Docetaxel

6. ADVERSE REACTIONS The most serious adverse reactions from docetaxel are: • Toxic Deaths [see Boxed Warning , Warning and Precautions (5.1) ] • Hepatotoxicity [see Boxed Warning , Warnings and Precautions (5.2) ] • Neutropenia [see Boxed Warning , Warnings and Precautions (5.3) ] • Hypersensitivity [see Boxed Warning , Warnings and Precautions (5.4) ] • Fluid Retention [see Boxed Warning , Warnings and Precautions (5.5) ] • Acute Myeloid Leukemia [see Warnings and Precautions (5.6) ] • Cutaneous Reactions [see Warnings and Precautions (5.7) ] • Neurologic Reactions [see Warnings and Precautions (5.8) ] • Eye Disorders [see Warnings and Precautions (5.9) ] • Asthenia [see Warnings and Precautions (5.10) ] • Alcohol Intoxication [see Warnings and Precautions (5.11) ] The most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication. Adverse reactions are described according to indication. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established. Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Breast Cancer Monotherapy with docetaxel for locally advanced or metastatic breast cancer after failure of prior chemotherapy Docetaxel 100 mg/m 2 : Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m 2 as a 1-hour infusion every 3 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. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving docetaxel for the treatment of breast cancer and in patients with other tumor types (See Table 4). Table 4 - Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m 2 Adverse Reaction All Tumor Types Normal LFTs* n=2045 % All Tumor Types Elevated LFTs** n=61 % Breast Cancer Normal LFTs* n=965 % Hematologic Neutropenia <2000 cells/mm 3 <500 cells/mm 3 Leukopenia <4000 cells/mm 3 <1000 cells/mm 3 Thrombocytopenia <100,000 cells/mm 3 Anemia <11 g/dL <8 g/dL Febrile Neutropenia*** 96 75 96 32 8 90 9 11 96 88 98 47 25 92 31 26 99 86 99 44 9 94 8 12 Septic Death Non-Septic Death 2 1 5 7 1 1 Infections Any Severe 22 6 33 16 22 6 Fever in Absence of Infection Any Severe 31 2 41 8 35 2 Hypersensitivity Reactions Regardless of Premedication Any Severe With 3-day Premedication Any Severe 21 4 n=92 15 2 20 10 n=3 33 0 18 3 n=92 15 2 Fluid Retention Regardless of Premedication Any Severe With 3-day Premedication Any Severe 47 7 n=92 64 7 39 8 n=3 67 33 60 9 n=92 64 7 Neurosensory Any Severe 49 4 34 0 58 6 Cutaneous Any Severe 48 5 54 10 47 5 Nail Changes Any Severe 31 3 23 5 41 4 Gastrointestinal Nausea Vomiting Diarrhea Severe 39 22 39 5 38 23 33 5 42 23 43 6 Stomatitis Any Severe 42 6 49 13 52 7 Alopecia 76 62 74 Asthenia Any Severe 62 13 53 25 66 15 Myalgia Any Severe 19 2 16 2 21 2 Arthralgia 9 7 8 Infusion Site Reactions 4 3 4 *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 5times ULN **Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ***Febrile Neutropenia: ANC grade 4 with fever >38 o C with intravenous antibiotics and/or hospitalization Hematologic Reactions Reversible marrow suppression was the major dose-limiting toxicity of docetaxel [see Warnings and Precautions (5.3) ]. The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm 3 ) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles. Febrile neutropenia (<500 cells/mm 3 with fever >38 o C 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/mm 3 ) associated with fatal gastrointestinal hemorrhage has been reported. Hypersensitivity Reactions Severe hypersensitivity reactions have been reported [see Boxed Warning , Warnings and Precautions (5.4) ] . 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 Retention Fluid retention can occur with the use of docetaxel [see Boxed Warning , Dosage and Administration (2.6) , Warnings and Precautions (5.5) ]. Cutaneous Reactions Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.7) ]. Reversible cutaneous reactions characterized by a 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 1 week after docetaxel 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 Reactions Neurologic reactions are discussed elsewhere in the label [see Warnings and Precautions (5.8) ] Gastrointestinal Reactions Nausea, vomiting and diarrhea were generally mild to moderate. Severe reactions occurred in 3 % to 5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. Cardiovascular Reactions Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely. Seven of 86 (8.1%) of metastatic breast cancer patients receiving docetaxel 100 mg/m 2 in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by ≥10% associated with a drop below the institutional lower limit of normal. Infusion Site Reactions Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein. Hepatic Reactions In patients with normal LFTs at baseline, bilirubin values > 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, increases in AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established. Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry abnormalities Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m 2 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 at 60 mg/m 2 who had normal LFTs (see Tables 5 and 6). Table 5 - Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m 2 with Normal or Elevated Liver Function Tests or 60 mg/m 2 with Normal Liver Function Tests Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2 Adverse Reaction Normal LFTs* n=730 % Elevated LFTs** n=18 % Normal LFTs* n=174 % Neutropenia Any <2000 cells/mm 3 Grade 4 <500 cells/mm 3 98 84 100 94 95 75 Thrombocytopenia Any <100,000 cells/mm 3 Grade 4 <20,000 cells/mm 3 11 1 44 17 14 1 Anemia ( <11 g/dL ) 95 94 65 Infection*** Any Grade 3 and 4 23 7 39 33 1 0 Febrile Neutropenia **** By Patient By Course 12 2 33 9 0 0 Septic Death 2 6 1 Non-Septic Death 1 11 0 *Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ***Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia. ****Febrile Neutropenia: For 100 mg/m 2 , ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m 2 , ANC grade 3/4 and fever >38.1°C Table 6 - Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m 2 with Normal or Elevated Liver Function Tests or 60 mg/m 2 with Normal Liver Function Tests Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2 Adverse Reaction Normal LFTs* n=730 % Elevated LFTs** n=18 % Normal LFTs* n=174 % Acute Hypersensitivity Reaction Regardless of Premedication Any Severe 13 1 6 0 1 0 Fluid Retention *** Regardless of Premedication Any Severe 56 8 61 17 13 0 Neurosensory Any Severe 57 6 50 0 20 0 Myalgia 23 33 3 Cutaneous Any Severe 45 5 61 17 31 0 Asthenia Any Severe 65 17 44 22 66 0 Diarrhea Any Severe 42 