WARNING
HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
" HEPATITIS B VIRUS (HBV) REACTIVATION, IN SOME CASES RESULTING IN FULMINANT HEPATITIS, HEPATIC FAILURE, AND DEATH, CAN OCCUR IN PATIENTS RECEIVING CD20-DIRECTED CYTOLYTIC ANTIBODIES, INCLUDING GAZYVA. SCREEN ALL PATIENTS FOR HBV INFECTION BEFORE TREATMENT INITIATION. MONITOR HBV POSITIVE PATIENTS DURING AND AFTER TREATMENT WITH GAZYVA. DISCONTINUE GAZYVA AND CONCOMITANT MEDICATIONS IN THE EVENT OF HBV REACTIVATION [SEE WARNINGS AND PRECAUTIONS].
" PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) INCLUDING FATAL PML, CAN OCCUR IN PATIENTS RECEIVING GAZYVA [SEE WARNINGS ANDPRECAUTIONS].
INDICATIONS
GAZYVA, IN COMBINATION WITH CHLORAMBUCIL, IS INDICATED FOR THE TREATMENT OF PATIENTS WITH PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) [SEECLINICAL STUDIES].
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
1000 MG/40ML (25 MG/ML) SINGLE USE VIAL.
STORAGE AND HANDLING
GAZYVA 1000 MG/40 ML (25 MG/ML) SINGLE-USE VIALS CONTAINING PRESERVATIVE-FREE SOLUTION (NDC 50242-070-01) ARE STABLE AT 2°C TO 8°C (36°F TO 46°F). DO NOT USE BEYOND EXPIRATION DATE STAMPED ON CARTON. GAZYVA VIALS SHOULD BE PROTECTED FROM LIGHT. DO NOT FREEZE. DO NOT SHAKE.
FOR THE DILUTED PRODUCT, CHEMICAL AND PHYSICAL STABILITY HAVE BEEN DEMONSTRATED IN 0.9% NACL AT CONCENTRATIONS OF 0.4 MG/ML TO 20 MG/ML FOR 24 HOURS AT 2°C TO 8°C (36°F TO 46°F) FOLLOWED BY 48 HOURS (INCLUDING INFUSION TIME) AT ROOM TEMPERATURE ( ? 30°C/86°F). GAZYVA DOES NOT CONTAIN ANTIMICROBIAL PRESERVATIVES. THEREFORE CARE MUST BE TAKEN TO ENSURE THAT THE SOLUTION FOR INFUSION IS NOT MICROBIOLOGICALLY COMPROMISED DURING PREPARATION. THE SOLUTION FOR INFUSION SHOULD BE USED IMMEDIATELY. IF NOT USED IMMEDIATELY, THE PREPARED SOLUTION MAY BE STORED UP TO 24 HOURS AT 2-8°C. NO INCOMPATIBILITIES BETWEEN GAZYVA AND POLYVINYL CHLORIDE OR POLYOLEFIN INFUSION MATERIALS HAVE BEEN OBSERVED IN CONCENTRATION RANGES FROM 0.4 MG/ML TO 20.0 MG/ML AFTER DILUTION OF GAZYVA WITH 0.9% SODIUM CHLORIDE.
MANUFACTURED BY: GENENTECH, INC., A MEMBER OF THE ROCHE GROUP, SOUTH SAN FRANCISCO, CA 94080-4990. REVISED: JUNE 2014
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSAGE REGIMEN
" PREMEDICATE BEFORE EACH INFUSION [SEE RECOMMENDED PREMEDICATION].
" ADMINISTER ONLY AS AN INTRAVENOUS INFUSION THROUGH A DEDICATED LINE [SEEPREPARATION AND ADMINISTRATION].
" DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
" MONITOR BLOOD COUNTS AT REGULAR INTERVALS.
" GAZYVA SHOULD ONLY BE ADMINISTERED BY A HEALTHCARE PROFESSIONAL WITH APPROPRIATE MEDICAL SUPPORT TO MANAGE SEVERE INFUSION REACTIONS THAT CAN BE FATAL IF THEY OCCUR [SEE WARNINGS AND PRECAUTIONS].
