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DOCETAXEL ANHYDROUS INJECTION, SOLUTION (docetaxel injection, USP) Adverse Reactions

6 ADVERSE REACTIONS

The most serious adverse reactions from docetaxel are:

The most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.

Adverse reactions are described according to indication. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established.

6.1 Clinical Trials Experience

Breast Cancer

Monotherapy with Docetaxel for Locally Advanced or Metastatic Breast Cancer after Failure of Prior Chemotherapy

Docetaxel 100 mg/m2: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to docetaxel. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving docetaxel for the treatment of breast cancer and in patients with other tumor types (see Table 3).

Table 3: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m2
Adverse ReactionAll Tumor Types
Normal LFTs*
n=2045
%
All Tumor Types
Elevated LFTs
n=61
%
Breast Cancer
Normal LFTs*
n=965
%
*
Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization
Hematologic
Neutropenia
  <2000 cells/mm3969699
  <500 cells/mm3758886
Leukopenia
  <4000 cells/mm3969899
  <1000 cells/mm3324744
Thrombocytopenia
  <100,000 cells/mm38259
Anemia
  <11 g/dL909294
  <8 g/dL 9318
Febrile Neutropenia112612
Septic Death251
Non-Septic Death171
Infections
  Any223322
  Severe 6166
Fever in Absence of Infection
  Any314135
  Severe282
Hypersensitivity Reactions
Regardless of Premedication
  Any212018
  Severe4103
With 3-day Premedicationn=92n=3n=92
  Any153315
  Severe 202
Fluid Retention
Regardless of Premedication
  Any473960
  Severe789
With 3-day Premedicationn=92n=3n=92
  Any646764
  Severe7337
Neurosensory
  Any493458
  Severe406
Cutaneous
  Any485447
  Severe5105
Nail Changes
  Any312341
  Severe354
Gastrointestinal
Nausea393842
Vomiting222323
Diarrhea393343
  Severe556
Stomatitis
  Any424952
  Severe6137
Alopecia766274
Asthenia
  Any625366
  Severe132515
Myalgia
  Any191621
  Severe222
Arthralgia978
Infusion Site Reactions434

Hematologic Reactions

Reversible marrow suppression was the major dose-limiting toxicity of docetaxel [see Warnings and Precautions (5.3)]. The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm3) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles.

Febrile neutropenia (<500 cells/mm3 with fever >38°C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids.

Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids.

Thrombocytopenia (<100,000 cells/mm3) associated with fatal gastrointestinal hemorrhage has been reported.

Hypersensitivity Reactions

Severe hypersensitivity reactions have been reported [see Boxed Warning, Warnings and Precautions (5.5)]. 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.

Fluid Retention

Fluid retention can occur with the use of docetaxel [see Boxed Warning, Dosage and Administration (2.6), Warnings and Precautions (5.6)].

Cutaneous Reactions

Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.8)]. 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.

Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain.

Neurologic Reactions

Neurologic reactions are discussed elsewhere in the label [see Warnings and Precautions (5.9)].

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.

Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids.

Cardiovascular Reactions

Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension have occurred. Seven of 86 (8.1%) 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.

Hepatic Reactions

In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT >1.5 times the ULN, or alkaline phosphatase >2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on docetaxel, increases in AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established.

Hematologic and Other Toxicity: Relation to Dose and Baseline Liver Chemistry Abnormalities

Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN); and 174 patients in Japanese studies given docetaxel at 60 mg/m2 who had normal LFTs (see Tables 4 and 5).

Table 4: Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests
Docetaxel
100 mg/m2
Docetaxel
60 mg/m2
Adverse Reaction Normal LFTs*
n=730
%
Elevated LFTs
n=18
%
Normal LFTs*
n=174
%
*
Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia.
§
Febrile Neutropenia: For 100 mg/m2, ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever >38.1°C
Neutropenia
  Any <2000 cells/mm39810095
  Grade 4 <500 cells/mm3849475
Thrombocytopenia
  Any <100,000 cells/mm3114414
  Grade 4 <20,000 cells/mm31171
Anemia <11 g/dL959465
Infection
  Any 23 391
  Grade 3 and 4 7330
Febrile Neutropenia§
  By Patient12330
  By Course290
Septic Death261
Non-Septic Death1110
Table 5: Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests
Docetaxel
100 mg/m2
Docetaxel
60 mg/m2
Normal LFTs*Elevated LFTsNormal LFTs*
Adverse Reactionn=730n=18n=174
%%%
NA = not available
*
Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Elevated Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m2 dose
Acute Hypersensitivity Reaction Regardless of Premedication
  Any136 1
  Severe100
Fluid Retention Regardless of Premedication
  Any5661 13
  Severe8170
Neurosensory
  Any575020
  Severe 600
Myalgia23 33 3
Cutaneous
  Any 4561 31
  Severe5170
Asthenia
  Any65 4466
  Severe17220
Diarrhea
  Any 4228NA
  Severe 611
Stomatitis
  Any536719
  Severe8391

