ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The most serious adverse reactions from Docetaxel Injection 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)] The most common adverse reactions across all Docetaxel Injection 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 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. 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)] Most common adverse reactions across all Docetaxel Injection 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 Actavis at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience. Breast CancerMonotherapy with Docetaxel Injection for locally advanced or metastatic breast cancer after failure of prior chemotherapyDocetaxel Injection 100 mg/m2: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received Docetaxel Injection administered at 100 mg/m2 as 1-hour infusion every weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to Docetaxel Injection. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving Docetaxel Injection for the treatment of breast cancer and in patients with other tumor types (See Table 3). Table - Summary of Adverse Reactions in Patients Receiving Docetaxel Injection at 100 mg/m2 All Tumor Types All Tumor Types Breast Cancer Normal LFTs Elevated LFTs Normal LFTs Adverse Reaction n=2045 n=61 n=965 % 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 times ULN Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN Febrile Neutropenia: ANC grade with fever >38C with intravenous antibiotics and/or hospitalization Hematologic Neutropenia <2000 cells/mm3 96 96 99 <500 cells/mm3 75 88 86 Leukopenia <4000 cells/mm3 96 98 99 <1000 cells/mm3 32 47 44 Thrombocytopenia <100,000 cells/mm3 25 Anemia <11 g/dL 90 92 94 <8 g/dL 31 Febrile Neutropenia 11 26 12 Septic Death 5 Non-Septic Death 7 Infections Any 22 33 22 Severe 16 Fever in Absence of Infection Any 31 41 35 Severe 8 Hypersensitivity Reactions Regardless of Premedication Any 21 20 18 Severe 10 With 3-day Premedication n=92 n=3 n=92 Any 15 33 15 Severe 0 Fluid Retention Regardless of Premedication Any 47 39 60 Severe 8 With 3-day Premedication n=92 n=3 n=92 Any 64 67 64 Severe 33 Neurosensory Any 49 34 58 Severe 0 Cutaneous Any 48 54 47 Severe 10 Nail Changes Any 31 23 41 Severe 5 Gastrointestinal Nausea 39 38 42 Vomiting 22 23 23 Diarrhea 39 33 43 Severe 5 Stomatitis Any 42 49 52 Severe 13 Alopecia 76 62 74 Asthenia Any 62 53 66 Severe 13 25 15 Myalgia Any 19 16 21 Severe 2 Arthralgia 7 Infusion Site Reactions 3 Hematologic ReactionsReversible marrow suppression was the major dose-limiting toxicity of Docetaxel Injection [see Warnings and Precautions (5.3)]. The median time to nadir was days, while the median duration of severe neutropenia (<500 cells/mm3) was days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than days in 2.9% of cycles. Febrile neutropenia (<500 cells/mm3 with fever >38C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids. 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/mm3) associated with fatal gastrointestinal hemorrhage has been reported. Hypersensitivity ReactionsSevere hypersensitivity reactions have been reported [see Boxed Warning, Warnings and Precautions (5.5)] Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy. Fluid RetentionFluid retention can occur with the use of Docetaxel Injection [see Boxed Warning, Dosage and Administration (2.6), Warnings and Precautions (5.6)]. Cutaneous ReactionsSevere skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.8)]. Reversible cutaneous reactions characterized by rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within week after Docetaxel Injection infusion, recovered before the next infusion, and were not disabling. Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain. Neurologic ReactionsNeurologic reactions are discussed elsewhere in the label [see Warnings and Precautions (5.9)]. Gastrointestinal ReactionsNausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in to 5% of patients with solid tumors and to 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 ReactionsHypotension 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 Injection 100 mg/m2 in randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by >=10% associated with drop below the institutional lower limit of normal. Infusion Site ReactionsInfusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein.Hepatic ReactionsIn 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 18.9% and 7.3% of patients, respectively. While on Docetaxel Injection, 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 abnormalitiesHematologic 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 Injection at 100 mg/m2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN); and 174 patients in Japanese studies given Docetaxel Injection at 60 mg/m2 who had normal LFTs (see Tables and 5). Table - Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel Injection 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests Docetaxel Injection Docetaxel Injection 100 mg/m 60 mg/m Normal LFTs Elevated LFTs Normal LFTs Adverse Reaction n=730 n=18 n=174 % 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 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; patients had concurrent grade neutropenia, and 46 patients had grade neutropenia. Febrile Neutropenia: For 100 mg/m2, ANC grade and fever >38C with intravenous antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever >38.1C Neutropenia Any <2000 cells/mm3 98 100 95 Grade <500 cells/mm3 84 94 75 Thrombocytopenia Any <100,000 cells/mm3 11 44 14 Grade <20,000 cells/mm3 17 Anemia <11 g/dL 95 94 65 Infection Any 23 39 Grade and 7 33 Febrile Neutropenia By Patient 12 33 By Course 9 Septic Death 6 Non-Septic Death 11 0Table - Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel Injection 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests Docetaxel Injection Docetaxel Injection 100 mg/m 60 mg/m Normal LFTs Elevated LFTs Normal LFTs Adverse Reaction n=730 n=18 n=174 % 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 times ULN Elevated Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 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/m2 dose NA not available Acute Hypersensitivity Reaction Regardless of Premedication Any 13 1 Severe 0 Fluid Retention Regardless of Premedication Any 56 61 13 Severe 17 Neurosensory Any 57 50 20 Severe 0 Myalgia 23 33 Cutaneous Any 45 61 31 Severe 17 Asthenia Any 65 44 66 Severe 17 22 Diarrhea Any 42 28 NA Severe 11 Stomatitis Any 53 67 19 Severe 39 1In the three-arm monotherapy trial, TAX313, which compared Docetaxel Injection 60 mg/m2, 75 mg/m2 and 100 mg/m2 in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with Docetaxel Injection 60 mg/m2 compared to 55.3% and 65.9% treated with 75 mg/m2 and 100 mg/m2, respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m2 versus 6.9% and 16.5% for patients treated at 75 and 100 mg/m2 respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m2 compared to 5.3% and 1.6% for patients treated at 75 mg/m2 and 100 mg/m2, respectively.The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m2, 75 mg/m2, and 100 mg/m2, respectively), thrombocytopenia (7%, 11% and 12%, respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14%, respectively), treatment-related grade 3/4 infection (2%, 3%, and 7%, respectively) and anemia (87%, 94%, and 97%, respectively). Combination therapy with Docetaxel Injection in the adjuvant treatment of breast cancerThe following table presents treatment emergent adverse reactions observed in 744 patients, who were treated with Docetaxel Injection 75 mg/m2 every weeks in combination with doxorubicin and cyclophosphamide (see Table 6). Table - Clinically Important Treatment Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel Injection in Combination with Doxorubicin and Cyclophosphamide (TAX316). Docetaxel Injection 75 mg/m + Fluorouracil 500 mg/m + Doxorubicin 50 mg/m + Doxorubicin 50 mg/m + Cyclophosphamide 500 mg/m (TAC) Cyclophosphamide 500 mg/m (FAC) n=744 n=736 COSTART term and grading system for events related to treatment. Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 92 72 Neutropenia 71 66 82 49 Fever in absence of infection 47 17 Infection 39 36 Thrombocytopenia 39 28 Febrile neutropenia 25 N/A N/A Neutropenic infection 12 N/A N/A Hypersensitivity reactions 13 4 Lymphedema 0 0 Fluid Retention 35 15 Peripheral edema 27 7 Weight gain 13 9 Neuropathy sensory 26 10 Neuro-cortical 1 1 Neuropathy motor 0 0 Neuro-cerebellar 0 0 Syncope 1 0 Alopecia 98 N/A 97 N/A Skin toxicity 27 18 Nail disorders 19 14 Nausea 81 88 10 Stomatitis 69 53 Vomiting 45 59 Diarrhea 35 28 Constipation 34 32 Taste perversion 28 15 Anorexia 22 18 Abdominal Pain 11 5 Amenorrhea 62 N/A 52 N/A Cough 14 10 Cardiac dysrhythmias 0 0 Vasodilatation 27 21 Hypotension 0 0 Phlebitis 0 0 Asthenia 81 11 71 Myalgia 27 10 Arthralgia 19 9 Lacrimation disorder 11 7 Conjunctivitis 0 0Of 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; death per arm was attributed to study drugs. Fever and InfectionDuring 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 3.9% and 2.2% of TAC-treated and FAC-treated patients, respectively. There were no septic deaths in either treatment arm during the treatment period. Gastrointestinal ReactionsIn addition to gastrointestinal reactions reflected in the table above, patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation versus one patient in the FAC arm. Five of the TAC-treated patients required treatment discontinuation; no deaths due to these events occurred during the treatment period. Cardiovascular ReactionsMore cardiovascular reactions were reported in the TAC arm versus the FAC arm during the treatment period: arrhythmias, all grades (6.2% vs 4.9%), and hypotension, all grades (1.9% vs 0.8%). 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 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 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 years). Nervous system disordersIn 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 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in patients (0.3%) in FAC arm.Skin and subcutaneous tissue disordersIn 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 (87.6%).At the end of the follow-up period (actual median follow-up time of years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).Reproductive system and breast disordersIn 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 (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).General disorders and administration site conditionsIn 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 (3.1%). At the end of the follow-up period (actual median follow-up time of years), peripheral edema was ongoing in 19 TAC patients (2.6%) and FAC patients (0.5%).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 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of years), lymphedema was observed to be ongoing in TAC patients (0.8%) and FAC patient (0.1%). 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 (24.5%). At the end of the follow-up period (actual median follow-up time of years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%). 