DailyMed Label: Docetaxel

DailyMed Label: Docetaxel

2024

DailyMed Prescription

Docetaxel

Docetaxel

Mylan Institutional LLC

NDC: 67457-781

NDC: 67457-781

Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate. Docetaxel (anhydrous) has the following structural formula: Docetaxel anhydrous, USP is a white or almost white crystalline powder with an empirical formula of C 43 H 53 NO 14 , and a molecular weight of 807.89. It is highly lipophilic, soluble in methanol and practically insoluble in water. One-vial Docetaxel Injection USP Docetaxel Injection USP is a sterile, non-pyrogenic, pale-yellow to brownish-yellow solution at 20 mg/mL concentration. Each mL contains 20 mg docetaxel anhydrous USP, in 4 mg anhydrous citric acid for pH adjustment, 520 mg polysorbate 80 and 395.5 mg dehydrated alcohol solution. Docetaxel Injection USP is available in multiple dose (160 mg/8 mL) vial containing 160 mg (8 mL) docetaxel anhydrous USP. Docetaxel Injection USP requires NO prior dilution with a diluent and is ready to add to the infusion solution. structural formula

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 ) 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.g., anaphylaxis). Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). 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. • 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-naïve: 75 mg/m 2 followed by cisplatin 75 mg/m 2 ( 2.2 ) • CRPC: 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-hour IV (days 1 to 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-hour IV (days 1 to 5), starting at end of cisplatin infusion; for 4 cycles ( 2.5 ) • SCCHN: 75 mg/m 2 followed by cisplatin 100 mg/m 2 IV (day 1), followed by fluorouracil 1000 mg/m 2 per day as a 24-hour IV (days 1 to 4); for 3 cycles ( 2.5 ) For all patients: • Premedicate with oral corticosteroids ( 2.6 ) • Adjust dose as needed ( 2.7 ) • 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) ] . • For treatment after failure of prior platinum-based chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m 2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials [see Boxed Warning , Dosage and Administration (2.7) , Warnings and Precautions (5) , Clinical Studies (14) ] . • For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin. The recommended dose of Docetaxel Injection is 75 mg/m 2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks [see Dosage and Administration (2.7) ] . • 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) ] . • 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) ] . 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. 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) ] . 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) ] . 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) ] . 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 . Do not retreat patients with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm 3   [see Contraindications (4) ] . Avoid retreating patients until 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 NCI-CTCAE grade: • Grade 2: Reduce cisplatin dose by 20%. • Grade 3: Discontinue treatment. Ototoxicity: In the case of grade 3 toxicity, discontinue treatment. Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2). For other cisplatin dosage adjustments, also refer to the manufacturers’ prescribing information. Table 2: Dose Reductions for Evaluation of Creatinine Clearance Creatinine clearance result before next cycle Cisplatin dose next cycle CrCl ≥60 mL/min Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle. CrCl between 40 and 59 mL/min Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was reinstituted at the next cycle. If no recovery was observed, then cisplatin was omitted from the next treatment cycle. CrCl <40 mL/min Dose of cisplatin was omitted in that treatment cycle only. If CrCl was still <40 mL/min at the end of cycle, cisplatin was discontinued. If CrCl was >40 and <60 mL/min at end of cycle, a 50% cisplatin dose was given at the next cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle. CrCl = Creatinine clearance Fluorouracil dose modifications and treatment delays For diarrhea and stomatitis, see Table 1. In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%. For other 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 coadministration of a strong CYP3A4 inhibitor [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] . 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 (16.3) ] . 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. One-vial Docetaxel Injection Docetaxel Injection requires NO prior dilution with a diluent and is ready to add to the infusion solution. Please follow the preparation instructions provided below. One-vial Docetaxel Injection Docetaxel Injection (20 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution. Use only a 21 gauge needle to withdraw Docetaxel from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates. 1. Docetaxel Injection vials should be stored between 15°C and 25°C (59°F and 77°F). 2. Using only a 21 gauge needle, aseptically withdraw the required amount of Docetaxel injection (20 mg docetaxel/mL) with a calibrated syringe and inject via a single injection (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 0.3 mg/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. 3. Thoroughly mix the infusion by gentle manual rotation. 4. As with all parenteral products, Docetaxel Injection should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Docetaxel Injection dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded. 5. 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 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).