In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m2, 75 mg/m2 and 100 mg/m2 in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with docetaxel 60 mg/m2 compared to 55.3% and 65.9% treated with 75 mg/m2 and 100 mg/m2, respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m2 versus 6.9% and 16.5% for patients treated at 75 mg/m2 and 100 mg/m2, respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m2 compared to 5.3% and 1.6% 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/m2 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)
Docetaxel 75
mg/m2 + Doxorubicin 50 mg/m2 + Cyclophosphamide 500 mg/m2 (TAC)
n=744
%
Fluorouracil 500 mg/m2 + Doxorubicin 50 mg/m2 + Cyclophosphamide 500 mg/m2 (FAC)
n=736
%
Adverse Reaction AnyGrade 3/4Any Grade 3/4
*
COSTART term and grading system for events related to treatment.
Anemia 92 4 72 2
Neutropenia 71668249
Fever in absence of infection47 1170
Infection 39 436 2
Thrombocytopenia39 2 28 1
Febrile neutropenia25 N/A 3 N/A
Neutropenic infection12N/A 6 N/A
Hypersensitivity reactions 13 140
Lymphedema4 0 1 0
Fluid Retention*351150
Peripheral edema2707 0
Weight gain1309 0
Neuropathy sensory 260100
Neuro-cortical5 161
Neuropathy motor4020
Neuro-cerebellar 2 02 0
Syncope 2 11 0
Alopecia98N/A 97N/A
Skin toxicity 271180
Nail disorders 190 14 0
Nausea81588 10
Stomatitis 697 532
Vomiting45 4 597
Diarrhea 354 28 2
Constipation 34 1 321
Taste perversion 281150
Anorexia222181
Abdominal Pain11150
Amenorrhea62N/A 52 N/A
Cough 140 100
Cardiac dysrhythmias 80 6 0
Vasodilatation 271211
Hypotension 2 010
Phlebitis1010
Asthenia 8111716
Myalgia 27 1100
Arthralgia1919 0
Lacrimation disorder 11070
Conjunctivitis 5070

Of the 744 patients treated with TAC, 36.3% experienced severe treatment-emergent adverse reactions compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1.1% 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.

Fever and Infection

During the treatment period, fever in the absence of infection was seen in 46.5% of TAC-treated patients and in 17.1% of FAC-treated patients. Grade 3/4 fever in the absence of infection was seen in 1.3% and 0% of TAC- and FAC-treated patients, respectively. Infection was seen in 39.4% of TAC-treated patients compared to 36.3% of FAC-treated patients. Grade 3/4 infection was seen in 3.9% and 2.2% 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.

Cardiovascular Reactions

More cardiovascular reactions were reported in the TAC arm versus the FAC arm during the treatment period: arrhythmias, all grades (6.2% vs. 4.9%), and hypotension, all grades (1.9% vs. 0.8%). Twenty-six (26) patients (3.5%) in the TAC arm and 17 patients (2.3%) 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).

Nervous System Disorders: In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.

Skin and Subcutaneous Tissue Disorders: In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%). At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

Reproductive System and Breast Disorders: In study TAX316, amenorrhea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

General Disorders and Administration Site Conditions: In study TAX316, peripheral edema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral edema was ongoing in 19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX316, lymphedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).

In study TAX316, asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS): AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at median follow-up time of 8 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years).

Myelodysplastic syndrome occurred in 2 of 744 (0.3%) patients who received TAC and in 1 of 736 (0.1%) 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/m2: 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.

