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 for docetaxel 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/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 2).
Table 2 - 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
| 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/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/mm
3) associated with fatal gastrointestinal hemorrhage has been reported.
Hypersensitivity Reactions
Severe hypersensitivity reactions have been reported
[see Boxed Warning, Warnings and Precautions (5.4)]. 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 DOCEFREZ
[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 patients (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 greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT > 1.5 times the ULN, or alkaline phosphatase > 2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on docetaxel, increases in AST and/or ALT > 1.5 times ULN concomitant with alkaline phosphatase > 2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established.
Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry abnormalities
Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m
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 3 and 4).
Table 3 - 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
Adverse Reaction | Docetaxel 100 mg/m2 | Docetaxel 60 mg/m2 |
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 4 - 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
Adverse Reaction | Docetaxel 100 mg/m2 | Docetaxel 60 mg/m2 |
Normal LFTs*
n=730 % | Elevated LFTs†
n=18 % | Normal LFTs*
n=174 % |
NA = not available
|
|
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).
Lung Cancer
Monotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy
Docetaxel 75 mg/m
2: Treatment emergent adverse drug reactions are shown in Table 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
| 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
|
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 6).
Table 6- 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
|
6.2 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.