`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 21-660/S-010
`
`
`Abraxane
`
`paclitaxel
`
`Abraxis BioScience, Inc.
`
`February 15, 2007
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
` 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.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`NDA 21-660/S-010
`
`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)
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-660/S-010
`NDA 21-660/S-010
`
`
`APPLICATION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`NDA 21-660/S-010
`
`Abraxis BioScience, Inc.
`Attention: Monica Batra
`Manager, Regulatory Affairs
`4503 Glencoe Ave.
`Marina Del Rey, CA 90292
`
`Dear Ms. Batra:
`
`Please refer to your supplemental new drug application dated April 14, 2006, received April 18, 2006,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for ABRAXANE® for
`Injectable Suspension (paclitaxel protein-bound particles for injectable suspension).
`
`We acknowledge receipt of your submissions dated June 14 and 29; July 21 and December 5, 2006;
`January 15; February 9 and 14 (electronic), 2007.
`
`This supplemental new drug application provides revised prescribing information with updated safety
`and efficacy information for ABRAXANE® Injectable Suspension (paclitaxel protein-bound particles
`for injectable suspension) in 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.
`
`We completed our review of this application, as amended. This application is approved, effective on
`the date of this letter, for use as recommended in the agreed-upon labeling text.
`
`Within 21 days of the date of this letter, submit content of labeling [21 CFR 314.50(l)] in structured
`product labeling (SPL) format, as described at http://www.fda.gov/oc/datacouncil/spl.html, that is
`identical in content to the enclosed labeling. Upon receipt and verification, we will transmit that
`version to the National Library of Medicine for public dissemination.
`
`The final printed labeling (FPL) for this supplement S-010 must be identical to the enclosed labeling
`(text for the package insert, and text for the patient package insert) submitted February 9, 2007. Please
`note that your final printed labeling submitted January 20, 2005, for this NDA has been superseded but
`will be retained in the file.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate this
`submission "FPL for approved supplement NDA 21-660/S-010.” Approval of this submission by FDA
`is not required before the labeling is used.
`
`We remind you of your postmarketing study commitment in your submission dated January 4, 2004,
`listed below.
`
`

`

`NDA 21-660/S-010
`Page 2
`
`
`2.
`
`You should evaluate ABRAXANE® safety and pharmacokinetics in subjects with
`hepatic impairment, to allow the determination of dosing adjustment for this population.
`
`Protocol Submission: April 2005
`Study Start: November/December 2005
`Final Report Submission: December 2006
`
`
`Per your submission of December 5, 2006, we understand that the final report submission for this
`postmarketing study commitment will be delayed until November 2007. This is acceptable.
`
`We have reviewed your submissions dated June 28 and August 12, 2005, and conclude that the
`following commitment from the January 7, 2005, approval letter was fulfilled.
`
`
`
`
`
`
`1.
`
`
`Survival data and analysis results should be submitted from randomized study CA012-0
`when 80% of the patients have died. Data should be available for submission
`approximately June 2005.
`
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last annual
`report, and, for clinical studies, number of patients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`“Postmarketing Study Commitment Protocol”, “Postmarketing Study Commitment Final
`Report”, or “Postmarketing Study Commitment Correspondence.”
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send copies of
`both the promotional materials and the package insert directly to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
`Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to
`the following address:
`
`
`
`
`
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`MEDWATCH
`Food and Drug Administration
`5515 Security Lane
`HFD-001, Suite 5100
`Rockville, MD 20852
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 21-660/S-010
`Page 3
`
`If you have any questions, please call Frank Cross, Project Manager, at (301) 796-0876.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Ann Farrell, M.D.
`Acting Deputy Division Director
`Division of Drug Oncology Products
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`
`Enclosure
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Ann Farrell
`2/15/2007 03:29:58 PM
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-660/S-010
`NDA 21-660/S-010
`
`
`APPLICATION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`Version: January 2007
`Rx Only
`
`ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for
`injectable suspension) (albumin-bound)
`
`(Patient Information Enclosed)
`
`
`WARNING
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for
`injectable suspension) should be administered under the supervision of a
`physician experienced in the use of cancer chemotherapeutic agents.
`Appropriate management of complications is possible only when adequate
`diagnostic and treatment facilities are readily available.
`
`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.
`
`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.
`
`
`
`DESCRIPTION
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable
`suspension) is an albumin-bound form of paclitaxel with a mean particle size of approximately
`130 nanometers. ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for
`reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion.
`Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin.
`Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. ABRAXANE is free
`of solvents.
`
`
`
`
`
`
`4
`
`
`
`

`

`The active agent in ABRAXANE® is paclitaxel, a natural product with antitumor activity.
`Paclitaxel is obtained from Taxus media. The chemical name for paclitaxel is 5β,20-Epoxy-
`1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-
`N-benzoyl-3-phenylisoserine.
`
`Paclitaxel has the following structural formula:
`
`Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and
`a molecular weight of 853.91. It is highly lipophilic, insoluble in water, and melts at
`approximately 216°C to 217°C.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable
`suspension) is an antimicrotubule agent that promotes the assembly of microtubules from tubulin
`dimers and stabilizes microtubules by preventing depolymerization. This stability results in the
`inhibition of the normal dynamic reorganization of the microtubule network that is essential for
`vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles”
`of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
`
`Human Pharmacokinetics
`The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of ABRAXANE
`at dose levels of 80 to 375 mg/m2 were determined in clinical studies. Dose levels of mg/m2 refer
`to mg of paclitaxel in ABRAXANE. Following intravenous administration of ABRAXANE,
`paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline
`
`
`
`
`
`5
`
`
`
`

`

`representing distribution to the peripheral compartment and the slower second phase representing
`drug elimination. The terminal half-life was about 27 hours.
`
`The drug exposure (AUCs) was dose proportional over 80 to 375 mg/m2 and the
`pharmacokinetics of paclitaxel for ABRAXANE® were independent of the duration of
`administration. At the recommended ABRAXANE clinical dose, 260 mg/m2, the mean
`maximum concentration of paclitaxel, which occurred at the end of the infusion, was 18,741
`ng/mL. The mean total clearance was 15 L/hr/m2. The mean volume of distribution was 632
`L/m2; the large volume of distribution indicates extensive extravascular distribution and/or tissue
`binding of paclitaxel.
`
`The pharmacokinetic data of 260 mg/m2 ABRAXANE administered over 30 minutes was
`compared to the pharmacokinetics of 175 mg/m2 paclitaxel injection over 3 hours. The clearance
`of ABRAXANE was larger (43%) than for the clearance of paclitaxel injection and the volume
`of distribution of ABRAXANE was also higher (53%). Differences in Cmax and Cmax corrected
`for dose reflected differences in total dose and rate of infusion. There were no differences in
`terminal half-lives.
`
`In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from
`0.1 to 50 µg/mL, indicate that between 89% to 98% of drug is bound; the presence of cimetidine,
`ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
`
`After a 30-minute infusion of 260 mg/m2 doses of ABRAXANE, the mean values for cumulative
`urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1%
`of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and
`3’-p-hydroxypaclitaxel. Fecal excretion was approximately 20% of the total dose administered.
`
`In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was
`metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’-p-
`hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of
`paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole,
`
`
`
`
`
`6
`
`
`
`

`

`verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and
`vincristine), but the concentrations used exceeded those found in vivo following normal
`therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific
`inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The
`pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with
`compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. (see
`PRECAUTIONS: Drug Interactions). The effect of renal or hepatic dysfunction on the
`disposition of ABRAXANE® has not been investigated.
`
`Possible interactions of paclitaxel with concomitantly administered medications have not been
`formally investigated.
`
`CLINICAL STUDIES
`Metastatic Breast Carcinoma:
`Data from 106 patients accrued in two single arm open label studies and from 460 patients
`enrolled in a randomized comparative study were available to support the use of ABRAXANE in
`metastatic breast cancer.
`
`Single Arm Open Label Studies- In one study, ABRAXANE was administered as a 30-minute
`infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial
`utilized a dose of 300 mg/m2 as a 30 minute infusion in 63 patients with metastatic breast cancer.
`Cycles were administered at 3 week intervals. Objective responses were observed in both
`studies.
`
`Randomized Comparative Study- This multicenter trial was conducted in 460 patients with
`metastatic breast cancer. Patients were randomized to receive ABRAXANE at a dose of 260
`mg/m2 given as a 30-minute infusion, or paclitaxel injection at 175 mg/m2 given as a 3-hour
`infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study
`entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the
`patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant
`setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-
`
`
`
`
`
`7
`
`
`
`

`

`nine percent received study drug as second or greater than second-line therapy. Seventy-seven
`
`percent of the patients had been previously exposed to anthracyclines.
`
`In this trial, patients in the ABRAXANE® treatment arm had a statistically significantly higher
`
`reconciled target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to
`
`26.7%), compared to 11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection
`
`treatment am. See Table 1. There was no statistically significant difference in overall survival
`
`between the two study arms.
`
`Table 1: Efficacy Results from Randomized Trial
`
`ABRAXANE
`
`Paclitaxel Injection
`
`260 mg/m2
`
`175 mg/m2
`
`Reconciled Target Lesion Response Rate (primary endpoint)
`
`Response Rate
`
`50/233 (21.5%)
`
`25/227 (11.1%)
`
`All randomized patients
`
`[95% CI]
`
`P—value b
`
`[16.19% — 26.73%]
`
`[6.94% - 15.09%]
`
`0.003
`
`Patients who had failed
`
`Response Rate
`
`20/129 (15.5%)
`
`12/143 (8.4%)
`
`combination chemotherapy
`
`[95% CI]
`
`[9.26% — 21.75%]
`
`[3.85% — 12.94%]
`
`of adjuvant chemotherapyc
`
`or relapsed within 6 months
`
`' Reconciled Target Lesion Response Rate (TLRR) was the prospectively defined protocol specific
`
`endpoint. based on independent radiologic assessment of tumor responses reconciled with
`
`investigator responses (which also included clinical information) for the first 6 cycles of therapy.
`
`The reconciled TLRR was lower than the investigator Reported Response Rates. which are based on
`
`all cycles of therapy.
`
`b From Cochran-Mantel—Haenszel test stratified by 1“ line vs. > 1" line therapy.
`
`c Prior therapy included an anthracycline unless clinically contraindicated
`
`

`

`INDICATION
`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.
`
`CONTRAINDICATIONS
`ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500
`cells/mm3.
`
`WARNINGS
`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 < 1,500
`cells/mm3. Frequent monitoring of blood counts should be instituted during ABRAXANE
`treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until
`neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000
`cells/mm3.
`
`The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In
`the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL
`or baseline serum creatinine >2 mg/dL.
`
`Pregnancy – Teratogenic Effects: Pregnancy Category D: ABRAXANE can cause fetal
`harm when administered to a pregnant woman. Administration of paclitaxel protein-bound
`particles to rats on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily
`maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as
`indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of
`litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal
`anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina,
`microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal
`
`
`
`
`
`9
`
`
`
`

`

`malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum
`recommended human dose on a mg/m2 basis).
`
`There are no adequate and well-controlled studies in pregnant women using 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 treatment with
`ABRAXANE.
`
`Use in Males: Men should be advised to not father a child while receiving treatment with
`ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility
`for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability).
`
`Albumin (Human): ABRAXANE contains albumin (human), a derivative of human blood.
`Based on effective donor screening and product manufacturing processes, it carries an extremely
`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.
`
`PRECAUTIONS
`Drug Interactions: No drug interaction studies have been conducted with ABRAXANE.
`
`The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal
`clinical drug interaction studies, caution should be exercised when administering ABRAXANE
`(paclitaxel protein-bound particles for injectable suspension) concomitantly with known
`substrates or inhibitors of CYP2C8 and CYP3A4 (see CLINICAL PHARMACOLOGY).
`
`Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (such
`as ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of
`CYP3A4, have not been evaluated in clinical trials.
`
`
`
`
`
`
`10
`
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`

`

`Hematology: ABRAXANE® therapy 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, it is recommended that frequent peripheral blood cell counts be performed on all
`patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of
`ABRAXANE until 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 for seven days or
`more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of
`therapy is recommended (see DOSAGE and ADMINISTRATION).
`
`Nervous System: 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).
`
`Injection Site Reaction: Injection site reactions occur infrequently with ABRAXANE and
`were mild in the randomized clinical trial. Given the possibility of extravasation, it is advisable
`to closely monitor the infusion site for possible infiltration during drug administration.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of
`ABRAXANE has not been studied.
`
`Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human
`lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the
`Ames test or the CHO/HGPRT gene mutation assay.
`
`Administration of paclitaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis
`(approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for
`11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility
`accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A
`low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12
`
`
`
`
`
`11
`
`
`
`

`

`mg/m2/week in this study (approximately 1 to 5% of the daily maximum recommended human
`exposure on a mg/m2 basis). Testicular atrophy/degeneration has also been observed in single-
`dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2
`and dogs administered 175 mg/m2 (see WARNINGS).
`
`Pregnancy: Teratogenic Effects: Pregnancy Category D: (See WARNINGS section).
`
`Nursing Mothers: It is not known whether paclitaxel is excreted in human milk. Following
`intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum,
`concentrations of radioactivity in milk were higher than in plasma and declined in parallel with
`the plasma concentrations. Because many drugs are excreted in human milk and because of the
`potential for serious adverse reactions in nursing infants, it is recommended that nursing be
`discontinued when receiving ABRAXANE® therapy.
`
`Pediatric Use: The safety and effectiveness of ABRAXANE in pediatric patients have not
`been evaluated.
`
`Geriatric use: Of the 229 patients in the randomized study who received ABRAXANE, 11%
`were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably
`more frequently among elderly patients who received ABRAXANE.
`
`Information for Patients: (See Patient Information Leaflet).
`
`
`
`
`
`
`12
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`

