Docetaxel

Docetaxel Manufacturers

• Mckesson Packaging Services A Business Unit Of Mckesson Corporation
  

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  Docetaxel | Actavis Pharma, Inc.

  

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  Apply a thin film of Clindamycin Phosphate Topical Solution USP, 1% twice daily to affected area. Keep container tightly closed.

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• Sandoz Inc
  

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  Docetaxel | Par Pharmaceutical Companies, Inc.

  

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  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  2.1 Hypercalcemia of Malignancy

  The maximum recommended dose of Zoledronic Acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zoledronic Acid Injection should have serum creatinine assessed prior to each treatment.

  Dose adjustments of Zoledronic Acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

  Patients should be adequately rehydrated prior to administration of Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

  Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic Acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

  Retreatment with Zoledronic Acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic

  Acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

  2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors

  The recommended dose of Zoledronic Acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

  Upon treatment initiation, the recommended Zoledronic Acid Injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

  Table 1: Reduced Doses for Patients with Baseline CrCl Less than or Equal to 60 mL/min Baseline Creatinine Clearance
  (mL/min) Zoledronic Acid Injection
  Recommended Dose*

  *Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75 mL/min)

  greater than 60 4 mg 50 – 60 3.5 mg 40 – 49 3.3 mg 30 – 39 3 mg

  During treatment, serum creatinine should be measured before each Zoledronic Acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

    For patients with normal baseline creatinine, increase of 0.5 mg/dL   For patients with abnormal baseline creatinine, increase of 1.0 mg/dL

  In the clinical studies, Zoledronic Acid Injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic Acid Injection should be reinitiated at the same dose as that prior to treatment interruption.

  Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily.

  2.3 Preparation of Solution

  Zoledronic Acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

  4 mg/5 mL Single-Use Vial

  Vials of Zoledronic Acid Injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

  To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zoledronic Acid Injection concentrate from the vial for the dose required (see Table 2).

  Table 2: Preparation of Reduced Doses – Zoledronic Acid Injection Concentrate Remove and Use
  Zoledronic Acid Injection Volume (mL) Dose (mg) 4.4 3.5 4.1 3.3 3.8 3.0

  The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

  If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

  2.4 Method of Administration

  Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic Acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings And Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic Acid Injection dose.

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• Winthrop U.s.
  

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  Docetaxel | Winthrop U.s.

  

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  For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7)].

  Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).

  2.1 Breast Cancer For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of docetaxel is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks. For the adjuvant treatment of operable node-positive breast cancer, the recommended docetaxel dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 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/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 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 is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30–60 minutes every 3 weeks [see Dosage and Administration (2.7)]. 2.3 Prostate Cancer For hormone-refractory metastatic prostate cancer, the recommended dose of docetaxel is 75 mg/m2 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 is 75 mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)]. 2.5 Head and Neck Cancer

  Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the docetaxel containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

  Induction chemotherapy followed by radiotherapy (TAX323)
  For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of docetaxel is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. [see Dosage and Administration (2.7)]. Induction chemotherapy followed by chemoradiotherapy (TAX324)
  For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of docetaxel is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)]. 2.6 Premedication Regimen

  All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to docetaxel 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 (5.4)].

  For hormone-refractory metastatic 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 infusion [see Warnings and Precautions (5.4)].

  2.7 Dosage Adjustments During Treatment

  Breast Cancer

  Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during docetaxel therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during docetaxel therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have docetaxel treatment discontinued entirely.

  Combination Therapy with Docetaxel in the Adjuvant Treatment of Breast Cancer

  Docetaxel in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. 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 dose reduced to 60 mg/m2. Patients who experience grade 3 or 4 stomatitis should have their docetaxel dose decreased to 60 mg/m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during docetaxel therapy should have their dosage of docetaxel reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, treatment should be discontinued.

  Non-Small Cell Lung Cancer

  Monotherapy with docetaxel for NSCLC treatment after failure of prior platinum-based chemotherapy

  Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during docetaxel treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have docetaxel treatment discontinued entirely.

  Combination therapy with docetaxel for chemotherapy-naïve NSCLC

  For patients who are dosed initially at docetaxel 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the docetaxel dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.

  Prostate Cancer

  Combination therapy with docetaxel for hormone-refractory metastatic prostate cancer

  Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during docetaxel therapy should have the dosage of docetaxel reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.

  Gastric or Head and Neck Cancer

  Docetaxel in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer

  Patients treated with docetaxel 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 dose should be reduced from 75 mg/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 mg/m2 to 60 mg/m2. Patients should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist. [see Warnings and Precautions (5.3)].

  Recommended dose modifications for toxicities in patients treated with docetaxel in combination with cisplatin and fluorouracil are shown in Table 1.

  Table 1 - Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel in Combination with Cisplatin and Fluorouracil Toxicity Dosage adjustment Diarrhea grade 3 First episode: reduce fluorouracil dose by 20%.
  Second episode: then reduce docetaxel dose by 20%. Diarrhea grade 4 First episode: reduce docetaxel 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 dose by 20%. Stomatitis/mucositis grade 4 First episode: stop fluorouracil only, at all subsequent cycles.
  Second episode: reduce docetaxel dose by 20%.

  Liver dysfunction:

  In case of AST/ALT >2.5 to ≤5 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 × ULN and AP >2.5 to ≤5 × ULN, docetaxel should be reduced by 20%.

  In case of AST/ALT >5 × ULN and/or AP >5 × ULN docetaxel should be stopped.

  The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:

  Cisplatin dose modifications and delays

  Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:

  Grade 2: Reduce cisplatin dose by 20%. Grade 3: Discontinue treatment.

  Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

  Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

  For other cisplatin dosage adjustments, also refer to the manufacturers' prescribing information.

  Table 2 – Dose Reductions for Evaluation of Creatinine Clearance Creatinine clearance result before next cycle Cisplatin dose next cycle CrCl = Creatinine clearance CrCl ≥60 mL/min Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle. CrCl between 40 and 59 mL/min Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was reinstituted at the next cycle.
  
  If no recovery was observed, then cisplatin was omitted from the next treatment cycle. CrCl <40 mL/min Dose of cisplatin was omitted in that treatment cycle only.
  
  If CrCl was still <40 mL/min at the end of cycle, cisplatin was discontinued.
  
  If CrCl was >40 and <60 mL/min at end of cycle, a 50% cisplatin dose was given at the next cycle.
  
  If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle.

  Fluorouracil dose modifications and treatment delays

  For diarrhea and stomatitis, see Table 1.

  In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.

  For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.

  For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information.

  Combination Therapy with Strong CYP3A4 inhibitors:

  Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor. [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  2.8 Administration Precautions

  Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing docetaxel solutions. The use of gloves is recommended. Please refer to [see How Supplied/ Storage and Handling (16.3)].

  If Docetaxel Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.

  Contact of the docetaxel concentrate 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 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 Concentrate)

  Docetaxel Injection Concentrate requires NO prior dilution with a diluent and is ready to add to the infusion solution.

  Please follow the preparation instructions provided below.

  2.9 Preparation and Administration

  DO NOT use the two-vial formulation (Injection Concentrate and diluent) with the one-vial formulation.

  One-vial Docetaxel (Injection Concentrate)

  Docetaxel Injection Concentrate (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.

  Docetaxel vials should be stored between 2 and 25°C (36 and 77°F). If the vials are stored under refrigeration, allow the appropriate number of vials of Docetaxel Injection Concentrate vials to stand at room temperature for approximately 5 minutes before use. Using only a 21 gauge needle, aseptically withdraw the required amount of docetaxel injection concentrate (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 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 gentle manual rotation. As with all parenteral products, docetaxel should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the docetaxel dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded. Docetaxel 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.

  2.10 Stability

  Docetaxel final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 6 hours. Docetaxel 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 and 46°F).

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• Pfizer Laboratories Div Pfizer Inc
  

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  Docetaxel | Air Liquide America L.p.

  

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  There is currently no dosage information available for this product. We apologize for any inconvenience.

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• Hospira, Inc.
  

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  Docetaxel | Hospira, Inc.

  

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  For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7)].

  Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).

  2.1 Breast Cancer

  For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection, USP is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.

  For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection, USP dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 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/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 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, USP is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30–60 minutes every 3 weeks [see Dosage and Administration (2.7)].

  2.3 Prostate Cancer

  For hormone-refractory metastatic prostate cancer, the recommended dose of Docetaxel Injection, USP is 75 mg/m2 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/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)].

  2.5 Head and Neck Cancer

  Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the Docetaxel Injection containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

  Induction chemotherapy followed by radiotherapy (TAX323)

  For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy [see Dosage and Administration (2.7)].

  Induction chemotherapy followed by chemoradiotherapy (TAX324)

  For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)].

  2.6 Premedication Regimen

  All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection, USP 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 (5.4)].

  For hormone-refractory metastatic 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, USP infusion [see Warnings and Precautions (5.4)].

  2.7 Dosage Adjustments During Treatment

  Breast Cancer

  Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during Docetaxel Injection, USP therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docetaxel Injection, USP therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection, USP treatment discontinued entirely.

  Combination Therapy with Docetaxel Injection, USP in the Adjuvant Treatment of Breast Cancer

  Docetaxel Injection, USP in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. 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, USP dose reduced to 60 mg/m2. Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection, USP dose decreased to 60 mg/m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection, USP therapy should have their dosage of Docetaxel Injection, USP reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, treatment should be discontinued.

  Non-Small Cell Lung Cancer

  Monotherapy with Docetaxel Injection, USP for NSCLC treatment after failure of prior platinum-based chemotherapy

  Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Docetaxel Injection, USP treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection, USP treatment discontinued entirely.

  Combination therapy with Docetaxel Injection, USP for chemotherapy-naïve NSCLC

  For patients who are dosed initially at Docetaxel Injection, USP 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the Docetaxel Injection, USP dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers’ prescribing information.

  Prostate Cancer

  Combination therapy with Docetaxel Injection, USP for hormone-refractory metastatic prostate cancer

  Docetaxel Injection, USP should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection, USP therapy should have the dosage of Docetaxel Injection, USP reduced from 75 mg to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, 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/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist [see Warnings and Precautions (5.3)].

  Recommended dose modifications for toxicities in patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil are shown in Table 1.

  Table 1 - Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel Injection in Combination with Cisplatin and Fluorouracil

  Toxicity

  Dosage Adjustment

  Diarrhea grade 3

  First episode: reduce fluorouracil dose by 20%. Second episode: then reduce Docetaxel Injection dose by 20%.

  Diarrhea grade 4

  First episode: reduce Docetaxel Injection and fluorouracil doses by 20%. Second episode: discontinue treatment.

  Stomatitis/mucositis grade 3

  First episode: reduce fluorouracil dose by 20%. Second episode: stop fluorouracil only, at all subsequent cycles. Third episode: reduce Docetaxel Injection dose by 20%.

  Stomatitis/mucositis grade 4

  First episode: stop fluorouracil only, at all subsequent cycles. Second episode: reduce Docetaxel Injection dose by 20%.

  Liver dysfunction: In case of AST/ALT >2.5 to ≤5 x ULN and AP ≤2.5 x ULN, or AST/ALT >1.5 to ≤5 x ULN and AP >2.5 to ≤5 x ULN, Docetaxel Injection should be reduced by 20%.

  In case of AST/ALT >5 x ULN and/or AP >5 x ULN Docetaxel Injection should be stopped. The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:

  Cisplatin dose modifications and delays

  Peripheral neuropathy 

  A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:

  Grade 2: Reduce cisplatin dose by 20%. Grade 3: Discontinue treatment. Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

  Nephrotoxicity

  In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

  For other cisplatin dosage adjustments, also refer to the 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 co-administration of a strong CYP3A4 inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  2.8 Administration Precautions

  Docetaxel Injection, USP is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docetaxel Injection, USP solutions. The use of gloves is recommended. Please refer to [see How Supplied/Storage and Handling (16.3)].

  If Docetaxel Injection, USP or diluted solution for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection, USP or diluted solution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water.

  Contact of the Docetaxel Injection, USP 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 Docetaxel Injection, USP diluted solution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

  Docetaxel Injection, USP requires dilution prior to administration.

  Please follow the preparation instructions provided below.

  2.9 Preparation and Administration

  Docetaxel Injection, USP (10 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution.

  Dilution for Infusion

  Aseptically withdraw the required amount of Docetaxel Injection, USP (10 mg docetaxel/mL) 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 mg/mL to 0.74 mg/mL.
  If a dose greater than 200 mg of docetaxel 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 gentle manual rotation. As with all parenteral products, Docetaxel Injection, USP should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Docetaxel Injection, USP or diluted solution is not clear or appears to have precipitation, it should be discarded.

  The Docetaxel Injection, USP diluted solution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.

  2.10 Stability

  Docetaxel Injection, USP infusion solution, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours in either 0.9% Sodium Chloride solution or 5% Dextrose solution. Use within 4 hours including the 1 hour intravenous administration.

  2.1 Breast Cancer

  For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection, USP is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.

  For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection, USP dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 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/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 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, USP is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30–60 minutes every 3 weeks [see Dosage and Administration (2.7)].

  2.3 Prostate Cancer

  For hormone-refractory metastatic prostate cancer, the recommended dose of Docetaxel Injection, USP is 75 mg/m2 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/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)].

  2.5 Head and Neck Cancer

  Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the Docetaxel Injection containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

  Induction chemotherapy followed by radiotherapy (TAX323)

  For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy [see Dosage and Administration (2.7)].

  Induction chemotherapy followed by chemoradiotherapy (TAX324)

  For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)].

  2.6 Premedication Regimen

  All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection, USP 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 (5.4)].

  For hormone-refractory metastatic 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, USP infusion [see Warnings and Precautions (5.4)].

  2.7 Dosage Adjustments During Treatment

  Breast Cancer

  Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during Docetaxel Injection, USP therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docetaxel Injection, USP therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection, USP treatment discontinued entirely.

  Combination Therapy with Docetaxel Injection, USP in the Adjuvant Treatment of Breast Cancer

  Docetaxel Injection, USP in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. 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, USP dose reduced to 60 mg/m2. Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection, USP dose decreased to 60 mg/m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection, USP therapy should have their dosage of Docetaxel Injection, USP reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, treatment should be discontinued.

  Non-Small Cell Lung Cancer

  Monotherapy with Docetaxel Injection, USP for NSCLC treatment after failure of prior platinum-based chemotherapy

  Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Docetaxel Injection, USP treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection, USP treatment discontinued entirely.

  Combination therapy with Docetaxel Injection, USP for chemotherapy-naïve NSCLC

  For patients who are dosed initially at Docetaxel Injection, USP 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the Docetaxel Injection, USP dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers’ prescribing information.

  Prostate Cancer

  Combination therapy with Docetaxel Injection, USP for hormone-refractory metastatic prostate cancer

  Docetaxel Injection, USP should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection, USP therapy should have the dosage of Docetaxel Injection, USP reduced from 75 mg to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, 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/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist [see Warnings and Precautions (5.3)].

  Recommended dose modifications for toxicities in patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil are shown in Table 1.

  Table 1 - Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel Injection in Combination with Cisplatin and Fluorouracil

  Toxicity

  Dosage Adjustment

  Diarrhea grade 3

  First episode: reduce fluorouracil dose by 20%. Second episode: then reduce Docetaxel Injection dose by 20%.

  Diarrhea grade 4

  First episode: reduce Docetaxel Injection and fluorouracil doses by 20%. Second episode: discontinue treatment.

  Stomatitis/mucositis grade 3

  First episode: reduce fluorouracil dose by 20%. Second episode: stop fluorouracil only, at all subsequent cycles. Third episode: reduce Docetaxel Injection dose by 20%.

  Stomatitis/mucositis grade 4

  First episode: stop fluorouracil only, at all subsequent cycles. Second episode: reduce Docetaxel Injection dose by 20%.

  Liver dysfunction: In case of AST/ALT >2.5 to ≤5 x ULN and AP ≤2.5 x ULN, or AST/ALT >1.5 to ≤5 x ULN and AP >2.5 to ≤5 x ULN, Docetaxel Injection should be reduced by 20%.

  In case of AST/ALT >5 x ULN and/or AP >5 x ULN Docetaxel Injection should be stopped. The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:

  Cisplatin dose modifications and delays

  Peripheral neuropathy 

  A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:

  Grade 2: Reduce cisplatin dose by 20%. Grade 3: Discontinue treatment. Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

  Nephrotoxicity

  In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

  For other cisplatin dosage adjustments, also refer to the 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 co-administration of a strong CYP3A4 inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  2.8 Administration Precautions

  Docetaxel Injection, USP is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docetaxel Injection, USP solutions. The use of gloves is recommended. Please refer to [see How Supplied/Storage and Handling (16.3)].

  If Docetaxel Injection, USP or diluted solution for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection, USP or diluted solution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water.

  Contact of the Docetaxel Injection, USP 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 Docetaxel Injection, USP diluted solution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

  Docetaxel Injection, USP requires dilution prior to administration.

  Please follow the preparation instructions provided below.

  2.9 Preparation and Administration

  Docetaxel Injection, USP (10 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution.

  Dilution for Infusion

  Aseptically withdraw the required amount of Docetaxel Injection, USP (10 mg docetaxel/mL) 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 mg/mL to 0.74 mg/mL.
  If a dose greater than 200 mg of docetaxel 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 gentle manual rotation. As with all parenteral products, Docetaxel Injection, USP should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Docetaxel Injection, USP or diluted solution is not clear or appears to have precipitation, it should be discarded.

  The Docetaxel Injection, USP diluted solution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.

  2.10 Stability

  Docetaxel Injection, USP infusion solution, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours in either 0.9% Sodium Chloride solution or 5% Dextrose solution. Use within 4 hours including the 1 hour intravenous administration.

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  For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7)].

  Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).

  2.1 Breast Cancer For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of docetaxel injection concentrate is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks. For the adjuvant treatment of operable node-positive breast cancer, the recommended docetaxel injection concentrate dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7)]. 2.2 Non-Small Cell Lung Cancer For treatment after failure of prior platinum-based chemotherapy, docetaxel injection concentrate was evaluated as monotherapy, and the recommended dose is 75 mg/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 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 injection concentrate was evaluated in combination with cisplatin. The recommended dose of docetaxel injection concentrate is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every 3 weeks [see Dosage and Administration (2.7)]. 2.3 Prostate Cancer For hormone-refractory metastatic prostate cancer, the recommended dose of docetaxel injection concentrate is 75 mg/m2 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 concentrate is 75 mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)]. 2.5 Head and Neck Cancer

  Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the docetaxel injection concentrate containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

  Induction chemotherapy followed by radiotherapy (TAX323)

  For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of docetaxel injection concentrate is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. [see Dosage and Administration (2.7)].

  Induction chemotherapy followed by chemoradiotherapy (TAX324)

  For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of docetaxel injection concentrate is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)].

  2.6 Premedication Regimen

  All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to docetaxel injection concentrate 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 (5.4)].

  For hormone-refractory metastatic 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 concentrate infusion [see Warnings and Precautions (5.4)].

  2.7 Dosage Adjustments During Treatment

  Breast Cancer

  Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during docetaxel injection concentrate therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during docetaxel injection concentrate therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have docetaxel injection concentrate treatment discontinued entirely.

  Combination Therapy with Docetaxel Injection Concentrate in the Adjuvant Treatment of Breast Cancer

  Docetaxel injection concentrate in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. 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 concentrate dose reduced to 60 mg/m². Patients who experience grade 3 or 4 stomatitis should have their docetaxel injection concentrate dose decreased to 60 mg/m². Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during docetaxel injection concentrate therapy should have their dosage of docetaxel injection concentrate reduced from 75 mg/m² to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², treatment should be discontinued.

  Non-Small Cell Lung Cancer

  Monotherapy with docetaxel injection concentrate for NSCLC treatment after failure of prior platinum-based chemotherapy

  Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during docetaxel injection concentrate treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have docetaxel injection concentrate treatment discontinued entirely.

  Combination therapy with docetaxel injection concentrate for chemotherapy-naïve NSCLC

  For patients who are dosed initially at docetaxel injection concentrate 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the docetaxel injection concentrate dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers’ prescribing information.

  Prostate Cancer

  Combination therapy with docetaxel injection concentrate for hormone-refractory metastatic prostate cancer

  Docetaxel injection concentrate should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during docetaxel injection concentrate therapy should have the dosage of docetaxel injection concentrate reduced from 75 mg/m² to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued.

  Gastric or Head and Neck Cancer

  Docetaxel injection concentrate in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer

  Patients treated with docetaxel injection concentrate 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 concentrate dose should be reduced from 75 mg/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the docetaxel injection concentrate dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the docetaxel injection concentrate dose should be reduced from 75 mg/m2 to 60 mg/m2. Patients should not be retreated with subsequent cycles of docetaxel injection concentrate until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist. [see Warnings and Precautions (5.3)].

  Recommended dose modifications for toxicities in patients treated with docetaxel injection concentrate in combination with cisplatin and fluorouracil are shown in Table 1.

  Table 1 - Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel Injection Concentrate 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 concentrate dose by 20%.   Diarrhea grade 4  First episode: reduce docetaxel injection concentrate 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 concentrate dose by 20%.   Stomatitis/mucositis grade 4  First episode: stop fluorouracil only, at all subsequent cycles. Second episode: reduce docetaxel injection concentrate 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 concentrate should be reduced by 20%.

  In case of AST/ALT >5 x ULN and/or AP >5 x ULN docetaxel injection concentrate should be stopped.

  The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:

  Cisplatin dose modifications and delays

  Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:

  Grade 2: Reduce cisplatin dose by 20%. Grade 3: Discontinue treatment.

  Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

  Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

  For other cisplatin dosage adjustments, also refer to the manufacturers’ prescribing information.

  Table 2 – Dose Reductions for Evaluation of Creatinine Clearance   Creatinine clearance result before next cycle   Cisplatin dose next cycle    CrCl = Creatinine clearance    CrCl ≥60 mL/min  Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle.     Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was   CrCl between 40 and 59 mL/min  >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.      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.         CrCl <40 mL/min  If CrCl was >40 and <60 mL/min at end of cycle, a 50% cisplatin dose was given at the next cycle.           If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle.

  Fluorouracil dose modifications and treatment delays

  For diarrhea and stomatitis, see Table 1.

  In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.

  For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.

  For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribing information.

  Combination Therapy with Strong CYP3A4 inhibitors:

  Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  2.8 Administration Precautions

  Docetaxel injection concentrate is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing docetaxel injection concentrate solutions. The use of gloves is recommended. Please refer to [see How Supplied/ Storage and Handling (16.3)].

  If docetaxel injection concentrate, or diluted infusion solution should come into contact with the skin or mucosa, wash immediately and thoroughly with soap and water.

  Do not use plasticized PVC equipment or devices that comes in direct contact with docetaxel injection solution during preparation and administration of solutions for infusion. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may leach from PVC infusion bags or sets, the diluted docetaxel infusion solution should be stored in bottles made of glass, polypropylene or plastic bags made with polypropylene, polyolefin and administered through polyethylene-lined administration sets.

  One-vial Docetaxel Injection Concentrate

  Docetaxel injection concentrate requires NO prior dilution with a diluent and is ready to add to the infusion solution.

  Please follow the preparation instructions provided below.

  2.9 Preparation and Administration

  DO NOT use the two-vial formulation (Injection Concentrate and diluent) with the one-vial formulation.

  One-vial Docetaxel Injection Concentrate

  Docetaxel injection concentrate (20 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution. Use only a 21 gauge needle to withdraw docetaxel injection concentrate from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates.

  Docetaxel injection concentrate vials should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) protected from light. Using only a 21 gauge needle, aseptically withdraw the required amount of docetaxel injection concentrate (20 mg docetaxel/mL) with a calibrated syringe and inject via a single injection 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 concentrate is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel injection concentrate is not exceeded. Thoroughly mix the infusion solution by gentle manual rotation. As with all parenteral products, docetaxel injection concentrate should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the docetaxel injection concentrate dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded.

  The docetaxel injection concentrate dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.

  2.10 Stability

  Docetaxel injection concentrate dilution for infusion is stable for 4 hours, if stored between 2°C and 25°C (36°F and 77°F).  Docetaxel injection concentrate dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).

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  For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7)].

  Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).

  2.1 Breast Cancer • For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection is 60 mg/m 2 to 100 mg/m 2 administered intravenously over 1 hour every 3 weeks. • For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7)]. 2.2 Non-Small Cell Lung Cancer • For treatment after failure of prior platinum-based chemotherapy, docetaxel 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 hormone-refractory metastatic prostate cancer, the recommended dose of Docetaxel Injection is 75 mg/m 2 every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration (2.7)]. 2.4 Gastric Adenocarcinoma • For gastric adenocarcinoma, the recommended dose of Docetaxel Injection is 75 mg/m 2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m 2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m 2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)]. 2.5 Head and Neck Cancer

  Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the docetaxel containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

  • Induction chemotherapy followed by radiotherapy (TAX323)

  For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. [see Dosage and Administration (2.7)].

  • Induction chemotherapy followed by chemoradiotherapy (TAX324)

  For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)].

  2.6 Premedication Regimen

  All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.4)].

  For hormone-refractory metastatic 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 (5.4)].

  2.7 Dosage Adjustments During Treatment

  Breast Cancer

  Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during Docetaxel Injection therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 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/mm3. 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/ m2. Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection dose decreased to 60 mg/ m2. 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/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/ m2, 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/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 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/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.

  Combination therapy with Docetaxel Injection for chemotherapy-naïve NSCLC

  For patients who are dosed initially at Docetaxel Injection 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, 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/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.

  Prostate Cancer

  Combination therapy with Docetaxel Injection for hormone-refractory metastatic prostate cancer

  Docetaxel Injection should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 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/m2 to 60 mg/ m2. If the patient continues to experience these reactions at 60 mg/m2, 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/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. 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 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 × ULN and AP >2.5 to ≤5 × ULN, Docetaxel Injection should be reduced by 20%.

  In case of AST/ALT >5 × ULN and/or AP >5 × ULN Docetaxel Injection should be stopped.

  The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:

  Cisplatin dose modifications and delays

  Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:

  • Grade 2: Reduce cisplatin dose by 20%. • Grade 3: Discontinue treatment.

  Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

  Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 × 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 Injection dose reduction if patients require co-administration of a strong CYP3A4 inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  2.8 Administration Precautions

  Docetaxel Injection is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docetaxel Injection solutions. The use of gloves is recommended. Please refer to [see How Supplied/Storage and Handling (16.3)].

  If Docetaxel Injection or diluted solution for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection or diluted solution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water.

  Contact of the Docetaxel Injection with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final Docetaxel Injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

  Docetaxel Injection requires dilution prior to administration. Please follow the preparation instructions provided below.

  2.9 Preparation and Administration

  Docetaxel Injection (10 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution.

  Dilution for Infusion

  1. Aseptically withdraw the required amount of Docetaxel Injection solution (10 mg docetaxel/mL) with a calibrated syringe and inject (as a single injection) 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 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. 2. Thoroughly mix the infusion bag or bottle manually by gentle inversion and rotation in a controlled manner and avoid foaming. Shaking or vigorous agitation should be avoided during preparation and transportation to the patient for administration. 3. 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 vial or diluted solution is not clear or appears to have precipitation, these should be discarded.

  The Docetaxel Injection diluted solution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature below 25°C (77°F) and lighting conditions.

  2.10 Stability

  Docetaxel Injection infusion solution, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours in either 0.9% Sodium Chloride solution or 5% Dextrose solution. Use within 4 hours including storage and administration. Do not freeze infusion solution.

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