DOCETAXEL- docetaxel_injection, solution

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. Absorption The pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20 mg/m 2 2 2 2 Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with initial rapid distribution phase and the late (terminal) phase. Distribution Mean steady state volume of distribution was 113 L. Docetaxel is approximately 94% protein bound in vitro in vitro Elimination With extended plasma sampling up to 8 to 22 days post infusion, the estimated mean total body clearance was 18 L/h/m 2 Metabolism Docetaxel is metabolized by the CYP3A4 isoenzyme in vitro [see Drug Interactions (7) Excretion In three cancer patients urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively, within 7 days. About 80% of the radioactivity recovered in feces was excreted during the first 48 hours as 1 major and 3 minor metabolites with less than 8% as unchanged drug. Specific Populations Effect of Age A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m 2 Effect of Gender The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel. Hepatic Impairment The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1. 5 times ULN concomitant with alkaline phosphatase >2. 5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with Docetaxel Injection. Patients with severe hepatic impairment have not been studied [ see Warnings and Precautions (5. 2) Use in Specific Populations (8. 6) Effect of Race Mean total body clearance for Japanese patients dosed at the range of 10 mg/m 2 2 2 Drug Interaction Studies Effect of Ketoconazole The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m 2 2 see Dosage and Administration (2. 7) Drug Interactions (7) Effect of Combination Therapies 2 2 2.

Docetaxel Injection is a microtubule inhibitor indicated for: Breast Cancer (BC): 1. 1 Non-small Cell Lung Cancer (NSCLC): 1. 2 Castration-Resistant Prostate Cancer (CRPC): 1. 3 Gastric Adenocarcinoma (GC): 1. 4 Squamous Cell Carcinoma of the Head and Neck (SCCHN): 1. 5 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. 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. Docetaxel Injection in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer. 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. 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).

For all indications, toxicities may warrant dosage adjustments [ see Dosage and Administration (2. 7) Administer in a facility equipped to manage possible complications (e. , anaphylaxis). Administer in a facility equipped to manage possible complications (e. Administer intravenously (IV) over 1 hour every 3 weeks. PVC equipment is not recommended. Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial. 2 2 2. 1 2 2 2 2. 1 2 2. 2 2 2 2. 2 2 2. 3 2 2 2 2. 4 2 2 2 2. 5 2 2 2 2. 5 For all patients: 2. 7 2 2 2 2 2 see Dosage and Administration (2. 7) 2 2 see Boxed Warning Dosage and Administration (2. 7) Warnings and Precautions (5) Clinical Studies (14) 2 2 see Dosage and Administration (2. 7) 2 see Dosage and Administration (2. 7) 2 2 2 see Dosage and Administration (2. 7) Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the Docetaxel Injection containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics. Induction Chemotherapy Followed by Radiotherapy (TAX323) For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m 2 2 2 see Dosage and Administration (2. 7) Induction Chemotherapy Followed by Chemoradiotherapy (TAX324) For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m 2 2 2 see Dosage and Administration (2. 7) All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e. , 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [ see Boxed Warning Warnings and Precautions (5. 5) For metastatic castration-resistant prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg at 12 hours, 3 hours, and 1 hour before the Docetaxel Injection infusion [ see Warnings and Precautions (5. 5) Breast Cancer Patients who are dosed initially at 100 mg/m 2 3 2 2 2 2 2 3 Combination Therapy with 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 >=1500 cells/mm 3 2 2 2 2 2 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 3 2 Combination Therapy with Docetaxel Injection for Chemotherapy-Naïve NSCLC For patients who are dosed initially at Docetaxel Injection 75 mg/m 2 3 2 2 Prostate Cancer Combination Therapy with Docetaxel Injection for Metastatic Castration-Resistant Prostate Cancer Docetaxel Injection should be administered when the neutrophil count is >=1500 cells/mm 3 3 2 2 2 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 2 2 2 2 2 3 see Contraindications (4) 3 see Warnings and Precautions (5. 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%. Diarrhea grade 4 First episode: reduce Docetaxel Injection and fluorouracil doses by 20%. Stomatitis/mucositis grade 3 First episode: reduce fluorouracil dose by 20%. Stomatitis/mucositis grade 4 First episode: stop fluorouracil only, at all subsequent cycles. Liver dysfunction: In case of AST/ALT >2. 5 to <=5 × ULN and AP <=2. 5 × ULN, or AST/ALT >1. 5 to <=5 × ULN and AP >2. 5 to <=5 × ULN, Docetaxel Injection should be reduced by 20%. In case of AST/ALT >5 × ULN and/or AP >5 × ULN Docetaxel Injection should be stopped. The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below. Cisplatin Dose Modifications and Delays Peripheral Neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCI-CTCAE grade: Ototoxicity: In the case of grade 3 toxicity, discontinue treatment. Nephrotoxicity: In the event of a rise in serum creatinine >=grade 2 (>1. 5 × normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2). For other cisplatin dosage adjustments, also refer to the manufacturers' prescribing information. Table 2: Dose Reductions for Evaluation of Creatinine Clearance CrCl = Creatinine clearance Creatinine Clearance Result Before Next Cycle Cisplatin Dose Next Cycle CrCl >=60 mL/min Full dose of cisplatin was given. CrCl was to be repeated 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. CrCl <40 mL/min Dose of cisplatin was omitted in that treatment cycle only. Fluorouracil Dose Modifications and Treatment Delays For diarrhea and stomatitis, see Table 1 In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%. For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade <=1 and then recommenced, if medically appropriate. For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information. Combination Therapy with Strong CYP3A4 Inhibitors Avoid using concomitant strong CYP3A4 inhibitors (e. , ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require coadministration of a strong CYP3A4 inhibitor [ see Drug Interactions (7) Clinical Pharmacology (12. Docetaxel Injection is a hazardous anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docetaxel Injection solutions. The use of gloves is recommended [ see How Supplied/Storage and Handling (16. If Docetaxel Injection or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water. Contact of the Docetaxel Injection with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final Docetaxel Injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. 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. 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 Injection from the vial because larger bore needles (e. , 18 and 19 gauge) may result in stopper coring and rubber particulates. Dilution for Infusion 1. The Docetaxel Injection dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions. Docetaxel Injection final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F), is stable for 6 hours. Docetaxel Injection final dilution for infusion (in either 0. 9% Sodium Chloride solution or 5% Dextrose solution) should be used within 6 hours (including the 1 hour intravenous administration). In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C (36°F and 46°F).

=2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization 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 Related to treatment 20 0 14 1 13 1 7 2 Edema only 13 0 7 0 12 1 6 1 Weight gain only 6 0 6 0 0 0 1 0 Dizziness 2 0 5 1 16 4 15 2 Neurosensory 18 1 11 1 14 1 14 0 Altered hearing 6 0 10 3 13 1 19 3 Neuromotor 2 1 4 1 9 0 10 2 Alopecia 81 11 43 0 68 4 44 1 Rash/itch 12 0 6 0 20 0 16 1 Dry skin 6 0 2 0 5 0 3 0 Desquamation 4 1 6 0 2 0 5 0 Nausea 47 1 51 7 77 14 80 14 Stomatitis 43 4 47 11 66 21 68 27 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 Includes superficial and deep vein thrombosis and pulmonary embolism 3 2 6 2 4 2 5 4 Ischemia myocardial 2 2 1 0 2 1 1 1 Tearing 2 0 1 0 2 0 2 0 Conjunctivitis 1 0 1 0 1 0 0. 4 0 The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole: Cardiovascular: Cutaneous: Gastrointestinal: Hearing: Hematologic: Hepatic: Hypersensitivity: Metabolism and nutrition disorders: Neurologic: Ophthalmologic: Respiratory: Renal: Second primary malignancies: see Warnings and Precautions (5. 7) Musculoskeletal disorder:.">The most serious adverse reactions from docetaxel are: see Boxed Warning Warnings and Precautions (5. 1) see Boxed Warning Warnings and Precautions (5. 2) see Boxed Warning Warnings and Precautions (5. 3) see Warnings and Precautions (5. 4) see Boxed Warning Warnings and Precautions (5. 5) see Boxed Warning Warnings and Precautions (5. 6) see Warnings and Precautions (5. 7) see Warnings and Precautions (5. 8) see Warnings and Precautions (5. 9) see Warnings and Precautions (5. 10) see Warnings and Precautions (5. 11) see Warnings and Precautions (5. 13) 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, and myalgia. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www. gov/medwatch Breast Cancer Monotherapy with Docetaxel for Locally Advanced or Metastatic Breast Cancer after Failure of Prior Chemotherapy Docetaxel 100 mg/m 2 2 Table 3: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m 2 Adverse Reaction All Tumor Types Normal LFTs 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 n=2045 % All Tumor Types Elevated LFTs Elevated Baseline LFTs: AST and/or ALT >1. 5 times ULN concurrent with alkaline phosphatase >2. 5 times ULN n=61 % Breast Cancer Normal LFTs n=965 % Hematologic Neutropenia <2000 cells/mm 3 96 96 99 <500 cells/mm 3 75 88 86 Leukopenia <4000 cells/mm 3 96 98 99 <1000 cells/mm 3 32 47 44 Thrombocytopenia <100,000 cells/mm 3 8 25 9 Anemia <11 g/dL 90 92 94 <8 g/dL 9 31 8 Febrile Neutropenia Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization 11 26 12 Septic Death 2 5 1 Non-Septic Death 1 7 1 Infections Any 22 33 22 Severe 6 16 6 Fever in Absence of Infection Any 31 41 35 Severe 2 8 2 Hypersensitivity Reactions Regardless of Premedication Any 21 20 18 Severe 4 10 3 With 3-day Premedication n=92 n=3 n=92 Any 15 33 15 Severe 2 0 2 Fluid Retention Regardless of Premedication Any 47 39 60 Severe 7 8 9 With 3-day Premedication n=92 n=3 n=92 Any 64 67 64 Severe 7 33 7 Neurosensory Any 49 34 58 Severe 4 0 6 Cutaneous Any 48 54 47 Severe 5 10 5 Nail Changes Any 31 23 41 Severe 3 5 4 Gastrointestinal Nausea 39 38 42 Vomiting 22 23 23 Diarrhea 39 33 43 Severe 5 5 6 Stomatitis Any 42 49 52 Severe 6 13 7 Alopecia 76 62 74 Asthenia Any 62 53 66 Severe 13 25 15 Myalgia Any 19 16 21 Severe 2 2 2 Arthralgia 9 7 8 Infusion Site Reactions 4 3 4 Hematologic Reactions Reversible marrow suppression was the major dose-limiting toxicity of docetaxel [ see Warnings and Precautions (5. 3) 3 Febrile neutropenia (<500 cells/mm 3 Severe infectious episodes occurred in 6. 1% of patients with solid tumors, in 6. 4% of patients with metastatic breast cancer, and in 5. 4% of 92 breast cancer patients premedicated with 3-day corticosteroids. Thrombocytopenia (<100,000 cells/mm 3 Hypersensitivity Reactions Severe hypersensitivity reactions have been reported [ see Boxed Warning Warnings and Precautions (5. 5) Fluid Retention Fluid retention can occur with the use of docetaxel [ see Boxed Warning Dosage and Administration (2. 6) Warnings and Precautions (5. 6) Cutaneous Reactions Severe skin toxicity is discussed elsewhere in the label [ see Warnings and Precautions (5. 8) Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis (in 0. 8% of patients with solid tumors) and pain. Neurologic Reactions Neurologic reactions are discussed elsewhere in the label [ see Warnings and Precautions (5. 9) Gastrointestinal Reactions Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3%en dash5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Severe stomatitis occurred in 5. 5% of patients with solid tumors, in 7. 4% of patients with metastatic breast cancer, and in 1. 1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. Cardiovascular Reactions Hypotension occurred in 2. 8% of patients with solid tumors; 1. 2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension have occurred. Seven of 86 (8. 1%) of metastatic breast cancer patients receiving docetaxel 100 mg/m 2 Infusion Site Reactions Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein. Hepatic Reactions In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8. 9% of patients. Increases in AST or ALT >1. 5 times the ULN, or alkaline phosphatase >2. 5 times ULN, were observed in 18. 3% of patients, respectively. While on docetaxel, increases in AST and/or ALT >1. 5 times ULN concomitant with alkaline phosphatase >2. 