HIGHLIGHTS OF PRESCRIBING INFORMATION
`
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` These highlights do not include all the information needed to use
`
` ABRAXANE safely and effectively. See full prescribing
`
`
`
`
` information for ABRAXANE.
`
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`ABRAXANE® for Injectable Suspension (paclitaxel protein-bound
`
`
`
`
`
`particles for injectable suspension)
`
`
`(albumin-bound)
`
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`Initial U.S. Approval: 2005
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`WARNING: NEUTROPENIA
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`See full prescribing information for complete boxed warning.
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`• Do not administer ABRAXANE therapy to patients with
`
`baseline neutrophil counts of less than 1,500 cells/mm3. (4)
`
`• It is recommended that frequent peripheral blood cell counts
`
`
`
`
`
`
`
`be performed to monitor the occurrence of bone marrow
`
`
`
`suppression. (4, 5.1, 6.1, 6.2, 6.3)
`
`
`
`DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL
`FORMULATIONS.
`
`
`
` -------------------------- RECENT MAJOR CHANGES -------------------------­
`
`
` • Warnings and Precautions, Hypersensitivity (5.5)
`
`
`
`
` 08/2018
`
`
`
` • Warnings and Precautions, Embryo-Fetal Toxicity (5.8)
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`
`
` 08/2018
` -------------------------- INDICATIONS AND USAGE ---------------------------­
`
`
`
`
` ABRAXANE is a microtubule inhibitor indicated for the treatment of:
`
`
`
` • Metastatic 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. (1.1)
`
` • Locally advanced or metastatic non-small cell lung cancer (NSCLC),
`
`
`
` as first-line treatment in combination with carboplatin, in patients who
`
`
`
` are not candidates for curative surgery or radiation therapy. (1.2)
`
`
` • Metastatic adenocarcinoma of the pancreas as first-line treatment, in
`
`
`
`
` combination with gemcitabine. (1.3)
`
`
`
` ----------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
` • Metastatic Breast Cancer: Recommended dosage of ABRAXANE is
`
`
`
`260 mg/m2 intravenously over 30 minutes every 3 weeks. (2.1)
`
`
`
`
`
`• Non-Small Cell Lung Cancer: Recommended dosage of ABRAXANE
`
`
`
`is 100 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 of
`
`
`
`
`
`
`each 21-day cycle; administer carboplatin on Day 1 of each 21-day
`
`
`cycle immediately after ABRAXANE. (2.2)
`
`
`
`
`• Adenocarcinoma of the Pancreas: Recommended dosage of
`
`ABRAXANE is 125 mg/m2 intravenously over 30-40 minutes on Days
`
`
`
`1, 8 and 15 of each 28-day cycle; administer gemcitabine on Days 1,
`
`
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`8 and 15 of each 28-day cycle immediately after ABRAXANE. (2.3)
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`• Do not administer ABRAXANE to any patient with AST > 10 x ULN or
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`bilirubin > 5 x ULN. Do not administer ABRAXANE to patients with
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`metastatic adenocarcinoma of the pancreas who have moderate to
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`
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`severe hepatic impairment. For diseases other than metastatic
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`
`
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`adenocarcinoma of the pancreas, reduce starting dose in patients
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`
`
`
`with moderate to severe hepatic impairment. (2.4)
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`• Dose Reductions: Dose reductions or discontinuation may be
`
`
`
`needed based on severe hematologic, neurologic, cutaneous, or
`
`
`gastrointestinal toxicities. (2.5)
`
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`• Use caution when handling cytotoxic drugs. Closely monitor the
`
`
`
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`infusion site for extravasation and infiltration. No premedication is
`
`
`required prior to administration. (2.6)
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`
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`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
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`For injectable suspension: lyophilized powder containing 100 mg of
`
`
`paclitaxel formulated as albumin-bound particles in single-use vial for
`
`
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`reconstitution. (3)
`
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`------------------------------ CONTRAINDICATIONS ----------------------------­
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`
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`• Neutrophil counts of < 1,500 cells/mm3. (4)
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`• Severe hypersensitivity reaction to ABRAXANE. (4)
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`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
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`• ABRAXANE causes myelosuppression. Monitor CBC and withhold
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`and/or reduce the dose as needed. (5.1)
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`• Sensory neuropathy occurs frequently and may require dose
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`reduction or treatment interruption. (5.2)
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`• Sepsis occurred in patients with or without neutropenia who received
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`ABRAXANE in combination with gemcitabine; interrupt ABRAXANE
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`and gemcitabine until sepsis resolves, and if neutropenia, until
`
`
`
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`neutrophils are at least 1500 cells/mm3, then resume treatment at
`
`
`
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`reduced dose levels. (5.3)
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`
`• Pneumonitis occurred with the use of ABRAXANE in combination
`
`
`
`with gemcitabine; permanently discontinue treatment with
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`ABRAXANE and gemcitabine. (5.4)
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`• Severe hypersensitivity reactions with fatal outcome have been
`
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`reported. Do not re-challenge with this drug. (5.5)
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`• Exposure and toxicity of paclitaxel can be increased in patients with
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`hepatic impairment; therefore administer with caution. (5.6)
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`
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`• ABRAXANE contains albumin derived from human blood, which has
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`a theoretical risk of viral transmission. (5.7)
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`• ABRAXANE can cause fetal harm. Advise patients of potential risk to
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`a fetus and to use effective contraception. (5.8, 8.1, 8.3)
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`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
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`• The most common adverse reactions (≥ 20%) in metastatic breast
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`cancer are alopecia, neutropenia, sensory neuropathy, abnormal
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`ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline
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`phosphatase elevation, anemia, nausea, infections, and
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`diarrhea. (6.1)
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`• The most common adverse reactions (≥ 20%) in NSCLC are anemia,
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`neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,
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`nausea, and fatigue. (6.2)
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`• The most common (≥ 20%) adverse reactions of ABRAXANE in
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`adenocarcinoma of the pancreas are neutropenia, fatigue, peripheral
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`neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia,
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`vomiting, decreased appetite, rash, and dehydration. (6.3)
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`
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`To report SUSPECTED ADVERSE REACTIONS, contact Celgene
`
`
`
`Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch.
`
`------------------------------ DRUG INTERACTIONS -----------------------------­
`
`
`
`
`
`Use caution when concomitantly administering ABRAXANE with
`inhibitors or inducers of either CYP2C8 or CYP3A4. (7)
`
`
`
`------------------------------- USE IN SPECIFIC POPULATIONS -------------­
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`• Lactation: Advise not to breastfeed. (8.2)
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`• Females and Males of Reproductive Potential: May impair fertility.
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`Counsel patients on pregnancy planning and prevention. (8.3)
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`See 17 for PATIENT COUNSELING INFORMATION and
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`
`FDA-approved patient labeling.
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`Revised: 08/2018
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`Reference ID: 4307748
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`
`1
`
`

