Docetaxel

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 ) Castration-Resistant Prostate Cancer (CRPC) : with prednisone in metastatic castration-resistant prostate cancer ( 1.3 ) Gastric Adenocarcinoma (GC) : with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction ( 1.4 ) Squamous Cell Carcinoma of the Head and Neck (SCCHN) : with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN ( 1.5 ) 1.1 Breast Cancer Docetaxel injection is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. Docetaxel injection in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. 1.2 Non-small Cell Lung Cancer Docetaxel injection as 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 metastatic castration-resistant prostate cancer. 1.4 Gastric Adenocarcinoma Docetaxel injection in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease. 1.5 Head and Neck Cancer Docetaxel injection in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

2 DOSAGE AND ADMINISTRATION Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) 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 IV (days 1-5), starting at end of cisplatin infusion ( 2.4 ) SCCHN: 75 mg/m 2 followed by cisplatin 75 mg/m 2 IV (day 1), followed by fluorouracil 750 mg/m 2 per day as a 24-hr IV (days 1-5), starting at end of cisplatin infusion; for 4 cycles ( 2.5 ) SCCHN: 75 mg/m 2 followed by cisplatin 100 mg/m 2 IV (day 1), followed by fluorouracil 1000 mg/m 2 per day as a 24-hr IV (days 1-4); for 3 cycles ( 2.5 ) For all patients: Premedicate with oral corticosteroids ( 2.6 ) Adjust dose as needed ( 2.7 ) 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). 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 G-CSF may be used to mitigate the risk of hematological toxicities [ see Dosage and Administration ( 2.7 ) ]. 2.2 Non-small Cell Lung Cancer For treatment after failure of prior platinum-based chemotherapy, docetaxel injection was evaluated as monotherapy, and the recommended dose is 75 mg/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 injection 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 30–60 minutes every 3 weeks [ see Dosage and Administration ( 2.7 ) ]. 2.3 Prostate Cancer For metastatic castration-resistant prostate cancer, the recommended dose of docetaxel injection is 75 mg/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 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 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 ( 5.5 ) ]. 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 ) ]. 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 metastatic castration-resistant 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 manufacturer's 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. 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. 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.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 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 and, as with other potentially toxic compounds, caution should be exercised when handling and preparing docetaxel injection solutions. The use of gloves is recommended . Please refer to [ see How Supplied/Storage and Handling ( 16.3 ) ] . If docetaxel injection, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If docetaxel injection initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water. Contact of the docetaxel injection with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final docetaxel injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. One-vial docetaxel injection USP Docetaxel injection USP 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 and diluent) with the one-vial formulation. One-vial Docetaxel Injection, USP Docetaxel injection USP (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.g., 18 and 19 gauge) may result in stopper coring and rubber particulates. Dilution for Infusion Docetaxel Injection vials should be stored between 2°C and 25°C (36°F and 77°F). If the vials are stored under refrigeration, allow the appropriate number of vials of docetaxel injection vials to stand at room temperature for approximately 5 minutes before use. 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 (one shot) 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 0.3mg/mL to 0.74 mg/mL. If a dose greater than 200 mg of docetaxel injection is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel injection is not exceeded. Thoroughly mix the infusion by gentle manual rotation. As with all parenteral products, docetaxel injection should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the docetaxel injection dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded. Docetaxel injection infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded. The docetaxel injection dilution for infusion should be administered intravenously as 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°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).