5 times ULN occurred in 4. 3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established. Hematologic and Other Toxicity: Relation to Dose and Baseline Liver Chemistry Abnormalities Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m 2 2 Table 4: Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m 2 2 Adverse Reaction Docetaxel 100 mg/m 2 Docetaxel 60mg/m 2 Normal LFTs Normal Baseline LFTs: Transaminases <=1. 5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN n=730 % Elevated LFTs Elevated Baseline LFTs: AST and/or ALT >1. 5 times ULN n=18 % Normal LFTs n=174 % Neutropenia Any <2000 cells/mm 3 98 100 95 Grade 4 <500 cells/mm 3 84 94 75 Thrombocytopenia Any <100,000 cells/mm 3 11 44 14 Grade 4 <20,000 cells/mm 3 1 17 1 Anemia 95 94 65 Infection 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. Any 23 39 1 Grade 3 and 4 7 33 0 Febrile Neutropenia Febrile Neutropenia: For 100 mg/m 2 2 By Patient 12 33 0 By Course 2 9 0 Septic Death 2 6 1 Non-Septic Death 1 11 0 Table 5: Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m 2 2 NA = not available Adverse Reaction Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2 Normal LFTs Normal Baseline LFTs: Transaminases <=1. 5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN n=730 % Elevated LFTs Elevated Baseline Liver Function: AST and/or ALT >1. 5 times ULN n=18 % Normal LFTs n=174 % Acute Hypersensitivity Reaction Regardless of Premedication Any 13 6 1 Severe 1 0 0 Fluid Retention 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 Regardless of Premedication Any 56 61 13 Severe 8 17 0 Neurosensory Any 57 50 20 Severe 6 0 0 Myalgia 23 33 3 Cutaneous Any 45 61 31 Severe 5 17 0 Asthenia Any 65 44 66 Severe 17 22 0 Diarrhea Any 42 28 NA Severe 6 11 Stomatitis Any 53 67 19 Severe 8 39 1 In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m 2 2 2 2 2 2 2 2 2 2 2 2 The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m 2 2 2 Combination Therapy with Docetaxel in the Adjuvant Treatment of Breast Cancer The following table presents treatment-emergent adverse reactions observed in 744 patients, who were treated with docetaxel 75 mg/m 2 Table 6: 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 2 2 n=744 % Fluorouracil 500 mg/m 2 2 2 n=736 % Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 92 4 72 2 Neutropenia 71 66 82 49 Fever in absence of infection 47 1 17 0 Infection 39 4 36 2 Thrombocytopenia 39 2 28 1 Febrile neutropenia 25 N/A 3 N/A Neutropenic infection 12 N/A 6 N/A Hypersensitivity reactions 13 1 4 0 Lymphedema 4 0 1 0 Fluid Retention COSTART term and grading system for events related to treatment. 35 1 15 0 Peripheral edema 27 0 7 0 Weight gain 13 0 9 0 Neuropathy sensory 26 0 10 0 Neuro-cortical 5 1 6 1 Neuropathy motor 4 0 2 0 Neuro-cerebellar 2 0 2 0 Syncope 2 1 1 0 Alopecia 98 N/A 97 N/A Skin toxicity 27 1 18 0 Nail disorders 19 0 14 0 Nausea 81 5 88 10 Stomatitis 69 7 53 2 Vomiting 45 4 59 7 Diarrhea 35 4 28 2 Constipation 34 1 32 1 Taste perversion 28 1 15 0 Anorexia 22 2 18 1 Abdominal Pain 11 1 5 0 Amenorrhea 62 N/A 52 N/A Cough 14 0 10 0 Cardiac dysrhythmias 8 0 6 0 Vasodilatation 27 1 21 1 Hypotension 2 0 1 0 Phlebitis 1 0 1 0 Asthenia 81 11 71 6 Myalgia 27 1 10 0 Arthralgia 19 1 9 0 Lacrimation disorder 11 0 7 0 Conjunctivitis 5 0 7 0 Of the 744 patients treated with TAC, 36. 3% experienced severe treatment-emergent adverse reactions compared to 26. 6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0. 1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1. 1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs. Fever and Infection During the treatment period, fever in the absence of infection was seen in 46. 5% of TAC-treated patients and in 17. 1% of FAC-treated patients. Grade 3/4 fever in the absence of infection was seen in 1. 3% and 0% of TAC- and FAC-treated patients, respectively. Infection was seen in 39. 4% of TAC-treated patients compared to 36. 3% of FAC-treated patients. Grade 3/4 infection was seen in 3. 2% of TAC-treated and FAC-treated patients, respectively. There were no septic deaths in either treatment arm during the treatment period. Gastrointestinal Reactions In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation versus one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred during the treatment period. Cardiovascular Reactions More cardiovascular reactions were reported in the TAC arm versus the FAC arm during the treatment period: arrhythmias, all grades (6. 9%), and hypotension, all grades (1. Twenty-six (26) patients (3. 5%) in the TAC arm and 17 patients (2. 3%) in the FAC arm developed CHF during the study period. All except one patient in each arm were diagnosed with CHF during the follow-up period. Two (2) patients in TAC arm and 4 patients in FAC arm died due to CHF. The risk of CHF was higher in the TAC arm in the first year, and then was similar in both treatment arms. Adverse Reactions during the Follow-Up Period (Median Follow-Up Time of 8 Years) In study TAX316, the most common adverse reactions that started during the treatment period and persisted into the follow-up period in TAC and FAC patients are described below (median follow-up time of 8 years). Nervous System Disorders: Skin and Subcutaneous Tissue Disorders: Reproductive System and Breast Disorders: General Disorders and Administration Site Conditions: In study TAX316, lymphedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1. 5%) and 1 of 736 FAC patients (0. At the end of the follow-up period (actual median follow-up time of 8 years), lymphedema was observed to be ongoing in 6 TAC patients (0. 8%) and 1 FAC patient (0. In study TAX316, asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31. 7%) and 180 of 736 FAC patients (24. At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3. 9%) and 16 FAC patients (2. Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS): Myelodysplastic syndrome occurred in 2 of 744 (0. 3%) patients who received TAC and in 1 of 736 (0. 1%) patients who received FAC. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. Lung Cancer Monotherapy with Docetaxel for Unresectable, Locally Advanced or Metastatic NSCLC Previously Treated with Platinum-Based Chemotherapy Docetaxel 75 mg/m 2 Table 7: Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel as Monotherapy for Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy Normal Baseline LFTs: Transaminases <=1. 5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN Adverse Reaction Docetaxel 75 mg/m 2 n=176 % Best Supportive Care n=49 % Vinorelbine/Ifosfamide n=119 % Neutropenia Any 84 14 83 Grade 3/4 65 12 57 Leukopenia Any 84 6 89 Grade 3/4 49 0 43 Thrombocytopenia Any 8 0 8 Grade 3/4 3 0 2 Anemia Any 91 55 91 Grade 3/4 9 12 14 Febrile Neutropenia Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization 6 NA Not Applicable 1 Infection Any 34 29 30 Grade 3/4 10 6 9 Treatment Related Mortality 3 NA 3 Hypersensitivity Reactions Any 6 0 1 Grade 3/4 3 0 0 Fluid Retention Any 34 ND Not Done 23 Severe 3 3 Neurosensory Any 23 14 29 Grade 3/4 2 6 5 Neuromotor Any 16 8 10 Grade 3/4 5 6 3 Skin Any 20 6 17 Grade 3/4 1 2 1 Gastrointestinal Nausea Any 34 31 31 Grade 3/4 5 4 8 Vomiting Any 22 27 22 Grade 3/4 3 2 6 Diarrhea Any 23 6 12 Grade 3/4 3 0 4 Alopecia 56 35 50 Asthenia Any 53 57 54 Severe COSTART term and grading system 18 39 23 Stomatitis Any 26 6 8 Grade 3/4 2 0 1 Pulmonary Any 41 49 45 Grade 3/4 21 29 19 Nail Disorder Any 11 0 2 Severe 1 0 0 Myalgia Any 6 0 3 Severe 0 0 0 Arthralgia Any 3 2 2 Severe 0 0 1 Taste Perversion Any 6 0 0 Severe 1 0 0 Combination Therapy with Docetaxel in Chemotherapy-Naïve Advanced Unresectable or Metastatic NSCLC Table 8 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 8: 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 2 n=406 % Vinorelbine 25 mg/m 2 2 n=396 % Neutropenia Any 91 90 Grade 3/4 74 78 Febrile Neutropenia 5 5 Thrombocytopenia Any 15 15 Grade 3/4 3 4 Anemia Any 89 94 Grade 3/4 7 25 Infection Any 35 37 Grade 3/4 8 8 Fever in absence of infection Any 33 29 Grade 3/4 <1 1 Hypersensitivity Reaction Replaces NCI term "Allergy" Any 12 4 Grade 3/4 3 <1 Fluid Retention COSTART term and grading system Any 54 42 All severe or life-threatening events 2 2 Pleural effusion Any 23 22 All severe or life-threatening events 2 2 Peripheral edema Any 34 18 All severe or life-threatening events <1 <1 Weight gain Any 15 9 All severe or life-threatening events <1 <1 Neurosensory Any 47 42 Grade 3/4 4 4 Neuromotor Any 19 17 Grade 3/4 3 6 Skin Any 16 14 Grade 3/4 <1 1 Nausea Any 72 76 Grade 3/4 10 17 Vomiting Any 55 61 Grade 3/4 8 16 Diarrhea Any 47 25 Grade 3/4 7 3 Anorexia Any 42 40 All severe or life-threatening events 5 5 Stomatitis Any 24 21 Grade 3/4 2 1 Alopecia Any 75 42 Grade 3 <1 0 Asthenia Any 74 75 All severe or life-threatening events 12 14 Nail Disorder Any 14 <1 All severe events <1 0 Myalgia Any 18 12 All severe events <1 <1 Deaths within 30 days of last study treatment occurred in 31 patients (7. 6%) in the docetaxel+cisplatin arm and 37 patients (9. 3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2. 2%) in the docetaxel+cisplatin arm and 8 patients (2. 0%) in the vinorelbine+cisplatin arm. The second comparison in the study, vinorelbine+cisplatin versus docetaxel+carboplatin (which did not demonstrate a superior survival associated with docetaxel, [ see Clinical Studies (14. 3) Prostate Cancer Combination Therapy with Docetaxel in Patients with Prostate Cancer The following data are based on the experience of 332 patients, who were treated with docetaxel 75 mg/m 2 Table 9: 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 n=332 % Mitoxantrone 12 mg/m 2 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 Related to treatment 24 1 5 0 Weight Gain 8 0 3 0 Peripheral Edema 18 0 2 0 Neuropathy Sensory 30 2 7 0 Neuropathy Motor 7 2 3 1 Rash/Desquamation 6 0 3 1 Alopecia 65 N/A 13 N/A Nail Changes 30 0 8 0 Nausea 41 3 36 2 Diarrhea 32 2 10 1 Stomatitis/Pharyngitis 20 1 8 0 Taste Disturbance 18 0 7 0 Vomiting 17 2 14 2 Anorexia 17 1 14 0 Cough 12 0 8 0 Dyspnea 15 3 9 1 Cardiac left ventricular function 10 0 22 1 Fatigue 53 5 35 5 Myalgia 15 0 13 1 Tearing 10 1 2 0 Arthralgia 8 1 5 1 Gastric Cancer Combination Therapy with Docetaxel Injection in Gastric Adenocarcinoma Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease who were treated with Docetaxel Injection 75 mg/m 2 Table 10: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study Clinically important treatment-emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction. Docetaxel Injection 75 mg/m 2 2 2 n=221 Cisplatin 100 mg/m 2 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 Related to treatment 15 0 4 0 Edema 13 0 3 0 Lethargy 63 21 58 18 Neurosensory 38 8 25 3 Neuromotor 9 3 8 3 Dizziness 16 5 8 2 Alopecia 67 5 41 1 Rash/itch 12 1 9 0 Nail changes 8 0 0 0 Skin desquamation 2 0 0 0 Nausea 73 16 76 19 Vomiting 67 15 73 19 Anorexia 51 13 54 12 Stomatitis 59 21 61 27 Diarrhea 78 20 50 8 Constipation 25 2 34 3 Esophagitis/dysphagia/odynophagia 16 2 14 5 Gastrointestinal pain/cramping 11 2 7 3 Cardiac dysrhythmias 5 2 2 1 Myocardial ischemia 1 0 3 2 Tearing 8 0 2 0 Altered hearing 6 0 13 2 Head and Neck Cancer Combination Therapy with Docetaxel Injection in Head and Neck Cancer Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with Docetaxel Injection 75 mg/m 2 Table 11: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with Docetaxel Injection in Combination with Cisplatin and Fluorouracil Followed by Radiotherapy (TAX323) or Chemoradiotherapy (TAX324) Clinically important treatment-emergent adverse reactions based upon frequency, severity, and clinical impact. TAX323 (n=355) TAX324 (n=494) Docetaxel Injection arm (n=174) Comparator arm (n=181) Docetaxel Injection arm (n=251) Comparator arm (n=243) Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Neutropenia 93 76 87 53 95 84 84 56 Anemia 89 9 88 14 90 12 86 10 Thrombocytopenia 24 5 47 18 28 4 31 11 Infection 27 9 26 8 23 6 28 5 Febrile neutropenia Febrile neutropenia: grade >=2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization 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 Related to treatment 20 0 14 1 13 1 7 2 Edema only 13 0 7 0 12 1 6 1 Weight gain only 6 0 6 0 0 0 1 0 Dizziness 2 0 5 1 16 4 15 2 Neurosensory 18 1 11 1 14 1 14 0 Altered hearing 6 0 10 3 13 1 19 3 Neuromotor 2 1 4 1 9 0 10 2 Alopecia 81 11 43 0 68 4 44 1 Rash/itch 12 0 6 0 20 0 16 1 Dry skin 6 0 2 0 5 0 3 0 Desquamation 4 1 6 0 2 0 5 0 Nausea 47 1 51 7 77 14 80 14 Stomatitis 43 4 47 11 66 21 68 27 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 Includes superficial and deep vein thrombosis and pulmonary embolism 3 2 6 2 4 2 5 4 Ischemia myocardial 2 2 1 0 2 1 1 1 Tearing 2 0 1 0 2 0 2 0 Conjunctivitis 1 0 1 0 1 0 0. 4 0 The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole: Cardiovascular: Cutaneous: Gastrointestinal: Hearing: Hematologic: Hepatic: Hypersensitivity: Metabolism and nutrition disorders: Neurologic: Ophthalmologic: Respiratory: Renal: Second primary malignancies: see Warnings and Precautions (5. 7) Musculoskeletal disorder:.

Docetaxel Injection is contraindicated in patients with: 3 see Warnings and Precautions (5. 3) see Warnings and Precautions (5. 5) 4 3 4.

