INDICATIONS
GRANIX IS INDICATED TO REDUCE THE DURATION OF SEVERE NEUTROPENIA IN PATIENTS WITH NON-MYELOID MALIGNANCIES RECEIVING MYELOSUPPRESSIVE ANTI-CANCER DRUGS ASSOCIATED WITH A CLINICALLY SIGNIFICANT INCIDENCE OF FEBRILE NEUTROPENIA.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
INJECTION: 300 MCG/0.5 ML SOLUTION IN SINGLE-USE PREFILLED SYRINGE
INJECTION: 480 MCG/0.8 ML SOLUTION IN SINGLE-USE PREFILLED SYRINGE
STORAGE AND HANDLING
GRANIX SOLUTION FOR INJECTION IS SUPPLIED AS A SINGLE-USE, PRESERVATIVE-FREE, PREFILLED SYRINGE OF TYPE I GLASS WHICH HAS A PERMANENTLY ATTACHED STAINLESS STEEL NEEDLE. SYRINGES MAY BE SUPPLIED WITH OR WITHOUT AN ULTRASAFE PASSIVE® NEEDLE GUARD.
THE ACTIVE SUBSTANCE IS TBO-FILGRASTIM.
GRANIX 300 MCG/0.5 ML: EACH PREFILLED SYRINGE CONTAINS 300 MCG OF TBO-FILGRASTIM IN 0.5 ML SOLUTION WITH A BLUE PLUNGER IN:
PACK OF 1 WITH A SAFETY NEEDLE GUARD IN BLISTER: NDC 63459-910-11
PACKS OF 10 WITH A SAFETY NEEDLE GUARD IN BLISTERS: NDC 63459-910-15
PACK OF 1 WITHOUT A SAFETY NEEDLE GUARD (FOR PATIENTS AND CAREGIVERS): NDC 63459-910-17
PACKS OF 5 WITHOUT A SAFETY NEEDLE GUARD (FOR PATIENTS AND CAREGIVERS): NDC 63459-910-36
GRANIX 480 MCG/0.8 ML: EACH PREFILLED SYRINGE CONTAINS 480 MCG OF TBO-FILGRASTIM IN 0.8 ML SOLUTION WITH A CLEAR PLUNGER IN:
PACK OF 1 WITH A SAFETY NEEDLE GUARD IN BLISTER: NDC 63459-912-11
PACKS OF 10 WITH A SAFETY NEEDLE GUARD IN BLISTERS: NDC 63459-912-15
PACK OF 1 WITHOUT A SAFETY NEEDLE GUARD (FOR PATIENTS AND CAREGIVERS): NDC 63459-912-17
PACKS OF 5 WITHOUT A SAFETY NEEDLE GUARD (FOR PATIENTS AND CAREGIVERS): NDC 63459-912-36
GRANIX SYRINGES SHOULD BE STORED IN A REFRIGERATOR AT 36° TO 46° F (2° TO 8° C). PROTECT FROM LIGHT. WITHIN ITS SHELF LIFE, THE PRODUCT MAY BE REMOVED FROM 36° TO 46° F (2° TO 8° C) STORAGE FOR A SINGLE PERIOD OF UP TO 5 DAYS BETWEEN 73° TO 81° F (23° TO 27° C). IF NOT USED WITHIN 5 DAYS, THE PRODUCT MAY BE RETURNED TO 36° TO 46° F (2° TO 8° C) UP TO THE EXPIRATION DATE.
AVOID SHAKING. THE SOLUTION SHOULD BE VISUALLY INSPECTED PRIOR TO USE. ONLY CLEAR SOLUTIONS WITHOUT PARTICLES SHOULD BE USED. EXPOSURE TO 23° TO 30° F (-1° TO -5 °C) FOR UP TO 72 HOURS AND TEMPERATURES AS LOW AS 5° TO -13° F (-15 TO -25° C) FOR UP TO 24 HOURS DO NOT ADVERSELY AFFECT THE STABILITY OF GRANIX.
