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 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 1–5), 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 1–5), 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 1–4); for 3 cycles ( 2.5 ) For all patients: • Premedicate with oral corticosteroids ( 2.6 ) • Adjust dose as needed ( 2.7 ) 2.1 Breast Cancer • For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection is 60 mg/m 2 to 100 mg/m 2 administered intravenously over 1 hour every 3 weeks. • For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [ see Dosage and Administration (2.7) ]. 2.2 Non-small Cell Lung Cancer • For treatment after failure of prior platinum-based chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m 2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials [ see Boxed Warning , Dosage and Administration (2.7) , Warnings and Precautions (5) , Clinical Studies (14) ]. • For chemotherapy-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 30–60 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 administr…

5 WARNINGS AND PRECAUTIONS • Second primary malignancies: In patients treated with Docetaxel Injection-containing regimens, monitor for delayed AML, MDS, NHL, and renal cancer. ( 5.7 ) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skin toxicity may require dose adjustment or permanent treatment discontinuation. ( 5.8 ) • Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. ( 5.9 ) • Eye disorders: Cystoid macular edema (CME) has been reported and requires treatment discontinuation. ( 5.10 ) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. ( 5.11 ) • Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to 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 ) 5.1 Toxic Deaths Breast Cancer 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. Non-small Cell Lung Cancer 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) ] . 5.2 Hepatic Impairment Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Avoid Docetaxel Injection in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN [ see Warnings and Precautions (5.1) ]. For patients with isolated elevations of transaminase >1.5 × ULN, consider Docetaxel Injection dose modifications [ see Dosage and Administration (2.7) ]. Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of Docetaxel Injection therapy. 5.3 Hematologic Effects Perform frequent peripheral blood cell counts on all patients receiving Docetaxel Injection. Do not retreat patients with subsequent cycles of Docetaxel Injection until neutrophils recover to 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 follo…

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was 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 )

8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action, Docetaxel Injection can cause fetal harm when administered to a pregnant woman [ see Clinical Pharmacology (12.1) ]. 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. Clinical Considerations 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. Data Animal data 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.

6 ADVERSE REACTIONS 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. Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Breast Cancer Monotherapy with Docetaxel for Locally Advanced or Metastatic Breast Cancer after Failure of Prior Chemotherapy Docetaxel 100 mg/m 2 : Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m 2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to docetaxel. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving docetaxel for the treatment of breast cancer and in patients with other tumor types (see Table 3). Table 3: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m 2 Adverse Reaction All Tumor Types Normal LFTs Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN n=2045 % All Tumor Types Elevated LFTs Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN n=61 % Breast Cancer Normal LFTs n=965 % Hematologic Neutropenia <2000 cells/mm 3 96 96 99 <500 cells/mm 3 75 88 86 Leukopenia <4000 cells/mm 3 96 …