RECOMMENDED DOSE
EACH DOSE OF GAZYVA IS 1000 MG, ADMINISTERED INTRAVENOUSLY, WITH THE EXCEPTION OF THE FIRST INFUSIONS IN CYCLE 1, WHICH ARE ADMINISTERED ON DAY 1 (100 MG) AND DAY 2 (900 MG).
TABLE 1: DOSE OF GAZYVA TO BE ADMINISTERED DURING 6 TREATMENT CYCLES EACH OF 28 DAYS DURATION
DAY OF TREATMENT CYCLE DOSE OF GAZYVA RATE OF INFUSION (IN THE ABSENCE OF INFUSION REACTIONS/HYPERSENSITIVITY DURING PREVIOUS INFUSIONS)
CYCLE 1 DAY 1 100 MG ADMINISTER AT 25 MG/HR OVER 4 HOURS. DO NOT INCREASE THE INFUSION RATE.
DAY 2 900 MG ADMINISTER AT 50 MG/HR. THE RATE OF THE INFUSION CAN BE ESCALATED IN INCREMENTS OF 50 MG/HR EVERY 30 MINUTES TO A MAXIMUM RATE OF 400 MG/HR.
DAY 8 1000 MG INFUSIONS CAN BE STARTED AT A RATE OF 100 MG/HR AND INCREASED BY 100 MG/HR INCREMENTS EVERY 30 MINUTES TO A MAXIMUM OF 400 MG/HR.
DAY 15 1000 MG
CYCLES 2-6 DAY 1 1000 MG
IF A PLANNED DOSE OF GAZYVA IS MISSED, ADMINISTER THE MISSED DOSE AS SOON AS POSSIBLE AND ADJUST DOSING SCHEDULE ACCORDINGLY. IF APPROPRIATE, PATIENTS WHO DO NOT COMPLETE THE DAY 1 CYCLE 1 DOSE MAY PROCEED TO THE DAY 2 CYCLE 1 DOSE.
IF A PATIENT EXPERIENCES AN INFUSION REACTION OF ANY GRADE DURING INFUSION, ADJUST THE INFUSION AS FOLLOWS [SEE WARNINGS AND PRECAUTIONS]:
" GRADE 4 (LIFE THREATENING): STOP INFUSION IMMEDIATELY AND PERMANENTLY DISCONTINUE GAZYVA THERAPY.
" GRADE 3 (SEVERE): INTERRUPT INFUSION AND MANAGE SYMPTOMS. UPON RESOLUTION OF SYMPTOMS, CONSIDER RESTARTING GAZYVA INFUSION AT NO MORE THAN HALF THE PREVIOUS RATE (THE RATE BEING USED AT THE TIME THAT THE INFUSION REACTION OCCURRED) AND, IF PATIENT DOES NOT EXPERIENCE ANY FURTHER INFUSION REACTION SYMPTOMS, INFUSION RATE ESCALATION MAY RESUME AT THE INCREMENTS AND INTERVALS AS APPROPRIATE FOR THE TREATMENT CYCLE DOSE. PERMANENTLY DISCONTINUE TREATMENT IF PATIENTS EXPERIENCE A GRADE 3 INFUSION RELATED SYMPTOM AT RE-CHALLENGE.
" GRADE 1-2 (MILD TO MODERATE): REDUCE INFUSION RATE OR INTERRUPT INFUSION AND TREAT SYMPTOMS. UPON RESOLUTION OF SYMPTOMS, CONTINUE OR RESUME INFUSION AND, IF PATIENT DOES NOT EXPERIENCE ANY FURTHER INFUSION REACTION SYMPTOMS, INFUSION RATE ESCALATION MAY RESUME AT THE INCREMENTS AND INTERVALS AS APPROPRIATE FOR THE TREATMENT CYCLE DOSE.
RECOMMENDED PREMEDICATION
PREMEDICATION IS RECOMMENDED TO REDUCE THE RISK OF INFUSION REACTIONS AS OUTLINED IN TABLE 2 [SEE WARNINGS AND PRECAUTIONS].
HYPOTENSION MAY OCCUR DURING GAZYVA INTRAVENOUS INFUSIONS. CONSIDER WITHHOLDING ANTIHYPERTENSIVE TREATMENTS FOR 12 HOURS PRIOR TO AND THROUGHOUT EACH GAZYVA INFUSION AND FOR THE FIRST HOUR AFTER ADMINISTRATION [SEEWARNINGS AND PRECAUTIONS].