`

`ADVERSE REACTIONS:
`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
`Paclitaxel Injection
`175/3hc,d
`(n=225)
`
`
`82
`22
`
` 2
`
`
`<1
`
`33
`1
`24
`2
`2
`
`
`
`
`
`
`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 Reactione
` All
` Severef
`Cardiovascular
` Vital Sign Changesg
` Bradycardia
` Hypotension
` Severe Cardiovascular Eventsf
`Abnormal ECG
` All patients
` Patients with Normal Baseline
`Respiratory
` Cough
` Dyspnea
`Sensory Neuropathy
` Any Symptoms
` Severe Symptomsf
`Myalgia / Arthralgia
` Any Symptoms
` Severe Symptomsf
`
` 3
`
`
`<1
`
`25
`<1
`20
`1
`2
`
`
`
`ABRAXANE®
`260/30minb
`(n=229)
`
`
`80
`9
`
`4
`0
`
`
`<1
`5
`3
`
`60
`35
`
`7
`12
`
`71
`10
`
`44
`8
`
`12
`2
`
`
`<1
`5
`4
`
`52
`30
`
`6
`9
`
`56
`2
`
`49
`4
`
`
`
`
`
`13
`
`
`
`

`

`Table 2: Frequencya of Important Treatment Emergent Adverse Events in the
`Randomized Study on an Every-3-Weeks Schedule, Continued
`
`
`
`
`
`
`
`ABRAXANE®
`260/30minb
`(n=229)
`
`47
`8
`
`10
`0
`
`
`30
`3
`
`18
`4
`
`27
`<1
`
`7
`<1
`90
`
`
`7
`36
`39
`<1
`
`Asthenia
` Any Symptoms
` Severe Symptomsf
`Fluid Retention/Edema
` Any Symptoms
` Severe Symptomsf
`Gastrointestinal
` Nausea
` Any symptoms
` Severe symptomsf
` Vomiting
` Any symptoms
` Severe Symptomsf
` Diarrhea
` Any Symptoms
` Severe Symptomsf
` Mucositis
` Any Symptoms
` Severe Symptomsf
`Alopecia
`Hepatic (Patients with Normal
`Baseline)
` Bilirubin Elevations
` Alkaline Phosphatase Elevations
` AST (SGOT) Elevations
`Injection Site Reaction
`a Based on worst grade
`b ABRAXANE dose in mg/m2/duration in minutes
`c paclitaxel injection dose in mg/m2/duration in hours
`d paclitaxel injection pts received premedication
`e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that
` began on a day of dosing.
`f Severe events are defined as at least grade 3 toxicity
`g During study drug dosing.
`
`Percent of Patients
`
`
`Paclitaxel Injection
`175/3hc,d
`(n=225)
`
`39
`3
`
`8
`<1
`
`
`22
`<1
`
`10
`1
`
`15
`1
`
`6
`0
`94
`
`
`7
`31
`32
`1
`
`
`
`
`
`14
`
`
`
`

`

`Myelosuppression and sensory neuropathy were dose related.
`
`Adverse Event Experiences by Body System: Unless otherwise noted, the following
`discussion refers to the primary safety database of 229 patients with metastatic breast cancer
`treated with single-agent ABRAXANE® in the randomized controlled trial. The frequency and
`severity of important adverse events for the study are presented above in tabular form. In some
`instances, rare severe events observed with paclitaxel injection may be expected to occur with
`ABRAXANE.
`
`Hematologic: Neutropenia, the most important hematologic toxicity, 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.
`
`In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of
`the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis,
`respiratory tract infections and pneumonia were the most frequently reported infectious
`complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and
`1% of patients in the paclitaxel injection arm.
`
`Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding
`episodes were reported in 2% of the patients in each treatment arm.
`
`Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the
`randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with
`normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia.
`
`Hypersensitivity Reactions (HSRs): In the randomized controlled metastatic breast cancer
`study, 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
`
`
`
`
`
`15
`
`
`
`

`

`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 in the
`randomized metastatic breast cancer trial. 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 in the randomized trial. These events included 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 rarely.
`
`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 in the metastatic breast
`cancer randomized trial. 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: Reports of dyspnea (12%) and cough (6%) were reported after treatment with
`ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after
`treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and
`pulmonary embolism have been received as part of the continuing surveillance of paclitaxel
`injection safety and may occur following ABRAXANE treatment. Rare reports of radiation
`pneumonitis have been received in paclitaxel injection patients receiving concurrent
`radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy.
`
`
`
`
`
`
`16
`
`
`
`

`

`Neurologic: The frequency and severity of neurologic manifestations were influenced by prior
`and/or concomitant therapy with neurotoxic agents.
`
`In general, the frequency and severity of neurologic manifestations were dose-dependent in
`patients receiving single-agent ABRAXANE®. In the randomized trial, sensory neuropathy was
`observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2%
`severe) in the paclitaxel injection arm. The frequency of sensory neuropathy increased with
`cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229
`(3%) patients in the randomized trial. In the randomized comparative study, 24 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 incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one
`incident of motor neuropathy (grade 2) was