docetaxel injection, USP 10 mg/ml VIAL 6 ADVERSE REACTIONS

Prescribing Information

6 ADVERSE REACTIONS

The most serious adverse reactions from docetaxel 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 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
* 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/mm3	96	96	99
<500 cells/mm3	75	88	86
Leukopenia
<4000 cells/mm3	96	98	99
<1000 cells/mm3	32	47	44
Thrombocytopenia
<100,000 cells/mm3	8	25	9
Anemia
<11 g/dL	90	92	94
<8 g/dL	9	31	8
Febrile Neutropenia‡	11	26	12
Septic Death	2	5	1
Non-Septic Death	1	7	1
Infections
Any	22	33	22
Severe	6	16	6
Fever in Absence of Infection
Any	31	41	35
Severe	2	8	2
Hypersensitivity Reactions
Regardless of Premedication
Any	21	20	18
Severe	4	10	3
With 3-day Premedication	n=92	n=3	n=92
Any	15	33	15
Severe	2	0	2
Fluid Retention
Regardless of Premedication
Any	47	39	60
Severe	7	8	9
With 3-day Premedication	n=92	n=3	n=92
Any	64	67	64
Severe	7	33	7
Neurosensory
Any	49	34	58
Severe	4	0	6
Cutaneous
Any	48	54	47
Severe	5	10	5
Nail Changes
Any	31	23	41
Severe	3	5	4
Gastrointestinal
Nausea	39	38	42
Vomiting	22	23	23
Diarrhea	39	33	43
Severe	5	5	6
Stomatitis
Any	42	49	52
Severe	6	13	7
Alopecia	76	62	74
Asthenia
Any	62	53	66
Severe	13	25	15
Myalgia
Any	19	16	21
Severe	2	2	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/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
* 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
Adverse Reaction	Docetaxel 100 mg/m2		Docetaxel 60 mg/m2
Adverse Reaction	Normal LFTs* n=730 %	Elevated LFTs† n=18 %	Normal LFTs* n=174 %
Neutropenia
Any <2000 cells/mm3	98	100	95
Grade 4 <500 cells/mm3	84	94	75
Thrombocytopenia
Any <100,000 cells/mm3	11	44	14
Grade 4 <20,000 cells/mm3	1	17	1
Anemia <11 g/dL	95	94	65
Infection‡
Any	23	39	1
Grade 3 and 4	7	33	0
Febrile Neutropenia§
By Patient	12	33	0
By Course	2	9	0
Septic Death	2	6	1
Non-Septic Death	1	11	0

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
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
	Docetaxel 100 mg/m2		Docetaxel 60 mg/m2
Adverse Reaction	Normal LFTs*	Elevated LFTs†	Normal LFTs*
Adverse Reaction	n=730	n=18	n=174
	%	%	%
Acute Hypersensitivity Reaction Regardless of Premedication
Any	13	6	1
Severe	1	0	0
Fluid Retention‡ Regardless of Premedication
Any	56	61	13
Severe	8	17	0
Neurosensory
Any	57	50	20
Severe	6	0	0
Myalgia	23	33	3
Cutaneous
Any	45	61	31
Severe	5	17	0
Asthenia
Any	65	44	66
Severe	17	22	0
Diarrhea
Any	42	28	NA
Severe	6	11
Stomatitis
Any	53	67	19
Severe	8	39	1

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)
* COSTART term and grading system for events related to treatment.
	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	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*	35	1	15	0
Peripheral edema	27	0	7	0
Weight gain	13	0	9	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 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*
* 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
Adverse Reaction	Docetaxel 75 mg/m2 n=176 %	Best Supportive Care n=49 %	Vinorelbine/Ifosfamide n=119 %
Neutropenia
Any	84	14	83
Grade 3/4	65	12	57
Leukopenia
Any	84	6	89
Grade 3/4	49	0	43
Thrombocytopenia
Any	8	0	8
Grade 3/4	3	0	2
Anemia
Any	91	55	91
Grade 3/4	9	12	14
Febrile Neutropenia†	6	NA‡	1
Infection
Any	34	29	30
Grade 3/4	10	6	9
Treatment Related Mortality	3	NA‡	3
Hypersensitivity Reactions
Any	6	0	1
Grade 3/4	3	0	0
Fluid Retention
Any	34	ND§	23
Severe	3		3
Neurosensory
Any	23	14	29
Grade 3/4	2	6	5
Neuromotor
Any	16	8	10
Grade 3/4	5	6	3
Skin
Any	20	6	17
Grade 3/4	1	2	1
Gastrointestinal
Nausea
Any	34	31	31
Grade 3/4	5	4	8
Vomiting
Any	22	27	22
Grade 3/4	3	2	6
Diarrhea
Any	23	6	12
Grade 3/4	3	0	4
Alopecia	56	35	50
Asthenia
Any	53	57	54
Severe¶	18	39	23
Stomatitis
Any	26	6	8
Grade 3/4	2	0	1
Pulmonary
Any	41	49	45
Grade 3/4	21	29	19
Nail Disorder
Any	11	0	2
Severe¶	1	0	0
Myalgia
Any	6	0	3
Severe¶	0	0	0
Arthralgia
Any	3	2	2
Severe¶	0	0	1
Taste Perversion
Any	6	0	0
Severe¶	1	0	0

