DOCETAXEL (Page 6 of 20)
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 (5.5)] . 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/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 4 and 5).
Docetaxel 100 mg/m 2 | Docetaxel 60 mg/m 2 | ||
---|---|---|---|
Normal LFTs * | Elevated LFTs † | Normal LFTs * | |
Adverse Reaction | n=730 | n=18 | n=174 |
% | % | % | |
| |||
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 | |||
| |||
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 versus 6.9% and 16.5% for patients treated at 75 and 100 mg/m 2 , respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m 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).
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