CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`021660Orig1s026
`
`Trade Name:
`
`ABRAXANE for Injectable Suspension
`
`Generic or Proper
`Name:
`
`paclitaxel protein-bound particles for injectable suspension
`(albumin-bound)
`
`Sponsor:
`
` Celgene Corporation
`
`Approval Date:
`
`December 23, 2011
`
`Indication:
`
`For the treatment of breast cancer after failure of
`combination chemotherapy for metastatic disease or replase
`within 6 months of adjuvant chemotherapy. Prior therapy
`should have included an anthracycline unless clinically
`contraindicated.
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`021660Orig1s026
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`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 / Virology 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
`X
`
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`021660Orig1s026
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 021660/S-025
`NDA 021660/S-026
`NDA 021660/S-029
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`Celgene Corporation
`Attention: Renu Vaish, M.S.
`Executive Director, Global Regulatory Affairs
`Therapeutic Franchise Leader - Oncology Solid Tumors
`400 Connell Drive, Suite 7000
`Berkeley Heights, NJ 07922
`
`
`Dear Ms. Vaish:
`
`Please refer to your Supplemental New Drug Applications (sNDA) dated March 30, 2010,
`received March 30, 2010, June 1, 2010, received June 2, 2010, and July 25, 2011, received July
`25, 2011, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable
`suspension) (albumin-bound), 100 milligram vial.
`
`
`We acknowledge receipt of your amendments dated December 8, 2010; February 25, 2011; July
`8, 2011; August 26, 2011; August 30, 2011; September 1, 2011; September 6, 2011; September 8
`(2), 2011; September 13, 2011; September 14, 2011; September 21, 2011, December 5, 2011;
`December 20, 2011, and December 22 (2), 2011.
`
`
`“Prior Approval” supplemental new drug application (S-025) provides for inclusion of pyrexia,
`dehydration, pancytopenia, congestive heart failure, and left ventricular dysfunction in Section 6,
`ADVERSE REACTIONS of the Package Insert.
`
`“Prior Approval” supplemental new drug application (S-026) provides for revised labeling in the
`Physican Labeling Rule format.
`
`“Prior Approval” supplemental new drug application (S-029) provides for inclusion of three
`adverse events: Stevens-Johnson syndrome, toxic epidermal necrolysis and extravasation in
`Section 6, ADVERSE REACTIONS of the Package Insert and minor administrative, editorial
`and grammatical revisions throughout the Package Insert.
`
`We have completed our review of these supplemental applications, as amended. They are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
`
`
`
`Reference ID: 3063210
`
`

`

`
`
`
` NDA 021660/S-025
`
` NDA 021660/S-026
`
` NDA 021660/S-029
`Page 2
`
`
` 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, text for the
`patient package insert), with the addition of any labeling changes in pending “Changes Being
`
`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).
`
`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.
`
`Because none of these criteria apply to your application, you are exempt from this requirement.
`
`
`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)
`
`
`
`Reference ID: 3063210
`
`

`

`
` NDA 021660/S-025
`
` NDA 021660/S-026
`
` NDA 021660/S-029
`Page 3
`
`
`
`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, call Yolanda Adkins, Regulatory Project Manager, at (301) 796-2850.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Amna Ibrahim, M.D.
`Deputy Director
`Division of Oncology Products 1
`Ofice of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE:
`Content of Labeling
`
`
`
`Reference ID: 3063210
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMNA IBRAHIM
`12/23/2011
`
`Reference ID: 3063210
`
`

`

` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`021660Orig1s026
`
`LABELING
`
`

