BEIZRAY - docetaxel

Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. Docetaxel exposure-response relationships and the time course of pharmacodynamic response are unknown. Absorption The pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20 mg/m 2 2 2 2 Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with initial rapid distribution phase and the late (terminal) phase. Distribution Mean steady state volume of distribution was 113 L. Docetaxel is approximately 94% protein bound in vitro in vitro Elimination With extended plasma sampling up to 8 to 22 days post infusion, the estimated mean total body clearance was 18 L/h/m 2 Metabolism Docetaxel is metabolized by the CYP3A4 isoenzyme in vitro [see Drug Interactions ( 7 Excretion In three cancer patients urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively, within 7 days. About 80% of the radioactivity recovered in feces was excreted during the first 48 hours as 1 major and 3 minor metabolites with less than 8% as unchanged drug. Specific Populations Effect of Age: A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m 2 Effect of Gender: The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel. Hepatic Impairment: The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1. 5 times ULN concomitant with alkaline phosphatase >2. 5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with docetaxel. Patients with severe hepatic impairment have not been studied [see Warnings and Precautions ( 5. 6 Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m 2 2 2 Drug Interaction Studies Effect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m 2 2 [see Dosage and Administration ( 2. 7 7 Effect of combination therapies Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone. Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone. Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug. Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with metastatic castration-resistant prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone. Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between docetaxel (75 mg/m 2 2 2.

BEIZRAY is a microtubule inhibitor indicated for: Breast Cancer (BC) 1. 1 Non-small Cell Lung Cancer (NSCLC) 1. 2 Castration-Resistant Prostate Cancer (CRPC) 1. 3 Gastric Adenocarcinoma (GC) 1. 4 Squamous Cell Carcinoma of the Head and Neck (SCCHN) 1. 5 BEIZRAY is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. BEIZRAY in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. BEIZRAY as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. BEIZRAY in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition. BEIZRAY in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer. BEIZRAY in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease. BEIZRAY in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Do not substitute BEIZRAY for other docetaxel products. 1 Administer in a facility equipped to manage possible complications (e. , anaphylaxis). Administer intravenously (IV) over 1 hour every 3 weeks. BC locally advanced or metastatic: 60 mg/m 2 2 2. 2 BC adjuvant: 75 mg/m 2 2 2 2. 2 NSCLC: after platinum therapy failure: 75 mg/m 2 2. 3 NSCLC: chemotherapy naive: 75 mg/m 2 2 2. 3 CRPC: 75 mg/m 2 2. 4 GC: 75 mg/m 2 2 2 2. 5 SCCHN: 75 mg/ m 2 2 2 2. 6 SCCHN: 75 mg/m 2 2 2 2. 6 For all patients: Premedicate with oral corticosteroids ( 2. 7 Adjust dose as needed ( 2. 8 Do not For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration ( 2. 8 Administer in a facility equipped to manage possible complications (e. anaphylaxis). See additional premedication recommendations for the indicated populations [ see Dosage and Administration ( 2. 7 For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dosage of BEIZRAY is 60 mg/m 2 2 For the adjuvant treatment of operable node-positive breast cancer, the recommended BEIZRAY dosage is 75 mg/m 2 2 2 [see Dosage and Administration ( 2. 7 For treatment after failure of prior platinum-based chemotherapy, the recommended dosage of BEIZRAY monotherapy is 75 mg/m 2 In patients previously treated with chemotherapy, a dosage of 100 mg/m 2 [see Dosage and Administration ( 2. 8 5 14 For chemotherapy-naive patients, the recommended dosage of BEIZRAY is 75 mg/m 2 2 [see Dosage and Administration ( 2. 7 For metastatic castration-resistant prostate cancer, the recommended dosage of BEIZRAY is 75 mg/m 2 [see Dosage and Administration ( 2. 7 For gastric adenocarcinoma, the recommended dosage of BEIZRAY is 75 mg/m 2 2 2 Repeat treatment every three weeks. Must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration ( 2. 7 Must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the BEIZRAY containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics. Induction Chemotherapy Followed by Radiotherapy (TAX323) For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of BEIZRAY is 75 mg/m 2 2 2 [see Dosage and Administration ( 2. 7 Induction Chemotherapy Followed by Chemoradiotherapy (TAX324) For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of BEIZRAY is 75 mg/m 2 2 2 [see Dosage and Administration ( 2. 7 All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e. , 8 mg twice daily) for 3 days starting 1 day prior to BEIZRAY administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning 5. 5 For metastatic castration-resistant prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg at 12 hours, 3 hours, and 1 hour before the BEIZRAY infusion [see Warnings and Precautions ( 5. 5 Breast Cancer Patients who are dosed initially at 100 mg/m 2 3 2 2 2 2 2 3 Combination Therapy with BEIZRAY in the Adjuvant Treatment of Breast Cancer BEIZRAY in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is >=1,500 cells/mm 3 2 2 2 2 2 Non-small Cell Lung Cancer Monotherapy with BEIZRAY for NSCLC treatment after failure of prior platinum-based chemotherapy Patients who are dosed initially at 75 mg/m 2 3 2 Combination therapy with BEIZRAY for chemotherapy-naive NSCLC For patients who are dosed initially at BEIZRAY 75 mg/m 2 3 2 2 Prostate Cancer Combination therapy with BEIZRAY for metastatic castration-resistant prostate cancer BEIZRAY should be administered when the neutrophil count is >=1,500 cells/mm 3 3 2 2 2 Gastric or Head and Neck Cancer BEIZRAY in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer Patients treated with BEIZRAY in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the BEIZRAY dose should be reduced from 75 mg/m 2 2 2 2 2 2 3 [see Contraindications ( 4 3 [see Warnings and Precautions ( 5. 