`infusion site for extravasation and infiltration. No premedication is
`required prior to administration. (2.5)
` --------------------- DOSAGE FORMS AND STRENGTHS --------------------
`• Single use vial containing 100 mg of paclitaxel. (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)
`• Severe hypersensitivity reactions with fatal outcome have been
`reported. Do not re-challenge with this drug. (5.3)
`• Exposure and toxicity of paclitaxel can be increased in patients with
`hepatic impairment; therefore administer with caution. (5.4)
`• ABRAXANE contains albumin derived from human blood, which has
`a theoretical risk of viral transmission. (5.5)
`• Fetal harm may occur when administered to a pregnant woman.
`Advise women of childbearing potential to avoid becoming pregnant
`while receiving ABRAXANE. (5.6)
`• Advise men not to father a child while on ABRAXANE. (5.7)
` ------------------------------ 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 when used
`in combination with carboplatin are anemia, neutropenia,
`thrombocytopenia, alopecia, peripheral neuropathy, nausea, and
`fatigue. (6.2)
`
`
`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)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling (Patient Information).
`
`
`Revised: October 2012
`
`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 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, 6.2)
`DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL
`FORMULATIONS.
` -------------------------- RECENT MAJOR CHANGES --------------------------
`• Indications and Usage. (1.2)
`10/2012
`• Dosage and Administration. (2.2)
`10/2012
`• Warnings and Precautions, Hypersensitivity. (5.3)
`09/2012
`-------------------------- 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)
` ----------------------- 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; carboplatin AUC 6 mg•min/mL is given
`intravenously on Day 1 of each 21 day cycle immediately after
`ABRAXANE administration. (2.2)
`• No adjustment is necessary for patients with mild hepatic
`impairment. Withhold ABRAXANE if AST > 10 x ULN or
`bilirubin > 5 x ULN. Reduce starting dose in patients with moderate
`to severe hepatic impairment. (2.3)
`• Dose Reductions: Dose reductions or discontinuation may be
`needed based on severe hematologic or neurologic toxicities. (2.4)
`
`
`
`
`
`
`
`
`1
`
`
`
`6.4 Accidental Exposure
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Hepatic Impairment
`8.7 Patients with Renal 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
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`16.3 Handling and Disposal
`17 PATIENT COUNSELING INFORMATION
`
`
` *
`
` Sections or subsections omitted from the full prescribing information
`are not listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: NEUTROPENIA
`1
`INDICATIONS AND USAGE
`1.1 Metastatic Breast Cancer
`1.2 Non-Small Cell Lung Cancer
`2 DOSAGE AND ADMINISTRATION
`2.1 Metastatic Breast Cancer
`2.2 Non-Small Cell Lung Cancer
`2.3 Dosage in Patients with Hepatic Impairment
`2.4 Dose Reduction/Discontinuation Recommendations
`2.5 Preparation and Administration Precautions
`2.6 Preparation for Intravenous Administration
`2.7 Stability
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hematologic Effects
`5.2 Nervous System
`5.3 Hypersensitivity
`5.4 Hepatic Impairment
`5.5 Albumin (Human)
`5.6 Use in Pregnancy
`5.7 Use in Men
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience in Metastatic Breast Cancer
`6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer
`6.3 Post-Marketing Experience with ABRAXANE and other
`Paclitaxel Formulations
`
`
`
`
`
`
`
`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, 6.2)].
`
`• 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
`
` 1
`
`
`
`
`Metastatic Breast Cancer
`1.1
`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
`1.2
`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.
`
`DOSAGE AND ADMINISTRATION
`
` 2
`
`
`
`
`Metastatic Breast Cancer
`2.1
`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.
`
`Non-Small Cell Lung Cancer
`2.2
`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. The recommended dose of carboplatin is AUC = 6 mg•min/mL on Day 1 only of each 21-day cycle,
`beginning immediately after the completion of ABRAXANE administration.
`
`Dosage in Patients with Hepatic Impairment
`2.3
`No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment
`treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or
`bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.
`
`For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe
`hepatic impairment in subsequent cycles based on individual tolerance.
`
`For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In
`subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated.
