ADVERSE REACTIONS

The most serious adverse reactions from Docetaxel Injection 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)]

The most common adverse reactions across all Docetaxel Injection 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 Injection for locally advanced or metastatic breast cancer after failure of prior chemotherapy

Docetaxel Injection 100 mg/m ²: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received Docetaxel Injection 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 Injection. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving Docetaxel Injection 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 Injection at 100 mg/m ²

A dverse Reaction	A l l Tumor Types Normal LFTs• n=2045 %	A l l Tumor Types Elevated LFTs•• n=61 %	B reast Cancer Normal LFTs• n=965 %
H e m atologic Neutropenia <2000 cells/mm ³ <500 cells/mm ³ Leukopenia <4000 cells/mm ³ <1000 cells/mm ³ Thrombocytopenia <100,000 cells/mm ³ Anemia <11 g/dL <8 g/dL Febrile Neutropenia•••	96 75 96 32 8 90 9 11	96 88 98 47 25 92 31 26	99 86 99 44 9 94 8 12
Septic Death N on-Septic Death	2 1	5 7	1 1
Infections Any Severe	22 6	33 16	22 6
F ever in Absence of Infection Any Severe	31 2	41 8	35 2
H ypersensitivity 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
N eurosensory Any Severe	49 4	34 0	58 6
C utaneous Any Severe	48 5	54 10	47 5
N ail Changes Any Severe	31 3	23 5	41 4
G astrointestinal 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
A l opecia	76	62	74
A st henia Any Severe	62 13	53 25	66 15
Myalgia Any Severe	19 2	16 2	21 2
A rthralgia	9	7	8
I n f usion Site Reactions	4	3	4

A dverse Reaction

A l l Tumor Types Normal LFTs•

n=2045

A l l Tumor Types Elevated LFTs••

n=61

B reast Cancer Normal LFTs•

n=965

H e m atologic

Neutropenia

<2000 cells/mm ³

<500 cells/mm ³

Leukopenia

<4000 cells/mm ³

<1000 cells/mm ³

Thrombocytopenia

<100,000 cells/mm ³

Anemia

<11 g/dL

<8 g/dL

Febrile Neutropenia•••

Septic Death

N on-Septic Death

Infections

Any

Severe

F ever in Absence of Infection

Any

Severe

H ypersensitivity Reactions

Regardless of Premedication

Any

Severe

With 3-day Premedication

Any

Severe

n=92

n=3

n=92

Fluid Retention

Regardless of Premedication

Any

Severe

With 3-day Premedication

Any

Severe

n=92

n=3

n=92

N eurosensory

Any

Severe

C utaneous

Any

Severe

N ail Changes

Any

Severe

G astrointestinal

Nausea

Vomiting

Diarrhea

Severe

Stomatitis

Any

Severe

A l opecia

A st henia

Any

Severe

Myalgia

Any

Severe

A rthralgia

I n f usion Site Reactions

•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 reactions

Reversible marrow suppression was the major dose-limiting toxicity of Docetaxel Injection [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/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/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 Injection [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 Injection 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 Injection 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 Injection, 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 Injection 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 Injection 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 Injection 100 mg/m ²with Normal or Elevated Liver Function Tests or 60 mg/m ²with Normal Liver Function Tests

A dverse Reaction

Docetaxel Injection

100 mg/m ²

Docetaxel Injection

60 mg/m ²

N ormal

L F T s •

n=730

E l evated

L F T s ••

n=18

N ormal

L F T s •

n=174

N eutropenia

Any <2000 cells/mm ³

Grade 4 <500 cells/mm ³

100

T hrombocytopenia

Any <100,000 cells/mm ³

Grade 4 <20,000 cells/mm ³

A nemia <11 g/dL

I n f ection•••

Any

Grade 3 and 4

F ebrile Neutropenia ••••

By Patient

By Course

Septic Death

N on-Septic Death

•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/m2, ANC grade 3/4 and fever >38.1°C

