Paclitaxel

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.

For injectable suspension: white to yellow lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in a single-dose vial for reconstitution. For injectable suspension: white to yellow, lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in single-dose vial for reconstitution. ( 3 )

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 protein bound paclitaxel [see Warnings and Precautions ( 5.5 )] Neutrophil counts of <1,500 cells/mm 3 . ( 4 ) Severe hypersensitivity reactions to protein bound paclitaxel. ( 4 )

Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. ( 5.2 ) Sepsis occurred in patients who received Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound); interrupt Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound) 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 protein bound paclitaxel 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 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/mm 3 [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 protein-bound paclitaxel for Injectable Suspension (albumin-bound) and every-3-week carboplatin after ANC recovers to at least 1,500 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 1,500 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) until fever resolves and ANC ≥1,500, 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 protein bound paclitaxel 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, protein-bound paclitaxel 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. […]

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 reactions in the randomized comparative trial for the patients who received either single-agent protein bound paclitaxel 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 Percent of Patients Protein Bound Paclitaxel 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 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. 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 protein bound paclitaxel. 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 protein bound paclitaxel 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 protein bound paclitaxel occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. […]

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 )] .

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, 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. 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 [see Use in Specific Populations ( 8.1 ) and Nonclinical Toxicology ( 13.1 )]. Infertility Females and Males Based on findings in animals, Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound) may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology ( 13.1 )] .

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pharmacokinetics, safety, and antitumor activity of Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound) 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 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 ( 2.3 ), Warnings and Precautions ( 5.6 ), and Clinical Pharmacology ( 12.3 )] . Reduce Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound) starting dose in patients with moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and ≤ 5 x ULN and AST ≤ 10 x ULN) [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . […]

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.