`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 21-660/S-022
`
`
` Abraxane
`
` paclitaxel
`
` Abraxis Bioscience, Inc.
`
`June 26, 2009
`
`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.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 21-660/S-022
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`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
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-660/S-022
`NDA 21-660/S-022
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`
`
` DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`Public Health Service
`
`Food and Drug Administration
`
`Rockville, MD 20857
`
`
`
`NDA 21-660/S-022
`
`
`Abraxis BioScience, Inc.
`Attention: Monica Batra
`Sr. Regulatory Scientist
`2730 Wilshire Blvd., Suite 500
`Santa Monica, CA 90403
`
`
`Dear Ms. Batra:
`
`
`Please refer to your supplemental new drug application dated July 31, 2008, and received August 1,
`2008, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Abraxane
`(paclitaxel protein-bound particles for injectable suspension) (albumin bound), 100 milligram vial.
`
`We also acknowledge receipt of your submission dated May 29 and electronic mail correspondence of
`June 18, 2009.
`
`This supplemental new drug application provides for the completed final report for CA037, A Phase I
`Study to Evaluate the Safety and Pharmacokinetics of ABI-007 in Patients with Advanced Solid
`Tumors and Hepatic Dysfunction to fulfill the January 7, 2005 postmarketing study commitment 2
`with labeling changes to include dosing adjustments for hepatically impaired patients as well as
`additional labeling changes proposed for consistency with company’s core data sheet and global
`labeling.
`
`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.
`
` As soon as possible, but no later than 14 days from the date of this letter, please submit the 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 to the enclosed labeling (text for the
`package insert, text for the patient package insert). Upon receipt, we will transmit that version to the
`National Library of Medicine for public dissemination. For administrative purposes, please designate
`this submission, “SPL for approved NDA 21-660.”
`
`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:
`
`
`
`
`
`
`

`

`NDA 21-660/S-022
`Page 2
`
`
`
`
`
`
`
`
`
`
` MEDWATCH
`
`
`Food and Drug Administration
`Suite 12B05
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`
`
`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 Janet Jamison, Acting Safety Regulatory Project Manager, at (301) 796­
`2313.
`
`
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Robert Justice, MD, MS
`
` Director
`Division of Drug Oncology Products
`Office of Oncology 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/
`
`---------------------
`Amna Ibrahim
`
`6/26/2009 12:37:28 PM
`
`For Dr Robert Justice
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21-660/S-013
`NDA 21-660/8-013
`
`
`APPLICATION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`NDA 21-660/S-022
`Page 3
`
`Version: May 2009
`
`
`Rx Only
`
`
`ABRAXANE®
`(albumin-bound)
`
`(Patient Information Enclosed)
`
`
`
`
` for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension)
`
`
`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.
`
`Paclitaxel exists in the particles in a non-crystalline, amorphous state. 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.
`
`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.
`
`
`

`

`NDA 21-660/S-022
`Page 4
`
`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 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.
`
`
`

`

`NDA 21-660/S-022
`Page 5
`
`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, 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 pharmacokinetic profile of ABRAXANE administered as a 30-minute infusion was evaluated in
`15 out of 30 solid tumor patients with mild to severe hepatic impairment defined by serum bilirubin
`levels and AST levels. Patients with AST > 10 x ULN and bilirubin > 5.0 x ULN were not enrolled.
`
`ABRAXANE doses were assigned based on the degree of hepatic impairment as described:
`ƒ Mild (bilirubin > ULN to ≤ 1.25 x ULN and AST > ULN and < 10 x ULN): 260 mg/m2
`
`
` ƒ Moderate (bilirubin 1.26 to 2.0 x ULN and AST > ULN and < 10 x ULN): 200 mg/m2
`
`
` ƒ Severe (bilirubin 2.01 to 5.0 x ULN and AST > ULN and < 10 x ULN): 130 mg/m2
`
`
`
`
`The 260 mg/m2 dose for mild impairment and the 200 mg/m2 dose for moderate hepatic impairment
`adjusted the paclitaxel exposure to the range seen in patients with normal hepatic function (mean
`AUC0-∞ = 14789 ± 6703). The 130 mg/m2 dose in patients with severe hepatic impairment resulted in
`
`lower paclitaxel exposures than those seen in normal subjects. In addition, patients with severe hepatic
`impairment had higher mean cycle 1 absolute neutrophil count (ANC) nadir values than those with
`mild and moderate hepatic impairment.
`
`Table 1: Exposure (AUC0-∞) of ABRAXANE administered IV over 30 minutes in
`patients with hepatic impairment.
`Mild
`(n=5)
`260 mg/m2
`
`
`Dose
`AUCinf (hr*ng/mL)
`
`14159 ± 13346
`17434 ± 11454
`
`
`Mean ± SD
`7866 (5919, 37613)
`13755 (7618, 35262)
`Median (range)
`
`
` a bilirubin 2.01 to 5.0 x ULN and AST > ULN and < 10 x ULN
`
`
`
`A starting dose of 130 mg/m2 is recommended in patients with severe hepatic impairment. Escalation
`of the dose up to 200 mg/m2 should be considered for subsequent cycles in patients with severe hepatic
`impairment based on individual tolerance. The 200 mg/m2 dose has not been evaluated in patients
`with severe hepatic impairment, but it is predicted to adjust the paclitaxel AUC to the range observed
`in patients with normal hepatic function. A starting dose reduction is also needed for patients with
`
`9187 ± 6475
`6134 (5627, 20684)
`
`Moderate
`(n=5)
`200 mg/m2
`
`Severea
`(n=5)
` 130 mg/m2
`
`
`
`

`

`NDA 21-660/S-022
`
`Page 6
`
`moderate hepatic impairment. There are no data for patients with AST > 10 x ULN and bilirubin > 5.0
`x ULN. (see DOSAGE and ADMINISTRATION: Hepatic Impairment).
`
`The effect of renal dysfrmction 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 (EC0G 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-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 ABRAXANEQ treatment arm had a statistically significantly higher
`reconciled target lesion response rate (the trial primary endpoint) of 2 1 .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 arm.
`See Table 2. There was no statistically significant difference in overall survival between the two study
`arms.
`
`Table 2: Efficacy Results from Randomized Trial
`
`Reconciled Target Lesion Response Rate (primary endpoint)
`
`ABRAXANE
`260 lug/m:
`
`Paclitaxel Injection
`175 mg/m2
`
`15.09 /o]
`
`All randomized patients
`
`Response Rate
`0
`[95 /0 Cl]
`
`50/233 (21.5%)
`0 _
`0
`[16.19 /o
`26.73 /o]
`
`25/227 (11.1%)
`0 _
`0
`[6.94 /o
`
`

`

`Response Rate
`[95% CI]
`
`
`12/143 (8.4%)
`[3.85% – 12.94%]
`
`NDA 21-660/S-022
`Page 7
`
`Patients who had failed
`
`combination chemotherapy
`
`or relapsed within 6 months
`of adjuvant chemotherapyc
`
`a 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 1st line vs. > 1st line therapy.
`c Prior therapy included an anthracycline unless clinically contraindicated.
`
`
`20/129 (15.5%)
`[9.26% – 21.75%]
`
`
`
`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 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 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.
`
`

`

`NDA 21-660/S-022
`Page 8
`
`
`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 concomitantly
`
`with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin,
`
`
`fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g.
`
`rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4. (see
`
`CLINICAL PHARMACOLOGY).
`
`
`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).
`
`
`Hepatic Impairment: Because the exposure and toxicity of paclitaxel can be increased with hepatic
`
`impairment, administration of ABRAXANE in patients with hepatic impairment should be performed
`
`with caution. The starting dose should be reduced for patients with moderate and severe hepatic
`
`impairment. (See CLINICAL PHARMACOLOGY and DOSAGE and ADMINISTRATION,
`
`Hepatic Impairment).
`
`
`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.
`
`
`
`

`

`NDA 21-660/S-022
`Page 9
`
`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 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.
`
`Ability to Drive and Use Machines: Adverse events such as fatigue, lethargy, and malaise may
`
`affect the ability to drive and use machines.
`
`Information for Patients: (See Patient Information Leaflet).
`
`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 3: 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)
`
`
`ABRAXANE®
`
`260/30minb
`
`(n=229)
`
`
`
`
`
`Bone Marrow
`
`
`

`

`NDA 21-660/S-022
`Page 10
`
`
`
`
`
` 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
`
`ABRAXANE®
`
`260/30minb
`
`(n=229)
`
`80
`9
`
`2
`<1
`
`33
`1
`24
`2
`2
`
`4
`0
`
`
`<1
`5
`3
`
`Percent of Patients
`Paclitaxel Injection
`175/3hc,d
`
`(n=225)
`
`82
`22
`
`3
`<1
`
`25
`<1
`20
`1
`2
`
`12
`2
`
`
`<1
`5
`4
`
`
`60
`35
`
`
`7
`12
`
`
`52
`30
`
`
`6
`9
`
`

`

`NDA 21-660/S-022
`Page 11
`
`
`Table 3: Frequencya of Important Treatment Emergent Adverse Events in the
`Randomized Study on an Every-3-Weeks Schedule, Continued
`Percent of Patients
`
`
`
`
`
`
`
`
`Sensory Neuropathy
`
` Any Symptoms
`
` Severe Symptomsf
`
`Myalgia / Arthralgia
`
` Any Symptoms
`
` Severe Symptomsf
`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
`
`ABRAXANE®
`
`260/30minb
`
`(n=229)
`
`71
`10
`
`44
`8
`
`47
`8
`
`10
`0
`
`
`30
`3
`
`18
`4
`
`27
`<1
`
`7
`<1
`90
`
`
`7
`36
`
`Paclitaxel Injection
`175/3hc,d
`
`(n=225)
`
`56
`2
`
`49
`4
`
`39
`3
`
`8
`<1
`
`
`22
`<1
`
`10
`1
`
`15
`1
`
`6
`0
`94
`
`
`7
`31
`
`

`

`NDA 21-660/S-022
`Page 12
`
`
`32
`1
`
`39
`<1
`
`AST (SGOT) Elevations
`Injection Site Reaction
`a Based on worst grade.
`
`
`b ABRAXANE dose in mg/m2/duration in minutes.
`
`
` paclitaxel injection dose in mg/m2/duration in hours.
`c
`
`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.
`
`
`
`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 ABRAXANE® in patients
`previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
`
`During postmarketing surveillance, rare occurrences of 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. Patients who
`experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the
`drug.
`
`
`

`

`NDA 21-660/S-022
`Page 13
`
`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.
`
`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 rando