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
* Replaces NCI term "Allergy" † COSTART term and grading system
Adverse Reaction	Docetaxel 75 mg/m2 + Cisplatin 75 mg/m2 n=406 %	Vinorelbine 25 mg/m2 + Cisplatin 100 mg/m2 n=396 %
Neutropenia
Any	91	90
Grade 3/4	74	78
Febrile Neutropenia	5	5
Thrombocytopenia
Any	15	15
Grade 3/4	3	4
Anemia
Any	89	94
Grade 3/4	7	25
Infection
Any	35	37
Grade 3/4	8	8
Fever in absence of infection
Any	33	29
Grade 3/4	<1	1
Hypersensitivity Reaction*
Any	12	4
Grade 3/4	3	<1
Fluid Retention†
Any	54	42
All severe or life-threatening events Pleural effusion	2	2
Any	23	22
All severe or life-threatening events Peripheral edema	2	2
Any	34	18
All severe or life-threatening events Weight gain	<1	<1
Any	15	9
All severe or life-threatening events	<1	<1
Neurosensory
Any	47	42
Grade 3/4	4	4
Neuromotor
Any	19	17
Grade 3/4	3	6
Skin
Any	16	14
Grade 3/4	<1	1
Nausea
Any	72	76
Grade 3/4	10	17
Vomiting
Any	55	61
Grade 3/4	8	16
Diarrhea
Any	47	25
Grade 3/4	7	3
Anorexia†
Any	42	40
All severe or life-threatening events	5	5
Stomatitis
Any	24	21
Grade 3/4	2	1
Alopecia
Any	75	42
Grade 3	<1	0
Asthenia†
Any	74	75
All severe or life-threatening events	12	14
Nail Disorder†
Any	14	<1
All severe events	<1	0
Myalgia†
Any	18	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)
* Related to treatment
	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	Any	Grade 3/4	Any	Grade 3/4
Anemia	67	5	58	2
Neutropenia	41	32	48	22
Thrombocytopenia	3	1	8	1
Febrile Neutropenia	3	N/A	2	N/A
Infection	32	6	20	4
Epistaxis	6	0	2	0
Allergic Reactions	8	1	1	0
Fluid Retention*	24	1	5	0
Weight Gain*	8	0	3	0
Peripheral Edema*	18	0	2	0
Neuropathy Sensory	30	2	7	0
Neuropathy Motor	7	2	3	1
Rash/Desquamation	6	0	3	1
Alopecia	65	N/A	13	N/A
Nail Changes	30	0	8	0
Nausea	41	3	36	2
Diarrhea	32	2	10	1
Stomatitis/Pharyngitis	20	1	8	0
Taste Disturbance	18	0	7	0
Vomiting	17	2	14	2
Anorexia	17	1	14	0
Cough	12	0	8	0
Dyspnea	15	3	9	1
Cardiac left ventricular function	10	0	22	1
Fatigue	53	5	35	5
Myalgia	15	0	13	1
Tearing	10	1	2	0
Arthralgia	8	1	5	1

Gastric Cancer

Combination Therapy with Docetaxel Injection in Gastric Adenocarcinoma

Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease who were treated with Docetaxel 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
Clinically important treatment-emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.
* Related to treatment
	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 %
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 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)
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
	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 %
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†	20	0	14	1	13	1	7	2
Edema only	13	0	7	0	12	1	6	1
Weight gain only	6	0	6	0	0	0	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

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.