`

` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
` WARNING: NEUTROPENIA
`
` INDICATIONS AND USAGE
`
`
` 1
`
` 1.1 Metastatic Breast Cancer
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`
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` 1.2 Non-Small Cell Lung Cancer
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` 1.3 Adenocarcinoma of the Pancreas
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` 2 DOSAGE AND ADMINISTRATION
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` 2.1 Metastatic Breast Cancer
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` 2.2 Non-Small Cell Lung Cancer
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` 2.3 Adenocarcinoma of the Pancreas
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` 2.4 Dosage in Patients with Hepatic Impairment
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` 2.5 Dose Reduction/Discontinuation Recommendations
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` 2.6 Preparation and Administration Precautions
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` 2.7 Preparation for Intravenous Administration
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` 2.8 Stability
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` 3 DOSAGE FORMS AND STRENGTHS
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` 4 CONTRAINDICATIONS
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`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 Hematologic Effects
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` 5.2 Nervous System
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` 5.3 Sepsis
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` 5.4 Pneumonitis
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` 5.5 Hypersensitivity
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` 5.6 Hepatic Impairment
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`
` 5.7 Albumin (Human)
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` 5.8 Embryo-Fetal Toxicity
`
` 6 ADVERSE REACTIONS
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`
`
`
` 6.1 Clinical Trials Experience in Metastatic Breast Cancer
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`
`
`
` 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer
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`
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` 6.3 Clinical Trials Experience in Adenocarcinoma of the
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`
`
` Pancreas
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` 6.4 Postmarketing Experience with ABRAXANE and other
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`
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` Paclitaxel Formulations
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` 6.5 Accidental Exposure
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` 7 DRUG INTERACTIONS
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` 8 USE IN SPECIFIC POPULATIONS
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`
` 8.1 Pregnancy
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`
` 8.2 Lactation
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` 8.3 Females and Males of Reproductive Potential
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` 8.4 Pediatric Use
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` 8.5 Geriatric Use
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` 8.6 Patients with Hepatic Impairment
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` 8.7 Patients with Renal Impairment
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`
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` 10 OVERDOSAGE
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` 11 DESCRIPTION
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`
` 12 CLINICAL PHARMACOLOGY
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` 12.1 Mechanism of Action
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` 12.3 Pharmacokinetics
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` 13 NONCLINICAL TOXICOLOGY
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` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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` 14 CLINICAL STUDIES
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` 14.1 Metastatic Breast Cancer
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`
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` 14.2 Non-Small Cell Lung Cancer
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`
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` 14.3 Adenocarcinoma of the Pancreas
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` 15 REFERENCES
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
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`
` 16.1 How Supplied
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` 16.2 Storage
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` 16.3 Handling and Disposal
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` 17 PATIENT COUNSELING INFORMATION
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` * Sections or subsections omitted from the full prescribing information
` are not listed.
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`Reference ID: 4307748
`
`
`
` 2
`
`

