HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ABRAXANE safely and effectively
`See full prescribing
`information for ABRAXANE
`
`ABRAXANE® for Injectable Suspension paclitaxel protein bound
`particles for injectable suspension
`albumin bound
`Initial US Approval 2005
`
`WARNING NEUTROPENIA
`See full prescribing information for complete boxed warning
`
`It
`
`Do not administer ABRAXANE therapy to patients with
`baseline neutrophil counts of less than 1500 cellsmm3 4
`is recommended that frequent peripheral blood cell counts
`be performed to monitor the occurrence of bone marrow
`suppression 4 51 61 62 63
`DO NOT SUBSTITUTE
`FOR OR WITH OTHER PACLITAXEL
`FORMULATIONS
`
`122014
`072015
`122014
`
`inhibitor
`
`indicated for the treatment of
`
`RECENT MAJOR CHANGES
`Dosage and Administration 24 28
`Dosage and Administration 27
`Warnings and Precautions Hepatic Impairment 56
`INDICATIONS AND USAGE
`ABRAXANE is a microtubule
`chemotherapy
`Metastatic breast cancer after failure of combination
`for metastatic disease or relapse within 6 months of adjuvant
`chemotherapy Prior therapy should have included an anthracycline
`unless clinically contraindicated 11
`lung cancer NSCLC
`Locally advanced or metastatic non small cell
`in combination with carboplatin in patients who
`as first
`line treatment
`for curative surgery or radiation therapy 12
`Metastatic adenocarcinoma
`of the pancreas as first line treatment in
`combination with gemcitabine 13
`
`are not candidates
`
`DOSAGE AND ADMINISTRATION
`
`dosage of ABRAXANE is
`Metastatic Breast Cancer Recommended
`260 mgm2 intravenously over 30 minutes every 3 weeks 21
`dosage of ABRAXANE
`Non Small Cell Lung Cancer Recommended
`is 100 mgm2 intravenously over 30 minutes on Days 1 8 and 15 of
`each 21 day cycle administer carboplatin on Day 1 of each 21 day
`cycle immediately after ABRAXANE 22
`of the Pancreas Recommended
`Adenocarcinoma
`dosage of
`ABRAXANE is 125 mgm2 intravenously over 3040 minutes on Days
`1 8 and 15 of each 28 day cycle administer gemcitabine on Days 1
`8 and 15 of each 28day cycle immediately after ABRAXANE 23
`Do not administer ABRAXANE to any patient with AST > 10 x ULN or
`bilirubin > 5 x ULN Do not administer ABRAXANE to patients with
`of the pancreas who have moderate to
`metastatic adenocarcinoma
`severe hepatic impairment For diseases other than metastatic
`adenocarcinoma
`reduce starting dose in patients
`of the pancreas
`with moderate to severe hepatic impairment 24
`Dose Reductions Dose reductions or discontinuation may be
`needed based on severe hematologic neurologic cutaneous or
`toxicities 25
`gastrointestinal
`Use caution when handling cytotoxic drugs Closely monitor the
`and infiltration
`No premedication
`infusion site for extravasation
`required prior to administration 26
`
`is
`
`paclitaxel
`
`at
`
`DOSAGE FORMS AND STRENGTHS
`100 mg of
`For injectable suspension lyophilized powder containing
`formulated as albumin bound particles in single use vial for
`reconstitution 3
`CONTRAINDICATIONS
`Neutrophil counts of < 1500 cellsmm3 4
`reaction to ABRAXANE 4
`Severe hypersensitivity
`WARNINGS AND PRECAUTIONS
`ABRAXANE causes myelosuppression Monitor CBC and withhold
`reduce the dose as needed 51
`andor
`Sensory neuropathy occurs frequently and may require dose
`interruption 52
`reduction or treatment
`Sepsis occurred in patients with or without neutropenia who received
`ABRAXANE in combination with gemcitabine interrupt ABRAXANE
`and gemcitabine until sepsis resolves and if neutropenia
`until
`least 1500 cellsmm3 then resume treatment
`neutrophils are at
`reduced dose levels 53
`Pneumonitis occurred with the use of ABRAXANE in combination
`with gemcitabine permanently discontinue treatment with
`ABRAXANE and gemcitabine 54
`reactions with fatal outcome have been
`Severe hypersensitivity
`reported Do not re challenge with this drug 55
`Exposure and toxicity of paclitaxel can be increased in patients with
`hepatic impairment therefore administer with caution 56
`ABRAXANE contains albumin derived from human blood which has
`risk of viral transmission 57
`a theoretical
`to a pregnant woman
`Fetal harm may occur when administered
