"Dec. 5, 2012 -- Doubling the time that breast cancer patients take tamoxifen cuts the risk that the cancer will come back and further lowers the risk of dying of the disease, a new study shows.
The study is expected to change the way"...
DOCEFREZ administered at 100 mg/m² was associated with deaths considered possibly or probably related to treatment in 2.0 % (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT > 1.5 times ULN together with AP > 2.5 times ULN). Among patients dosed at 60 mg/m², mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.
Non-Small Cell Lung Cancer
DOCEFREZ administered at a dose of 100 mg/m² in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m² dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m² dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see DOSAGE AND ADMINISTRATION, Clinical Studies].
Perform frequent peripheral blood cell counts on all patients receiving DOCEFREZ. Patients should not be retreated with subsequent cycles of DOCEFREZ until neutrophils recover to a level > 1,500 cells/mm³ and platelets recover to a level > 100,000 cells/mm³.
A 25% reduction in the dose of DOCEFREZ is recommended during subsequent cycles following severe neutropenia ( < 500 cells/mm³ ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a DOCEFREZ cycle [see DOSAGE AND ADMINISTRATION].
Neutropenia ( < 2000 neutrophils/mm³ ) occurs in virtually all patients given 60 mg/m² to 100 mg/m² of docetaxel and grade 4 neutropenia ( < 500 cells/mm³ ) occurs in 85% of patients given 100 mg/m² and 75% of patients given 60 mg/m² . Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. DOCEFREZ should not be administered to patients with neutrophils < 1,500 cells/mm³.
Febrile neutropenia occurred in about 12% of patients given 100 mg/m² but was very uncommon in patients given 60 mg/m² . Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see ADVERSE REACTIONS, Clinical Studies].
Three breast cancer patients with severe liver impairment (bilirubin > 1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
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].
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]. 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).
Acute Myeloid Leukemia
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]. 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]. 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]. 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.
Use In Pregnancy
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].
Patient Counseling Information
See FDA-Approved Patient Labeling
- Explain to patients the possible effects of the alcohol content in Docetaxel Injection, including possible effects on the central nervous system. Patients in whom alcohol should be avoided or minimized should consider the alcohol content of Docetaxel Injection. Alcohol could impair their ability to drive or use machines immediately after infusion.
- DOCEFREZ may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives if receiving DOCEFREZ [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
- Obtain detailed allergy and concomitant drug information from the patient prior to DOCEFREZ administration.
- Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report if they were not compliant with oral corticosteroid regimen.
- Instruct patients to immediately report signs of a hypersensitivity reaction.
- Tell patients to watch for signs of fluid retention such as peripheral edema in the lower extremities, weight gain and dyspnea.
- Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.
- Instruct patients to report myalgia, cutaneous, or neurologic reactions.
- Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, fatigue, excessive tearing, infusion site reactions, and hair loss are associated with docetaxel administration.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies with docetaxel have not been performed.
Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m² basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.
Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50th the recommended human dose on a mg/m² basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended human dose on a mg/m² basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.
Use In Specific Populations
Pregnancy Category D
[see 'WARNINGS AND PRECAUTIONS' section]
Based on its mechanism of action and findings in animals, DOCEFREZ can cause fetal harm when administered to a pregnant woman. 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. DOCEFREZ can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥ 0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m² basis), administered during the period of organogenesis, have shown that docetaxel is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity.
It is not known whether docetaxel is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from DOCEFREZ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of docetaxel in pediatric patients receiving monotherapy was consistent with the known safety profile in adults.
Docetaxel has been studied in a total of 239 pediatric patients in 2 trials with monotherapy.
Docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1-22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m² as a 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia.
The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1-26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma.
Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m² to 235 mg/m² in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m² .
In summary, the body surface area adjusted clearance of docetaxel monotherapy in children was comparable to those in adults [see CLINICAL PHARMACOLOGY].
The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients [see WARNINGS AND PRECAUTIONS].
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.
Non-Small Cell Lung Cancer
In a study conducted in chemotherapy-na´ve patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively).
When docetaxel was combined with carboplatin for the treatment of chemotherapy-na´ve, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin.
Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the following treatment emergent adverse reactions occurred at rates ≥ 10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively.
Patients with bilirubin > ULN should not receive docetaxel. Also, patients with AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN should not receive docetaxel. [see BOXED WARNING, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
The alcohol content of Docetaxel Injection should be taken into account when given to patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/21/2015
Additional Docefrez Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find support and advances in treatment.