One-vial formulation Docetaxel (Injection) Docetaxel Injection USP: 160 mg/8 mL solution in multiple-dose vials • Injection: One-vial Docetaxel Injection: Multiple dose vials 160 mg/8 mL ( 3 )

Docetaxel Injection is contraindicated in patients with: • neutrophil counts of <1500 cells/mm 3   [see Warnings and Precautions (5.3) ] . • a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions (5.5) ] . • Hypersensitivity to docetaxel or polysorbate 80 ( 4 ) • Neutrophil counts of <1500 cells/mm 3 ( 4 )

• Second primary malignancies: In patients treated with Docetaxel Injection-containing regimens, monitor for delayed AML, MDS, NHL, and renal cancer. ( 5.7 ) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skin toxicity may require dose adjustment or permanent treatment discontinuation. ( 5.8 ) • Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. ( 5.9 ) • Eye disorders: Cystoid macular edema (CME) has been reported and requires treatment discontinuation. ( 5.10 ) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. ( 5.11 ) • Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.12 , 8.1 , 8.3 ) • Alcohol content: The alcohol content in a dose of Docetaxel Injection may affect the central nervous system. This may include impairment of a patient’s ability to drive or use machines immediately after infusion. ( 5.13 ) • Tumor lysis syndrome: Tumor lysis syndrome has been reported. Patients at risk should be well hydrated and closely monitored during treatment. ( 5.14 ) Docetaxel administered at 100 mg/m 2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m 2 , mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths. Docetaxel administered at a dose of 100 mg/m 2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m 2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m 2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see Dosage and Administration (2.2) , Clinical Studies (14) ] . Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Avoid Docetaxel Injection in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN [see Warnings and Precautions (5.1) ] . For patients with isolated elevations of transaminase >1.5 × ULN, consider Docetaxel Injection dose modifications [see Dosage and Administration (2.7) ] . Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of Docetaxel Injection therapy. Perform frequent peripheral blood cell counts on all patients receiving Docetaxel Injection. Do not retreat patients with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1500 cells/mm 3   [see Contraindications (4) ] . Avoid retreating patients until platelets recover to a level >100,000 cells/mm 3 . A 25% reduction in the dose of Docetaxel Injection is recommended during subsequent cycles following severe neutropenia (<500 cells/mm 3 ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Docetaxel Injection cycle [see Dosage and Administration (2.7) ] . Neutropenia (<2000 neutrophils/mm 3 ) occurs in virtually all patients given 60 mg/m 2 to 100 mg/m 2 of docetaxel and grade 4 neutropenia (<500 cells/mm 3 ) occurs in 85% of patients given 100 mg/m 2 and 75% of patients given 60 mg/m 2 . Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Docetaxel Injection should not be administered to patients with neutrophils <1500 cells/mm 3 . Febrile neutropenia occurred in about 12% of patients given 100 mg/m 2 but was very uncommon in patients given 60 mg/m 2 . Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see Adverse Reactions (6.1) , Clinical Studies (14) ] . Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection [see Dosage and Administration (2.7) , Adverse Reactions (6) ] . Enterocolitis and neutropenic colitis (typhlitis) have occurred in patients treated with Docetaxel Injection alone and in combination with other chemotherapeutic agents, despite the coadministration of G-CSF. Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Enterocolitis and neutropenic enterocolitis may develop at any time, and could lead to death as early as the first day of symptom onset. Monitor patients closely from onset of any symptoms of gastrointestinal toxicity. Inform patients to contact their healthcare provider with new, or worsening symptoms of gastrointestinal toxicity [see Dosage and Administration (2) , Warnings and Precautions (5.3) , Adverse Reactions (6.2) ] . Monitor patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and aggressive therapy. Do not rechallenge patients with a history of severe hypersensitivity reactions with Docetaxel Injection [see Contraindications (4) ] . Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a hypersensitivity reaction to docetaxel that may include severe or fatal reactions such as anaphylaxis. Monitor patients with a previous history of hypersensitivity to paclitaxel closely during initiation of docetaxel therapy. Hypersensitivity reactions may occur within a few minutes following initiation of a Docetaxel Injection infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Docetaxel Injection [see Dosage and Administration (2.6) ] . Severe fluid retention has been reported following docetaxel therapy. Patients should be premedicated with oral corticosteroids prior to each Docetaxel Injection administration to reduce the incidence and severity of fluid retention [see Dosage and Administration (2.6) ] . Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions. When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg. Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m 2 . Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m 2 . Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s). Second primary malignancies, notably acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL), and renal cancer, have been reported in patients treated with docetaxel-containing regimens. These adverse reactions may occur several months or years after docetaxel-containing therapy. Treatment-related AML or MDS has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel, doxorubicin, and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin, and cyclophosphamide [see Clinical Studies (14.2) ] . In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies [see Adverse Reactions (6.1) ] . Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended [see Dosage and Administration (2.7) ] . The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued docetaxel due to skin toxicity. Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Permanent treatment discontinuation should be considered in patients who experience SCARs. Severe neurosensory symptoms (e.g., paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued [see Dosage and Administration (2.7) ] . Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965). Cystoid macular edema (CME) has been reported in patients treated with Docetaxel Injection. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, Docetaxel Injection treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered. Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease. Based on findings from 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) ] . Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify pregnancy status in females of reproductive potential prior to initiating Docetaxel Injection. Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of Docetaxel Injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of Docetaxel Injection [see Use in Specific Populations (8.1 , 8.3) ] . Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in a dose of Docetaxel Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Docetaxel Injection on the ability to drive or use machines immediately after the infusion. Each administration of Docetaxel Injection at 100 mg/m 2 delivers 1.8 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 , this would deliver 3.6 grams of ethanol [see Description (11) ] . Other docetaxel products may have a different amount of alcohol. Tumor lysis syndrome has been reported with docetaxel [see Adverse Reactions (6.2) ] . Patients at risk of tumor lysis syndrome (e.g., with renal impairment, hyperuricemia, bulky tumor) should be closely monitored prior to initiating Docetaxel Injection and periodically during treatment. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment.

The most serious adverse reactions from docetaxel are:

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

• Lactation: Advise women not to breastfeed. ( 8.2 ) • Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of Docetaxel Injection. ( 8.3 ) 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) ] . Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Docetaxel Injection contains alcohol which can interfere with neurobehavioral development ( see Clinical Considerations ). In animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively ( see Data ). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Docetaxel Injection contains alcohol [see Warnings and Precautions (5.13) ] . Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Intravenous administration of ≥0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. Maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively. 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) ] . Verify pregnancy status in females of reproductive potential prior to initiating Docetaxel Injection. Based on genetic toxicity findings, advice females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of Docetaxel Injection. 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. Based on findings in animal studies, Docetaxel Injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) ] . 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 was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1 to 22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m 2 as a 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia. The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1 to 26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma. Docetaxel 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 ) in combination with cisplatin (75 mg/m 2 ) and 5-fluorouracil (750 mg/m 2 ) (TCF) or to cisplatin (80 mg/m 2 ) and 5-fluorouracil (1000 mg/m 2 /day) (CF). The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response. Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m 2 to 235 mg/m 2 in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m 2 . Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m 2 in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9±8.75 L/h/m 2 , corresponding to an AUC of 4.20±2.57 mcg•h/mL. In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults [see Clinical Pharmacology (12.3) ] . In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients. 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. 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. 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. 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. 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 (5.13) ] .

One-vial Docetaxel Injection USP Docetaxel Injection USP is supplied in multiple-dose (160 mg/8 mL) vial as a sterile, pyrogen-free, non-aqueous solution. Docetaxel Injection USP Multiple-Dose Vials Docetaxel Injection USP 160 mg/8 mL: The vial is in one carton. NDC 67457-781-08 Store between 15°C and 25°C (59°F and 77°F). Retain in the original package to protect from light. Freezing does not adversely affect the product. After initial puncture, Docetaxel Injection USP multiple dose vials are stable for 28 days when stored at room temperature, with protection from light. Docetaxel Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1

