ABRAXANE

Abraxis BioScience, LLC

HIGHLIGHTS OF PRESCRIBING INFORMATION BOXED WARNING WARNING: NEUTROPENIA See full prescribing information for complete boxed warning. 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 Indications and Usage. (1.3)     09/2013 Dosage and Administration. (2.3, 2.5)     09/2013 Warnings and Precautions, Hematologic Effects (5.1), Nervous System (5.2), Sepsis (5.3), Pneumonitis (5.4)      09/2013 INDICATIONS AND USAGEABRAXANE 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, 8 and 15 of each 28-day cycle immediately after ABRAXANE. (2.3) No adjustment is necessary for patients with mild hepatic impairment. Withhold ABRAXANE if AST > 10 x ULN or bilirubin > 5 x ULN. Reduce starting dose in patients with moderate to severe hepatic impairment. (2.4) Dose Reductions: Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicities. (2.5) Use caution when handling cytotoxic drugs. Closely monitor the infusion site for extravasation and infiltration. No premedication is required prior to administration. (2.6) DOSAGE FORMS AND STRENGTHS For injectable suspension: lyophilized powder containing 100 mg of paclitaxel in single-use vial for reconstitution. (3) CONTRAINDICATIONS Neutrophil counts of < 1,500 cells/mm3. (4) Severe hypersensitivity reaction to ABRAXANE. (4) WARNINGS AND PRECAUTIONS ABRAXANE causes myelosuppression. Monitor CBC and withhold and/or reduce the dose as needed. (5.1) Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. (5.2) Sepsis occurred in patients with or without neutropenia who received ABRAXANE in combination with gemcitabine; interrupt ABRAXANE and gemcitabine until sepsis resolves, and if neutropenic, until neutrophils are at least 1500 cells/mm3, then resume treatment at reduced dose levels. (5.3) Pneumonitis occurred with the use of ABRAXANE in combination with gemcitabine; permanently discontinue treatment with ABRAXANE and gemcitabine. (5.4) Severe hypersensitivity reactions with fatal outcome have been reported. Do not re-challenge with this drug. (5.5) Exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment; therefore administer with caution. (5.6) ABRAXANE contains albumin derived from human blood, which has a theoretical risk of viral transmission. (5.7) Fetal harm may occur when administered to a pregnant woman. Advise women of childbearing potential to avoid becoming pregnant while receiving ABRAXANE. (5.8) Advise men not to father a child while on ABRAXANE. (5.9) Side Effects The most common adverse reactions (≥ 20%) in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea. (6.1) The most common adverse reactions (≥ 20%) in NSCLC are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue. (6.2) The most common (≥ 20%) adverse reactions of ABRAXANE in adenocarcinoma of the pancreas are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. (6.3) 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)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: NEUTROPENIA
• 1 ABRAXANE INDICATIONS AND USAGE
  • 1.1 Metastatic Breast Cancer
  • 1.2 Non-Small Cell Lung Cancer
  • 1.3 Adenocarcinoma of the Pancreas
• 2 ABRAXANE DOSAGE AND ADMINISTRATION
  • 2.1 Metastatic Breast Cancer
  • 2.2 Non-Small Cell Lung Cancer
  • 2.3 Adenocarcinoma of the Pancreas
  • 2.4 Dosage in Patients with Hepatic Impairment
  • 2.5 Dose Reduction/Discontinuation Recommendations
  • 2.6 Preparation and Administration Precautions
  • 2.7 Preparation for Intravenous Administration
  • 2.8 Stability
• 3 DOSAGE FORMS AND STRENGTHS
• 4 ABRAXANE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hematologic Effects
  • 5.2 Nervous System
  • 5.3 Sepsis
  • 5.4 Pneumonitis
  • 5.5 Hypersensitivity
  • 5.6 Hepatic Impairment
  • 5.7 Albumin (Human)
  • 5.8 Use in Pregnancy
  • 5.9 Use in Men
• 6 ABRAXANE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience in Metastatic Breast Cancer
  • 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer
  • 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas
  • 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations
  • 6.5 Accidental Exposure
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Patients with Hepatic Impairment
  • 8.7 Patients with Renal Impairment
• 10 OVERDOSAGE
• 11 ABRAXANE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Metastatic Breast Cancer
  • 14.2 Non-Small Cell Lung Cancer
  • 14.3 Adenocarcinoma of the Pancreas
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage
  • 16.3 Handling and Disposal
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

ABRAXANE^® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

1 INDICATIONS AND USAGE

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.