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 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. One TAC patient (0.1%) and FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of years). Myelodysplastic syndrome occurred in of 744 (0.3%) patients who received TAC and in of 736 (0.1%) patients who received FAC. AML occurs at higher frequency when these agents are given in combination with radiation therapy. Lung CancerMonotherapy with Docetaxel Injection for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy Docetaxel Injection 75 mg/m2: Treatment emergent adverse drug reactions are shown in Table 7. Included in this table are safety data for total of 176 patients with non-small cell lung carcinoma and history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted. Table - Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel Injection as Monotherapy for Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy Docetaxel Injection Vinorelbine/ 75 mg/m Best Supportive Care Ifosfamide n=176 n=49 n=119 Adverse Reaction % 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 times ULN Febrile Neutropenia: ANC grade with fever >38C with intravenous antibiotics and/or hospitalization COSTART term and grading system +Not Applicable; ++ Not Done Neutropenia Any 84 14 83 Grade 3/4 65 12 57 Leukopenia Any 84 89 Grade 3/4 49 43 Thrombocytopenia Any 0 Grade 3/4 0 Anemia Any 91 55 91 Grade 3/4 12 14 Febrile Neutropenia NA+ Infection Any 34 29 30 Grade 3/4 10 9 Treatment Related Mortality NA+ Hypersensitivity Reactions Any 0 Grade 3/4 0 Fluid Retention Any 34 ND++ 23 Severe 3 Neurosensory Any 23 14 29 Grade 3/4 6 Neuromotor Any 16 10 Grade 3/4 6 Skin Any 20 17 Grade 3/4 2 Gastrointestinal Nausea Any 34 31 31 Grade 3/4 4 Vomiting Any 22 27 22 Grade 3/4 2 Diarrhea Any 23 12 Grade 3/4 0 Alopecia 56 35 50 Asthenia Any 53 57 54 Severe 18 39 23 Stomatitis Any 26 8 Grade 3/4 0 Pulmonary Any 41 49 45 Grade 3/4 21 29 19 Nail Disorder Any 11 2 Severe 0 Myalgia Any 0 Severe 0 Arthralgia Any 2 Severe 0 Taste Perversion Any 0 Severe 0 0Combination therapy with Docetaxel Injection in chemotherapy-naive advanced unresectable or metastatic NSCLC Table 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 - Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naive Advanced Non-Small Cell Lung Cancer Patients Receiving Docetaxel Injection in Combination with Cisplatin Docetaxel Injection 75 mg/m Vinorelbine 25 mg/m2 + Cisplatin Cisplatin 75 mg/m 100 mg/m2 Adverse Reaction n=406 n=396 % Replaces NCI term Allergy COSTART term and grading system Neutropenia Any 91 90 Grade 3/4 74 78 Febrile Neutropenia 5 Thrombocytopenia Any 15 15 Grade 3/4 4 Anemia Any 89 94 Grade 3/4 25 Infection Any 35 37 Grade 3/4 8 Fever in absence of infection Any 33 29 Grade 3/4 1 Hypersensitivity Reaction Any 12 Grade 3/4 < Fluid Retention Any 54 42 All severe or life-threatening events 2 Pleural effusion Any 23 22 All severe or life-threatening events 2 Peripheral edema Any 34 18 All severe or life-threatening events <1 <1 Weight gain Any 15 All severe or life-threatening events <1 <1 Neurosensory Any 47 42 Grade 3/4 4 Neuromotor Any 19 17 Grade 3/4 6 Skin Any 16 14 Grade 3/4 <1 Nausea Any 72 76 Grade 3/4 10 17 Vomiting Any 55 61 Grade 3/4 16 Diarrhea Any 47 25 Grade 3/4 3 Anorexia Any 42 40 All severe or life-threatening events 5 Stomatitis Any 24 21 Grade 3/4 1 Alopecia Any 75 42 Grade <1 Asthenia Any 74 75 All severe or life-threatening events 12 14 Nail Disorder Any 14 <1 All severe events <1 Myalgia Any 18 12 All severe events <1 <1Deaths 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 patients (2.2%) in the docetaxel+cisplatin arm and patients (2.0%) in the vinorelbine+cisplatin arm. The second comparison in the study, vinorelbine+cisplatin versus Docetaxel Injection+carboplatin (which did not demonstrate superior survival associated with Docetaxel Injection [see Clinical Studies (14.3)]) demonstrated higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the Docetaxel Injection+carboplatin arm, while higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm. Prostate CancerCombination therapy with Docetaxel Injection in patients with prostate cancer The following data are based on the experience of 332 patients, who were treated with Docetaxel Injection 75 mg/m2 every weeks in combination with prednisone mg orally twice daily (see Table 9). Table - Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel Injection in Combination with Prednisone (TAX327) Docetaxel Injection 75 mg/m Mitoxantrone 12 mg/m every weeks every weeks prednisone mg twice daily prednisone mg twice daily n=332 n=335 % Adverse Reaction Any Grade 3/4 Any Grade 3/4 Related to treatment Anemia 67 58 Neutropenia 41 32 48 22 Thrombocytopenia 1 1 Febrile neutropenia N/A N/A Infection 32 20 Epistaxis 0 0 Allergic Reactions 1 0 Fluid Retention 24 5 Weight Gain 0 0 Peripheral Edema 18 2 Neuropathy Sensory 30 7 Neuropathy Motor 2 1 Rash/Desquamation 0 1 Alopecia 65 N/A 13 N/A Nail Changes 30 8 Nausea 41 36 Diarrhea 32 10 Stomatitis/Pharyngitis 20 8 Taste Disturbance 18 7 Vomiting 17 14 Anorexia 17 14 Cough 12 8 Dyspnea 15 9 Cardiac left ventricular function 10 22 Fatigue 53 35 Myalgia 15 13 Tearing 10 2 Arthralgia 1 1Gastric CancerCombination therapy with Docetaxel Injection 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 Injection 75 mg/m2 in combination with cisplatin and fluorouracil (see Table 10). Table 10 Clinically Important Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study Docetaxel Injection 75 mg/m + cisplatin 75 mg/m + Cisplatin 100 mg/m + fluorouracil 750 mg/m fluorouracil 1000 mg/m n=221 n=224 Adverse Reaction Any Grade 3/4 Any Grade 3/4 Clinically important treatment emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction. Related to treatment % % Anemia 97 18 93 26 Neutropenia 96 82 83 57 Fever in the absence of infection 36 23 Thrombocytopenia 26 39 14 Infection 29 16 23 10 Febrile neutropenia 16 N/A N/A Neutropenic infection 16 N/A 10 N/A Allergic reactions 10 6 Fluid retention 15 4 Edema 13 3 Lethargy 63 21 58 18 Neurosensory 38 25 Neuromotor 3 3 Dizziness 16 8 Alopecia 67 41 Rash/itch 12 9 Nail changes 0 0 Skin desquamation 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 Constipation 25 34 Esophagitis/dysphagia/odynophagia 16 14 Gastrointestinal pain/cramping 11 7 Cardiac dysrhythmias 2 1 Myocardial ischemia 0 2 Tearing 0 0 Altered hearing 0 13 2Head and Neck CancerCombination therapy with Docetaxel Injection in head and neck cancer Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with Docetaxel Injection 75 mg/m2 in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients). The treatment regimens are described in Section 14.6.Table 11 Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with Docetaxel Injection in Combination with Cisplatin and Fluorouracil Followed by Radiotherapy (TAX323) or Chemoradiotherapy (TAX324) TAX323 TAX324 (n=355) (n=494) Docetaxel Injection arm Comparator arm Docetaxel Injection arm Comparator arm (n=174) (n=181) (n=251) (n=243) Clinically important treatment emergent adverse reactions based upon frequency, severity, and clinical impact. Febrile neutropenia: grade >=2 fever concomitant with grade neutropenia requiring intravenous antibiotics and/or hospitalization. Related to treatment. Includes superficial and deep vein thrombosis and pulmonary embolism Any Grade Any Grade Any Grade Any Grade Adverse Reaction 3/4 3/4 3/4 3/4 (by Body System) % % Neutropenia 93 76 87 53 95 84 84 56 Anemia 89 88 14 90 12 86 10 Thrombocytopenia 24 47 18 28 31 11 Infection 27 26 23 28 Febrile neutropenia N/A N/A 12 N/A N/A Neutropenic infection 14 N/A N/A 12 N/A N/A Cancer pain 21 16 17 20 11 Lethargy 41 38 61 56 10 Fever in the absence of infection 32 37 30 28 Myalgia 10 7 7 7 Weight loss 21 27 14 14 Allergy 0 0 0 0 Fluid retention 20 14 13 7 Edema only 13 7 12 6 Weight gain only 0 0 0 0 Dizziness 0 1 16 15 Neurosensory 18 11 14 14 Altered hearing 0 10 13 19 Neuromotor 1 1 0 10 Alopecia 81 11 43 68 44 Rash/itch 12 6 20 16 Dry skin 0 0 0 0 Desquamation 1 0 0 0 Nausea 47 51 77 14 80 14 Stomatitis 43 47 11 66 21 68 27 Vomiting 26 39 56 63 10 Diarrhea 33 24 48 40 Constipation 17 16 27 38 Anorexia 16 25 40 12 34 12 Esophagitis/dysphagia/ Odynophagia 13 18 25 13 26 10 Taste, sense of smell altered 10 5 20 17 Gastrointestinal pain/cramping 1 1 15 10 Heartburn 0 0 13 13 Gastrointestinal bleeding 2 0 1 1 Cardiac dysrhythmia 2 1 3 3 Venous 2 2 2 4 Ischemia myocardial 2 0 1 1 Tearing 0 0 0 0 Conjunctivitis 0 0 0 0.4 0. 6.2 Post-Marketing Experiences. The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because these reactions are reported from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as whole: diffuse pain, chest pain, radiation recall phenomenon, injection site recall reaction (recurrence of skin reaction at site of previous extravasation following administration of docetaxel at different site) at the site of previous extravasation. Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Ventricular arrhythmia, including ventricular tachycardia, in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide may be associated with fatal outcome. Cutaneous: cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, scleroderma-like changes (usually preceded by peripheral lymphedema), severe palmar-plantar erythrodysesthesia, and permanent alopecia. Gastrointestinal: enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, which may be fatal. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as consequence of gastrointestinal events. Hearing: ototoxicity, hearing disorders and/or hearing loss, including during use with other ototoxic drugs. Hematologic: bleeding episodes, disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure. Hepatic: hepatitis, sometimes fatal, primarily in patients with pre-existing liver disorders. Hypersensitivity: anaphylactic shock with fatal outcome in patients who received premedication. Severe hypersensitivity reactions with fatal outcome with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel. Metabolism and nutrition disorders: electrolyte imbalance, including hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia. Tumor lysis syndrome, sometimes fatal.Neurologic: confusion, seizures or transient loss of consciousness, sometimes appearing during the infusion of the drug. Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis, cystoid macular edema (CME). Excessive tearing which may be attributable to lacrimal duct obstruction. Transient visual disturbances (flashes, flashing lights, scotomata), typically occurring during drug infusion and reversible upon discontinuation of the infusion, in association with hypersensitivity reactions. Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis, which may be fatal. Radiation pneumonitis in patients receiving concomitant radiotherapy. Renal: renal insufficiency and renal failure, the majority of cases were associated with concomitant nephrotoxic drugs. Second primary malignancies: second primary malignancies, including AML, MDS, NHL, and renal cancer [see Warnings and Precautions (5.7)]. Musculoskeletal disorder: myositis.

BOXED WARNING SECTION.

