Docetaxel (Page 5 of 12)

5.7 Cutaneous Reactions

Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended [see Dosage and Administration (2.7)]. The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued docetaxel due to skin toxicity.

5.8 Neurologic Reactions

Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued [see Dosage and Administration (2.7)]. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).

5.9 Eye Disorders

Cystoid macular edema (CME) has been reported in patients treated with Docetaxel Injection. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, Docetaxel Injection treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.

5.10 Asthenia

Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

5.11 Alcohol Content

Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in a dose of Docetaxel Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Docetaxel Injection on the ability to drive or use machines immediately after the infusion.

For Two-vial formulation (Injection with Diluent)
Each administration of Docetaxel Injection at 100 mg/m 2 delivers 0.15 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 , this would deliver 0.3 grams of ethanol [ see Description (11) ]. Other docetaxel products may have a different amount of alcohol.

For One-vial formulation (Injection) Each administration of Docetaxel Injection at 100 mg/m 2 delivers 1.975 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 , this would deliver 3.95 grams of ethanol [ see Description (11) ]. Other docetaxel products may have a different amount of alcohol.

5.12 Use in Pregnancy

Docetaxel Injection can cause fetal harm when administered to a pregnant woman. Docetaxel caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis.

There are no adequate and well-controlled studies in pregnant women using Docetaxel Injection. If Docetaxel Injection is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Docetaxel Injection [see Use in Specific Populations (8.1)].

6. ADVERSE REACTIONS

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)]
Acute Myeloid Leukemia [see Warnings and Precautions (5.6)]
Cutaneous Reactions [see Warnings and Precautions (5.7)]
Neurologic Reactions [see Warnings and Precautions (5.8)]
Eye Disorders [see Warnings and Precautions (5.9)]
Asthenia [see Warnings and Precautions (5.10)]
Alcohol Intoxication [see Warnings and Precautions (5.11)]

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 Trial Experience

Breast Cancer

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

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

Table 4 — Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m 2
Adverse Reaction All Tumor Types Normal LFTs * n=2045 % All Tumor Types Elevated LFTs n=61 % Breast Cancer Normal LFTs * n=965 %
*
Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization

Hematologic

Neutropenia

<2000 cells/mm 3

96

96

99

<500 cells/mm 3

75

88

86

Leukopenia

<4000 cells/mm 3

96

98

99

<1000 cells/mm 3

32

47

44

Thrombocytopenia

<100,000 cells/mm 3

8

25

9

Anemia

<11 g/dL

90

92

94

<8 g/dL

9

31

8

Febrile Neutropenia

11

26

12

Septic Death

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/mm 3) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles.

Febrile neutropenia (<500 cells/mm 3 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 to 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/m 2 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 > the ULN occurred in 8.9% of patients. Increases in AST or ALT >1.5 times the ULN, or alkaline phosphatase >2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on docetaxel, increases in AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established.

Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry abnormalities

Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m 2 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/m 2 who had normal LFTs (see Tables 5 and 6).

Table 5 — Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m 2 with Normal or Elevated Liver Function Tests or 60 mg/m 2 with Normal Liver Function Tests
Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2
Normal LFTs * Elevated LFTs Normal LFTs *
Adverse Reaction n=730 n=18 n=174
% % %
*
Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia.
§
Febrile Neutropenia: For 100 mg/m 2, ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m 2, ANC grade 3/4 and fever >38.1°C

Neutropenia

Any <2000 cells/mm 3

98

100

95

Grade 4 <500 cells/mm 3

84

94

75

Thrombocytopenia

Any <100,000 cells/mm 3

11

44

14

Grade 4 <20,000 cells/mm 3

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

Docetaxel 100 mg/m 2 Docetaxel 60 mg/m 2
Normal LFTs * Elevated LFTs Normal LFTs *
Adverse Reaction n=730 n=18 n=174
% % %
NA = not available
*
Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Elevated Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m 2 dose

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

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

Combination therapy with docetaxel in the adjuvant treatment of breast cancer

The following table presents treatment emergent adverse reactions observed in 744 patients, who were treated with docetaxel 75 mg/m 2 every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 7).