Medication Guide

MEDICATION GUIDE

This Patient Information has been approved by the U.S. Food and Drug Administration.		Revised: May 2023
Patient Information Docetaxel (doe-se-TAKS-el) Injection for intravenous use
What is the most important information I should know about Docetaxel Injection? Docetaxel Injection can cause serious side effects, including death. • The chance of death in people who receive Docetaxel Injection is higher if you: o have liver problems o receive high doses of Docetaxel Injection o have non-small cell lung cancer and have been treated with chemotherapy medicines that contain platinum • Docetaxel Injection can affect your blood cells. Your healthcare provider should do routine blood tests during treatment with Docetaxel Injection. This will include regular checks of your white blood cell counts. If your white blood cells are too low, your healthcare provider may not treat you with Docetaxel Injection until you have enough white blood cells. People with low white blood cell counts can develop life-threatening infections. The earliest sign of infection may be fever. Follow your healthcare provider's instructions for how often to take your temperature during treatment with Docetaxel Injection. Call your healthcare provider right away if you have a fever. • Swelling (inflammation) of the small intestine and colon. This can happen at any time during treatment and could lead to death as early as the first day you get symptoms. Tell your healthcare provider right away if you develop new or worse symptoms of intestinal problems, including stomach (abdominal) pain or tenderness or diarrhea, with or without fever. • Severe allergic reactions are medical emergencies that can happen in people who receive Docetaxel Injection and can lead to death. You may be at higher risk of developing a severe allergic reaction to Docetaxel Injection if you are allergic to paclitaxel. Your healthcare provider will monitor you closely for allergic reactions during your Docetaxel Injection infusion. Tell your healthcare provider right away if you have any of these signs of a severe allergic reaction: o trouble breathing o sudden swelling of your face, lips, tongue, throat, or trouble swallowing o hives (raised bumps), rash, or redness all over your body • Your body may hold too much fluid (severe fluid retention) during treatment with Docetaxel Injection. This can be life threatening. To decrease the chance of this happening, you must take another medicine, a corticosteroid, before each Docetaxel Injection treatment. You must take the corticosteroid exactly as your healthcare provider tells you. Tell your healthcare provider or nurse before your Docetaxel Injection treatment if you forgot to take your corticosteroid dose or do not take it as your healthcare provider tells you. Tell your healthcare provider right away if you have swelling in your legs or feet, weight gain or shortness of breath. • Risk of new cancers. An increase in new (second) cancers has happened in people treated with Docetaxel Injection together with certain other anticancer treatments. This includes certain blood cancers, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), non-Hodgkin's Lymphoma (NHL), and kidney cancer. o Changes in blood counts due to leukemia and other blood disorders may occur years after treatment with Docetaxel Injection. Your healthcare provider will check you for new cancers during and after your treatment with Docetaxel Injection. • Severe skin problems. Tell your healthcare provider right away if you have any of these signs of a severe skin reaction: o redness and swelling of your arms and legs. o blistering, peeling, or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet) with or without a rash. You may also have flu-like symptoms such as fever, chills, or muscle aches. o red, scaly rash all over your body with blisters, small red or white bumps under the skin that contain pus (pustules), and fever.
What is Docetaxel Injection? Docetaxel Injection is a prescription anticancer medicine used to treat certain people with: • breast cancer • non-small cell lung cancer • prostate cancer • stomach cancer • head and neck cancer It is not known if Docetaxel Injection is effective in children.
Do not receive Docetaxel Injection if you: • have a low white blood cell count. • have had a severe allergic reaction to: o docetaxel, the active ingredient in Docetaxel Injection, or o any other medicines that contain polysorbate 80. Ask your healthcare provider or pharmacist if you are not sure. See "What is the most important information I should know about Docetaxel Injection?" for the signs and symptoms of a severe allergic reaction. See the end of this Patient Information for a complete list of the ingredients in Docetaxel Injection.
Before you receive Docetaxel Injection, tell your healthcare provider about all of your medical conditions, including if you: • are allergic to any medicines, including paclitaxel. See "Do not receive Docetaxel Injection if you". • have liver problems • have kidney problems • are pregnant or plan to become pregnant. Docetaxel Injection can harm your unborn baby. You should not become pregnant during treatment with Docetaxel Injection. Tell your healthcare provider if you become pregnant or you think you may be pregnant during treatment with Docetaxel Injection. Females who are able to become pregnant: o Your healthcare provider will check to see if you are pregnant before you start treatment with Docetaxel Injection. o You should use effective birth control (contraception) during treatment with Docetaxel Injection and for 2 months after the last dose. Males with female partners who are able to become pregnant should use effective birth control during treatment with Docetaxel Injection and for 4 months after the last dose. Talk to your healthcare provider if you have questions about birth control options that are right for you. • are breastfeeding or plan to breastfeed. It is not known if Docetaxel Injection passes into your breast milk. Do not breastfeed during treatment with Docetaxel Injection and for 1 week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Docetaxel Injection may affect the way other medicines work, and other medicines may affect the way Docetaxel Injection works. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How will I receive Docetaxel Injection? • Docetaxel Injection will be given to you as an intravenous (IV) injection into your vein, usually over 1 hour. • Docetaxel Injection is usually given every 3 weeks. • Your healthcare provider will decide how long you will receive treatment with Docetaxel Injection. • Your healthcare provider will check your blood cell counts and other blood tests during your treatment with Docetaxel Injection to check for side effects of Docetaxel Injection. • Your healthcare provider may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving Docetaxel Injection.
What are the possible side effects of Docetaxel Injection? Docetaxel Injection may cause serious side effects including death. • See "What is the most important information I should know about Docetaxel Injection?" • Neurologic problems. Neurologic symptoms are common in people who receive Docetaxel Injection but can be severe. Tell your healthcare provider right away if you have numbness, tingling, or burning in your hands or feet (peripheral neuropathy) or weakness of your legs, feet, arms, or hands (motor weakness). • Vision problems including blurred vision or loss of vision. Tell your healthcare provider right away if you have any vision changes. • Docetaxel Injection contains alcohol. The alcohol content in Docetaxel Injection may impair your ability to drive or use machinery right after receiving Docetaxel Injection. Consider whether you should drive, operate machinery or do other dangerous activities right after you receive Docetaxel Injection treatment. • Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, or heart problems, and may lead to death. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with Docetaxel Injection. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with Docetaxel Injection, including:
	o nausea o vomiting o confusion o shortness of breath	o irregular heartbeat o dark or cloudy urine o reduced amount of urine o unusual tiredness o muscle cramps
• You may experience side effects of Docetaxel Injection that may impair your ability to drive, use tools, or operate machines. If this happens, do not drive or use any tools or machines before discussing with your healthcare provider. The most common side effects of Docetaxel Injection include:
	• infections • low white blood cells (help fight infections), low red blood cells (anemia), and low platelets (help blood to clot) • allergic reactions (See "What is the most important information I should know about Docetaxel Injection?") • changes in your sense of taste • shortness of breath • constipation • decreased appetite • changes in your fingernails or toenails • swelling of your hands, face, or feet	• feeling weak or tired • joint and muscle pain • nausea and vomiting • diarrhea • mouth or lip sores • hair loss: in some people, permanent hair loss has been reported • redness of the eye, excess tearing • skin reactions at the site of Docetaxel Injection administration such as increased skin pigmentation, redness, tenderness, swelling, warmth or dryness of the skin • tissue damage if Docetaxel Injection leaks out of the vein into the tissues
Tell your healthcare provider if you have a fast or irregular heartbeat, severe shortness of breath, dizziness or fainting during your infusion. If any of these events occurs after your infusion, get medical help right away. Docetaxel Injection may affect fertility in males. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects of Docetaxel Injection. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Docetaxel Injection. Medicines are sometimes prescribed for purposes other than those listed in this Patient Information. You can ask your pharmacist or healthcare provider for information about Docetaxel Injection that is written for health professionals.
What are the ingredients in Docetaxel Injection? Active ingredient: docetaxel (anhydrous) Inactive ingredients: (10 mg injection): polysorbate 80, anhydrous citric acid, dehydrated alcohol and polyethylene glycol. Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA LAB-1366-5.0 For more information, call 1-800-441-4100, or go to www.pfizer.com

Every three-week injection of Docetaxel Injection for breast, non-small cell lung and stomach, and head and neck cancers
Take your oral corticosteroid medicine as your healthcare provider tells you.

Oral corticosteroid dosing:
Day 1                       Date:                        Time:                        AM                        PM
Day 2                       Date:                        Time:                        AM                        PM

(Docetaxel Injection Treatment Day)
Day 3                       Date:                        Time:                        AM                        PM

Every three-week injection of Docetaxel Injection for prostate cancer
Take your oral corticosteroid medicine as your healthcare provider tells you.

Oral corticosteroid dosing:
Date:                        Time:
Date:                        Time:

(Docetaxel Injection Treatment Day)
                                Time:

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