Version: May 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.
`
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`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
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`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,
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`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
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`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 arm. 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
`260 mg/m2
`
`Paclitaxel Injection
`175 mg/m2
`
` 25/227 (11.1%)
`[6.94% – 15.09%]
`
`a
`
` Reconciled Target Lesion Response Rate (primary endpoint)
`
`Response Rate
`
` 50/233 (21.5%)
`[95% CI]
`[16.19% – 26.73%]
`
`All randomized patients
`P-value b
`
`0.003
`Response Rate
`[95% CI]
`
` 12/143 (8.4%)
`[3.85% – 12.94%]
`
`20/129 (15.5%)
`[9.26% – 21.75%]
`
`
`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.
`
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`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
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`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.
`
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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
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`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).
`
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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
`
`3
`<1
`
`25
`<1
`20
`1
`2
`
`ABRAXANE®
`
`260/30minb
`
`(n=229)
`
`
`80
`9
`
`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
`
`
`
`
`
`12
`2
`
`
`<1
`5
`4
`
`52
`30
`
`6
`9
`
`56
`2
`
`49
`4
`
`4
`0
`
`
`<1
`5
`3
`
`60
`35
`
`7
`12
`
`71
`10
`
`44
`8
`
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`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
`
`
`Percent of Patients
`
`
`Paclitaxel Injection
`175/3hc,d
`
`(n=225)
`
`39
`3
`
`8
`<1
`
`
`22
`<1
`
`10
`1
`
`15
`1
`
`6
`0
`94
`
`
`
`
`
`
`
`
`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.
`
`
` 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.
`
`
`
`7
`36
`39
`<1
`
`7
`31
`32
`1
`
`11
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`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
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`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.
`
`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
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`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 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 observed in either arm of the controlled trial.
`
`Cranial nerve palsies have been reported during postmarketing surveillance of ABRAXANE.
`Because these events have been reported during clinical practice, true estimates of frequency
`
`cannot be made and a causal relationship to the events has not been established.
`
`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
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`vision) were reported in patients in a single arm study who received higher doses than those
`recommended (300 or 375 mg/m2). 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
`arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient,
`occurred two or three days after ABRAXANE® administration, and resolved within a few days.
`
`
` 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 11% 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.
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` 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.
`
`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 Stevens-Johnson syndrome, toxic epidermal
`necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of
`ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and
`pruritis have been observed. Additionally, there have been case reports of photosensitivity
`reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine,
`reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during
`
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`clinical practice, true estimates of frequency cannot be made and a causal relationship to the
`events has not been established.
`
` 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
`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 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe
`neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180
`mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed
`by a dose reduction for all subsequent courses of ABRAXANE.
`
`Preparation and Administration