SINGLE-USE SYRINGE - DISCARD UNUSED PORTION. ANY UNUSED PRODUCT OR WASTE MATERIAL SHOULD BE DISPOSED OF IN ACCORDANCE WITH LOCAL REQUIREMENTS.
MANUFACTURED BY: SICOR BIOTECH UAB VILNIUS, LITHUANIA. DISTRIBUTED BY: TEVA PHARMACEUTICALS USA, INC. NORTH WALES, PA 19454. REVISION 12/2014
DOSAGE AND ADMINISTRATION
DOSAGE
THE RECOMMENDED DOSE OF GRANIX IS 5 MCG/KG PER DAY ADMINISTERED AS A SUBCUTANEOUS INJECTION. ADMINISTER THE FIRST DOSE OF GRANIX NO EARLIER THAN 24 HOURS FOLLOWING MYELOSUPPRESSIVE CHEMOTHERAPY. DO NOT ADMINISTER GRANIX WITHIN 24 HOURS PRIOR TO CHEMOTHERAPY [SEE WARNINGS AND PRECAUTIONS].
DAILY DOSING WITH GRANIX SHOULD CONTINUE UNTIL THE EXPECTED NEUTROPHIL NADIR IS PASSED AND THE NEUTROPHIL COUNT HAS RECOVERED TO THE NORMAL RANGE. MONITOR COMPLETE BLOOD COUNT (CBC) PRIOR TO CHEMOTHERAPY AND TWICE PER WEEK UNTIL RECOVERY.
GENERAL CONSIDERATIONS FOR ADMINISTRATION
GRANIX MAY BE ADMINISTERED BY EITHER A HEALTHCARE PROFESSIONAL OR BY A PATIENT OR CAREGIVER. BEFORE A DECISION IS MADE TO ALLOW GRANIX TO BE ADMINISTERED BY A PATIENT OR CAREGIVER, ENSURE THAT THE PATIENT IS AN APPROPRIATE CANDIDATE FOR SELF-ADMINISTRATION OR ADMINISTRATION BY A CAREGIVER. PROPER TRAINING ON STORAGE, PREPARATION, AND ADMINISTRATION TECHNIQUE SHOULD BE PROVIDED. IF A PATIENT OR CAREGIVER IS NOT AN APPROPRIATE CANDIDATE FOR ANY REASON, THEN IN SUCH PATIENTS, GRANIX SHOULD BE ADMINISTERED BY A HEALTHCARE PROFESSIONAL.
DISPENSE ONLY THE PRE-FILLED SYRINGE WITHOUT A SAFETY NEEDLE GUARD DEVICE TO PATIENT OR CAREGIVER. INSTRUCT PATIENTS AND CAREGIVERS TO FOLLOW THE INSTRUCTIONS FOR USE PROVIDED WITH THE GRANIX PRE-FILLED SYRINGE TO PROPERLY ADMINISTER AN INJECTION AFTER TRAINING BY A HEALTHCARE PROFESSIONAL.
VISUALLY INSPECT PARENTERAL DRUG PRODUCTS FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION. DO NOT ADMINISTER GRANIX IF DISCOLORATION OR PARTICULATES ARE OBSERVED.
THE PREFILLED SYRINGE IS FOR SINGLE USE ONLY. DISCARD UNUSED PORTIONS.
RECOMMENDED SITES FOR SUBCUTANEOUS GRANIX INJECTIONS INCLUDE THE ABDOMEN (EXCEPT FOR THE TWO-INCH AREA AROUND THE NAVEL), THE FRONT OF THE MIDDLE THIGHS, THE UPPER OUTER AREAS OF THE BUTTOCKS, OR THE UPPER BACK PORTION OF THE UPPER ARMS. THE INJECTION SITE SHOULD BE VARIED DAILY. GRANIX SHOULD NOT BE INJECTED INTO AN AREA THAT IS TENDER, RED, BRUISED OR HARD, OR THAT HAS SCARS OR STRETCH MARKS.
