Nanoparticle Albumin-Bound (NAB) Paclitaxel

Nanoparticle Albumin-Bound (NAB) Paclitaxel is used for: Metastatic Breast Cancer, Non-Small Cell Lung Cancer, Adenocarcinoma of the Pancreas

Pancreatic Cancer Indicated for metastatic adenocarcinoma of the pancreas as first-line treatment in combination with gemcitabine 125 mg/m² IV infused over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle Administer gemcitabine 1000 mg/m² IV infused over 30-40 minutes immediately after paclitaxel protein bound on Days 1, 8 and 15 of each 28-day cycle Dosage modifications (pancreatic cancer) 1st dose reduction: 100 mg/m² (paclitaxel); 800 mg/m² (gemcitabine) 2nd dose reduction: 75 mg/m² (paclitaxel); 600 mg/m² (gemcitabine) Discontinue if additional dose reduction required Dosage modifications (pancreatic cancer – hematologic toxicities) Cycle Day 1: ANC <1500/mm³ or platelets <100,000/mm³ - Delay doses until recovery Cycle Day 8: ANC 500 to <1000/mm³ or platelets 50,000 to <75,000/mm³ - Reduce 1 dose level Cycle Day 8: ANC <500/mm³ or platelets <50,000/mm³ - Withhold doses Cycle Day 15: ANC 500 to <1000/mm³ or platelets 50,000 to <75,000/mm³ - Reduce 1 dose level from Day 8 Cycle Day 15: ANC <500/mm³ or platelets <50,000/mm³ - Withhold doses Cycle Day 15 (if Day 8 doses withheld): ANC >1000/mm³ or platelets ?75,000/mm³ - Reduce 1 dose level from Day 1 Cycle Day 15 (if Day 8 doses withheld): ANC 500 to <1000/mm³ or platelets 50,000 to <75,000/mm³ - Reduce 2 dose levels from Day 1 Cycle Day 15 (if Day 8 doses withheld): ANC <500/mm³ or platelets <50,000 /mm³ - Withhold doses Dosage modifications (pancreatic cancer – other toxicities) Febrile neutropenia (grade 3 or 4): Withhold until fever resolves and ANC ?1500/mm³ - Resume at next lower dose level Peripheral neuropathy (Grade 3 or 4): Withhold paclitaxel until improves to ? Grade 1, then resume at next lower dose (no need to reduce gemcitabine) 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 Breast Cancer Microtubule inhibitor 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 contraindicated 260 mg/m² IV infused over 30 minutes q3weeks Dosage modfications (breast cancer) Severe neutropenia (<500 cells/mm³) or severe sensory neuropathy: Decrease dose to 220 mg/m² Recurrence of severe neutropenia or severe sensory neuropathy: Decrease dose to 180 mg/m² Grade 3 sensory neuropathy: Hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses Non-Small Cell Lung Cancer Indicated for 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 100 mg/m² IV infused over 30 minutes on Days 1, 8, and 15 of each 21-day cycle, PLUS Carboplatin AUC 6 mg•min/mL IV on Day 1 of each 21 day cycle immediately after paclitaxel protein bound infusion Dosage modifications (NSCLS) Do not administer on Day 1 of a cycle until ANC is at least 1500 cells/mm³ and platelet count is at least 100,000 cells/mm³ Severe neutropenia or thrombocytopenia: Withhold treatment until counts recover to an ANC of 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 Grade 3-4 peripheral neuropathy: Withhold dose; resume paclitaxel protein bound and carboplatin at reduced doses when peripheral neuropathy improves to Grade 1 or completely resolves Permanent dose reductions (NSCLC) Neutropenic fever (ANC <500/mm³ and fever >38°C) or next cycle delayed by >7 days for ANC <1500/mm³ or ANC <500/mm³ for >7 days or severe sensory neuropathy (grade 3 or 4): -First occurrence: reduce dose to 75 mg/m² (and decrease carboplatin dose to 4.5 AUC mg•min/mL) -Second occurrence: reduce dose to 50 mg/m² (and decrease carboplatin dose to 3 AUC mg•min/mL) -Third occurrence: Discontinue treatment Platelets <50,000/mm³: -First occurrence: reduce dose to 75 mg/m² (and decrease carboplatin dose to 4.5 AUC mg•min/mL) -Second occurrence: Discontinue treatment Hepatic Impairment Breast cancer Mild (AST <10 x ULN; bilirubin >ULN to 1.25 X ULN): No dose adjustment required Moderate (AST <10 x ULN; bilirubin 1.26-2 x ULN): Reduce starting dose to 200 mg/m² Severe: (AST <10 x ULN; bilirubin 2.01-5 x ULN): Reduce starting dose to 130 mg/m²; may increase up to 200 mg/m² in subsequent cycles based on individual tolerance AST >10 x ULN or bilirubin >5 X ULN: Do not administer paclitaxel protein bound NSCLC Mild (AST <10 x ULN; bilirubin >ULN to 1.25 X ULN): No dose adjustment required Moderate (AST <10 x ULN; bilirubin 1.26-2 x ULN): Reduce starting dose to 75 mg/m² Severe: (AST <10 x ULN; bilirubin 2.01-5 x ULN): Reduce starting dose to 50 mg/m²; may increase up to 75 mg/m2 in subsequent cycles based on individual tolerance AST >10 x ULN or bilirubin >5 X ULN: Do not administer paclitaxel protein bound Pancreatic cancer Mild (AST <10 x ULN; bilirubin >ULN to 1.25 X ULN): No dose adjustment required Moderate-to-severe (AST <10 x ULN; bilirubin 1.26-5 x ULN): Not recommended AST >10 x ULN or bilirubin >5 X ULN: Do not administer paclitaxel protein bound

