Abraxane (Paclitaxel)

• •
  Do not administer ABRAXANE therapy to patients with baseline neutrophil counts of less than 1,500 cells/mm³

  [see

  4 CONTRAINDICATIONS

  ABRAXANE is contraindicated in patients with:

  • •
    Baseline neutrophil counts of < 1,500 cells/mm³

    [see Warnings and Precautions (5.1)]
  • •
    A history of severe hypersensitivity reactions to ABRAXANE

    [see Warnings and Precautions (5.5)]

  • •Neutrophil counts of < 1,500 cells/mm³.
  • •Severe hypersensitivity reactions to ABRAXANE.

  ].
• •
  Monitor for neutropenia, which may be severe and result in infection or sepsis

  [see

  5.1 Severe Myelosuppression

  Severe myelosuppression (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 severe neutropenia and thrombocytopenia 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

  [see Contraindications (4)]

  .

  In the case of severe neutropenia (<500 cells/mm³for 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/mm³and platelets recover to a level >100,000 cells/mm³. In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm³and platelet count of at least 100,000 cells/mm³on Day 1 or to an ANC of at least 500 cells/mm³and platelet count of at least 50,000 cells/mm³on Days 8 or 15 of the cycle

  [see Dosage and Administration (2.6)].

  In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm³or platelets are less than 50,000 cells/mm³and delay initiation of the next cycle if the ANC is less than 1500 cells/mm³or platelet count is less than 100,000 cells/mm³on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

  [see Dosage and Administration (2.6)].

  ,

  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 (2.6)]

  .

  ].
• •
  Perform frequent complete blood cell counts on all patients receiving ABRAXANE

  [see

  5.1 Severe Myelosuppression

  Severe myelosuppression (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 severe neutropenia and thrombocytopenia 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

  [see Contraindications (4)]

  .

  In the case of severe neutropenia (<500 cells/mm³for 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/mm³and platelets recover to a level >100,000 cells/mm³. In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm³and platelet count of at least 100,000 cells/mm³on Day 1 or to an ANC of at least 500 cells/mm³and platelet count of at least 50,000 cells/mm³on Days 8 or 15 of the cycle

  [see Dosage and Administration (2.6)].

  In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm³or platelets are less than 50,000 cells/mm³and delay initiation of the next cycle if the ANC is less than 1500 cells/mm³or platelet count is less than 100,000 cells/mm³on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

  [see Dosage and Administration (2.6)].

  ,

  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 (2.6)]

  .

  ].

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 Metastatic Breast Cancer

  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.
  )
• •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 Non-Small Cell Lung Cancer

  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.
  )
• •Metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with gemcitabine. (
  1.3 Adenocarcinoma of the Pancreas

  ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.
  )

• •
  Do not substitute ABRAXANE for other paclitaxel products. (

  2.1 Important Administration Instructions

  DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. ABRAXANE has different dosage and administration instructions from other paclitaxel products.

  Closely monitor the infusion site for extravasation or drug infiltration during administration. Limiting the infusion of ABRAXANE to 30 minutes may reduce the risk of infusion-related reactions

  [see Adverse Reactions (6.2)]

  .

  Consider premedication in patients who have had prior hypersensitivity reactions to ABRAXANE. Do not re-challenge patients who experience a severe hypersensitivity reaction to ABRAXANE

  [see Contraindications (4)and Warnings and Precautions (5.5)]

  .

  )
• •
  Extravasation
  : Closely monitor the infusion site for extravasation and infiltration. (
  2.1 Important Administration Instructions

  DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. ABRAXANE has different dosage and administration instructions from other paclitaxel products.

  Closely monitor the infusion site for extravasation or drug infiltration during administration. Limiting the infusion of ABRAXANE to 30 minutes may reduce the risk of infusion-related reactions

  [see Adverse Reactions (6.2)]

  .

  Consider premedication in patients who have had prior hypersensitivity reactions to ABRAXANE. Do not re-challenge patients who experience a severe hypersensitivity reaction to ABRAXANE

  [see Contraindications (4)and Warnings and Precautions (5.5)]

  .
  )
• •
  Metastatic Breast Cancer (MBC)
  : Recommended dosage of ABRAXANE is 260 mg/m² intravenously over 30 minutes every 3 weeks. (
  2.2 Recommended Dosage for Metastatic Breast Cancer

  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/m²administered intravenously over 30 minutes every 3 weeks.
  )
• •
  Non-Small Cell Lung Cancer (NSCLC)
  : 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. (
  2.3 Recommended Dosage for Non-Small Cell Lung Cancer

  The recommended dose of ABRAXANE is 100 mg/m²administered 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
  : 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, 8, and 15 of each 28-day cycle immediately after ABRAXANE. (
  2.4 Recommended Dosage for Adenocarcinoma of the Pancreas

  The recommended dose of ABRAXANE is 125 mg/m²administered 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)].
  )
• •
  Use in Patients with Hepatic Impairment:
  ABRAXANE is not recommended for use in patients with AST > 10 × ULN; or bilirubin > 5 × ULN or with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment. For MBC or NSCLC, reduce starting dose in patients with moderate to severe hepatic impairment. (
  2.5 Dosage Modifications for Hepatic Impairment

  For patients with moderate or severe hepatic impairment, reduce the starting dose of ABRAXANE as shown in Table 1.

  Table 1: Recommendations for Starting Dose in Patients with Moderate and Severe Hepatic Impairment

  AST = Aspartate Aminotransferase; MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer; ULN = Upper limit of normal. aDosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. bA dose increase to 260 mg/m2for patients with metastatic breast cancer or 100 mg/m2for patients with non-small cell lung cancer in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles. cPatients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.
  	AST Levels		Bilirubin Levels	ABRAXANE Dosea
  				MBC	NSCLCc	Adenocarcinoma of Pancreasc
  Moderate	< 10 x ULN	AND	> 1.5 to ≤ 3 x ULN	200 mg/m2 b	80 mg/m2 b	not recommended
  Severe	< 10 x ULN	AND	> 3 to ≤ 5 x ULN	200 mg/m2 b	80 mg/m2 b	not recommended
  	> 10 x ULN	OR	> 5 x ULN	not recommended	not recommended	not recommended
  )
• •
  Dose Reductions for Adverse Reactions
  : Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicities. (
  2.6 Dosage Modifications for Adverse Reactions

  Metastatic Breast Cancer

  
  
  Patients who experience severe neutropenia (neutrophils less than 500 cells/mm³for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m²for 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/mm³and platelet count is at least 100,000 cells/mm³
    [see Contraindications (4), Warnings and Precautions (5.1)and Adverse Reactions (6.1)].
  • •In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm³and platelet count of at least 100,000 cells/mm³on Day 1 or to an absolute neutrophil count of at least 500 cells/mm³and platelet count of at least 50,000 cells/mm³on 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 (6.1)]
    .

  Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Reactions in NSCLC

  Adverse Reaction	Occurrence	Weekly ABRAXANE Dose (mg/m2)	Every 3-Week Carboplatin Dose (AUC mg•min/mL)
  Neutropenic Fever (ANC less than 500/mm3with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3for more than 7 days	First	75	4.5
  	Second	50	3
  	Third	Discontinue Treatment
  Platelet count less than 50,000/mm3	First	75	4.5
  	Second	Discontinue Treatment
  Severe sensory Neuropathy – Grade 3 or 4	First	75	4.5
  	Second	50	3
  	Third	Discontinue Treatment

  Adenocarcinoma of the Pancreas

  
  
  Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4and 5, are provided in Table 3.

  Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas

  Dose Level	ABRAXANE (mg/m2)	Gemcitabine (mg/m2)
  Full dose	125	1000
  1stdose reduction	100	800
  2nddose reduction	75	600
  If additional dose reduction required	Discontinue	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 = Absolute Neutrophil Count
  Cycle Day	ANC (cells/mm3)		Platelet count (cells/mm3)	ABRAXANE / Gemcitabine
  Day 1	< 1500	OR	< 100,000	Delay doses until recovery
  Day 8	500 to < 1000	OR	50,000 to < 75,000	Reduce 1 dose level
  	< 500	OR	< 50,000	Withhold doses
  Day 15: If Day 8 doses were reduced or given without modification:
  	500 to < 1000	OR	50,000 to < 75,000	Reduce 1 dose level from Day 8
  	< 500	OR	< 50,000	Withhold doses
  Day 15: If Day 8 doses were withheld:
  	≥ 1000	OR	≥ 75,000	Reduce 1 dose level from Day 1
  	500 to < 1000	OR	50,000 to < 75,000	Reduce 2 dose levels from Day 1
  	< 500	OR	< 50,000	Withhold doses

  Recommended dose modifications for other adverse reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

  Table 5: Dose Modifications for Other Adverse Reactions in Patients with Adenocarcinoma of the Pancreas

  Adverse Reaction	ABRAXANE	Gemcitabine
  Febrile Neutropenia: Grade 3 or 4	Withhold until fever resolves and ANC ≥ 1500; resume at next lower dose level
  Peripheral Neuropathy: Grade 3 or 4	Withhold until improves to ≤ Grade 1; resume at next lower dose level	No dose reduction
  Cutaneous Toxicity: Grade 2 or 3	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
  )

For injectable suspension, for intravenous use: white to yellow, sterile lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in single-dose vial for reconstitution.

• •
  Lactation
  : Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There are no data on the presence of paclitaxel in human milk, or its effect on the breastfed child or on milk production. In animal studies, paclitaxel and/or its metabolites were excreted into the milk of lactating rats (see Data). Because of the potential for serious adverse reactions in a breastfed child from ABRAXANE, advise lactating women not to breastfeed during treatment with ABRAXANE and for two weeks after the last dose.

  Data

  Animal Data

  Following intravenous administration of radiolabeled 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.
  )