3 Risk Summary Based on findings in animal reproduction studies and its mechanism of action, Docetaxel Injection can cause fetal harm when administered to a pregnant woman [ see Clinical Pharmacology (12. 1) see Clinical Considerations see Data The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Docetaxel Injection contains alcohol [ see Warnings and Precautions (5. 13) Data Animal data Intravenous administration of >=0. 03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. Maternal toxicity was also observed at these doses, which were approximately 0. 003 times the daily maximum recommended human dose based on body surface area, respectively. Risk Summary There is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. No lactation studies in animals have been conducted. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Docetaxel Injection and for 1 week after the last dose. Based on findings in animals, Docetaxel Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8. 1) Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating Docetaxel Injection. Contraception Females Based on genetic toxicity findings, advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of Docetaxel Injection. Males Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of Docetaxel Injection. Infertility Based on findings in animal studies, Docetaxel Injection may impair fertility in males of reproductive potential [ see Nonclinical Toxicology (13. The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients [ see Warnings and Precautions (5. 13) The efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of docetaxel in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults. Docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluorouracil (TCF). Docetaxel Monotherapy Docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12. 5 years, range 1en dash22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m 2 The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1en dash26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0. 6%) in a patient with undifferentiated sarcoma to four partial responses (2. 2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma. Docetaxel in Combination Docetaxel was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to docetaxel (75 mg/m 2 2 2 2 2 Pharmacokinetics Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m 2 2 2 Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m 2 2 In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults [ see Clinical Pharmacology (12. 3) In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients. Non-small Cell Lung Cancer In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10. 3 months (95% CI: 9. 1 months, 11. 8 months) and patients 65 years or older had a median survival of 12. 1 months (95% CI: 9. 3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). When docetaxel was combined with carboplatin for the treatment of chemotherapy-naïve, 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 Injection 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 Injection in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. These clinical studies of Docetaxel Injection in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients. Avoid Docetaxel Injection in patients with bilirubin > ULN and patients with AST and/or ALT >1. 5 × ULN concomitant with alkaline phosphatase >2. 5 × ULN [ see Boxed Warning Warnings and Precautions (5. 2) Clinical Pharmacology (12. 3) The alcohol content of Docetaxel Injection should be taken into account when given to patients with hepatic impairment [ see Warnings and Precautions (5.

Docetaxel is a CYP3A4 substrate. In vitro In vivo see Dosage and Administration (2. 7) Clinical Pharmacology (12. 3) 7.

OVERDOSAGE
There is no known antidote for Docetaxel Injection overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. In two reports of overdose, one patient received 150 mg/m 2 2 2 2 2 2 2
NONCLINICAL TOXICOLOGY
Carcinogenicity studies with docetaxel have not been performed. Docetaxel was genotoxic by an aneugenic mechanism in the in vitro 1 in vivo th th 2 Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0. 3 mg/kg (about 1/50 th 2 rd th 2.
CLINICAL STUDIES
The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating 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 2 2 Table 12: 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. 7 months Risk Ratio For the risk ratio, a value less than 1. 00 favors docetaxel. Median Time to Progression 4. 5 months Risk Ratio Progression (Docetaxel: Control) Overall Response Rate Complete Response Rate 28. 0001 Chi Square In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 2 Table 13: 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 Risk Ratio For the risk ratio, a value less than 1. Median Time to Progression 6. 3 months Risk Ratio Overall Response Rate Complete Response Rate 45. 004 Chi Square In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m 2 2 2 2 2 2 2 2 Single Arm Studies Docetaxel at a dose of 100 mg/m 2 Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m 2 2 A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1en dash3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m 2 2 2 2 2 2 Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0. 74; 2-sided 95% CI=0. 92, stratified log rank p=0. The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25. 7% for TAC-treated patients (see Figure 1). At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0. 69, 2-sided 95% CI=0. 90) (see Figure 2). There will be further analysis at the time survival data mature. The following table describes the results of subgroup analyses for DFS and OS (see Table 14). Table 14: Subset Analyses-Adjuvant Breast Cancer Study Disease Free Survival Overall Survival Patient subset Number of patients Hazard ratio A hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC. 95% CI Hazard ratio 95% CI No. of positive nodes Overall 744 0. 90) 1en dash3 467 0. 70) 4+ 277 0. 32) Receptor status Positive 566 0. 99) Negative 178 0. 98) Figure 1 Figure 2 The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve. Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy Two randomized, controlled trials established that a docetaxel dose of 75 mg/m 2 2 see Boxed Warning Dosage and Administration (2. 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 2 2 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 2 2 2 2 Table 15: 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 Vinorelbine/Ifosfamide ) n=123 Overall Survival Log-rank Test Risk Ratio a value less than 1. 00 favors docetaxel Median Survival 7. 5 months p<=0. 6 months % 1-year Survival 37% uncorrected for multiple comparisons 12% 30% 20% Time to Progression 12. 6 weeks Response Rate 5. 5% Not Applicable 5. 8% Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m 2 Patients treated with docetaxel at a dose of 75 mg/m 2 Figure 3 Figure 4 Combination Therapy with Docetaxel for Chemotherapy-Naïve NSCLC In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m 2 2 2 2 The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 16. Table 16: 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. 0 months p-value From the superiority test (stratified log rank) comparing docetaxel+cisplatin to vinorelbine+cisplatin 0. 122 Estimated Hazard Ratio Hazard ratio of docetaxel+cisplatin versus vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that docetaxel+cisplatin is associated with a longer survival. 88 Adjusted 95% CI Adjusted for interim analysis and multiple comparisons. 06) The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9. 1 months for docetaxel+carboplatin compared to 10. 0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 17). Table 17: Response and TTP Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC Endpoint Docetaxel + Cisplatin Vinorelbine + Cisplatin p-value Objective Response Rate Adjusted for multiple comparisons. 4% Not Significant Median Time to Progression Kaplan-Meier estimates. 1 weeks Not Significant The safety and efficacy of docetaxel in combination with prednisone in patients with metastatic castration-resistant prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) >=60 were randomized to the following treatment groups: 2 2 2 All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously. In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 18 and Figure 5. Table 18: Efficacy of Docetaxel in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (Intent-to-Treat Analysis) Docetaxel + Prednisone every 3 weeks Mitoxantrone + Prednisone every 3 weeks Number of patients 335 337 Median survival (months) 18. 5 95% CI (17. 6) Hazard ratio 0. 761 em dash 95% CI (0. 619en dash0. 936) em dash p-value Stratified log-rank test. Threshold for statistical significance = 0. 0175 because of 3 arms. 0094 em dash Figure 5 A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of Docetaxel Injection for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either Docetaxel Injection (T) (75 mg/m 2 2 2 2 2 Table 19: Efficacy of Docetaxel Injection in the Treatment of Patients with Gastric Adenocarcinoma Endpoint TCF n=221 CF n=224 Median TTP (months) 5. 7 Hazard ratio For the hazard ratio (TCF/CF), values less than 1. 00 favor the Docetaxel Injection arm. Unstratified log-rank test 0. 68 Median survival (months) 9. 6 Hazard ratio 0. 77 Overall Response Rate (CR+PR) (%) 36. 4 p-value 0. 0106 Subgroup analyses were consistent with the overall results across age, gender and race. Figure 6 Figure 7 Induction Chemotherapy Followed by Radiotherapy (TAX323) The safety and efficacy of Docetaxel Injection in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in 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 Injection arm received Docetaxel Injection (T) 75 mg/m 2 2 2 2 2 The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0. 0077 (median PFS: 11. 3 months, respectively) with an overall median follow-up time of 33. Median overall survival with a median follow-up of 51. 2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18. 2 months, respectively). Efficacy results are presented in Table 20 and Figures 8 and 9. Table 20: Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Inoperable Locally Advanced SCCHN (Intent-to-Treat Analysis) A Hazard ratio of less than 1 favors Docetaxel Injection+cisplatin+fluorouracil Endpoint Docetaxel Injection + Cisplatin + Fluorouracil n=177 Cisplatin + Fluorouracil n=181 Median progression free survival (months) 11. 3 Adjusted Hazard ratio Stratified log-rank test based on primary tumor site 0. 71 Median survival (months) 18. 2 Hazard ratio Stratified log-rank test, not adjusted for multiple comparisons 0. 71 Best overall response (CR + PR) to chemotherapy (%) 67. 6 (95% CI) Chi square test, not adjusted for multiple comparisons 0. 006 Best overall response (CR + PR) to study treatment [chemotherapy +/- radiotherapy] (%) 72. 6 (95% CI) 0. 006 Figure 8 Figure 9 Induction Chemotherapy Followed by Chemoradiotherapy (TAX324) The safety and efficacy of Docetaxel Injection in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in 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 Injection arm received Docetaxel Injection (T) 75 mg/m 2 2 2 2 2 All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1. 5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70en dash72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT. The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p = 0. 0058) with the Docetaxel Injection-containing regimen compared to PF [median OS: 70. 1 months, respectively, hazard ratio (HR) = 0. 70, 95% confidence interval (CI) = 0. Overall survival results are presented in Table 21 and Figure 10. Table 21: Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Locally Advanced SCCHN (Intent-to-Treat Analysis) A Hazard ratio of less than 1 favors Docetaxel Injection+cisplatin+fluorouracil NE - not estimable Endpoint Docetaxel Injection + Cisplatin + Fluorouracil n=255 Cisplatin + Fluorouracil n=246 Median overall survival (months) 70. 1 Hazard ratio: unadjusted log-rank test 0. 70 Figure 10.
REFERENCES
1. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Hospira, Inc.

DOCETAXEL- docetaxel_injection, solution Product manual source documgent