INSTRUCTIONS FOR USE OF THE SAFETY NEEDLE GUARD DEVICE BY HEALTHCARE PROFESSIONALS
HOLD THE SYRINGE ASSEMBLY BY THE OPEN SIDES OF THE DEVICE AND REMOVE THE NEEDLE SHIELD.
EXPEL ANY EXTRA VOLUME DEPENDING ON DOSE NEEDED.
INJECT GRANIX SUBCUTANEOUSLY AS RECOMMENDED [SEE GENERAL CONSIDERATIONS FOR ADMINISTRATION].
PUSH THE PLUNGER AS FAR AS IT WILL GO TO INJECT ALL THE MEDICATION. INJECTION OF THE ENTIRE PREFILLED SYRINGE CONTENTS IS NECESSARY TO ACTIVATE THE NEEDLE GUARD.
WITH THE PLUNGER STILL PRESSED ALL THE WAY DOWN, REMOVE THE NEEDLE FROM THE SKIN.
SLOWLY LET GO OF THE PLUNGER AND ALLOW THE EMPTY SYRINGE TO MOVE UP INSIDE THE DEVICE UNTIL THE ENTIRE NEEDLE IS GUARDED.
DISCARD THE SYRINGE ASSEMBLY IN APPROVED CONTAINERS.
SIDE EFFECTS
THE FOLLOWING POTENTIAL SERIOUS ADVERSE REACTIONS ARE DISCUSSED IN GREATER DETAIL IN OTHER SECTIONS OF THE LABELING:
" SPLENIC RUPTURE [SEE WARNINGS AND PRECAUTIONS]
" ACUTE RESPIRATORY DISTRESS SYNDROME [SEE WARNINGS AND PRECAUTIONS]
" SERIOUS ALLERGIC REACTIONS [SEE WARNINGS AND PRECAUTIONS]
" USE IN PATIENTS WITH SICKLE CELL DISEASE [SEE WARNINGS AND PRECAUTIONS]
" CAPILLARY LEAK SYNDROME [SEE WARNINGS AND PRECAUTIONS]
" POTENTIAL FOR TUMOR GROWTH STIMULATORY EFFECTS ON MALIGNANT CELLS [SEE WARNINGS AND PRECAUTIONS]
THE MOST COMMON TREATMENT-EMERGENT ADVERSE REACTION THAT OCCURRED AT AN INCIDENCE OF AT LEAST 1% OR GREATER IN PATIENTS TREATED WITH GRANIX AT THE RECOMMENDED DOSE AND WAS NUMERICALLY TWO TIMES MORE FREQUENT THAN IN THE PLACEBO GROUP WAS BONE PAIN.
CLINICAL TRIALS EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
GRANIX CLINICAL TRIALS SAFETY DATA ARE BASED UPON THE RESULTS OF THREE RANDOMIZED CLINICAL TRIALS IN PATIENTS RECEIVING MYELOABLATIVE CHEMOTHERAPY FOR BREAST CANCER (N=348), LUNG CANCER (N=240) AND NON-HODGKIN'S LYMPHOMA (N=92). IN THE BREAST CANCER STUDY, 99% OF PATIENTS WERE FEMALE, THE MEDIAN AGE WAS 50 YEARS, AND 86% OF PATIENTS WERE CAUCASIAN. IN THE LUNG CANCER STUDY, 80% OF PATIENTS WERE MALE, THE MEDIAN AGE WAS 58 YEARS, AND 95% OF PATIENTS WERE CAUCASIAN. IN THE NON-HODGKIN'S LYMPHOMA STUDY, 52% OF PATIENTS WERE MALE, THE MEDIAN AGE WAS 55 YEARS, AND 88% OF PATIENTS WERE CAUCASIAN. IN ALL THREE STUDIES A PLACEBO (CYCLE 1 OF THE BREAST CANCER STUDY ONLY) OR A NON-US-APPROVED FILGRASTIM PRODUCT WERE USED AS CONTROLS. BOTH GRANIX AND THE NON-US-APPROVED FILGRASTIM PRODUCT WERE ADMINISTERED AT 5 MCG/KG SUBCUTANEOUSLY ONCE DAILY BEGINNING ONE DAY AFTER CHEMOTHERAPY FOR AT LEAST FIVE DAYS AND CONTINUED TO A MAXIMUM OF 14 DAYS OR UNTIL AN ANC OF ? 10,000 X 106/L AFTER NADIR WAS REACHED.
