Paclitaxel

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.

DOSAGE & ADMINISTRATION Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. All patients should be premedicated prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before paclitaxel. For patients with carcinoma of the ovary the following regimen is recommended (see CLINICAL STUDIES, Ovarian Carcinoma ): For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS, Disease-Specific Adverse Event Experiences) . Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2 ;or Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2 . In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear (See CLINICAL STUDIES, Ovarian Carcinoma ). The recommended regimen is paclitaxel 135 mg/m 2 or 175 mg/m 2 administered intravenously over 3 hours every 3 weeks. For patients with carcinoma of the breast , the following is recommended (see CLINICAL STUDIES, Breast Carcinoma ): For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m 2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES, Breast Carcinoma ). After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m 2 administered intravenously over 3 hours every 3 weeks has been shown to be effective. For patients with non-small cell lung carcinoma , the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin, 75 mg/m 2 . For patients with AIDS-related Kaposi’s sarcoma , paclitaxel administered at a dose of 135 mg/m 2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m 2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m 2 /week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma ), the former schedule (135 mg/m 2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m 2 every 2 weeks). Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients: Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm 3 ; Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm 3 for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinicallyindicated. For the therapy of patients with solid tumors (ovary, breast and NSCLC), courses of paclitaxel should not be repeated until the neutrophil count is at least 1,500 cells/mm 3 and the platelet count is at least 100,000 cells/mm 3 . Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm 3 . Patients who experience severe neutropenia (neutrophil <500 cells/mm 3 for a week or longer) or severe peripheral neuropathy during paclitaxel therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose. Preparation and Administration Precautions Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling paclitaxel. The use of gloves is recommended. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Hepatic Impairment Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Hepatic ). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression. TABLE 17. RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT BASED ON CLINICAL TRIAL DATA a Degree of Hepatic Impairment Recommended Paclitaxel Dose c Transaminase Bilirubin Levels b Levels 24-Hour Infusion <2 x ULN and ≤1.5 mg/dL 135 mg/m 2 2 to <10 x ULN and ≤1.5 mg/dL 100 mg/m 2 <10 x ULN and 1.6 to 7.5 mg/dL 50 mg/m 2 ≥10 x ULN or >7.5 mg/dL Not recommended 3-Hour Infusion <10 x ULN and ≤1.25 x ULN 175 mg/m 2 <10 x ULN and 1.26 to 2 x ULN 135 mg/m 2 <10 x ULN and 2.01 to 5 x ULN 90 mg/m 2 ≥10 x ULN or >5.0 x ULN Not recommended a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m 2 over 24 hours or 175 mg/m 2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma). b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design. c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance. Preparation and Administration Precautions Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. (See PRECAUTIONS, Injection Site Reaction ). Preparation for Intravenous Administration Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride In

WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. (5.2) Sepsis occurred in patients with or without neutropenia who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine; interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine until sepsis resolves, and if neutropenia, until neutrophils are at least 1500 cells/mm3, then resume treatment at reduced dose levels. (5.3) Pneumonitis occurred with the use of paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound). 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound) and every-3-week carboplatin after ANC recovers to at least 1500 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 1500 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) and gemcitabine 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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 paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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

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 )

Drug Interactions: In a Phase I trial using escalating doses of paclitaxel (110 to 200 mg/m 2 ) and cisplatin (50 or 75 mg/m 2 ) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e., paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin. The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. (See CLINICAL PHARMACOLOGY section.) Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. (See CLINICAL PHARMACOLOGY . ) Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials. Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination. Hematology: Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm 3 . In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not be retreated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3 . In the case of severe neutropenia (<500 cells/mm 3 for seven days or more) during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended. For patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm 3 . Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to products containing Polyoxyl 35 Castor Oil, NF (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H 2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel. Cardiovascular: Hypotension, bradycardia, and hypertension have been observed during administration of Paclitaxel Injection, USP, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (See WARNINGS section.) When paclitaxel is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. (See ADVERSE REACTIONS . ) Nervous System: Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel. Paclitaxel contains Dehydrated Alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol. (See PRECAUTIONS: Pediatric Use section.) Hepatic: There is limited evidence that the myelotoxicity of Paclitaxel may be exacerbated in patients with serum total bilirubin >2 times ULN (See CLINICAL PHARMACOLOGY ). Extreme caution should be exercised when administering Paclitaxel to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION , TABLE 17 . Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., “recall”, has been reported. More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days. A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