6 28 11 NA Stomatitis Any Severe 53 8 67 39 19 1 *Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN ** Elevated Baseline 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/m 2 dose NA = not available In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m 2 , 75 mg/m 2 and 100 mg/m 2 in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49% of patients treated with docetaxel 60 mg/m 2 compared to 55.3% and 65.9% treated with 75 mg/m 2 and 100 mg/m 2 respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m 2 vs. 6.9% and 16.5% for patients treated at 75 mg/m 2 and 100 mg/m 2 respectively. Deaths within 30 days of last treatment occurred in 4% of patients treated with 60 mg/m 2 compared to 5.3% and 1.6% for patients treated at 75 mg/m 2 and 100 mg/m 2 respectively. The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m 2 , 75 mg/m 2 , and 100 mg/m 2 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 in the adjuvant treatment of breast cancer The following table presents treatment emergent adverse reactions observed in 744 patients, who were treated with docetaxel 75 mg/m 2 every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 7). Table 7- Clinically Important Treatment Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316). Docetaxel 75 mg/m 2 + Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 (TAC) n=744 % Fluorouracil 500 mg/m 2 + Doxorubicin 50 mg/m 2 + Cyclophosphamide 500 mg/m 2 (FAC) n=736 % Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 92 4 72 2 Neutropenia 71 66 82 49 Fever in absence of infection 47 1 17 0 Infection 39 4 36 2 Thrombocytopenia 39 2 28 1 Febrile neutropenia 25 N/A 3 N/A Neutropenic infection 12 N/A 6 N/A Hypersensitivity reactions 13 1 4 0 Lymphedema 4 0 1 0 Fluid Retention* Peripheral edema Weight gain 35 27 13 1 0 0 15 7 9 0 0 0 Neuropathy sensory 26 0 10 0 Neuro-cortical 5 1 6 1 Neuropathy motor 4 0 2 0 Neuro-cerebellar 2 0 2 0 Syncope 2 1 1 0 Alopecia 98 N/A 97 N/A Skin toxicity 27 1 18 0 Nail disorders 19 0 14 0 Nausea 81 5 88 10 Stomatitis 69 7 53 2 Vomiting 45 4 59 7 Diarrhea 35 4 28 2 Constipation 34 1 32 1 Taste perversion 28 1 15 0 Anorexia 22 2 18 1 Abdominal Pain 11 1 5 0 Amenorrhea 62 N/A 52 N/A Cough 14 0 10 0 Cardiac dysrhythmias 8 0 6 0 Vasodilatation 27 1 21 1 Hypotension 2 0 1 0 Phlebitis 1 0 1 0 Asthenia 81 11 71 6 Myalgia 27 1 10 0 Arthralgia 19 1 9 0 Lacrimation disorder 11 0 7 0 Conjunctivitis 5 0 7 0 * COSTART term and grading system for events related to treatment. Of the 744 patients treated with TAC, 36.3% experienced severe treatment emergent adverse reactions compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1.1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs. Fever and Infection 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. Gastrointestinal Reactions In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation vs. one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred. Cardiovascular Reactions More cardiovascular reactions were reported in the TAC arm vs. the FAC arm; dysrhythmias, all grades (7.9% vs. 6%), hypotension, all grades (2.6% vs. 1.1%) and CHF (2.3% vs. 0.9%, at 70 months median follow-up). One patient in each arm died due to heart failure. Acute Myeloid Leukemia (AML) Treatment-related acute myeloid leukemia or myelodysplasia is known to occur in patients treated with anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at 5 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. This risk of AML is comparable to the risk observed for other anthracyclines/ cyclophosphamide containing adjuvant breast chemotherapy regimens. Lung Cancer Monotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy Treatment emergent adverse drug reactions are shown in Table 8. Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a 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 8 - Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel as Monotherapy for Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy* Adverse Reaction Docetaxel 75 mg/m 2 n=176 % Best Supportive Care n=49 % Vinorelbine/Ifosfamide n=119 % Neutropenia Any Grade 3/4 84 65 14 12 83 57 Leukopenia Any Grade 3/4 84 49 6 0 89 43 Thrombocytopenia Any Grade 3/4 8 3 0 0 8 2 Anemia Any Grade 3/4 91 9 55 12 91 14 Febrile Neutropenia** 6 NA † 1 Infection Any Grade 3/4 34 10 29 6 30 9 Treatment Related Mortality 3 NA † 3 Hypersensitivity Reactions Any Grade 3/4 6 3 0 0 1 0 Fluid Retention Any Severe 34 3 ND †† 23 3 Neurosensory Any Grade 3/4 23 2 14 6 29 5 Neuromotor Any Grade 3/4 16 5 8 6 10 3 Skin Any Grade 3/4 20 1 6 2 17 1 Gastrointestinal Nausea Any Grade 3/4 Vomiting Any Grade 3/4 Diarrhea Any Grade 3/4 34 5 22 3 23 3 31 4 27 2 6 0 31 8 22 6 12 4 Alopecia 56 35 50 Asthenia Any Severe*** 53 18 57 39 54 23 Stomatitis Any Grade 3/4 26 2 6 0 8 1 Pulmonary Any Grade 3/4 41 21 49 29 45 19 Nail Disorder Any Severe*** 11 1 0 0 2 0 Myalgia Any Severe*** 6 0 0 0 3 0 Arthralgia Any Severe*** 3 0 2 0 2 1 Taste Perversion Any Severe*** 6 1 0 0 0 0 * Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN ** Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization *** COSTART term and grading system † Not Applicable; †† Not Done Combination therapy with docetaxel in chemotherapy-naïve advanced unresectable or metastatic NSCLC Table 9 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted. Table 9 – Adverse Reactions Regardless of relationship to Treatment in Chemotherapy-Naïve Advanced Non-Small Cell Lung Cancer Patients Receiving Docetaxel in Combination with Cisplatin Adverse Reaction Docetaxel 75 mg/m 2 + Cisplatin 75 mg/m 2 n=406 % Vinorelbine 25 mg/m 2 + Cisplatin 100 mg/m 2 n=396 % Neutropenia Any Grade 3/4 91 74 90 78 Febrile Neutropenia 5 5 Thrombocytopenia Any Grade 3/4 15 3 15 4 Anemia Any Grade 3/4 89 7 94 25 Infection Any Grade 3/4 35 8 37 8 Fever in absence of infection Any Grade 3/4 33 < 1 29 1 Hypersensitivity Reaction* Any Grade 3/4 12 3 4 < 1 Fluid Retention** Any All severe or life-threatening events Pleural effusion Any All severe or life-threatening events Peripheral edema Any All severe or life-threatening events Weight gain Any All severe or life-threatening events 54 2 23 2 34 <1 15 <1 42 2 22 2 18 <1 9 <1 Neurosensory Any Grade 3/4 47 4 42 4 Neuromotor Any Grade 3/4 19 3 17 6 Skin Any Grade 3/4 16 <1 14 1 Nausea Any Grade 3/4 72 10 76 17 Vomiting Any Grade 3/4 55 8 61 16 Diarrhea Any Grade 3/4 47 7 25 3 Anorexia** Any All severe or life-threatening events 42 5 40 5 Stomatitis Any Grade 3/4 24 2 21 1 Alopecia Any Grade 3 75 <1 42 0 Asthenia** Any All severe or life-threatening events 