`

`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
` ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)
`
`
` WARNING: NEUTROPENIA
`
`
` • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500
`
`
`
`
`
`
` cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which
`
`
`
`
`
`
`
`
`
`
`
`
`may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be
`
`
`
`
`
`
`
`performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1)
`
`
`and Adverse Reactions (6.1, 6.2, 6.3)].
`
`• 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.
`
`
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`
`
` INDICATIONS AND USAGE
`
`
`
`
`1
`
`
`
`
`Metastatic Breast Cancer
`1.1
`
`
`
`
`
`
`ABRAXANE 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.
`
`
`
`Non-Small Cell Lung Cancer
`1.2
`
`
`
`
`ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with
`
`
`
`
`carboplatin, in patients who are not candidates for curative surgery or radiation therapy.
`
`
`
`
`Adenocarcinoma of the Pancreas
`1.3
`
`
`ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with
`
`gemcitabine.
`
`2
`
`
`
`
`Metastatic Breast Cancer
`2.1
`
`
`
`
`
`
`
`After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the
`
`recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.
`
`
`
`Non-Small Cell Lung Cancer
`2.2
`
`
`The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and
`
`
`15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies
`
`
`
`
`(14.2)].
`
`
`Adenocarcinoma of the Pancreas
`2.3
`
`
`
`The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and
`
`
`
`
`
`
`
`15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see
`
`Clinical Studies (14.3)].
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`Dosage in Patients with Hepatic Impairment
`2.4
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`For patients with mild hepatic impairment (total bilirubin greater than ULN and less than or equal to 1.5 x ULN and aspartate
`
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`
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`aminotransferase [AST] less than or equal to 10 x ULN), no dose adjustments are required, regardless of indication.
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`Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic
`
`impairment.
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`Do not administer ABRAXANE to patients with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN regardless of
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`indication as these patients have not been studied.
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`Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.
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` DOSAGE AND ADMINISTRATION
`
`
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`
`
`Reference ID: 4307748
`
`
`
` 3
`
`