ADVERSE REACTIONS Pooled Analysis of Adverse Event Experiences from Single-Agent Studies Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent Paclitaxel Injection. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m 2 administered over 24 hours (in 4 of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m 2 ) and 2 schedules (3 or 24 hours) of paclitaxel. Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m 2 ) administered over 3 hours in a controlled study. TABLE 10. SUMMARY a OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT PACLITAXEL Percent of Patients (n=812) Bone Marrow - Neutropenia <2,000/mm 3 <500/mm 3 - Leukopenia <4,000/mm 3 <1,000/mm 3 - Thrombocytopenia <100,000/mm 3 <50,000/mm 3 - Anemia <11 g/dL <8 g/dL - Infections - Bleeding - Red Cell Transfusions - Platelet Transfusions 90 52 90 17 20 7 78 16 30 14 25 2 Hypersensitivity Reaction b - All - Severe † 41 2 Cardiovascular - Vital Sign Changes c - Bradycardia (n=537) - Hypotension (n=532) - Significant Cardiovascular Events 3 12 1 Abnormal ECG - All Pts - Pts with normal baseline (n=559) 23 14 Peripheral Neuropathy - Any symptoms - Severe symptoms † 60 3 Myalgia/Arthralgia - Any symptoms - Severe symptoms † 60 8 Gastrointestinal - Nausea and vomiting - Diarrhea - Mucositis 52 38 31 Alopecia 87 Hepatic (Pts with normal baseline and on study data) - Bilirubin elevations (n=765) - Alkaline phosphatase elevations (n=575) - AST (SGOT) elevations (n=591) 7 22 19 Injection Site Reaction 13 a Based on worst course analysis. b All patients received premedication. c During the first 3 hours of infusion † Severe events are defined as at least Grade III toxicity. None of the observed toxicities were clearly influenced by age. Disease-Specific Adverse Event Experiences First-Line Ovary in Combination For the 1,084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG- 111 study and up to 9 courses for the Intergroup study). TABLE 11. FREQUENCY a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES Percent of Patients Intergroup GOG-111 T175/3 b c75 c (n=339) C750 c c75 c (n=336) T135/24 b c75 c (n=196) C750 c c75 c (n=213) Bone Marrow - Neutropenia <2,000/mm 3 91 d 95 d 96 92 <500/mm 3 33 d 43 d 81 d 58 d - Thrombocytopenia <100,000/mm 3e 21 d 33 d 26 30 <50,000/mm 3 3 d 7 d 10 9 - Anemia <11 g/dL f 96 97 88 86 <8 g/dL 3 d 8 d 13 9 - Infections 25 27 21 15 - Febrile Neutropenia 4 7 15 d 4 d Hypersensitivity Reaction - All 11 d 6 d 8 d,g 1 d,g - Severe † 1 1 3 d,g - d,g Neurotoxicity h - Any symptoms 87 d 52 d 25 20 - Severe symptoms † 21 d 2 d 3 d - d Nausea and Vomiting - Any symptoms 88 93 65 69 - Severe symptoms † 18 24 10 11 Myalgia/Arthralgia - Any symptoms 60 d 27 d 9 d 2 d - Severe symptoms † 6 d 1 d 1 - Diarrhea - Any symptoms 37 d 29 d 16 d 8 d - Severe symptoms † 2 3 4 1 Athenia - Any symptoms NC NC 17 d 10 d - Severe symptoms † NC NC 1 1 Alopecia - Any symptoms 96 d 89 d 55 d 37 d - Severe symptoms † 51 d 21 d 6 8 a Based on worst course analysis. b Paclitaxel (T) dose in mg/m 2 /infusion duration in hours. c Cyclophosphamide (C) or cisplatin (c) dose in mg/m 2 . d p<0.05 by Fisher exact test. e <130,000/mm 3 in the Intergroup study. f <12 g/dL in the Intergroup study. g All patients received premedication. h In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxicity was collected as either neuromotor or neurosensory symptoms. † Severe events are defined as at least Grade III toxicity. NC Not Collected. Second-Line Ovary: For the 403 patients who received single-agent paclitaxel injection in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events. TABLE 12. FREQUENCY a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY Percent of Patients 175/3 b (n=95) 175/24 b (n=105) 135/3 b (n=98) 135/24 b (n=105) Bone Marrow - Neutropenia <2,000/mm 3 <500/mm 3 - Thrombocytopenia <100,000/mm 3 <50,000/mm 3 - Anemia <11 g/dL <8 g/dL - Infections 78 27 4 1 84 11 26 98 75 18 7 90 12 29 78 14 8 2 68 6 20 98 67 6 1 88 10 18 Hypersensitivity Reaction c - All - Severe † 41 2 45 0 38 2 45 1 Peripheral Neuropathy - Any symptoms - Severe symptoms † 63 1 60 2 55 0 42 0 Mucositis - Any symptoms - Severe symptoms † 17 0 35 3 21 0 25 2 a Based on worst course analysis. b Paclitaxel dose in mg/m 2 /infusion duration in hours. c All patients received premedication. † Severe events are defined as at least Grade III toxicity. Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development of severe hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose-related, but schedule did not appear to affect the incidence. Adjuvant Breast For the Phase 3 adjuvant breast carcinoma study, the following table shows the incidence of important severe adverse events for the 3121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population) who, per the study protocol, were monitored more intensively than other patients. TABLE 13. FREQUENCY a OF IMPORTANT SEVERE b ADVERSE EVENTS IN THE PHASE 3 ADJUVANT BREAST CARCINOMA STUDY Percent of Patients Early Population Total Population AC c (n=166) AC c followed by T d (n=159) AC c (n=1551) AC c followed by T d (n=1570) Bone Marrow e - Neutropenia <500/mm 3 79 76 48 50 - Thrombocytopenia <50,000/mm 3 27 25 11 11 - Anemia <8 g/dL 17 21 8 8 - Infections 6 14 5 6 - Fever Without Infection – 3 <1 1 Hypersensitivity Reaction f 1 4 1 2 Cardiovascular Events 1 2 1 2 Neuromotor Toxicity 1 1 <1 1 Neurosensory Toxicity – 3 <1 3 Myalgia/Arthralgia – 2 <1 2 Nausea/Vomiting 13 18 8 9 Mucositis 13 4 6 5 a Based on worst course analysis. b Severe events are defined as at least Grade III toxicity. c Patients received 600 mg/m 2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m 2 , 75 mg/m 2 , or 90 mg/m 2 (with prophylactic G-CSF support and ciprofloxacin), every 3 weeks for 4 courses. d Paclitaxel (T) following 4 courses of AC at a dose of 175 mg/m 2 /3 hours every 3 weeks for 4 courses. e The incidence of febrile neutropenia was not reported in this study. f All patients were to receive premedication. The incidence of an adverse event for the total population likely represents an underestimation of the actual incidence given that safety data were collected differently based on enrollment cohort. However, since safety data were collected consistently across regimens, the safety of the sequential addition of paclitaxel following AC therapy may be compared with AC therapy alone. Compared to patients who received AC alone, patients who received AC followed by paclitaxel experienced more Grade III/IV neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu-like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%). During the additional 4 courses of treatment with paclitaxel, 2 deaths (0.1%) were attributed to treatment. During paclitaxel treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%

CLINICAL PHARMACOLOGY Paclitaxel is a novel antimicrotubule agent 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. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Following intravenous administration of paclitaxel, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment. Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of paclitaxel at dose levels of 135 and 175 mg/m 2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table: Table 1. Summary of Pharmacokinetic Parameters – Mean Values C max = Maximum plasma concentration AUC (0-∞) = Area under the plasma concentration-time curve from time 0 to infinity CL T = Total body clearance Dose (mg/m 2 ) Infusion Duration (h) N (patients) C max (ng/mL) AUC (0-∞) (ng•h/mL) T-HALF (h) CL T (L/h/m 2 ) 135 24 2 195 6300 52.7 21.7 175 24 4 365 7993 15.7 23.8 135 3 7 2170 7952 13.1 17.7 175 3 5 3650 15007 20.2 12.2 It appeared that with the 24-hour infusion of paclitaxel, a 30% increase in dose (135 mg/m 2 versus 175 mg/m 2 ) increased the C max by 87%, whereas the AUC (0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the C max and AUC (0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of paclitaxel, ranged from 227 to 688 L/m 2 indicating extensive extravascular distribution and/or tissue binding of paclitaxel. The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15 to 135 mg/m 2 given by 1-hour infusions (n=15), 30 to 275 mg/m 2 given by 6-hour infusions (n=36), and 200 to 275 mg/m 2 given by 24-hour infusions (n=54) in Phase 1 & 2 studies. Values for CL T and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of paclitaxel in patients with AIDS-related Kaposi's sarcoma have not been studied. In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 mcg/mL, indicate that between 89% to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. After intravenous administration of 15 to 275 mg/m 2 doses of Paclitaxel Injection, USP as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In five patients administered a 225 or 250 mg/m 2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3'- p -hydroxypaclitaxel and 6α, 3'- p -dihydroxy-paclitaxel, by CYP3A4. In vitro , the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro . The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. (See PRECAUTIONS: Drug Interactions section.) The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN) administered 175 mg/m 2 was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m 2 ), but no observed increase in plasma exposure. (See PRECAUTIONS: Hepatic and DOSAGE AND ADMINISTRATION . ) The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated. Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.