Table 7- Clinically Important Treatment Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316).
Docetaxel 75 mg/m 2 + Doxorubicin 50 mg/m 2 + Cyclophosphamide 500 mg/m 2 (TAC) n=744 % Fluorouracil 500 mg/m 2 + Doxorubicin 50 mg/m 2 + Cyclophosphamide 500 mg/m 2 (FAC) n=736 %
Adverse Reaction Any Grade 3/4 Any Grade 3/4
*
COSTART term and grading system for events related to treatment.

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

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

Treatment emergent adverse drug reactions are shown in Table 8. Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted.

Table 8 — Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel as Monotherapy for Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy *
Adverse Reaction Docetaxel 75 mg/m 2 n=176 % Best Supportive Care n=49 % Vinorelbine/Ifosfamide n=119 %
*
Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization
Not Applicable;
§
Not Done
COSTART term and grading system

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

3

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 9 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted.

Table 9 — Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy- Naïve Advanced Non-Small Cell Lung Cancer Patients Receiving Docetaxel in Combination with Cisplatin
Adverse Reaction Docetaxel 75 mg/m 2 + Cisplatin 75 mg/m 2 n=406 % Vinorelbine 25 mg/m 2 + Cisplatin 100 mg/m 2 n=396 %
*
Replaces NCI term “Allergy”
COSTART term and grading system

Neutropenia

Any

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

2

2

Pleural effusion

Any

23

22

All severe or life-threatening events

2

2

Peripheral edema

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

The second comparison in the study, vinorelbine+cisplatin versus docetaxel + carboplatin (which did not demonstrate a superior survival associated with docetaxel [see Clinical Studies (14.3)] ) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the docetaxel + carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm.

Prostate Cancer

Combination therapy with docetaxel in patients with prostate cancer

The following data are based on the experience of 332 patients, who were treated with docetaxel 75 mg/m 2 every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 10).

Table 10 — Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel in Combination with Prednisone (TAX327)
Docetaxel 75 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=332 % Mitoxantrone 12 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=335 %
Adverse Reaction Any Grade 3/4 Any Grade 3/4
*
Related to treatment

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 in gastric adenocarcinoma

Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease, who were treated with docetaxel 75 mg/m 2 in combination with cisplatin and fluorouracil (see Table 11).

Table 11 — Clinically Important Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study
Docetaxel 75 mg/m 2 + cisplatin 75 mg/m 2 + fluorouracil 750 mg/m 2 n=221 Cisplatin 100 mg/m 2 + fluorouracil 1000 mg/m 2 n=224
Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 %
Clinically important treatment emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.
*
Related to treatment

Anemia

97

18

93

26

Neutropenia

96

82

83

57

Fever in the absence of infection

36

2

23

1

Thrombocytopenia

26

8

39

14

Infection

29

16

23

10

Febrile neutropenia

16

N/A

5

N/A

Neutropenic infection

16

N/A

10

N/A

Allergic reactions

10

2

6

0

Fluid retention *

15

0

4

0

Edema *

13

0

3

0

Lethargy

63

21

58

18

Neurosensory

38

8

25

3

Neuromotor

9

3

8

3

Dizziness

16

5

8

2

Alopecia

67

5

41

1

Rash/itch

12

1

9

0

Nail changes

8

0

0

0

Skin desquamation

2

0

0

0

Nausea

73

16

76

19

Vomiting

67

15

73

19

Anorexia

51

13

54

12

Stomatitis

59

21

61

27

Diarrhea

78

20

50

8

Constipation

25

2

34

3

Esophagitis/dysphagia/odynophagia

16

2

14

5

Gastrointestinal pain/cramping

11

2

7

3

Cardiac dysrhythmias

5

2

2

1

Myocardial ischemia

1

0

3

2

Tearing

8

0

2

0

Altered hearing

6

0

13

2

Head and Neck Cancer

Combination therapy with docetaxel in head and neck cancer

Table 12 summarizes the safety data obtained from patients that received induction chemotherapy with docetaxel 75 mg/m 2 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 12 – Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with Docetaxel in Combination with cisplatin and fluorouracil followed by radiotherapy (TAX323) or chemoradiotherapy (TAX324)
TAX323 (n=355) TAX324 (n=494)
Docetaxel arm (n=174) Comparator arm (n=181) Docetaxel arm (n=251) Comparator arm (n=243)
Adverse Reaction (by Body System) Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 %
Clinically important treatment emergent adverse reactions based upon frequency, severity, and clinical impact.
*
Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization.
Related to treatment.
Includes superficial and deep vein thrombosis and pulmonary embolism

Neutropenia

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

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