`Advise women of childbearing potential
`to avoid becoming pregnant
`while receiving ABRAXANE 58
`Advise men not to father a child while on ABRAXANE 59
`
`ADVERSE REACTIONS
`
`The most common adverse reactions 20 in metastatic breast
`abnormal
`cancer are alopecia neutropenia sensory neuropathy
`ECG fatigueasthenia myalgiaarthralgia AST elevation
`phosphatase elevation anemia nausea infections and
`diarrhea 61
`The most common adverse reactions 20 in NSCLC are anemia
`nausea and fatigue 62
`The most common 20 adverse reactions of ABRAXANE in
`
`alkaline
`
`neutropenia
`
`thrombocytopenia alopecia peripheral neuropathy
`
`adenocarcinoma
`of the pancreas are neutropenia fatigue peripheral
`neuropathy nausea alopecia peripheral edema diarrhea pyrexia
`vomiting decreased appetite rash and dehydration 63
`To report SUSPECTED ADVERSE REACTIONS contact Celgene
`or FDA at 1 800 FDA 1088 or
`Corporation at 18884235436
`wwwfdagovImedwatch
`
`DRUG INTERACTIONS
`administering ABRAXANE with
`Use caution when concomitantly
`inhibitors or inducers of either CYP2C8 or CYP3A4 7
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA approved patient labeling
`
`Revised 072015
`
`Reference ID 3793488
`
`1
`
`Abraxis EX2011
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`FULL PRESCRIBING INFORMATION CONTENTS
`
`1
`
`2
`
`6
`
`Dosage in Patients with Hepatic Impairment
`Dose ReductionDiscontinuation
`Recommendations
`Preparation and Administration Precautions
`Preparation for Intravenous Administration
`
`Stability
`
`WARNING
`NEUTROPENIA
`INDICATIONS AND USAGE
`11
`Metastatic Breast Cancer
`12
`Non Small Cell Lung Cancer
`13
`Adenocarcinoma
`of the Pancreas
`DOSAGE AND ADMINISTRATION
`21
`Metastatic Breast Cancer
`22
`Non Small Cell Lung Cancer
`23
`Adenocarcinoma
`of the Pancreas
`24
`25
`26
`27
`28
`DOSAGE FORMS AND STRENGTHS
`3
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`51
`Hematologic Effects
`52
`Nervous System
`53
`Sepsis
`54
`Pneumonitis
`55
`Hypersensitivity
`56
`Hepatic Impairment
`57 Albumin Human
`58
`Use in Pregnancy
`59
`Use in Men
`ADVERSE REACTIONS
`61
`Clinical Trials Experience in Metastatic Breast Cancer
`62
`Clinical Trials Experience in Non Small Cell Lung Cancer
`63
`Clinical Trials Experience in Adenocarcinoma
`of the
`Pancreas
`
`64
`
`7
`
`8
`
`Pregnancy
`Nursing Mothers
`Pediatric Use
`Geriatric Use
`
`Postmarketing Experience with ABRAXANE and other
`Paclitaxel Formulations
`65
`Accidental Exposure
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`81
`83
`84
`85
`86
`Patients with Hepatic Impairment
`87
`Patients with Renal
`Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`121 Mechanism of Action
`123 Pharmacokinetics
`13 NONCLINICAL
`TOXICOLOGY
`131 Carcinogenesis Mutagenesis
`14 CLINICAL STUDIES
`141 Metastatic Breast Cancer
`142 Non Small Cell Lung Cancer
`143 Adenocarcinoma
`of the Pancreas
`15 REFERENCES
`16 HOW SUPPLIEDSTORAGE AND HANDLING
`How Supplied
`161
`162 Storage
`163 Handling and Disposal
`17 PATIENT COUNSELING INFORMATION
`
`Impairment of Fertility
`
`Sections or subsections omitted from the Full Prescribing Information
`are not
`listed
`
`Reference ID 3793488
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`ABRAXANE® for Injectable Suspension paclitaxel protein bound particles for injectable suspension albumin bound
`
`WARNING NEUTROPENIA
`
`Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500
`the occurrence of bone marrow suppression primarily neutropenia which
`cellsImm3
`In order to monitor
`is recommended that frequent peripheral blood cell counts be
`may be severe and result in infection it
`performed on all patients receiving ABRAXANE see Contraindications 4 Warnings and Precautions 51
`and Adverse Reactions 61 62 63
`
`Note An albumin form of paclitaxel may substantially affect a drugs functional properties relative to those
`FOR OR WITH OTHER PACLITAXEL
`FORMULATIONS
`of drug in solution DO NOT SUBSTITUTE
`
`1
`
`INDICATIONS AND USAGE
`
`Metastatic Breast Cancer
`11
`ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy
`for metastatic disease or
`relapse within 6 months of adjuvant chemotherapy Prior therapy should have included an anthracycline unless clinically