3 Recommended dose modifications for toxicities in patients treated with BEIZRAY in combination with cisplatin and fluorouracil are shown in Table 1. Table 1: Recommended Dose Modifications for Toxicities in Patients Treated with BEIZRAY in Combination with Cisplatin and Fluorouracil Toxicity Dosage adjustment Diarrhea grade 3 First episode: reduce fluorouracil dose by 20%. Diarrhea grade 4 First episode: reduce BEIZRAY and fluorouracil doses by 20%. Stomatitis/mucositis grade 3 First episode: reduce fluorouracil dose by 20%. Stomatitis/mucositis grade 4 First episode: stop fluorouracil only, at all subsequent cycles. Liver dysfunction: In case of AST/ALT >2. 5 to <=5 × ULN and AP <=2. 5 × ULN, or AST/ALT >1. 5 to <=5 × ULN and AP >2. 5 to <=5 × ULN, BEIZRAY should be reduced by 20%. In case of AST/ALT >5 × ULN and/or AP >5 × ULN BEIZRAY should be stopped. The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below. Cisplatin dose modifications and delays Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCI-CTCAE grade: Grade 2: Reduce cisplatin dose by 20%. Grade 3: Discontinue treatment. Ototoxicity: In the case of grade 3 toxicity, discontinue treatment. Nephrotoxicity: In the event of a rise in serum creatinine >=grade 2 (>1. 5 × normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2). For other cisplatin dosage adjustments, also refer to the manufacturers' prescribing information. Table 2: Dose Reductions for Evaluation of Creatinine Clearance CrCl = Creatinine clearance Creatinine clearance result before next cycle Cisplatin dose next cycle CrCl >=60 mL/min Full dose of cisplatin was given. CrCl was to be repeated CrCl between 40 and 59 mL/min Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl <40 mL/min Dose of cisplatin was omitted in that treatment cycle only. Fluorouracil dose modifications and treatment delays For diarrhea and stomatitis, see Table 1. In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%. For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade <=1 and then recommenced, if medically appropriate. For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information. Combination Therapy with Strong CYP3A4 Inhibitors Avoid using concomitant strong CYP3A4 inhibitors (e. , ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require coadministration of a strong CYP3A4 inhibitor [see Drug Interactions ( 7 12. 3 BEIZRAY is a hazardous anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing BEIZRAY solutions. The use of gloves is recommended [see How Supplied/Storage and Handling ( 16. 3 If BEIZRAY or final infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If BEIZRAY or final infusion solution should come into contact with mucosa, immediately and thoroughly wash with water. The final BEIZRAY infusion solution should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin). Please follow the preparation instructions provided below. BEIZRAY is available in two packaging configurations: Co-packaged kit containing BEIZRAY vial(s) and IV Solution Stabilizer (25% Albumin Human USP) Carton containing one BEIZRAY vial only Preparation Read this entire section carefully before mixing and diluting. Inject 25% Albumin Human USP (IV Solution Stabilizer) directly into the 0. 9% Sodium Chloride Injection bag. Do not use 25% Albumin Human USP (IV Solution Stabilizer) to dilute BEIZRAY. To prevent precipitation, BEIZRAY needs to be diluted with a prepared infusion bag containing Albumin Human USP and 0. 9% Sodium Chloride Injection to ensure a final concentration between 0. 14 mg/mL and 0. Follow the preparation instructions provided below. Step 1 en dash Calculate the required amount of BEIZRAY Calculate the required amount of BEIZRAY using the following formula: Required amount of BEIZRAY (mL) = prescribed BEIZRAY dose (mg/m 2 2 Step 2 en dash Determine the required amount of 0. 9% Sodium Chloride Injection Based on the calculated amount of BEIZRAY from Step 1, determine the required amount of 0. 9% Sodium Chloride Injection in Table 3. Table 3: The amount required for 0. 9% Sodium Chloride Injection based on calculated amount of BEIZRAY in mL Calculated amount of BEIZRAY Size of 0. 9% Sodium Chloride Injection Infusion Bag BEIZRAY <= 8. 8 mL 500 mL BEIZRAY > 8. 8 mL 1,000 mL Step 3 en dash Calculate the required amount of 25% Albumin Human USP (IV Solution Stabilizer) Calculate the required amount of 25% Albumin Human USP (IV Solution Stabilizer) using the following formula: Required amount of 25% Albumin Human USP (IV Solution Stabilizer) (mL) = Required amount of BEIZRAY (mL) × 6 Step 4 en dash Add 25% Albumin Human USP (IV Solution Stabilizer) to the infusion bag Withdraw the calculated amount of 25% Albumin Human USP (IV Solution Stabilizer) from the vial and inject into a 0. Thoroughly mix the diluted solution by gently inverting the bag for at least 5 times. Do not shake. This solution should be used immediately after preparation. Step 5 en dash Add BEIZRAY to the final infusion solution Aseptically withdraw the calculated amount of BEIZRAY with a calibrated syringe and inject via a single injection into the infusion bag containing the initial diluted solution with 25% Albumin Human USP (IV Solution Stabilizer) to produce a final concentration between 0. After injection, remove the syringe and immediately thoroughly mix the final infusion solution by gently inverting the bag for at least 10 times. Discard any unused portion of BEIZRAY vial(s) and 25% Albumin Human USP (IV Solution Stabilizer) vial(s). Administration Prior to administration, visually inspect BEIZRAY final infusion solution for particulate matter or discoloration whenever the solution and container permit. Discard the diluted BEIZRAY infusion solution if the solution is not clear, discolored or appears to have precipitation, it should be discarded. BEIZRAY infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must be discarded. The BEIZRAY infusion solution should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25℃) and lighting conditions. BEIZRAY final infusion solution should be used immediately. However, if stored between 2°C and 8°C (36°F and 46°F), the final infusion solution is stable for 24 hours. If stored at 25°C (77°F), the final infusion solution is stable for 4 hours. BEIZRAY final infusion solution (in 0. 9% Sodium Chloride Injection) should be used within 4 hours (including the 1 hour intravenous administration).