FOR PATIENTS WITH HIGH TUMOR BURDEN AND/OR HIGH CIRCULATING ABSOLUTELYMPHOCYTE COUNTS (GREATER THAN 25 X 109/L), PREMEDICATE WITH ANTI-HYPERURICEMICS (E.G., ALLOPURINOL) BEGINNING 12-24 HOURS PRIOR TO START OF THERAPY AND ENSURE ADEQUATE HYDRATION FOR PROPHYLAXIS OF TUMOR LYSISSYNDROME [SEE WARNINGS AND PRECAUTIONS].
TABLE 2 : PREMEDICATION FOR GAZYVA INFUSION TO REDUCE INFUSION-RELATED REACTIONS
PREMEDICATION FOR ANTI-MICROBIAL PROPHYLAXIS
PATIENTS WITH NEUTROPENIA ARE STRONGLY RECOMMENDED TO RECEIVE ANTIMICROBIALPROPHYLAXIS THROUGHOUT THE TREATMENT PERIOD. ANTIVIRAL AND ANTIFUNGALPROPHYLAXIS SHOULD BE CONSIDERED.
TREATMENT INTERRUPTION FOR TOXICITY
CONSIDER TREATMENT INTERRUPTION, IF PATIENTS EXPERIENCE AN INFECTION, GRADE 3 OR 4 CYTOPENIA, OR A ? GRADE 2 NON-HEMATOLOGIC TOXICITY.
PREPARATION AND ADMINISTRATION
PREPARATION
PREPARE THE SOLUTION FOR INFUSION, USING ASEPTIC TECHNIQUE, AS FOLLOWS:
" INSPECT VISUALLY FOR ANY PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION.
" DILUTE INTO A 0.9% SODIUM CHLORIDE PVC OR NON-PVC POLYOLEFIN INFUSION BAG. DO NOT USE OTHER DILUENTS SUCH AS DEXTROSE (5%).
" PREPARATION OF SOLUTION FOR INFUSION ON DAY 1 (100 MG) AND DAY 2 (900 MG) OF CYCLE 1:
" WITHDRAW 40 ML OF GAZYVA SOLUTION FROM THE VIAL.
" DILUTE 4 ML (100 MG) OF GAZYVA INTO A 100 ML 0.9% SODIUM CHLORIDE INFUSION BAG FOR IMMEDIATE ADMINISTRATION.
" DILUTE THE REMAINING 36 ML (900 MG) INTO A 250 ML 0.9% SODIUM CHLORIDE INFUSION BAG AT THE SAME TIME FOR USE ON DAY 2 AND STORE AT 2°C TO 8°C (36°F TO 46°F) FOR UP TO 24 HOURS. AFTER ALLOWING THE DILUTED BAG TO COME TO ROOM TEMPERATURE, USE IMMEDIATELY.
" CLEARLY LABEL EACH INFUSION BAG.
" PREPARATION OF SOLUTION FOR INFUSION ON DAY 8 AND 15 OF CYCLE 1 AND DAY 1 CYCLES 2- 6:
" WITHDRAW 40 ML OF GAZYVA SOLUTION FROM THE VIAL.
" DILUTE 40 ML (1000 MG) INTO A 250 ML 0.9% SODIUM CHLORIDE INFUSION BAG.
" MIX DILUTED SOLUTION BY GENTLE INVERSION. DO NOT SHAKE OR FREEZE.
" FOR MICROBIOLOGICAL STABILITY, THE DILUTED GAZYVA INFUSION SOLUTION SHOULD BE USED IMMEDIATELY. DILUTE UNDER APPROPRIATE ASEPTIC CONDITIONS. IF NOT USED IMMEDIATELY, THE SOLUTION MAY BE STORED IN A REFRIGERATOR AT 2°C TO 8°C (36°F TO 46°F) FOR UP TO 24 HOURS PRIOR TO USE.
THE PRODUCT CAN BE ADMINISTERED AT A FINAL CONCENTRATION OF 0.4 MG/ML TO 4 MG/ML.
ADMINISTRATION
" ADMINISTER AS AN INTRAVENOUS INFUSION ONLY.
" DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
" DO NOT MIX GAZYVA WITH OTHER DRUGS.
