Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the DOCEFREZ infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with DOCEFREZ.Hypersensitivity reactions may occur within a few minutes following initiation of a DOCEFREZ infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of DOCEFREZ [see Dosage and Administration (2.6)].
Severe fluid retention has been reported following docetaxel therapy. Patients should be premedicated with oral corticosteroids prior to each DOCEFREZ administration to reduce the incidence and severity of fluid retention [see Dosage and Administration (2.6)]. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.
When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.
Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2. Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1,021 mg/m2.Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).
Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. The risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up.
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.
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).
Cystoid macular edema (CME) has been reported in patients treated with DOCEFREZ. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, DOCEFREZ treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.
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.
Each administration of Docetaxel Injection at 100 mg/m2 delivers 1.425 g/m2 of ethanol. For a patient with a BSA of 2.0 m2 , this would deliver 2.85 grams of ethanol [see Description (11)]. Other docetaxel products may have a different amount of alcohol.
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.
DOCEFREZ 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 DOCEFREZ. If DOCEFREZ 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 DOCEFREZ [see Use in Specific Populations (8.1)].
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 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.
Monotherapy with docetaxel for locally advanced or metastatic breast cancer after failure of prior chemotherapy
Docetaxel 100 mg/m2 : Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to docetaxel. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving docetaxel for the treatment of breast cancer and in patients with other tumor types (See Table 2).
|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 ‡||96759632890911||9688984725923126||99869944994812|
|Septic Death Non-Septic Death||21||57||11|
|Fever in Absence of Infection AnySevere||312||418||352|
|Hypersensitivity Reactions Regardless of Premedication AnySevere With 3-day PremedicationAnySevere||214n=92152||2010n=3330||183n=92152|
|Fluid Retention Regardless of PremedicationAnySevereWith 3-day PremedicationAnySevere||477n=92647||398n=36733||609n=92647|
|Nail Changes AnySevere||313||235||414|
|Infusion Site Reactions||4||3||4|
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.
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.
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 are discussed elsewhere in the label [ see Warnings and Precautions (5.8)].
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.
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/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.
In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT > 1.5 times the ULN, or alkaline phosphatase > 2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on docetaxel, increases in AST and/or ALT > 1.5 times ULN concomitant with alkaline phosphatase > 2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established.
Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry abnormalities
Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT > 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN); and 174 patients in Japanese studies given docetaxel at 60 mg/m2 who had normal LFTs (see Tables 3 and 4).
|Adverse Reaction||Docetaxel 100 mg/m2||Docetaxel 60 mg/m2|
|Normal LFTs * n=730 %||Elevated LFTs †n=18 %||NormalLFTs * n=174 %|
|Neutropenia Any <2000 cells/mm3 Grade 4 <500 cells/mm3||9884||10094||9575|
|Thrombocytopenia Any <100,000 cells/mm3 Grade 4 <20,000 cells/mm3||111||4417||141|
|Anemia <11 g/dL||95||94||65|
|Infection ‡AnyGrade 3 and 4||237||3933||10|
|Febrile Neutropenia §By PatientBy Course||122||339||00|
|Adverse Reaction||Docetaxel 100 mg/m2||Docetaxel 60 mg/m2|
|Normal LFTs * n=730 %||Elevated LFTs † n=18 %||Normal LFTs * n=174 %|
|Acute Hypersensitivity Reaction Regardless of Premedication AnySevere||131||60||10|
|Fluid Retention ‡Regardless of Premedication AnySevere||568||6117||130|
|Diarrhea AnySevere||426||2811||NA §|
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 mg/m2 and 100 mg/m2 respectively.
The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m2 , 75 mg/m2 , and 100 mg/m2 respectively), thrombocytopenia (7%, 11%, and 12% respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14% respectively), treatment-related grade 3/4 infection (2%, 3%, and 7% respectively) and anemia (87%, 94%, and 97% respectively).
Monotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapyDocetaxel 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.
|Adverse Reaction||Docetaxel 75 mg/m2 n=176 %||Best Supportive Care n=49 %||Vinorelbine/ Ifosfamide n=119 %|
|Neutropenia AnyGrade 3/4||8465||1412||8357|
|Leukopenia AnyGrade 3/4||8449||60||8943|
|Thrombocytopenia AnyGrade 3/4||83||00||82|
|Anemia AnyGrade 3/4||919||5512||9114|
|Febrile Neutropenia †||6||NA ‡||1|
|Infection AnyGrade 3/4||3410||296||309|
|Treatment Related Mortality||3||NA ‡||3|
|Hypersensitivity Reactions AnyGrade 3/4||63||00||10|
|Fluid Retention AnySevere||343||ND §||233|
|Neurosensory AnyGrade 3/4||232||146||295|
|Neuromotor AnyGrade 3/4||165||86||103|
|Skin AnyGrade 3/4||201||62||171|
|Gastrointestinal NauseaAnyGrade 3/4VomitingAnyGrade 3/4DiarrheaAnyGrade 3/4||345223233||31427260||318226124|
|Asthenia AnySevere ¶||5318||5739||5423|
|Stomatitis AnyGrade 3/4||262||60||81|
|Pulmonary AnyGrade 3/4||4121||4929||4519|
|Nail Disorder AnySevere ¶||111||00||20|
|Myalgia AnySevere ¶||60||00||30|
|Arthralgia AnySevere ¶||30||20||21|
|Taste Perversion AnySevere ¶||61||00||00|
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.
|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||9174||9078|
|Thrombocytopenia Any Grade 3/4||153||154|
|Fever in absence of infection||33||29|
|Grade 3/4||< 1||1|
|Hypersensitivity Reaction *||12||4|
|Grade 3/4||3||< 1|
|Fluid Retention †||54||42|
|All severe or life-threatening events||2||2|
|All severe or life-threatening events||2||2|
|All severe or life-threatening events||<1||<1|
|All severe or life-threatening events||<1||<1|
|All severe or life-threatening events||5||5|
|All severe or life-threatening events||12||14|
|Nail Disorder †|
|All severe events||<1||0|
|All severe events||<1||<1|
Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2%) 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 DOCEFREZ, [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.
Combination therapy with docetaxel in patients with prostate cancerThe 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 7).
|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|
|Fluid Retention *Weight Gain *Peripheral Edema *||24818||100||532||000|
|Cardiac left ventricular function||10||0||22||1|
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