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION Treatment-related mortality associated with Docetaxel Injection is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and history of prior treatment with platinum-based chemotherapy who receive Docetaxel Injection as single agent at dose of 100 mg/m2 [see Warnings and Precautions (5.1)]. Avoid the use of Docetaxel Injection in patients with bilirubin upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 ULN concomitant with alkaline phosphatase >2.5 ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 ULN also had higher rate of febrile neutropenia. Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of Docetaxel Injection [see Warnings and Precautions (5.2)]. Do not administer Docetaxel Injection to patients with neutrophil counts of <1500 cells/mm3. Monitor blood counts frequently as neutropenia may be severe and result in infection [see Warnings and Precautions (5.3)]. Do not administer Docetaxel Injection to patients who have history of severe hypersensitivity reactions to Docetaxel Injection or to other drugs formulated with polysorbate 80 [see Contraindications (4)]. Severe hypersensitivity reactions have been reported in patients despite dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docetaxel infusion and administration of appropriate therapy [see Warnings and Precautions (5.5)].Severe fluid retention occurred in 6.5% (6/92) of patients despite use of dexamethasone premedication. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites) [see Warnings and Precautions (5.6)].. WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTIONSee full prescribing information for complete boxed warning.Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving Docetaxel Injection at 100 mg/m2 (5.1)Avoid use of Docetaxel Injection if bilirubin ULN, or if AST and/or ALT >1.5 ULN concomitant with alkaline phosphatase >2.5 ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (5.2)Do not administer Docetaxel Injection to patients with neutrophil counts <1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4, 5.3)Severe hypersensitivity, including fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.5)Contraindicated if history of severe hypersensitivity reactions to Docetaxel Injection or to drugs formulated with polysorbate 80 (4)Severe fluid retention may occur despite dexamethasone (5.6). Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving Docetaxel Injection at 100 mg/m2 (5.1). Avoid use of Docetaxel Injection if bilirubin ULN, or if AST and/or ALT >1.5 ULN concomitant with alkaline phosphatase >2.5 ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (5.2). Do not administer Docetaxel Injection to patients with neutrophil counts <1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4, 5.3). Severe hypersensitivity, including fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.5). Contraindicated if history of severe hypersensitivity reactions to Docetaxel Injection or to drugs formulated with polysorbate 80 (4). Severe fluid retention may occur despite dexamethasone (5.6).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action. 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. Docetaxels binding to microtubules does not alter the number of protofilaments in the bound microtubules, feature which differs from most spindle poisons currently in clinical use. 12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20 mg/m2 to 115 mg/m2 in phase studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion times of to hours. Docetaxels pharmacokinetic profile is consistent with three-compartment pharmacokinetic model, with half-lives for the , and phases of min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m2. DistributionThe initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to 1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel. Metabolism In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 [see Drug Interactions (7)]. EliminationA study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as major and minor metabolites with very small amounts (less than 8%) of unchanged drug.Specific PopulationsEffect of Age: population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m2. Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase studies. The pharmacokinetics of docetaxel was not influenced by age. 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 38% increase in systemic exposure (AUC). This average, however, includes 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 Injection. Patients with severe hepatic impairment have not been studied [see Warnings and Precautions (5.2), Use in Specific Populations (8.6)]. Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m2 to 90 mg/m2 was similar to that of European/American populations dosed at 100 mg/m2, suggesting no significant difference in the elimination of docetaxel in the two populations. Drug Interaction StudiesEffect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in cancer patients. Patients were randomized to receive either docetaxel (100 mg/m2 intravenous) alone or docetaxel (10 mg/m2 intravenous) in combination with ketoconazole (200 mg orally once daily for days) in crossover design with 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was co-administered with ketoconazole [see Dosage and Administration (2.7), Drug Interactions (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: 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: study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between docetaxel (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) when administered in combination. The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy.. 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: 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: study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between docetaxel (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) when administered in combination. The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Locally Advanced or Metastatic Breast Cancer. The efficacy and safety of Docetaxel Injection have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens). Randomized TrialsIn one randomized trial, patients with history of prior treatment with an anthracycline-containing regimen were assigned to treatment with Docetaxel Injection (100 mg/m2 every weeks) or the combination of mitomycin (12 mg/m2 every weeks) and vinblastine (6 mg/m2 every weeks). Two hundred three patients were randomized to Docetaxel Injection and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the Docetaxel Injection arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results (See Table 12). Table 12 Efficacy of Docetaxel Injection in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis) Efficacy Parameter Docetaxel Mitomycin/ p-value Vinblastine (n=203) (n=189) For the risk ratio, value less than 1.00 favors docetaxel. Median Survival 11.4 months 8.7 months Risk Ratio, Mortality (Docetaxel: Control) 0.73 p=0.01 Log Rank 95% CI (Risk Ratio) 0.58 to 0.93 Median Time to Progression 4.3 months 2.5 months Risk Ratio, Progression p=0.01 (Docetaxel: Control) 0.75 Log Rank 95% CI (Risk Ratio) 0.61 to 0.94 Overall Response Rate 28.1% 9.5% p<0.0001 Complete Response Rate 3.4% 1.6% Chi SquareIn second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with Docetaxel Injection (100 mg/m2) or doxorubicin (75 mg/m2) every weeks. One hundred sixty-one patients were randomized to Docetaxel Injection and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below (See Table 13). Table 13 Efficacy of Docetaxel Injection in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis) Efficacy Parameter Docetaxel Doxorubicin p-value (n=161) (n=165) For the risk ratio, value less than 1.00 favors docetaxel. Median Survival 14.7 months 14.3 months Risk Ratio, Mortality (Docetaxel: Control) 0.89 p=0.39 Log Rank 95% CI (Risk Ratio) 0.68 to 1.16 Median Time to Progression 6.5 months 5.3 months Risk Ratio, Progression (Docetaxel: Control) 0.93 p=0.45 Log Rank 95% CI (Risk Ratio) 0.71 to 1.16 Overall Response Rate 45.3% 29.7% p=0.004 Complete Response Rate 6.8% 4.2% Chi SquareIn 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 Injection monotherapy 60 mg/m2 (n=151), 75 mg/m2 (n=188) or 100 mg/m2 (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with Docetaxel Injection dose: 19.9% for the 60 mg/m2 group compared to 22.3% for the 75 mg/m2 and 29.8% for the 100 mg/m2 group; pair-wise comparison between the 60 mg/m2 and 100 mg/m2 groups was statistically significant (p=0.037). Single Arm StudiesDocetaxel Injection at dose of 100 mg/m2 was studied in six single arm studies involving total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% CI: 31.0 to 44.8) and the complete response rate was 2.1%. Docetaxel Injection was also studied in three single arm Japanese studies at dose of 60 mg/m2, in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% CI: 17.2 to 55.7), similar to the response rate in single arm studies of 100 mg/m2. 14.2 Adjuvant Treatment of Breast Cancer. multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of Docetaxel Injection 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 to 3, 4+), 1491 patients were randomized to receive either Docetaxel Injection 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 (FAC arm). Both regimens were administered every weeks for cycles. Docetaxel Injection was administered as 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Results from 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=0.60, 0.92, stratified log rank p=0.0047). 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=0.53, 0.90). (See Figure 2.) There will be further analysis at the time survival data mature. Figure - TAX316 Disease Free Survival K-M curveFigure - TAX316 Overall Survival K-M CurveThe following table describes the results of subgroup analyses for DFS and OS (See Table 14).Table 14 Subset Analyses-Adjuvant Breast Cancer Study Disease Free Survival Overall Survival Patient subset Number of Hazard 95% CI Hazard 95% CI patients ratio ratio hazard ratio of less than indicates that TAC is associated with longer disease free survival or overall survival compared to FAC. No. of positive nodes Overall 744 0.74 (0.60, 0.92) 0.69 (0.53, 0.90) to 467 0.64 (0.47, 0.87) 0.45 (0.29, 0.70) 4+ 277 0.84 (0.63, 1.12) 0.93 (0.66, 1.32) Receptor status Positive 566 0.76 (0.59, 0.98) 0.69 (0.48, 0.99) Negative 178 0.68 (0.48, 0.97) 0.66 (0.44, 0.98). c3e54dbf-figure-02. c3e54dbf-figure-03. 