NO INCOMPATIBILITIES BETWEEN GAZYVA AND POLYVINYLCHLORIDE (PVC) OR NON-PVC POLYOLEFIN BAGS AND ADMINISTRATION SETS HAVE BEEN OBSERVED [SEESTORAGE AND HANDLING].
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE DISCUSSED IN GREATER DETAIL IN OTHER SECTIONS OF THE LABEL:
" HEPATITIS B REACTIVATION [SEE WARNINGS AND PRECAUTIONS]
" PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY [SEE WARNINGS ANDPRECAUTIONS]
" INFUSION REACTIONS [SEE WARNINGS AND PRECAUTIONS]
" TUMOR LYSIS SYNDROME [SEE WARNINGS AND PRECAUTIONS]
" INFECTIONS [SEE WARNINGS AND PRECAUTIONS]
" NEUTROPENIA [SEE WARNINGS AND PRECAUTIONS]
" THROMBOCYTOPENIA [SEE WARNINGS AND PRECAUTIONS]
THE MOST COMMON ADVERSE REACTIONS (INCIDENCE ? 10%) WERE: INFUSION REACTIONS, NEUTROPENIA, THROMBOCYTOPENIA, ANEMIA, PYREXIA, COUGH, AND MUSCULOSKELETAL DISORDERS.
CLINICAL TRIAL EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLYCOMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
THE DATA DESCRIBED IN TABLES 3 AND 4 BELOW ARE BASED ON A TOTAL OF 356 PREVIOUSLY UNTREATED PATIENTS WITH CLL DURING TREATMENT WITH GAZYVA IN COMBINATION WITH CHLORAMBUCIL OR WITH CHLORAMBUCIL ALONE. PATIENTS RECEIVED THREE 1000 MG DOSES OF GAZYVA ON THE FIRST CYCLE AND A SINGLE DOSE OF 1000 MG ONCE EVERY 28 DAYS FOR 5 ADDITIONAL CYCLES IN COMBINATION WITH CHLORAMBUCIL (6 CYCLES OF 28 DAYS EACH IN TOTAL). IN THE LAST 45 PATIENTS ENROLLED, THE FIRST DOSE OF GAZYVA WAS SPLIT BETWEEN DAY 1 (100 MG) AND DAY 2 (900 MG) [SEE DOSAGE AND ADMINISTRATION]. IN TOTAL, 81% OF PATIENTS RECEIVED ALL 6 CYCLES (OF 28 DAYS EACH) OF GAZYVA BASED THERAPY.
TABLE 3 : SUMMARY OF ADVERSE REACTIONS REPORTED WITH ? 5% INCIDENCE AND ? 2% GREATER IN THE GAZYVA TREATED ARM
ADVERSE REACTIONS (MEDDRAA)
SYSTEM ORGAN CLASS GAZYVA + CHLORAMBUCIL
N = 240 CHLORAMBUCIL
N = 116
ALL GRADES % GRADES 3-4B % ALL GRADES % GRADES 3-4B %
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
INFUSION RELATED REACTIONS 69 21 0 0
BLOOD AND LYMPHATIC SYSTEM DISORDERSC
NEUTROPENIA 40 34 18 16
THROMBOCYTOPENIA 15 11 7 3
ANEMIA 12 4 10 5
LEUKOPENIA 7 5 0 0
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
PYREXIA 10 < 1 7 0
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
COUGH 10 0 7 < 1
AMEDDRA CODED ADVERSE REACTIONS AS REPORTED BY INVESTIGATORS.
B NO GRADE 5 ADVERSE REACTIONS HAVE BEEN OBSERVED WITH A DIFFERENCE OF ? 2% BETWEEN THE TREATMENT ARMS.
C ADVERSE EVENTS REPORTED UNDER 'BLOOD AND LYMPHATIC SYSTEM DISORDERS' REFLECT THOSE REPORTED BY INVESTIGATOR AS CLINICALLY SIGNIFICANT.
TABLE 4 : POST-BASELINE LABORATORY ABNORMALITIES BY CTCAE GRADE WITH ? 5% INCIDENCE AND ? 2 % GREATER IN THE GAZYVA TREATED ARM
INVESTIGATIONS GAZYVA + CHLORAMBUCIL
N = 240 CHLORAMBUCIL
N = 116
ALL GRADES % GRADES 3-4 % ALL GRADES % GRADES 3-4 %
HEMATOLOGY
NEUTROPENIA 77 46 53 27
LYMPHOPENIA 80 40 9 2
LEUKOPENIA 84 36 12 < 1
THROMBOCYTOPENIA 47 14 50 11
CHEMISTRY
HYPOCALCEMIA 32 3 29 < 1
HYPERKALEMIA 31 5 17 2
HYPONATREMIA 29 8 11 2
AST (SGOT INCREASED) 28 < 1 12 0
CREATININE INCREASED 28 < 1 18 < 1
ALT (SGPT INCREASED) 25 < 1 14 0
HYPOALBUMINEMIA 22 < 1 14 < 1
ALKALINE PHOSPHATASE INCREASED 16 0 11 0
HYPOKALEMIA 13 1 4 < 1
INFUSION REACTIONS
THE INCIDENCE OF INFUSION REACTIONS WAS 69% WITH THE FIRST INFUSION OF GAZYVA. THE INCIDENCE OF GRADE 3 OR 4 INFUSION REACTIONS WAS 21% WITH 8% OF PATIENTS DISCONTINUING THERAPY. THE INCIDENCE OF REACTIONS WITH SUBSEQUENT INFUSIONS WAS 3% WITH THE SECOND 1000 MG AND < 1% THEREAFTER. NO GRADE 3 OR 4 INFUSION REACTIONS WERE REPORTED BEYOND THE FIRST 1000 MG INFUSED.
OF THE FIRST 53 PATIENTS RECEIVING GAZYVA ON THE TRIAL, 47 (89%) EXPERIENCED AN INFUSION REACTION. AFTER THIS EXPERIENCE, STUDY PROTOCOL MODIFICATIONS WERE MADE TO REQUIRE PREMEDICATION WITH A CORTICOSTEROID, ANTI-HISTAMINE, ANDACETAMINOPHEN. THE FIRST DOSE WAS ALSO DIVIDED INTO TWO INFUSIONS (100 MG ON DAY 1 AND 900 MG ON DAY 2). FOR THE 45 PATIENTS FOR WHOM THESE MITIGATION MEASURES WERE IMPLEMENTED, 21 PATIENTS (47%) EXPERIENCED A REACTION WITH THE FIRST 1000 MG AND < 2% THEREAFTER [SEE DOSAGE AND ADMINISTRATION].
NEUTROPENIA
THE INCIDENCE OF NEUTROPENIA REPORTED AS AN ADVERSE REACTION WAS 40% IN THE GAZYVA TREATED ARM AND 18% IN THE CHLORAMBUCIL ALONE ARM WITH THE INCIDENCE OF SERIOUS ADVERSE EVENTS BEING 1% AND 0%, RESPECTIVELY (TABLE 3). CASES OF LATE ONSET NEUTROPENIA (OCCURRING 28 DAYS AFTER COMPLETION OF TREATMENT OR LATER) WERE 16% IN THE GAZYVA TREATED ARM AND 12% IN THE CHLORAMBUCIL ALONE ARM.
INFECTION
THE INCIDENCE OF INFECTIONS WAS SIMILAR BETWEEN ARMS. THIRTY-EIGHT PERCENT OF PATIENTS IN THE GAZYVA TREATED ARM EXPERIENCED AN INFECTION, 9% WERE GRADE 3-4 AND NONE WERE FATAL.
THROMBOCYTOPENIA
THE INCIDENCE OF THROMBOCYTOPENIA REPORTED AS AN ADVERSE REACTION WAS 15% IN THE GAZYVA TREATED ARM AND 7% IN THE CHLORAMBUCIL ALONE ARM (TABLE 3). FIVE PERCENT OF PATIENTS IN THE GAZYVA TREATED ARM EXPERIENCED ACUTE THROMBOCYTOPENIA (OCCURRING WITHIN 24 HOURS AFTER THE GAZYVA INFUSION). THE NUMBER OF FATAL HEMORRHAGIC EVENTS WAS SIMILAR BETWEEN THE TREATMENT ARMS, WITH 4 IN THE GAZYVA TREATED ARM. HOWEVER, ALL FATAL HEMORRHAGIC EVENTS IN PATIENTS TREATED WITH GAZYVA OCCURRED IN CYCLE 1.