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. The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m 2 to 115 mg/m 2 in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m 2 to 115 mg/m 2 with infusion times of 1 to 2 hours. Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with initial rapid distribution phase and the late (terminal) phase. Mean steady state volume of distribution was 113 L. Docetaxel is approximately 94% protein bound in vitro , mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was approximately 97%. Dexamethasone does not affect the protein binding of docetaxel. With extended plasma sampling up to 8 to 22 days post infusion, the estimated mean total body clearance was 18 L/h/ m 2 (range of means: 14 to 23) and mean terminal elimination half-life was 116 hours (range of means: 92 to 135). Docetaxel is metabolized by the CYP3A4 isoenzyme in vitro [see Drug Interactions (7) ] . 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. A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m 2 . Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were not influenced by age. The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel. 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) ] . 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. The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m 2 intravenous) alone or docetaxel (10 mg/m 2 intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2 fold and its clearance was reduced by 49% when docetaxel was coadministered with ketoconazole [see Dosage and Administration (2.7) , Drug Interactions (7) ] . • Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone. • Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone. • Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug. • Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with metastatic castration-resistant prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone. • Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between docetaxel (75 mg/m 2 ), doxorubicin (50 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) 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.

Carcinogenicity studies with docetaxel have not been performed. Docetaxel was genotoxic by an aneugenic mechanism in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m 2 basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays. Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50th the recommended human dose on a mg/m 2 basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended human dose on a mg/m 2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