14.3 Non-Small Cell Lung Cancer (NSCLC). The efficacy and safety of Docetaxel Injection 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 Injection for NSCLC Previously Treated with Platinum-Based ChemotherapyTwo randomized, controlled trials established that Docetaxel Injection dose of 75 mg/m2 was tolerable and yielded favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel Injection at dose of 100 mg/m2, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5.3)]. One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status <=2 to Docetaxel Injection or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to Docetaxel Injection 100 mg/m2 or best supportive care, but early toxic deaths at this dose led to dose reduction to Docetaxel Injection 75 mg/m2. total of 104 patients were randomized in this amended study to either Docetaxel Injection 75 mg/m2 or best supportive care. In second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, history of prior platinum-based chemotherapy, and an ECOG performance status <=2 were randomized to Docetaxel Injection 75 mg/m2, Docetaxel Injection 100 mg/m2 and treatment in which the investigator chose either vinorelbine 30 mg/m2 days 1, 8, and 15 repeated every weeks or ifosfamide g/m2 days to repeated every weeks. Forty percent of the patients in this study had history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the Docetaxel Injection 75 mg/m2 arm and the comparator arms are summarized in Table 15 and Figures and showing the survival curves for the two studies. Table 15 Efficacy of Docetaxel Injection in the Treatment of Non-Small Cell Lung Cancer Patients Previously Treated with Platinum-Based Chemotherapy Regimen (Intent-to-Treat Analysis) TAX317 TAX320 Docetaxel Best Docetaxel Control 75 mg/m Supportive Care 75 mg/m (V/I) n=55 n=49 n=125 n=123 Vinorelbine/Ifosfamide p<=0.05 uncorrected for multiple comparisons ++ value less than 1.00 favors docetaxel Overall Survival Log-rank Test p=0.01 p=0.13 Risk Ratio++, Mortality (Docetaxel: Control) 0.56 0.82 95% CI (Risk Ratio) (0.35, 0.88) (0.63, 1.06) Median Survival 7.5 months 4.6 months 5.7 months 5.6 months 95% CI (5.5, 12.8) (3.7, 6.1) (5.1, 7.1) (4.4, 7.9) 1-year Survival 37%+ 12% 30%+ 20% 95% CI (24, 50) (2, 23) (22, 39) (13, 27) Time to Progression 12.3 weeks 7.0 weeks 8.3 weeks 7.6 weeks 95% CI (9.0, 18.3) (6.0, 9.3) (7.0, 11.7) (6.7, 10.1) Response Rate 5.5% 5.7% 0.8% Not 95% CI (1.1, 15.1) Applicable (2.3, 11.3) (0.0, 4.5)Only one of the two trials (TAX317) showed 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 Injection 75 mg/m2. Figure - TAX317 Survival K-M Curves Docetaxel Injection 75 mg/m2 vs. Best Supportive CareFigure - TAX320 Survival K-M Curves Docetaxel Injection 75 mg/m2 vs. Vinorelbine or Ifosfamide ControlPatients treated with Docetaxel Injection at dose of 75 mg/m2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials. Combination Therapy with Docetaxel Injection for Chemotherapy-Naive NSCLCIn 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 Injection 75 mg/m2 as 1 hour infusion immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every weeks; vinorelbine 25 mg/m2 administered over to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day of cycles repeated every weeks; or combination of Docetaxel Injection and carboplatin. The primary efficacy endpoint was overall survival. Treatment with Docetaxel Injection+cisplatin did not result in 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 Injection to cisplatin results in an outcome ranging from 6% inferior to 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of 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 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the Docetaxel Injection+cisplatin arm and the comparator arm are summarized in Table 16. Table 16 Survival Analysis of Docetaxel Injection in Combination Therapy for Chemotherapy-Naive NSCLC Comparison Docetaxel Injection+Cisplatin Vinorelbine+Cisplatin n=408 n=405 From the superiority test (stratified log rank) comparing Docetaxel Injection+cisplatin to vinorelbine+cisplatin bHazard ratio of Docetaxel Injection+cisplatin vs. vinorelbine+cisplatin. hazard ratio of less than indicates that Docetaxel Injection+cisplatin is associated with longer survival. cAdjusted for interim analysis and multiple comparisons. Kaplan-Meier Estimate of Median Survival 10.9 months 10.0 months p-valuea 0.122 Estimated Hazard Ratiob 0.88 Adjusted 95% CIc (0.74, 1.06)The second comparison in the same three-arm study, vinorelbine+cisplatin versus Docetaxel Injection+carboplatin, did not demonstrate superior survival associated with the Docetaxel Injection arm (Kaplan-Meier estimate of median survival was 9.1 months for Docetaxel Injection+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the Docetaxel Injection+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 Injection+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 17). Table 17 Response and TTP Analysis of Docetaxel Injection in Combination Therapy for Chemotherapy-Naive NSCLC Endpoint Docetaxel Injection+Cisplatin Vinorelbine+Cisplatin p-value aAdjusted for multiple comparisons. bKaplan-Meier estimates. Objective Response Rate 31.6% 24.4% Not Significant (95% CI)a (26.5%, 36.8%) (19.8%, 29.2%) Median Time to Progressionb 21.4 weeks 22.1 weeks Not Significant (95% CI)a (19.3, 24.6) (18.1, 25.6) c3e54dbf-figure-04. c3e54dbf-figure-05. 14.4 Castration-Resistant Prostate Cancer. The safety and efficacy of Docetaxel Injection in combination with prednisone in patients with metastatic castration-resistant prostate cancer were evaluated in randomized multicenter active control trial. total of 1006 patients with Karnofsky Performance Status (KPS) >=60 were randomized to the following treatment groups: Docetaxel Injection 75 mg/m2 every weeks for 10 cycles. Docetaxel Injection 30 mg/m2 administered weekly for the first weeks in 6-week cycle for cycles. Mitoxantrone 12 mg/m2 every weeks for 10 cycles. All regimens were administered in combination with prednisone mg twice daily, continuously. In the Docetaxel Injection every three week arm, statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the Docetaxel Injection weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the Docetaxel Injection every week arm versus the control arm are summarized in Table 18 and Figure 5. Table 18 Efficacy of Docetaxel Injection in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (Intent-to-Treat Analysis) Docetaxel Injection+Prednisone Mitoxantrone+Prednisone every weeks every weeks Stratified log rank test. Threshold for statistical significance 0.0175 because of arms. Number of patients 335 337 Median survival (months) 18.9 16.5 95% CI (17.0 to 21.2) (14.4 to 18.6) Hazard ratio 0.761 -- 95% CI (0.619 to 0.936) -- p-value 0.0094 --Figure - TAX327 Survival K-M Curves. Docetaxel Injection 75 mg/m2 every weeks for 10 cycles. Docetaxel Injection 30 mg/m2 administered weekly for the first weeks in 6-week cycle for cycles. Mitoxantrone 12 mg/m2 every weeks for 10 cycles. c3e54dbf-figure-06. 14.5 Gastric Adenocarcinoma. multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of Docetaxel Injection for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. total of 445 patients with KPS >70 were treated with either Docetaxel Injection (T) (75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and fluorouracil (F) (750 mg/m2 per day for days) or cisplatin (100 mg/m2 on day 1) and fluorouracil (1000 mg/m2 per day for days). The length of treatment cycle was weeks for the TCF arm and weeks for the CF arm. The demographic characteristics were balanced between the two treatment arms. The median age was 55 years, 71% were male, 71% were Caucasian, 24% were 65 years of age or older, 19% had prior curative surgery and 12% had palliative surgery. The median number of cycles administered per patient was (with range of to 16) for the TCF arm compared to (with range of to 12) for the CF arm. Time to progression (TTP) was the primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization. The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19 to 1.83) with significantly longer TTP (p=0.0004) in the TCF arm. Approximately 75% of patients had died at the time of this analysis. Overall survival was significantly longer (p=0.0201) in the TCF arm with HR of 1.29 (95% CI: 1.04 to 1.61). Efficacy results are summarized in Table 19 and Figures and 7. Table 19 Efficacy of Docetaxel Injection in the Treatment of Patients with Gastric Adenocarcinoma Endpoint TCF CF n=221 n=224 Unstratified log-rank test +For the hazard ratio (TCF/CF), values less than 1.00 favor the Docetaxel Injection arm. Median TTP (months) 5.6 3.7 (95% CI) (4.86 to 5.91) (3.45 to 4.47) Hazard ratio+ 0.68 (95% CI) (0.55 to 0.84) p-value 0.0004 Median survival (months) 9.2 8.6 (95% CI) (8.38 to 10.58) (7.16 to 9.46) Hazard ratio+ 0.77 (95% CI) (0.62 to 0.96) p-value 0.0201 Overall Response Rate (CR+PR) (%) 36.7 25.4 p-value 0.0106Subgroup analyses were consistent with the overall results across age, gender and race.Figure - Gastric Cancer Study (TAX325) Time to Progression K-M CurveFigure - Gastric Cancer Study (TAX325) Survival K-M Curve. c3e54dbf-figure-07. c3e54dbf-figure-08. 14.6 Head and Neck Cancer. Induction chemotherapy followed by radiotherapy (TAX323)The safety and efficacy of Docetaxel Injection in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status or 1, were randomized to one of two treatment arms. Patients on the Docetaxel Injection arm received Docetaxel Injection (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 on Day 1, followed by fluorouracil (F) 750 mg/m2 per day as continuous infusion on Days to 5. The cycles were repeated every three weeks for cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 on Day 1, followed by fluorouracil (F) 1000 mg/m2/day as continuous infusion on Days to 5. The cycles were repeated every three weeks for cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with minimal interval of weeks and maximal interval of weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with conventional fraction regimen (1.8 Gy to 2.0 Gy once day, days per week for total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice day, with minimum interfraction interval of hours, days per week, for total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy. 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: 11.4 vs. 8.3 months respectively) with an overall median follow-up time of 33.7 months. Median overall survival with median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months, respectively). Efficacy results are presented in Table 20 and Figures and 9. Table 20 Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Inoperable Locally Advanced SCCHN (Intent-to-Treat Analysis) Endpoint Docetaxel Injection+ Cisplatin+ Cisplatin+ Fluorouracil Fluorouracil n=177 n=181 Hazard ratio of less than favors Docetaxel Injection+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 Median progression free survival (months) 11.4 8.3 (95% CI) (10.1 to 14.0) (7.4 to 9.1) Adjusted Hazard ratio 0.71 (95% CI) (0.56 to 0.91) p-value 0.0077 Median survival (months) 18.6 14.2 (95% CI) (15.7 to 24.0) (11.5 to 18.7) Hazard ratio 0.71 (95% CI) (0.56 to 0.90) p-value 0.0055 Best overall response (CR PR) to chemotherapy (%) 67.8 53.6 (95% CI) (60.4 to 74.6) (46.0 to 61.0) p-value 0.006 Best overall response (CR PR) to study treatment [chemotherapy +/- radiotherapy] (%) 72.3 58.6 (95% CI) (65.1 to 78.8) (51.0 to 65.8) p-value 0.006Figure - TAX323 Progression-Free Survival K-M CurveFigure - TAX323 Overall Survival K-M CurveInduction chemotherapy followed by chemoradiotherapy (TAX324)The safety and efficacy of Docetaxel Injection in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and WHO performance status of or 1, were randomized to one of two treatment arms. Patients on the Docetaxel Injection arm received Docetaxel Injection (T) 75 mg/m2 by intravenous infusion on day followed by cisplatin (P) 100 mg/m2 administered as 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m2/day from day to day 4. The cycles were repeated every weeks for cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m2 as 30-minute to three-hour intravenous infusion on day followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m2/day from day to day 5. The cycles were repeated every weeks for cycles. All patients in both treatment arms who did not have progressive disease were to receive weeks of chemoradiotherapy (CRT) following induction chemotherapy to weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as one-hour intravenous infusion for maximum of doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, days per week for weeks for total dose of 70 to 72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT. The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the Docetaxel Injection-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 0.90]. Overall survival results are presented in Table 21 and Figure 10.Table 21 Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Locally Advanced SCCHN (Intent-to-Treat Analysis) Docetaxel Injection+ Cisplatin+ Cisplatin+Fluorouracil Fluorouracil Endpoint n=255 n=246 Hazard ratio of less than favors Docetaxel Injection+cisplatin+fluorouracil un-adjusted log-rank test NE not estimable Median overall survival (months) 70.6 30.1 (95% CI) (49.0 to NE) (20.9 to 51.5) Hazard ratio: 0.70 (95% CI) (0.54 to 0.90) p-value 0.0058Figure 10 TAX324 Overall Survival K-M Curve. c3e54dbf-figure-09. c3e54dbf-figure-10. c3e54dbf-figure-11.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Docetaxel Injection is contraindicated in patients with: neutrophil counts of <1500 cells/mm3 [see Warnings and Precautions (5.3)]. history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions (5.5)]. neutrophil counts of <1500 cells/mm3 [see Warnings and Precautions (5.3)]. a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions (5.5)]. Hypersensitivity to docetaxel or polysorbate 80 (4) Neutrophil counts of <1500 cells/mm3 (4) Hypersensitivity to docetaxel or polysorbate 80 (4) Neutrophil counts of <1500 cells/mm3 (4).

DESCRIPTION SECTION.