=2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization. **Related to treatment. ***Includes superficial and deep vein thrombosis and pulmonary embolism TAX323 (n=355) TAX324 (n=494) Docetaxel arm (n=174) Comparator arm (n=181) Docetaxel arm (n=251) Comparator arm (n=243) Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Neutropenia 93 76 87 53 95 84 84 56 Anemia 89 9 88 14 90 12 86 10 Thrombocytopenia 24 5 47 18 28 4 31 11 Infection 27 9 26 8 23 6 28 5 Febrile neutropenia* 5 N/A 2 N/A 12 N/A 7 N/A Neutropenic infection 14 N/A 8 N/A 12 N/A 8 N/A Cancer pain 21 5 16 3 17 9 20 11 Lethargy 41 3 38 3 61 5 56 10 Fever in the absence of infection 32 1 37 0 30 4 28 3 Myalgia 10 1 7 0 7 0 7 2 Weight loss 21 1 27 1 14 2 14 2 Allergy 6 0 3 0 2 0 0 0 Fluid retention** 20 0 14 1 13 1 7 2 Edema only 13 0 7 0 12 1 6 1 Weight gain only 6 0 6 0 0 0 1 0 Dizziness 2 0 5 1 16 4 15 2 Neurosensory 18 1 11 1 14 1 14 0 Altered hearing 6 0 10 3 13 1 19 3 Neuromotor 2 1 4 1 9 0 10 2 Alopecia 81 11 43 0 68 4 44 1 Rash/itch 12 0 6 0 20 0 16 1 Dry skin 6 0 2 0 5 0 3 0 Desquamation 4 1 6 0 2 0 5 0 Nausea 47 1 51 7 77 14 80 14 Stomatitis 43 4 47 11 66 21 68 27 Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Vomiting 26 1 39 5 56 8 63 10 Diarrhea 33 3 24 4 48 7 40 3 Constipation 17 1 16 1 27 1 38 1 Anorexia 16 1 25 3 40 12 34 12 Esophagitis/dysphagia/ Odynophagia 13 1 18 3 25 13 26 10 Taste, sense of smell altered 10 0 5 0 20 0 17 1 Gastrointestinal pain/cramping 8 1 9 1 15 5 10 2 Heartburn 6 0 6 0 13 2 13 1 Gastrointestinal bleeding 4 2 0 0 5 1 2 1 Cardiac dysrhythmia 2 2 2 1 6 3 5 3 Venous*** 3 2 6 2 4 2 5 4 Ischemia myocardial 2 2 1 0 2 1 1 1 Tearing 2 0 1 0 2 0 2 0 Conjunctivitis 1 0 1 0 1 0 0. 4 0 The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole Cardiovascular: Cutaneous: Gastrointestinal: Hearing: Hematologic: Hepatic: Hypersensitivity: Metabolism and nutrition disorders: Ophthalmologic: Respiratory: Renal: Second primary malignancies: [see Warnings and Precautions ( 5. 7 Musculoskeletal disorder:.">The most serious adverse reactions from BEIZRAY are: Toxic Deaths [see Boxed Warning, Warnings and Precautions ( 5. 1 Hepatic Impairment [see Boxed Warning, Warnings and Precautions ( 5. 2 Hematologic Effects [see Boxed Warning, Warnings and Precautions ( 5. 3 Enterocolitis and Neutropenic Colitis [see Warnings and Precautions ( 5. 4 Hypersensitivity Reactions [see Boxed Warning, Warnings and Precautions ( 5. 5 Fluid Retention [see Boxed Warning, Warnings and Precautions ( 5. 6 Second Primary Malignancies [see Warnings and Precautions ( 5. 7 Cutaneous Reactions [see Warnings and Precautions ( 5. 8 Neurologic Reactions [see Warnings and Precautions ( 5. 9 Eye Disorders [see Warnings and Precautions ( 5. 10 Asthenia [see Warnings and Precautions ( 5. 11 Alcohol Content [see Warnings and Precautions ( 5. 13 Tumor Lysis Syndrome [see Warnings and Precautions ( 5. 14 The most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication. Adverse reactions are described according to indication. 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. Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established. Most common adverse reactions across all BEIZRAY indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Breast Cancer Monotherapy with docetaxel for locally advanced or metastatic breast cancer after failure of prior chemotherapy Docetaxel 100 mg/m 2 2 Table 4: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m 2 *Normal Baseline LFTs: Transaminases <=1. 5 times ULN or alkaline phosphatase <=2. 5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Elevated Baseline LFTs: AST and/or AL >1. 5 times ULN concurrent with alkaline phosphatase >2. 5 times ULN ***Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization Adverse Reaction All Tumor Types Normal LFTs* n=2045 % All Tumor Types Elevated LFTs** n=61 % Breast Cancer Normal LFTs* n=965 % Hematologic Neutropenia <2000 cells/mm 3 96 96 99 <500 cells/mm 3 75 88 86 Leukopenia <4000 cells/mm 3 96 98 99 <1000 cells/mm 3 32 47 44 Thrombocytopenia <100,000 cells/mm 3 8 25 9 Anemia <11 g/dL 90 92 94 <8 g/dL 9 31 8 Febrile Neutropenia*** 11 26 12 Septic Death 2 5 1 Non-Septic Death 1 7 1 Infections Any 22 33 22 Severe 6 16 6 Fever in Absence of Infection Any 31 41 35 Severe 2 8 2 Hypersensitivity Reactions Regardless of Premedication Any 21 20 18 Severe 4 10 3 With 3-day Premedication n=92 n=3 n=92 Any 15 33 15 Severe 2 0 2 Fluid Retention Regardless of Premedication Any 47 39 60 Severe 7 8 9 With 3-day Premedication n=92 n=3 n=92 Any 64 67 64 Severe 7 33 7 Neurosensory Any 49 34 58 Severe 4 0 6 Cutaneous Any 48 54 47 Severe 5 10 5 Nail Changes Any 31 23 41 Severe 3 5 4 Gastrointestinal Nausea 39 38 42 Vomiting 22 23 23 Diarrhea 39 33 43 Severe 5 5 6 Stomatitis Any 42 49 52 Severe 6 13 7 Alopecia 76 62 74 Asthenia Any 62 53 66 Severe 13 25 15 Myalgia Any 19 16 21 Severe 2 2 2 Arthralgia 9 7 8 Infusion Site Reactions 4 3 4 Hematologic reactions Reversible marrow suppression was the major dose-limiting toxicity of docetaxel [see Warnings and Precautions ( 5. 3 3 Febrile neutropenia (<500 cells/mm 3 Severe infectious episodes occurred in 6. 1% of patients with solid tumors, in 6. 4% of patients with metastatic breast cancer, and in 5. 4% of 92 breast cancer patients premedicated with 3-day corticosteroids. Thrombocytopenia (<100,000 cells/mm 3 Hypersensitivity reactions Severe hypersensitivity reactions have been reported [see Boxed Warning, Warnings and Precautions ( 5. 5 Fluid retention Fluid retention can occur with the use of docetaxel [see Boxed Warning, Dosage and Administration ( 2. 6 Cutaneous reactions Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions ( 5. 