Table 5: Non-hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel Injection100 mg/m ²with Normal or Elevated Liver Function Tests or 60 mg/m ²with Normal Liver Function Tests

A dverse Reaction	Docetaxel Injection 100 mg/m ²	Docetaxel Injection 60 mg/m ²
A cute Hypersensitivity Reaction Regardless of Premedication Any Severe	13 1	6 0	1 0
Fluid Retention ••• R egardless of Premedication Any Severe	56 8	61 17	13 0
N eurosensory Any Severe	57 6	50 0	20 0
Myalgia	23	33	3
C utaneous Any Severe	45 5	61 17	31 0
A st henia Any Severe	65 17	44 22	66 0
D i arrhea Any Severe	42 6	28 11	NA
Stomatitis Any Severe	53 8	67 39	19 1

A dverse Reaction

Docetaxel Injection

100 mg/m ²

Docetaxel Injection 60 mg/m ²

N ormal

L F T s •

n=730

E l evated

L F T s ••

n=18

N ormal

L F T s •

n=174

A cute Hypersensitivity Reaction Regardless of Premedication

Any

Severe

Fluid Retention •••

R egardless of Premedication

Any

Severe

N eurosensory

Any

Severe

Myalgia

C utaneous

Any

Severe

A st henia

Any

Severe

D i arrhea

Any

Severe

Stomatitis

Any

Severe

•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

In the three-arm monotherapy trial, TAX313, which compared Docetaxel Injection 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 Injection 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 Injection in the adjuvant treatment of breast cancer

The following table presents treatment-emergent adverse reactions observed in 744 patients, who were treated with Docetaxel Injection 75 mg/m ²every 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 DocetaxelInjection in Combination with Doxorubicin and Cyclophosphamide (TAX316).

Docetaxel Injection 75 mg/m ² + D oxorubicin 50 mg/m ² + Cyclophosphamide 500 mg/m ² ( TAC) n=744 %		F l uorouracil 500 mg/m ² + D oxorubicin 50 mg/m ² + Cyclophosphamide 500 mg/m ² ( F AC) n=736 %
A dverse Reaction	A ny	G rade 3/4	A ny	G rade 3/4
A nemia	92	4	72	2
N eutropenia	71	66	82	49
F ever in absence of infection	47	1	17	0
Infection	39	4	36	2
T hrombocytopenia	39	2	28	1
F ebrile neutropenia	25	N/A	3	N/A
N eutropenic infection	12	N/A	6	N/A
H ypersensitivity reactions	13	1	4	0
L ymphedema	4	0	1	0
Fluid Retention• Peripheral edema Weight gain	35 27 13	1 0 0	15 7 9	0 0 0
N europathy sensory	26	0	10	0
N euro-cortical	5	1	6	1
N europathy motor	4	0	2	0
N euro-cerebellar	2	0	2	0
Syncope	2	1	1	0
A l opecia	98	N/A	97	N/A
Skin toxicity	27	1	18	0
N ail disorders	19	0	14	0
N ausea	81	5	88	10
Stomatitis	69	7	53	2
V omiting	45	4	59	7
D i arrhea	35	4	28	2
C onstipation	34	1	32	1
T aste perversion	28	1	15	0
A norexia	22	2	18	1
A bdominal Pain	11	1	5	0
A m enorrhea	62	N/A	52	N/A
C ough	14	0	10	0
C ardiac dysrhythmias	8	0	6	0
V asodilatation	27	1	21	1
H ypotension	2	0	1	0
P h l ebitis	1	0	1	0
A sthenia	81	11	71	6
Myalgia	27	1	10	0
A rthralgia	19	1	9	0
L acrimation disorder	11	0	7	0
C onjunctivitis	5	0	7	0

• COSTART term and grading system for events related to treatment.

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.

S kin 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%).

A cute 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 Injection for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy

Docetaxel Injection 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.

Table 7: Treatment-Emergent Adverse Reactions Regardless of Relationship toTreatment in Patients Receiving Docetaxel Injection as Monotherapy for Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy•

A dverse Reaction	Docetaxel Injection 75 mg/m ² n=176 %	B est Supportive C are n=49 %	V i norelbine/ Ifosfamide n=119 %
N eutropenia Any Grade 3/4	84 65	14 12	83 57
L eukopenia Any Grade 3/4	84 49	6 0	89 43
T hrombocytopenia Any Grade 3/4	8 3	0 0	8 2
A nemia Any Grade 3/4	91 9	55 12	91 14
F ebrile N eutropenia••	6	NA†	1
Infection Any Grade 3/4	34 10	29 6	30 9
T reatment Related Mortality	3	NA†	3
H ypersensitivity Reactions Any Grade 3/4	6 3	0 0	1 0
F l uid Retention Any Severe	34 3	ND††	23 3
N eurosensory Any Grade 3/4	23 2	14 6	29 5
N euromotor Any Grade 3/4	16 5	8 6	10 3
Skin Any Grade 3/4	20 1	6 2	17 1
G astrointestinal 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
A l opecia	56	35	50
A st henia Any Severe•••	53 18	57 39	54 23
Stomatitis Any Grade 3/4	26 2	6 0	8 1
P u lm onary Any Grade 3/4	41 21	49 29	45 19
N ail Disorder Any Severe•••	11 1	0 0	2 0
Myalgia Any Severe•••	6 0	0 0	3 0
A rthralgia Any Severe•••	3 0	2 0	2 1
T aste Perversion Any Severe•••	6 1	0 0	0 0

A dverse Reaction

Docetaxel Injection 75 mg/m ²

n=176

B est Supportive C are n=49

V i norelbine/ Ifosfamide

n=119

N eutropenia

Any

Grade 3/4

L eukopenia

Any

Grade 3/4

T hrombocytopenia

Any

Grade 3/4

A nemia

Any

Grade 3/4

F ebrile N eutropenia••

NA†

Infection

Any

Grade 3/4

T reatment Related Mortality

NA†

H ypersensitivity Reactions

Any

Grade 3/4

F l uid Retention

Any

Severe

ND††

N eurosensory

Any

Grade 3/4

N euromotor

Any

Grade 3/4

Skin

Any

Grade 3/4

G astrointestinal

Nausea

Any

Grade 3/4

Vomiting

Any

Grade 3/4

Diarrhea

Any

Grade 3/4

A l opecia

A st henia

Any

Severe•••

Stomatitis

Any

Grade 3/4

P u lm onary

Any

Grade 3/4

N ail Disorder

Any

Severe•••

Myalgia

Any

Severe•••

A rthralgia

Any

Severe•••

T aste Perversion

Any

Severe•••

•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

Combination therapy with Docetaxel Injection 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- Naive Advanced Non-small Cell Lung Cancer Patients Receiving Docetaxel Injection in Combination with Cisplatin

A dverse Reaction	Docetaxel Injection 75 mg/m ² + Cisplatin 75 mg/m ² n=406 %	V i norelbine 25 mg/m ² + Cisplatin 100 mg/m ² n=396 %
N eutropenia Any Grade 3/4	91 74	90 78
F ebrile Neutropenia	5	5
T hrombocytopenia Any Grade 3/4	15 3	15 4
A nemia Any Grade 3/4	89 7	94 25
Infection Any Grade 3/4	35 8	37 8
F ever in absence of infection Any Grade 3/4	33 <1	29 1
H ypersensitivity 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
N eurosensory Any Grade 3/4	47 4	42 4
N euromotor Any Grade 3/4	19 3	17 6
Skin Any Grade 3/4	16 <1	14 1
N ausea Any Grade 3/4	72 10	76 17
V omiting Any Grade 3/4	55 8	61 16
D i arrhea Any Grade 3/4	47 7	25 3
A norexia•• Any All severe or life-threatening events	42 5	40 5
Stomatitis Any Grade 3/4	24 2	21 1
A l opecia Any Grade 3	75 <1	42 0
A st henia•• Any All severe or life-threatening events	74 12	75 14
N ail Disorder•• Any All severe events	14 <1	<1 0
Myalgia•• Any All severe events	18 <1	12 <1

A dverse Reaction

Docetaxel Injection 75 mg/m ² + Cisplatin

75 mg/m ²

n=406

V i norelbine 25 mg/m ² + Cisplatin

100 mg/m ²

n=396

N eutropenia

Any

Grade 3/4

F ebrile Neutropenia

T hrombocytopenia

Any

Grade 3/4

A nemia

Any

Grade 3/4

Infection

Any

Grade 3/4

F ever in absence of infection

Any

Grade 3/4

H ypersensitivity Reaction•

Any

Grade 3/4

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

N eurosensory

Any

Grade 3/4

N euromotor

Any

Grade 3/4

Skin

Any

Grade 3/4

N ausea

Any

Grade 3/4

V omiting

Any

Grade 3/4

D i arrhea

Any

Grade 3/4

A norexia••

Any

All severe or life-threatening events

Stomatitis

Any

Grade 3/4

A l opecia

Any

Grade 3

A st henia••

Any

All severe or life-threatening events

N ail Disorder••

Any

All severe events

Myalgia••

Any

All severe events

• Replaces NCI term “Allergy”

•• COSTART term and grading system

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 Injection +carboplatin (which did not demonstrate a superior survival associated with Docetaxel Injection [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 Injection +carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm.

P r o state Cancer

Combination therapy with Docetaxel Injection in patients with prostate cancer

The following data are based on the experience of 332 patients, who were treated with Docetaxel Injection 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 Injection in Combination with Prednisone (TAX327)

Docetaxel Injection 75 mg/m ² every 3 w eeks + prednisone 5 mg twice daily n=332 %		Mitoxantrone 12 mg/m ² e very 3 weeks + prednisone 5 mg twice daily n=335 %
A dverse Reaction	A ny	G rade 3/4	A ny	G rade 3/4
A nemia	67	5	58	2
N eutropenia	41	32	48	22
T hrombocytopenia	3	1	8	1
F ebrile neutropenia	3	N/A	2	N/A
Infection	32	6	20	4
E pistaxis	6	0	2	0
A ll ergic Reactions	8	1	1	0
Fluid Retention• Weight Gain• Peripheral Edema •	24 8 18	1 0 0	5 3 2	0 0 0
N europathy Sensory	30	2	7	0
N europathy Motor	7	2	3	1
R ash/Desquamation	6	0	3	1
A l opecia	65	N/A	13	N/A
N ail Changes	30	0	8	0
N ausea	41	3	36	2
D i arrhea	32	2	10	1
Stomatitis/Pharyngitis	20	1	8	0
T aste Disturbance	18	0	7	0
V omiting	17	2	14	2
A norexia	17	1	14	0
C ough	12	0	8	0
D yspnea	15	3	9	1
C ardiac left ventricular function	10	0	22	1
F a ti gue	53	5	35	5
Myalgia	15	0	13	1
T earing	10	1	2	0
A rthralgia	8	1	5	1

•Related to treatment

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 ofRelationship to Treatment in the Gastric Cancer Study

