`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 21-660/S-031
`
`
`Abraxane
`
`paclitaxel protein-bound particles for injectable
`suspension
`Abraxis BioSciences
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indication:
`
`
`
`October 11, 2012
`
`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.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`NDA 21-660/S-031
`
`CONTENTS
`Reviews / Information Included in this NDA Review.
`
`X
`
`X
`
`X
`X
`
`
`X
`X
`
`
`X
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`
`
`X
`X
`
`
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-660/S-031
`NDA 21-660/8-031
`
`APPLICATION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
` NDA 21660/S-031
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`Abraxis BioScience, LLC, a wholly-owned subsidiary of Celgene Corporation
`Attention: Deborah Tady, PharmD, RPh, MBA, RAC
`Director, Global Regulatory Affairs
`9225 Indian Creek Parkway, Suite 900
`Overland Park, KS 66210
`
`
`Dear Dr. Tady:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated December 9, 2011, and
`received on December 12, 2011, submitted pursuant to section 505(b)(2) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for ABRAXANE for Injectable Suspension (paclitaxel protein-
`bound particles for injectable suspension) (albumin-bound), 100 mg vial.
`
`We acknowledge receipt of your amendments dated January 13, 2012; February 17, 2012; March
`2, 2012; March 9, 2012; March 30, 2012; May 9, 2012; July 12, 2012; August 2, 2012; August
`13, 2012; August 15, 2012; August 23, 2012; September 28, 2012; October 5, 2012; and October
`11, 2012.
`
`This Prior Approval supplemental new drug application proposes to include a new indication for
`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.
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling text for the package insert and text for the
`patient package insert, with the addition of any labeling changes in pending “Changes Being
`
`Reference ID: 3202204
`
`

`

`NDA 21660/S-031
`Page 2
`
`
`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
`labeling.
`
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To
`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels submitted on October 11, 2012, as soon as they are available, but no more than
`30 days after they are printed.
`
`Please submit these labels electronically according to the guidance for industry titled “Providing
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Product
`Correspondence – Final Printed Carton and Container Labels for approved NDA 21660/S-
`031.” Approval of this submission by FDA is not required before the labeling is used.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for this application because necessary studies are
`impossible or highly impracticable because the disease/condition does not exist in children.
`
`
`Reference ID: 3202204
`
`

`

`NDA 21660/S-031
`Page 3
`
`
`PROMOTIONAL MATERIALS
`
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`FDA 2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Office of Prescription Drug Promotion (OPDP), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, contact Monica Hughes, M.S., Lead Regulatory Project Manager, at
`(301) 796-9225.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Patricia Keegan, M.D.
`Director
`
`Division of Oncology Products 2
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`
`
`
`
`Reference ID: 3202204
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PATRICIA KEEGAN
`10/11/2012
`
`Reference ID: 3202204
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-660/S-031
`NDA 21-660/8-031
`
`APPLICATION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`• Use caution when handling cytotoxic drugs. Closely monitor the
`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 a bumin 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 --------------------------
`10/2012
`• Indications and Usage. (1.2)
`• 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
`
`
`
`< 10 x ULN
`
`Bilirubin Levels
`
`> 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 poss bility 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.
`
`
`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.
`
`3.
`
`4.
`
`5.
`
`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 vis ble 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
`