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.

2.1 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/m2 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/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 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/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 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.

2.6 Dosage Modifications for Adverse Reactions

2.7 Preparation for Intravenous Administration

Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is a hazardous 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, events may include tingling, burning and redness. If Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) contacts mucous membranes, the membranes 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.

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 (i.e., 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.

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 20ºC to 25ºC (68ºF to 77ºF) (see USP Controlled Room Temperature) in the original package. Neither freezing nor refrigeration adversely affects the stability of the product.

5.1 Severe Myelosuppression

Severe myelosuppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of protein bound paclitaxel. 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/mm3 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/mm3 and platelets recover to a level >100,000 cells/mm3. 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/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 (2.6)].

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/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 (2.6)].

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 protein bound paclitaxel 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 protein bound paclitaxel 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 protein bound paclitaxel 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 pregnant woman. In animal reproduction studies, administration of protein bound paclitaxel 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.

Advise females of reproductive potential of the potential risk to a fetus. 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 [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

Based on findings from genetic toxicity and animal reproduction studies, advise male patients 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 [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of protein bound paclitaxel or with paclitaxel injection and may be expected to occur with protein bound paclitaxel. 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.

8.1 Pregnancy

8.2 Lactation

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)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Pharmacokinetics, safety, and antitumor activity of protein bound paclitaxel were assessed in an open-label, dose escalation, dose expansion study (NCT01962103) in 96 pediatric patients aged 1.4 to < 17 years with recurrent or refractory pediatric solid tumors. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. No new safety signals were observed in pediatric patients across these studies.

Paclitaxel protein-bound exposures normalized by dose were higher in 96 pediatric patients (aged 1.4 to < 17 years) as compared to those in adults.

8.5 Geriatric Use

Of the 229 patients in the randomized study who received protein bound paclitaxel for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. This study of protein bound paclitaxel did not include a sufficient number of patients with metastatic breast cancer who were 65 years and older to determine whether they respond differently from younger patients.

A subsequent pooled analysis was conducted in 981 patients receiving protein bound paclitaxel monotherapy for metastatic breast cancer, of which 15% were 65 years of age or older and 2% were 75 years of age or older. A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was found in patients 65 years of age or older.

Of the 514 patients in the randomized study who received protein bound paclitaxel 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 protein bound paclitaxel 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 protein bound paclitaxel 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 Renal Impairment

No adjustment of the starting Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) dose is required for patients with mild to moderate renal impairment (estimated creatinine clearance 30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min).

8.7 Hepatic Impairment

No adjustment of the starting Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) dose is required for patients with mild hepatic impairment (total bilirubin > ULN and ≤ 1.5 x ULN and aspartate aminotransferase [AST] ≤ 10 x ULN). Reduce Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) starting dose in patients with moderate to severe hepatic impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is not recommended for use in patients with total bilirubin > 5 x ULN or AST > 10 x ULN [see Dosage and Administration (2.5), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)]. Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is not recommended for use in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment [see Dosage and Administration (2.5)].

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.

12.3 Pharmacokinetics

The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of protein bound paclitaxel at dose levels of 80 to 375 mg/m2 (0.31 to 1.15 times the maximum approved recommended dosage) were determined in clinical studies. Dose levels of mg/m2 refer to mg of paclitaxel in protein bound paclitaxel. Following intravenous administration of protein bound paclitaxel to patients with solid tumors, 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.

Following protein bound paclitaxel infusion, paclitaxel exhibited linear drug exposure (AUC) across clinical doses ranging from 80 to 300 mg/m2 (0.31 to 1.15 times the maximum approved recommended dosage). The pharmacokinetics of paclitaxel in protein bound paclitaxel were independent of the duration of intravenous administration.

The pharmacokinetic data of 260 mg/m2 protein bound paclitaxel administered over a 30-minute infusion was compared to the pharmacokinetics of 175 mg/m2 paclitaxel injection over a 3-hour infusion. Clearance was larger (43%) and the volume of distribution was higher (53%) for protein bound paclitaxel than for paclitaxel injection. There were no differences in terminal half-lives.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) has not been studied.

Paclitaxel was clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel formulated as albumin-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 dose of 42 mg/m2 also reduced male reproductive organ weights, mating performance, and sperm production. Testicular atrophy/degeneration was observed in single-dose toxicology studies in animals administered paclitaxel formulated as albumin-bound particles at doses lower than the recommended human dose; doses were 54 mg/m2 in rodents and 175 mg/m2 in dogs. Similar testicular degeneration was seen in monkeys administered three weekly doses of 108 mg/m2 paclitaxel formulated as albumin bound particles.

Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats. Paclitaxel caused reduced fertility and reproductive indices, and increased embryo-fetal toxicity.

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 protein bound paclitaxel in metastatic breast cancer.

14.2 Non-Small Cell Lung Cancer

A multicenter, randomized, open-label study was conducted in 1052 chemotherapy naive patients with Stage IIIb/IV non-small cell lung cancer to compare protein bound paclitaxel in combination with carboplatin to paclitaxel injection in combination with carboplatin as first- line treatment in patients with advanced non-small cell lung cancer. Protein bound paclitaxel 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 protein bound paclitaxel/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 protein bound paclitaxel/carboplatin arm had a statistically significantly higher overall response rate compared to patients in the paclitaxel injection/carboplatin arm [(33% versus 25%) see Table 12]. 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 protein bound paclitaxel 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 protein bound paclitaxel/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 protein bound paclitaxel/gemcitabine received protein bound paclitaxel 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 13.

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)

Severe Myelosuppression

• Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their healthcare provider immediately for fever or evidence of infection [see Warnings and Precautions (5.1), (5.3)].

Severe Neuropathy

• Patients must be informed that sensory neuropathy occurs frequently with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and patients should advise their healthcare providers of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)].

Pneumonitis

• Instruct patients to contact their healthcare provider immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

Severe Hypersensitivity

• Instruct patients to contact their healthcare provider for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)].

Common Adverse Reactions

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound).
• Instruct patients to contact their healthcare providers for persistent vomiting, diarrhea, or signs of dehydration [see Adverse Reactions (6)].

Embryo-Fetal Toxicity

• Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) injection can cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Females of reproductive potential should use effective contraception 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) [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1, 8.3)].
• Advise male patients 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 (8.3)].

Lactation

• Advise patients not to breastfeed while taking Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and for two weeks after receiving the last dose [see Use in Specific Populations (8.2)].

Infertility

• Advise males and females of reproductive potential that Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) may impair fertility [see Use in Specific Populations (8.3)].

Manufactured for: HBT Labs, Inc., Brea, CA 92821