Paclitaxel

2 DOSAGE AND ADMINISTRATION Do not substitute paclitaxel protein-bound particles for injectable suspension (albumin-bound) for other paclitaxel products. ( 2.1 ) Extravasation : Closely monitor the infusion site for extravasation and infiltration. ( 2.1 ) Metastatic Breast Cancer (MBC) : Recommended dosage of paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 260 mg/m 2 intravenously over 30 minutes every 3 weeks. ( 2. 2 ) Non-Small Cell Lung Cancer (NSCLC) : Recommended dosage of paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 100 mg/m 2 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound). ( 2.2 ) Adenocarcinoma of the Pancreas : Recommended dosage of paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 125 mg/m 2 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound). ( 2.4 ) Use in Patients with Hepatic Impairment: Paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 ) Dose Reductions for Adverse Reactions : Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicities. ( 2.6 ) 2.1 Important Administration Instructions DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound). Do not re-challenge patients who experience a severe hypersensitivity reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Contraindications (4) and Warnings and Precautions (5.5) ] . 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 260 mg/m 2 administered intravenously over 30 minutes every 3 weeks. 2.3 Recommended Dosage for Non-Small Cell Lung Cancer The recommended dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 100 mg/m 2 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Clinical Studies (14.2) ] . 2.4 Recommended Dosage for Adenocarcinoma of the Pancreas The recommended dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 125 mg/m 2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Administer gemcitabine immediately after paclitaxel protein-bound particles for injectable suspension (albumin-bound) on Days 1, 8, and 15 of each 28-day cycle [see Clinical Studies (14.3) ]. 2.5 Dosage Modifications for Hepatic Impairment For patients with moderate or severe hepatic impairment, reduce the starting dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 260 mg/m 2 for patients with metastatic breast cancer or 100 mg/m 2 for patients with non-small cell lung cancer in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer. AST Levels Bilirubin Levels Paclitaxel protein-bound particles for injectable suspension (albumin-bound) Dose a MBC NSCLC c Adenocarcinoma of Pancreas c Moderate 1.5 to ≤ 3 x ULN 200 mg/m 2 b 80 mg/m 2 b not recommended Severe 3 to ≤ 5 x ULN 200 mg/m 2 b 80 mg/m 2 b not recommended > 10 x ULN OR > 5 x ULN not recommended not recommended not recommended 2.6 Dosage Modifications for Adverse Reactions Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophils less than 500 cells/mm 3 for a week or longer) or severe sensory neuropathy during paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy should have dosage reduced to 220 mg/m 2 for subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound). For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m 2 . For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Contraindications (4) , Warnings and Precautions (5.1 , 5.2) and Adverse Reactions (6.1) ]. Non-Small Cell Lung Cancer Do not administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm 3 and platelet count is at least 100,000 cells/mm 3 [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/mm 3 and platelet count of at least 100,000 cells/mm 3 on Day 1 or to an absolute neutrophil count 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. Upon resumption of dosing, permanently reduce paclitaxel protein-bound particles for injectable suspension (albumin-bound) and carboplatin doses as outlined in Table 2 . Withhold paclitaxel protein-bound particles for injectable suspension (albumin-bound) for Grade 3-4 peripheral neuropathy. Resume paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 Paclitaxel protein-bound particles for injectable suspension (albumin-bound) Dose (mg/m 2 ) Every 3-Week Carboplatin Dose (AUC mg•min/mL) Neutropenic Fever (ANC less than 500/mm 3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm 3 OR ANC less than 500/mm 3 for more than 7 days First 75 4.5 Second 50 3 Third Discontinue Treatment Platelet count less than 50,000/mm 3 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 4 and 5 , are provided in Table 3 . Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level Paclitaxel protein-bound particles for injectable suspension (albumin-bound) (mg/m 2 ) Gemcitabine (mg/m 2 ) Full dose 125 1000 1 st dose reduction 100 800 2 nd dose 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/mm 3 ) Platelet count (cells/mm 3 ) Paclitaxel protein-bound particles for injectable suspension (albumin-bound) / 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 Paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 2.7 Preparation for Intravenous Administration Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 The use of gloves is recommended. If paclitaxel protein-bound particles for injectable suspension (albumin-bound) (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel protein-bound particles for injectable suspension (albumin-bound), events may include tingling, burning, and redness. If paclitaxel protein-bound particles for injectable suspension (albumin-bound) contacts mucous membranes, the menbranes should be flushed thoroughly with water. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is supplied as a sterile lyophilized powder for reconstitution before use. Read the entire preparation instructions prior to reconstitution. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient and slowly withdraw the dosing volume of the reconstituted suspension from the vial(s) into a syringe: Dosing volume (mL)=Total dose (mg)/5 (mg/mL). Inject the appropriate amount of reconstituted paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound) infusions. The use of medical devices containing silicone oil as a lubricant (ie, syringes and intravenous bags) to reconstitute and administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) may result in the formation of proteinaceous strands. Visually inspect the reconstituted paclitaxel protein-bound particles for injectable suspension (albumin-bound) suspension in the intravenous bag prior to administration. Discard the reconstituted suspension if proteinaceous strands, particulate matter, or discoloration are observed. image description 2.8 Stability Unopened vials of paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 24 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion. Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion when prepared as recommended in an infusion bag should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a maximum of 24 hours. The total combined refrigerated storage time of reconstituted paclitaxel protein-bound particles for injectable suspension (albumin-bound) in the vial and in the infusion bag is 24 hours. This may be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of 4 hours. Discard any unused portion.

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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.