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.

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.

2 DOSAGE AND ADMINISTRATION

2.1 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/m² administered intravenously over 30 minutes every 3 weeks.

2.2 Non-Small Cell Lung Cancer

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)].

2.3 Adenocarcinoma of the Pancreas

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)].

2.4 Dosage in Patients with Hepatic Impairment

No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.

For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m² up to 200 mg/m² in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.

For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m² in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m² as tolerated.

Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.5 Dose Reduction/Discontinuation Recommendations

Metastatic Breast Cancer
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 [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)].

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.

Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.

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

2.6 Preparation and Administration Precautions

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.

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.

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) = Total dose (mg)/5 (mg/mL).

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.

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 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.

2.8 Stability

Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F) 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 2°C to 8°C (36°F to 46°F) for a maximum of 8 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 stored at ambient temperature (approximately 25°C) and lighting conditions for up to 4 hours. Discard any unused portion.

3 DOSAGE FORMS AND STRENGTHS

For injectable suspension: lyophilized powder containing 100 mg of paclitaxel 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 WARNINGS AND PRECAUTIONS

5.1 Hematologic Effects

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)].

5.2 Nervous System

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)].

5.4 Pneumonitis

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.

5.5 Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.

5.6 Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.7 Albumin (Human)

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.

5.8 Use in Pregnancy

ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-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.

There are no adequate and well-controlled studies in pregnant women receiving 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 ABRAXANE [see Use in Specific Populations (8.1)].

5.9 Use in Men

Men should be advised not to father a child while receiving ABRAXANE [see 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.

The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)].

The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)] The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).

In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).

6.1 Clinical Trials Experience in Metastatic Breast Cancer

Table 6 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.

Adverse Event Experiences by Body System

Hematologic Disorders
Neutropenia 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. Pancytopenia has been observed in clinical trials.

Infections
Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

Hypersensitivity Reactions (HSRs)
Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular
Hypotension, during the 30-minute infusion, occurred in 5% of patients. 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. These events included cardiac ischemia/infarction, 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.

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. 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
Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE.

Neurologic
The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four 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 Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.

Vision Disorders
Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m²). These effects generally have been reversible.

Arthralgia/Myalgia
The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.

Hepatic
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.

Renal
Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Other Clinical Events
Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.

6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer

Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m² on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m², following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion.
The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.

The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group).

Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE.

6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas

Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:

Infections & infestations: oral candidiasis, pneumonia
Vascular disorders: hypertension
Cardiac disorders: tachycardia, congestive cardiac failure
Eye disorders: cystoid macular edema

Peripheral Neuropathy
Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.

Sepsis
Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.

Pneumonitis
Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.

6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations

Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE.

Hypersensitivity Reactions
Severe and sometimes fatal 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.

Cardiovascular
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory
There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE.

Neurologic
Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders
Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.

Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.

Hepatic
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.

Gastrointestinal (GI)
There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported 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. 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.

Other Clinical Events
Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.

6.5 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.

7 DRUG INTERACTIONS

The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.9)].

There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. 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 ABRAXANE.

Administration of paclitaxel protein-bound particles to rats during pregnancy, 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 embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m² (approximately 1% of the daily maximum recommended human dose on a mg/m² basis).

8.3 Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

8.5 Geriatric Use

Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE.

Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.

Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.

8.6 Patients with Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.

8.7 Patients with Renal Impairment

The use of ABRAXANE has not been studied in patients with renal impairment.

10 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.

11 DESCRIPTION

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. ABRAXANE is free of solvents.

The active agent in ABRAXANE is paclitaxel, a microtubule inhibitor. 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ABRAXANE is a microtubule inhibitor 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.

12.3 Pharmacokinetics

Absorption
The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of ABRAXANE at dose levels of 80 to 375 mg/m² were determined in clinical studies. Dose levels of mg/m² refer to mg of paclitaxel in ABRAXANE. Following intravenous administration of ABRAXANE, paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing drug elimination. The terminal half-life was approximately 27 hours.

The drug exposure (AUCs) was dose proportional over 80 to 375 mg/m² and the pharmacokinetics of paclitaxel were independent of the duration of ABRAXANE administration. At the dose of 260 mg/m² for metastatic breast cancer, 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 indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetic data of 260 mg/m² ABRAXANE administered over a 30-minute infusion was compared to the pharmacokinetics of 175 mg/m² paclitaxel injection over a 3-hour infusion. The clearance was larger (43%) and the volume of distribution was also higher (53%) for ABRAXANE than for paclitaxel injection. Differences in the maximum concentration (C_max) and dose-corrected C_max reflected differences in total dose and rate of infusion. There were no differences in terminal half-lives.

Distribution
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 µg/mL, indicated that between 89% to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

Metabolism
In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 [see Drug Interactions (7)].

Excretion
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.

Effect of Hepatic Impairment
The pharmacokinetic profile of ABRAXANE administered as a 30-minute infusion was evaluated in 15 out of 30 solid tumor patients with mild to severe hepatic impairment defined by serum bilirubin levels and AST levels. Patients with AST > 10 x ULN or bilirubin > 5 x ULN were not enrolled. ABRAXANE doses were assigned based on the degree of hepatic impairment as described:

• Mild (bilirubin > ULN to ≤ 1.25 x ULN and AST > ULN and < 10 x ULN): 260 mg/m²
• Moderate (bilirubin 1.26 to 2 x ULN and AST > ULN and < 10 x ULN): 200 mg/m²
• Severe (bilirubin 2.01 to 5 x ULN and AST > ULN and < 10 x ULN): 130 mg/m²

The 260 mg/m² dose for mild hepatic impairment and the 200 mg/m² dose for moderate hepatic impairment resulted in paclitaxel exposures within the range seen in patients with normal hepatic function (mean AUC_0-∞ = 14,789 ± 6,703 hr*ng/mL). The 130 mg/m² dose in patients with severe hepatic impairment resulted in lower paclitaxel exposures than those seen in normal subjects. In addition, patients with severe hepatic impairment had higher mean cycle 1 absolute neutrophil count (ANC) nadir values than those with mild and moderate hepatic impairment. Table 11 summarizes the AUC values observed in the study. The 200 mg/m² dose has not been evaluated in patients with severe hepatic impairment, but it is predicted to adjust the paclitaxel AUC to the range observed in patients with normal hepatic function. There are no data for patients with AST > 10 x ULN or bilirubin >5 x ULN [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

Effect of Renal Impairment
The effect of renal impairment on the disposition of ABRAXANE has not been studied [see Use in Specific Populations (8.7)].

Pharmacokinetic Interactions between and ABRAXANE and Carboplatin
Administration of carboplatin immediately after the completion of the ABRAXANE infusion to patients with NSCLC did not cause clinically meaningful changes in paclitaxel exposure. The observed mean AUC_inf of free carboplatin was approximately 23% higher than the targeted value (6 min*mg/mL), but its mean half-life and clearance were consistent with those reported in the absence of paclitaxel.

Pharmacokinetic Interactions between and ABRAXANE and Gemcitabine
Pharmacokinetic interactions between ABRAXANE and gemcitabine have not been studied in humans.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of ABRAXANE has not been studied.

Paclitaxel was 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 body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m²/week in this study (approximately 1 to 5% of the daily maximum recommended human exposure on a mg/m² basis). Testicular atrophy/degeneration was observed in single-dose toxicology studies in rodents administered paclitaxel protein-bound particles at doses lower than the recommended human dose; doses were 54 mg/m² in rodents and 175 mg/m² in dogs.

14 CLINICAL STUDIES

14.1 Metastatic Breast Cancer

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-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 12. There was no statistically significant difference in overall survival between the two study arms.

14.2 Non-Small Cell Lung Cancer

A multicenter, randomized, open-label study was conducted in 1052 chemonaive patients with Stage IIIb/IV non-small cell lung cancer to compare ABRAXANE in combination with carboplatin to paclitaxel injection in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m² on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m², following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. Treatment was administered until disease progression or development of an unacceptable toxicity. The major efficacy outcome measure was overall response rate as determined by a central independent review committee using RECIST guidelines (Version 1.0).

In the intent-to-treat (all-randomized) population, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1, and 73% were current or former smokers. Patients received a median of 6 cycles of treatment in both study arms.