`

`
` Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment
`
`
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` SGOT (AST)
`
` Bilirubin
`
`
` Levels
` Levels
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`
` ABRAXANE Dosea
`
`
`
` MBC
`
`
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` NSCLC c
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`
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`
`
`
`
`
`
`
` 100 mg/m2
`
` 80 mg/m2 b
`
`
` 80 mg/m2 b
`
`not recommended
`
`
`
` Pancreatic c
`
`
` Adenocarcinoma
` 125 mg/m2
`
`
`
` not recommended
`
`
` not recommended
`not recommended
`
`
`
`
`
` Mild
`
` 260 mg/m2
`
`
`
`
` > ULN to ≤ 1.5 x ULN
`
` AND
`
`
` < 10 x ULN
`
`
` 200 mg/m2 b
`
`
` > 1.5 to ≤ 3 x ULN
`
`
`
` AND
`
`
` < 10 x ULN
`
` Moderate
`200 mg/m2 b
`> 3 to ≤ 5 x ULN
`AND
`< 10 x ULN
`Severe
`
`
`
`
`
`
`
`
`not recommended
`> 5 x ULN
`OR
`> 10 x ULN
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`MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.
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`a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses
`
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`should be based on individual tolerance.
`
`b A dose increase to 260 mg/m2 for patients with metastatic breast cancer or 100 mg/m2 for patients with non-small cell lung cancer
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`
`
`
`
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`in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles.
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`
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`
`
` c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.
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`
`
`
` 2.5
`
` Metastatic Breast Cancer
`
`Patients who experience severe neutropenia (neutrophils less than 500 cells/mm3 for a week or longer) or severe sensory
`
`
`
`
`
`
`
`
`neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For
`
`
`
`
`
`recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For
`
`
`
`Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses
`
`of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].
`
`
`
`Non-Small Cell Lung Cancer
`
`
`
`
`
`
`
`
`
`
`• Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet
`
`
`
`
`count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)].
`
`
`
`
`
`
`• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil
`
`
`
`
`
`
`
`
`count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at
`
`
`
`
`
`
`
`
`
`least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing,
`
`
`
`
`permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.
`
`
`
`
`• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2)
`
`
`
`
`when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse
`
`
`
`
`Reactions (6.2)].
`
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`
`
` Dose Reduction/Discontinuation Recommendations
`
`
`
`
`
`
`
`Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC
`
`
`
`Adverse Drug Reaction
`
`
`Occurrence
`
`
`Weekly
`
`
`ABRAXANE Dose
`(mg/m2)
`
`
`
`Every 3-Week
`
`
`Carboplatin Dose
`(AUC mg•min/mL)
`
`
` Neutropenic Fever (ANC less than 500/mm3 with
`
` fever >38°C)
`
`
`
`
`
`
`
` OR
`
`
`
` Delay of next cycle by more than 7 days for ANC less than
`1500/mm3
`
`
`
`OR
`ANC less than 500/mm3 for more than 7 days
`
`
`
`
`
`
`
`Platelet count less than 50,000/mm3
`
`
`
`
`Severe sensory Neuropathy – Grade 3 or 4
`
`
`
`
`
`
`
`
`Reference ID: 4307748
`
`First
`
`
`Second
`
`
`Third
`
`
`
`First
`
`Second
`
`
`First
`
`
`Second
`
`
`Third
`
`
`75
`
`
`50
`
`
`
`75
`
`75
`
`
`50
`
`
`4.5
`
`
`3
`
`
`Discontinue Treatment
`
`
`
`4.5
`
`Discontinue Treatment
`
`
`4.5
`
`
`3
`
`
`Discontinue Treatment
`
`
`
`
` 4
`
`

`

`
`
` Adenocarcinoma of the Pancreas
` Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.
`
`
`
`
`
`
`
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`
`
`
`
`Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas
`
`
`
`Dose Level
`
`Full dose
`
` 1st dose reduction
`
`
`
` 2nd dose reduction
`
`If additional dose reduction required
`
`
`
`ABRAXANE (mg/m2)
`
`125
`
`
` 100
`
` 75
`Discontinue
`
`
`
`Gemcitabine (mg/m2)
`1000
`
`
` 800
`
` 600
`Discontinue
`
`
`
`Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are
`
`
`provided in Table 4.
`
`
`
`Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or
`
`
`within a Cycle for Patients with Adenocarcinoma of the Pancreas
`
`
`
`
`ANC (cells/mm3)
`
`
`
`
`
`Platelet count (cells/mm3)
`
`Cycle
`Day
`
`Day 1
`
`Day 8
`
`
`Day 15: If Day 8 doses were reduced or given without modification:
`
`
`
`
`
`
`< 1500
`
`500 to < 1000
`
`< 500
`
`
`OR
`
`OR
`
`OR
`
`
`< 100,000
`
`50,000 to < 75,000
`
`< 50,000
`
`
`
`
`
`500 to < 1000
`
`< 500
`
`
`OR
`
`OR
`
`
`50,000 to < 75,000
`
`
`< 50,000
`
`
`Day 15: If Day 8 doses were withheld:
`
`
`
`
`ABRAXANE / Gemcitabine
`
`
`Delay doses until recovery
`
`Reduce 1 dose level
`
`Withhold doses
`
`
`Reduce 1 dose level from Day 8
`
`
`Withhold doses
`
`
`OR
`
`OR
`
`OR
`
`
`≥ 75,000
`
`
`50,000 to < 75,000
`
`
`< 50,000
`
`
`Reduce 1 dose level from Day 1
`
`
`Reduce 2 dose levels from Day 1
`
`
`Withhold doses
`
`
`
`≥ 1000
`
`
`
`500 to < 1000
`
`
`< 500
`
`ANC = Absolute Neutrophil Count
`
`
`
`Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in
`
`Table 5.
`
`
`
`Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas
`
`
`
`
`
`
`Adverse Drug Reaction
`
`
`Febrile Neutropenia:
`
`Grade 3 or 4
`
`
`Peripheral Neuropathy:
`
`Grade 3 or 4
`
`
`Cutaneous Toxicity:
`
`
`Grade 2 or 3
`
`ABRAXANE
`
`
`Gemcitabine
`
`
`Withhold until fever resolves and ANC ≥ 1500; resume at next lower dose level
`
`
`
`
`
`
`
`
`Withhold until improves to ≤ Grade 1;
`
`
`
`
`resume at next lower dose level
`
`
`
`
`No dose reduction
`
`
`Reduce to next lower dose level; discontinue treatment if toxicity persists
`
`
`
`
`
`Gastrointestinal Toxicity:
`
`
`
`Grade 3 mucositis or diarrhea
`
`Withhold until improves to ≤ Grade 1;
`
`
`
`
`
`resume at next lower dose level
`
`
`
`
`
`Preparation and Administration Precautions
`2.6
`
`
`
`
`ABRAXANE is a cytotoxic drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling
`
`
`
`
`
`ABRAXANE. The use of gloves is recommended. If ABRAXANE (lyophilized cake or reconstituted suspension) contacts the skin,
`
`
`
`
`
`
`wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling,
`
`burning and redness. If ABRAXANE contacts mucous membranes, the membranes should be flushed thoroughly with water.
`
`
`
`
`
`
`
`
`
`Reference ID: 4307748
`
`
`
` 5
`
`