6 ADVERSE REACTIONS 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 at 1-888-557-1212 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The most serious adverse reactions from docetaxel are: Toxic Deaths [ see Boxed Warning , Warnings and Precautions ( 5.1 ) ] Hepatic Impairment [ see Boxed Warning , Warnings and Precautions ( 5.2 ) ] Hematologic Effects [ see Boxed Warning , Warnings and Precautions ( 5.3 ) ] Enterocolitis and Neutropenic Colitis [ see Warnings and Precautions ( 5.4 ) ] Hypersensitivity Reactions [ see Boxed Warning, Warnings and Precautions ( 5.5 ) ] Fluid Retention [ see Boxed Warning , Warnings and Precautions ( 5.6 ) ] Second Primary Malignancies [ see Warnings and Precautions ( 5.7 ) ] Cutaneous Reactions [ see Warnings and Precautions ( 5.8 ) ] Neurologic Reactions [ see Warnings and Precautions ( 5.9 ) ] Eye Disorders [ see Warnings and Precautions ( 5.10 ) ] Asthenia [ see Warnings and Precautions ( 5.11 ) ] Alcohol Content [ see Warnings and Precautions ( 5.13 ) ] The most common adverse reactions across all docetaxel 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. 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/m²: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m² 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 3). Table 3: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m 2 * Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN. ** Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN. *** Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization. Adverse Reaction All Tumor Types All Tumor Types Breast Cancer Normal LFTs* Elevated LFTs** Normal LFTs* n=2045 n=61 n=965 % % % Hematologic Neutropenia <2000 cells/mm 3 96 96 99 <500 cells/mm 3 75 88 86 Leukopenia <4000 cells/mm 3 96 98 99 <1000 cells/mm 3 32 47 44 Thrombocytopenia <100,000 cells/mm 3 8 25 9 Anemia <11 g/dL 90 92 94 <8 g/dL 9 31 8 Febrile Neutropenia*** 11 26 12 Septic Death 2 5 1 Non-Septic Death 1 7 1 Infections Any 22 33 22 Severe 6 16 6 Fever in Absence of Infection Any 31 41 35 Severe 2 8 2 Hypersensitivity Reactions Regardless of Premedication Any 21 20 18 Severe 4 10 3 With 3-day Premedication n=92 n=3 n=92 Any 15 33 15 Severe 2 0 2 Fluid Retention Regardless of Premedication Any 47 39 60 Severe 7 8 9 With 3-day Premedication n=92 n=3 n=92 Any 64 67 64 Severe 7 33 7 Neurosensory Any 49 34 58 Severe 4 0 6 Cutaneous Any 48 54 47 Severe 5 10 5 Nail Changes Any 31 23 41 Severe 3 5 4 Gastrointestinal Nausea 39 38 42 Vomiting 22 23 23 Diarrhea 39 33 43 Severe 5 5 6 Stomatitis Any 42 49 52 Severe 6 13 7 Alopecia 76 62 74 Asthenia Any 62 53 66 Severe 13 25 15 Myalgia Any 19 16 21 Severe 2 2 2 Arthralgia 9 7 8 Infusion Site Reactions 4 3 4 Hematologic Reactions Reversible marrow suppression was the major dose-limiting toxicity of docetaxel [ see Warnings and Precautions ( 5.3 ) ]. The median time to nadir was 7 days, 3while 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°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) associated with fatal gastrointestinal hemorrhage has been reported. Hypersensitivity reactions Severe hypersensitivity reactions have been reported [ see Boxed Warning , Warnings and Precautions ( 5.5 ) ] . Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy. Fluid 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 ) ]. 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 ( 5.9 ) ]. Gastrointestinal reactions Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3-5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. Cardiovascular reactions Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely. Seven of 86 (8.1%) of metastatic breast cancer patients receiving docetaxel 100 mg/m² 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 greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT >1.5 times the ULN, or alkaline phosphatase >2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on docetaxel, 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/m² in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN); and 174 patients in Japanese studies given docetaxel at 60 mg/m² who had normal LFTs (see Tables 4 and 5). Table 4: 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 * 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 Docetaxel Docetaxel 100 mg/m 2 60 mg/m 2 Adverse Reaction Normal LFTs* Elevated LFTs** Normal LFTs* n=730 n=18 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 <11 g/dL 95 94 65 Infection*** Any 23 39 1 Grade 3 and 4 7 33 0 Febrile Neutropenia**** By Patient 12 33 0 By Course 2 9 0 Septic Death 2 6 1 Non-Septic Death 1 11 0 Table 5: 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 * 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 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 17 1 In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m², 75 mg/m² and 100 mg/m² in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with docetaxel 60 mg/m² compared to 55.3% and 65.9% treated with 75 mg/m² and 100 mg/m², respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m² vs. 6.9% and 16.5% for patients treated at 75 and 100 mg/m², respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m² compared to 5.3% and 1.6% for patients treated at 75 mg/m² and 100 mg/m², respectively. The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m², 