BONE PAIN WAS THE MOST FREQUENT TREATMENT-EMERGENT ADVERSE REACTION THAT OCCURRED IN AT LEAST 1% OR GREATER IN PATIENTS TREATED WITH GRANIX AT THE RECOMMENDED DOSE AND WAS NUMERICALLY TWO TIMES MORE FREQUENT THAN IN THE PLACEBO GROUP. THE OVERALL INCIDENCE OF BONE PAIN IN CYCLE 1 OF TREATMENT WAS 3.4% (3.4% GRANIX, 1.4% PLACEBO, 7.5% NON-US-APPROVED FILGRASTIM PRODUCT).
LEUKOCYTOSIS
IN CLINICAL STUDIES, LEUKOCYTOSIS (WBC COUNTS > 100,000 X 106/L) WAS OBSERVED IN LESS THAN 1% PATIENTS WITH NON-MYELOID MALIGNANCIES RECEIVING GRANIX. NO COMPLICATIONS ATTRIBUTABLE TO LEUKOCYTOSIS WERE REPORTED IN CLINICAL STUDIES.
ADDITIONAL ADVERSE REACTIONS
OTHER ADVERSE REACTIONS KNOWN TO OCCUR FOLLOWING ADMINISTRATION OF HUMAN GRANULOCYTE COLONY-STIMULATING FACTORS INCLUDE MYALGIA, HEADACHE, VOMITING, SWEET'S SYNDROME (ACUTE FEBRILE NEUTROPHILIC DERMATOSIS), CUTANEOUS VASCULITIS AND THROMBOCYTOPENIA.
IMMUNOGENICITY
AS WITH ALL THERAPEUTIC PROTEINS, THERE IS A POTENTIAL FOR IMMUNOGENICITY. THE INCIDENCE OF ANTIBODY DEVELOPMENT IN PATIENTS RECEIVING GRANIX HAS NOT BEEN ADEQUATELY DETERMINED.
READ THE GRANIX (TBO-FILGRASTIM INJECTION, FOR SUBCUTANEOUS USE) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
TBO-FILGRASTIM IS A HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) PRODUCED BY RECOMBINANT DNA TECHNOLOGY. TBO-FILGRASTIM BINDS TO G-CSF RECEPTORS AND STIMULATES PROLIFERATION OF NEUTROPHILS. G-CSF IS KNOWN TO STIMULATE DIFFERENTIATION COMMITMENT AND SOME END-CELL FUNCTIONAL ACTIVATION, WHICH INCREASES NEUTROPHIL COUNTS AND ACTIVITY.
PHARMACODYNAMICS
IN THE CLINICAL TRIALS OF PATIENTS WITH CANCER, THE TIME TO THE ANCMAX WAS BETWEEN 3 TO 5 DAYS AND RETURNED TO BASELINE BY 21 DAYS FOLLOWING COMPLETION OF CHEMOTHERAPY. IN THE HEALTHY VOLUNTEER TRIALS, DOUBLING THE TBO-FILGRASTIM SUBCUTANEOUS DOSE FROM 5 TO 10 MCG/KG RESULTED IN A 16%-19% INCREASE IN THE ANCMAX AND A 33%-36% INCREASE IN THE AREA UNDER THE EFFECT CURVE FOR ANC.