8 Severe nail disorders were characterized by hypo or hyperpigmentation, and occasionally by onycholysis (in 0. 8% of patients with solid tumors) and pain. Neurologic reactions Neurologic reactions are discussed elsewhere in the label [see Warnings and Precautions ( 5. 9 Gastrointestinal reactions Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3%-5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Severe stomatitis occurred in 5. 5% of patients with solid tumors, in 7. 4% of patients with metastatic breast cancer, and in 1. 1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. Cardiovascular reactions Hypotension occurred in 2. 8% of patients with solid tumors; 1. 2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension have occurred. Seven of 86 (8. 1%) of metastatic breast cancer patients receiving docetaxel 100 mg/m 2 Infusion site reactions Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein. Hepatic reactions In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8. 9% of patients. Increases in AST or ALT >1. 5 times the ULN, or alkaline phosphatase >2. 5 times ULN, were observed in 18. 3% of patients, respectively. While on docetaxel, increases in AST and/or ALT >1. 5 times ULN concomitant with alkaline phosphatase >2. 5 times ULN occurred in 4. 3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established. Hematologic and other toxicity: Relation to dose and baseline liver chemistry abnormalities Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m 2 2 Table 5: Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m 2 2 *Normal Baseline LFTs: Transaminases <=1. 5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Elevated Baseline LFTs: AST and/or ALT>1. 5 times ULN concurrent with alkaline phosphatase>2. 5 times ULN ***Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8. 5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia. ****Febrile Neutropenia: For 100 mg/m 2 2 Adverse Reaction Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2 Normal LFTs* n=730 % Elevated LFTs** n=18 % Normal LFTs* n=174 % Neutropenia Any <2000 cells/mm 3 98 100 95 Grade 4 <500 cells/mm 3 84 94 75 Thrombocytopenia Any <100,000 cells/mm 3 11 44 14 Grade 4 <20,000 cells/mm 3 1 17 1 Anemia 95 94 65 Infection*** Any 23 39 1 Grade 3 and 4 7 33 0 Febrile Neutropenia**** By Patient 12 33 0 By Course 2 9 0 Septic Death 2 6 1 Non-Septic Death 1 11 0 Table 6: Non-hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m 2 2 *Normal Baseline LFTs: Transaminases <=1. 5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Elevated Baseline Liver Function: AST and/or ALT >1. 5 times ULN ***Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m 2 NA = not available Adverse Reaction Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2 Normal LFTs* n=730 % Elevated LFTs** n=18 % Normal LFTs* n=174 % Acute Hypersensitivity Reaction Regardless of Premedication Any 13 6 1 Severe 1 0 0 Fluid Retention*** Regardless of Premedication Any 56 61 13 Severe 8 17 0 Neurosensory Any 57 50 20 Severe 6 0 0 Myalgia 23 33 3 Cutaneous Any 45 61 31 Severe 5 17 0 Asthenia Any 65 44 66 Severe 17 22 0 Diarrhea Any 42 28 NA Severe 6 11 Stomatitis Any 53 67 19 Severe 8 39 1 In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m 2 2 2 2 2 2 2 2 2 2 2 The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m 2 2 2 Combination therapy with Docetaxel in the adjuvant treatment of breast cancer The following table presents treatment-emergent adverse reactions observed in 744 patients, who were treated with docetaxel 75 mg/m 2 Table 7: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316). * COSTART term and grading system for events related to treatment. Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 n=744 % Fluorouracil 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 n=736 % Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 92 4 72 2 Neutropenia 71 66 82 49 Fever in absence of infection 47 1 17 0 Infection 39 4 36 2 Thrombocytopenia 39 2 28 1 Febrile neutropenia 25 N/A 3 N/A Neutropenic infection 12 N/A 6 N/A Hypersensitivity reactions 13 1 4 0 Lymphedema 4 0 1 0 Fluid Retention* 35 1 15 0 Peripheral edema 27 0 7 0 Weight gain 13 0 9 0 Neuropathy sensory 26 0 10 0 Neuro-cortical 5 1 6 1 Neuropathy motor 4 0 2 0 Neuro-cerebellar 2 0 2 0 Syncope 2 1 1 0 Alopecia 98 N/A 97 N/A Skin toxicity 27 1 18 0 Nail disorders 19 0 14 0 Nausea 81 5 88 10 Stomatitis 69 7 53 2 Vomiting 45 4 59 7 Diarrhea 35 4 28 2 Constipation 34 1 32 1 Taste perversion 28 1 15 0 Anorexia 22 2 18 1 Abdominal Pain 11 1 5 0 Amenorrhea 62 N/A 52 N/A Cough 14 0 10 0 Cardiac dysrhythmias 8 0 6 0 Vasodilatation 27 1 21 1 Hypotension 2 0 1 0 Phlebitis 1 0 1 0 Asthenia 81 11 71 6 Myalgia 27 1 10 0 Arthralgia 19 1 9 0 Lacrimation disorder 11 0 7 0 Conjunctivitis 5 0 7 0 Of the 744 patients treated with TAC, 36. 3% experienced severe treatment-emergent adverse reactions compared to 26. 6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0. 1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1. 1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs. Fever and infection During the treatment period, fever in the absence of infection was seen in 46. 5% of TAC-treated patients and in 17. 1% of FAC-treated patients. Grade 3/4 fever in the absence of infection was seen in 1. 3% and 0% of TAC and FAC-treated patients, respectively. Infection was seen in 39. 4% of TAC-treated patients compared to 36. 3% of FAC-treated patients. Grade 3/4 infection was seen in 3. 