ABRAXANE (Taxanes) — FDA Approved Drug

Indications & Usage

1 INDICATIONS AND USAGE Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 ) 1.1 Metastatic Breast Cancer Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Contraindications

4 CONTRAINDICATIONS Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is contraindicated in patients with: • Baseline neutrophil counts of < 1,500 cells/mm 3 [see Warnings and Precautions (5.1) ] • A history of severe hypersensitivity reactions to Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) [see Warnings and Precautions (5.5) ] • Neutrophil counts of < 1,500 cells/mm 3 . ( 4 ) • Severe hypersensitivity reactions to Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound). ( 4 )

Indications & Usage

Contraindications

Warnings & Precautions

5 WARNINGS AND PRECAUTIONS • Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. ( 5.2 ) • Sepsis occurred in patients with or without neutropenia who received Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in combination with gemcitabine; interrupt Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine until sepsis resolves, and if neutropenia, until neutrophils are at least 1500 cells/mm 3 , then resume treatment at reduced dose levels. ( 5.3 ) • Pneumonitis occurred with the use of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in combination with gemcitabine; permanently discontinue treatment with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine. ( 5.4 ) • Severe hypersensitivity reactions with fatal outcome have been reported. Do not rechallenge with this drug. ( 4 , 5.5 ) • Exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, consider dose reduction and closely monitor patients with hepatic impairment. ( 2.5 , 5.6 ) • Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) contains albumin derived from human blood, which has a theoretical risk of viral transmission. ( 5.7 ) • Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 ) 5.1 Severe Myelosuppression Severe myelosuppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound). 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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/mm 3 for seven days or more) during a course of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) therapy, reduce the dose of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) after ANC recovers to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3 . In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm 3 and platelet count of at least 100,000 cells/mm 3 on Day 1 or to an ANC of at least 500 cells/mm 3 and platelet count of at least 50,000 cells/mm 3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.6) ]. In patients with adenocarcinoma of the pancreas, withhold Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine if the ANC is less than 500 cells/mm 3 or platelets are less than 50,000 cells/mm 3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm 3 or platelet count is less than 100,000 cells/mm 3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.6) ]. 5.2 Severe Neuropathy Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1) ] . If ≥ Grade 3 sensory neuropathy develops, withhold Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) [see Dosage and Administration (2.6) ] . 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.6) ] . 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine. 5.5 Severe Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Do not rechallenge patients who experience a severe hypersensitivity reaction to Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) with this drug [see Contraindications (4) ] . Cross-hypersensitivity between Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and other taxane products has been reported and may include severe reactions such as anaphylaxis. Closely monitor patients with a previous history of hypersensitivity to other taxanes during initiation of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) therapy. 5.6 Use in Patients with Hepatic Impairment The exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment. Closely monitor patients with hepatic impairment for severe myelosuppression. Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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). Reduce the starting dose for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.5) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 5.7 Albumin (Human) Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Embryo-Fetal Toxicity Based on mechanism of action and findings in animals, Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) can cause fetal harm when administered to a

Adverse Reactions

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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.1) ]. The most common serious adverse reactions of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration [see Adverse Reactions (6.1) ] . The most common serious adverse reactions of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) (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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) are peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%). • 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. ( 6.1 ) • The most common (≥ 20%) adverse reactions of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in adenocarcinoma of the pancreas are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals USA, Inc. at 1-844-518-2989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Metastatic Breast Cancer Table 6 shows the frequency of important adverse reactions in the randomized comparative trial for the patients who received either single-agent Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) or paclitaxel injection for the treatment of metastatic breast cancer. Table 6: Adverse Reactions in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule a Paclitaxel injection patients received premedication. b Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. c Severe events are defined as at least Grade 3 toxicity. Percent of Patients Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 260 mg/m 2 over 30 min (n=229) Paclitaxel Injection 175 mg/m 2 over 3 h a (n=225) Bone Marrow Neutropenia < 2.0 x 10 9 /L 80 82 < 0.5 x 10 9 /L 9 22 Thrombocytopenia < 100 x 10 9 /L 2 3 < 50 x 10 9 /L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reaction b All 4 12 Severe c 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Events c 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptoms c 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptoms c 8 4 Asthenia Any Symptoms 47 39 Severe Symptoms c 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptoms c 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptoms c 3 <1 Vomiting Any Symptoms 18 10 Severe Symptoms c 4 1 Diarrhea Any Symptoms 27 15 Severe Symptoms c <1 1 Mucositis Any Symptoms 7 6 Severe Symptoms c <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 Other Adverse Reactions Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm 3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m 2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m 2 . Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound). 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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 Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tach

ABRAXANE(PACLITAXEL)

Indications & Usage

Contraindications

ABRAXANE(PACLITAXEL)

Indications & Usage

Contraindications

Warnings & Precautions

Adverse Reactions

Drug Interactions

Use in Pregnancy & Lactation

Active Ingredients