There is no known antidote for DOCEFREZ overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic granulocyte – colony stimulating factor (G-CSF) as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.
In two reports of overdose, one patient received 150 mg/m² and the other received 200 mg/m² as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.
In mice, lethality was observed following single intravenous doses that were ≥ 154 mg/kg (about 4.5 times the human dose of 100 mg/m² on a mg/m² basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m² basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m² on a mg/m² basis) and was associated with abnormal mitosis and necrosis of multiple organs.
The most serious adverse reactions from docetaxel are:
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.
Clinical Trial Experience Breast CancerMonotherapy 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).
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/mm | 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/mm | 8 | 25 | 9 |
| Anemia | |||
| < 11 g/dL | 90 | 92 | 94 |
| < 8 g/dL | 9 | 31 | 8 |
| Febrile Neutropenia*** | 11 | 26 | 12 |
| Septic Death Non-Septic Death | |||
| Infections | 2 1 | 5 7 | 1 1 |
| 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 |
| *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 |
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Reversible marrow suppression was the major dose-limiting toxicity of docetaxel. 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/mm³with 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 ReactionsSevere hypersensitivity reactions have been reported. 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 RetentionFluid retention can occur with the use of DOCEFREZ.
Cutaneous ReactionsSevere skin toxicity is discussed elsewhere in the label. 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 ReactionsNeurologic reactions are discussed elsewhere in the label .
Gastrointestinal ReactionsNausea, 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 ReactionsHypotension 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 ReactionsInfusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein.
Hepatic ReactionsIn 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 AbnormalitiesHematologic 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).
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/mm | 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 |
| *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/m², ANC grade 4 and fever > 38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m², ANC grade 3/4 and fever > 38.1°C |
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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% |
|
| 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 |
| *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/m² dose NA = not available |
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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).
Lung CancerMonotherapy With Docetaxel For Unresectable, Locally Advanced Or Metastatic NSCLC Previously Treated With Platinum-Based Chemotherapy
Docetaxel 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.
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 |
| *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 ***COSTART term and grading system †Not Applicable; †† Not Done |
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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.
Table 6 : Adverse Reactions Regardless of Relationship
to Treatment in Chemotherapy-Naïve Advanced Non-Small Cell Lung Cancer Patients
Receiving Docetaxel in Combination with Cisplatin
| Docetaxel 75 mg/m + Cisplatin 75 mg/m² n=406 % |
Vinorelbine 25 mg/m + Cisplatin 100 mg/m² n=396 % |
|
| 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 | < 1 | < 1 |
| Weight gain | ||
| 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 |
DOCEFREZ is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.
Non-Small Cell Lung CancerDOCEFREZ as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.
DOCEFREZ in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.
Prostate CancerDOCEFREZ in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m² to 115 mg/m² in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m² to 115 mg/m² with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hour, respectively. Mean total body clearance was 21 L/h/m².
DistributionThe initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.
MetabolismIn vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.
EliminationA study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.
Effect of AgeA population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m². Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were not influenced by age.
Effect of GenderThe population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel.
Hepatic ImpairmentThe population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT > 1.5 times ULN concomitant with alkaline phosphatase > 2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with DOCEFREZ. Patients with severe hepatic impairment have not been studied..
Effect of RaceMean total body clearance for Japanese patients dosed at the range of 10 mg/m² to 90 mg/m² was similar to that of European/American populations dosed at 100 mg/m², suggesting no significant difference in the elimination of docetaxel in the two populations.
Effect of KetoconazoleThe effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m² intravenous) alone or docetaxel (10 mg/m² intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was co-administration with ketoconazole.
Effect of Combination Therapies: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.
DOCEFREZ 80 mg
DOCEFREZ (docetaxel) for Injection 80 mg: 80 mg docetaxel and Diluent for DOCEFREZ 80 mg (35.4% (w/w) ethanol in polysorbate 80). Both items are in a tray in one carton.
DOCEFREZ 20 mg
DOCEFREZ (docetaxel) for Injection 20 mg: 20 mg docetaxel and Diluent for DOCEFREZ 20 mg (35.4% (w/w) ethanol in polysorbate 80). Both items are in a tray in one carton.