75 mg/m², and 100 mg/m² respectively), thrombocytopenia (7%, 11% and 12% respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14% respectively), treatment-related grade 3/4 infection (2%, 3%, and 7% respectively) and anemia (87%, 94%, and 97% respectively). Combination therapy with docetaxel 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 6). Table 6: Clinically Important Treatment Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316). * COSTART term and grading system for events related to treatment. Docetaxel 75 mg/m 2 + Doxorubicin 50 mg/m 2 + Cyclophosphamide 500 mg/m 2 (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* 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 3.9% and 2.2% of TAC-treated and FAC-treated patients respectively. There were no septic deaths in either treatment arm during the treatment period. Gastrointestinal 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 (6.2% vs 4.9%), and hypotension, all grades (1.9% vs 0.8%). Twenty-six (26) patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm developed CHF during the study period. All except one patient in each arm were diagnosed with CHF during the follow-up period. Two (2) patients in TAC arm and 4 patients in FAC arm died due to CHF. The risk of CHF was higher in the TAC arm in the first year, and then was similar in both treatment arms. Adverse reactions during the follow-up period (median follow-up time of 8 Years) In study TAX316, the most common adverse reactions that started during the treatment period and persisted into the follow-up period in TAC and FAC patients are described below (median follow-up time of 8 years). Nervous system disorders In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm. Skin and subcutaneous tissue disorders In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%).At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%). Reproductive system and breast disorders In study TAX316, amenorrhea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%). General disorders and administration site conditions In study TAX316, peripheral edema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral edema was ongoing in 19 TAC patients (2.6%) and 4 FAC patients (0.5%). In study TAX316, lymphedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). 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 (0.1%). In study TAX316, asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%). Acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS) AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at median follow-up time of 8 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome occurred in 2 of 744 (0.3%) patients who received TAC and in 1 of 736 (0.1%) patients who received FAC. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. Lung Cancer Monotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy Docetaxel 75 mg/m 2 : Treatment emergent adverse drug reactions are shown in Table 7. 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 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 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 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 21 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 0 0 Arthralgia Any Severe*** 3 0 2 0 2 1 Taste Perversion Any Severe*** 6 1 0 0 0 0 Combination therapy with docetaxel in chemotherapy-naive 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 * Replaces NCI term "Allergy". ** COSTART term and grading system. Adverse Reaction Docetaxel 75 mg/m 2 + Cisplatin 75 mg/m 2 n=406 % Vinorelbine 25 mg/m 2 + Cisplatin 100 mg/m 2 n=396 % Neutropenia Any 91 90 Grade 3/4 74 78 Febrile Neutropenia 5 5 Thrombocytopenia Any 15 15 Grade 3/4 3 4 Anemia Any 89 94 Grade 3/4 7 25 Infection Any 35 37 Grade 3/4 8 8 Fever in absence of infection Any 33 29 Grade 3/4 <1 1 Hypersensitivity Reaction* Any 12 4 Grade 3/4 3 <1 Fluid Retention** Any 54 42 All severe or life-threatening events 2 2 Pleural effusion Any 23 22 All severe or life-threatening events 2 2 Peripheral edema Any 34 18 All severe or life-threatening events <1 <1 Weight gain Any 15 9 All severe or life-threatening events <1 <1 Neurosensory Any 47 42 Grade 3/4 4 4 Neuromotor Any 19 17 Grade 3/4 3 6 Skin Any 16 14 Grade 3/4 <1 1 Nausea Any 72 76 Grade 3/4 10 17 Vomiting Any 55 61 Grade 3/4 8 16 Diarrhea Any 47 25 Grade 3/4 7 3 Anorexia** Any 42 40 All severe or life-threatening events 5 5 Stomatitis Any 24 21 Grade 3/4 2 1 Alopecia Any 75 42 Grade 3 <1 0 Asthenia** Any 74 75 All severe or life-threatening events 12 14 Nail Disorder** Any 14 <1 All severe events <1 0 Myalgia** Any 18 12 All severe events <1 <1 Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2.0%) in the vinorelbine+cisplatin arm. The second comparison in the study, vinorelbine+cisplatin versus docetaxel+carboplatin (which did not demonstrate a superior survival associated with docetaxel, [ see Clinical Studies ( 14.3 ) ]) 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 9). Table 9: Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel in Combination with Prednisone (TAX327) * Related to treatment Docetaxel 75 mg/m 2 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* 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 75 mg/m 2 in