2% of TAC-treated and FAC-treated patients, respectively. There were no septic deaths in either treatment arm during the treatment period. Gastrointestinal reactions In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation versus one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred during the treatment period. Cardiovascular reactions More cardiovascular reactions were reported in the TAC arm versus the FAC arm during the treatment period: arrhythmias, all grades (6. 9%), and hypotension, all grades (1. Twenty-six (26) patients (3. 5%) in the TAC arm and 17 patients (2. 3%) in the FAC arm developed CHF during the study period. All except one patient in each arm were diagnosed with CHF during the follow-up period. Two (2) patients in TAC arm and 4 patients in FAC arm died due to CHF. The risk of CHF was higher in the TAC arm in the first year, and then was similar in both treatment arms. Adverse reactions during the follow-up period (median follow-up time of 8 years) In study TAX316, the most common adverse reactions that started during the treatment period and persisted into the follow-up period in TAC and FAC patients are described below (median follow-up time of 8 years). Nervous system disorders In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11. 3%) in TAC arm and 15 patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1. 3%) in TAC arm, and in 2 patients (0. 3%) in FAC arm. Skin and subcutaneous tissue disorders In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92. 3%) and 645 of 736 FAC patients (87. At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3. 9%) and 16 FAC patients (2. Reproductive system and breast disorders In study TAX316, amenorrhea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27. 2%) and 125 of 736 FAC patients (17. Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16. 3%) and 86 FAC patients (11. General disorders and administration site conditions In study TAX316, peripheral edema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16. 0%) and 23 of 736 FAC patients (3. At the end of the follow-up period (actual median follow-up time of 8 years), peripheral edema was ongoing in 19 TAC patients (2. 6%) and 4 FAC patients (0. In study TAX316, lymphedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1. 5%) and 1 of 736 FAC patients (0. At the end of the follow-up period (actual median follow-up time of 8 years), lymphedema was observed to be ongoing in 6 TAC patients (0. 8%) and 1 FAC patient (0. In study TAX316, asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31. 7%) and 180 of 736 FAC patients (24. At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3. Acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS) AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at median follow-up time of 8 years in TAX316 was 0. 4% for TAC-treated patients and 0. 1% for FAC-treated patients. One TAC patient (0. 1%) and 1 FAC patient (0. 1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome occurred in 2 of 744 (0. 3%) patients who received TAC and in 1 of 736 (0. 1%) patients who received FAC. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. Lung Cancer Monotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy Docetaxel 75 mg/m 2 Table 8: Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel as Monotherapy for Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy* *Normal Baseline LFTs: Transaminases <=1. 5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization ***COSTART term and grading system daggerNot Applicable daggerdaggerNot Done Adverse Reaction Docetaxel 75 mg/m 2 n=176 % Best Supportive Care n=49 % Vinorelbine/ Ifosfamide n=119 % Neutropenia Any 84 14 83 Grade 3/4 65 12 57 Leukopenia Any 84 6 89 Grade 3/4 49 0 43 Thrombocytopenia Any 8 0 8 Grade 3/4 3 0 2 Anemia Any 91 55 91 Grade 3/4 9 12 14 Febrile Neutropenia** 6 NAdagger 1 Infection Any 34 29 30 Grade 3/4 10 6 9 Treatment Related Mortality 3 NAdagger 3 Hypersensitivity Reactions Any 6 0 1 Grade 3/4 3 0 0 Fluid Retention Any 34 NDdaggerdagger 23 Severe 3 3 Neurosensory Any 23 14 29 Grade 3/4 2 6 5 Neuromotor Any 16 8 10 Grade 3/4 5 6 3 Skin Any 20 6 17 Grade 3/4 1 2 1 Gastrointestinal Nausea Any 34 31 31 Grade 3/4 5 4 8 Vomiting Any 22 27 22 Grade 3/4 3 2 6 Diarrhea Any 23 6 12 Grade 3/4 3 0 4 Alopecia 56 35 50 Asthenia Any 53 57 54 Severe*** 18 39 23 Stomatitis Any 26 6 8 Grade 3/4 2 0 1 Pulmonary Any 41 49 45 Grade 3/4 21 29 19 Nail Disorder Any 11 0 2 Severe*** 1 0 0 Myalgia Any 6 0 3 Severe*** 0 0 0 Arthralgia Any 3 2 2 Severe*** 0 0 1 Taste Perversion Any 6 0 0 Severe*** 1 0 0 Combination therapy with docetaxel in chemotherapy-naive advanced unresectable or metastatic NSCLC Table 9 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted. Table 9: Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy Naive Advanced Non-small Cell Lung Cancer Patients Receiving Docetaxel in Combination with Cisplatin *Replaces NCI term "Allergy" **COSTART term and grading system Adverse Reaction Docetaxel 75 mg/m 2 + Cisplatin 75 mg/m 2 n=406 % Vinorelbine 25 mg/m 2 Cisplatin 100 mg/m 2 n=396 % Neutropenia Any 91 90 Grade 3/4 74 78 Febrile Neutropenia 5 5 Thrombocytopenia Any 15 15 Grade 3/4 3 4 Anemia Any 89 94 Grade 3/4 7 25 Infection Any 35 37 Grade 3/4 8 8 Fever in absence of infection Any 33 29 Grade 3/4 <1 1 Hypersensitivity Reaction* Any 12 4 Grade 3/4 3 <1 Fluid Retention** Any 54 42 All severe or life-threatening events 2 2 Pleural effusion Any 23 22 All severe or life-threatening events 2 2 Peripheral edema Any 34 18 All severe or life-threatening events <1 <1 Weight gain Any 15 9 All severe or life-threatening events <1 <1 Neurosensory Any 47 42 Grade 3/4 4 4 Neuromotor Any 19 17 Grade 3/4 3 6 Skin Any 16 14 Grade 3/4 <1 1 Nausea Any 72 76 Grade 3/4 10 17 Vomiting Any 55 61 Grade 3/4 8 16 Diarrhea Any 47 25 Grade 3/4 7 3 Anorexia** Any 42 40 All severe or life-threatening events 5 5 Stomatitis Any 24 21 Grade 3/4 2 1 Alopecia Any 75 42 Grade 3 <1 0 Asthenia** Any 74 75 All severe or life-threatening events 12 14 Nail Disorder** Any 14 <1 All severe events <1 0 Myalgia** Any 18 12 All severe events <1 <1 Deaths within 30 days of last study treatment occurred in 31 patients (7. 6%) in the docetaxel+cisplatin arm and 37 patients (9. 3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2. 2%) in the docetaxel+cisplatin arm and 8 patients (2. 0%) in the vinorelbine+cisplatin arm. The second comparison in the study, vinorelbine+cisplatin versus docetaxel+carboplatin (which did not demonstrate a superior survival associated with docetaxel [see Clinical Studies ( 14. 3 Prostate Cancer Combination therapy with docetaxel in patients with prostate cancer The following data are based on the experience of 332 patients, who were treated with docetaxel 75 mg/m 2 Table 10: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer Who Received Docetaxel in Combination with Prednisone (TAX327) *Related to treatment Docetaxel 75 mg/m 2 3 weeks + prednisone 5 mg twice daily n=332 % Mitoxantrone 12 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=335 % Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 67 5 58 2 Neutropenia 41 32 48 22 Thrombocytopenia 3 1 8 1 Febrile neutropenia 3 N/A 2 N/A Infection 32 6 20 4 Epistaxis 6 0 2 0 Allergic Reactions 8 1 1 0 Fluid Retention* 24 1 5 0 Weight Gain* 8 0 3 0 Peripheral Edema* 18 0 2 0 Neuropathy Sensory 30 2 7 0 Neuropathy Motor 7 2 3 1 Rash/Desquamation 6 0 3 1 Alopecia 65 N/A 13 N/A Nail Changes 30 0 8 0 Nausea 41 3 36 2 Diarrhea 32 2 10 1 Stomatitis/Pharyngitis 20 1 8 0 Taste Disturbance 18 0 7 0 Vomiting 17 2 14 2 Anorexia 17 1 14 0 Cough 12 0 8 0 Dyspnea 15 3 9 1 Cardiac left ventricular function 10 0 22 1 Fatigue 53 5 35 5 Myalgia 15 0 13 1 Tearing 10 1 2 0 Arthralgia 8 1 5 1 Gastric Cancer Combination therapy with docetaxel in gastric adenocarcinoma Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease who were treated with docetaxel 75 mg/m 2 Table 11: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study Clinically important treatment-emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction. *Related to treatment Docetaxel 75 mg/m 2 cisplatin 75 mg/m 2 fluorouracil 750 mg/m 2 n=221 Cisplatin 100 mg/m 2 fluorouracil 1000 mg/m 2 n=224 Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Anemia 97 18 93 26 Neutropenia 96 82 83 57 Fever in the absence of infection 36 2 23 1 Thrombocytopenia 26 8 39 14 Infection 29 16 23 10 Febrile neutropenia 16 N/A 5 N/A Neutropenic infection 16 N/A 10 N/A Allergic reactions 10 2 6 0 Fluid retention* 15 0 4 0 Edema* 13 0 3 0 Lethargy 63 21 58 18 Neurosensory 38 8 25 3 Neuromotor 9 3 8 3 Dizziness 16 5 8 2 Alopecia 67 5 41 1 Rash/itch 12 1 9 0 Nail changes 8 0 0 0 Skin desquamation 2 0 0 0 Nausea 73 16 76 19 Vomiting 67 15 73 19 Anorexia 51 13 54 12 Stomatitis 59 21 61 27 Diarrhea 78 20 50 8 Constipation 25 2 34 3 Esophagitis/dysphagia/odynophagia 16 2 14 5 Gastrointestinal pain/cramping 11 2 7 3 Cardiac dysrhythmias 5 2 2 1 Myocardial ischemia 1 0 3 2 Tearing 8 0 2 0 Altered hearing 6 0 13 2 Head and Neck Cancer Combination therapy with docetaxel in head and neck cancer Table 12 summarizes the safety data obtained from patients that received induction chemotherapy with docetaxel 75 mg/m 2 14. 6 Table 12: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with Docetaxel in Combination with Cisplatin and Fluorouracil Followed by Radiotherapy (TAX323) or Chemoradiotherapy (TAX324) Clinically important treatment-emergent adverse reactions based upon frequency, severity, and clinical impact. *Febrile neutropenia: grade >=2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization. **Related to treatment. ***Includes superficial and deep vein thrombosis and pulmonary embolism TAX323 (n=355) TAX324 (n=494) Docetaxel arm (n=174) Comparator arm (n=181) Docetaxel arm (n=251) Comparator arm (n=243) Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Neutropenia 93 76 87 53 95 84 84 56 Anemia 89 9 88 14 90 12 86 10 Thrombocytopenia 24 5 47 18 28 4 31 11 Infection 27 9 26 8 23 6 28 5 Febrile neutropenia* 5 N/A 2 N/A 12 N/A 7 N/A Neutropenic infection 14 N/A 8 N/A 12 N/A 8 N/A Cancer pain 21 5 16 3 17 9 20 11 Lethargy 41 3 38 3 61 5 56 10 Fever in the absence of infection 32 1 37 0 30 4 28 3 Myalgia 10 1 7 0 7 0 7 2 Weight loss 21 1 27 1 14 2 14 2 Allergy 6 0 3 0 2 0 0 0 Fluid retention** 20 0 14 1 13 1 7 2 Edema only 13 0 7 0 12 1 6 1 Weight gain only 6 0 6 0 0 0 1 0 Dizziness 2 0 5 1 16 4 15 2 Neurosensory 18 1 11 1 14 1 14 0 Altered hearing 6 0 10 3 13 1 19 3 Neuromotor 2 1 4 1 9 0 10 2 Alopecia 81 11 43 0 68 4 44 1 Rash/itch 12 0 6 0 20 0 16 1 Dry skin 6 0 2 0 5 0 3 0 Desquamation 4 1 6 0 2 0 5 0 Nausea 47 1 51 7 77 14 80 14 Stomatitis 43 4 47 11 66 21 68 27 Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Vomiting 26 1 39 5 56 8 63 10 Diarrhea 33 3 24 4 48 7 40 3 Constipation 17 1 16 1 27 1 38 1 Anorexia 16 1 25 3 40 12 34 12 Esophagitis/dysphagia/ Odynophagia 13 1 18 3 25 13 26 10 Taste, sense of smell altered 10 0 5 0 20 0 17 1 Gastrointestinal pain/cramping 8 1 9 1 15 5 10 2 Heartburn 6 0 6 0 13 2 13 1 Gastrointestinal bleeding 4 2 0 0 5 1 2 1 Cardiac dysrhythmia 2 2 2 1 6 3 5 3 Venous*** 3 2 6 2 4 2 5 4 Ischemia myocardial 2 2 1 0 2 1 1 1 Tearing 2 0 1 0 2 0 2 0 Conjunctivitis 1 0 1 0 1 0 0. 4 0 The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole Cardiovascular: Cutaneous: Gastrointestinal: Hearing: Hematologic: Hepatic: Hypersensitivity: Metabolism and nutrition disorders: Ophthalmologic: Respiratory: Renal: Second primary malignancies: [see Warnings and Precautions ( 5. 7 Musculoskeletal disorder:.

BEIZRAY is contraindicated in patients with: neutrophil counts of <1500 cells/mm 3 [see Warnings and Precautions ( 5. 3 a history of severe hypersensitivity reactions to docetaxel. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions ( 5. 5 Hypersensitivity to docetaxel ( 4 Neutrophil counts of <1500 cells/mm 3 4.

Lactation: Advise women not to breastfeed. 2 Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of BEIZRAY. 3 Risk Summary Based on findings in animal reproduction studies and its mechanism of action, BEIZRAY can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12. 1 [see Clinical Considerations] [see Data] The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. 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. Clinical Considerations BEIZRAY contains alcohol [see Warnings and Precautions ( 5. 13 Data Animal data Intravenous administration of >= 0. 03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. Maternal toxicity was also observed at these doses, which were approximately 0. 003 times the daily maximum recommended human dose based on body surface area, respectively. Risk Summary There is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. No lactation studies in animals have been conducted. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with BEIZRAY and for 1 week after the last dose. Based on findings in animals, BEIZRAY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8. 1 Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating BEIZRAY. Contraception Females Based on genetic toxicity findings, advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of BEIZRAY. Males Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of BEIZRAY. Infertility Based on findings in animal studies, BEIZRAY may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13. 1 The alcohol content of BEIZRAY Injection should be taken into account when given to pediatric patients [see Warnings and Precautions ( 5. 13 The efficacy of BEIZRAY in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of BEIZRAY in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults. Docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluorouracil (TCF). Docetaxel Monotherapy Docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12. 5 years, range 1-22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m 2 The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1-26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0. 6%) in a patient with undifferentiated sarcoma to four partial responses (2. 2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma. Docetaxel in Combination Docetaxel was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to docetaxel (75 mg/m 2 2 2 2 2 Pharmacokinetics Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m 2 2 2 Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m2 in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17. 75 L/h/m2, corresponding to an AUC of 4. 57 mug∙h/mL. In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults [see Clinical Pharmacology ( 12. 3 In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients. Non-small Cell Lung Cancer In a study conducted in chemotherapy-naive patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10. 3 months (95% CI: 9. 1 months, 11. 8 months) and patients 65 years or older had a median survival of 12. 1 months (95% CI: 9. 3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). When docetaxel was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. Prostate Cancer Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the following treatment-emergent adverse reactions occurred at rates >=10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs 59%), infection (37% vs 24%), nail changes (34% vs 23%), anorexia (21% vs 10%), weight loss (15% vs 5%), respectively. Breast Cancer In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients. Gastric Cancer Among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates >=10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored. Head and Neck Cancer Among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. These clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients. Avoid BEIZRAY in patients with bilirubin >ULN and patients with AST and/or ALT >1. 5 × ULN concomitant with alkaline phosphatase >2. 5 × ULN [see Boxed Warning, Warnings and Precautions ( 5. 3 The alcohol content of BEIZRAY Injection should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions ( 5.

Docetaxel is a CYP3A4 substrate. In vitro In vivo [see Dosage and Administration ( 2. 3 Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism.

OVERDOSAGE
There is no known antidote for BEIZRAY overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. In two reports of overdose, one patient received 150 mg/m 2 2 In mice, lethality was observed following single intravenous doses that were >=154 mg/kg (about 4.5 times the human dose of 100 mg/m 2 2 2 2 2
NONCLINICAL TOXICOLOGY
Carcinogenicity studies with docetaxel have not been performed. Docetaxel was genotoxic by an aneugenic mechanism in the in vitro 1 in vivo th th 2 Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50 th 2 rd th 2
CLINICAL STUDIES
The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agenten dashcontaining regimens or anthracycline-containing regimens). Randomized Trials In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 2 2 Table 13: Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis) *For the risk ratio, a value less than 1. 00 favors docetaxel. Efficacy Parameter Docetaxel (n=203) Mitomycin/ Vinblastine (n=189) p-value Median Survival 11. 7 months p=0. 01 Risk Ratio*, Mortality 0. 73 95% CI (Risk Ratio) 0. 93 Median Time to 4. 5 months p=0. 01 Risk Ratio*, Progression 0. 75 95% CI (Risk Ratio) 0. 94 Overall Response Rate 28. 0001 Complete Response Rate 3. 6% In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 2 Table 14: Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis) Efficacy Parameter Docetaxel (n=161) Doxorubicin (n=165) p-value Median Survival 14. 7 months 14. 3 months p=0. 39 Risk Ratio*, Mortality 0. 89 95% CI (Risk Ratio) 0. 16 Median Time to 6. 45 Risk Ratio*, Progression 0. 93 95% CI (Risk Ratio) 0. 16 Overall Response Rate 45. 004 Complete Response Rate 6. 2% *For the risk ratio, a value less than 1. In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m 2 2 2 2 2 2 2 2 Single Arm Studies Docetaxel at a dose of 100 mg/m 2 Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m 2 2 A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m 2 2 2 2 2 2 Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0. 74; 2-sided 95% CI=0. 92, stratified log rank p=0. The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25. 7% for TAC-treated patients. (See Figure 1. ) At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0. 69, 2-sided 95% CI=0. (See Figure 2. ) There will be further analysis at the time survival data mature. Figure 1: TAX316 Disease Free Survival K-M curve Figure 2: TAX316 Overall Survival K-M Curve The following table describes the results of subgroup analyses for DFS and OS (see Table 15). Table 15: Subset Analyses-Adjuvant Breast Cancer Study * a hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC. Patient subset Number of patients Disease Free Survival Overall Survival Hazard ratio* 95% CI Hazard ratio* 95% CI No. of positive nodes Overall 744 0. 90) 1-3 467 0. 70) 4+ 277 0. 32) Receptor status Positive 566 0. 99) Negative 178 0. 98) The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy naive. Monotherapy with docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy Two randomized, controlled trials established that a docetaxel dose of 75 mg/m 2 2 [see Boxed Warning, Dosage and Administration ( 2. 3 One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status <=2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m 2 2 2 In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic nonsmall cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status <=2 were randomized to docetaxel 75 mg/m 2 2 2 2 2 Table 16: Efficacy of Docetaxel in the Treatment of Non-small Cell Lung Cancer Patients Previously Treated with a Platinum-Based Chemotherapy Regimen (Intent-toTreat Analysis) *Vinorelbine/Ifosfamide **p<=0. 05 daggeruncorrected for multiple comparisons daggerdaggera value less than 1. 00 favors docetaxel TAX317 TAX320 Docetaxel 75 mg/m 2 n=55 Best Supportive Care n=49 Docetaxel 75 mg/m 2 n=125 Control (V/I*) n=123 Overall Survival p=0. 13 Risk Ratio daggerdagger 0. 82 95% CI (Risk Ratio) (0. 06) Median Survival 7. 5 months** 4. 6 months % 1-year Survival 37%** dagger 12% 30%** dagger 20% Time to Progression 12. 3 weeks** 7. 6 weeks Response Rate 5. 5% Not Applicable 5. 8% Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m 2 Figure 3: TAX317 Survival K-M Curves - Docetaxel 75 mg/m 2 Figure 4: TAX320 Survival K-M Curves - Docetaxel 75 mg/m 2 Patients treated with docetaxel at a dose of 75 mg/m 2 Combination Therapy with docetaxel for Chemotherapy-Naive NSCLC In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m 2 2 2 2 The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 17. Table 17: Survival Analysis of Docetaxel in Combination Therapy for Chemotherapy- Naive NSCLC a b docetaxel+cisplatin is associated with a longer survival. c Comparison Docetaxel + Cisplatin n=408 Vinorelbine + Cisplatin n=405 Kaplan-Meier Estimate of Median 10. 9 months 10. 0 months p-value a 0. 122 Estimated Hazard Ratio b 0. 88 Adjusted 95% CI c (0. 06) The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9. 1 months for docetaxel+carboplatin compared to 10. 0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 18). Table 18: Response and TTP Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naive NSCLC a b Endpoint Docetaxel + Cisplatin Vinorelbine + Cisplatin p-value Objective Response Rate a 31. 4% Not Median Time to b a 21. 1 weeks Not The safety and efficacy of docetaxel in combination with prednisone in patients with metastatic castration-resistant prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) >=60 were randomized to the following treatment groups: Docetaxel 75 mg/m 2 Docetaxel 30 mg/m 2 Mitoxantrone 12 mg/m 2 All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously. In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 19 and Figure 5. Table 19: Efficacy of Docetaxel in the Treatment of Patients with Metastatic Castration Resistant Prostate Cancer (Intent-to-Treat Analysis) *Stratified log-rank test. Threshold for statistical significance = 0. 0175 because of 3 arms. Docetaxel + Prednisone every 3 weeks Mitoxantrone + Prednisone every 3 weeks Number of patients 335 337 Median survival (months) 18. 5 95% CI (17. 6) Hazard ratio 0. 761 -- 95% CI (0. 936) -- p-value* 0. 0094 -- Figure 5: TAX327 Survival K-M Curves A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either docetaxel (T) (75 mg/m 2 2 2 2 2 Table 20: Efficacy of Docetaxel in the Treatment of Patients with Gastric Adenocarcinoma *Unstratified log-rank test Endpoint TCF n=221 CF n=224 Median TTP (months) 5. 7 (95% CI) (4. 47) Hazard ratio dagger 0. 68 (95% CI) (0. 84) *p-value 0. 0004 Median survival (months) 9. 6 (95% CI) (8. 46) Hazard ratio dagger 0. 77 (95% CI) (0. 96) *p-value 0. 0201 Overall Response Rate (CR+PR) (%) 36. 4 p-value 0. 0106 dagger Subgroup analyses were consistent with the overall results across age, gender and race. Figure 6: Gastric Cancer Study (TAX325) Time to Progression K-M Curve Figure 7: Gastric Cancer Study (TAX325) Survival K-M Curve Induction Chemotherapy Followed by Radiotherapy (TAX323) The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2 2 2 2 2 The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0. 0077 (median PFS: 11. 3 months, respectively) with an overall median follow-up time of 33. Median overall survival with a median follow-up of 51. 2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18. 2 months, respectively). Efficacy results are presented in Table 21 and Figures 8 and 9. Table 21: Efficacy of Docetaxel in the Induction Treatment of Patients with Inoperable Locally Advanced SCCHN (Intent-to-Treat Analysis) A Hazard ratio of less than 1 favors docetaxel+cisplatin+fluorouracil *Stratified log-rank test based on primary tumor site **Stratified log-rank test, not adjusted for multiple comparisons ***Chi square test, not adjusted for multiple comparisons Endpoint Docetaxel + Cisplatin + Fluorouracil n=177 Cisplatin + Fluorouracil n=181 Median progression free survival (months) 11. 3 (95% CI) (10. 1) Adjusted Hazard ratio 0. 71 (95% CI) (0. 91) *p-value 0. 0077 Median survival (months) 18. 2 (95% CI) (15. 7) Hazard ratio 0. 90) **p-value 0. 0055 Best overall response (CR + PR) to chemotherapy (%) 67. 6 (95% CI) (60. 0) ***p-value 0. 006 Best overall response (CR + PR) to study treatment 72. 6 (95% CI) (65. 8) ***p-value 0. 006 Figure 8: TAX323 Progression-Free Survival K-M Curve Figure 9: TAX323 Overall Survival K-M Curve Induction Chemotherapy Followed by Chemoradiotherapy (TAX324) The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2 2 2 2 2 All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1. 5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT. The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0. 0058) with the docetaxel-containing regimen compared to PF (median OS: 70. 1 months, respectively, hazard ratio [HR]=0. 70, 95% confidence interval [CI]=0. Overall survival results are presented in Table 22 and Figure 10. Table 22: Efficacy of Docetaxel in the Induction Treatment of Patients with Locally Advanced SCCHN (Intent-to-Treat Analysis) A Hazard ratio of less than 1 favors docetaxel+cisplatin+fluorouracil *unadjusted log-rank test NE - not estimable Endpoint Docetaxel + Cisplatin + Fluorouracil n=255 Cisplatin + Fluorouracil n=246 Median overall survival (months) 70. 1 (95% CI) (49. 5) Hazard ratio: 0. 70 (95% CI) (0. 90) *p-value 0. 0058 Figure 10: TAX324 Overall Survival K-M Curve Image Image Image Image Image Image Image Image Image Image.
REFERENCES
1. "OSHA Hazardous Drugs." http://www.osha.gov/SLTC/hazardousdrugs/index.html

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