IV Preparation Aseptically reconstitute vial by slowly injecting 20 mL 0.9% NaCl over 1 min by allowing fluid to fall down inside wall of tube (this will avoid foaming) Swirl or invert to mix (do not shake) Resulting reconstituted suspension should be milky and homogenous without visible particulates Resulting solution is 5 mg/mL If foaming occurs stand solution for at least 15 min until foaming subsides Inject the appropriate amount of reconstituted suspension into an empty, sterile IV bag (PVC containers, PVC or non-PVC type IV bag) The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer paclitaxel protein bound infusions The use of an in-line filter is not recommended IV Administration Infuse IV over 30 min Do not use in-line filter

Neutrophils <1500 cells/mm³ Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions reported; do not rechallenge in patients who experience severe hypersensitivity

Causes myelosuppression; monitor CBC and withhold and/or reduce the dose as needed (see Dosage Modifications) Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption (see Dosage Modifications) Sepsis occurred in 5% of patients with or without neutropenia; biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis Pneumonitis, including fatalities, occurred in 4% of patients Exposure and toxicity increased with hepatic impairment; particularly from myelosuppression; closely monitor for development of profound myelosuppression; monitor AST and bilirubin and adjust dose if needed (see Dosage Modifications) Contains albumin derived from human blood which has a theoretical risk of viral transmission Fetal harm may occur when administered to a pregnant woman; women of childbearing potential should avoid becoming pregnant Men should not father a child while taking paclitaxel CYP3A4 and CYP2C8 substrate; inducers or inhibitors of these isoenzymes may alter metabolism; if coadministered, monitor closely

Pregnancy Based on its mechanism of action and findings in animals, therapy can cause fetal harm when administered to a pregnant woman; there are no available human data to inform drug-associated risk In animal reproduction studies, administration of paclitaxel formulated as albumin-bound particles to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at doses approximately 2% of the daily maximum recommended human dose on a mg/m² basis; advise females of reproductive potential of potential risk to fetus Females of reproductive potential should have a pregnancy test prior to starting treatment Contraception Females: Therapy can cause fetal harm when administered to a pregnant woman; advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment and for at least six months after last dose Males: Based on findings in genetic toxicity and animal reproduction studies, advise males with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment and for at least three months after last dose Infertility Based on findings in animals, therapy may impair fertility in females and males of reproductive potential Lactation There are no data on presence of drug in human milk, or effect on breastfed child or on milk production; in animal studies, paclitaxel and/or its metabolites were excreted into milk of lactating rats; because of potential for serious adverse reactions in a breastfed child from therapy, advise lactating women not to breastfeed during treatment and for two weeks after last dose

Side effects of Nanoparticle Albumin-Bound (NAB) Paclitaxel : >10% Alopecia (90%) Neutropenia (<2 x 10^9/L) (80%) Sensory neuropathy, any (71%) Abnormal EKG, all patients (60%) Asthenia (47%) Myalgia/arthralgia (44%) AST increased (39%) Alkaline phosphatase increased (36%) Abnormal EKG, patients normal at baseline (35%) Anemia (<11 g/dL) (33%) Nausea (30%) Diarrhea (27%) Infections (24%) Vomiting (18%) Dyspnea (12%) Neutropenia (grade 3-4) NSCLC (47%) Pancreatic cancer (38%) Metastatic breast cancer (34%) 1-10% Sensory neuropathy, severe (10%) Edema (10%) Neutropenia (<0.5 x 10^9/L) (9%) Cough (7%) Mucositis (7%) Bilirubin increased (7%) Hypotension, during infusion (5%) Hypersensitivity reactions (4%) Thrombocytopenia (2%) Febrile neutropenia (2%) Bleeding (2%) Anemia (<8 g/dL) (1%)

Microtubular inhibitor (albumin-conjugated formulation); natural taxane, prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition