ADVERSE REACTIONS

The most serious adverse reactions from BEIZRAY are:

Toxic Deaths [see Boxed Warning, Warnings and Precautions (5.1 )]
Hepatic Impairment [see Boxed Warning, Warnings and Precautions (5.2 )]
Hematologic Effects [see Boxed Warning, Warnings and Precautions (5.3 )]
Enterocolitis and Neutropenic Colitis [see Warnings and Precautions (5.4 )]
Hypersensitivity Reactions [see Boxed Warning, Warnings and Precautions (5.5 )]
Fluid Retention [see Boxed Warning, Warnings and Precautions (5.6 )]
Second Primary Malignancies [see Warnings and Precautions (5.7 )]
Cutaneous Reactions [see Warnings and Precautions (5.8 )]
Neurologic Reactions [see Warnings and Precautions (5.9 )]
Eye Disorders [see Warnings and Precautions (5.10 )]
Asthenia [see Warnings and Precautions (5.11 )]
Alcohol Content [see Warnings and Precautions (5.13 )]
Tumor Lysis Syndrome [see Warnings and Precautions (5.14 )]

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.

Clinical Trials Experience

Breast Cancer

Monotherapy with docetaxel for locally advanced or metastatic breast cancer after failure of prior chemotherapy

Docetaxel 100 mg/m ²: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m ²as 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 4 .)

Table 4: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m ²
• Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN.
•• Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN.
••• Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization.
Adverse Reaction	All Tumor Types Normal LFTs • n=2045 %	All Tumor Types Elevated LFTs•• n=61 %	Breast Cancer Normal LFTs• n=965 %
Hematologic
Neutropenia
<2000 cells/mm ³	96	96	99
<500 cells/mm ³	75	88	86
Leukopenia
<4000 cells/mm ³	96	98	99
<1000 cells/mm ³	32	47	44
Thrombocytopenia
<100,000 cells/mm ³	8	25	9
Anemia
<11 g/dL	90	92	94
<8 g/dL	9	31	8
Febrile Neutropenia•••	11	26	12
Septic Death Non-Septic Death	2 1	5 7	1 1
Infections Any Severe	22 6	33 16	22 6
Fever in Absence of Infection Any Severe	31 2	41 8	35 2
Hypersensitivity Reactions Regardless of Premedication Any Severe With 3-day Premedication Any Severe	21 4 n=92 15 2	20 10 n=3 33 0	18 3 n=92 15 2
Fluid Retention Regardless of Premedication Any Severe With 3-day Premedication Any Severe	47 7 n=92 64 7	39 8 n=3 67 33	60 9 n=92 64 7
Neurosensory Any Severe	49 4	34 0	58 6
Cutaneous Any Severe	48 5	54 10	47 5
Nail Changes Any Severe	31 3	23 5	41 4
Gastrointestinal Nausea Vomiting Diarrhea Severe	39 22 39 5	38 23 33 5	42 23 43 6
Stomatitis Any Severe	42 6	49 13	52 7
Alopecia	76	62	74
Asthenia Any Severe	62 13	53 25	66 15
Myalgia Any Severe	19 2	16 2	21 2
Arthralgia	9	7	8
Infusion Site Reactions	4	3	4

Hematologic reactions
Reversible marrow suppression was the major dose-limiting toxicity of docetaxel [see Warnings and Precautions (5.3 )] . The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm ³) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles.

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

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

Thrombocytopenia (<100,000 cells/mm ³) associated with fatal gastrointestinal hemorrhage has been reported.

Hypersensitivity reactions
Severe hypersensitivity reactions have been reported [see Boxed Warning, Warnings and Precautions (5.5 )] . 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/m ²in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by 10% associated with a drop below the institutional lower limit of normal.

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

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

Hematologic and other toxicity: Relation to dose and baseline liver chemistry abnormalities
Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m ²in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN); and 174 patients in Japanese studies given docetaxel at 60 mg/m ²who had normal LFTs (see Tables 5 and 6 ).

Table 5: Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m ²with Normal or Elevated Liver Function Tests or 60 mg/m ²with Normal Liver Function Tests
Adverse Reaction	Docetaxel 100 mg/m ²		Docetaxel 60 mg/m ²
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/m ², ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m ², ANC grade 3/4 and fever >38.1°C.
Neutropenia Any <2000 cells/mm ³ Grade 4 <500 cells/mm ³	98 84	100 94	95 75
Thrombocytopenia Any <100,000 cells/mm ³ Grade 4 <20,000 cells/mm ³	11 1	44 17	14 1
Anemia <11 g/dL	95	94	65
Infection••• Any Grade 3 and 4	23 7	39 33	1 0
Febrile Neutropenia•••• By Patient By Course	12 2	33 9	0 0
Septic Death	2	6	1
Non-Septic Death	1	11	0

Table 6: Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m ²with Normal or Elevated Liver Function Tests or 60 mg/m ²with Normal Liver Function Tests
Adverse Reaction	Docetaxel 100 mg/m ²		Docetaxel 60 mg/m ²
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 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/m ²dose.
NA = not available
Acute Hypersensitivity Reaction Regardless of Premedication Any Severe	13 1	6 0	1 0
Fluid Retention••• Regardless of Premedication Any Severe	56 8	61 17	13 0
Neurosensory Any Severe	57 6	50 0	20 0
Myalgia	23	33	3
Cutaneous Any Severe	45 5	61 17	31 0
Asthenia Any Severe	65 17	44 22	66 0
Diarrhea Any Severe	42 6	28 11	NA
Stomatitis Any Severe	53 8	67 39	19 1

In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m ², 75 mg/m ²and 100 mg/m ²in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with docetaxel 60 mg/m ²compared to 55.3% and 65.9% treated with 75 mg/m ²and 100 mg/m ², respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m ²versus 6.9% and 16.5% for patients treated at 75 and 100 mg/m ², respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m ²compared to 5.3% and 1.6% for patients treated at 75 mg/m ²and 100 mg/m ², respectively.

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

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 ²every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 7 ).

Table 7: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316)
Docetaxel 75 mg/m ² + Doxorubicin 50 mg/m ² + Cyclophosphamide 500 mg/m ² (TAC) n=744 %		Fluorouracil 500 mg/m ² + Doxorubicin 50 mg/m ² + Cyclophosphamide 500 mg/m ² (FAC) n=736 %
• COSTART term and grading system for events related to treatment.
Adverse Reaction	Any	Grade 3/4	Any	Grade 3/4
Anemia	92	4	72	2
Neutropenia	71	66	82	49
Fever in absence of infection	47	1	17	0
Infection	39	4	36	2
Thrombocytopenia	39	2	28	1
Febrile neutropenia	25	N/A	3	N/A
Neutropenic infection	12	N/A	6	N/A
Hypersensitivity reactions	13	1	4	0
Lymphedema	4	0	1	0
Fluid Retention• Peripheral edema Weight gain	35 27 13	1 0 0	15 7 9	0 0 0
Neuropathy sensory	26	0	10	0
Neuro-cortical	5	1	6	1
Neuropathy motor	4	0	2	0
Neuro-cerebellar	2	0	2	0
Syncope	2	1	1	0
Alopecia	98	N/A	97	N/A
Skin toxicity	27	1	18	0
Nail disorders	19	0	14	0
Nausea	81	5	88	10
Stomatitis	69	7	53	2
Vomiting	45	4	59	7
Diarrhea	35	4	28	2
Constipation	34	1	32	1
Taste perversion	28	1	15	0
Anorexia	22	2	18	1
Abdominal Pain	11	1	5	0
Amenorrhea	62	N/A	52	N/A
Cough	14	0	10	0
Cardiac dysrhythmias	8	0	6	0
Vasodilatation	27	1	21	1
Hypotension	2	0	1	0
Phlebitis	1	0	1	0
Asthenia	81	11	71	6
Myalgia	27	1	10	0
Arthralgia	19	1	9	0
Lacrimation disorder	11	0	7	0
Conjunctivitis	5	0	7	0