Table 7: Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel as Monotherapy for Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy*
Adverse Reaction Docetaxel 75 mg/m2
n=176
%
Best Supportive Care
n=49
%
Vinorelbine/Ifosfamide
n=119
%
*
Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization
Not Applicable
§
Not Done
COSTART term and grading system
Neutropenia
  Any841483
  Grade 3/4651257
Leukopenia
  Any84689
  Grade 3/449043
Thrombocytopenia
  Any808
  Grade 3/4302
Anemia
  Any915591
  Grade 3/4 91214
Febrile Neutropenia6NA1
Infection
  Any342930
  Grade 3/41069
Treatment Related Mortality3NA3
Hypersensitivity Reactions
  Any601
  Grade 3/4300
Fluid Retention
  Any34ND§23
  Severe33
Neurosensory
  Any231429
  Grade 3/4265
Neuromotor
  Any16810
  Grade 3/4 563
Skin
   Any20617
  Grade 3/4121
Gastrointestinal
Nausea
  Any343131
  Grade 3/4548
Vomiting
  Any222722
  Grade 3/4326
Diarrhea
  Any23612
  Grade 3/4304
Alopecia 563550
Asthenia
  Any535754
  Severe183923
Stomatitis
  Any2668
  Grade 3/4201
Pulmonary
  Any414945
  Grade 3/4212919
Nail Disorder
  Any1102
  Severe100
Myalgia
  Any 603
  Severe000
Arthralgia
  Any322
  Severe001
Taste Perversion
  Any600
  Severe100

Combination Therapy with Docetaxel in Chemotherapy-Naïve 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
Adverse ReactionDocetaxel 75 mg/m2 + Cisplatin 75 mg/m2
n=406
%
Vinorelbine 25 mg/m2 + Cisplatin 100 mg/m2
n=396
%
*
Replaces NCI term "Allergy"
COSTART term and grading system
Neutropenia
  Any9190
  Grade 3/47478
Febrile Neutropenia55
Thrombocytopenia
  Any1515
  Grade 3/434
Anemia
  Any8994
  Grade 3/4 725
Infection
  Any 3537
  Grade 3/488
Fever in absence of infection
  Any 3329
  Grade 3/4 <11
Hypersensitivity Reaction*
  Any124
  Grade 3/43<1
Fluid Retention
  Any5442
  All severe or life-threatening events
Pleural effusion
22
  Any2322
  All severe or life-threatening events
Peripheral edema
22
  Any 3418
  All severe or life-threatening events
Weight gain
<1<1
  Any159
  All severe or life-threatening events<1<1
Neurosensory
  Any4742
  Grade 3/444
Neuromotor
  Any 19 17
  Grade 3/4 36
Skin
  Any1614
  Grade 3/4 <11
Nausea
  Any7276
  Grade 3/41017
Vomiting
  Any5561
  Grade 3/4816
Diarrhea
  Any4725
  Grade 3/4 73
Anorexia
  Any4240
  All severe or life-threatening events55
Stomatitis
  Any2421
  Grade 3/421
Alopecia
  Any7542
  Grade 3<10
Asthenia
  Any7475
  All severe or life-threatening events1214
Nail Disorder
  Any14<1
  All severe events <10
Myalgia
  Any18 12
  All severe events <1<1

Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2.0%) in the vinorelbine+cisplatin arm.

The second comparison in the study, vinorelbine+cisplatin versus docetaxel+carboplatin (which did not demonstrate a superior survival associated with docetaxel, [see Clinical Studies (14.3)]) 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/m2 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)
Docetaxel 75 mg/m2 every 3 weeks + prednisone 5 mg twice daily
n=332
%
Mitoxantrone 12 mg/m2 every 3 weeks + prednisone 5 mg twice daily
n=335
%
Adverse Reaction AnyGrade 3/4Any Grade 3/4
*
Related to treatment
Anemia 67 5582
Neutropenia41324822
Thrombocytopenia3181
Febrile Neutropenia 3N/A 2N/A
Infection 32 6 20 4
Epistaxis 6 0 2 0
Allergic Reactions 8110
Fluid Retention*24150
Weight Gain*8030
Peripheral Edema*18020
Neuropathy Sensory 30270
Neuropathy Motor 723 1
Rash/Desquamation 6031
Alopecia 65 N/A13N/A
Nail Changes 30 080
Nausea41336 2
Diarrhea 322 101
Stomatitis/Pharyngitis 20 18 0
Taste Disturbance 18 0 7 0
Vomiting172142
Anorexia 171 14 0
Cough 12080
Dyspnea15 3 91
Cardiac left ventricular function 10022 1
Fatigue 535355
Myalgia 150 131
Tearing 1012 0
Arthralgia8 151