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). In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 every 3 weeks) or the combination of mitomycin (12 mg/m 2 every 6 weeks) and vinblastine (6 mg/m 2 every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results (see Table 12). 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 11.4 months 8.7 months p=0.01 Log Rank Risk Ratio For the risk ratio, a value less than 1.00 favors docetaxel. , Mortality (Docetaxel: Control) 0.73 95% CI (Risk Ratio) 0.58 to 0.93 Median Time to Progression 4.3 months 2.5 months p=0.01 Log Rank Risk Ratio , Progression (Docetaxel: Control) 0.75 95% CI (Risk Ratio) 0.61 to 0.94 Overall Response Rate 28.1% 9.5% p<0.0001 Chi Square Complete Response Rate 3.4% 1.6% In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 ) or doxorubicin (75 mg/m 2 ) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below (see Table 13). 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 p=0.39 Log Rank Risk Ratio For the risk ratio, a value less than 1.00 favors docetaxel. , Mortality (Docetaxel: Control) 0.89 95% CI (Risk Ratio) 0.68 to 1.16 Median Time to Progression 6.5 months 5.3 months p=0.45 Log Rank Risk Ratio , Progression (Docetaxel: Control) 0.93 95% CI (Risk Ratio) 0.71 to 1.16 Overall Response Rate 45.3% 29.7% p=0.004 Chi Square Complete Response Rate 6.8% 4.2% In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m 2 (n=151), 75 mg/m 2 (n=188) or 100 mg/m 2 (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with docetaxel dose: 19.9% for the 60 mg/m 2 group compared to 22.3% for the 75 mg/m 2 and 29.8% for the 100 mg/m 2 group; pair-wise comparison between the 60 mg/m 2 and 100 mg/m 2 groups was statistically significant (p=0.037). Docetaxel at a dose of 100 mg/m 2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline‑containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% CI: 31.0 to 44.8) and the complete response rate was 2.1%. Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m 2 , in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% CI: 17.2 to 55.7), similar to the response rate in single arm studies of 100 mg/m 2 . A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1 to 3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m 2 administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 (TAC arm), or doxorubicin 50 mg/m 2 followed by fluorouracil 500 mg/m 2 and cyclophosphamide 500 mg/m 2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients (see Figure 1). At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90) (see Figure 2). There will be further analysis at the time survival data mature. Figure 1 - TAX316 Disease Free Survival K M Curve Figure 2 - TAX316 Overall Survival K M Curve The following table describes the results of subgroup analyses for DFS and OS (see Table 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 0.74 (0.60, 0.92) 0.69 (0.53, 0.90) 1 to 3 467 0.64 (0.47, 0.87) 0.45 (0.29, 0.70) 4+ 277 0.84 (0.63, 1.12) 0.93 (0.66, 1.32) Receptor status Positive 566 0.76 (0.59, 0.98) 0.69 (0.48, 0.99) Negative 178 0.68 (0.48, 0.97) 0.66 (0.44, 0.98) 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. Two randomized, controlled trials established that a docetaxel dose of 75 mg/m 2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m 2 , however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [see Boxed Warning , Dosage and Administration (2.7) , Warnings and Precautions (5.3) ] . One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m 2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m 2 . A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m 2 or best supportive care. In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to docetaxel 75 mg/m 2 , docetaxel 100 mg/m 2 and a treatment in which the investigator chose either vinorelbine 30 mg/m 2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m 2 days 1 to 3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the docetaxel 75 mg/m 2 arm and the comparator arms are summarized in Table 15 and Figures 3 and 4 showing the survival curves for the two studies. 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 p=0.01 p=0.13 Risk Ratio a value less than 1.00 favors docetaxel , Mortality (Docetaxel: Control) 0.56 0.82 95% CI (Risk Ratio) (0.35, 0.88) (0.63, 1.06) Median Survival 7.5 months p≤0.05 4.6 months 5.7 months 5.6 months 95% CI (5.5, 12.8) (3.7, 6.1) (5.1, 7.1) (4.4, 7.9) % 1-year Survival 37% uncorrected for multiple comparisons 12% 30% 20% 95% CI (24, 50) (2, 23) (22, 39) (13, 27) Time to Progression 12.3 weeks 7.0 weeks 8.3 weeks 7.6 weeks 95% CI (9.0, 18.3) (6.0, 9.3) (7.0, 11.7) (6.7, 10.1) Response Rate 5.5% Not Applicable 5.7% 0.8% 95% CI (1.1, 15.1) (2.3, 11.3) (0.0, 4.5) Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m 2 . Figure 3 - TAX317 Survival K-M Curves - Docetaxel 75 mg/m 2 vs. Best Supportive Care Figure 4 - TAX320 Survival K-M Curves - Docetaxel 75 mg/m 2 vs. Vinorelbine or Ifosfamide Control Patients treated with docetaxel at a dose of 75 mg/m 2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials. Figure 3 Figure 4 In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m 2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m 2 administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m 2 administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin. The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 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. 0.88 Adjusted 95% CI Adjusted for interim analysis and multiple comparisons. (0.74, 1.06) 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 31.6% 24.4% Not Significant (95% CI) Adjusted for multiple comparisons. (26.5%, 36.8%) (19.8%, 29.2%) Median Time to Progression Kaplan-Meier estimates. 21.4 weeks 22.1 weeks Not Significant (95% CI) (19.3, 24.6) (18.1, 25.6) The safety and efficacy of docetaxel in combination with prednisone in patients with metastatic castration-resistant prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups: • Docetaxel 75 mg/m 2 every 3 weeks for 10 cycles. • Docetaxel 30 mg/m 2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles. • Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles. All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously. In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 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) 18.9 16.5 95% CI (17.0 to 21.2) (14.4 to 18.6) Hazard ratio 0.761 — 95% CI (0.619 to 0.936) — p-value Stratified log-rank test. Threshold for statistical significance = 0.0175 because of 3 arms. 0.0094 —   Figure 5 - TAX327 Survival K-M Curves 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 (T) (75 mg/m 2 on day 1) in combination with cisplatin (C) (75 mg/m 2 on day 1) and fluorouracil (F) (750 mg/m 2 per day for 5 days) or cisplatin (100 mg/m 2 on day 1) and fluorouracil (1000 mg/m 2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The demographic characteristics were balanced between the two treatment arms. The median age was 55 years, 71% were male, 71% were Caucasian, 24% were 65 years of age or older, 19% had a prior curative surgery and 12% had palliative surgery. The median number of cycles administered per patient was 6 (with a range of 1 to 16) for the TCF arm compared to 4 (with a range of 1 to 12) for the CF arm. Time to progression (TTP) was the primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization. The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19 to 1.83) with a significantly longer TTP (p=0.0004) in the TCF arm. Approximately 75% of patients had died at the time of this analysis. Overall survival was significantly longer (p=0.0201) in the TCF arm with a HR of 1.29 (95% CI: 1.04 to 1.61). Efficacy results are summarized in Table 19 and Figures 6 and 7. Table 19: Efficacy of Docetaxel Injection in the Treatment of Patients with Gastric Adenocarcinoma Endpoint TCF n=221 CF n=224 Median TTP (months) 5.6 3.7 (95% CI) (4.86 to 5.91) (3.45 to 4.47) Hazard ratio For the hazard ratio (TCF/CF), values less than 1.00 favor the Docetaxel Injection arm. 0.68 (95% CI) (0.55 to 0.84) Unstratified log-rank test p-value 0.0004 Median survival (months) 9.2 8.6 (95% CI) (8.38 to 10.58) (7.16 to 9.46) Hazard ratio 0.77 (95% CI) (0.62 to 0.96) p-value 0.0201 Overall Response Rate (CR+PR) (%) 36.7 25.4 p-value 0.0106   Subgroup analyses were consistent with the overall results across age, gender and race. Figure 6 - Gastric Cancer Study (TAX325) Time to Progression K-M Curve Figure 7 - Gastric Cancer Study (TAX325) Survival K-M Curve Figure 6 Figure 7 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 followed by cisplatin (P) 75 mg/m 2 on Day 1, followed by fluorouracil (F) 750 mg/m 2 per day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m 2 on Day 1, followed by fluorouracil (F) 1000 mg/m 2 /day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy to 2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy. The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3 months, respectively) with an overall median follow-up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months, respectively). Efficacy results are presented in Table 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) 11.4 8.3 (95% CI) (10.1 to 14.0) (7.4 to 9.1) Adjusted Hazard ratio 0.71 (95% CI) (0.56 to 0.91) Stratified log-rank test based on primary tumor site p-value 0.0077 Median survival (months) 18.6 14.2 (95% CI) (15.7 to 24.0) (11.5 to 18.7) Hazard ratio 0.71 (95% CI) (0.56 to 0.90) Stratified log-rank test, not adjusted for multiple comparisons p-value 0.0055 Best overall response (CR + PR) to hemotherapy (%) 67.8 53.6 (95% CI) (60.4 to 74.6) (46.0 to 61.0) Chi square test, not adjusted for multiple comparisons p-value 0.006 Best overall response (CR + PR) to study treatment [chemotherapy +/- radiotherapy] %) 72.3 58.6 (95% CI) (65.1 to 78.8) (51.0 to 65.8) p-value 0.006   Figure 8 - TAX323 Progression-Free Survival K-M Curve Figure 9 - TAX323 Overall Survival K-M Curve Figure 8 Figure 9 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 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m 2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2 /day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m 2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2 /day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70 to 72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT. The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p = 0.0058) with the Docetaxel Injection-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54 to 0.90]. Overall survival results are presented in Table 21 and Figure 10. Table 21: Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Locally Advanced SCCHN (Intent-to-Treat Analysis) 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) 70.6 30.1 (95% CI) (49.0 to NE) (20.9 to 51.5) Hazard ratio: 0.70 (95% CI) (0.54 to 0.90) unadjusted log-rank test p-value 0.0058   Figure 10 - TAX324 Overall Survival K-M Curve Figure 10

NDC 67457-781-08 Docetaxel Injection, USP 160 mg/8 mL (20 mg/mL) For Intravenous Infusion only READY TO ADD TO INFUSION SOLUTION CAUTION: HAZARDOUS DRUG Sterile Rx only Multiple-Dose Vial ONE-VIAL FORMULATION Each mL contains 20 mg docetaxel anhydrous USP, 4 mg anhydrous citric acid for pH adjustment, 520 mg polysorbate 80 and 395.5 mg dehydrated alcohol. Ready to add to infusion solution. Withdraw the required amount of docetaxel anhydrous USP (20 mg/mL) from the vial and add it directly into the infusion solution for administration.   See package insert for complete instructions. Multiple-Dose Vial. Use within 28 days after initial puncture. Dosage and Administration: See package insert for dosage information, directions for use and handling. WARNING: Hazardous drug. Keep out of reach of children. Storage: Store between 15° to 25°C (59° to 77°F). Protect from light. Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Made in India Code No.: KR/DRUGS/ KTK/28/381/2008 Mylan.com 160 mg/8 mL (20 mg/mL)