Docetaxel Injection 75 mg/m ² + cisplatin 75 mg/m ² + fl uorouracil 750 mg/m ² n=221		C is platin 100 mg/m ² + fl uorouracil 1000 mg/m ² n=224
A dverse Reaction	A ny %	G rade 3/4 %	A ny %	G rade 3/4 %
A nemia	97	18	93	26
N eutropenia	96	82	83	57
F ever in the absence of infection	36	2	23	1
T hrombocytopenia	26	8	39	14
Infection	29	16	23	10
F ebrile neutropenia	16	N/A	5	N/A
N eutropenic infection	16	N/A	10	N/A
A ll ergic reactions	10	2	6	0
Fluid retention•	15	0	4	0
E dema•	13	0	3	0
L ethargy	63	21	58	18
N eurosensory	38	8	25	3
N euromotor	9	3	8	3
D i zz i ness	16	5	8	2
A l opecia	67	5	41	1
R ash/itch	12	1	9	0
N ail changes	8	0	0	0
Skin desquamation	2	0	0	0
N ausea	73	16	76	19
V omiting	67	15	73	19
A norexia	51	13	54	12
Stomatitis	59	21	61	27
D i arrhea	78	20	50	8
C onstipation	25	2	34	3
E s ophagitis/dysphagia/odynophagia	16	2	14	5
G astrointestinal pain/cramping	11	2	7	3
C ardiac dysrhythmias	5	2	2	1
Myocardial ischemia	1	0	3	2
T earing	8	0	2	0
A lt ered hearing	6	0	13	2

Clinically important treatment-emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.

•Related to treatment

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)

TAX 323 ( n=355)				TAX 324 ( n=494)
Docetaxel arm (n=174)		C omparator arm (n=181)		Docetaxel arm (n=251)		C omparator arm (n=243)
A dverse Reaction (by Body System)	A ny %	G rade3/4 %	A ny %	G rade 3/4 %	A ny %	G rade 3/4 %	A ny %	G rade 3/4 %
N eutropenia	93	76	87	53	95	84	84	56
A nemia	89	9	88	14	90	12	86	10
T hrombocytopenia	24	5	47	18	28	4	31	11
Infection	27	9	26	8	23	6	28	5
F ebrile neutropenia•	5	N/A	2	N/A	12	N/A	7	N/A
N eutropenic infection	14	N/A	8	N/A	12	N/A	8	N/A
C ancer pain	21	5	16	3	17	9	20	11
L ethargy	41	3	38	3	61	5	56	10
F ever 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
A ll ergy	6	0	3	0	2	0	0	0
Fluid retention•• E dema 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
D i zz i ness	2	0	5	1	16	4	15	2
N eurosensory	18	1	11	1	14	1	14	0
A lt ered hearing	6	0	10	3	13	1	19	3
N euromotor	2	1	4	1	9	0	10	2
A l opecia	81	11	43	0	68	4	44	1
R ash/itch	12	0	6	0	20	0	16	1
D ry skin	6	0	2	0	5	0	3	0
D esquamation	4	1	6	0	2	0	5	0
N ausea	47	1	51	7	77	14	80	14
Stomatitis	43	4	47	11	66	21	68	27
V omiting	26	1	39	5	56	8	63	10
D i arrhea	33	3	24	4	48	7	40	3
C onstipation	17	1	16	1	27	1	38	1
A norexia	16	1	25	3	40	12	34	12
E s ophagitis/dysphagia/ Odynophagia	13	1	18	3	25	13	26	10
T aste, sense of smell altered	10	0	5	0	20	0	17	1
G astrointestinal pain/cramping	8	1	9	1	15	5	10	2
H eartburn	6	0	6	0	13	2	13	1
G astrointestinal bleeding	4	2	0	0	5	1	2	1
C ardiac dysrhythmia	2	2	2	1	6	3	5	3
V enous•••	3	2	6	2	4	2	5	4
I schemia myocardial	2	2	1	0	2	1	1	1
T earing	2	0	1	0	2	0	2	0
C onjunctivitis	1	0	1	0	1	0	0.4	0

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

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.

B ody 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.

G astrointestinal : 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.

Met abolism 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.

S ec ond primary malignancies : second primary malignancies, including AML, MDS, NHL, and renal cancer [see Warnings and Precautions (5.7)].

M u sculoskeletal disorder : myositis.

Antidote Health Coverage for Docetaxel - Docetaxel injection

Health Exchange - HMO - Health Insurance Exchange