CONCENTRATION ? 1 ?MOL/L AT 15 MINUTES THAT WAS SUSTAINED FOR UP TO 8 DAYS FOLLOWING THE INITIAL INJECTION.
OF THE 22 PATIENTS IN THE EFFICACY DATASET, THE MEDIAN AGE WAS 15.5 YEARS (5 TO 84 YEARS); 59% WERE MALE, AND THE MOST COMMON UNDERLYING CANCERS WERE OSTEOGENIC SARCOMA (50%) AND LEUKEMIA OR LYMPHOMA (45%).
TEN OF THE 22 PATIENTS ACHIEVED RSCIR [45% (95% CI 27, 65%)]. OF THE 12 PATIENTS WHO FAILED TO ACHIEVE RSCIR, 5 PATIENTS (23%) ATTAINED A TRANSIENT PLASMA METHOTREXATE CONCENTRATION OF ? 1 ?MOL/L. IN THESE 5 PATIENTS, THE MEDIAN INCREASE OF PLASMA METHOTREXATE CONCENTRATION FROM THEIR NADIR WAS 1.4 ?MOL/L (0.3 TO 2.5 ?MOL/L).
TABLE 2 SUMMARIZES THE RESULTS OF RSCIR AND EXPLORATORY ANALYSES FOLLOWING THE FIRST DOSE ADMINISTRATION OF VORAXAZE. AN EXPLORATORY ANALYSIS IN SUBGROUPS DETERMINED BY PRE-VORAXAZE METHOTREXATE CONCENTRATION SUGGESTS THAT THE LIKELIHOOD OF ATTAINING A RSCIR FOLLOWING THE FIRST VORAXAZE INJECTION CORRELATES WITH THE PRE-VORAXAZE METHOTREXATE CONCENTRATION (TABLE 2). IN AN ADDITIONAL EXPLORATORY ANALYSIS, ALL 9 PATIENTS WITH PRE-GLUCARPIDASE METHOTREXATE CONCENTRATIONS > 50 ?MOL/L ACHIEVED GREATER THAN A 95% REDUCTION IN METHOTREXATE CONCENTRATIONS FOR UP TO 8 DAYS FOLLOWING THE INITIAL INJECTION OF VORAXAZE ALTHOUGH NONE OF THEM ACHIEVED A RSCIR.
TABLE 2: RESULTS OF RSCIR AND EXPLORATORY ANALYSES FOLLOWING THE FIRST DOSE OF VORAXAZE
PRE-VORAXAZE METHOTREXATE CONCENTRATION (?MOL/L) NUMBER OF PATIENTS PATIENTS ACHIEVING RSCIR N (%) PATIENTS WITH >95% RAPID REDUCTION IN METHOTREXATE CONCENTRATION AND MAINTAINED UP TO 8 DAYS N (%)
> 1 22 10 (45%) 20 (91%)
> 1 TO ? 50 13 10 (77%) 11 (85%)
> 50 TO ? 100 2 0 2 (100%)
> 100 7 0 7 (100%)
RSCIR: RAPID AND SUSTAINED CLINICALLY IMPORTANT REDUCTION IN METHOTREXATE CONCENTRATION.
LACK OF EFFICACY WITH A SECOND DOSE OF VORAXAZE
SIX OF THE SEVEN PATIENTS WITH PRE-FIRST DOSE VORAXAZE METHOTREXATE CONCENTRATIONS > 100 ?MOL/L RECEIVED A SECOND 50 UNITS/KG DOSE OF VORAXAZE ADMINISTERED 48 HOURS AFTER THE FIRST DOSE. AMONG THEM, NONE OF THE FOUR PATIENTS WITH PRE-SECOND DOSE VORAXAZE METHOTREXATE CONCENTRATIONS > 1 ?MOL/L ACHIEVED A RSCIR. THE REMAINING TWO PATIENTS ACHIEVED A RSCIR BUT THEIR PRE-SECOND DOSE VORAXAZE METHOTREXATE CONCENTRATIONS WERE ALREADY ? 1 ?MOL/L.
DEATHS ATTRIBUTABLE TO METHOTREXATE TOXICITY
THERE ARE NO CONTROLLED TRIALSCOMPARING VORAXAZE PLUS SUPPORTIVE CARE TO SUPPORTIVE CARE MEASURES ALONE IN PATIENTS WITH TOXIC PLASMA METHOTREXATE CONCENTRATIONS DUE TO IMPAIRED RENAL FUNCTION, THEREFORE THERE ARE NO DATA REGARDING THE EFFECT OF VORAXAZE ON SURVIVAL OR TOXIC DEATHS DUE TO METHOTREXATE. VORAXAZE DID NOT PREVENT FATAL METHOTREXATE TOXICITY IN 3% OF PATIENTS IN THE SAFETY POPULATION.