TUMOR LYSIS SYNDROME
THE INCIDENCE OF GRADE 3 OR 4 TUMOR LYSIS SYNDROME WAS 2% IN THE GAZYVA TREATED ARM VERSUS 0% IN THE CHLORAMBUCIL ARM.
MUSCULOSKELETAL DISORDERS
ADVERSE EVENTS RELATED TO MUSCULOSKELETAL DISORDERS, INCLUDING PAIN (SYSTEM ORGAN CLASS) HAVE BEEN REPORTED WITH GAZYVA WITH HIGHER INCIDENCE THAN IN THECOMPARATOR ARM (17% VS. 13%).
IMMUNOGENICITY
SERUM SAMPLES FROM PATIENTS WITH PREVIOUSLY UNTREATED CLL WERE TESTED DURING AND AFTER TREATMENT FOR ANTIBODIES TO GAZYVA. APPROXIMATELY 13% (9/70) OF GAZYVA TREATED PATIENTS TESTED POSITIVE FOR ANTI-GAZYVA ANTIBODIES AT ONE OR MORE TIME POINTS DURING THE 12 MONTH FOLLOW-UP PERIOD. NEUTRALIZING ACTIVITY OF ANTI-GAZYVA ANTIBODIES HAS NOT BEEN ASSESSED.
IMMUNOGENICITY DATA ARE HIGHLY DEPENDENT ON THE SENSITIVITY AND SPECIFICITY OF THE TEST METHODS USED. ADDITIONALLY, THE OBSERVED INCIDENCE OF A POSITIVE RESULT IN A TEST METHOD MAY BE INFLUENCED BY SEVERAL FACTORS, INCLUDING SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, DRUG INTERFERENCE, CONCOMITANT MEDICATION AND THE UNDERLYING DISEASE. THEREFORE, COMPARISON OF THE INCIDENCE OF ANTIBODIES TO GAZYVA WITH THE INCIDENCE OF ANTIBODIES TO OTHER PRODUCTS MAY BE MISLEADING. CLINICAL SIGNIFICANCE OF ANTI-GAZYVA ANTIBODIES IS NOT KNOWN.
ADDITIONAL CLINICAL TRIAL EXPERIENCE
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY: PML HAS BEEN REPORTED WITH GAZYVA [SEE WARNINGS AND PRECAUTIONS].
WORSENING OF PRE-EXISTING CARDIAC CONDITIONS: FATAL CARDIAC EVENTS HAVE BEEN REPORTED IN PATIENTS TREATED WITH GAZYVA.
HEPATITIS B REACTIVATION: HEPATITIS B VIRUS REACTIVATION HAS BEEN REPORTED WITH GAZYVA [SEE WARNINGS AND PRECAUTIONS].
READ THE GAZYVA (OBINUTUZUMAB INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
THERE HAS BEEN NO EXPERIENCE WITH OVERDOSE IN HUMAN CLINICAL TRIALS. DOSES RANGING FROM 50 MG UP TO AND INCLUDING 2000 MG PER INFUSION HAVE BEEN ADMINISTERED IN CLINICAL TRIALS. FOR PATIENTS WHO EXPERIENCE OVERDOSE, TREATMENT SHOULD CONSIST OF IMMEDIATE INTERRUPTION OR REDUCTION OF GAZYVA AND SUPPORTIVE THERAPY.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
OBINUTUZUMAB IS A MONOCLONAL ANTIBODY THAT TARGETS THE CD20 ANTIGENEXPRESSED ON THE SURFACE OF PRE B- AND MATURE B-LYMPHOCYTES. UPON BINDING TO CD20, OBINUTUZUMAB MEDIATES B-CELL LYSIS THROUGH (1) ENGAGEMENT OF IMMUNE EFFECTOR CELLS, (2) BY DIRECTLY ACTIVATING INTRACELLULAR DEATH SIGNALING PATHWAYS AND/OR (3) ACTIVATION OF THE COMPLEMENT CASCADE. THE IMMUNE EFFECTOR CELL MECHANISMS INCLUDE ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY AND ANTIBODY-DEPENDENT CELLULAR PHAGOCYTOSIS.