`

`
`
`
`
`
`
`
`
`
` Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug
` administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions
`
`
`
`
` [see Adverse Reactions (6.4)].
`
` Premedication to prevent hypersensitivity reactions is generally not needed prior to the administration of ABRAXANE.
`
`
`
`
`
`
` Premedication may be needed in patients who have had prior hypersensitivity reactions to ABRAXANE. Patients who experience a
` severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug [see Warnings and Precautions (5.5)].
`
`
`
`
`
` 2.7
` 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.
`
`
`
`
`
` 1.
`
` 2.
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`3.
`
`
`4.
`
`
`5.
`
`
`6.
`
`
`
`Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
`
`
`
`
`
`
`The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the
`
`
`
`
`
`
`vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if
`
`
`
`
`precipitates are observed. Discard any unused portion.
`
`
`
`Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient and slowly withdraw the dosing volume of
`
`
`
`
`
`the reconstituted suspension from the vial(s) into a syringe: Dosing volume (mL)=Total dose (mg)/5 (mg/mL).
`
`
`
`
`
`
`Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile intravenous bag [plasticized polyvinyl chloride
`
`
`
`(PVC) containers, PVC or non-PVC type intravenous bag]. The use of specialized DEHP-free solution containers or administration
`
`
`
`
`
`
`sets is not necessary to prepare or administer ABRAXANE infusions. The use of medical devices containing silicone oil as a
`
`
`
`
`
`
`lubricant (ie, syringes and intravenous bags) to reconstitute and administer ABRAXANE may result in the formation of proteinaceous
`
`
`
`
`
`
`
`
`strands.
`
`
`Visually inspect the reconstituted ABRAXANE suspension in the intravenous bag prior to administration. Discard the reconstituted
`
`
`
`
`
`
`
`suspension if proteinaceous strands, particulate matter or discoloration are observed.
`
`
`
`Stability
`2.8
`
`
`Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20ºC to 25ºC (68ºF to 77ºF)
`
`
`
`
`
`in the original package. Neither freezing nor refrigeration adversely affects the stability of the product.
`
`
`
`
`
`
`Stability of Reconstituted Suspension in the Vial
`
`
`Reconstituted ABRAXANE in the vial should be used immediately, but may be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for a
`
`
`
`maximum of 24 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original
`
`
`
`
`
`carton to protect it from bright light. Discard any unused portion.
`
`
`
`
`Stability of Reconstituted Suspension in the Infusion Bag
`
`The suspension for infusion when prepared as recommended in an infusion bag should be used immediately, but may be
`
`
`
`refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a maximum of 24 hours.
`
`
`
`
`
`
`The total combined refrigerated storage time of reconstituted ABRAXANE in the vial and in the infusion bag is 24 hours. This may
`
`
`
`
`be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of
`
`
`
`
`
`
`4 hours.
`
`
`
`
`
`
`Reference ID: 4307748
`
`
`
` 6
`
`

