`
`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), for intravenous use
`
`Initial U.S. Approval: 2005
`
`
`
`
`
`WARNING: NEUTROPENIA
`
`
`See full prescribing information for complete boxed warning.
`
`
` Do not administer ABRAXANE therapy to patients with
`
`baseline neutrophil counts of less than 1,500 cells/mm3. (4)
` It is recommended that frequent peripheral blood cell
`
`
`counts be performed to monitor the occurrence of bone
`
`marrow suppression. (4, 5.1, 6.1)
`DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL
`FORMULATIONS.
`
`-------------------------- INDICATIONS AND USAGE -----------------------------
`
`
`ABRAXANE is a microtubule inhibitor indicated for the treatment of:
`
` Metastatic 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. (1.1)
`
` Locally advanced or metastatic non-small cell lung cancer (NSCLC),
`
`as first-line treatment in combination with carboplatin, in patients who
`are not candidates for curative surgery or radiation therapy. (1.2)
`
` Metastatic adenocarcinoma of the pancreas as first-line treatment, in
`
`combination with gemcitabine. (1.3)
`
`----------------------- DOSAGE AND ADMINISTRATION ----------------------
`
`
`
` Metastatic Breast Cancer: Recommended dosage of ABRAXANE is
`
`260 mg/m2 intravenously over 30 minutes every 3 weeks. (2.1)
`
`  Non-Small Cell Lung Cancer: Recommended dosage of ABRAXANE
`
`
`
`
` is 100 mg/m2 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. (2.2)
`
`  Adenocarcinoma of the Pancreas: Recommended dosage of
`
` ABRAXANE is 125 mg/m2 intravenously over 30-40 minutes on Days
`
`
` 1, 8 and 15 of each 28-day cycle; administer gemcitabine on Days 1,
`
`8 and 15 of each 28-day cycle immediately after ABRAXANE. (2.3)
`
`  Hepatic Impairment: Do not administer ABRAXANE to any patient
`with AST > 10 x ULN or bilirubin > 5 x ULN. Do not administer
`
`
`
`ABRAXANE to patients with metastatic adenocarcinoma of the
`pancreas who have moderate to severe hepatic impairment. For
`diseases other than metastatic adenocarcinoma of the pancreas,
`reduce starting dose in patients with moderate to severe hepatic
`impairment. (2.4)
`
` Dose Reductions: Dose reductions or discontinuation may be
`
`
`needed based on severe hematologic, neurologic, cutaneous, or
`gastrointestinal toxicities. (2.5)
` Use caution when handling cytotoxic drugs. Closely monitor the
`
`infusion site for extravasation and infiltration. No premedication is
`required prior to administration. (2.6)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`
`
`For injectable suspension: white to yellow, sterile, lyophilized powder
`
`
`containing 100 mg of paclitaxel formulated as albumin-bound particles
`in single-dose vial for reconstitution. (3)
`------------------------------ CONTRAINDICATIONS -----------------------------
`
`
` Neutrophil counts of < 1,500 cells/mm3. (4)
`
` Severe hypersensitivity reaction to ABRAXANE. (4)
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`
` ABRAXANE causes myelosuppression. Monitor CBC and withhold
`
`and/or reduce the dose as needed. (5.1)
`
` Sensory neuropathy occurs frequently and may require dose
`
`reduction or treatment interruption. (5.2)
`
` 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
`neutrophils are at least 1500 cells/mm3, then resume treatment at
`reduced dose levels. (5.3)
`
` Pneumonitis occurred with the use of ABRAXANE in combination
`
`with gemcitabine; permanently discontinue treatment with
`ABRAXANE and gemcitabine. (5.4)
` Severe hypersensitivity reactions with fatal outcome have been
`
`reported. Do not re-challenge with this drug. (5.5)
`
` Exposure and toxicity of paclitaxel can be increased in patients with
`
`
`hepatic impairment; therefore administer with caution. (5.6)
`
` ABRAXANE contains albumin derived from human blood, which has
`
`a theoretical risk of viral transmission. (5.7)
`
` ABRAXANE can cause fetal harm. Advise patients of potential risk to
`
`a fetus and to use effective contraception. (5.8, 8.1, 8.3)
`
` ------------------------------ ADVERSE REACTIONS -----------------------------
`
`
` The most common adverse reactions (≥ 20%) in metastatic breast
`
`cancer are alopecia, neutropenia, sensory neuropathy, abnormal
`
`ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline
`phosphatase elevation, anemia, nausea, infections, and
`diarrhea. (6.1)
`
` The most common adverse reactions (≥ 20%) in NSCLC are anemia,
`
`neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,
`nausea, and fatigue. (6.11)
`
` The most common (≥ 20%) adverse reactions of ABRAXANE in
`
`adenocarcinoma of the pancreas are neutropenia, fatigue, peripheral
`neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia,
`
`vomiting, decreased appetite, rash, and dehydration. (6.11)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Celgene
`Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`------------------------------ DRUG INTERACTIONS ------------------------------
`
`
`Use caution when concomitantly administering ABRAXANE with
`
`inhibitors or inducers of either CYP2C8 or CYP3A4. (7)
`
`------------------------------- USE IN SPECIFIC POPULATIONS -------------­
` Lactation: Advise not to breastfeed. (8.2)
`
` Females and Males of Reproductive Potential: May impair fertility.
`
`
`Counsel patients on pregnancy planning and prevention. (8.3)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`
`
`Revised: 12/2019
`
`
`
`Reference ID: 4530324
`
`1
`
`
`