74 12 75 14 Nail Disorder** Any All severe events 14 <1 <1 0 Myalgia** Any All severe events 18 <1 12 <1 * Replaces NCI term “Allergy” ** COSTART tern and grading system Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2%) in the vinorelbine+cisplatin arm. The second comparison in the study, vinorelbine+cisplatin versus docetaxel+carboplatin (which did not demonstrate a superior survival associated with docetaxel [see Clinical Studies (14.3) ] ) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the docetaxel+carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm. Prostate Cancer Combination therapy with docetaxel in patients with prostate cancer The following data are based on the experience of 332 patients, who were treated with docetaxel 75 mg/m 2 every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 10). Table 10 - Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel in Combination with Prednisone (TAX327) Docetaxel 75 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=332 % Mitoxantrone 12 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=335 % Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 67 5 58 2 Neutropenia 41 32 48 22 Thrombocytopenia 3 1 8 1 Febrile neutropenia 3 N/A 2 N/A Infection 32 6 20 4 Epistaxis 6 0 2 0 Allergic Reactions 8 1 1 0 Fluid Retention* Weight Gain* Peripheral Edema * 24 8 18 1 0 0 5 3 2 0 0 0 Neuropathy Sensory 30 2 7 0 Neuropathy Motor 7 2 3 1 Rash/Desquamation 6 0 3 1 Alopecia 65 N/A 13 N/A Nail Changes 30 0 8 0 Nausea 41 3 36 2 Diarrhea 32 2 10 1 Stomatitis/Pharyngitis 20 1 8 0 Taste Disturbance 18 0 7 0 Vomiting 17 2 14 2 Anorexia 17 1 14 0 Cough 12 0 8 0 Dyspnea 15 3 9 1 Cardiac left ventricular function 10 0 22 1 Fatigue 53 5 35 5 Myalgia 15 0 13 1 Tearing 10 1 2 0 Arthralgia 8 1 5 1 *Related to treatment Gastric Cancer Combination therapy with docetaxel in gastric adenocarcinoma Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease, who were treated with docetaxel 75 mg/m 2 in combination with cisplatin and fluorouracil (see Table 11). Table 11 - Clinically Important Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study Docetaxel 75 mg/m 2 + cisplatin 75 mg/m 2 + fluorouracil 750 mg/m 2 n=221 Cisplatin 100 mg/m 2 + fluorouracil 1000 mg/m 2 n=224 Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Anemia 97 18 93 26 Neutropenia 96 82 83 57 Fever in the absence of infection 36 2 23 1 Thrombocytopenia 26 8 39 14 Infection 29 16 23 10 Febrile neutropenia 16 N/A 5 N/A Neutropenic infection 16 N/A 10 N/A Allergic reactions 10 2 6 0 Fluid retention* 15 0 4 0 Edema* 13 0 3 0 Lethargy 63 21 58 18 Neurosensory 38 8 25 3 Neuromotor 9 3 8 3 Dizziness 16 5 8 2 Alopecia 67 5 41 1 Rash/itch 12 1 9 0 Nail changes 8 0 0 0 Skin desquamation 2 0 0 0 Nausea 73 16 76 19 Vomiting 67 15 73 19 Anorexia 51 13 54 12 Stomatitis 59 21 61 27 Diarrhea 78 20 50 8 Constipation 25 2 34 3 Esophagitis/dysphagia/ odynophagia 16 2 14 5 Gastrointestinal pain/cramping 11 2 7 3 Cardiac dysrhythmias 5 2 2 1 Myocardial ischemia 1 0 3 2 Tearing 8 0 2 0 Altered hearing 6 0 13 2 Clinically important treatment emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction. *Related to treatment Head and Neck Cancer Combination therapy with docetaxel in head and neck cancer Table 12 summarizes the safety data obtained from patients that received induction chemotherapy with docetaxel 75 mg/m 2 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 12– Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with Docetaxel in Combination with Cisplatin and Fluorouracil followed by Radiotherapy (TAX323) or Chemoradiotherapy (TAX324) TAX323 (n=355) TAX324 (n=494) Docetaxel arm (n=174) Comparator arm (n=181) Docetaxel arm (n=251) Comparator arm (n=243) Adverse Reaction (by Body System) Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Neutropenia 93 76 87 53 95 84 84 56 Anemia 89 9 88 14 90 12 86 10 Thrombocytopenia 24 5 47 18 28 4 31 11 Infection 27 9 26 8 23 6 28 5 Febrile neutropenia* 5 N/A 2 N/A 12 N/A 7 N/A Neutropenic infection 14 N/A 8 N/A 12 N/A 8 N/A Cancer pain 21 5 16 3 17 9 20 11 Lethargy 41 3 38 3 61 5 56 10 Fever in the absence of infection 32 1 37 0 30 4 28 3 Myalgia 10 1 7 0 7 0 7 2 Weight loss 21 1 27 1 14 2 14 2 Allergy 6 0 3 0 2 0 0 0 Fluid retention** Edema only Weight gain only 20 13 6 0 0 0 14 7 6 1 0 0 13 12 0 1 1 0 7 6 1 2 1 0 Dizziness 2 0 5 1 16 4 15 2 Neurosensory 18 1 11 1 14 1 14 0 Altered hearing 6 0 10 3 13 1 19 3 Neuromotor 2 1 4 1 9 0 10 2 Alopecia 81 11 43 0 68 4 44 1 Rash/itch 12 0 6 0 20 0 16 1 Dry skin 6 0 2 0 5 0 3 0 Desquamation 4 1 6 0 2 0 5 0 Nausea 47 1 51 7 77 14 80 14 Stomatitis 43 4 47 11 66 21 68 27 Vomiting 26 1 39 5 56 8 63 10 Diarrhea 33 3 24 4 48 7 40 3 Constipation 17 1 16 1 27 1 38 1 Anorexia 16 1 25 3 40 12 34 12 Esophagitis/dysphagia/ Odynophagia 13 1 18 3 25 13 26 10 Taste, sense of smell altered 10 0 5 0 20 0 17 1 Gastrointestinal pain/cramping 8 1 9 1 15 5 10 2 Heartburn 6 0 6 0 13 2 13 1 Gastrointestinal bleeding 4 2 0 0 5 1 2 1 Cardiac dysrhythmia 2 2 2 1 6 3 5 3 Venous*** 3 2 6 2 4 2 5 4 Ischemia myocardial 2 2 1 0 2 1 1 1 Tearing 2 0 1 0 2 0 2 0 Conjunctivitis 1 0 1 0 1 0 0.4 0 Clinically important treatment emergent adverse reactions based upon frequency, severity, and clinical impact. *Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization. **Related to treatment. *** Includes superficial and deep vein thrombosis and pulmonary embolism. 6.2 Post-Marketing Experiences The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made. Body as a whole : diffuse pain, chest pain, radiation recall phenomenon. Cardiovascular : atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Cutaneous : very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported. Cases of permanent alopecia have been reported. Gastrointestinal: abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported. Hematologic: bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with docetaxel when used in combination with other chemotherapy agents and/or radiotherapy. Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication. Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported. Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug. Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of cystoid macular edema (CME) have been reported in patients treated with docetaxel. Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs. Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy. Renal: renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs. Metabolism and nutrition disorders: cases of hyponatremia have been reported.