`

`
`
`
`
`
`
`
`
` Discard any unused portion.
`
` DOSAGE FORMS AND STRENGTHS
`3
`
`
`
` For injectable suspension: lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in single-use
`
`
` vial for reconstitution.
`
`4
`
`
`
`
` CONTRAINDICATIONS
`
`
`
` • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.
`
`
`
` • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.
`
`
`
`
`
`5
`
` Hematologic Effects
` 5.1
`
`
` Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies,
`
`
`
`
`
`
`
` Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung
` cancer (NSCLC), and 38% of patients with pancreatic cancer.
`
`
`
`
`
`
`
`
`
`
`
`
` Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and
`
`
` Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute
`
`
`
`
` neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more)
`
`
`
`
`
`
`
`
`during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or
`
`
`
`
`
`NSCLC.
`
`
`In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3
`
`
`
`
`
`
`
`
`
`
`and platelets recover to a level >100,000 cells/mm3.
`
`
`
`
`
`
`In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced
`
`
`
`doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count
`
`
`
`
`
`
`
`
`
`
`of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on
`
`
`
`
`Days 8 or 15 of the cycle [see Dosage and Administration (2.5)].
`
`
`
`
`
`In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or
`
`
`
`
`
`
`
`
`platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count
`
`
`
`
`
`
`
`
`
`
`is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see
`
`Dosage and Administration (2.5)].
`
`
`
`Nervous System
`5.2
`
`
`
`
`
`Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2
`
`
`
`
`
`sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE
`
`
`
`
`
`
`
`
`treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic
`
`
`
`
`
`
`cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].
`
`
`
`5.3 Sepsis
`
`
`
`
`
`
`
`
`Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary
`
`
`
`
`
`obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC)
`
`
`
`
`
`
`initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves
`
`
`
`
`
`
`
`and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].
`
`
`Pneumonitis
`5.4
`
`
`
`
`
`
`Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with
`
`
`
`
`
`
`
`gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation
`
`
`
`
`of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue
`
`
`treatment with ABRAXANE and gemcitabine.
`
`
`
`Hypersensitivity
`5.5
`
`
`
`
`Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who
`
`experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug. Cross-hypersensitivity
`
`
`between ABRAXANE and other taxane products has been reported and may include severe reactions such as anaphylaxis.
`
`
`
`Patients with a previous history of hypersensitivity to other taxanes should be closely monitored during initiation of ABRAXANE
`
`
`
`
`
`
`
`
`therapy.
`
`
`
`
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
`
`
`
`
`Reference ID: 4307748
`
`
`
` 7
`
`

`

` Hepatic Impairment
` 5.6
`
`
`
`
` 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. Patients with hepatic impairment may be at increased risk of toxicity,
`
`
`
`
`
`
`
`
` particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression.
`
`
`
`
`
`
`
`
`
` ABRAXANE is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, ABRAXANE is not
`
`
`
`
`
` recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total
`
`
`
`
`
` bilirubin >1.5 x ULN and AST ≤10 x ULN). The starting dose should be reduced for patients with moderate or severe hepatic
`
`
`
`
`
`
`
`
` impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`
`
`
`Albumin (Human)
`5.7
`
`
`ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing
`
`
`
`
`
`processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease
`
`
`
`
`
`(CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
`
`
`
`
`
`
`
`Embryo-Fetal Toxicity
`5.8
`
`
`Based on mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman.
`
`
`
`
`
`
`In animal reproduction studies, administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy at doses
`
`
`
`
`
`
`lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including
`
`
`intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.
`
`
`
`
`
`
`
`
`
`
`
`
`Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective
`contraception and avoid becoming pregnant during treatment with ABRAXANE and for at least six months after the last dose of
`
`
`
`
`
`ABRAXANE [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
`
`
`
`
`
`
`
`
`
`
`Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive
`potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months
`
`
`
`
`after the last dose of ABRAXANE [see Use in Specific Populations (8.1, 8.3) and Nonclinical Toxicology (13.1)].
`
`
`
`
`
`
`6
` ADVERSE REACTIONS
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug
` cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`
`
`
`
`
`
`