`contraindicated
`
`Non Small Cell Lung Cancer
`12
`ABRAXANE is indicated for the first line treatment of locally advanced or metastatic non small cell
`carboplatin in patients who are not candidates for curative surgery or radiation therapy
`
`lung cancer
`
`in combination with
`
`Adenocarcinoma of the Pancreas
`13
`ABRAXANE is indicated for the first line treatment of patients with metastatic adenocarcinoma
`gemcitabine
`
`of the pancreas
`
`in combination with
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`21
`Metastatic Breast Cancer
`for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy the
`After failure of combination chemotherapy
`regimen for ABRAXANE is 260 mgm2 administered
`intravenously over 30 minutes every 3 weeks
`recommended
`
`Non Small Cell Lung Cancer
`22
`dose of ABRAXANE is 100 mgm2 administered as an intravenous infusion over 30 minutes on Days 1 8 and
`The recommended
`Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE see Clinical Studies
`15 of each 21 day cycle
`142
`
`Adenocarcinoma of the Pancreas
`23
`dose of ABRAXANE is 125 mgm2 administered as an intravenous infusion over 3040 minutes on Days 1 8 and
`The recommended
`15 of each 28 day cycle Administer gemcitabine immediately after ABRAXANE on Days 1 8 and 15 of each 28 day cycle see
`Clinical Studies 143
`
`24
`Dosage in Patients with Hepatic
`Impairment
`to 15 x ULN and aspartate
`than ULN and less than or equal
`For patients with mild hepatic impairment total bilirubin greater
`aminotransferase AST less than or equal
`to 10 x ULN no dose adjustments are required regardless of indication
`
`Do not administer ABRAXANE to patients with metastatic adenocarcinoma
`impairment
`
`of the pancreas who have moderate to severe hepatic
`
`Do not administer ABRAXANE to patients with total bilirubin greater
`indication as these patients have not been studied
`
`than 5 x ULN or AST greater
`
`than 10 x ULN regardless of
`
`Recommendations
`
`for dosage adjustment
`
`for the first course of therapy are shown in Table 1
`
`Reference ID 3793488
`
`3
`
`

`

`Table 1 Recommendations for Starting Dose in Patients with Hepatic
`
`Impairment
`
`SGOT AST
`Levels
`
`Bilirubin
`Levels
`
`ABRAXANE Dose
`
`MBC
`
`NSCLC
`
`Mild
`
`< 10 x ULN
`
`Moderate
`
`< 10 x ULN
`
`Severe
`
`< 10 x ULN
`
`AND
`
`AND
`
`AND
`
`> ULN to
`
`1 5x ULN
`
`260 mgm2
`
`100 mgm2
`
`> 15 to
`
`3 x ULN
`
`> 3 to
`
`5 xULN
`
`200 mgm2b
`
`200 mgm2 b
`
`80 mgm2b
`
`not recommended
`
`80 mgm2b
`
`not recommended
`
`Pancreatic
`Adenocarcinoma
`125 mgm2
`
`a
`
`OR
`> 5 x ULN
`> 10 x ULN
`not recommended
`MBC = Metastatic Breast Cancer NSCLC = Non Small Cell Lung Cancer
`Dosage recommendations
`are for the first course of therapy The need for further dose adjustments
`should be based on individual
`tolerance
`b A dose increase to 260 mgm 2
`for patients with metastatic breast cancer or 100 mgim2 for patients with non small cell
`in subsequent courses should be considered if
`tolerates the reduced dose for two cycles
`the patient
`limit of normal were excluded from clinical
`a Patients with bilirubin levels above the upper
`trials for pancreatic or lung cancer
`
`not recommended
`
`not recommended
`
`in subsequent courses
`
`lung cancer
`
`25
`
`Dose ReductionDiscontinuation
`
`Recommendations
`
`Metastatic Breast Cancer
`Patients who experience severe neutropenia neutrophils less than 500 cellsmm3 for a week or longer or severe sensory
`neuropathy during ABRAXANE therapy should have dosage reduced to 220 mgm2for subsequent courses of ABRAXANE For
`recurrence of severe neutropenia or severe sensory neuropathy additional dose reduction should be made to 180 mgm2 For
`Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2 followed by a dose reduction for all subsequent courses
`of ABRAXANE see Contraindications 4 Warnings and Precautions 51 52 and Adverse Reactions 61
`Non Small Cell Lung Cancer
`Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count ANC is at
`least 100000 cellsmm3 see Contraindications 4 Warnings and Precautions 51 and Adverse Reactions 62
`count
`In patients who develop severe neutropenia or thrombocytopenia
