Paclitaxel

INDICATIONS AND USAGE(1.2, 1.3) 02/2025 DOSAGE AND ADMINISTRATION(2.3, 2.4, 2.5, 2.6) 02/2025 WARNINGS AND PRECAUTIONS(5.1, 5.2, 5.6) 02/2025

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.

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 C …

3 DOSAGE FORMS AND STRENGTHS For injectable suspension, for intravenous use: white to yellow, sterile lyophilized powder or cake containing 100 mg of paclitaxel formulated as albumin-bound particles in single-dose vial for reconstitution. For injectable suspension: white to yellow, sterile, lyophilized powder or cake containing 100 mg of paclitaxel formulated as albumin-bound particles in single-dose vial for reconstitution. ( 3 )

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 )

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Severe Myelosuppression [see Warnings and Precautions ( 5.1 )] Severe Neuropathy [see Warnings and Precautions ( 5.2 )] Sepsis [see Warnings and Precautions ( 5.3 )] Pneumonitis [see Warnings and Precautions ( 5.4 )] Severe Hypersensitivity [see Warnings and Precautions ( 5.5 )] 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 protein bound paclitaxel 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 Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 protein bound paclitaxel 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 protein bound paclitaxel 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 protein bound paclitaxel 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 protein bound paclitaxel are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of protein bound paclitaxel are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in protein bound paclitaxel dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of protein bound paclitaxel 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 protein bound paclitaxel 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 protein bound paclitaxel (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 protein bound paclitaxel are peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of protein bound paclitaxel are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in protein bound paclitaxel dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%). Metastatic Breast Cancer Table 6 shows the frequency of important adverse reaction …

7 DRUG INTERACTIONS Use caution when concomitantly administering Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound) with inhibitors or inducers of either CYP2C8 or CYP3A4. ( 7 ) 7.1 Effect of Other Drugs on Paclitaxel Protein-Bound Particles for Injectable Suspension The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised when administering protein bound paclitaxel concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on its mechanism of action and findings in animals, paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available human data on paclitaxel protein-bound particles for injectable suspension (albumin-bound) use in pregnant women to inform the 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/m 2 basis (see Data ). Advise females of reproductive potential of the potential risk to a fetus. The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies, intravenous administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m 2 (approximately 2% of the daily maximum recommended human dose on a mg/m 2 basis) caused embryo-fetal 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. 8.2 Lactation Risk Summary There are no data on the presence of paclitaxel in human milk, or its effect on the breastfed child or on milk production. In animal studies, paclitaxel and/or its metabolites were excreted into the milk of lactating rats (see Data ). Because of the potential for serious adverse reactions in a breastfed child from paclitaxel protein-bound particles for injectable suspension (albumin-bound), advise lactating women not to breastfeed during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for two weeks after the last dose. Data Animal Data Following intravenous administration of radiolabeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. 8.3 Females and Males of Reproductive Potential Based on animal studies and mechanism of action, paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound). Contraception Females Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for at least six months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound). 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 with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for at least three months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1) ]. Inferti …

12.1 Mechanism of Action Paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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.

11 DESCRIPTION Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is paclitaxel formulated as albumin‐bound nanoparticles with a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. Paclitaxel is a microtubule inhibitor. The chemical name for paclitaxel is 5β,20Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2 R ,3 S )- N -benzoyl-3phenylisoserine. The empirical formula is C 47 H 51 NO 14 and the molecular weight is 853.91. Paclitaxel has the following structural formula: Paclitaxel is a white to off-white powder. It is highly lipophilic, insoluble in water, and melts at approximately 213°C to 216°C. Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is supplied as a white to yellow, sterile, lyophilized powder or cake for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single‐dose 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 formulated as albumin‐bound particles. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is free of solvents. Paclitaxel Structural Formula

10 OVERDOSAGE There is no known antidote for paclitaxel protein-bound particles for injectable suspension (albumin-bound) overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound) is supplied as a white to yellow, sterile, lyophilized powder for reconstitution and is available as follows: NDC 0480-3290-01 100 mg of paclitaxel in a single-dose vial, individually packaged in a carton. Store vial in original carton at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Retain in the original package to protect from light. Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound) is a hazardous drug. Follow applicable special handling and disposal procedures. 1