Patients in the ABRAXANE/carboplatin arm had a statistically significantly higher overall response rate compared to patients in the paclitaxel injection/carboplatin arm [(33% versus 25%) see Table 13]. There was no statistically significant difference in overall survival between the two study arms.

14.3 Adenocarcinoma of the Pancreas

A multicenter, multinational, randomized, open-label study was conducted in 861 patients comparing ABRAXANE plus gemcitabine versus gemcitabine monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. Key eligibility criteria were Karnofsky Performance Status (KPS) ≥70, normal bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the ULN for patients with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting or for metastatic disease, no ongoing active infection requiring systemic therapy, and no history of interstitial lung disease. Patients with rapid decline in KPS (≥10%) or serum albumin (≥20%) during the 14 day screening period prior to study randomization were ineligible.

A total of 861 patients were randomized (1:1) to the ABRAXANE/gemcitabine arm (N=431) or to the gemcitabine arm (N=430). Randomization was stratified by geographic region (Australia, Western Europe, Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). Patients randomized to ABRAXANE/gemcitabine received ABRAXANE 125 mg/m² as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m² as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients randomized to gemcitabine received 1000 mg/m² as an intravenous infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period in Cycle 1 then as 1000 mg/m² on Days 1, 8 and 15 of each subsequent 28-day cycle. Patients in both arms received treatment until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST (version 1.0).

In the intent to treat (all randomized) population, the median age was 63 years (range 27-88 years) with 42% ≥ 65 years of age; 58% were men; 93% were White and KPS was 90-100 in 60%. Disease characteristics included 46% of patients with 3 or more metastatic sites; 84% of patients had liver metastasis; and the location of the primary pancreatic lesion was in the head of pancreas (43%), body (31%), or tail (25%).

Results for overall survival, progression-free survival, and overall response rate are shown in Table 14.

In exploratory analyses conducted in clinically relevant subgroups with a sufficient number of subjects, the treatment effects on overall survival were similar to that observed in the overall study population.

Figure 1: Kaplan-Meier Curve of Overall Survival (Intent-to-treat Population)

15 REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Product No.: 103450
NDC No.: 68817-134-50        100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

16.2 Storage

Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light.

16.3 Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling

• ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].
• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].
• Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].
• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration.
• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)].
• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE
• Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal. [see Warnings and Precautions (5.5)].
• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for:       Celgene Corporation
                                  Summit, NJ 07901

ABRAXANE^® is a registered trademark of Abraxis BioScience, LLC.
©2005-2013 Abraxis BioScience, LLC.
All Rights Reserved.
Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABRPI.007/PPI.007 10/13

Patient Information

ABRAXANE^® (ah-BRAKS-ane)
(paclitaxel protein-bound particles for injectable suspension)
(albumin-bound)

Read this Patient Information before you start receiving ABRAXANE and before each infusion. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is ABRAXANE?

ABRAXANE is a prescription medicine used to treat:

• advanced breast cancer in people who have already received certain other medicines for their cancer.
• advanced non-small cell lung cancer, in combination with carboplatin in people who cannot be treated with surgery or radiation.
• and advanced pancreatic cancer, when used in combination with gemcitabine as the first medicine for advanced pancreatic cancer.

It is not known if ABRAXANE is safe or effective in children.

Who should not receive ABRAXANE?

Do not receive ABRAXANE if:

• your white blood cell count is below 1,500 cells/ mm³.
• you have had a severe allergic reaction to ABRAXANE.

What should I tell my doctor before receiving ABRAXANE?
Before you receive ABRAXANE, tell your doctor if you:

• have liver or kidney problems.
• have any other medical conditions.
• are a man planning to father a child. You should not father a child during your treatment with ABRAXANE. ABRAXANE can harm the unborn baby of your partner. Talk to your doctor if this is a concern to you.
• are pregnant or plan to become pregnant. ABRAXANE can harm your unborn baby. You should not become pregnant while receiving ABRAXANE. Women who may become pregnant should use effective birth control (contraception). Talk to your doctor about the best way to prevent pregnancy while receiving ABRAXANE.
• are breastfeeding or plan to breastfeed. It is not known if ABRAXANE passes into your breast milk. You and your doctor should decide if you will receive ABRAXANE or breastfeed.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list to show your doctor and pharmacist when you get a new medicine.

How will I receive ABRAXANE?

• Your doctor will prescribe ABRAXANE in an amount that is right for you.
• Premedication to prevent allergic reactions is generally not needed to receive ABRAXANE. Premedication may be needed if you have had an allergic reaction to ABRAXANE. In case of severe allergic reaction, ABRAXANE should not be used again.
• ABRAXANE will be given to you by intravenous infusion into your vein.
• Your doctor should do regular blood tests while you receive ABRAXANE.

What are the possible side effects of ABRAXANE?

ABRAXANE may cause serious side effects, including:

• decreased blood cell counts. ABRAXANE can cause a severe decrease in neutrophils (a type of white blood cells important in fighting against bacterial infections) and platelets (important for clotting and to control bleeding). Your doctor will check your blood cell count during your treatment with ABRAXANE and after you have stopped your treatment.
• numbness, tingling, pain, or weakness in your hands or feet (neuropathy).
• severe infection (sepsis). If you receive ABRAXANE in combination with gemcitabine, infections can be severe and lead to death. Tell your doctor right away if you have a fever (temperature of greater than 100.4° F) or develop signs of infection.
• lung or breathing problems. If you receive ABRAXANE in combination with gemcitabine, lung or breathing problems may be severe and can lead to death. Tell your doctor right away if you have a sudden onset of persistent dry cough or shortness of breath.
• allergic reactions. Allergic reactions to ABRAXANE may be severe and can lead to death.

The most common side effects of ABRAXANE include:

• hair loss
• numbness, tingling, pain, or weakness in the hands or feet
• abnormal heart beat
• tiredness
• joint and muscle pain
• changes in your liver function tests
• rash
• low red blood cell count (anemia). Red blood cells carry oxygen to your body tissues. Tell your doctor if you feel weak, tired or short of breath.
• nausea and vomiting
• infections. If you have a fever (temperature of greater than 100.4° F) or other signs of infection, tell your doctor right away.
• Diarrhea
• Loss of body fluid (dehydration)
• Swelling in the hands or feet

These are not all the possible side effects of ABRAXANE. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of ABRAXANE.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

This Patient Information leaflet summarizes the important information about ABRAXANE. If you would like more information, talk to your doctor. You can ask your doctor or pharmacist for information about ABRAXANE that is written for health professionals.

For more information, call 1-888-423-5436.

What are the ingredients in ABRAXANE?

Active ingredient: paclitaxel (bound to human albumin).

Other ingredient: human albumin (containing sodium caprylate and sodium acetyltryptophanate)

This Patient Information has been approved by the U.S. Food and Drug Administration.

Revised: October 2013

Manufactured for:      Celgene Corporation
                                 Summit, NJ 07901

ABRAXANE^® is a registered trademark of Abraxis BioScience, LLC.
©2005-2013 Abraxis BioScience, LLC.
All Rights Reserved.
Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABRPPI.007 10/13

PRINCIPAL DISPLAY PANEL - 100 mg Vial

NDC 68817-134-50
103450

Abraxane^®
for Injectable Suspension

(paclitaxel protein-bound particles for injectable suspension)
(albumin-bound)

100 mg per vial
Single Use Vial

Discard any unused portion.

For Intravenous Use Only
Rx only

Functional properties differ from other
paclitaxel products. DO NOT SUBSTITUTE.

PRINCIPAL DISPLAY PANEL - 100 mg Vial

NDC 68817-134-50
103450

Abraxane^®
for Injectable Suspension

(paclitaxel protein-bound particles for injectable suspension)
(albumin-bound)

100 mg per vial
Single Use Vial

Discard any unused portion.

For Intravenous Use Only
Rx only

Functional properties differ from other
paclitaxel products. DO NOT SUBSTITUTE.

PRINCIPAL DISPLAY PANEL - 100 mg Vial Carton

NDC 68817-134-50
103450

Abraxane^®
for Injectable Suspension

(paclitaxel protein-bound particles for injectable suspension)
(albumin-bound)

100 mg per vial
Single Use Vial

Discard any unused portion.

For Intravenous Use Only
Rx only

Functional properties differ from other
paclitaxel products. DO NOT SUBSTITUTE.