Storage And Handling DOCEFREZ (Lyophilized Powder for Injection and Diluent)DOCEFREZ (docetaxel) for Injection is supplied in a single use vial as a sterile, lyophilized powder with an accompanying sterile, non-pyrogenic, Diluent (35.4% w/w ethanol in polysorbate 80) vial.
DOCEFREZ (docetaxel) for Injection, 80 mg (NDC 47335-286-41) DOCEFREZ (docetaxel) for Injection 80 mg: 80 mg docetaxel and Diluent for docetaxel 80 mg (35.4% (w/w) ethanol in polysorbate 80). Both items are in a tray in one carton.
DOCEFREZ (docetaxel) for Injection 20 mg (NDC 47335-285-41) DOCEFREZ (docetaxel) for Injection 20 mg: 20 mg docetaxel and Diluent for docetaxel 20 mg (35.4% (w/w) ethanol in polysorbate 80). Both items are in a tray in one carton.
StorageStore between 2°C and 8°C (36°F and 46°F). Retain in the original package to protect from bright light.
Handling And DisposalProcedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.
Distributed by: Caraco Pharmaceutical Laboratories, Ltd., 1150 Elijah McCoy Drive, Detroit, MI 48202. Manufactured by: Sun Pharmaceutical Ind. Ltd., Halol-Baroda Highway, Halol-389 350, Gujarat, India. 10/2014 Â
Included as part of the PRECAUTIONS section.
PRECAUTIONS Toxic Deaths Breast CancerDOCEFREZ 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 CancerDOCEFREZ 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.
Hepatic ImpairmentPatients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with DOCEFREZ.
Hematologic EffectsPerform 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.
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.
Three breast cancer patients with severe liver impairment (bilirubin > 1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia..
Hypersensitivity ReactionsPatients 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.
Fluid RetentionSevere 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  . 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 LeukemiaTreatment-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.
Cutaneous ReactionsLocalized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended. 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.
Neurologic ReactionsSevere 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. 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).
Eye DisordersCystoid 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.
Alcohol ContentCases 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. Other docetaxel products may have a different amount of alcohol.
AstheniaSevere 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 PregnancyDOCEFREZ 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.
Patient Counseling InformationSee FDA-Approved Patient Labeling
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 Pregnancy Category DBased 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.
Nursing MothersIt 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.
Pediatric UseThe 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 MonotherapyDocetaxel 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.
PharmacokineticsPharmacokinetic 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.
The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients.
Geriatric UseIn 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-naïve 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-naïve, 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.
Prostate CancerOf 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.
Hepatic ImpairmentPatients 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..
The alcohol content of Docetaxel Injection should be taken into account when given to patients with hepatic impairment.
For all indications, toxicities may warrant dosage adjustments. Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).
Breast CancerAll patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to DOCEFREZ administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.
For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the DOCEFREZ infusion.
Dosage Adjustments During Treatment Breast CancerPatients who are dosed initially at 100 mg/m² and who experience either febrile neutropenia, neutrophils < 500 cells/mm³for more than 1 week, or severe or cumulative cutaneous reactions during DOCEFREZ therapy should have the dosage adjusted from 100 mg/m² to 75 mg/m². If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m² to 55 mg/m² or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m² and who do not experience febrile neutropenia, neutrophils < 500 cells/mm³for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during DOCEFREZ therapy may tolerate higher doses. Patients who develop ≥ grade 3 peripheral neuropathy should have DOCEFREZ treatment discontinued entirely.
Non-Small Cell Lung CancerMonotherapy With DOCEFREZ For NSCLC Treatment After Failure Of Prior Platinum-Based Chemotherapy
Patients who are dosed initially at 75 mg/m² and who experience either febrile neutropenia, neutrophils < 500 cells/mm³for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 nonhematological toxicities during DOCEFREZ treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m². Patients who develop ≥ grade 3 peripheral neuropathy should have DOCEFREZ treatment discontinued entirely.
Combination Therapy With DOCEFREZ For Chemotherapy-Naïve NSCLC
For patients who are dosed initially at DOCEFREZ 75 mg/m² in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is < 25,000 cells/mm³ , in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the DOCEFREZ dosage in subsequent cycles should be reduced to 65 mg/m². In patients who require a further dose reduction, a dose of 50 mg/m² is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.