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 followup 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 TACtreated 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/m ²: Treatment-emergent adverse drug reactions are shown in Table 8 . 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 8: 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/m ² 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.
••• COSTART term and grading system
^†Not Applicable
^††Not Done
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	20 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	3 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 9 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 9: Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naïve Advanced Non-small Cell Lung Cancer Patients Receiving Docetaxel in Combination with Cisplatin
Adverse Reaction	Docetaxel 75 mg/m ² + Cisplatin 75 mg/m ² n=406 %	Vinorelbine 25 mg/m ² + Cisplatin 100 mg/m ² n=396 %
• Replaces NCI term “Allergy”
•• COSTART term and grading system
Neutropenia Any Grade 3/4	91 74	90 78
Febrile Neutropenia	5	5
Thrombocytopenia Any Grade 3/4	15 3	15 4
Anemia Any Grade 3/4	89 7	94 25
Infection Any Grade 3/4	35 8	37 8
Fever in absence of infection Any Grade 3/4	33 <1	29 1
Hypersensitivity Reaction• Any Grade 3/4	12 3	4 <1
Fluid Retention •• Any All severe or life-threatening events Pleural effusion Any All severe or life-threatening events Peripheral edema Any All severe or life-threatening events Weight gain Any All severe or life-threatening events	54 2 23 2 34 <1 15 <1	42 2 22 2 18 <1 9 <1
Neurosensory Any Grade 3/4	47 4	42 4
Neuromotor Any Grade 3/4	19 3	17 6
Skin Any Grade 3/4	16 <1	14 1
Nausea Any Grade 3/4	72 10	76 17
Vomiting Any Grade 3/4	55 8	61 16
Diarrhea Any Grade 3/4	47 7	25 3
Anorexia•• Any All severe or life-threatening events	42 5	40 5
Stomatitis Any Grade 3/4	24 2	21 1
Alopecia Any Grade 3	75 <1	42 0
Asthenia •• Any All severe or life-threatening events	74 12	75 14
Nail Disorder •• Any All severe events	14 <1	<1 0
Myalgia •• Any All severe events	18 <1	12 <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/m ²every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 10 ).

Table 10: 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/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 %
• Related to treatment
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• Weight Gain• Peripheral Edema•	24 8 18	1 0 0	5 3 2	0 0 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 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 ²in combination with cisplatin and fluorouracil (see Table 11 ).

Table 11: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study
Docetaxel Injection 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
Clinically important treatment-emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.
• Related to treatment.
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 12 summarizes the safety data obtained from patients that received induction chemotherapy with docetaxel 75 mg/m ²in 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 12: 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)
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
Adverse Reaction (by Body System)	Any %	Grade 3/4 %	Any %	Grade 3/4 %	Any %	Grade 3/4 %	Any %	Grade 3/4 %
Neutropenia	93	76	87	53	95	84	84	56
Anemia	89	9	88	14	90	12	86	10
Thrombocytopenia	24	5	47	18	28	4	31	11
Infection	27	9	26	8	23	6	28	5
Febrile neutropenia•	5	N/A	2	N/A	12	N/A	7	N/A
Neutropenic infection	14	N/A	8	N/A	12	N/A	8	N/A
Cancer pain	21	5	16	3	17	9	20	11
Lethargy	41	3	38	3	61	5	56	10
Fever in the absence of infection	32	1	37	0	30	4	28	3
Myalgia	10	1	7	0	7	0	7	2
Weight loss	21	1	27	1	14	2	14	2
Allergy	6	0	3	0	2	0	0	0
Fluid retention•• Edema only Weight gain only	20 13 6	0 0 0	14 7 6	1 0 0	13 12 0	1 1 0	7 6 1	2 1 0
Dizziness	2	0	5	1	16	4	15	2
Neurosensory	18	1	11	1	14	1	14	0
Altered hearing	6	0	10	3	13	1	19	3
Neuromotor	2	1	4	1	9	0	10	2
Alopecia	81	11	43	0	68	4	44	1
Rash/itch	12	0	6	0	20	0	16	1
Dry skin	6	0	2	0	5	0	3	0
Desquamation	4	1	6	0	2	0	5	0
Nausea	47	1	51	7	77	14	80	14
Stomatitis	43	4	47	11	66	21	68	27
Vomiting	26	1	39	5	56	8	63	10
Diarrhea	33	3	24	4	48	7	40	3
Constipation	17	1	16	1	27	1	38	1
Anorexia	16	1	25	3	40	12	34	12
Esophagitis/dysphagia/ Odynophagia	13	1	18	3	25	13	26	10
Taste , sense of smell altered	10	0	5	0	20	0	17	1
Gastrointestinal pain/cramping	8	1	9	1	15	5	10	2
Heartburn	6	0	6	0	13	2	13	1
Gastrointestinal bleeding	4	2	0	0	5	1	2	1
Cardiac dysrhythmia	2	2	2	1	6	3	5	3
Venous •••	3	2	6	2	4	2	5	4
Ischemia myocardial	2	2	1	0	2	1	1	1
Tearing	2	0	1	0	2	0	2	0
Conjunctivitis	1	0	1	0	1	0	0.4	0

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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