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 Injection 75 mg/m2 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
Docetaxel Injection 75 mg/m2 + cisplatin 75 mg/m2 + fluorouracil 750 mg/m2
n=221
Cisplatin 100 mg/m2 + fluorouracil 1000 mg/m2
n=224
Adverse Reaction Any %Grade 3/4 %Any %Grade 3/4 %
Clinically important treatment-emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.
*
Related to treatment
Anemia 97 189326
Neutropenia96 82 83 57
Fever in the absence of infection 36 2 23 1
Thrombocytopenia26 8 39 14
Infection 29162310
Febrile neutropenia16N/A5N/A
Neutropenic infection16N/A10 N/A
Allergic reactions 10 260
Fluid retention*15040
Edema*13030
Lethargy 63215818
Neurosensory38825 3
Neuromotor 9383
Dizziness16 582
Alopecia 67 541 1
Rash/itch12 190
Nail changes 8 000
Skin desquamation 2000
Nausea 73167619
Vomiting671573 19
Anorexia 51 135412
Stomatitis59 216127
Diarrhea 78 20 50 8
Constipation 252343
Esophagitis/dysphagia/ odynophagia162 145
Gastrointestinal pain/cramping 112 7 3
Cardiac dysrhythmias 5 2 21
Myocardial ischemia1 0 3 2
Tearing 802 0
Altered hearing 6 0 132

Head and Neck Cancer

Combination Therapy with Docetaxel Injection in Head and Neck Cancer

Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with Docetaxel Injection 75 mg/m2 in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients). The treatment regimens are described in Section 14.6.

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)
TAX323 (n=355)TAX324 (n=494)
Docetaxel Injection arm
(n=174)
Comparator arm
(n=181)
Docetaxel Injection arm
(n=251)
Comparator arm (n=243)
Adverse Reaction (by Body System) Any
%
Grade 3/4
%
Any
%
Grade 3/4
%
Any
%
Grade 3/4
%
Any
%
Grade 3/4
%
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
Neutropenia 9376875395848456
Anemia 899881490128610
Thrombocytopenia 24547182843111
Infection 279268236285
Febrile neutropenia*5N/A2N/A12N/A7N/A
Neutropenic infection 14N/A8N/A12N/A8N/A
Cancer pain 2151631792011
Lethargy 4133836155610
Fever in the absence of infection 321370304283
Myalgia 101707072
Weight loss 211271142142
Allergy 60302000
Fluid retention20014113172
Edema only1307012161
Weight gain only 60600010
Dizziness 2051164152
Neurosensory181111141140
Altered hearing 60103131193
Neuromotor 214190102
Alopecia 8111430684441
Rash/itch 12060200161
Dry skin60205030
Desquamation 41602050
Nausea 47151777148014
Stomatitis434471166216827
Vomiting 2613955686310
Diarrhea 333244487403
Constipation 171161271381
Anorexia 16125340123412
Esophagitis/dysphagia/ Odynophagia 13118325132610
Taste, sense of smell altered 10050200171
Gastrointestinal pain/cramping 8191155102
Heartburn6060132131
Gastrointestinal bleeding42005121
Cardiac dysrhythmia22216353
Venous32624254
Ischemia myocardial22102111
Tearing20102020
Conjunctivitis 1010100.40

6.2 Postmarketing Experience

The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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, in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide may be associated with fatal outcome.

Cutaneous: cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis, scleroderma-like changes (usually preceded by peripheral lymphedema), severe palmar-plantar erythrodysesthesia, and permanent alopecia.

Gastrointestinal: enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, which may be fatal. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence of gastrointestinal events.

Hearing: ototoxicity, hearing disorders and/or hearing loss, including during use with other ototoxic drugs.

Hematologic: bleeding episodes, disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure.

Hepatic: hepatitis, sometimes fatal, primarily in patients with pre-existing liver disorders.

Hypersensitivity: anaphylactic shock with fatal outcome in patients who received premedication. Severe hypersensitivity reactions with fatal outcome with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Metabolism and Nutrition Disorders: electrolyte imbalance, including hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia. Tumor lysis syndrome, sometimes fatal.

Neurologic: confusion, seizures or transient loss of consciousness, sometimes appearing during the infusion of the drug.

Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis, cystoid macular edema (CME). Excessive tearing which may be attributable to lacrimal duct obstruction. Transient visual disturbances (flashes, flashing lights, scotomata), typically occurring during drug infusion and reversible upon discontinuation of the infusion, in association with hypersensitivity reactions.

Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis, which may be fatal. Radiation pneumonitis in patients receiving concomitant radiotherapy.

Renal: renal insufficiency and renal failure, the majority of cases were associated with concomitant nephrotoxic drugs.

Second Primary Malignancies: second primary malignancies, including AML, MDS, NHL, and renal cancer [see Warnings and Precautions (5.7)].

Musculoskeletal Disorder: myositis.

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