`

`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: NEUTROPENIA
`
`INDICATIONS AND USAGE
`1
`
`1.1 Metastatic Breast Cancer
`
`
`1.2 Non-Small Cell Lung Cancer
`
`
`1.3 Adenocarcinoma of the Pancreas
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage for Metastatic Breast Cancer
`
`2.2 Recommended Dosage for Non-Small Cell Lung Cancer
`
`
`2.3 Recommended Dosage for Adenocarcinoma of the
`
`Pancreas
`
` Dosage Modifications for Hepatic Impairment
`
`2.4
`
` Dosage Modifications for Adverse Reactions
`
`2.5
`2.6 Preparation and Administration Precautions
`
`2.7 Preparation for Intravenous Administration
`
` Stability
`
`2.8
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
` Hematologic Effects
`5.1
`
` Nervous System
`
`5.2
`
`5.3
` Sepsis
`5.4
` Pneumonitis
`5.5
` Hypersensitivity
`5.6
` Hepatic Impairment
`5.7
` Albumin (Human)
`5.8
` Embryo-Fetal Toxicity
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2
` Postmarketing Experience
`
`
`
`
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.2
` Lactation
`8.3 Females and Males of Reproductive Potential
`
`8.4
` Pediatric Use
` Geriatric Use
`
`8.5
`
` Renal Impairment
`8.6
`8.7
` Hepatic Impairment
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`14.1 Metastatic Breast Cancer
`
`
`14.2 Non-Small Cell Lung Cancer
`
`
`14.3 Adenocarcinoma of the Pancreas
`
`
`15 REFERENCES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`
`* Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`Reference ID: 4530324
`
`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 1,500
`
`
`
`cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which
`may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be
`
`
`
`performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1)
`
`
`and Adverse Reactions (6.1)].
`
`
` Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those
`
`
`
`
`of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`1
`
`1.1
`Metastatic Breast Cancer
`
`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.
`
`
`1.2
`Non-Small Cell Lung Cancer
`ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with
`
`carboplatin, in patients who are not candidates for curative surgery or radiation therapy.
`
`Adenocarcinoma of the Pancreas
`1.3
`ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with
`gemcitabine.
`
`2
`
`2.1
`Recommended Dosage for Metastatic Breast Cancer
`
`After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the
`
`recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.
`
`
`2.2
`Recommended Dosage for Non-Small Cell Lung Cancer
`
`The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion 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 [see Clinical Studies
`
`
`(14.2)].
`
`
`2.3
`Recommended Dosage for Adenocarcinoma of the Pancreas
`The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and
`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 (14.3)].
`
`
`2.4
`Dosage Modifications for Hepatic Impairment
`
`For patients with moderate or severe hepatic impairment, reduce the starting dose of ABRAXANE as shown in Table 1.
`
`
`
`
`AST Levels
`
`
`
`
`
`ABRAXANE Dosea
`
`
`Table 1: Recommendations for Starting Dose in Patients with Moderate and Severe Hepatic Impairment
`Bilirubin
`Levels
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4530324
`
`
`
`
`
`MBC
`
`
`
` NSCLC c
`
`Adenocarcinoma
`
`of Pancreasc
`not recommended
`80 mg/m2 b
`200 mg/m2 b
`AND
` Moderate
`> 1.5 to ≤ 3 x ULN
`
` < 10 x ULN
`
`not recommended
`80 mg/m2 b
`
` 200 mg/m2 b
`
`
`> 3 to ≤ 5 x ULN
`AND
`< 10 x ULN
`Severe
`not recommended
`not recommended
`not recommended
`> 5 x ULN
`OR
`> 10 x ULN
`
`
`
`
`AST = Aspartate Aminotransferase; MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer; ULN = Upper
`
`limit of normal.
`
`a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses
`
`
`should be based on individual tolerance.
`
`
`
`b A dose increase to 260 mg/m2 for patients with metastatic breast cancer or 100 mg/m2 for patients with non-small cell lung
`
`
`cancer in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles.
`
`
`c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.
`
`
`3
`
`

`

`
`
`
`
`
`Dosage Modifications for Adverse Reactions
`
`2.5
`
`
`Metastatic Breast Cancer
` Patients who experience severe neutropenia (neutrophils less than 500 cells/mm3 for a week or longer) or severe sensory
`
`neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For
`recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. 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 (5.1, 5.2) and Adverse Reactions (6.1)].
`
`Non-Small Cell Lung Cancer
`
` Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet
`
` count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
`
`
`
` In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil
`
`
`count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at
`least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing,
`permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.
`
` Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2)
`
`when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse
`Reactions (6.11)].
`
`Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Reactions in NSCLC
`
`Weekly
`Every 3-Week
`
`ABRAXANE Dose
`Carboplatin Dose
`(mg/m2)
`(AUC mg•min/mL)
`
`Occurrence
`
`
`Adverse Reaction
`
`
`
`
` Neutropenic Fever (ANC less than 500/mm3 with
`
` fever >38°C)
`
` OR
`
`Delay of next cycle by more than 7 days for ANC less than
`
` 1500/mm3
`
`
`OR
`
`ANC less than 500/mm3 for more than 7 days
`
`Platelet count less than 50,000/mm3
`
`
`Severe sensory Neuropathy – Grade 3 or 4
`
`
`
`First
`
`Second
`
`Third
`
`First
`
`Second
`
`First
`
`Second
`
`Third
`
`75
`
`50
`
`75
`
`75
`
`50
`
`4.5
`
`3
`
`Discontinue Treatment
`
`4.5
`
`Discontinue Treatment
`
`4.5
`
`3
`
`Discontinue Treatment
`
`
`Adenocarcinoma of the Pancreas
`
`
`Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.
`
`
`
`
`Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas
`
`
`Dose Level
`Full dose
`1st dose reduction
`2nd dose reduction
`If additional dose reduction required
`
`ABRAXANE (mg/m2)
`
`125
`100
`75
`Discontinue
`
`Gemcitabine (mg/m2)
`
`1000
`800
`600
`Discontinue
`
`
`Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are
`provided in Table 4.
`
`
`
`
`Reference ID: 4530324
`
`4
`
`

`

`
`
`Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or
`within a Cycle for Patients with Adenocarcinoma of the Pancreas
`
`ANC (cells/mm3)
`
`Platelet count (cells/mm3)
`
`ABRAXANE / Gemcitabine
`
`
`
`Cycle
`
`Day
`Day 1
`
`Day 8
`
`
`
`< 1500
`
`
`
`500 to < 1000
`
`< 500
`
`OR
`
`
`OR
`
`OR
`
`
`< 100,000
`
`
`50,000 to < 75,000
`< 50,000
`
`
`Day 15: If Day 8 doses were reduced or given without modification:
`
`
`
`
`
`
`500 to < 1000
`
`< 500
`
`OR
`
`OR
`
`
`50,000 to < 75,000
`< 50,000
`
`
`Day 15: If Day 8 doses were withheld:
`
`
`
`Delay doses until recovery
`
`
`Reduce 1 dose level
`Withhold doses
`
`Reduce 1 dose level from Day 8
`
`
`Withhold doses
`
`Reduce 1 dose level from Day 1
`
`
`Reduce 2 dose levels from Day 1
`
`Withhold doses
`
`
`≥ 1000
`
`
`500 to < 1000
`
`
`< 500
`ANC = Absolute Neutrophil Count
`
`
`OR
`
`OR
`
`OR
`
`
`≥ 75,000
`
`50,000 to < 75,000
`< 50,000
`
`
`
`Recommended dose modifications for other adverse reactions in patients with adenocarcinoma of the pancreas are provided in
`Table 5.
`
`
`
`Table 5: Dose Modifications for Other Adverse Reactions in Patients with Adenocarcinoma of the Pancreas
`
`
`
`Adverse Reaction
`
`Febrile Neutropenia:
`
`Grade 3 or 4
`
`Peripheral Neuropathy:
`
`Grade 3 or 4
`
`Cutaneous Toxicity:
`
`
`Grade 2 or 3
`Gastrointestinal Toxicity:
`
`
`Grade 3 mucositis or diarrhea
`
`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
`
`
`Withhold until improves to ≤ Grade 1;
`resume at next lower dose level
`
`
`2.6
`Preparation and Administration Precautions
`
`
`
`ABRAXANE is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 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.
`
`
`
`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 (6.1)].
`
`
`Premedication to prevent hypersensitivity reactions is generally not needed prior to the administration of ABRAXANE.
`
`
`Premedication may be needed in patients who have had prior hypersensitivity reactions to ABRAXANE. Patients who experience a
`severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug [see Warnings and Precautions (5.5)].
`
`Preparation for Intravenous Administration
`2.7
`ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE
`
`PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.
`
`
`
`
`
`
`Reference ID: 4530324
`
`5
`
`

`

`
`
`1.
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.
`Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the
`
`sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL.
`
`
`DO NOT INJECT the 0.9% 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 cake/powder.
`Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder
`occurs. Avoid generation of foam.
`
`If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.
`
`
`Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
`
`The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the
`vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if
`precipitates are observed. Discard any unused portion.
`
`Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient and slowly withdraw the dosing volume of
`
`
`the reconstituted suspension from the vial(s) into a syringe: Dosing volume (mL)=Total dose (mg)/5 (mg/mL).
`
`
`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 DEHP-free solution containers or administration
`
`sets is not necessary to prepare or administer ABRAXANE infusions. The use of medical devices containing silicone oil as a
`lubricant (ie, syringes and intravenous bags) to reconstitute and administer ABRAXANE may result in the formation of proteinaceous
`
`strands.
`
`Visually inspect the reconstituted ABRAXANE suspension in the intravenous bag prior to administration. Discard the reconstituted
`suspension if proteinaceous strands, particulate matter or discoloration are observed.
`
`Stability
`2.8
`Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20ºC to 25ºC (68ºF to 77ºF)
`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 2ºC to 8ºC (36ºF to 46ºF) for a
`
`maximum of 24 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original
`carton to protect it from bright light. Discard any unused portion.
`
`
`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
`
`refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a maximum of 24 hours.
`
`The total combined refrigerated storage time of reconstituted ABRAXANE in the vial and in the infusion bag is 24 hours. This may
`be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of
`
`4 hours.
`
`
`Discard any unused portion.
`
`
`DOSAGE FORMS AND STRENGTHS
` 3
`
`
` For injectable suspension: white to yellow, sterile lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound
`particles in single-dose vial for reconstitution.
`
`4
`
`
`
`
`
`
` CONTRAINDICATIONS
`
`ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.
`
` Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.
`
`
`
`
`
`
`Reference ID: 4530324
`
`6
`
`