11 DESCRIPTION Docetaxel, USP is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel, USP is (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5-20-epoxy-1,2,4,7,10,13-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, anhydrous. Docetaxel, USP has the following structural formula: Docetaxel, USP is white to almost-white powder with an empirical formula of C43H53NO14, and molecular weight of 807.88. It is highly lipophilic and practically insoluble in water. One-vial Docetaxel Injection, USPDocetaxel Injection, USP is sterile, non-pyrogenic, clear, viscous, colorless to pale yellow solution, without macroscopic particles in solution at 20 mg/mL docetaxel concentration.Each mL contains 20 mg docetaxel, USP, citric acid anhydrous (6 mg), kollidon 12 PF (povidone P12) (100 mg), polysorbate 80 (424 mg) and ethanol (400 mg, 50% v/v).Docetaxel Injection, USP is available in single-dose vials containing 20 mg (1 mL), 80 mg (4 mL), or 160 mg (8 mL) docetaxel. Docetaxel Injection, USP requires NO prior dilution with diluent and is ready to add to the infusion solution.. c3e54dbf-figure-01.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7)]. Administer in facility equipped to manage possible complications (e.g. anaphylaxis). Administer in facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over hr every weeks. PVC equipment is not recommended. Use only 21 gauge needle to withdraw Docetaxel Injection from the vial. BC locally advanced or metastatic: 60 mg/m2 to 100 mg/m2 single agent (2.1)BC adjuvant: 75 mg/m2 administered hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every weeks for cycles (2.1) NSCLC: after platinum therapy failure: 75 mg/m2 single agent (2.2)NSCLC: chemotherapy-naive: 75 mg/m2 followed by cisplatin 75 mg/m2 (2.2) HRPC: 75 mg/m2 with mg prednisone twice day continuously (2.3) GC: 75 mg/m2 followed by cisplatin 75 mg/m2 (both on day only) followed by fluorouracil 750 mg/m2 per day as 24-hr IV (days to 5), starting at end of cisplatin infusion (2.4) SCCHN: 75 mg/m2 followed by cisplatin 75 mg/m2 IV (day 1), followed by fluorouracil 750 mg/m2 per day as 24-hr IV (days to 5), starting at end of cisplatin infusion; for cycles (2.5) SCCHN: 75 mg/m2 followed by cisplatin 100 mg/m2 IV (day 1), followed by fluorouracil 1000 mg/m2 per day as 24-hr IV (days to 4); for cycles (2.5) For all patients: Premedicate with oral corticosteroids (2.6) Adjust dose as needed (2.7) BC locally advanced or metastatic: 60 mg/m2 to 100 mg/m2 single agent (2.1). BC adjuvant: 75 mg/m2 administered hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every weeks for cycles (2.1) NSCLC: after platinum therapy failure: 75 mg/m2 single agent (2.2). NSCLC: chemotherapy-naive: 75 mg/m2 followed by cisplatin 75 mg/m2 (2.2) HRPC: 75 mg/m2 with mg prednisone twice day continuously (2.3) GC: 75 mg/m2 followed by cisplatin 75 mg/m2 (both on day only) followed by fluorouracil 750 mg/m2 per day as 24-hr IV (days to 5), starting at end of cisplatin infusion (2.4) SCCHN: 75 mg/m2 followed by cisplatin 75 mg/m2 IV (day 1), followed by fluorouracil 750 mg/m2 per day as 24-hr IV (days to 5), starting at end of cisplatin infusion; for cycles (2.5) SCCHN: 75 mg/m2 followed by cisplatin 100 mg/m2 IV (day 1), followed by fluorouracil 1000 mg/m2 per day as 24-hr IV (days to 4); for cycles (2.5) Premedicate with oral corticosteroids (2.6) Adjust dose as needed (2.7) 2.1 Breast Cancer. For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection is 60 mg/m2 to 100 mg/m2 administered intravenously over hour every weeks. For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m2 administered hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every weeks for courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7)]. For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection is 60 mg/m2 to 100 mg/m2 administered intravenously over hour every weeks. For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m2 administered hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every weeks for courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7)]. 2.2 Non-Small Cell Lung Cancer. For treatment after failure of prior platinum-based chemotherapy, Docetaxel Injection was evaluated as monotherapy, and the recommended dose is 75 mg/m2 administered intravenously over hour every weeks. dose of 100 mg/m2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5), Clinical Studies (14)]. For chemotherapy-naive patients, Docetaxel Injection was evaluated in combination with cisplatin. The recommended dose of Docetaxel Injection is 75 mg/m2 administered intravenously over hour immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every weeks [see Dosage and Administration (2.7)]. For treatment after failure of prior platinum-based chemotherapy, Docetaxel Injection was evaluated as monotherapy, and the recommended dose is 75 mg/m2 administered intravenously over hour every weeks. dose of 100 mg/m2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5), Clinical Studies (14)]. For chemotherapy-naive patients, Docetaxel Injection was evaluated in combination with cisplatin. The recommended dose of Docetaxel Injection is 75 mg/m2 administered intravenously over hour immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every weeks [see Dosage and Administration (2.7)]. 2.3 Prostate Cancer. For metastatic castration-resistant prostate cancer, the recommended dose of Docetaxel Injection is 75 mg/m2 every weeks as 1 hour intravenous infusion. Prednisone mg orally twice daily is administered continuously [see Dosage and Administration (2.7)]. For metastatic castration-resistant prostate cancer, the recommended dose of Docetaxel Injection is 75 mg/m2 every weeks as 1 hour intravenous infusion. Prednisone mg orally twice daily is administered continuously [see Dosage and Administration (2.7)]. 2.4 Gastric Adenocarcinoma. For gastric adenocarcinoma, the recommended dose of Docetaxel Injection is 75 mg/m2 as 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as 1 to hour intravenous infusion (both on day only), followed by fluorouracil 750 mg/m2 per day given as 24-hour continuous intravenous infusion for days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)]. For gastric adenocarcinoma, the recommended dose of Docetaxel Injection is 75 mg/m2 as 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as 1 to hour intravenous infusion (both on day only), followed by fluorouracil 750 mg/m2 per day given as 24-hour continuous intravenous infusion for days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)]. 2.5 Head and Neck Cancer. Patients 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 Docetaxel Injection 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 Docetaxel Injection is 75 mg/m2 as 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over hour, on day one, followed by fluorouracil as continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every weeks for cycles. Following chemotherapy, patients should receive radiotherapy [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 Docetaxel Injection is 75 mg/m2 as 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as 30-minute to hour infusion, followed by fluorouracil 1000 mg/m2/day as continuous infusion from day to day 4. This regimen is administered every weeks for cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)].. Induction chemotherapy followed by radiotherapy (TAX323) For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over hour, on day one, followed by fluorouracil as continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every weeks for cycles. Following chemotherapy, patients should receive radiotherapy [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 Docetaxel Injection is 75 mg/m2 as 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as 30-minute to hour infusion, followed by fluorouracil 1000 mg/m2/day as continuous infusion from day to day 4. This regimen is administered every weeks for cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)].. 2.6 Premedication Regimen. All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., mg twice daily) for days starting day prior to Docetaxel Injection administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.5)]. For metastatic castration-resistant prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone mg at 12 hours, hours, and hour before the Docetaxel Injection infusion [see Warnings and Precautions (5.5)]. 2.7 Dosage Adjustments During Treatment. Breast CancerPatients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than week, or severe or cumulative cutaneous reactions during Docetaxel Injection therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docetaxel Injection therapy may tolerate higher doses. Patients who develop >=grade peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely. Combination Therapy with Docetaxel Injection in the Adjuvant Treatment of Breast CancerDocetaxel Injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is >=1,500 cells/mm3. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their Docetaxel Injection dose reduced to 60 mg/m2. Patients who experience grade or stomatitis should have their Docetaxel Injection dose decreased to 60 mg/m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have their dosage of Docetaxel Injection reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, treatment should be discontinued. Non-Small Cell Lung CancerMonotherapy with Docetaxel Injection for NSCLC treatment after failure of prior platinum-based chemotherapy Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Docetaxel Injection treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop >=grade peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely. Combination therapy with Docetaxel Injection for chemotherapy-naive NSCLCFor patients who are dosed initially at Docetaxel Injection 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the Docetaxel Injection dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require further dose reduction, dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers prescribing information. Prostate CancerCombination therapy with Docetaxel Injection for metastatic castration-resistant prostate cancer Docetaxel Injection should be administered when the neutrophil count is >=1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have the dosage of Docetaxel Injection reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.Gastric or Head and Neck CancerDocetaxel Injection in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer Patients treated with Docetaxel Injection 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 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. Do not retreat patients with subsequent cycles of Docetaxel Injection until neutrophils recover to level >1,500 cells/mm3 [see Contraindications (4)]. Avoid retreating patients until platelets recover to level >100,000 cells/mm3. Discontinue treatment if these toxicities persist [see Warnings and Precautions (5.3)]. Recommended dose modifications for toxicities in patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil are shown in Table 1.Table - Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel Injection in Combination with Cisplatin and FluorouracilToxicityDosage adjustmentDiarrhea grade First episode: reduce fluorouracil dose by 20%. Second episode: then reduce Docetaxel Injection dose by 20%. Diarrhea grade First episode: reduce Docetaxel Injection and fluorouracil doses by 20%. Second episode: discontinue treatment. Stomatitis/mucositis grade First episode: reduce fluorouracil dose by 20%. Second episode: stop fluorouracil only, at all subsequent cycles. Third episode: reduce Docetaxel Injection dose by 20%. Stomatitis/mucositis grade First episode: stop fluorouracil only, at all subsequent cycles. Second episode: reduce Docetaxel Injection dose by 20%. 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, Docetaxel Injection should be reduced by 20%. In case of AST/ALT >5 ULN and/or AP >5 ULN Docetaxel Injection should be stopped. The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below.Cisplatin dose modifications and delaysPeripheral neuropathy: neurological examination should be performed before entry into the study, and then at least every 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 toxicity, discontinue treatment. Nephrotoxicity: In the event of rise in serum creatinine >=grade (>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 - Dose Reductions for Evaluation of Creatinine Clearance Creatinine clearance result before next cycle Cisplatin dose next cycle CrCl Creatinine clearance CrCl >=60 mL/min Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle. Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was CrCl between 40 and 59 mL/min>60 mL/min at end of cycle, full cisplatin dose was reinstituted at the next cycle. If no recovery was observed, then cisplatin was omitted from the next treatment cycle. Dose of cisplatin was omitted in that treatment cycle only. If CrCl was still <40 mL/min at the end of cycle, cisplatin was discontinued. CrCl <40 mL/minIf CrCl was >40 and <60 mL/min at end of cycle, 50% cisplatin dose was given at the next cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle. Fluorouracil dose modifications and treatment delaysFor diarrhea and stomatitis, see Table 1. In the event of grade or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%. For other greater than grade toxicities, except alopecia and anemia, chemotherapy should be delayed (for maximum of 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 InhibitorsAvoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from pharmacokinetic study with ketoconazole in patients, consider 50% docetaxel dose reduction if patients require co-administration of strong CYP3A4 inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Grade 2: Reduce cisplatin dose by 20%. Grade 3: Discontinue treatment. 