PHARMACODYNAMICS
IN CLINICAL TRIALS IN PATIENTS WITH CLL, GAZYVA CAUSED CD19 B-CELL DEPLETION (DEFINED AS CD19 B-CELL COUNTS < 0.07 X 109/L). INITIAL CD19 B-CELL RECOVERY WAS OBSERVED IN SOME PATIENTS APPROXIMATELY 9 MONTHS AFTER THE LAST GAZYVA DOSE. AT 18 MONTHS OF FOLLOW UP, SOME PATIENTS REMAIN B-CELL DEPLETED. ALTHOUGH THE DEPLETION OF B-CELLS IN THE PERIPHERAL BLOOD IS A MEASURABLE PHARMACODYNAMIC EFFECT, IT IS NOT DIRECTLY CORRELATED WITH THE DEPLETION OF B-CELLS IN SOLID ORGANS OR IN MALIGNANT DEPOSITS. B-CELL DEPLETION HAS NOT BEEN SHOWN TO BE DIRECTLY CORRELATED TO CLINICAL RESPONSE.
CARDIAC ELECTROPHYSIOLOGY
THE POTENTIAL EFFECTS OF GAZYVA ON THE QTC INTERVAL HAVE NOT BEEN STUDIED.
PHARMACOKINETICS
BASED ON A POPULATION PHARMACOKINETIC (POP-PK) ANALYSIS, THE GEOMETRIC MEAN (CV%) VOLUME OF DISTRIBUTION OF OBINUTUZUMAB AT STEADY STATE IS APPROXIMATELY 3.8 (23) L.
THE ELIMINATION OF OBINUTUZUMAB IS COMPRISED OF A LINEAR CLEARANCE PATHWAY AND A TIMEDEPENDENT NON-LINEAR CLEARANCE PATHWAY. AS GAZYVA TREATMENT PROGRESSES, THE IMPACT OF THE TIME-DEPENDENT PATHWAY DIMINISHES IN A MANNER SUGGESTING TARGET MEDIATED DRUG DISPOSITION (TMDD). BASED ON A POP-PK ANALYSIS, THE GEOMETRIC MEAN (CV%) TERMINAL OBINUTUZUMAB CLEARANCE AND HALF-LIFE ARE APPROXIMATELY 0.09 (46%) L/DAY AND 28.4 (43%) DAYS, RESPECTIVELY.
SPECIFIC POPULATIONS
AGE: AGE DID NOT AFFECT THE PHARMACOKINETICS OF GAZYVA.
BODY WEIGHT: VOLUME OF DISTRIBUTION AND STEADY STATE CLEARANCE BOTH INCREASED WITH BODY WEIGHT, HOWEVER, THE EXPECTED CHANGE IN EXPOSURE DOES NOT WARRANT A DOSE MODIFICATION.
RENAL IMPAIRMENT: BASED ON THE POPULATION PHARMACOKINETIC ANALYSIS, A BASELINE CREATININE CLEARANCE (CLCR) > 30 ML/MIN DOES NOT AFFECT THE PHARMACOKINETICS OF GAZYVA. GAZYVA HAS NOT BEEN STUDIED IN PATIENTS WITH A BASELINE CLCR < 30 ML/MIN.
HEPATIC IMPAIRMENT: GAZYVA HAS NOT BEEN STUDIED IN PATIENTS WITH HEPATIC IMPAIRMENT.
CLINICAL STUDIES
CHRONIC LYMPHOCYTIC LEUKEMIA
GAZYVA WAS EVALUATED IN A THREE ARM, OPEN-LABEL, ACTIVE CONTROL, RANDOMIZED, MULTICENTER TRIAL (STUDY 1) IN PATIENTS WITH PREVIOUSLY UNTREATED CD20+ CHRONIC LYMPHOCYTIC LEUKEMIA REQUIRING TREATMENT AND HAD COEXISTING MEDICAL CONDITIONS OR REDUCED RENAL FUNCTION AS MEASURED BY CREATININE CLEARANCE (CRCL) < 70 ML/MIN. PATIENTS WITH CRCL < 30 ML/MIN, ACTIVE INFECTIONS, POSITIVE HEPATITIS B (HBSAG OR ANTI-HBC POSITIVE, PATIENTS POSITIVE FOR ANTI-HBC COULD BE INCLUDED IF HEPATITIS B VIRAL DNA WAS NOT DETECTABLE) AND HEPATITIS C SEROLOGY, OR IMMUNIZATION WITH LIVE VIRUS VACCINE WITHIN 28 DAYS PRIOR TO RANDOMIZATION WERE EXCLUDED FROM THE TRIAL. PATIENTS WERE TREATED WITH CHLORAMBUCIL CONTROL (ARM 1), GAZYVA IN COMBINATION WITH CHLORAMBUCIL (ARM 2) OR RITUXIMAB IN COMBINATION WITH CHLORAMBUCIL (ARM 3). THE SAFETY AND EFFICACY OF GAZYVA WAS EVALUATED IN A COMPARISON OF ARM 1 VS. ARM 2 IN 356 PATIENTS. DATACOMPARING ARM 2 VS. ARM 3 ARE NOT AVAILABLE AT THIS TIME.