`withhold treatment until counts recover to an absolute neutrophil
`least 100000 cellsmm3 on Day 1 or to an absolute neutrophil count of at
`least 1500 cellsmm3 and platelet count of at
`count of at
`least 50000 cellsmm3 on Days 8 or 15 of the cycle Upon resumption of dosing
`least 500 cellsmm3 and platelet count of at
`reduce ABRAXANE and carboplatin doses as outlined in Table 2
`permanently
`Withhold ABRAXANE for Grade 34 peripheral neuropathy Resume ABRAXANE and carboplatin at reduced doses see Table 2
`resolves see Warnings and Precautions 52 and Adverse
`when peripheral neuropathy improves to Grade 1 or completely
`Reactions 62
`Table 2 Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC
`
`least 1500 cellsmm3 and platelet
`
`is at
`
`Adverse Drug Reaction
`
`Occurrence
`
`Weekly
`ABRAXANE Dose
`mgm2
`
`Every 3 Week
`Carboplatin Dose
`AUC mgminlmL
`
`Neutropenic Fever ANC less than 500mm3 with fever
`>38°C
`
`OR
`Delay of next cycle by more than 7 days for ANC less than
`1500mm3
`
`OR
`ANC less than 500mm3 for more than 7 days
`
`Platelet count
`
`less than 50000mm3
`
`Severe sensory Neuropathy
`
`Grade 3 or 4
`
`First
`
`Second
`
`Third
`
`First
`
`Second
`
`First
`
`Second
`
`Third
`
`75
`
`50
`
`75
`
`75
`
`50
`
`45
`
`3
`
`45
`
`45
`
`3
`
`Discontinue Treatment
`
`Discontinue Treatment
`
`Discontinue Treatment
`
`Reference ID 3793488
`
`4
`
`

`

`of the Pancreas
`Adenocarcinoma
`Dose level reductions for patients with adenocarcinoma
`
`of the pancreas
`
`as referenced in Tables 4 and 5 are provided in Table 3
`
`Dose Level
`
`Full dose
`
`1st dose reduction
`
`2nd dose reduction
`
`Table 3 Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas
`
`ABRAXANE mgm2
`
`Gemcitabine mgm2
`
`125
`
`100
`
`75
`
`1000
`
`800
`
`600
`
`If additional dose reduction required
`
`Discontinue
`
`Discontinue
`
`Recommended
`dose modifications
`provided in Table 4
`
`for neutropenia and thrombocytopenia
`
`for patients with adenocarcinoma
`
`of the pancreas are
`
`Table 4 Dose Recommendation and Modifications for Neutropenia andor Thrombocytopenia at the Start of a Cycle or
`within a Cycle for Patients with Adenocarcinoma of the Pancreas
`
`Cvc le
`Day
`
`Day 1
`
`Day 8
`
`ANC cellsImm3
`
`Platelet count cellsImm3
`
`ABRAXANE I Gemcitabine
`
`<1500
`
`500 to <1000
`
`<500
`
`OR
`
`OR
`
`OR
`
`<100000
`
`50000 to <75000
`
`<50000
`
`Delay doses until recovery
`
`Reduce 1 dose level
`
`Withhold doses
`
`Day 15 If Day 8 doses were reduced or given without modification
`
`500 to < 1000
`
`<500
`
`OR
`
`OR
`
`50000 to <75000
`
`<50000
`
`Reduce 1 dose level from Day 8
`
`Withhold doses
`
`Day 15 If Day 8 doses were withheld
`
`1000
`
`500 to < 1000
`
`<500
`ANC = Absolute Neutrophil Count
`
`OR
`
`OR
`
`OR
`
`75000
`
`50000 to <75000
`
`<50000
`
`Reduce 1 dose level from Day 1
`
`Reduce 2 dose levels from Day 1
`
`Withhold doses
`
`Recommended
`Table 5
`
`dose modifications
`
`for other adverse drug reactions in patients with adenocarcinoma
`
`of the pancreas are provided in
`
`Table 5 Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas
`
`Adverse Drug Reaction
`
`Febrile Neutropenia
`
`Grade 3 or 4
`
`Peripheral Neuropathy
`
`Grade 3 or 4
`
`Cutaneous Toxicity
`
`Grade 2 or 3
`
`ABRAXANE
`
`Gemcitabine
`
`Withhold until
`
`fever
`
`resolves and ANC
`
`1500 resume at next lower dose level
`
`Withhold until
`
`improves to Grade 1
`
`resume at next lower dose level
`
`No dose reduction
`
`Reduce to next lower dose level discontinue treatment
`
`if toxicity persists
`
`Gastrointestinal Toxicity
`Grade 3 mucositis or diarrhea
`
`Withhold until
`
`improves to Grade 1
`resume at next lower dose level
`
`26
`Preparation and Administration Precautions
`ABRAXANE is a cytotoxic drug and as with other potentially toxic paclitaxel compounds
`caution should be exercised in handling
`ABRAXANE The use of gloves is recommended If ABRAXANE lyophilized cake or reconstituted suspension contacts the skin
`wash the skin immediately and thoroughly with soap and water Following topical exposure to paclitaxel events may include
`tingling burning and redness If ABRAXANE contacts mucous membranes the membranes
`should be flushed thoroughly with
`water
`
`Reference ID 3793488