4. CONTRAINDICATIONS • Docetaxel Injection is contraindicated in patients who have 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 (5.4) ] . • Docetaxel Injection should not be used in patients with neutrophil counts of <1500 cells/mm 3 . • Hypersensitivity to docetaxel or polysorbate 80 ( 4 ) • Neutrophil counts of <1500 cells/mm 3 ( 4 )

11. DESCRIPTION Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel anhydrous USP is (2R, 3S)-N-carboxy-3-phenylisoserine, N- tert -butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate. Docetaxel has the following structural formula: Docetaxel anhydrous, USP is a white or almost white crystalline powder with an empirical formula of C 43 H 53 NO 14 , and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water. One-vial formulation (Injection) Docetaxel Injection, USP is a sterile, non-pyrogenic, pale yellow to brownish-yellow solution at 20 mg/mL concentration. Each mL contains 20 mg docetaxel anhydrous USP, 4 mg anhydrous citric acid, 520 mg polysorbate 80 and 395.5 mg dehydrated alcohol solution. Docetaxel Injection, USP is available in multiple-dose vials containing 160 mg (8 mL) docetaxel anhydrous, USP. Docetaxel Injection, USP requires NO prior dilution with a diluent and is ready to add to the infusion solution. Structure

2. DOSAGE AND ADMINISTRATION For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7) ] . Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously over 1 hr every 3 weeks. PVC equipment is not recommended. Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial. • BC: locally advanced or metastatic: 60 mg/m 2 to 100 mg/m 2 single agent ( 2.1 ) • BC adjuvant: 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 cycles ( 2.1 ) • NSCLC: after platinum therapy failure: 75 mg/m 2 single agent ( 2.2 ) • NSCLC: chemotherapy-naive: 75 mg/m 2 followed by cisplatin 75 mg/m 2 ( 2.2 ) • HRPC: 75 mg/m 2 with 5 mg prednisone twice a day continuously ( 2.3 ) • GC: 75 mg/m 2 followed by cisplatin 75 mg/m 2 (both on day 1 only) followed by fluorouracil 750 mg/m 2 per day as a 24-hr intravenous infusion (days 1 to 5), starting at end of cisplatin infusion ( 2.4 ) • SCCHN: 75 mg/m 2 followed by cisplatin 75 mg/m 2 intravenously (day 1), followed by fluorouracil 750 mg/m 2 per day as a 24-hr intravenous infusion (days 1 to 5), starting at end of cisplatin infusion; for 4 cycles ( 2.5 ) • SCCHN: 75 mg/m 2 followed by cisplatin 100 mg/m 2 intravenously (day 1), followed by fluorouracil 1000 mg/m 2 per day as a 24-hr intravenous infusion (days 1 to 4); for 3 cycles ( 2.5 ) For all patients: • 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/m 2 to 100 mg/m 2 administered intravenously over 1 hour every 3 weeks. • For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m 2 administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 courses. Prophylactic granulocyte-colony stimulating factor (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 was evaluated as monotherapy, and the recommended dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m 2 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 was evaluated in combination with cisplatin. The recommended dose of Docetaxel Injection is 75 mg/m 2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks [see Dosage and Administration (2.7) ] . 2.3 Prostate Cancer • For hormone-refractory metastatic prostate cancer, the recommended dose of Docetaxel Injection is 75 mg/m 2 every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 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/m 2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m 2 , as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m 2 per day given as a 24-hour continuous intravenous infusion for 5 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 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/m 2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m 2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m 2 per day for five days. This regimen is administered every 3 weeks for 4 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/m 2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m 2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m 2 /day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 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., 8 mg twice daily) for 3 days starting 1 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 (5.4) ] . • For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the Docetaxel Injection infusion [see Warnings and Precautions (5.4) ] . 2.7 Dosage Adjustments During Treatment Breast Cancer Patients who are dosed initially at 100 mg/m 2 and who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for more than 1 week, or severe or cumulative cutaneous reactions during Docetaxel Injection therapy should have the dosage adjusted from 100 mg/m 2 to 75 mg/m 2 . If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m 2 to 55 mg/m 2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m 2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm 3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docetaxel Injection therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely. Combination Therapy with Docetaxel Injection in the Adjuvant Treatment of Breast Cancer Docetaxel Injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm 3 . 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/m 2 . Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection dose decreased to 60 mg/m 2 . 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/m 2 to 60 mg/m 2 . If the patient continues to experience these reactions at 60 mg/m 2 , treatment should be discontinued. Non-Small Cell Lung Cancer Monotherapy with Docetaxel Injection for NSCLC treatment after failure of prior platinum-based chemotherapy Patients who are dosed initially at 75 mg/m 2 and who experience either febrile neutropenia, neutrophils < 500 cells/mm 3 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/m 2 . Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely. Combination therapy with Docetaxel Injection for chemotherapy-naive NSCLC For patients who are dosed initially at Docetaxel Injection 75 mg/m 2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is < 25,000 cells/mm 3 , 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/m 2 . In patients who require a further dose reduction, a dose of 50 mg/m 2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information. Prostate Cancer Combination therapy with Docetaxel Injection for hormone-refractory metastatic prostate cancer Docetaxel Injection should be administered when the neutrophil count is ≥1,500 cells/mm 3 . Patients who experience either febrile neutropenia, neutrophils <500 cells/mm 3 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/m 2 to 60 mg/m 2 . If the patient continues to experience these reactions at 60 mg/m 2 , the treatment should be discontinued. Gastric or Head and Neck Cancer Docetaxel 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 7 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/m 2 to 60 mg/m 2 . If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m 2 to 45 mg/m 2 . In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m 2 to 60 mg/m 2 . Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3 . 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 1 - Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel Injection in Combination with Cisplatin and Fluorouracil Toxicity Dosage adjustment Diarrhea grade 3 First episode: reduce fluorouracil dose by 20%. Second episode: then reduce Docetaxel Injection dose by 20%. Diarrhea grade 4 First episode: reduce Docetaxel Injection and fluorouracil doses by 20%. Second episode: discontinue treatment. Stomatitis/mucositis grade 3 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 4 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 x ULN and AP ≤2.5 x ULN, or AST/ALT >1.5 to ≤5 x ULN and AP >2.5 to ≤5 x ULN, Docetaxel Injection should be reduced by 20%. In case of AST/ALT >5 x ULN and/or AP >5 x 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 delays Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade: • Grade 2: Reduce cisplatin dose by 20%. • Grade 3: Discontinue treatment. Ototoxicity: In the case of grade 3 toxicity, discontinue treatment. Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2). For other cisplatin dosage adjustments, also refer to the manufacturers' prescribing information. Table 2 – Dose Reductions for Evaluation of Creatinine Clearance Creatinine clearance result before next cycle Cisplatin dose next cycle CrCl ≥60 mL/min Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle. CrCl between 40 and 59 mL/min Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was >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. CrCl <40 mL/min 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. If CrCl was >40 and <60 mL/min at end of cycle, a 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. CrCl = Creatinine clearance Fluorouracil dose modifications and treatment delays For diarrhea and stomatitis, see Table 1. In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%. For other >grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate. For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information. Combination Therapy with Strong CYP3A4 inhibitors: Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% Docetaxel Injection dose reduction if patients require co-administration of a strong CYP3A4 inhibitor. [see Drug Interactions (7) , Clinical Pharmacology (12.3) ]. 2.8 Administration Precautions Docetaxel Injection is a cytotoxic anticancer drug. Follow special handling and disposal procedures when preparing Docetaxel Injection solutions. 1 If Docetaxel Injection dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection, 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 formulation (Injection) Docetaxel Injection requires NO prior dilution with a 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 with diluent) with the one-vial formulation. One-vial formulation (Injection) Docetaxel Injection (20 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution. Use only a 21 gauge needle to withdraw docetaxel from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates. 1. Docetaxel Injection vials should be stored between 15° and 25°C (59° and 77°F). 2. Using only a 21 gauge needle, aseptically withdraw the required amount of Docetaxel Injection (20 mg docetaxel/mL) with a calibrated syringe and inject via a single injection into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 mg/mL to 0.74 mg/mL. If a dose > 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded. 3. Thoroughly mix the infusion by gentle manual rotation. 4. 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. The docetaxel dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions. 2.10 Stability Docetaxel Injection final dilution for infusion, if stored between 2° and 25°C (36° and 77°F) is stable for 4 hours. Docetaxel Injection final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).

1. INDICATIONS AND USAGE Docetaxel Injection, is a 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 ) • Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic 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 Cancer (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 a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. 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 androgen independent (hormone refractory) metastatic 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).

10. OVERDOSAGE There is no known antidote for docetaxel overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. In two reports of overdose, one patient received 150 mg/m 2 and the other received 200 mg/m 2 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/m 2 on a mg/m 2 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/m 2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m 2 on a mg/m 2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.

7. DRUG INTERACTIONS Docetaxel is a 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 co-administered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of docetaxel 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 a docetaxel injection dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3) ]. • Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism. ( 7 )

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. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. 12.3 Human Pharmacokinetics Absorption: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m 2 to 115 mg/m 2 in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m 2 to 115 mg/m 2 with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m 2 . Distribution: The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a 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 α 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) ]. Elimination: A study of 14 C-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 7 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 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug. Effect of Age: A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/ m 2 . Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were 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 a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with docetaxel injection. Patients with severe hepatic impairment have not been studied . [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6) ] Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m 2 to 90 mg/m 2 was similar to that of European/American populations dosed at 100 mg/m 2 , suggesting no significant difference in the elimination of docetaxel in the two populations. Effect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m 2 intravenous) alone or docetaxel (10 mg/m 2 intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 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-administration with ketoconazole [see Dosage and Administration (2.7) and Drug-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: A population pharmacokinetic analysis of plasma data from 40 patients with hormone-refractory metastatic prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone. • Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug-interactions between docetaxel (75 mg/m 2 ), doxorubicin (50 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) when administered in combination. The co-administration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to co-administration 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.

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. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use.

20190620

2

3. DOSAGE FORMS AND STRENGTHS One-vial formulation (Injection in Multiple Dose Vial) Docetaxel Injection, USP 160 mg/8 mL solution. • One vial Docetaxel Injection: Multipl-dose vial 160 mg/8 mL ( 3 )

Docetaxel Docetaxel DOCETAXEL DOCETAXEL ANHYDROUS POLYSORBATE 80 ALCOHOL ANHYDROUS CITRIC ACID

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-K 1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60 th to 1/15 th the recommended human dose on a mg/m 2 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 1/50 th the recommended human dose on a mg/m 2 basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3 rd and 1/15 th the recommended human dose on a mg/m 2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

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-K 1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60 th to 1/15 th the recommended human dose on a mg/m 2 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 1/50 th the recommended human dose on a mg/m 2 basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3 rd and 1/15 th the recommended human dose on a mg/m 2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

ANDA208137

Docetaxel

Docetaxel

67457-781

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 67457-781-08 Docetaxel Injection, USP 160 mg/8 mL (20 mg/mL) For Intravenous Infusion Only READY TO ADD TO INFUSION SOLUTION CAUTION: CYTOTOXIC AGENT Sterile Mylan Rx only MULTIPLE-Dose Vial Carton MDV

17. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Docetaxel Injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives if receiving docetaxel injection [see Warnings and Precautions (5.12 ) and Use in Specific Populations (8.1) ]. • Obtain detailed allergy and concomitant drug information from the patient prior to docetaxel injection administration. • Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report if they were not compliant with oral corticosteroid regimen. • Instruct patients to immediately report signs of a hypersensitivity reaction. • Tell patients to watch for signs of fluid retention such as peripheral edema in the lower extremities, weight gain and dyspnea. • Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever. • Instruct patients to report myalgia, cutaneous, or neurologic reactions. • Explain to patients the possible effects of the alcohol content in docetaxel injection, including possible effects on the central nervous system. Patients in whom alcohol should be avoided or minimized should consider the alcohol content of docetaxel injection. Alcohol could impair their ability to drive or use machines immediately after infusion. • Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, fatigue, excessive tearing, infusion site reactions, and hair loss (cases of permanent hair loss has been reported) are associated with docetaxel administration.

14. CLINICAL STUDIES 14.1 Locally Advanced or Metastatic Breast Cancer The efficacy and safety of another formulation of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens). Randomized Trials In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 every 3 weeks) or the combination of mitomycin (12 mg/m 2 every 6 weeks) and vinblastine (6 mg/m 2 every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel 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 13). Table 13 - Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis) Efficacy Parameter Docetaxel (n=203) Mitomycin/ Vinblastine (n=189) p-value Median Survival 11.4 months 8.7 months p=0.01 Risk Ratio*, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) 0.73 0.58 to 0.93 Log Rank Median Time to Progression 4.3 months 2.5 months p=0.01 Risk Ratio*, Progression (Docetaxel: Control) 95% CI (Risk Ratio) 0.75 0.61 to 0.94 Log Rank Overall Response Rate Complete Response Rate 28.1% 3.4% 9.5% 1.6% p (<0.0001) Chi Square * For the risk ratio, a value,1.00 favors docetaxel. In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 ) or doxorubicin (75 mg/m 2 ) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel 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 14). Table 14 - Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis) Efficacy Parameter Docetaxel (n=161) Doxorubicin (n=165) p-value Median Survival 14.7 months 14.3 months p=0.39 Risk Ratio*, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) 0.89 0.68 to 1.16 Log Rank Median Time to Progression 6.5 months 5.3 months p=0.45 Log Rank Risk Ratio*, Progression (Docetaxel: Control) 95% CI (Risk Ratio) 0.93 0.71 to 1.16 Overall Response Rate Complete Response Rate 45.3% 6.8% 29.7% 4.2% p=0.004 Chi Square *For the risk ratio, a value < 1.00 favors docetaxel. In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m 2 (n=151), 75 mg/m 2 (n=188) or 100 mg/m 2 (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 dose: 19.9% for the 60 mg/m 2 group compared to 22.3% for the 75 mg/m 2 and 29.8% for the 100 mg/m 2 group; pair-wise comparison between the 60 mg/m 2 and 100 mg/m 2 groups was statistically significant (p=0.037). Single Arm Studies Docetaxel at a dose of 100 mg/m 2 was studied in six single arm studies involving a 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% C.I.: 31 to 44.8) and the complete response rate was 2.1%. Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m 2 , 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% C.I.: 17.2 to 55.7), similar to the response rate in single arm studies of 100 mg/m 2 . 14.2 Adjuvant Treatment of Breast Cancer A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of another formulation of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1 to 3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m 2 administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 (TAC arm), or doxorubicin 50 mg/m 2 followed by fluorouracil 500 mg/m 2 and cyclosphosphamide 500 mg/m 2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel was administered as a 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 5 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 a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 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 1 - TAX316 Disease Free Survival K-M curve Figure 2 - TAX316 Overall Survival K-M Curve The following table describes the results of subgroup analyses for DFS and OS (See Table 15). Table 15 - Subset Analyses-Adjuvant Breast Cancer Study Disease Free Survival Overall Survival Patient subset Number of patients Hazard ratio* 95% CI Hazard ratio* 95% CI No. of positive nodes Overall 1 to 3 4+ 744 467 277 0.74 0.64 0.84 (0.60, 0.92) (0.47, 0.87) (0.63, 1.12) 0.69 0.45 0.93 (0.53, 0.90) (0.29, 0.70) (0.66, 1.32) Receptor status Positive Negative 566 178 0.76 0.68 (0.59, 0.98) (0.48, 0.97) 0.69 0.66 (0.48, 0.99) (0.44, 0.98) *a hazard ratio of <1 indicates that TAC is associated with a longer diseasefree survival or overall survival compared to FAC. Graph 1 Graph 2 14.3 Non-Small Cell Lung Cancer (NSCLC) The efficacy and safety of another formulation of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naive. Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy Two randomized, controlled trials established that a docetaxel dose of 75 mg/m 2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m 2 , 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, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m 2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m 2 . A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m 2 or best supportive care. In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to docetaxel 75 mg/m 2 , docetaxel 100 mg/m 2 and a treatment in which the investigator chose either vinorelbine 30 mg/m 2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m 2 days 1 to 3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the docetaxel 75 mg/m 2 arm and the comparator arms are summarized in Table 16 and Figures 3 and 4 showing the survival curves for the two studies. Table 16 - Efficacy of Docetaxel in the Treatment of Non-Small Cell Lung Cancer Patients Previously Treated with a Platinum-Based Chemotherapy Regimen (Intent-to-Treat Analysis) TAX317 TAX320 Docetaxel 75 mg/m 2 n=55 Best Supportive Care n=49 Docetaxel 75 mg/m 2 n=125 Control (V/I*) n=123 Overall Survival Log-rank Test p=0.01 p=0.13 Risk Ratio †† , Mortality (Docetaxel: Control) 95% CI (Risk Ratio) 0.56 (0.35, 0.88) 0.82 (0.63, 1.06) Median Survival 95% CI 7.5 months** (5.5, 12.8) 4.6 months (3.7, 6.1) 5.7 months (5.1, 7.1) 5.6 months (4.4, 7.9) % 1-year Survival 95% CI 37% **† (24, 50) 12% (2, 23) 30% **† (22, 39) 20% (13, 27) Time to Progression 95% CI 12.3 weeks** (9, 18.3) 7 weeks (6, 9.3) 8.3 weeks (7, 11.7) 7.6 weeks (6.7, 10.1) Response Rate 95% CI 5.5% (1.1, 15.1) Not Applicable 5.7% (2.3, 11.3) 0.8% (0, 4.5 * Vinorelbine/Ifosfamide ** p ≤0.05 † uncorrected for multiple comparisons †† a value <1.00 favors docetaxel Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m 2 . Figure 3 - TAX317 Survival K-M Curves – Docetaxel 75 mg/m 2 vs. Best Supportive Care Figure 4 - TAX320 Survival K-M Curves – Docetaxel 75 mg/m 2 vs. Vinorelbine or Ifosfamide Control Patients treated with docetaxel at a dose of 75 mg/m 2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials. Combination Therapy with Docetaxel for Chemotherapy-Naive NSCLC In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m 2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m 2 administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m 2 administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin. The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 17. Table 17 - Survival Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC Comparison Docetaxel+Cisplatin n=408 Vinorelbine+Cisplatin n=405 Kaplan-Meier Estimate of Median Survival 10.9 months 10 months p-value a 0.122 Estimated Hazard Ratio b 0.88 Adjusted 95% CI c (0.74, 1.06) a From the superiority test (stratified log rank) comparing docetaxel+cisplatin to vinorelbine+cisplatin b Hazard ratio of docetaxel+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of <1 indicates that docetaxel+cisplatin is associated with a longer survival. c Adjusted for interim analysis and multiple comparisons. The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 18). Table 18 - Response and TTP Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC Endpoint Docetaxel+Cisplatin Vinorelbine+Cisplatin p-value Objective Response Rate (95% CI) a 31.6% (26.5%, 36.8%) 24.4% (19.8%, 29.2%) Not Significant Median Time to Progression b (95% CI) a 21.4 weeks (19.3, 24.6) 22.1 weeks (18.1, 25.6) Not Significant a Adjusted for multiple comparisons. b Kaplan-Meier estimates. Graph 3 Graph 4 14.4 Hormone Refractory Prostate Cancer The safety and efficacy of another formulation of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups: • Docetaxel 75 mg/m 2 every 3 weeks for 10 cycles. • Docetaxel 30 mg/m 2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles. • Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles. All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously. In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 19 and Figure 5. Table 19 - Efficacy of Docetaxel in the Treatment of Patients with Androgen Independent (Hormone Refractory) Metastatic Prostate Cancer (Intent-to-Treat Analysis) Docetaxel + Prednisone every 3 weeks Mitoxantrone + Prednisone every 3 weeks Number of patients Median survival (months) 95% CI Hazard ratio 95% CI p-value* 335 18.9 (17.0 to 21.2) 0.761 (0.619 to 0.936) 0.0094 337 16.5 (14.4 to 18.6) -- -- -- * Stratified log rank test. Threshold for statistical significance = 0.0175 because of 3 arms. Figure 5-TAX327 Survival K-M Curves Graph 5 14.5 Gastric Adenocarcinoma A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of another formulation of docetaxel for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either docetaxel (T) (75 mg/m 2 on day 1) in combination with cisplatin (C) (75 mg/m 2 on day 1) and fluorouracil (F) (750 mg/m 2 per day for 5 days) or cisplatin (100 mg/m 2 on day 1) and fluorouracil (1000 mg/m 2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 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 a prior curative surgery and 12% had palliative surgery. The median number of cycles administered per patient was 6 (with a range of 1 to 16) for the TCF arm compared to 4 (with a range of 1 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 a 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 a HR of 1.29 (95% CI: 1.04 to 1.61). Efficacy results are summarized in Table 20 and Figures 6 and 7. Table 20 - Efficacy of Docetaxel in the treatment of patients with gastric adenocarcinoma Endpoint TCF n=221 CF n=224 Median TTP (months) (95%CI) Hazard ratio † (95%CI) *p-value 5.6 (4.86 to 5.91) 3.7 (3.45 to 4.47) 0.68 (0.55 to 0.84) 0.0004 Median survival (months) (95%CI) Hazard ratio † (95%CI) *p-value 9.2 (8.38 to 10.58) 8.6 (7.16 to 9.46) 0.77 (0.62 to 0.96) 0.0201 Overall Response Rate (CR+PR) (%) p-value 36.7 25.4 0.0106 * Unstratified log-rank test † For the hazard ratio (TCF/CF), values <1.00 favor the docetaxel arm. Subgroup analyses were concictent with the overall results across age, gender and race. Figure 6 - Gastric Cancer Study (TAX325) Time to Progression K-M Curve Figure 7 - Gastric Cancer Study (TAX325) Survival K-M Curve Graph 6 Graph 7 14.6 Head and Neck Cancer Induction chemotherapy followed by radiotherapy (TAX323) The safety and efficacy of another formulation of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2 followed by cisplatin (P) 75 mg/m 2 on Day 1, followed by fluorouracil (F) 750 mg/m 2 per day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 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/m 2 on Day 1, followed by fluorouracil (F) 1000 mg/m 2 /day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy to 2 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a 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 a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively). Efficacy results are presented in Table 21 and Figures 8 and 9. Table 21 - Efficacy of Docetaxel in the induction treatment of patients with inoperable locally advanced SCCHN (Intent-to-Treat Analysis) ENDPOINT Docetaxel+ Cisplatin+ Fluorouracil n=177 Cisplatin+ Fluorouracil n=181 Median progression free survival (months) (95%CI) 11.4 (10.1 to 14.0) 8.3 (7.4 to 9.1) Adjusted Hazard ratio (95%CI) *p-value 0.71 (0.56 to 0.91) 0.0077 Median survival (months) (95%CI) 18.6 (15.7 to 24.0) 14.2 (11.5 to 18.7) Hazard ratio (95%CI) **p-value 0.71 (0.56 to 0.9) 0.0055 Best overall response (CR + PR) to chemotherapy (%) 67.8 (60.4 to 74.6) 53.6 (46.0 to 61.0) (95%CI) ***p-value 0.006 Best overall response (CR + PR) to study treatment [chemotherapy +/- radiotherapy] (%) (95%CI) 72.3 (65.1 to 78.8) 58.6 (51.0 to 65.8) ***p-value 0.006 A Hazard ratio of <1 favors docetaxel + Cisplatin + Fluorouracil * Stratified log-rank test based on primary tumor site ** Stratified log-rank test, not adjusted for multiple comparisons *** Chi square test, not adjusted for multiple comparisons Figure 8 – TAX323 Progression-Free Survival K-M Curve Figure 9 - TAX323 Overall Survival K-M Curve Induction chemotherapy followed by chemoradiotherapy (TAX324) The safety and efficacy of another formulation of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/ m 2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/ m 2 /day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/ m 2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2 /day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70 to 72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT. The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the docetaxel-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 to 0.90]. Overall survival results are presented in Table 22 and Figure 10. Table 22 -Efficacy of Docetaxel in the induction treatment of patients with locally advanced SCCHN (Intent-to-Treat Analysis) ENDPOINT Docetaxel+ Cisplatin+ Fluorouracil n=255 Cisplatin+ Fluorouracil n=246 Median progression free survival (months) (95%CI) 70.6 (49.0 to NE) 30.1 (20.9 to 51.5) Hazard ratio (95%CI) *p-value 0.70 (0.54 to 0.90) 0.0058 A Hazard ratio of <1 favors docetaxel+cisplatin+fluorouracil * un-adjusted log-rank test NE -not estimable Figure 10 - TAX324 Overall Survival K-M Curve Graph 8 Graph 9 Graph 10

15. REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

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 Cancer In a study conducted in chemotherapy-naive patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients < 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients < the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). When docetaxel was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. Prostate Cancer Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the following treatment emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively. Breast Cancer In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients. Gastric Cancer Among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored. Head and Neck Cancer Among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. These clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients.

8.4 Pediatric Use The safety and effectiveness of Docetaxel Injection in pediatric patients have not been established. The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients [see Warnings and Precautions (5.11) ] .

8.1 Pregnancy Pregnancy Category D [see 'Warnings and Precautions' section] Based on its mechanism of action and findings in animals, Docetaxel injection can cause fetal harm when administered to a pregnant woman. If Docetaxel Injection is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Docetaxel Injection. Docetaxel Injection can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m 2 basis), administered during the period of organogenesis, have shown that docetaxel is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity.

8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see 'Warnings and Precautions' section] Based on its mechanism of action and findings in animals, Docetaxel injection can cause fetal harm when administered to a pregnant woman. If Docetaxel Injection is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Docetaxel Injection. Docetaxel Injection can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m 2 basis), administered during the period of organogenesis, have shown that docetaxel is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity. 8.3 Nursing Mothers It is not known whether docetaxel is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from docetaxel injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of Docetaxel Injection in pediatric patients have not been established. The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients [see Warnings and Precautions (5.11) ] . 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 Cancer In a study conducted in chemotherapy-naive patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients < 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients < the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). When docetaxel was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. Prostate Cancer Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the following treatment emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively. Breast Cancer In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients. Gastric Cancer Among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored. Head and Neck Cancer Among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. These clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients. 8.6 Hepatic Impairment Patients with bilirubin >ULN should not receive docetaxel injection. Also, patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN should not receive docetaxel injection. [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 (5.11) ] .

16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied One-vial formulation (Injection) Docetaxel Injection, USP is supplied in multiple-dose vial as a sterile, pyrogen-free, non-aqueous solution. Docetaxel Injection, USP Multiple-Dose Vial Docetaxel Injection, USP 160 mg/8 mL: The vial is in one carton. NDC 67457-781-08 16.2 Storage Store between 15° and 25°C (59° and 77°F). Retain in the original package to protect from light. Freezing does not adversely affect the product. After initial puncture, Docetaxel Injection, USP multiple-dose vials are stable for 28 days when stored at room temperature, with protection from light. 16.3 Handling and Disposal Follow procedures for proper handling and disposal of anticancer drugs. 1

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, AND FLUID RETENTION The incidence of treatment-related mortality associated with docetaxel therapy is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive docetaxel as a single agent at a dose of 100 mg/m 2 [see Warnings and Precautions (5.1) ]. Docetaxel Injection should not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 x ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of Docetaxel Injection therapy. [see Warnings and Precautions (5.2) ] . Docetaxel Injection therapy should not be given to patients with neutrophil counts of <1500 cells/mm 3 . In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving Docetaxel Injection. [see Warnings and Precautions (5.3) ] . Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received a 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and administration of appropriate therapy [see Warnings and Precautions (5.4) ] . Docetaxel Injection must not be given to patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80 [see Contraindications (4) ]. Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. 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 (5.5) ]. WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See 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 at 100 mg/m 2 ( 5.1 ) • Should not be given if bilirubin >ULN, or if AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle ( 8.6 ) • Should not be given if neutrophil counts are <1500 cells/mm 3 . Obtain frequent blood counts to monitor for neutropenia ( 4 ) • Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy ( 5.4 ) • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 ( 4 ) • Severe fluid retention may occur despite dexamethasone ( 5.5 )