2.8 Administration Precautions. Docetaxel Injection is cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docetaxel Injection solutions. The use of gloves is recommended [see How Supplied/Storage and Handling (16.3)]. If Docetaxel Injection initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.Contact of the Docetaxel Injection 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, the final Docetaxel Injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. One-vial Docetaxel InjectionDocetaxel Injection requires NO prior dilution with diluent and is ready to add to the infusion solution. Please follow the preparation instructions provided below. 2.9 Preparation and Administration. DO NOT use the two-vial formulation (Injection and diluent) with the one-vial formulation. One-vial Docetaxel InjectionDocetaxel Injection (20 mg/mL) requires NO prior dilution with diluent and is ready to add to the infusion solution. Use only 21 gauge needle to withdraw Docetaxel Injection from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates. Docetaxel Injection vials should be stored at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) protected from light. Using only 21 gauge needle, aseptically withdraw the required amount of Docetaxel Injection (20 mg docetaxel/mL) with calibrated syringe and inject via single injection (one shot) into 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce final concentration of 0.3 mg/mL to 0.74 mg/mL. If dose greater than 200 mg of Docetaxel Injection is required, use larger volume of the infusion vehicle so that concentration of 0.74 mg/mL Docetaxel Injection is not exceeded. Thoroughly mix the infusion by gentle manual rotation. As with all parenteral products, Docetaxel Injection should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Docetaxel Injection dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded.Docetaxel Injection infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.The Docetaxel Injection dilution for infusion should be administered intravenously as 1-hour infusion under ambient room temperature (below 25C) and lighting conditions.. Docetaxel Injection vials should be stored at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) protected from light. Using only 21 gauge needle, aseptically withdraw the required amount of Docetaxel Injection (20 mg docetaxel/mL) with calibrated syringe and inject via single injection (one shot) into 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce final concentration of 0.3 mg/mL to 0.74 mg/mL. If dose greater than 200 mg of Docetaxel Injection is required, use larger volume of the infusion vehicle so that concentration of 0.74 mg/mL Docetaxel Injection is not exceeded. Thoroughly mix the infusion by gentle manual rotation. As with all parenteral products, Docetaxel Injection should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Docetaxel Injection dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded.. Docetaxel Injection infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.. 2.10 Stability. Docetaxel Injection final dilution for infusion, if stored between 2C and 25C (36F and 77F) is stable for hours. Docetaxel Injection final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within hours (including the hour intravenous administration).In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2C and 8C (36F and 46F).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS One-vial Docetaxel Injection, USPDocetaxel Injection, USP is available as 20 mg/mL, 80 mg/4 mL, and 160 mg/8 mL in single-dose vials.. Injection: One-vial Docetaxel: Single dose vials 20 mg/mL, 80 mg/4 mL and 160 mg/8 mL (3). Injection: One-vial Docetaxel: Single dose vials 20 mg/mL, 80 mg/4 mL and 160 mg/8 mL (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Docetaxel is CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of Docetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with Docetaxel Injection, close monitoring for toxicity and Docetaxel Injection dose reduction could be considered if systemic administration of potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)]. Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism. (7). Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism. (7).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied. Docetaxel Injection, USP is supplied as sterile, pyrogen-free, non-aqueous solution in single-dose, flip-top glass vials, as clear, viscous, colorless to pale yellow solution, without macroscopic particles in solution at 20 mg/mL concentration, in the following package strengths: Docetaxel Injection USP, 20 mg/mL available as one vial per carton NDC 45963-734-54Docetaxel Injection USP, 80 mg/4 mL (20 mg/mL) available as one vial per carton NDC 45963-765-52Docetaxel Injection USP, 160 mg/8 mL (20 mg/mL) available as one vial per carton NDC 45963-790-56Discard unused portion. The vial stopper is not made with natural rubber latex. 16.2 Storage. Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). Retain in the original package to protect from light.. 16.3 Handling and Disposal. Docetaxel Injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE . Docetaxel Injection is microtubule inhibitor indicated for: Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC (1.1) Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC (1.2)Castration-Resistant Prostate Cancer (CRPC): with prednisone in metastatic castration-resistant prostate cancer (1.3) Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction (1.4) Squamous Cell Carcinoma of the Head and Neck (SCCHN): with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN (1.5) Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC (1.1) Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC (1.2). Castration-Resistant Prostate Cancer (CRPC): with prednisone in metastatic castration-resistant prostate cancer (1.3) Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction (1.4) Squamous Cell Carcinoma of the Head and Neck (SCCHN): with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN (1.5) 1.1 Breast Cancer. Docetaxel Injection is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. Docetaxel Injection in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. 1.2 Non-Small Cell Lung Cancer. Docetaxel Injection as 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. Docetaxel Injection 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. 1.3 Prostate Cancer. Docetaxel Injection in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer. 1.4 Gastric Adenocarcinoma. Docetaxel Injection 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. 1.5 Head and Neck Cancer. Docetaxel Injection 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved Patient Labeling (Patient Information).Bone Marrow SuppressionAdvise patients that periodic assessment of their blood count will be performed to detect neutropenia, thrombocytopenia, and/ or anemia [see Contraindications (4), Warnings and Precautions (5.3)]. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.Enterocolitis and Neutropenic ColitisAdvise patients of the symptoms of colitis, such as abdominal pain or tenderness, and/or diarrhea, with or without fever, and instruct patients to promptly contact their healthcare provider if they experience these symptoms [see Dosage and Administration (2.7), Warnings and Precautions (5.4)].Hypersensitivity ReactionsAsk patients whether they have previously received paclitaxel therapy, and if they have experienced hypersensitivity reaction to paclitaxel. Instruct patients to immediately report to their healthcare provider signs of hypersensitivity reaction [see Contraindications (4), Warnings and Precautions (5.5)].Fluid RetentionAdvise patients to report signs of fluid retention such as peripheral edema in the lower extremities, weight gain, and dyspnea immediately to their healthcare provider [see Warnings and Precautions (5.6)].Second Primary MalignanciesAdvise patients on the risk of second primary malignancies during treatment with Docetaxel Injection [see Warnings and Precautions (5.7)].Cutaneous Reactions Advise patients that localized erythema of the extremities and severe skin toxicities may occur. Instruct patients to immediately report severe cutaneous reactions to their healthcare provider [see Dosage and Administration (2.7) and Warnings and Precautions (5.8)].Neurologic ReactionsAdvise patients that neurosensory symptoms or peripheral neuropathy may occur. Instruct patients to immediately report neurologic reactions to their healthcare provider [see Dosage and Administration (2.7) and Warnings and Precautions (5.9)].Eye DisordersAdvise patients that vision disturbances and excessive tearing are associated with Docetaxel Injection administration. Instruct patients to immediately report any vision changes to their healthcare provider [see Warnings and Precautions (5.10)].Gastrointestinal ReactionsExplain to patients that nausea, vomiting, diarrhea, and constipation are associated with Docetaxel Injection administration. Instruct patients to report any severe events to their healthcare provider [see Adverse Reactions (6)].Cardiac DisordersAdvise patients to report any irregular and/or rapid heartbeat, severe shortness of breath, dizziness, and/or fainting immediately to their healthcare provider [see Adverse Reactions (6)].Other Common Adverse ReactionsAdvise patients that other common adverse reactions associated with Docetaxel Injection may include alopecia (cases of permanent hair loss have been reported), asthenia, anorexia, dysgeusia, mucositis, myalgia, nail disorders, or pain. Instruct patients to report these reactions to their healthcare provider if serious events occur [see Adverse Reactions (6)].Importance of CorticosteroidsExplain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report to their healthcare provider if they were not compliant with the oral corticosteroid regimen [see Dosage and Administration (2.6)].Embryo-Fetal ToxicityDocetaxel Injection can cause fetal harm. Advise patients to inform their healthcare provider of known or suspected pregnancy. Advise patients to avoid becoming pregnant while receiving this drug. Advise female patients of reproductive potential to use effective contraceptives during treatment and for months after the last dose of Docetaxel Injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose of Docetaxel Injection [see Warnings and Precautions (5.12), and Use in Specific Populations (8.1, 8.3)]. LactationAdvise women not to breastfeed during Docetaxel Injection treatment and for week after the last dose [see Use in Specific Populations (8.2)].InfertilityAdvise males of reproductive potential that Docetaxel Injection may impair fertility [see Nonclinical Toxicology (13.1)].Alcohol Content in Docetaxel InjectionExplain to patients the possible effects of the alcohol content in Docetaxel Injection, including possible effects on the central nervous system [see Warnings and Precautions (5.13)].Tumor Lysis SyndromeAdvise patients of the potential risk of tumor lysis syndrome and to immediately report any signs or symptoms associated with this event (nausea, vomiting, confusion, shortness of breath, seizure, irregular heartbeat, dark or cloudy urine, reduced amount of urine, unusual tiredness, muscle cramps) to their healthcare provider. Advise patients of the importance of keeping scheduled appointment for blood work or other laboratory tests and of drinking adequate fluids to avoid dehydration. [see Warnings and Precautions (5.14)].Ability to Drive or Operate MachinesExplain to patients that Docetaxel Injection may impair their ability to drive or operate machines due to its side effects [see Adverse Reactions (6)] or due to the alcohol content of Docetaxel Injection [see Warnings and Precautions (5.13)]. Advise them not to drive or use machines if they experience these side effects during treatment.Drug InteractionsInform patients about the risk of drug interactions and the importance of providing list of prescription and non-prescription drugs to their healthcare provider [see Drug Interactions (7)].Manufactured In Italy By: Actavis Italy Spa Socio Unico Nerviano, Italy, 20014Or Manufactured In Romania By: Sindan Pharma SRL Bucharest 1, Romania 011171Distributed By: Actavis Pharma, Inc. Parsippany, NJ 07054 USARev. 11/2020.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 breastfed child, advise women not to breastfeed during treatment with Docetaxel Injection and for week after the last dose.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies with docetaxel have not been performed. Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on mg/m2 basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays. Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50th the recommended human dose on mg/m2 basis), but decreased testicular weights were reported. This correlates with findings of 10-cycle toxicity study (dosing once every 21 days for months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended human dose on mg/m2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

OVERDOSAGE SECTION.

10 OVERDOSAGE There is no known antidote for Docetaxel Injection overdosage. In case of overdosage, the patient should be kept in 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/m2 and the other received 200 mg/m2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident. In mice, lethality was observed following single intravenous doses that were >=154 mg/kg (about 4.5 times the human dose of 100 mg/m2 on mg/m2 basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m2 basis). In male and female rats, lethality was observed at dose of 20 mg/kg (comparable to the human dose of 100 mg/m2 on mg/m2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. ActavisRx OnlyNDC 45963-734-54Docetaxel Injection20 mg/mLFor Intravenous Infusion OnlyREADY TO ADD TOINFUSION SOLUTIONCAUTION: Cytotoxic AgentContains mLSingle-Dose VialDiscard Unused Portion.. 20 mg/mL.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Warnings and Precautions (5.4, 5.5) 7/2019 Warnings and Precautions (5.7, 5.12) 7/2019. Warnings and Precautions (5.8, 5.14) 7/2020.

REFERENCES SECTION.

15 REFERENCES OSHA Hazardous Drugs. http://www.osha.gov/SLTC/hazardousdrugs/index.html. OSHA Hazardous Drugs. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. Docetaxel (doe-se-tax-el) Injection for intravenous use What is the most important information should know about Docetaxel Injection Docetaxel Injection can cause serious side effects, including death. The chance of death in people who receive Docetaxel Injection is higher if you:have liver problems receive high doses of Docetaxel Injection have non-small cell lung cancer and have been treated with chemotherapy medicines that contain platinum Docetaxel Injection can affect your blood cells. Your healthcare provider should do routine blood tests during treatment with Docetaxel Injection. This will include regular checks of your white blood cell counts. If your white blood cells are too low, your healthcare provider may not treat you with Docetaxel Injection until you have enough white blood cells. People with low white blood cell counts can develop life-threatening infections. The earliest sign of infection may be fever. Follow your healthcare providers instructions for how often to take your temperature during treatment with Docetaxel Injection. Call your healthcare provider right away if you have fever.Swelling (inflammation) of the small intestine and colon. This can happen at any time during treatment and could lead to death as early as the first day you get symptoms. Tell your healthcare provider right away if you develop new or worse symptoms of intestinal problems, including stomach (abdominal) pain or tenderness or diarrhea, with or without fever.Severe allergic reactions are medical emergencies that can happen in people who receive Docetaxel Injection and can lead to death. You may be at higher risk of developing severe allergic reaction to Docetaxel Injection if you are allergic to paclitaxel. Your healthcare provider will monitor you closely for allergic reactions during your Docetaxel Injection infusion. Tell your healthcare provider right away if you have any of these signs of severe allergic reaction: trouble breathing sudden swelling of your face, lips, tongue, throat, or trouble swallowing hives (raised bumps), rash, or redness all over your body Your body may hold too much fluid (severe fluid retention) during treatment with Docetaxel Injection. This can be life threatening. To decrease the chance of this happening, you must take another medicine, corticosteroid, before each Docetaxel Injection treatment. You must take the corticosteroid exactly as your healthcare provider tells you. Tell your healthcare provider or nurse before your Docetaxel Injection treatment if you forgot to take your corticosteroid dose or do not take it as your healthcare provider tells you. Tell your healthcare provider right away if you have swelling in your legs or feet, weight gain or shortness of breath. Risk of new cancers. An increase in new (second) cancers has happened in people treated with Docetaxel Injection together with certain other anticancer treatments. This includes certain blood cancers, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), non-Hodgkins Lymphoma (NHL), and kidney cancer. Changes in blood counts due to leukemia and other blood disorders may occur years after treatment with Docetaxel Injection. Your healthcare provider will check you for new cancers during and after your treatment with Docetaxel Injection. Severe skin problems Tell your healthcare provider right away if you have any of these signs of severe skin reaction: redness and swelling of your arms and legs.blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet) with or without rash. You may also have flu-like symptoms such as fever, chills, or muscle aches.red, scaly rash all over your body with blisters small red or white bumps under the skin that contain pus (pustules) and fever. What is Docetaxel Injection Docetaxel Injection is prescription anticancer medicine used to treat certain people with: breast cancernon-small cell lung cancerprostate cancer stomach cancerhead and neck cancer It is not known if Docetaxel Injection is effective in children. Do not receive Docetaxel Injection if you: have low white blood cell count.have had severe allergic reaction to: docetaxel, the active ingredient in Docetaxel Injection, or any other medicines that contain polysorbate 80. Ask your healthcare provider or pharmacist if you are not sure. See What is the most important information should know about Docetaxel Injection for the signs and symptoms of severe allergic reaction. See the end of this Patient Information for complete list of the ingredients in Docetaxel Injection. Before you receive Docetaxel Injection, tell your healthcare provider about all of your medical conditions, including if you: are allergic to any medicines, including paclitaxel. See Do not receive Docetaxel Injection if you.have kidney problemshave liver problemsare pregnant or plan to become pregnant. Docetaxel Injection can harm your unborn baby. You should not become pregnant during treatment with Docetaxel Injection. Tell your healthcare provider if you become pregnant or you think you may be pregnant during treatment with Docetaxel Injection. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with Docetaxel Injection.You should use effective birth control (contraception) during treatment with Docetaxel Injection and for months after the last dose. Males with female partners who are able to become pregnant should use effective birth control during treatment with Docetaxel Injection and for months after the last dose. Talk to your healthcare provider if you have questions about birth control options that are right for you. are breastfeeding or plan to breastfeed. It is not known if Docetaxel Injection passes into your breast milk. Do not breastfeed during treatment with Docetaxel Injection and for week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Docetaxel Injection may affect the way other medicines work, and other medicines may affect the way Docetaxel Injection works. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. How will receive Docetaxel Injection Docetaxel Injection will be given to you as an intravenous (IV) injection into your vein, usually over hour. Docetaxel Injection is usually given every weeks. Your healthcare provider will decide how long you will receive treatment with Docetaxel Injection. Your healthcare provider will check your blood cell counts and other blood tests during your treatment with Docetaxel Injection to check for side effects of Docetaxel Injection. Your healthcare provider may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving Docetaxel Injection. What are the possible side effects of Docetaxel Injection Docetaxel Injection may cause serious side effects including death. See What is the most important information should know about Docetaxel Injection Neurologic problems. Neurologic symptoms are common in people who receive Docetaxel Injection but can be severe. Tell your healthcare provider right away if you have numbness, tingling, or burning in your hands or feet (peripheral neuropathy) or weakness of your legs, feet, arms, or hands (motor weakness). Vision problems including blurred vision or loss of vision. Tell your healthcare provider right away if you have any vision changes.Docetaxel Injection contains alcohol. The alcohol content in Docetaxel Injection may impair your ability to drive or use machinery right after receiving Docetaxel Injection. Consider whether you should drive, operate machinery or do other dangerous activities right after you receive Docetaxel Injection treatment.Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, or heart problems, and may lead to death. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with Docetaxel Injection. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with Docetaxel Injection, including: nausea irregular heartbeat vomiting dark or cloudy urine confusion reduced amount of urine shortness of breath unusual tiredness muscle cramps You may experience side effects of Docetaxel Injection that may impair your ability to drive, use tools, or operate machines. If this happens, do not drive or use any tools or machines before discussing with your healthcare provider. The most common side effects of Docetaxel Injection include: infections feeling weak or tired low white blood cells (help fight infections), low red blood cells (anemia) and low platelets (help blood to clot) joint and muscle pain allergic reactions (See What is the most important information should know about Docetaxel Injection) nausea and vomiting changes in your sense of taste diarrhea shortness of breath mouth or lip sores constipation hair loss: in some people, permanent hair loss has been reported decreased appetite redness of the eye, excess tearing changes in your fingernails or toenails skin reactions at the site of Docetaxel Injection administration such as increased skin pigmentation, redness, tenderness, swelling, warmth or dryness of the skin swelling of your hands, face or feet tissue damage if Docetaxel Injection leaks out of the vein into the tissues Tell your healthcare provider if you have fast or irregular heartbeat, severe shortness of breath, dizziness or fainting during your infusion. If any of these events occurs after your infusion, get medical help right away. Docetaxel Injection may affect fertility in males. Talk to your healthcare provider if this is concern for you. These are not all the possible side effects of Docetaxel Injection. For more information ask your healthcare provider or pharmacist.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of Docetaxel Injection. Medicines are sometimes prescribed for purposes other than those listed in this Patient Information. You can ask your pharmacist or healthcare provider for information about Docetaxel Injection that is written for health professionals. What are the ingredients in Docetaxel Injection Active ingredient: docetaxel Inactive ingredients: citric acid anhydrous, kollidon 12 PF (povidone P12), polysorbate 80 and ethanol. Manufactured In Italy By: Actavis Italy Spa Socio Unico, Nerviano, Italy, 20014 Or Manufactured In Romania By: Sindan Pharma SRL, Bucharest 1, Romania 011171 Distributed By: Actavis Pharma, Inc., Parsippany, NJ 07054 USA For more information call 1-888-838-2872. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 7/2020. The chance of death in people who receive Docetaxel Injection is higher if you:have liver problems receive high doses of Docetaxel Injection have non-small cell lung cancer and have been treated with chemotherapy medicines that contain platinum have liver problems receive high doses of Docetaxel Injection have non-small cell lung cancer and have been treated with chemotherapy medicines that contain platinum Docetaxel Injection can affect your blood cells. Your healthcare provider should do routine blood tests during treatment with Docetaxel Injection. This will include regular checks of your white blood cell counts. If your white blood cells are too low, your healthcare provider may not treat you with Docetaxel Injection until you have enough white blood cells. People with low white blood cell counts can develop life-threatening infections. The earliest sign of infection may be fever. Follow your healthcare providers instructions for how often to take your temperature during treatment with Docetaxel Injection. Call your healthcare provider right away if you have fever.. Swelling (inflammation) of the small intestine and colon. This can happen at any time during treatment and could lead to death as early as the first day you get symptoms. Tell your healthcare provider right away if you develop new or worse symptoms of intestinal problems, including stomach (abdominal) pain or tenderness or diarrhea, with or without fever.. Severe allergic reactions are medical emergencies that can happen in people who receive Docetaxel Injection and can lead to death. You may be at higher risk of developing severe allergic reaction to Docetaxel Injection if you are allergic to paclitaxel. Your healthcare provider will monitor you closely for allergic reactions during your Docetaxel Injection infusion.. trouble breathing sudden swelling of your face, lips, tongue, throat, or trouble swallowing hives (raised bumps), rash, or redness all over your body Your body may hold too much fluid (severe fluid retention) during treatment with Docetaxel Injection. This can be life threatening. To decrease the chance of this happening, you must take another medicine, corticosteroid, before each Docetaxel Injection treatment. You must take the corticosteroid exactly as your healthcare provider tells you. Tell your healthcare provider or nurse before your Docetaxel Injection treatment if you forgot to take your corticosteroid dose or do not take it as your healthcare provider tells you. Tell your healthcare provider right away if you have swelling in your legs or feet, weight gain or shortness of breath.. Risk of new cancers. An increase in new (second) cancers has happened in people treated with Docetaxel Injection together with certain other anticancer treatments. This includes certain blood cancers, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), non-Hodgkins Lymphoma (NHL), and kidney cancer.. Changes in blood counts due to leukemia and other blood disorders may occur years after treatment with Docetaxel Injection.. Severe skin problems. redness and swelling of your arms and legs.. blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet) with or without rash. You may also have flu-like symptoms such as fever, chills, or muscle aches.. red, scaly rash all over your body with blisters small red or white bumps under the skin that contain pus (pustules) and fever.. breast cancer. non-small cell lung cancer. prostate cancer. stomach cancer. head and neck cancer. have low white blood cell count.. have had severe allergic reaction to: docetaxel, the active ingredient in Docetaxel Injection, or docetaxel, the active ingredient in Docetaxel Injection, or any other medicines that contain polysorbate 80. Ask your healthcare provider or pharmacist if you are not sure. are allergic to any medicines, including paclitaxel. See Do not receive Docetaxel Injection if you.. have kidney problems. have liver problems. are pregnant or plan to become pregnant. Docetaxel Injection can harm your unborn baby. You should not become pregnant during treatment with Docetaxel Injection. Tell your healthcare provider if you become pregnant or you think you may be pregnant during treatment with Docetaxel Injection.. Your healthcare provider will check to see if you are pregnant before you start treatment with Docetaxel Injection.. You should use effective birth control (contraception) during treatment with Docetaxel Injection and for months after the last dose.. are breastfeeding or plan to breastfeed. It is not known if Docetaxel Injection passes into your breast milk. Do not breastfeed during treatment with Docetaxel Injection and for week after the last dose.. Docetaxel Injection will be given to you as an intravenous (IV) injection into your vein, usually over hour. Docetaxel Injection is usually given every weeks. Your healthcare provider will decide how long you will receive treatment with Docetaxel Injection. Your healthcare provider will check your blood cell counts and other blood tests during your treatment with Docetaxel Injection to check for side effects of Docetaxel Injection. Your healthcare provider may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving Docetaxel Injection. See What is the most important information should know about Docetaxel Injection Neurologic problems. Neurologic symptoms are common in people who receive Docetaxel Injection but can be severe. Tell your healthcare provider right away if you have numbness, tingling, or burning in your hands or feet (peripheral neuropathy) or weakness of your legs, feet, arms, or hands (motor weakness). Vision problems including blurred vision or loss of vision. Tell your healthcare provider right away if you have any vision changes.. Docetaxel Injection contains alcohol. The alcohol content in Docetaxel Injection may impair your ability to drive or use machinery right after receiving Docetaxel Injection. Consider whether you should drive, operate machinery or do other dangerous activities right after you receive Docetaxel Injection treatment.. Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, or heart problems, and may lead to death. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with Docetaxel Injection. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with Docetaxel Injection, including: You may experience side effects of Docetaxel Injection that may impair your ability to drive, use tools, or operate machines. If this happens, do not drive or use any tools or machines before discussing with your healthcare provider.. infections. feeling weak or tired. low white blood cells (help fight infections), low red blood cells (anemia) and low platelets (help blood to clot). joint and muscle pain. allergic reactions (See What is the most important information should know about Docetaxel Injection). nausea and vomiting. changes in your sense of taste. diarrhea. shortness of breath. mouth or lip sores. constipation. hair loss: in some people, permanent hair loss has been reported. decreased appetite. redness of the eye, excess tearing. changes in your fingernails or toenails. skin reactions at the site of Docetaxel Injection administration such as increased skin pigmentation, redness, tenderness, swelling, warmth or dryness of the skin swelling of your hands, face or feet. tissue damage if Docetaxel Injection leaks out of the vein into the tissues. chart.

SPL UNCLASSIFIED SECTION.

1.1 Breast Cancer. Docetaxel Injection is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. Docetaxel Injection in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . Lactation: Advise women not to breastfeed. (8.2)Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of Docetaxel Injection. (8.3). Lactation: Advise women not to breastfeed. (8.2). Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of Docetaxel Injection. (8.3). 8.1 Pregnancy. Risk SummaryBased on findings in animal reproduction studies and its mechanism of action, Docetaxel Injection can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Docetaxel Injection contains alcohol which can interfere with neurobehavioral development [see Clinical Considerations]. In animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDocetaxel Injection contains alcohol [see Warnings and Precautions (5.13)]. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.DataAnimal dataIntravenous administration of >=0.3 and 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 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively.. 8.2 Lactation. Risk SummaryThere 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 breastfed child, advise women not to breastfeed during treatment with Docetaxel Injection and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating Docetaxel Injection.ContraceptionFemalesDocetaxel Injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for months after the last dose of Docetaxel Injection.Males Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose of Docetaxel Injection.InfertilityBased on findings in animal studies, Docetaxel Injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients [see Warnings and Precautions (5.13)].The efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of docetaxel in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.Docetaxel has been studied in total of 289 pediatric patients: 239 in trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluorouracil (TCF).Docetaxel MonotherapyDocetaxel monotherapy was evaluated in dose-finding phase trial in 61 pediatric patients (median age 12.5 years, range to 22 years) with variety of refractory solid tumors. The recommended dose was 125 mg/m2 as 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia.The recommended dose for docetaxel monotherapy was evaluated in phase single-arm trial in 178 pediatric patients (median age 12 years, range to 26 years) with variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in 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 CombinationDocetaxel 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 to 21 years) were randomized (2:1) to docetaxel (75 mg/m2) in combination with cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2) (TCF) or to cisplatin (80 mg/m2) and 5-fluorouracil (1000 mg/m2/day) (CF). The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had complete response while none of the 25 patients in the CF group had complete response. PharmacokineticsPharmacokinetic parameters for docetaxel were determined in pediatric solid tumor trials. Following docetaxel administration at 55 mg/m2 to 235 mg/m2 in 1-hour intravenous infusion every weeks in 25 patients aged to 20 years (median 11 years), docetaxel clearance was 17.3+-10.9 L/h/m2.Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m2 in 1-hour intravenous infusion day in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9+-8.75 L/h/m2, corresponding to an AUC of 4.20+-2.57 mcgh/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)].. 8.5 Geriatric Use. 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 CancerIn study conducted in chemotherapy-naive patients with NSCLC (TAX326), 148 patients (36%) in the Docetaxel Injection+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 Injection+cisplatin group, patients less than 65 years of age had median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with Docetaxel Injection+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 Injection+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 Injection 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 Injection+cisplatin, and higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. Prostate CancerOf the 333 patients treated with Docetaxel Injection 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 Injection 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 CancerIn the adjuvant breast cancer trial (TAX316), Docetaxel Injection 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 CancerAmong the 221 patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 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 CancerAmong the 174 and 251 patients who received the induction treatment with Docetaxel Injection 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 Injection 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. 8.6 Hepatic Impairment. Avoid Docetaxel Injection 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 (5.2), Clinical Pharmacology (12.3)].The alcohol content of Docetaxel Injection should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions (5.13)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS . Second primary malignancies: In patients treated with Docetaxel Injection-containing regimens, monitor for delayed AML, MDS, NHL, and renal cancer. (5.7)Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skin toxicity may require dose adjustment or permanent treatment discontinuation. (5.8)Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.9)Eye disorders: Cystoid macular edema (CME) has been reported and requires treatment discontinuation. (5.10)Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.11)Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.12, 8.1, 8.3) Alcohol content: The alcohol content in dose of Docetaxel Injection may affect the central nervous system. This may include impairment of patients ability to drive or use machines immediately after infusion. (5.13)Tumor lysis syndrome: Tumor lysis syndrome has been reported. Patients at risk should be well hydrated and closely monitored during treatment. (5.14). Second primary malignancies: In patients treated with Docetaxel Injection-containing regimens, monitor for delayed AML, MDS, NHL, and renal cancer. (5.7). Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skin toxicity may require dose adjustment or permanent treatment discontinuation. (5.8). Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.9). Eye disorders: Cystoid macular edema (CME) has been reported and requires treatment discontinuation. (5.10). Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.11). Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.12, 8.1, 8.3) Alcohol content: The alcohol content in dose of Docetaxel Injection may affect the central nervous system. This may include impairment of patients ability to drive or use machines immediately after infusion. (5.13). Tumor lysis syndrome: Tumor lysis syndrome has been reported. Patients at risk should be well hydrated and closely monitored during treatment. (5.14). 5.1 Toxic Deaths. Breast CancerDocetaxel Injection administered at 100 mg/m2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m2, mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in of patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths. Non-Small Cell Lung CancerDocetaxel Injection administered at dose of 100 mg/m2 in patients with locally advanced or metastatic non-small cell lung cancer who had history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m2 dose level, of patients had an ECOG PS of at study entry [see Dosage and Administration (2.2), Clinical Studies (14)]. 5.2 Hepatic Impairment. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.Avoid Docetaxel Injection in patients with bilirubin upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 ULN concomitant with alkaline phosphatase >2.5 ULN [see Warnings and Precautions (5.1)]. For patients with isolated elevations of transaminase >1.5 ULN, consider Docetaxel Injection dose modifications [see Dosage and Administration (2.7)].Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of Docetaxel Injection therapy.. 5.3 Hematologic Effects. Perform frequent peripheral blood cell counts on all patients receiving Docetaxel Injection. Do not retreat patients with subsequent cycles of Docetaxel Injection until neutrophils recover to level >1500 cells/mm3 [see Contraindications (4)]. Avoid retreating patients until platelets recover to level >100,000 cells/mm3. 25% reduction in the dose of Docetaxel Injection is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting days or more, febrile neutropenia, or grade infection in Docetaxel Injection cycle [see Dosage and Administration (2.7)]. Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 100 mg/m2 of Docetaxel Injection and grade neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Docetaxel Injection should not be administered to patients with neutrophils <1500 cells/mm3. Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was very uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see Adverse Reactions (6.1), Clinical Studies (14)]. Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection [see Dosage and Administration (2.7), Adverse Reactions (6)].. 5.4 Enterocolitis and Neutropenic Colitis. Enterocolitis and neutropenic colitis (typhlitis) have occurred in patients treated with Docetaxel Injection alone and in combination with other chemotherapeutic agents, despite the co-administration of G-CSF. Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Enterocolitis and neutropenic enterocolitis may develop at any time, and could lead to death as early as the first day of symptom onset. Monitor patients closely from onset of any symptoms of gastrointestinal toxicity. Inform patients to contact their healthcare provider with new, or worsening symptoms of gastrointestinal toxicity [see Dosage and Administration (2), Warnings and Precautions (5.3), Adverse Reactions (6.2)].. 5.5 Hypersensitivity Reactions. Monitor patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or fatal anaphylaxis, have been reported in patients pre-medicated with days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and aggressive therapy. Do not rechallenge patients with history of severe hypersensitivity reactions with Docetaxel Injection [see Contraindications (4)]. Patients who have previously experienced hypersensitivity reaction to paclitaxel may develop hypersensitivity reaction to docetaxel that may include severe or fatal reactions such as anaphylaxis. Monitor patients with previous history of hypersensitivity to paclitaxel closely during initiation of Docetaxel Injection therapy. Hypersensitivity reactions may occur within few minutes following initiation of Docetaxel Injection infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Docetaxel Injection [see Dosage and Administration (2.6)]. 5.6 Fluid Retention. Severe fluid retention has been reported following Docetaxel Injection therapy. Patients should be premedicated with oral corticosteroids prior to each Docetaxel Injection administration to reduce the incidence and severity of fluid retention [see Dosage and Administration (2.6)]. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions. When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with median weight gain of kg. Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2. Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: patients discontinued with severe fluid retention; the remaining had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m2. Fluid retention was completely, but sometimes slowly, reversible with median of 16 weeks from the last infusion of Docetaxel Injection to resolution (range: to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).. 5.7Second Primary Malignancies. Second primary malignancies, notably acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), Non-Hodgkins Lymphoma (NHL), and renal cancer, have been reported in patients treated with docetaxel-containing regimens. These adverse reactions may occur several months or years after docetaxel-containing therapy.Treatment-related AML or MDS has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in of 744 patients who received Docetaxel Injection, doxorubicin and cyclophosphamide (TAC) and in of 736 patients who received fluorouracil, doxorubicin, and cyclophosphamide [see Clinical Studies (14.2)]. In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies [see Adverse Reactions (6.1)].. 5.8 Cutaneous Reactions. Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended [see Dosage and Administration (2.7)]. The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued Docetaxel Injection due to skin toxicity. Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Permanent treatment discontinuation should be considered in patients who experience SCARs.. 5.9 Neurologic Reactions. Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued [see Dosage and Administration (2.7)]. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with median of weeks from onset (range: to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965). 5.10 Eye Disorders. Cystoid macular edema (CME) has been reported in patients treated with Docetaxel Injection. Patients with impaired vision should undergo prompt and comprehensive ophthalmologic examination. If CME is diagnosed, Docetaxel Injection treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.. 5.11 Asthenia. Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease. 5.12 Embryo-Fetal Toxicity. Based on findings from animal reproduction studies and its mechanism of action, Docetaxel Injection can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively.Advise pregnant women and females of reproductive potential of the potential risk to fetus. Verify pregnancy status in females of reproductive potential prior to initiating Docetaxel Injection. Advise females of reproductive potential to use effective contraception during treatment and for months after the last dose of Docetaxel Injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose of Docetaxel Injection [see Use in Specific Populations (8.1, 8.3)].. 5.13 Alcohol Content. Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in dose of Docetaxel Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Docetaxel Injection on the ability to drive or use machines immediately after the infusion. Each administration of Docetaxel Injection at 100 mg/m2 delivers 2.0 g/m2 of ethanol. For patient with BSA of 2.0 m2, this would deliver 4.0 grams of ethanol [see Description (11)]. Other docetaxel products may have different amount of alcohol.. 5.14 Tumor Lysis Syndrome. Tumor lysis syndrome has been reported with docetaxel [see Adverse Reactions (6.2)]. Patients at risk of tumor lysis syndrome (e.g., with renal impairment, hyperuricemia, bulky tumor) should be closely monitored prior to initiating Docetaxel Injection and periodically during treatment. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment.