Docetaxel

This regimen is administered every 3 weeks for 4 cycles. 7 ) ]. Induction Chemotherapy Followed by Chemoradiotherapy (TAX324) For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of docetaxel injection is 75 mg/m 2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m 2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m 2 /day as a continuous infusion from day 1 to day 4.

This regimen is administered every 3 weeks for 3 cycles. 7 ) ]. 5 ) ]. 5 ) ]. 7 Dosage Adjustments During Treatment Breast Cancer Patients who are dosed initially at 100 mg/m 2 and who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for more than 1 week, or severe or cumulative cutaneous reactions during docetaxel injection therapy should have the dosage adjusted from 100 mg/m 2 to 75 mg/m 2 .

If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m 2 to 55 mg/m 2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m 2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm 3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during docetaxel injection therapy may tolerate higher doses.

Patients who develop ≥grade 3 peripheral neuropathy should have docetaxel injection treatment discontinued entirely. Combination Therapy with docetaxel injection in the Adjuvant Treatment of Breast Cancer Docetaxel injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm 3 .

Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their docetaxel injection dose reduced to 60 mg/m 2 . Patients who experience grade 3 or 4 stomatitis should have their docetaxel injection dose decreased to 60 mg/m 2 .

Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during docetaxel injection therapy should have their dosage of docetaxel injection reduced from 75 mg/m 2 to 60 mg/m 2 .

If the patient continues to experience these reactions at 60 mg/m 2 , treatment should be discontinued. Non-Small Cell Lung Cancer Monotherapy with docetaxel injection for NSCLC treatment after failure of prior platinum-based chemotherapy Patients who are dosed initially at 75 mg/m 2 and who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during docetaxel injection treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m 2 .

Patients who develop ≥grade 3 peripheral neuropathy should have docetaxel injection treatment discontinued entirely. Combination therapy with docetaxel injection for chemotherapy-naive NSCLC For patients who are dosed initially at docetaxel injection 75 mg/m 2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm 3 , in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the docetaxel injection dosage in subsequent cycles should be reduced to 65 mg/m 2 .

In patients who require a further dose reduction, a dose of 50 mg/m 2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information. Prostate Cancer Combination therapy with docetaxel injection for metastatic castration-resistant prostate cancer Docetaxel injection should be administered when the neutrophil count is ≥1,500 cells/mm 3 .

Patients who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during docetaxel injection therapy should have the dosage of docetaxel injection reduced from 75 mg/m 2 to 60 mg/m 2 .

If the patient continues to experience these reactions at 60 mg/m 2 , the treatment should be discontinued. Gastric or Head and Neck Cancer Docetaxel injection in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer Patients treated with docetaxel injection in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines.

In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the docetaxel injection dose should be reduced from 75 mg/m 2 to 60 mg/m 2 .

If subsequent episodes of complicated neutropenia occur the docetaxel injection dose should be reduced from 60 mg/m 2 to 45 mg/m 2 . In case of grade 4 thrombocytopenia the docetaxel injection dose should be reduced from 75 mg/m 2 to 60 mg/m 2 .

Patients should not be retreated with subsequent cycles of docetaxel injection until neutrophils recover to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3 . 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%. 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. 5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2). For other cisplatin dosage adjustments, also refer to the manufacturer's prescribing information.

Table 2:

Dose Reductions for Evaluation of Creatinine Clearance CrCl = Creatinine clearance Creatinine clearance result before next cycle Cisplatin Dose next cycle CrCl ≥60 mL/min Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle.

CrCl between 40 and 59 mL/min Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was reinstituted at the next cycle. If no recovery was observed, then cisplatin was omitted from the next treatment cycle CrCl <40 mL/min Dose of cisplatin was omitted in that treatment cycle only.

If CrCl was still <40 mL/min at the end of cycle, cisplatin was discontinued. If CrCl was >40 and <60 mL/min at end of cycle, a 50% cisplatin dose was given at the next cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle.

Fluorouracil dose modifications and treatment delays For diarrhea and stomatitis, see Table 1. In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.

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

For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information. , 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. 3 ) ] . 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 . 3 ) ] . If docetaxel injection, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If docetaxel injection initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.

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

One-vial docetaxel injection USP Docetaxel injection USP requires NO prior dilution with a diluent and is ready to add to the infusion solution. Please follow the preparation instructions provided below. 9 Preparation and Administration DO NOT use the two-vial formulation (Injection and diluent) with the one-vial formulation.

One-vial Docetaxel Injection, USP Docetaxel injection USP (20 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution. , 18 and 19 gauge) may result in stopper coring and rubber particulates. Dilution for Infusion Docetaxel Injection vials should be stored between 2°C and 25°C (36°F and 77°F).

If the vials are stored under refrigeration, allow the appropriate number of vials of docetaxel injection vials to stand at room temperature for approximately 5 minutes before use. 74 mg/mL. 74 mg/mL docetaxel injection is not exceeded.

Thoroughly mix the infusion by gentle manual rotation. As with all parenteral products, docetaxel injection should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit.

If the docetaxel injection dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded. Docetaxel injection infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

The docetaxel injection dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions. 10 Stability Docetaxel injection final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 6 hours.

9% Sodium Chloride solution or 5% Dextrose solution) should be used within 6 hours (including the 1 hour intravenous administration). In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C (36°F and 46°F).

5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN. 5 times ULN. *** Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization. 3 ) ]. The median time to nadir was 7 days, 3while the median duration of severe neutropenia (<500 cells/mm 3 ) was 7 days.

9% of cycles. 8% of 92 breast cancer patients premedicated with 3-day corticosteroids. 4% of 92 breast cancer patients premedicated with 3-day corticosteroids. Thrombocytopenia (<100,000 cells/mm) associated with fatal gastrointestinal hemorrhage has been reported.

5 ) ] . Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy.

6 ) ]. 8 ) ]. Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after docetaxel infusion, recovered before the next infusion, and were not disabling.

8% of patients with solid tumors) and pain. 9 ) ]. Gastrointestinal reactions Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3-5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients.

The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. 1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. 2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely.

1%) of metastatic breast cancer patients receiving docetaxel 100 mg/m² in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by ≥10% associated with a drop below the institutional lower limit of normal.

Infusion site reactions Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein. 9% of patients. 3% of patients, respectively.

3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established.

Hematologic and other toxicity:

Relation to dose and baseline liver chemistry abnormalities Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). 5 times ULN); and 174 patients in Japanese studies given docetaxel at 60 mg/m² who had normal LFTs (see Tables 4 and 5).

5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia. 9% treated with 75 mg/m² and 100 mg/m², respectively. 3% of patients treated with 60 mg/m² vs.

5% for patients treated at 75 and 100 mg/m², respectively. 6% for patients treated at 75 mg/m² and 100 mg/m², respectively. The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m², 75 mg/m², and 100 mg/m² respectively), thrombocytopenia (7%, 11% and 12% respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14% respectively), treatment-related grade 3/4 infection (2%, 3%, and 7% respectively) and anemia (87%, 94%, and 97% respectively).

Combination therapy with docetaxel in the adjuvant treatment of breast cancer The following table presents treatment emergent adverse reactions observed in 744 patients, who were treated with docetaxel 75 mg/m 2 every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 6).

Table 6:

Clinically Important Treatment Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316). * COSTART term and grading system for events related to treatment.

6% of the 736 patients treated with FAC. 1% of cycles in the FAC arm. 1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs.

1% of FAC-treated patients. 3% and 0% of TAC- and FAC-treated patients respectively. 3% of FAC-treated patients. 2% of TAC-treated and FAC-treated patients respectively. There were no septic deaths in either treatment arm during the treatment period.

Gastrointestinal Reactions In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation versus one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred during the treatment period.

8%). 3%) in the FAC arm developed CHF during the study period. All except one patient in each arm were diagnosed with CHF during the follow-up period. Two (2) patients in TAC arm and 4 patients in FAC arm died due to CHF. The risk of CHF was higher in the TAC arm in the first year, and then was similar in both treatment arms.

Adverse reactions during the follow-up period (median follow-up time of 8 Years) In study TAX316, the most common adverse reactions that started during the treatment period and persisted into the follow-up period in TAC and FAC patients are described below (median follow-up time of 8 years).

3%) in TAC arm and 15 patients (2%) in FAC arm. 3%) in FAC arm. 2%). 0%). 7%). 1%). 5%). 1%). 1%). 5%). 2%). Acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS) AML occurred in the adjuvant breast cancer trial (TAX316). 1% for FAC-treated patients.

1%) died due to AML during the follow-up period (median follow-up time of 8 years). 1%) patients who received FAC. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. Lung Cancer Monotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy Docetaxel 75 mg/m 2 : Treatment emergent adverse drug reactions are shown in Table 7.

Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted.

5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN. ** Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization. *** COSTART term and grading system † Not Applicable ††Not Done Adverse Reaction Docetaxel 75 mg/m 2 n=176 % Best Supportive Care n=49 % Vinorelbine/ Ifosfamide n=119 % Neutropenia Any Grade 3/4 84 65 14 12 83 57 Leukopenia Any Grade 3/4 84 49 6 0 89 43 Thrombocytopenia Any Grade 3/4 8 3 0 0 8 2 Anemia Any Grade 3/4 91 9 55 12 91 14 Febrile Neutropenia** 6 NA † 1 Infection Any Grade 3/4 34 10 29 6 30 9 Treatment Related Mortality 3 NA † 3 Hypersensitivity Reactions Any Grade 3/4 6 3 0 0 1 0 Fluid Retention Any Severe 34 3 ND †† 23 3 Neurosensory Any Grade 3/4 23 2 14 6 29 5 Neuromotor Any Grade 3/4 16 5 8 6 10 3 Skin Any Grade 3/4 21 1 6 2 17 1 Gastrointestinal Nausea Any Grade 3/4 Vomiting Any Grade 3/4 Diarrhea Any Grade 3/4 34 5 22 3 23 3 31 4 27 2 6 0 31 8 22 6 12 4 Alopecia 56 35 50 Asthenia Any Severe*** 53 18 57 39 54 23 Stomatitis Any Grade 3/4 26 2 6 0 8 1 Pulmonary Any Grade 3/4 41 21 49 29 45 19 Nail Disorder Any Severe*** 11 1 0 0 2 0 Myalgia Any Severe*** 6 0 0 0 0 0 Arthralgia Any Severe*** 3 0 2 0 2 1 Taste Perversion Any Severe*** 6 1 0 0 0 0 Combination therapy with docetaxel in chemotherapy-naive advanced unresectable or metastatic NSCLC Table 8 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy.

Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted.

Table 8:

Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naïve Advanced Non-small Cell Lung Cancer Patients Receiving Docetaxel in Combination with Cisplatin * Replaces NCI term "Allergy". ** COSTART term and grading system.

3%) in the vinorelbine+cisplatin arm. 0%) in the vinorelbine+cisplatin arm. 3 ) ]) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the docetaxel+carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm.

Prostate Cancer Combination therapy with docetaxel in patients with prostate cancer The following data are based on the experience of 332 patients, who were treated with docetaxel 75 mg/m 2 every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 9).

Table 9:

Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel in Combination with Prednisone (TAX327) * Related to treatment Docetaxel 75 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=332% Mitoxantrone 12 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=335% Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 67 5 58 2 Neutropenia 41 32 48 22 Thrombocytopenia 3 1 8 1 Febrile Neutropenia 3 N/A 2 N/A Infection 32 6 20 4 Epistaxis 6 0 2 0 Allergic Reactions 8 1 1 0 Fluid Retention* 24 1 5 0 Weight Gain* 8 0 3 0 Peripheral Edema* 18 0 2 0 Neuropathy Sensory 30 2 7 0 Neuropathy Motor 7 2 3 1 Rash/Desquamation 6 0 3 1 Alopecia 65 N/A 13 N/A Nail Changes 30 0 8 0 Nausea 41 3 36 2 Diarrhea 32 2 10 1 Stomatitis/Pharyngitis 20 1 8 0 Taste Disturbance 18 0 7 0 Vomiting 17 2 14 2 Anorexia 17 1 14 0 Cough 12 0 8 0 Dyspnea 15 3 9 1 Cardiac left ventricular function 10 0 22 1 Fatigue 53 5 35 5 Myalgia 15 0 13 1 Tearing 10 1 2 0 Arthralgia 8 1 5 1 Gastric Cancer Combination therapy with docetaxel injection in gastric adenocarcinoma Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease, who were treated with docetaxel 75 mg/m 2 in combination with cisplatin and fluorouracil (see Table 10).

Table 10:

Clinically Important Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study Clinically important treatment emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.

*Related to treatment Docetaxel 75 mg/m 2 + cisplatin 75 mg/m 2 + fluorouracil 750 mg/m 2 n=221 Cisplatin 100 mg/m 2 + fluorouracil 1000 mg/m 2 n=224 Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Anemia 97 18 93 26 Neutropenia 96 82 83 57 Fever in the absence of infection 36 2 23 1 Thrombocytopenia 26 8 39 14 Infection 29 16 23 10 Febrile neutropenia 16 N/A 5 N/A Neutropenic infection 16 N/A 10 N/A Allergic reactions 10 2 6 0 Fluid retention* 15 0 4 0 Edema* 13 0 3 0 Lethargy 63 21 58 18 Neurosensory 38 8 25 3 Neuromotor 9 3 8 3 Dizziness 16 5 8 2 Alopecia 67 5 41 1 Rash/itch 12 1 9 0 Nail changes 8 0 0 0 Skin desquamation 2 0 0 0 Nausea 73 16 76 19 Vomiting 67 15 73 19 Anorexia 51 13 54 12 Stomatitis 59 21 61 27 Diarrhea 78 20 50 8 Constipation 25 2 34 3 Esophagitis/dysphagia/ odynophagia 16 2 14 5 Gastrointestinal pain/cramping 11 2 7 3 Cardiac dysrhythmias 5 2 2 1 Myocardial ischemia 1 0 3 2 Tearing 8 0 2 0 Altered hearing 6 0 13 2 Head and Neck Cancer Combination therapy with docetaxel in head and neck cancer Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with docetaxel injection 75 mg/m 2 in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients).

6 .

Table 11:

Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with Docetaxel Injection in Combination with Cisplatin and Fluorouracil Followed by Radiotherapy (TAX323) or Chemoradiotherapy (TAX324) Clinically important treatment emergent adverse reactions based upon frequency, severity, and clinical impact.

* Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization. ** Related to treatment. *** Includes superficial and deep vein thrombosis and pulmonary embolism. 2 Postmarketing Experience The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance.

Because they are reported from a population of unknown size, precise estimates of frequency cannot be made. Body as a whole: diffuse pain, chest pain, radiation recall phenomenon, injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) at the site of previous extravasation.

Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Ventricular arrhythmia including ventricular tachycardia has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide, and may be associated with fatal outcome.

Cutaneous: very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema.

In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported. Cases of permanent alopecia have been reported. Gastrointestinal: enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, has been reported with a potential fatal outcome.

Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence to gastrointestinal events have been reported.

Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs. Hematologic: bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported.

Hepatic : rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported. Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.

Hypersensitivity reactions with potential fatal outcome have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel. Metabolism and nutrition disorders: electrolyte imbalance, including cases of hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia, has been reported.

Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug. Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis.

Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported.

These were reversible upon discontinuation of the infusion. Cases of cystoid macular edema (CME) have been reported in patients treated with docetaxel. Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome.

Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy Renal: renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.

7 ) ] .

1 ), Clinical Studies ( 14 ) ]. 7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug induced thrombocytopenia. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not.

7 ), Adverse Reactions ( 6 ) ]. 4 Enterocolitis and Neutropenic Colitis Enterocolitis and neutropenic colitis (typhlitis) have occurred in patients treated with docetaxel alone and in combination with other chemotherapeutic agents, despite the co-administration of G-CSF.

Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Enterocolitis and neutropenic enterocolitis may develop at any time, and could lead to death as early as the first day of symptom onset.

Monitor patients closely from onset of any symptoms of gastrointestinal toxicity. 2 )]. 5 Hypersensitivity Reactions Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions.

Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the docetaxel infusion and aggressive therapy.

Patients with a history of severe hypersensitivity reactions should not be rechallenged with docetaxel. Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a hypersensitivity reaction to docetaxel that may include severe or fatal reactions such as anaphylaxis.

Monitor patients with a previous history of hypersensitivity to paclitaxel closely during initiation of docetaxel therapy. Hypersensitivity reactions may occur within a few minutes following initiation of a docetaxel infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required.

6 ) ]. 6 Fluid Retention Severe fluid retention has been reported following docetaxel therapy. 6 ) ]. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions. When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.

5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m². 8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention.

The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m². Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks).

, salt restriction, oral diuretic(s). 7 Second Primary Malignancies Second primary malignancies, notably acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), Non-Hodgkin's Lymphoma (NHL), and renal cancer, have been reported in patients treated with docetaxel-containing regimens.

These adverse reactions may occur several months or years after docetaxel-containing therapy. Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer.

2 ) ]. In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. 1 ) ]. 8 Cutaneous Reaction Localized erythema of the extremities with edema followed by desquamation has been observed.

7 ) ]. 6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued docetaxel due to skin toxicity.

g. 1%. When these symptoms occur, dosage must be adjusted. 7 ) ]. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks).

4% (42/965). 10 Eye Disorders Cystoid macular edema (CME) has been reported in patients treated with docetaxel. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, docetaxel injection treatment should be discontinued and appropriate treatment initiated.

Alternative non-taxane cancer treatment should be considered. 8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

1 ) ]. Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

003 times the recommended human dose based on body surface area, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify pregnancy status in females of reproductive potential prior to initiating docetaxel.

Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of docetaxel. 3 ) ]. 13 Alcohol Content Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content.

The alcohol content in a dose of docetaxel Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in docetaxel Injection on the ability to drive or use machines immediately after the infusion.

0 g/m² of ethanol. 0 grams of ethanol [ see Description ( 11 ) ]. Other docetaxel products may have a different amount of alcohol.