combination with cisplatin and fluorouracil (see Table 10). Table 10: Clinically Important Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study Clinically important treatment emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction. *Related to treatment Docetaxel 75 mg/m 2 + cisplatin 75 mg/m 2 + fluorouracil 750 mg/m 2 n=221 Cisplatin 100 mg/m 2 + fluorouracil 1000 mg/m 2 n=224 Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Anemia 97 18 93 26 Neutropenia 96 82 83 57 Fever in the absence of infection 36 2 23 1 Thrombocytopenia 26 8 39 14 Infection 29 16 23 10 Febrile neutropenia 16 N/A 5 N/A Neutropenic infection 16 N/A 10 N/A Allergic reactions 10 2 6 0 Fluid retention* 15 0 4 0 Edema* 13 0 3 0 Lethargy 63 21 58 18 Neurosensory 38 8 25 3 Neuromotor 9 3 8 3 Dizziness 16 5 8 2 Alopecia 67 5 41 1 Rash/itch 12 1 9 0 Nail changes 8 0 0 0 Skin desquamation 2 0 0 0 Nausea 73 16 76 19 Vomiting 67 15 73 19 Anorexia 51 13 54 12 Stomatitis 59 21 61 27 Diarrhea 78 20 50 8 Constipation 25 2 34 3 Esophagitis/dysphagia/ odynophagia 16 2 14 5 Gastrointestinal pain/cramping 11 2 7 3 Cardiac dysrhythmias 5 2 2 1 Myocardial ischemia 1 0 3 2 Tearing 8 0 2 0 Altered hearing 6 0 13 2 Head and Neck Cancer Combination therapy with docetaxel in head and neck cancer Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with docetaxel injection 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 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. * Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization. ** Related to treatment. *** Includes superficial and deep vein thrombosis and pulmonary embolism. TAX323 (n=355) TAX324 (n=494) Docetaxel injection arm (n=174) Comparator arm (n=181) Docetaxel injection 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** 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*** 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 6.2 Postmarketing Experience The following adverse reactions have been identified from clinical trials and/or postmarketing 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, injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) at the site of previous extravasation. Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Ventricular arrhythmia including ventricular tachycardia has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide, and may be associated with fatal outcome. 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: enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, has been reported with a potential fatal outcome. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence to gastrointestinal events have been reported. Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs. Hematologic: bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Hepatic : rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported. Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication. Hypersensitivity reactions with potential fatal outcome have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel. Metabolism and nutrition disorders: electrolyte imbalance, including cases of hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia, has 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. 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. Second primary malignancies: second primary malignancies, including AML, MDS, NHL, and renal cancer, have been reported in patients treated with docetaxel injection-containing regimens [ see Warnings and Precautions ( 5.7 ) ] .

12.3 Pharmacokinetics Absorption The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m² to 115 mg/m² in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m² to 115 mg/m² 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/m². 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 α1-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 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 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. Specific Populations Effect of Age: A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m². Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel was not influenced by age. Effect of Gender: The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel. Hepatic Impairment: The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with docetaxel. Patients with severe hepatic impairment have not been studied. [ see Warnings and Precautions ( 5.2 ) 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. 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/m² intravenous) alone or docetaxel (10 mg/m² 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 coadministration with ketoconazole [ see Dosage and Administration ( 2.7 ), Drug Interactions ( 7 ) ]. Effect of Combination Therapies: ● Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone. ● Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone. ● Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug. ● Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with metastatic castration-resistant prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone. ● Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between docetaxel (75 mg/m²), doxorubicin (50 mg/m²), and cyclophosphamide (500 mg/m²) when administered in combination. The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy.