CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-660
`
`APPROVED LABELING
`
`
`
`

`

`Version: Jan 7, 2005
`
`Rx Only
`
`ABRAXANETM for lnjectable Suspension (paciitaxel 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
`
`
`SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.
`
`functional properties relative to those of drug in solution. DO NOT
`
`DESCRIPTION
`
`ABRAXANE for Injectable Suspension (paclitaxel protein—bound particles for injectable
`
`suspension) is an albumin—bound form of paclitaxcl 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.
`
`

`

`
`
`The active agent in ABRAXANE is paclitaxel, a natural product with antitumor activity.
`
`Paclitaxel is obtained from Taxus media. The chemical name for paciitaxel is 5B,20-Epoxy-
`
`1,2u,4,7[3,10B,l3u-hexahydroxytax-l1-en~9-one 4,10—diacetate 2-benzoate 13-ester with (2R,3S)—
`
`N—benzoyl-3-phenylisoserine.
`
`I’aclitaxel has the following structural formula:
`
`
`
`Paclitaxel is a white to off-white crystalline powder with the empirical formula CHI-{5111014 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 [80-minute infusions of
`
`ABRAXANE at dose levels of 80—375 rng/m2 were determined in clinical studies. 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/mz, the mean
`
`maximum concentration of paclitaxel, which occurred at the end of the infusion, was 18741
`
`ng/mL. The mean total clearance was 15 L/hrfmz. The mean volume of distribution was 632
`
`L/ml; the large volume of distribution indicates extensive extravascular distribution and/0r tissue
`
`binding of paclitaxel.
`
`The pharmacokinetic data of 260 mg/m2 ABRAXANE administered over 30 minutes was
`
`compared to the pharmacokinetics of 175 mg/m?‘ 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 Cum and Cam 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 ug/mL, indicate that between 89%—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 mgi’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 (id—hydroxypaclitaxel and
`
`3‘-p—hydrcxypaclitaxel. 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 60t—hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’—p-
`
`hydroxypaclitaxel and 60., 3’—p—dihydroxypaclitaxel, by CYP3A4.
`
`In vitro, the metabolism of
`
`paclitaxel to 6d—hydroxypaclitaxel was inhibited by a number of agents (ketoconazole,
`
`

`

`veraparnil, diazepam, quinidine, dexarnethasone, cyclosporin, teniposide, etoposide, and
`
`vincristine), but the concentrations used exceeded those found in viva following normal
`
`therapeutic doses. Testosterone, ITu-ethinyl estradiol, retinoic acid, and quercetin, a specific
`
`inhibitor of CYPZCS, also inhibited the formation of 6a-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 CYPZCS 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/rn2 to 43 patients with metastatic breast cancer. The second trial
`
`utilized a dose of 300 mg/m‘j' as a 30 minute infiision 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
`
`rng/m2 given as a 30-minute infusion, or paclitaxel injection at 175 mgl’m2 given as a 3-hour
`
`infusion. Sixty—four percent of patients had impaired performance status (ECOG l 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 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 paclitaxei injection
`
`treatment arm. See table below.
`
`Table 1: Efficacy Results from Randomized Trial
`
`ABRAXANE '
`
`Paclitaxel Injection
`
`260 mgim1
`
`175 mgim1
`
`a
`
`of adjuvant chemotherapyc
`
`Reconciled Target Lesion Response Rate (primary endpoint) ~
`
`..
`
`.
`
`Response Rate
`
`50/233 (21.5%)
`
`25/227 (1 1.1%)
`
`All randomized patients
`
`[95% CI]
`
`[16.19% - 26.73%]
`
`[6.94% - 15.09%]
`
`' Patients who had failed
`
`Response Rate
`
`' 20/129 (15.5%)
`
`12/143 (8.4%)
`
`combination chemotherapy
`
`195% C11
`
`[9.26% — 21 15%]
`
`[3.85% - 12.94%]
`
`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 oftherapy.
`
`b From Cochran-Mantel-Haenszcl test stratified by 1" line vs. > 1St line therapy.
`
`5 Prior therapy should have included an anthracycline unless clinically contraindicated
`
`
`
`

`

`IlNDICATION
`
`ABRAXANETM for lnjectable SuSpension (paclitaxel protein-bound particles for inj ectable
`
`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/mm}. 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 >l.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—17 at doses of 6 rug/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/In2 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 aibumin (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 CID 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 nelfmavir), which are substrates andfor inhibitors of
`
`CYP3A4, have not been evaluated in clinical trials.
`
`
`
`

`

`Hematology: ABRAXANE therapy should not be administered to patients with baseline
`
`neutrophil counts of less than 1,500 cells/m3. 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/mm}.
`
`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
`
`
`
`

`

`mg/mziweek in this study (approximately 1 to 5% of the daily maximum recommended human
`
`exposure on a mgl’m2 basis). Testicular atrophy/degeneration has also been observed in single—
`
`dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m31
`
`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).
`
`
`
`

`

`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 paelitaxel
`
`injection for the treatment of metastatic breast cancer.
`
`Table 2: Frequency8 of Important Treatment Emergent Adverse Events in the
`
`Randomized Study on an Every-S-Weeks Schedule
`
`—_
`
`
`
`
`
`
`ABRAXANE
`
`
`Paclitaxel Injection
`260/30min"
`l75/3h""
`
`
`
`Bone Marrow
`
`
`
`
`
`82
`22
`
`MN
`
`Neutropenia
`< 2.0 x 109/1.
`< 0.5 x 10%
`
`
`Thromboeytopenia
`< 100 x l0°fL
`< 50 x 10%
`
`80
`9
`
`2
`<1
`
`33
`
`—_
`__—
`Bleedin_
`Hypersensitivity Reactione
`
`
`
`Severef
`Cardiovascular
`
`
`
`
`.—
`
`H otension
`Severe Cardiovascular Eventsf
`
`
`
`All patients
`
`Sensory Neuropathy
`
`
`
`
`
`
`
`
`
`
`
`—1.;
`
`5.! _.
`
`.h.n
`
`LnLAm
`
`J;\D
`4
`
`
`
`
`
`10
`
`

`

`
`
`Table 2: Frequency“ of Important Treatment Emergent Adverse Events in the
`
`Randomized Study on an Every-3—Weeks Schedule, Continued
`
`
`
`
`Percent of Patients
`
`A BRAXAN E
`260/30min"
`
`A--J
`
`
`
`
`Paelitaxel Injection
`175/3h"d
`
`
`
`Asthenia
`
`Any Symptoms
`Severe Symptoms
`Fluid Retention/Edema
`
`Any Symptoms
`Severe Symptoms
`Gastromtestinal
`Nausea
`
`Any symptoms
`Severe symptoms
`Vomiting
`Any symptoms
`Severe Symptoms
`Diarrhea
`
`Any Symptoms
`Severe Symptoms
`Mucosms
`
`Any Symptoms
`Severe Symptoms
`Alopeeia
`Hepatic (Patients With Normal
`Baseline
`Bilirubin Elevations
`
`
`
`
`
`
`I_
`
`.
`
`MU\
`
`
`
`
`NDC)
`
`
`
`r—4 \JI
`
`94
`
`Alkaline Phosphatase Elevations
`
`AST (SGOT) Elevations
`Injection Site Reaction
`
`_.
`
`_mt...):il
`
`3hBased on worst grade
`hABRAXANE dosein mg/rn2."durationin minutes
`c paclitaxel injection dosein mg/m2I'durationin hours
`d paclitaxel injection pts received premedication
`° Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that
`began on a day of dosing.
`r Severe events are defined as at least grade 3 toxicity
`3' During study drug closing.
`
`"11
`
`

`

`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/mz.
`
`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 controlied 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 (ali <1%). The use of
`
`12
`
`
`
`

`

`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 metastastic 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 pnuemothorax 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.
`
`13
`
`
`
`

`

`
`
`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 1) was observed in either arm of the controlled trial.
`
`Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the
`
`continuing surveillance of paclitaxel injection safety.
`
`Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in
`
`single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred
`
`vision) were reported in patients in a single arm study who received higher doses than those
`
`recommended (300 or 375 mg/mz). These effects generally have been reversible. However, rare
`
`reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel
`
`injection have suggested persistent optic nerve damage.
`
`Arthralgia/Myalgia: Forty-four percent of patients treated in the randomized trial experienced
`
`arthralgiafmyalgia; 8% experienced severe symptoms. The symptoms were usually transient,
`
`occurred two or three days after ABRAXANE administration, and resolved within a few days.
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`Hepatic: Among patients with normal baseline liver function treated with ABRAXANE in the
`
`randomized trial, 7%, 36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST
`
`(SGOT), respectively. 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.
`
`Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received
`
`as part of the continuing surveillance of paclitaxel injection safety and may occur following
`
`ABRAXANE treatment.
`
`Renal: Overall 1 1% of patients experienced creatinine elevation, 1% severe. No
`
`discontinuations, dose reductions, or dose delays were caused by renal toxicities.
`
`Gastrointestinal (GI): Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%,
`
`and 7% of ABRAXANE treated patients in the randomized trial.
`
`Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis
`
`have been received as part of the continuing surveillance of paclitaxel injection safety and may
`
`occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis),
`
`despite the coadministration of G—CSF, were observed in patients treated with paclitaxel
`
`injection alone and in combination with other chemotherapeutic agents.
`
`Injection Site Reaction:
`Injection site reactions have occurred infrequently with ABRAXANE
`' and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous
`
`extravasation following administration of paclitaxel injection at a different site, i.e., “recall", has
`
`been reported rarely.
`
`Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation,
`
`necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel
`
`injection safety. In some cases the onset of the injection site reaction in paclitaxel injection
`
`patients either occurred during a prolonged infusion or was delayed by a week to ten days.
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`Given the possibility of extravasation, it is advisable to closely monitor the infusion site for
`
`possible infiltration during drug administration.
`
`Asthenia: Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE in
`
`the randomized trial. Asthenia included reports of asthenia, fatigue, weakness, lethargy and
`
`malaise.
`
`Other Clinical Events: Rare cases of cardiac ischemia/infarction and thrombosis/embolism
`
`possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost
`
`all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were
`
`uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no
`
`patients had severe edema.
`
`The following rare adverse events have been reported as part of the continuing surveillance of
`
`paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities
`
`related to radiation recall as well as reports of maculopapular rash, Stevens-Johnson syndrome,
`
`toxic epidermal necrolysis, conjunctivitis, and increased lacrimation.
`
`Accidental Exposure: No reports of accidental exposure to ABRAXANE have been received.
`
`However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and
`
`nausea have been reported. Following topical exposure, events have included tingling, burning,
`
`and redness.
`
`OVERDOSAGE
`
`There is no known antidote for ABRAXANE overdosage. The primary anticipated
`
`complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity,
`
`and mucositis.
`
`DOSAGE AND ADMINISTRATION
`
`After failure of combination chemotherapy for metastatic breast cancer or relapse within 6
`
`months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable
`
`16
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`Suspension (paclitaxel protein—bound particles for injectable suspension) is 260 mg/m2
`
`administered intravenously over 30 minutes every 3 weeks.
`
`Hepatic Impairment: The appropriate dose of ABRAXANE for patients with bilirubin greater
`
`than 1.5 mg/dL is not known.
`
`Dose Reduction: 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 rug/m2 for subsequent courses of ABRAXANE. For recurrence of severe
`
`neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180
`
`rug/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade I or 2, followed
`
`by a dose reduction for all subsequent courses of ABRAXANE.
`
`Preparation and Administration Precautions: ABRAXANE is a cytotoxic anticancer
`
`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 PRECAUTIONS:
`
`Injection Site Reaction).
`
`No premedication to prevent hypersensitivity reactions is required prior to administration of
`
`ABRAXANE.
`
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`Preparation for intravenous Administration: ABRAXANE is supplied as a sterile
`
`lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE
`
`PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.
`
`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) 2 Total dose (mg) / 5 (mg/mL)
`
`18
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`

`

`
`
`The reconstituted sample should be milky and homogenous without visible patticulates. If
`
`paniculates or settling are visible, the vial should be gently inverted again to ensure complete
`
`resuspension prior to use.
`
`Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile, polyvinyl
`
`chloride (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: Unopened vials of ABRAXANE are stable until the date indicated on the package
`
`when stored between 20"C to 25°C (68DF to 77°F), in the original package. Reconstituted
`
`ABRAXANE should be used immediately, but may be refrigerated at 2°C to 8°C (36°C to 46°F)
`
`for a maximum of 8 hours if necessary. If not used immediately, each vial of reconstitute