`
`5
`
`

`

`Given the possibility of extravasation it
`is advisable to closely monitor the infusion site for possible infiltration during drug
`administration Limiting the infusion of ABRAXANE to 30 minutes as directed reduces the likelihood of infusion related reactions
`see Adverse Reactions 64
`
`of ABRAXANE
`reactions is generally not needed prior to the administration
`Premedication
`to prevent hypersensitivity
`reactions to ABRAXANE Patients who experience a
`Premedication may be needed in patients who have had prior hypersensitivity
`reaction to ABRAXANE should not be re challenged with this drug see Warnings and Precautions 55
`severe hypersensitivity
`
`before use AVOID ERRORS READ ENTIRE
`
`27
`Preparation for Intravenous Administration
`ABRAXANE is supplied as a sterile lyophilized powder
`for reconstitution
`PREPARATION INSTRUCTIONS
`PRIOR TO RECONSTITUTION
`each vial by injecting 20 mL of 09 Sodium Chloride Injection USP
`the 20 mL of 09 Sodium Chloride Injection USP over a minimum of 1 minute using the
`Slowly inject
`sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL
`
`Aseptically reconstitute
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`DO NOT INJECT the 09 Sodium Chloride Injection USP directly onto the lyophilized cake as this will
`
`result in foaming
`
`Once the injection is complete allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of
`the lyophilized cakepowder
`
`Gently swirl andor invert the vial slowly for at
`occurs Avoid generation of foam
`
`least 2 minutes until complete dissolution of any cakepowder
`
`If foaming or clumping occurs
`
`stand solution for at
`
`least 15 minutes until
`
`foam subsides
`
`Each mL of the reconstituted formulation will contain 5 mgmL paclitaxel
`
`suspension should be milky and homogenous without visible particulates
`The reconstituted
`If particulates or settling are visible the
`prior to use Discard the reconstituted
`vial should be gently inverted again to ensure complete resuspension
`suspension if
`precipitates are observed Discard any unused portion
`
`Calculate the exact
`
`the reconstituted
`
`total dosing volume of 5 mgmL suspension required for the patient and slowly withdraw the dosing volume of
`suspension from the vials into a syringe Dosing volume mL=Total dose mg5 mgmL
`
`Inject
`
`the appropriate amount of reconstituted ABRAXANE into an empty sterile intravenous bag plasticized polyvinyl chloride
`PVC containers PVC or non PVC type intravenous bag The use of specialized DEHPfree solution containers or administration
`sets is not necessary to prepare or administer ABRAXANE infusions The use of medical devices containing silicone oil as a
`and administer ABRAXANE may result
`ie syringes and intravenous bags to reconstitute
`lubricant
`in the formation of proteinaceous
`strands
`
`the reconstituted ABRAXANE suspension in the intravenous
`bag prior to administration Discard the reconstituted
`Visually inspect
`strands particulate matter or discoloration are observed
`suspension if proteinaceous
`
`28
`Stability
`Unopened vials of ABRAXANE are stable until
`the date indicated on the package when stored between 20°C to 25°C 68°F to 77°F
`in the original package Neither
`freezing nor refrigeration adversely affects the stability of the product
`
`Stability of Reconstituted Suspension in the Vial
`Reconstituted ABRAXANE in the vial should be used immediately but may be refrigerated at 2°C to 8°C 36°F to 46°F for a
`maximum of 24 hours if necessary If not used immediately each vial of reconstituted
`suspension should be replaced in the original
`light Discard any unused portion
`it from bright
`carton to protect
`
`Stability of Reconstituted Suspension in the Infusion Bag
`The suspension for infusion when prepared as recommended
`in an infusion bag should be used immediately but may be
`light for a maximum of 24 hours
`refrigerated at 2°C to 8°C 36°F to 46°F and protected from bright
`
`The total combined refrigerated storage time of reconstituted ABRAXANE in the vial and in the infusion bag is 24 hours This may
`temperature approximately 25°C and lighting conditions for a maximum of
`be followed by storage in the infusion bag at ambient