THE MAJORITY OF PATIENTS RECEIVED 1000 MG OF GAZYVA ON DAYS 1, 8, AND 15 OF THE FIRST CYCLE, FOLLOWED BY TREATMENT ON THE FIRST DAY OF 5 SUBSEQUENT CYCLES (TOTAL OF 6 CYCLES, 28 DAYS EACH). THE FIRST DOSE OF GAZYVA WAS DIVIDED BETWEEN DAY 1 (100 MG) AND DAY 2 (900 MG) [SEE DOSAGE AND ADMINISTRATION], WHICH WAS IMPLEMENTED IN 45 PATIENTS. CHLORAMBUCIL WAS GIVEN ORALLY AT 0.5 MG/KG ON DAY 1 AND DAY 15 OF ALL TREATMENT CYCLES (1 TO 6).
IN STUDY 1, THE MEDIAN AGE WAS 73 YEARS, 60% WERE MALE, AND 95% WERE CAUCASIAN. SIXTY-EIGHT PERCENT HAD A CRCL < 70 ML/MIN AND 76% HAD MULTIPLE COEXISTING MEDICAL CONDITIONS. TWENTY-TWO PERCENT OF PATIENTS WERE BINET STAGE A, 42% WERE STAGE B, AND 36% WERE STAGE C. THE MEDIAN ESTIMATED CRCL WAS 61 ML/MIN. EIGHTY-ONE PERCENT OF PATIENTS TREATED WITH GAZYVA IN COMBINATION WITH CHLORAMBUCIL RECEIVED ALL 6 CYCLESCOMPARED TO 67% OF PATIENTS IN THE CHLORAMBUCIL ALONE ARM.
THE MEDIAN PROGRESSION FREE SURVIVAL (PFS) IN THE GAZYVA IN COMBINATION WITH CHLORAMBUCIL ARM WAS 23.0 MONTHS AND 11.1 MONTHS IN THE CHLORAMBUCIL ALONE ARM (MEDIAN OBSERVATION TIME 14.2 MONTHS) AS ASSESSED BY INDEPENDENT REVIEW AND IS CONSISTENT WITH INVESTIGATOR ASSESSED PFS. EFFICACY RESULTS ARE SHOWN IN TABLE 5 AND THE KAPLAN-MEIER CURVE FOR PFS IS SHOWN IN FIGURE 1.
TABLE 5 : EFFICACY RESULTS FOR STUDY 1
ENDPOINT GAZYVA + CHLORAMBUCIL CHLORAMBUCIL
MEDIAN PROGRESSION-FREE SURVIVALA 23.0 MONTHS 11.1 MONTHS
(HR 0.16 [0.11; 0.24], P-VALUE < 0.0001 STRATIFIED LOG-RANK TEST)
OVERALL RESPONSE RATEB 75.9% 32.1%
COMPLETE RESPONSE 27.8% 0.9%
MEDIAN DURATION OF RESPONSE 15.2 MONTHS 3 . 5 MONTHS
A AS DEFINED BY INDEPENDENT REVIEW. INVESTIGATOR ASSESSED PFS WAS CONSISTENT WITH DATA FROM INDEPENDENT REVIEW.
B AS DEFINED AS BEST OVERALL RESPONSE RATE (ORR=CR+PR)
FIGURE 1: KAPLAN-MEIER CURVE OF PROGRESSION-FREE SURVIVAL IN PATIENTS WITH CLL IN STUDY 1