you feel [1,500:<500 cells/mm 3 for more than 1 week, or severe or cumulative cutaneous reactions during Docefrez 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 Docefrez therapy may tolerate higher doses. Patients who develop grade 3 peripheral neuropathy should have Docefrez treatment discontinued entirely. Non-Small Cell Lung Cancer Monotherapy with Docefrez 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 Docefrez 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 Docefrez treatment discontinued entirely. Combination therapy with Docefrez for chemotherapy-naïve NSCLC For patients who are dosed initially at Docefrez 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 Docefrez 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 Docefrez for hormone-refractory metastatic prostate cancer Docefrez 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 Docefrez therapy should have the dosage of Docefrez reduced from 75 mg/m to 60 mg/m . If the patient continues to experience these reactions at 60 mg/m , the treatment should be discontinued. 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 )] . Administration Precautions Docefrez is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docefrez solutions. The use of gloves is recommended . Please refer to [see How Supplied/ Storage and Handling ( 16.3 )]. If Docefrez lyophilized powder, reconstituted solution, or infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docefrez lyophilized powder, reconstituted solution or infusion solution should come into contact with mucosa, immediately and thoroughly wash with water. Contact of the Docefrez reconstituted solution 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 Docefrez infusion solution should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Docefrez (Lyophilized Powder for Injection and Diluent) Docefrez for Injection requires reconstitution with Diluent and one further dilution with infusion solution prior to administration. Please follow the preparation instructions provided below. The table below provides the fill range of the Diluent, the volume of Diluent to be added for the reconstitution and the concentration of the reconstituted solution for Docefrez 20 mg and Docefrez 80 mg (See Table 1). Table 1- Reconstitution of Docefrez (docetaxel) for Injection Product Fill Range of the Diluent (35.4% w/w ethanol in polysorbate 80) Volume of Diluent to be added for the reconstitution Concentration of the reconstituted solution Docetaxel 20 mg vial 1.10 1.15 mL 1 mL 20 mg/0.8 mL Docetaxel 80 mg vial 4.13 4.29 mL 4 mL 24 mg/mL Preparation and Administration Docefrez (Lyophilized Powder for Injection and Diluent) A. Preparation of the Reconstituted Solution Docefrez vials should be stored between 2 C and 8 C (36 F and 46 F). Allow the appropriate number of vials of Docefrez (docetaxel) for Injection and diluent (35.4% ethanol in polysorbate 80) vials to stand at room temperature for approximately 5 minutes. a) For Docefrez 20: Use 1 mL syringe with needle of 18- to 21-gauge, 1 -inch for withdrawing diluent for Docefrez 20. b) For Docefrez 80: Use 4 mL syringe with needle of 18- to 21-gauge, 1 -inch for withdrawing diluent for Docefrez 80. a) For Docefrez 20: Aseptically withdraw 1 mL from the diluent vial into a syringe by partially inverting the vial, and transfer it to product vial of Docefrez (docetaxel) for Injection. b) For Docefrez 80: Aseptically withdraw 4 mL from the diluent vial into a syringe by partially inverting the vial, and transfer it to product vial of Docefrez (docetaxel) for Injection . Shake the reconstituted vial well in order to completely dissolve the docetaxel powder present in the vial. For the 20 mg vial, the resultant concentration is 20 mg/0.8 mL. For the 80 mg vial, the resultant concentration is 24 mg/mL . The reconstituted Docefrez solution should be clear; however, there may be some air bubbles in the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any air bubbles to dissipate. The reconstituted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours. B. Preparation of the Infusion Solution Aseptically withdraw the required amount of reconstituted Docefrez solution with a calibrated syringe and inject 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 to 0.74 mg/mL. If a dose greater than 200 mg of Docefrez is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded. Thoroughly mix the infusion by manual rotation. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If the Docefrez reconstituted solution or infusion solution is not clear or appears to have precipitation, these should be discarded. Docefrez reconstituted solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded. The final Docefrez infusion solution should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25 C) and lighting conditions. Stability Docefrez infusion solution, if stored between 2 C and 25 C (36 F and 77 F) is stable for 6 hours. Docefrez infusion solution (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). Dosage Forms and Strengths Docefrez (Lyophilized Powder for Injection and Diluent) Docefrez 80 mg Docefrez (docetaxel) for Injection 80 mg: 80 mg docetaxel and Diluent for Docefrez 80 mg (35.4% (w/w) ethanol in polysorbate 80). Both items are in a tray in one carton. Docefrez 20 mg Docefrez (docetaxel) for Injection 20 mg: 20 mg docetaxel and Diluent for Docefrez 20 mg (35.4% (w/w) ethanol in polysorbate 80). Both items are in a tray in one carton. Contraindications Docefrez is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions ( 5.4 )]. Docefrez should not be used in patients with neutrophil counts of> <1,500 cells/mm 3 . Warnings and Precautions Toxic Deaths Breast Cancer Docefrez 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 Docefrez 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 )]. Hepatic Impairment Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Docefrez [see Boxed Warning, Use in Specific Populations ( 8.6 ), Clinical studies ( 14 )]. Hematologic Effects Perform frequent peripheral blood cell counts on all patients receiving Docefrez. Patients should not be retreated with subsequent cycles of Docefrez until neutrophils recover to a level > 1,500 cells/mm 3 and platelets recover to a level > 100,000 cells/mm 3 . A 25% reduction in the dose of Docefrez 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 Docefrez 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. Docefrez should not be administered to patients with neutrophils> <1,500 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. [see Dosage and Administration ( 2.7 ), Adverse Reactions ( 6 )] . Hypersensitivity Reactions Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Docefrez infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with Docefrez. Hypersensitivity reactions may occur within a few minutes following initiation of a Docefrez 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 Docefrez [see Dosage and Administration ( 2.6 )]. Fluid Retention Severe fluid retention has been reported following docetaxel therapy. Patients should be premedicated with oral corticosteroids prior to each Docefrez 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 1,021 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). Acute Myeloid Leukemia Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. The risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Cutaneous Reactions 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. Neurologic Reactions 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). Eye Disorders Cystoid macular edema (CME) has been reported in patients treated with Docefrez. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, Docefrez treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered. Alcohol Content 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 1.425 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 , this would deliver 2.85 grams of ethanol [see Description ( 11 )] . Other docetaxel products may have a different amount of alcohol. Asthenia 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. Use in Pregnancy Docefrez can cause fetal harm when administered to a pregnant woman. Docetaxel caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis. There are no adequate and well-controlled studies in pregnant women using Docefrez. If Docefrez is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Docefrez [see Use in Specific Populations ( 8.1 )] . Adverse Reactions The most serious adverse reactions from docetaxel are: Toxic Deaths [see Boxed Warning, Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Boxed Warning, Warnings and Precautions ( 5.2 )] Neutropenia [see Boxed Warning, Warnings and Precautions ( 5.3 )] Hypersensitivity [see Boxed Warning, Warnings and Precautions ( 5.4 )] Fluid Retention [see Boxed Warning, Warnings and Precautions ( 5.5 )] 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 for docetaxel 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. Clinical Trial 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 2). Table 2 - Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m 2 * Normal Baseline LFTs: Transaminases 1.5 times ULN or alkaline phosphatase 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN Febrile Neutropenia: ANC grade 4 with fever >38oC with intravenous antibiotics and/or hospitalization Adverse Reaction All Tumor Types Normal LFTs * n=2045 % All Tumor Types Elevated LFTs n=61 % Breast Cancer Normal LFTs * n=965 % Hematologic Neutropenia <2000 cells/mm 3> <500 cells/mm 3 Leukopenia> <4000 cells/mm 3> <1000 cells/mm 3 Thrombocytopenia> <100,000 cells/mm 3 Anemia> <11 g/dL> <8 g/dL Febrile Neutropenia 96 75 96 32 8 90 9 11 96 88 98 47 25 92 31 26 99 86 99 44 9 94 8 12 Septic Death Non-Septic Death 2 1 5 7 1 1 Infections Any Severe 22 6 33 16 22 6 Fever in Absence of Infection Any Severe 31 2 41 8 35 2 Hypersensitivity Reactions Regardless of Premedication Any Severe With 3-day Premedication Any Severe 21 4 n=92 15 2 20 10 n=3 33 0 18 3 n=92 15 2 Fluid Retention Regardless of Premedication Any Severe With 3-day Premedication Any Severe 47 7 n=92 64 7 39 8 n=3 67 33 60 9 n=92 64 7 Neurosensory Any Severe 49 4 34 0 58 6 Cutaneous Any Severe 48 5 54 10 47 5 Nail Changes Any Severe 31 3 23 5 41 4 Gastrointestinal Nausea Vomiting Diarrhea Severe 39 22 39 5 38 23 33 5 42 23 43 6 Stomatitis Any Severe 42 6 49 13 52 7 Alopecia 76 62 74 Asthenia Any Severe 62 13 53 25 66 15 Myalgia Any Severe 19 2 16 2 21 2 Arthralgia 9 7 8 Infusion Site Reactions 4 3 4 Hematologic Reactions Reversible marrow suppression was the major dose-limiting toxicity of docetaxel [see Warnings and Precautions ( 5.3 )]. The median time to nadir was 7 days, while the median duration of severe neutropenia (> <500 cells/mm 3 ) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles. Febrile neutropenia (> <500 cells/mm 3 with fever> 38 C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids. Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids. Thrombocytopenia ( <100,000 cells/mm 3 ) associated with fatal gastrointestinal hemorrhage has been reported. Hypersensitivity Reactions Severe hypersensitivity reactions have been reported [see Boxed Warning, Warnings and Precautions ( 5.4 )] . Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy. Fluid Retention Fluid retention can occur with the use of Docefrez [see Boxed Warning, Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.5 )] . Cutaneous Reactions Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions ( 5.7 )]. Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after docetaxel infusion, recovered before the next infusion, and were not disabling. Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain. Neurologic Reactions Neurologic reactions are discussed elsewhere in the label [ seeWarnings and Precautions ( 5.8 )]. Gastrointestinal Reactions Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3-5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. Cardiovascular Reactions Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely. Seven of 86 patients (8.1%) of metastatic breast cancer patients receiving docetaxel 100 mg/m 2 in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by 10% associated with a drop below the institutional lower limit of normal. Infusion Site Reactions Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein. Hepatic Reactions In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT> 1.5 times the ULN, or alkaline phosphatase > 2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on docetaxel, increases in AST and/or ALT > 1.5 times ULN concomitant with alkaline phosphatase > 2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established. Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry abnormalities Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m 2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT > 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN); and 174 patients in Japanese studies given docetaxel at 60 mg/m 2 who had normal LFTs (see Tables 3 and 4). Table 3 - Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m 2 with Normal or Elevated Liver Function Tests or 60 mg/m 2 with Normal Liver Function Tests * Normal Baseline LFTs: Transaminases 1.5 times ULN or alkaline phosphatase 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN. Elevated Baseline LFTs: AST and/or ALT > 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN. Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia. Febrile Neutropenia: For 100 mg/m2 , ANC grade 4 and fever > 38 C with intravenous antibiotics and/or hospitalization; for 60 mg/m2 , ANC grade 3/4 and fever > 38.1 C. Adverse Reaction Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2 Normal LFTs * n=730 % Elevated LFTs n=18 % NormalLFTs * n=174 % Neutropenia Any <2000 cells/mm 3 Grade 4> <500 cells/mm 3 98 84 100 94 95 75 Thrombocytopenia Any> <100,000 cells/mm 3 Grade 4> <20,000 cells/mm 3 11 1 44 17 14 1 Anemia> <11 g/dL 95 94 65 Infection Any Grade 3 and 4 23 7 39 33 1 0 Febrile Neutropenia By Patient By Course 12 2 33 9 0 0 Septic Death 2 6 1 Non-Septic Death 1 11 0 Table 4 - Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests * Normal Baseline LFTs: Transaminases 1.5 times ULN or alkaline phosphatase 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN.. Elevated Baseline Liver Function: AST and/or ALT> 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN.. Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m2 dose NA = not available Adverse Reaction Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2 Normal LFTs * n=730 % Elevated LFTs n=18 % Normal LFTs * n=174 % Acute Hypersensitivity Reaction Regardless of Premedication Any Severe 13 1 6 0 1 0 Fluid Retention Regardless of Premedication Any Severe 56 8 61 17 13 0 Neurosensory Any Severe 57 6 50 0 20 0 Myalgia 23 33 3 Cutaneous Any Severe 45 5 61 17 31 0 Asthenia Any Severe 65 17 44 22 66 0 Diarrhea Any Severe 42 6 28 11 NA Stomatitis Any Severe 53 8 67 39 19 1 In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m 2 , 75 mg/m 2 and 100 mg/m 2 in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with docetaxel 60 mg/m 2 compared to 55.3% and 65.9% treated with 75 mg/m 2 and 100 mg/m 2 respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m 2 vs. 6.9% and 16.5% for patients treated at 75 mg/m 2 and 100 mg/m 2 respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m 2 compared to 5.3% and 1.6% for patients treated at 75 mg/m 2 and 100 mg/m 2 respectively. The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m 2 , 75 mg/m 2 , and 100 mg/m 2 respectively), thrombocytopenia (7%, 11%, and 12% respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14% respectively), treatment-related grade 3/4 infection (2%, 3%, and 7% respectively) and anemia (87%, 94%, and 97% respectively). Lung Cancer Monotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy Docetaxel 75 mg/m 2 : Treatment emergent adverse drug reactions are shown in Table 5. Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except f a unusual
wade through Docefrez most opulent
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