`
`Monitor patients closely [see Warnings and Precautions (5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
`
`
`
`
`Mild
`
`Moderate
`
`Severe
`
`Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment
`ABRAXANE Dosea
`NSCLC
`MBC
`260 mg/m2
`100 mg/m2
`
`SGOT (AST) Levels
`
`
`
`Bilirubin Levels
`
`< 10 x ULN
`
`> ULN to ≤ 1.25 x ULN
`
`< 10 x ULN
`
`< 10 x ULN
`
`AND
`
`1.26 to 2 x ULN
`
`2.01 to 5 x ULN
`
`200 mg/m2
`
`130 mg/m2 b
`
`75 mg/m2
`
`50 mg/m2 c
`
`> 5 x ULN
`OR
`> 10 x ULN
`
`MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.
`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 200 mg/m2 in subsequent courses should be considered based on individual tolerance.
`c Increase dose to 75 mg/m2 in subsequent courses, as tolerated.
`
`
`not eligible
`
`not eligible
`
`
`
`3
`
`
`
`Dose Reduction/Discontinuation Recommendations
`
`2.4
`
`Metastatic Breast Cancer
`Patients who experience severe neutropenia (neutrophil <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 (6.2)].
`• 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 (6.2)].
`
`
`
`Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC
`
`Adverse Drug Reaction
`
`Occurrence
`
`Weekly
`ABRAXANE Dose
`(mg/m2)
`
`Every 3-Week
`Carboplatin Dose
`(AUC mg•min/mL)
`
`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
`
`
`Preparation and Administration Precautions
`2.5
`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.
`
`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 (6.3)].
`
`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 (5.3)].
`
`
`
`
`4
`
`
`
`Preparation for Intravenous Administration
`
`2.6
`
`ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE
`PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.
`
`1.
`2.
`
`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.
`
`3.
`
`4.
`
`5.
`
`
`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.
`
`6.
`
`Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
`
`Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5
`(mg/mL).
`
`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.
`
`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 an in-line filter is not recommended.
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever
`solution and container permit.
`
`Stability
`2.7
`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 8 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 stored at
`ambient temperature (approximately 25ºC) and lighting conditions for up to 4 hours. Discard any unused portion.
`
` 3
`
`DOSAGE FORMS AND STRENGTHS
`
`Single use vials containing 100 mg of paclitaxel.
`
`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.
`
`5
`
` 4
`
`
`
`
`
`
`
`
`
`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) and 47% of patients with non-small cell
`lung cancer (NSCLC).
`
`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). 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 (2.4)].
`
`Nervous System
`5.2
`Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2)]. The occurrence of Grade 1 or 2 sensory
`neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld
`until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction
`for all subsequent courses of ABRAXANE [see Dosage and Administration (2.4)].
`
`Hypersensitivity
`5.3
`Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who
`experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.
`
`Hepatic Impairment
`5.4
`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. The starting dose should be reduced for patients with moderate or
`severe hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology
`(12.3)].
`
`Albumin (Human)
`5.5
`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.
`
`Use in Pregnancy
`5.6
`ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to
`rats during pregnancy at doses 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.
`
`There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy,
`or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
`Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific
`Populations (8.1)].
`
`Use in Men
`5.7
`Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)].
`
` 6
`
`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 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 (6.2)] 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 were
`neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose
`reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse
`reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia
`(16%).
`
`
`
`6
`
`
`
`
`Clinical Trials Experience in Metastatic Breast Cancer
`6.1
`Table 3 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 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast
`Cancer Study on an Every-3-Weeks Schedule
`
`Percent of Patients
`ABRAXANE
`Paclitaxel Injection
`260 mg/m2 over 30 min
`175 mg/m2 over 3 hb
`(n=229)
`(n=225)
`
`
`
`
`80
`82
`9
`22
`
` 3
`
`
`<1
`
`25
`<1
`20
`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
`0
`94
`
` 2
`
`
`<1
`
`33
`1
`24
`2
`2
`
`4
`0
`
`
`<1
`5
`3
`
`60
`35
`
`7
`12
`
`71
`10
`
`44
`8
`
`47
`8
`
`10
`0
`
`
`30
`3
`
`18
`4
`
`27
`<1
`
`7
`<1
`90
`
`
`
`
`
`
`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
` Bleeding
`Hypersensitivity Reactionc
` All
` Severed
`Cardiovascular
` Vital Sign Changes During Administration
` Bradycardia
` Hypotension
` Severe Cardiovascular Eventsd
`Abnormal ECG
` All Patients
` Patients with Normal Baseline
`Respiratory
` Cough
` Dyspnea
`Sensory Neuropathy
` Any Symptoms
` Severe Symptomsd
`Myalgia / Arthralgia
` Any Symptoms
` Severe Symptomsd
`Asthenia
` Any Symptoms
` Severe Symptomsd
`Fluid Retention/Edema
` 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
`
`
`
`7
`
`
`
`
`
`
`Percent of Patients
`ABRAXANE
`Paclitaxel Injection
`260 mg/m2 over 30 min
`175 mg/m2 over 3 hb
`(n=229)
`(n=225)
`Hepatic (Patients with Normal Baseline)
`
`
`7
`7
` Bilirubin Elevations
`36
`31
` Alkaline Phosphatase Elevations
`39
`32
` AST (SGOT) Elevations
`Injection Site Reaction
`<1
`1
`a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2.
`b Paclitaxel injection patients received premedication.
`c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began
`on a day of dosing.
`d Severe events are defined as at least grade 3 toxicity.
`
`Adverse Event Experiences by Body System
`
`Hematologic Disorders
`Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil
`counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients
`receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials.
`
`Infections
`Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and
`pneumonia were the most frequently reported infectious complications.
`
`Hypersensitivity Reactions (HSRs)
`Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension,
`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
`Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1%
`of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment
`discontinuation.
`
`Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events
`included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary
`thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks
`have been reported.
`
`Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually
`result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among
`patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most
`frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.
`
`Respiratory
`Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE.
`
`
`Neurologic
`The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of
`ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3
`peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed
`treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without
`documented improvement, 4 discontinued the study due to peripheral neuropathy.
`
`No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of
`the controlled trial.
`
`Vision Disorders
`Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases
`(keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2).
`These effects generally have been reversible.
`
`Arthralgia/Myalgia
`The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.
`
`Hepatic
`
`
`
`8
`
`
`
`Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with
`paclitaxel injection in the randomized trial.
`
`Renal
`Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were
`caused by renal toxicities.
`
`Other Clinical Events
`Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no
`patients had severe edema. Dehydration and pyrexia were also reported.
`
`Clinical Trials Experience in Non-Small Cell Lung Cancer
`6.2
`Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated
`patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer
`(NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes
`at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion
`over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL
`was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion.
`The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent
`adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were
`White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms
`received a median of 6 cycles of treatment.
`
`The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-
`treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%,
`asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the
`ABRAXANE plus carboplatin treatment group).
`
`Table 4 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all
`grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus
`carboplatin-treated patients.
`
`
`Table 4: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4)
`or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups
`
`
`
`ABRAXANE (100 mg/m2 weekly)
`plus carboplatin
`
`Paclitaxel Injection (200 mg/m2 every 3 weeks)
`plus carboplatin
`
`Grades 1-4 (%)
`91
`83
`55
`
`Grade 3-4 (%)
`7
`58
`9
`
`
`
`
`
`MedDRA v 12.1
`Preferred Term
`Peripheral neuropathya
`
`Grade 1-4
`Toxicity
`(%)
`48
`
`Grade 3-4
`Toxicity
`(%)
`3
`
`
`
`
`
`System Organ
`Class
`Nervous system
`disorders
`General disorders
`and administration
`site conditions
`Respiratory
`thoracic and
`
`Edema peripheral
`
`Epistaxis
`
`10
`
`7
`
`0
`
`0
`
`4
`
`2
`
`<1
`
`0
`
`
`
`9
`
`Grade 3-4 (%)
`Grades 1-4 (%)
`Anemia1,2
`28
`98
`Neutropenia 1,3
`47
`85
`Thrombocytopenia1,3
`18
`68
`1 508 patients assessed in ABRAXANE/carboplatin-treated group
`2 514 patients assessed in paclitaxel injection/carboplatin-treated group
`3 513 patients assessed in paclitaxel injection/carboplatin-treated group
`
`Table 5 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or
`≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524
`patients who received paclitaxel injection