`

`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.
`
` ABRAXANE therapy should not be administered 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
`-------------------------- RECENT MAJOR CHANGES --------------------------
`--------------------------- INDICATIONS AND USAGE ---------------------------
`ABRAXANE is a microtubule inhibitor 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.
`----------------------- DOSAGE AND ADMINISTRATION ----------------------
` Recommended dosage: 260 mg/m2 IV over 30 min every 3 weeks
`(2.1)
` No adjustment is necessary for patients with mild hepatic
`impairment. Patients should not receive ABRAXANE if AST > 10 x
`ULN or bilirubin > 5.0 x ULN. Reduce starting dose in patients with
`moderate to severe hepatic impairment. (2.2)
` In case of severe neutropenia or severe sensory neuropathy reduce
`dose to 220 mg/m2 for subsequent courses. In case of recurrence,
`further reduce dose 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. (2.3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNINGS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 General
`2.2 Dosage in Patients with Hepatic Impairment
`2.3 Dose Reduction: in Case of Severe Neutropenia or Severe
`Sensory Neuropathy
`2.4 Preparation and Administration Precautions
`2.5 Preparation for Intravenous Administration
`2.6 Stability
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hematologic Effects
`5.2 Nervous System
`5.3 Hepatic Impairment
`5.4 Albumin (Human)
`5.5 Use in Pregnancy
`5.6 Use in Men
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-Marketing Experience with ABRAXANE and other
`Paclitaxel Formulations
`6.3 Accidental Exposure
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Reference ID: 3063210
`
` Use caution when handling cytotoxic drugs. Closely monitor the
`infusion site for extravasation and infiltration. No premedication is
`required prior to administration. (2.4)
`--------------------- 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)
` Exposure and toxicity of paclitaxel can be increased in patients with
`hepatic impairment; therefore administer with caution. (5.3)
` ABRAXANE contains albumin derived from human blood which has
`a theoretical risk of viral transmission. (5.4)
` Fetal harm may occur when administered to a pregnant woman.
`Women of childbearing potential should avoid becoming pregnant
`while receiving ABRAXANE. (5.5)
` Men should not father a child while on ABRAXANE. (5.6)
`------------------------------ ADVERSE REACTIONS -----------------------------
`The most common adverse reactions (≥ 20%) are alopecia,
`neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,
`myalgia/arthralgia, AST elevation, alkaline phosphatase elevation,
`anemia, nausea, infections, and diarrhea. (6.1)
`
`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 see
`FDA-approved patient labeling.
`
`Revised: 12/2011
`
`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 Carcinoma
`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.
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)
`
`WARNING: NEUTROPENIA
` ABRAXANE therapy should not be administered to patients with metastatic breast cancer 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
`1
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) 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.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`General
`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.
`
`Dosage in Patients with Hepatic Impairment
`2.2
`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. Patients should not receive ABRAXANE if AST >
`10 x ULN or bilirubin > 5.0 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.
`The dose of ABRAXANE can be increased up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based
`on individual tolerance. Patients should be monitored closely [see Clinical Pharmacology (12.3) and Warnings and Precautions
`(5.3) and Use in Specific Populations (8.6)].
`
`Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment
`
`SGOT (AST) Levels
`
`Bilirubin Levels
`
`ABRAXANE a
`
`Mild
`
`Moderate
`
`Severe
`
`< 10 x ULN
`
`< 10 x ULN
`
`< 10 x ULN
`
`> ULN to ≤ 1.25 x ULN
`
`AND
`
`1.26 to 2.0 x ULN
`
`2.01 to 5.0 x ULN
`
`260 mg/m2
`
`200 mg/m2
`
`130 mg/m2 b
`
`not eligible
`> 5.0 x ULN
`OR
`> 10 x ULN
`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.
`
`Dose Reduction: in Case of Severe Neutropenia or Severe Sensory Neuropathy
`2.3
`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 and 5.2) and Adverse Reactions (6.1)].
`
`Preparation and Administration Precautions
`2.4
`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 (6.2)].
`
`No premedication to prevent hypersensitivity reactions is required prior to administration of ABRAXANE.
`
`2
`
`Reference ID: 3063210
`
`

`

`Preparation for Intravenous Administration
`2.5
`ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE
`PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.
`
`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.
`
`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 vis ble, 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 IV bag [plasticized polyvinyl chloride (PVC)
`containers, PVC or non-PVC type IV 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
`2.6
`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.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Single use vials containing 100 mg of paclitaxel.
`
`CONTRAINDICATIONS
`4
`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
`
`WARNINGS AND PRECAUTIONS
`
`Hematologic Effects
`5.1
`Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be
`administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of
`myelotoxicity, perform frequent peripheral blood cell counts. Retreat with subsequent cycles of ABRAXANE after neutrophils recover
`to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3
`
`3
`
`Reference ID: 3063210
`
`

`

`for seven days or more) during a course of ABRAXANE therapy, dose reduce for subsequent courses of therapy. [see Dosage and
`Administration (2.3)].
`
`Nervous System
`5.2
`Sensory neuropathy occurs frequently with ABRAXANE. 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
`followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.3)].
`
`Hepatic Impairment
`5.3
`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 and
`severe hepatic impairment [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology
`(12.3)].
`
`Albumin (Human)
`5.4
`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
`5.5
`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
`5.6
`Men should be advised not to father a child while receiving ABRAXANE. [see 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%) are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,
`myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, diarrhea.
`
`Clinical Trials Experience
`6.1
`The following table 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 2: Frequencya of Important Treatment Emergent Adverse Events in the Randomized 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=225)
`(n=229)
`
`80
`9
`
`2
`<1
`
`33
`1
`24
`2
`2
`
`4
`0
`
`82
`22
`
`3
`<1
`
`25
`<1
`20
`1
`2
`
`12
`2
`
`4
`
`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
`
`Reference ID: 3063210
`
`

`

`Percent of Patients
`ABRAXANE®
`Paclitaxel Injection
`260 mg/m2 over 30 min
`175 mg/m2 over 3 hb
`(n=225)
`(n=229)
`
`<1
`5
`4
`
`52
`30
`
`6
`9
`
`56
`2
`
`49
`4
`
`39
`3
`
`8
`<1
`
`<1
`5
`3
`
`60
`35
`
`7
`12
`
`71
`10
`
`44
`8
`
`47
`8
`
`10
`0
`
`30
`3
`
`18
`4
`
`27
`<1
`
`7
`<1
`90
`
`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
`Hepatic (Patients with Normal Baseline)
`7
`7
`Bilirubin Elevations
`
`31
`36
`Alkaline Phosphatase Elevations
`
`32
`39
`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 pts 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.
`
`
`22
`<1
`
`10
`1
`
`15
`1
`
`6
`0
`94
`
`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.
`
`5
`
`Reference ID: 3063210
`
`

`

`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 revers ble.
`
`Arthralgia/Myalgia
`The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.
`
`Hepatic
`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.
`
`Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations
`6.2
`Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use
`of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
`reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed
`with paclitaxel injection may be expected to occur with ABRAXANE.
`
`Hypersensitivity Reactions
`Severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting
`hypersensitivity to paclitaxel injection or human albumin has not been studied.
`
`Cardiovascular
`There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were
`previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.
`
`Respiratory
`There have been reports of interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of
`radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the
`
`6
`
`Reference ID: 3063210
`
`

`

`continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE.
`
`Neurologic
`Cranial nerve palsies and vocal cord paresis have been reported as has autonomic neuropathy resulting in paralytic