`4 hours
`
`Reference ID 3793488
`
`6
`
`

`

`Discard any unused portion
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`For injectable suspension lyophilized powder containing
`vial for reconstitution
`
`100 mg of paclitaxel
`
`formulated as albumin bound particles in single use
`
`4
`
`5
`
`CONTRAINDICATIONS
`ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cellsmm3
`Patients who experience a severe hypersensitivity
`reaction to ABRAXANE should not be rechallenged with the drug
`
`WARNINGS AND PRECAUTIONS
`
`51
`Hematologic Effects
`Bone marrow suppression primarily neutropenia is dose dependent and a dose limiting toxicity of ABRAXANE In clinical studies
`Grade 34 neutropenia occurred in 34 of patients with metastatic breast cancer MBC 47 of patients with nonsmall cell
`lung
`cancer NSCLC and 38 of patients with pancreatic cancer
`
`for MBC and
`by performing complete blood cell counts frequently including prior to dosing on Day 1
`Monitor for myelotoxicity
`Days 1 8 and 15 for NSCLC and for pancreatic cancer
`Do not administer ABRAXANE to patients with baseline absolute
`neutrophil counts ANC of less than 1500 cellsmm3 In the case of severe neutropenia <500 cellsmm3 for seven days or more
`courses in patients with either MBC or
`during a course of ABRAXANE therapy reduce the dose of ABRAXANE in subsequent
`NSCLC
`
`In patients with MBC resume treatment with every 3 week cycles of ABRAXANE after ANC recovers to a level >1500 cellsmm3
`to a level >100000 cellsmm3
`and platelets recover
`
`of at
`
`see Dosage and Administration Table 2 at permanently
`In patients with NSCLC resume treatment
`if recommended
`reduced
`doses for both weekly ABRAXANE and every 3 week carboplatin after ANC recovers to at
`least 1500 cellsmm3 and platelet count
`least 100000 cellsmm3 on Day 1 or to an ANC of at
`least 500 cellsmm3 and platelet count of at least 50000 cellsmm3 on
`Days 8 or 15 of the cycle see Dosage and Administration 25
`the ANC is less than 500 cellsmm3 or
`of the pancreas withhold ABRAXANE and gemcitabine if
`In patients with adenocarcinoma
`platelets are less than 50000 cellsmm i and delay initiation of the next cycle if the ANC is less than 1500 cellsmm3 or platelet count
`is less than 100000 cellsmm3 on Day 1 of the cycle Resume treatment with appropriate dose reduction if recommended
`see
`Dosage and Administration 25
`
`52
`
`until
`
`cancer
`
`Nervous System
`is dose and schedule dependent see Adverse Reactions 61 62 63 The occurrence of Grade 1 or 2
`Sensory neuropathy
`sensory neuropathy does not generally require dose modification If Grade 3 sensory neuropathy develops withhold ABRAXANE
`resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to Grade 1 for NSCLC and pancreatic
`treatment
`courses of ABRAXANE see Dosage and Administration 25
`followed by a dose reduction for all subsequent
`Sepsis occurred in 5 of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine Biliary
`obstruction or presence of biliary stent were risk factors for severe or fatal sepsis If a patient becomes febrile regardless of ANC
`initiate treatment with broad spectrum antibiotics For febrile neutropenia interrupt ABRAXANE and gemcitabine
`1500 then resume treatment at reduced dose levels see Dosage and Administration 25
`and ANC
`Pneumonitis including some cases that were fatal occurred in 4 of patients receiving ABRAXANE in combination with
`gemcitabine Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation
`infectious etiology and upon making a diagnosis of pneumonitis permanently discontinue
`of suspected pneumonitis After ruling out
`treatment with ABRAXANE and gemcitabine
`
`53
`
`Sepsis
`
`54
`
`Pneumonitis
`
`until fever resolves
`
`55
`Hypersensitivity
`reactions have been reported Patients who
`Severe and sometimes fatal hypersensitivity
`reaction to ABRAXANE should not be rechallenged with this drug
`experience a severe hypersensitivity
`
`reactions including anaphylactic
`
`Reference ID 3793488
`
`7
`
`

`

`56
`Hepatic
`Impairment
`Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment administration of ABRAXANE in patients
`with hepatic impairment should be performed with caution Patients with hepatic impairment may be at
