Docetaxel Side Effects

Brand Names: Docefrez, Taxotere

Please note - some side effects for Docetaxel may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Docetaxel - for the Consumer

Docetaxel

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Docetaxel:

Color changes of the toenails or fingernails; constipation; diarrhea; dizziness; hair loss; increased tear production; loss of appetite; mild pain, swelling, or redness at the injection site; muscle or joint pain; nausea; numbness, tingling, pain, burning, or weakness in the hands, arms, legs, or feet; taste changes; vomiting; weakness or tiredness.

Seek medical attention right away if any of these SEVERE side effects occur when using Docetaxel:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); back pain; black or bloody stools; change of skin color; chest pain or tightness; decreased urination; fainting; fast, slow, or irregular heartbeat; fever, chills, or sore throat; flushing; increased or painful urination; mouth or lip sores or inflammation; red, swollen, hardened, blistered, or peeling skin; severe or persistent dizziness or headache; severe or persistent nausea, vomiting, diarrhea, or stomach pain; severe or persistent weakness or tiredness; shortness of breath; stomach swelling; sudden, unusual weight gain; swelling of the hands, feet, or ankles; swollen lymph glands; trouble swallowing; unusual bruising or bleeding; vision problems; vomit that looks like coffee grounds; warm sensation while you are receiving Docetaxel; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Docetaxel Side Effects - for the Professional

Docetaxel

The most serious adverse reactions from Docetaxel are:

• Toxic Deaths [see Boxed Warning, Warnings and Precautions (5.1)]
• Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.2)]
• Neutropenia [see Boxed Warning, Warnings and Precautions (5.3)]
• Hypersensitivity [see Boxed Warning, Warnings and Precautions (5.4)]
• Fluid Retention [see Boxed Warning, Warnings and Precautions (5.5)]

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 Trial 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.

Table 1 - Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m2

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   <500 cells/mm3 Leukopenia   <4000 cells/mm3  <1000 cells/mm3 Thrombocytopenia   <100,000 cells/mm3 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 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
*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 [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 (5.4)]. 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 (5.5)].

Cutaneous Reactions

Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.7)]. 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 (5.8)].

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 occurred rarely. 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.

Table 2 - Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests

	Docetaxel 100 mg/m2		Docetaxel 60 mg/m2
	Normal LFTs* n=730 %	Elevated LFTs** n=18 %	Normal LFTs*
Adverse Reaction			n=174
			%
Neutropenia   Any <2000 cells/mm3    Grade 4 <500 cells/mm3	98 84	100 94	95 75
Thrombocytopenia   Any <100,000 cells/mm3    Grade 4 <20,000 cells/mm3	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
*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

Table 3 - Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests

	Docetaxel 100 mg/m2		Docetaxel 60 mg/m2
	Normal LFTs* n=730 %	Elevated LFTs** n=18 %	Normal LFTs*
Adverse Reaction			n=174
			%
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
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

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 vs. 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 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.

Table 4 - Clinically Important Treatment Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316).

	Docetaxel 75 mg/m2+ Doxorubicin 50 mg/m2+ Cyclophosphamide 500 mg/m2 (TAC) n=744 %		Fluorouracil 500 mg/m2+ Doxorubicin 50 mg/m2+ Cyclophosphamide 500 mg/m2 (FAC) n=736 %
Adverse Reaction	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
*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

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.

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 vs. one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred.

Cardiovascular Reactions

More cardiovascular reactions were reported in the TAC arm vs. the FAC arm; dysrhythmias, all grades (7.9% vs. 6.0%), hypotension, all grades (2.6% vs. 1.1%) and CHF (2.3% vs. 0.9%, at 70 months median follow-up). One patient in each arm died due to heart failure.

Acute Myeloid Leukemia (AML)

Treatment-related acute myeloid leukemia or myelodysplasia is known to occur in patients treated with anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at 5 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. This risk of AML is comparable to the risk observed for other anthracyclines/cyclophosphamide containing adjuvant breast chemotherapy regimens.

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 5. 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 5 - Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel as Monotherapy for Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy*

Adverse Reaction	Docetaxel 75 mg/m2 n=176 %	Best Supportive Care n=49 %	Vinorelbine/Ifosfamide n=119 %
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
*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

Combination therapy with Docetaxel in chemotherapy-naïve advanced unresectable or metastatic NSCLC

Table 6 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 6 - 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/m2 + Cisplatin 75 mg/m2 n=406 %	Vinorelbine 25 mg/m2 + Cisplatin 100 mg/m2 n=396 %
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
*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+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.

Table 7 - Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel in Combination with Prednisone (TAX327)

	Docetaxel 75 mg/m2 every 3 weeks + prednisone 5 mg twice daily n=332 %		Mitoxantrone 12 mg/m2 every 3 weeks + prednisone 5 mg twice daily n=335 %
Adverse Reaction	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
*Related to treatment

Post-Marketing Experiences

The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Body as a whole: diffuse pain, chest pain, radiation recall phenomenon.

Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.

Cutaneous: very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported.

Gastrointestinal: abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.

Hematologic: bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with Docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.

Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.

Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.

Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.

Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion.

Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.

Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome, interstitial pneumonia. Pulmonary fibrosis has been rarely reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

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

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Hematologic side effects including bone marrow suppression have been the major dose-limiting toxicity. A reversible and not cumulative neutropenia has also been reported. A median of 8 days to nadir and median duration of severe neutropenia (less than 500 cells/mm3) of 7 days has been reported. A fatal gastrointestinal hemorrhage associated with thrombocytopenia has been reported in one patient. Three patients with severe liver dysfunction developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported during postmarketing experience.

Patients carrying the GSTP1 A/B and 3435TT genotypes may have excessive hematologic toxicity.

In a summary of 37 clinical trials (n = 1,495), neutropenia (less than 2,000 cells/mm3) has been reported in 96.3% of patients with normal LFTs at baseline and 96% of patients with elevated LFTs. Neutropenia (less than 500 cells/mm3) has been reported in 76% of patients with normal LFTs at baseline and 86% of patients with elevated LFTs.

Leukopenia (less than 4,000 cells/mm3) has been reported in 96.5% of patients with normal LFTs at baseline and 98.1% of patients with elevated LFTs. Leukopenia (less than 1,000 cells/mm3) has been reported in 31% of patients with normal LFTs at baseline and 44.2% of patients with elevated LFTs. Thrombocytopenia (less than 100,000 cells/mm3) has been reported in 7.5% of patients with normal LFTs at baseline and 27.3% of patients with elevated LFTs.

Anemia (less than 11 g/dL) has been reported in 89.5% of patients with normal LFTs at baseline and 92.7% of patients with elevated LFTs. Anemia (less than 8 g/dL) has been reported in 8.4% of patients with normal LFTs and 30.9% of patients with elevated LFTs.

Febrile neutropenia has been reported in 11.8% of patients with normal LFTs at baseline and 26.4% of patients with elevated LFTs.

Hypersensitivity

In one institution's experience with 623 courses of docetaxel therapy (n = 168), hypersensitivity reactions decreased from 50% to 5% once patients began receiving systemic prophylaxis including corticosteroids and antihistamines.

Hypersensitivity side effects may occur within a few minutes following initiation of a docetaxel infusion. Severe hypersensitivity reactions characterized by hypotension and/or bronchospasm, or generalized rash/erythema occurred in 0.9% of patients who received the recommended dexamethasone premedication. Hypersensitivity reactions requiring discontinuation of therapy have been reported in 5 of 1260 patients who did not receive premedication. Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever or chills have also been reported and resolved after discontinuation of the infusion and initiation of appropriate therapy. Bullous eruption including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely. Rare cases of anaphylactic shock have been reported during postmarketing experience. Very rarely, these cases resulted in a fatal outcome in patients who received premedication.

General

General side effects including diffuse pain, chest pain, and radiation recall phenomenon have been reported.

Severe adverse events have been reported in 49% 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 events 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 at a rate of 4.0% in 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.

Cardiovascular

Cardiovascular side effects including hypotension have been reported in 3.6% of patients (3.4% required treatment). Heart failure, sinus tachycardia, atrial fibrillation, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, myocardial infarction, and hypertension have also been reported.

Renal

Renal side effects including severe fluid retention (generally renal in origin and generally after four to five courses of therapy) have been reported in patients using a five day dexamethasone premedication regimen. The fluid retention was characterized by one or more of the following events; poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites). Renal insufficiency has been reported during postmarketing experience with the majority of these cases associated with concomitant nephrotoxic drugs.

Moderate fluid retention (17.4%), severe fluid retention (6%) and discontinuation (1.7%) have been reported among 229 patients with normal liver function using a five day dexamethasone premedication regimen. Fluid retention was completely, but sometimes slowly reversible resolving in a median of 29 weeks following discontinuation. The median cumulative dose to the onset of moderate or severe fluid retention was 705 mg/m2 (in patients receiving premedication). In a summary of 37 clinical trials (n = 1,495), fluid retention was reported in 48.5% of patients with normal LFTs at baseline and 66.7% of patients with elevated LFTs. In the same trials, severe fluid retention was reported in 5.2% of patients with normal LFTs at baseline and 33.3% of patients with elevated LFTs. Patients developing peripheral edema may be treated with standard measures including salt restriction, diuretics (e.g. spironolactone), etc.

Nervous system

Spontaneous reversal of symptoms occurred in a median of 9 weeks from onset. Approximately 3.8% of the 134 patients required discontinuation of therapy due to neurotoxicity. In a summary of 37 clinical trials (n = 1,495), neurosensory symptoms were reported in 53.7% of patients with normal LFTs at baseline and 41.8% of patients with elevated LFTs. In the same trials, severe neurosensory symptoms were reported in 3.9% of patients with normal LFTs at baseline and none of the patients with elevated LFTs. In a study (n = 46) of 209 cycles, peripheral neurotoxicity was reported in 30% of patients. In another study (n = 186), 11% of patients developed mild to moderate sensory neuropathy at cumulative doses ranging from 50 to 750 mg/m2 and doses of 10 to 115 mg/m2.