`

`
`
`WARNINGS AND PRECAUTIONS
`
`5
`
` Hematologic Effects
`5.1
`
`Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies,
`
`Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung
`cancer (NSCLC), and 38% of patients with pancreatic cancer.
`
`Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and
`
`
`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 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more)
`during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or
`NSCLC.
`
`
`In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3
`
`and platelets recover to a level >100,000 cells/mm3.
`
`In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced
`doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count
`of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on
`Days 8 or 15 of the cycle [see Dosage and Administration (2.5)].
`
`
`
`In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or
`platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count
`is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see
`
`
`Dosage and Administration (2.5)].
`
`5.2
`Nervous System
`
`
`Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1)]. The occurrence of Grade 1 or 2 sensory
`
`neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE
`
`treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic
`cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].
`
`5.3
`Sepsis
`
`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 until fever resolves
`and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].
`
`
`5.4
`Pneumonitis
`
`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
`of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue
`
`treatment with ABRAXANE and gemcitabine.
`
`5.5
`Hypersensitivity
`
`Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who
`
`experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug. Cross-hypersensitivity
`
`
`between ABRAXANE and other taxane products has been reported and may include severe reactions such as anaphylaxis.
`Patients with a previous history of hypersensitivity to other taxanes should be closely monitored during initiation of ABRAXANE
`
`
`therapy.
`
`5.6
`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
`
`
`recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total
`bilirubin >1.5 x ULN and AST ≤10 x ULN). The starting dose should be reduced for patients with moderate or severe hepatic
`impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
`
`5.7
`Albumin (Human)
`
`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 Creutzfeldt-Jakob Disease
`(CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for
`albumin.
`
`5.8
`Embryo-Fetal Toxicity
`
`Based on mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman.
`
`In animal reproduction studies, administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy at doses
`
`
`
`Reference ID: 4530324
`
`7
`
`

`

`
`
`lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including
`intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.
`
`Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective
`contraception and avoid becoming pregnant during treatment with ABRAXANE and for at least six months after the last dose of
`
`ABRAXANE [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
`
`
`
`Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive
`potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months
`after the last dose of ABRAXANE [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
`
`
` ADVERSE REACTIONS
` 6
`
`
` 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 practice.
`
`The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia,
`
` neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase
` elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)].
`
`
`
`The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are
`
`anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.1)]. The
`most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia
`
`(4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are
`neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose
`reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions
`leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).
`
`
`In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical
`Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are
`neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite,
`rash, and dehydration [see Adverse Reactions (6.1)]. The most common serious adverse reactions of ABRAXANE (with a ≥ 1%
`
`higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions
`resulting in permanent 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%).
`
`
`6.1
`
`Metastatic Breast Cancer
`
`Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either
`single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.
`
`
`Table 6:
`
`
`
` Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic
`
`
`
`
`Breast Cancer Study on an Every-3-Weeks Schedule
`
`
`Clinical Trials Experience
`
`
`
`
`
`
`Bone Marrow
` Neutropenia
` < 2.0 x 109/L
`
` < 0.5 x 109/L
` Thrombocytopenia
` < 100 x 109/L
`< 50 x 109/L
`Anemia
`< 11 g/dL
`
` < 8 g/dL
`Infections
` Febrile Neutropenia
` Neutropenic Sepsis
`Bleeding
`Hypersensitivity Reactionc
`
` All
`Severed
`
`
`
`
`
`
`Percent of Patients
`ABRAXANE
`Paclitaxel Injection
`
`
`260 mg/m2 over 30 min
`175 mg/m2 over 3 hb
`
`
`
`(n=229)
`(n=225)
`
`
`82
`22
`
`3
`<1
`
`25
`<1
`20
`
`1
`<1
`
`2
`
`12
`
` 2
`
`
`80
`9
`
`2
`<1
`
`33
`1
`24
`2
`<1
`2
`
`4
`0
`
`
`
`
`
`
`
`Reference ID: 4530324
`
`8
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`<1
`5
`3
`
`60
`35
`
`7
`12
`
`71
`10
`
`44
`8
`
`47
`8
`
`10