`increased risk of toxicity
`particularly from myelosuppression such patients should be closely monitored for development
`of profound myelosuppression
`ABRAXANE is not recommended
`in patients who have total bilirubin >5 x ULN or AST >10 x ULN In addition ABRAXANE is not
`of the pancreas who have moderate to severe hepatic impairment total
`recommended
`in patients with metastatic adenocarcinoma
`0 x ULN The starting dose should be reduced for patients with moderate or severe hepatic
`bilirubin >15 x ULN and AST
`impairment see Dosage and Administration 24 Use in Specific Populations 86 and Clinical Pharmacology 123
`Albumin Human
`57
`ABRAXANE contains albumin human a derivative of human blood Based on effective donor screening and product manufacturing
`processes it carries a remote risk for transmission of viral diseases A theoretical
`risk for transmission of CreutzfeldtJakob Disease
`CJD also is considered extremely remote No cases of transmission of viral diseases or CJD have ever been identified for
`albumin
`
`Use in Pregnancy
`58
`ABRAXANE can cause fetal harm when administered
`to a pregnant woman Administration of paclitaxel
`formulated as
`albumin bound particles to rats during pregnancy at doses lower than the maximum recommended
`human dose based on body
`toxicities including intrauterine mortality increased resorptions reduced numbers of live fetuses
`surface area caused embryo fetal
`and malformations
`
`There are no adequate and well controlled studies in pregnant women receiving ABRAXANE If this drug is used during pregnancy
`the patient becomes pregnant while receiving this drug the patient should be apprised of the potential hazard to the fetus
`or if
`Women of childbearing
`potential should be advised to avoid becoming pregnant while receiving ABRAXANE see Use in Specific
`Populations 81
`
`59
`Use in Men
`Men should be advised not to father a child while receiving ABRAXANE see Nonclinical Toxicology 131
`
`6
`
`neutropenia
`
`ADVERSE REACTIONS
`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
`the rates observed in practice
`trials of another drug and may not reflect
`The most common adverse reactions 20 with single agent use of ABRAXANE in metastatic breast cancer are alopecia
`sensory neuropathy abnormal ECG fatigueasthenia myalgiaarthralgia AST elevation alkaline phosphatase
`elevation anemia nausea infections and diarrhea see Adverse Reactions 61
`The most common adverse reactions 20 of ABRAXANE in combination with carboplatin for non small cell
`peripheral neuropathy nausea and fatigue see Adverse Reactions 62 The
`anemia neutropenia
`4 and pneumonia 3 The most common adverse reactions resulting in permanent discontinuation
`thrombocytopenia alopecia
`most common serious adverse reactions of ABRAXANE in combination with carboplatin for non small cell
`lung cancer are anemia
`neutropenia 3 thrombocytopenia 3 and peripheral neuropathy 1 The most common adverse reactions resulting in dose
`of ABRAXANE are
`reduction of ABRAXANE are neutropenia 24 thrombocytopenia 13 and anemia 6 The most common adverse reactions
`or delay in ABRAXANE dosing are neutropenia 41 thrombocytopenia 30 and anemia 16
`trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma
`Studies 143 the most common 20 selected with a 5 higher
`see Clinical
`incidence adverse reactions of ABRAXANE are
`nausea alopecia peripheral edema diarrhea pyrexia vomiting decreased appetite
`rash and dehydration The most common serious adverse reactions of ABRAXANE with a 1 higher
`6 dehydration 5 pneumonia 4 and vomiting 4 The most common adverse reactions resulting in permanent
`incidence are pyrexia
`discontinuation of ABRAXANE are peripheral neuropathy 8 fatigue 4 and thrombocytopenia 2 The most common
`adverse reactions resulting in dose reduction of ABRAXANE are neutropenia 10 and peripheral neuropathy 6 The most
`common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia 16 thrombocytopenia 12
`fatigue 8 peripheral neuropathy 15 anemia 5 and diarrhea 5
`
`lung cancer are
`
`leading to withholding
`
`In a randomized open label
`
`neutropenia
`
`fatigue peripheral neuropathy
`
`61