Nervous system side effects including paresthesia, dysesthesia, and pain (7%) have been reported in one study (n = 134). Confusion and rare cases of seizures or transient loss of consciousness have been reported, sometimes appearing during the infusion of the drug.

Hepatic

Hepatic side effects including various increases in blood levels have been reported. In patients with normal LFTs at baseline, bilirubin values greater than the upper limit of normal (ULN) occurred in 8.9% of patients. Increases in SGOT or SGPT greater than 1.5 times the ULN, or alkaline phosphatase greater than 2.5 times the ULN were observed in 18.1% and 7.6% of patients, respectively. Increases in SGOT and/or SGPT greater than 1.5 times the ULN concomitant with alkaline phosphatase greater than 2.5 times the ULN occurred in 4.5% of patients with normal LFTs at baseline. Rare cases of hepatitis have been reported during postmarketing experience.

Gastrointestinal

In a summary of 37 clinical trials (n = 1,495), nausea has been reported in 40.4% of patients with normal LFTs at baseline and 40% of patients with elevated LFTs. Diarrhea has been reported in 40.4% of patients with normal LFTs at baseline and 32.7% of patients with elevated LFTs. Vomiting has been reported in 24% of patients with normal LFTs at baseline and 25.5% of patients with elevated LFTs. Severe GI reactions were reported in 8.2% of patients.

Stomatitis has been reported in 42.3% of patients with normal LFTs at baseline and 47.3% of patients with elevated LFTs. Severe stomatitis has been reported in 5.3% of patients with normal LFTs at baseline and 14.5% of patients with elevated LFTs. Stomatitis appears to be dose dependent.

Gastrointestinal (GI) side effects including nausea, vomiting, diarrhea, stomatitis abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, GI hemorrhage, GI perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis, ischemic colitis, and dehydration as a consequence to GI events have been reported.

Dermatologic

Dermatologic side effects including 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 (and usually associated with pruritus) have been reported. Severe hand and foot syndrome has been reported. Severe nail disorders (2.6%), alopecia, and localized erythema of the extremities with edema followed by desquamation have also been reported. Very rare cases of cutaneous lupus erythematosus have been reported. Scleroderma-like changes usually preceded by peripheral lymphedema have been reported. One case of supravenous discoloration of the skin due to docetaxel treatment has been reported.

Eruptions generally occurred within one week after dosage administration and were not disabling. Recovery generally occurred before the next infusion.

In a summary of 37 clinical trials (n = 1,495), cutaneous adverse events have been reported in 58.5% of patients with normal LFTs at baseline and 61.8% of patients with elevated LFTs. In the same trials, severe cutaneous adverse events have been reported in 5.6% of patients with normal LFTs at baseline and 10.9% of patients with elevated LFTs. The discontinuation rate due to skin toxicity was 1.7%. Alopecia has been reported in 80% of patients with normal LFTs at baseline and 61.8% of patients with elevated LFTs. In one study (n = 46) of 209 cycles, alopecia was reported in 91% of patients. In one institution's experience with 623 courses of docetaxel therapy (n = 168), dermatologic toxicity decreased from 53% to 14% once patients began receiving systemic prophylaxis including corticosteroids and antihistamines.

Severe nail disorder were characterized by hypo- or hyperpigmentation and occasionally by onycholysis (0.8%) and pain.

Local

Local side effects consisting of infusion site reactions have been reported. These reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation or swelling of the vein. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported during postmarketing experience. These were reversible upon discontinuation of the infusion.

Other

In a summary of 37 clinical trials (n = 1,495), asthenia has been reported in 61.5% of patients with normal LFTs at baseline and 54.5% of patients with elevated LFTs. In the same trials, severe asthenia has been reported in 11.1% of patients with normal LFTs at baseline and 23.6% of patients with elevated LFTs. In a study (n = 46) of 209 cycles, malaise was reported in 52% of patients.

Other side effects have included asthenia (11.1% to 61.5%) and malaise (52%). Fatigue and weakness have been reported to have lasted a few days to several weeks and were occasionally associated with deterioration of performance status in patients with progressive disease. Rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs. A case of docetaxel-induced recall dermatitis on previous laser treatment sites has also been reported.

Ocular

Ocular side effects including conjunctivitis and lacrimation have been reported. Canalicular and nasolacrimal duct obstruction has been a common side effect of weekly docetaxel therapy and has even been reported to occur when docetaxel is used in the neoadjuvant setting according to one study. Excessive tearing which may be attributable to lacrimal duct obstruction has also been reported.

Respiratory

Respiratory side effects including dyspnea, acute pulmonary edema, acute respiratory distress syndrome, and interstitial pneumonia have been reported. Pulmonary fibrosis has been rarely reported.

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