CARDIAC ELECTROPHYSIOLOGY
AT THE MAXIMUM RECOMMENDED INTRAVENOUS DOSE OF 5 ?G/KG, TBO-FILGRASTIM DID NOT PROLONG THE QT INTERVAL TO ANY CLINICALLY RELEVANT EXTENT.
PHARMACOKINETICS
IN HEALTHY SUBJECTS, THE ABSOLUTE BIOAVAILABILITY OF 5 MCG/KG SUBCUTANEOUS TBO-FILGRASTIM WAS 33%. INCREASING THE DOSE OF TBO-FILGRASTIM FROM 5 TO 10 MCG/KG IN THESE HEALTHY SUBJECTS RESULTED IN AN APPROXIMATELY 200% INCREASE IN BOTH THE MAXIMUM CONCENTRATION (CMAX) AND THE AREA UNDER THE CURVE (AUC0-48H) OF THE DRUG.
IN THE CLINICAL TRIALS OF PATIENTS WITH CANCER, THE AUC AND CMAX WERE GREATER AND MORE VARIABLE COMPARED TO HEALTHY VOLUNTEERS RECEIVING THE SAME DOSE OF TBO-FILGRASTIM SUBCUTANEOUSLY. THE MEDIAN TIME TO MAXIMUM CONCENTRATION WAS BETWEEN 4 TO 6 HOURS AND THE MEDIAN ELIMINATION HALF-LIFE WAS BETWEEN 3.2 TO 3.8 HOURS. ACCUMULATION WAS NOT OBSERVED AFTER REPEATED DOSING.
PHARMACOKINETICS IN SPECIFIC POPULATIONS
AGE: NOT EVALUATED.
GENDER: NO GENDER-RELATED DIFFERENCES WERE OBSERVED.
RENAL IMPAIRMENT: MILD RENAL IMPAIRMENT (CREATININE CLEARANCE 60 - 89 ML/MIN) HAD NO EFFECT ON TBOFILGRASTIM PHARMACOKINETICS (N=11). THE PHARMACOKINETIC PROFILE IN PATIENTS WITH MODERATE AND SEVERE RENAL IMPAIRMENT HAS NOT BEEN ASSESSED.
HEPATIC IMPAIRMENT: THE PHARMACOKINETIC PROFILE IN PATIENTS WITH HEPATIC IMPAIRMENT HAS NOT BEEN ASSESSED.
CLINICAL STUDIES
THE EFFICACY OF GRANIX WAS EVALUATED IN A MULTINATIONAL, MULTICENTER, RANDOMIZED AND CONTROLLED PHASE 3 STUDY IN 348 CHEMOTHERAPY-NAIVE PATIENTS WITH HIGH-RISK STAGE II, STAGE III, OR STAGE IV BREAST CANCER RECEIVING DOXORUBICIN (60 MG/M²) AND DOCETAXEL (75 MG/M²) COMPARING GRANIX TO PLACEBO AND A NONUS-APPROVED FILGRASTIM PRODUCT AS CONTROLS. THE MEDIAN AGE OF THE PATIENTS WAS 50 YEARS (RANGE 25 TO 75 YEARS) WITH 99% FEMALE AND 86% CAUCASIAN.
GRANIX, PLACEBO, AND THE NON-US-APPROVED FILGRASTIM PRODUCT WERE ADMINISTERED AT 5 MCG/KG SUBCUTANEOUSLY ONCE DAILY BEGINNING ONE DAY AFTER CHEMOTHERAPY FOR AT LEAST FIVE DAYS AND CONTINUED TO A MAXIMUM OF 14 DAYS OR UNTIL AN ANC OF ? 10,000 X 106/L AFTER NADIR WAS REACHED.
GRANIX WAS SUPERIOR TO PLACEBO IN DURATION OF SEVERE NEUTROPENIA (DSN) WITH A STATISTICALLY SIGNIFICANT REDUCTION IN DSN (1.1 DAYS VS. 3.8 DAYS, P < 0.0001).