Prostate CancerCombination therapy With DOCEFREZ For Hormone-Refractory Metastatic Prostate Cancer
DOCEFREZ should be administered when the neutrophil count is ≥ 1,500 cells/mm³. Patients who experience either febrile neutropenia, neutrophils < 500 cells/mm³for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during DOCEFREZ therapy should have the dosage of DOCEFREZ reduced from 75 mg/m² to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued.
Combination Therapy with Strong CYP3A4 inhibitors: Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor..
Administration PrecautionsDOCEFREZ is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing DOCEFREZ solutions. The use of gloves is recommended. Please refer to.
If DOCEFREZ lyophilized powder, reconstituted solution, or infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If DOCEFREZ lyophilized powder, reconstituted solution or infusion solution should come into contact with mucosa, immediately and thoroughly wash with water.
Contact of the DOCEFREZ reconstituted solution with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the DOCEFREZ infusion solution should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
DOCEFREZ (Lyophilized Powder for Injection and Diluent)DOCEFREZ for Injection requires reconstitution with Diluent and one further dilution with infusion solution prior to administration. Please follow the preparation instructions provided below.
The table below provides the fill range of the Diluent, the volume of Diluent to be added for the reconstitution and the concentration of the reconstituted solution for DOCEFREZ 20 mg and DOCEFREZ 80 mg (See Table 1).
Table 1 : Reconstitution of DOCEFREZ (docetaxel) for
Injection
| Product | Fill Range of the Diluent (35.4% w/w ethanol in polysorbate 80) | Volume of Diluent to be added for the reconstitution | Concentration of the reconstituted solution |
| Docetaxel 20 mg vial | 1.10-1.15 mL | 1 mL | 20 mg/0.8 mL |
| Docetaxel 80 mg vial | 4.13-4.29 mL | 4 mL | 24 mg/mL |
Preparation of the Reconstituted Solution
The reconstituted DOCEFREZ solution should be clear; however, there may be some air bubbles in the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any air bubbles to dissipate.
The reconstituted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours.
Preparation of the Infusion Solution
The final DOCEFREZ infusion solution should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25o C) and lighting conditions.
StabilityDOCEFREZ infusion solution, if stored between 2°C and 25°C (36°F and 77°F) is stable for 6 hours. DOCEFREZ infusion solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 6 hours (including the 1 hour intravenous administration).
In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C (36°F and 46°F).
The most serious adverse reactions from docetaxel are:
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.
Clinical Trial Experience Breast CancerMonotherapy 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).
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/mm | 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/mm | 8 | 25 | 9 |
| Anemia | |||
| < 11 g/dL | 90 | 92 | 94 |
| < 8 g/dL | 9 | 31 | 8 |
| Febrile Neutropenia*** | 11 | 26 | 12 |
| Septic Death Non-Septic Death | |||
| Infections | 2 1 | 5 7 | 1 1 |
| 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 |
| *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 |
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Reversible marrow suppression was the major dose-limiting toxicity of docetaxel. 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/mm³with 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 ReactionsSevere hypersensitivity reactions have been reported. 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 RetentionFluid retention can occur with the use of DOCEFREZ.
Cutaneous ReactionsSevere skin toxicity is discussed elsewhere in the label. 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 ReactionsNeurologic reactions are discussed elsewhere in the label .
Gastrointestinal ReactionsNausea, 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 ReactionsHypotension 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 ReactionsInfusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein.
Hepatic ReactionsIn 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 AbnormalitiesHematologic 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).
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/mm | 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 |
| *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/m², ANC grade 4 and fever > 38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m², ANC grade 3/4 and fever > 38.1°C |
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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% |
|
| 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 |
| *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/m² dose NA = not available |
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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).
Lung CancerMonotherapy With Docetaxel For Unresectable, Locally Advanced Or Metastatic NSCLC Previously Treated With Platinum-Based Chemotherapy
Docetaxel 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.
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 |
| *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 ***COSTART term and grading system †Not Applicable; †† Not Done |
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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.
Table 6 : Adverse Reactions Regardless of Relationship
to Treatment in Chemotherapy-Naïve Advanced Non-Small Cell Lung Cancer Patients
Receiving Docetaxel in Combination with Cisplatin
| Docetaxel 75 mg/m + Cisplatin 75 mg/m² n=406 % |
Vinorelbine 25 mg/m + Cisplatin 100 mg/m² n=396 % |
|
| 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 | < 1 | < 1 |
| Weight gain | ||
| 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 | |