`Clinical Trials Experience in Metastatic Breast Cancer
`Table 6 shows the frequency of important adverse events in the randomized comparative trial
`single agent ABRAXANE or paclitaxel
`injection for the treatment of metastatic breast cancer
`
`for the patients who received either
`
`Reference ID 3793488
`
`8
`
`

`

`Table 6 Frequency of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast
`Cancer Study on an Every3 Weeks Schedule
`
`Percent of Patients
`ABRAXANE
`260 mgm2 over 30 min
`n=229
`
`Paclitaxel
`Injection
`175 mgm2 over 3 hb
`n=225
`
`Bone Marrow
`
`Neutropenia
`< 20 x 109L
`< 05 x 109L
`
`Throm bocytopenia
`< 100 x 109L
`< 50 x 109L
`
`Anemia
`< 11 gdL
`< 8 gdL
`Infections
`
`Febrile Neutropenia
`
`Neutropenic Sepsis
`
`Bleeding
`Hypersensitivity Reaction
`
`All
`Severed
`
`Cardiovascular
`
`Vital Sign Changes During Administration
`
`Bradycardia
`Hypotension
`Severe Cardiovascular
`Abnormal ECG
`All Patients
`
`Eventsd
`
`Patients with Normal Baseline
`
`Respiratory
`
`Cough
`Dyspnea
`
`Sensory Neuropathy
`Any Symptoms
`Severe Symptomsd
`Myalgia I Arthralgia
`Any Symptoms
`Severe Symptomsd
`Asthenia
`Any Symptoms
`Severe Symptomsd
`Fluid RetentionEdema
`Any Symptoms
`Severe Symptomsd
`Gastrointestinal
`
`Nausea
`Any Symptoms
`Severe Symptomsd
`
`Vomiting
`Any Symptoms
`Severe Symptomsd
`Diarrhea
`Any Symptoms
`Severe Symptomsd
`Mucositis
`Any Symptoms
`Severe Symptomsd
`Alopecia
`Hepatic Patients with Normal Baseline
`Bilirubin Elevations
`
`Alkaline Phosphatase Elevations
`AST SGOT Elevations
`
`80
`9
`
`2
`
`<1
`
`33
`
`1
`
`24
`
`2
`
`<1
`2
`
`4
`o
`
`<1
`
`5
`
`3
`
`60
`
`35
`
`7
`
`12
`
`71
`
`10
`
`44
`
`8
`
`47
`
`8
`
`10
`
`0
`
`30
`
`3
`
`18
`
`4
`
`27
`
`<1
`
`7
`
`<1
`
`90
`
`7
`
`36
`39
`
`82
`22
`
`3
`
`<1
`
`25
`
`<1
`20
`
`1
`
`<1
`2
`
`12
`2
`
`<1
`
`5
`
`4
`
`52
`
`30
`
`6
`
`9
`
`56
`
`2
`
`49
`
`4
`
`39
`
`3
`
`8
`
`<1
`
`22
`
`<1
`
`10
`
`1
`
`15
`
`1
`
`6
`
`o
`
`94
`
`7
`
`31
`32
`
`Reference ID 3793488
`
`9
`
`

`

`Percent of Patients
`ABRAXANE
`260 mgm2 over 30 min
`n=229
`<1
`
`Paclitaxel
`Injection
`175 mgm2 over 3 hb
`n=225
`
`1
`
`Injection Site Reaction
`a Based on worst grade by NCI Common Terminology Criteria for Adverse Events CTCAE version 2
`b Paclitaxel
`injection patients received premedication
`Includes treatment related events related to hypersensitivity eg flushing dyspnea chest pain hypotension that began
`on a day of dosing
`d Severe events are defined as at
`
`a
`
`Adverse Event Experiences by Body System
`
`least grade 3 toxicity
`
`Hematologic Disorders
`Neutropenia was dose dependent and reversible Among patients with metastatic breast cancer
`
`in the randomized trial neutrophil
`
`counts declined below 500 cellsmm3 Grade 4 in 9 of the patients treated with a dose of 260 mgm2 compared to 22 in patients
`injection at a dose of 175 mgm2 Pancytopenia
`
`receiving paclitaxel
`
`has been observed in clinical
`
`trials
`
`Infections
`
`Infectious episodes were reported in 24 of the patients treated with ABRAXANE Oral candidiasis respiratory tract
`pneumonia were the most
`frequently reported infectious complications
`
`infections and
`
`and consisted of dyspnea 1 and flushing hypotension
`Hypersensitivity Reactions HSRs
`Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration
`chest pain and arrhythmia all <1 The use of ABRAXANE in patients previously exhibiting hypersensitivity
`
`to paclitaxel
`
`injection
`
`or human albumin has not been studied
`
`Cardiovascular
`
`during the 30 minute infusion occurred in 5 of patients Bradycardia during the 30 minute infusion occurred in <1
`
`Hypotension
`of patients These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment
`discontinuation
`
`events possibly related to single agent ABRAXANE occurred in approximately 3 of patients These events
`
`Severe cardiovascular
`edema thrombosis pulmonary
`included cardiac ischemiainfarction chest pain cardiac arrest supraventricular
`tachycardia
`thromboembolism pulmonary emboli and hypertension Cases of cerebrovascular
`attacks strokes and transient
`ischemic attacks
`have been reported
`
`result
`
`Electrocardiogram ECG abnormalities were common among patients at