Taxotere

Taxotere

docetaxel

Manufacturer:

sanofi-aventis

Distributor:

Zuellig
Full Prescribing Info
Contents
Docetaxel.
Description
Each 1 mL in 50/50 (v/v) polysorbate 80/ethanol (anhydrous) contains: Docetaxel as trihydrate 20 mg.
Each 4 mL in 50/50 (v/v) polysorbate 80/ethanol (anhydrous) contains: Docetaxel as trihydrate 80 mg.
Action
Pharmacology: Pharmacodynamics: Mode of Action/Pharmacodynamic Characteristics: Docetaxel acts by promoting the assembly of tubulin into stable microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The binding of docetaxel to microtubules does not alter the number of protofilaments.
Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is essential for vital mitotic and interphase cellular functions.
Docetaxel was found to be cytotoxic in vitro against various murine and human tumour cell lines and against freshly excised human tumour cells in clonogenic assays.
Docetaxel achieves high intracellular concentrations with a long cell residence time.
Docetaxel was found to be active on some but not all cell lines overexpressing the p glycoprotein which is encoded by the multidrug resistance gene.
In vivo, docetaxel is schedule independent and has a broad spectrum of experimental antitumour activity against advanced murine and human grafted tumours.
Clinical Efficacy/Clinical Studies: Breast cancer: Adjuvant breast cancer: Docetaxel (Taxotere) in combination with doxorubicin and cyclophosphamide; Patients with operable node positive breast cancer (TAX316).
Data from a multicenter open label randomized trial support the use of Docetaxel (Taxotere) for the adjuvant treatment of patients with operable node-positive breast cancer and KPS ≥80%. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either Docetaxel (Taxotere) 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (FAC arm). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel (Taxotere) was administered as a 1 hour infusion, all other drugs were given as IV bolus on day-1. G-CSF was administered as secondary prophylaxis to patients who experienced febrile neutropenia, prolonged neutropenia or neutropenic infection. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Two interim analyses and one final analysis were performed. The first interim and final analysis were performed: first analysis was performed with a median follow up of 56 months and final analysis was performed at the end of 10 years. The first interim analysis was planned 3 years after the date when half of study enrollment was done. The second interim analysis was done after 400 DFS events have been recorded overall, which led to a median follow-up of 55 months. The final analysis was performed when all patient have reached their 10-year follow-up visit (unless they had a DFS event or were lost to follow-up before). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint.
A final analysis was performed with an actual median follow up of 96 months. Significantly longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of relapses at 10 years was reduced in patients receiving TAC compared to those who received FAC (39% versus 45%, respectively) i.e. an absolute risk reduction by 6% (p = 0.0043). Overall survival at 10 years was also significantly increased with TAC compared to FAC (76% versus 68%, respectively) i.e. an absolute reduction of the risk of death by 7% (p = 0.002). As the benefit observed in patient with 4+ nodes was not statistically significant on DFS and OS, the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis.
Overall, the study results demonstrate a positive benefit risk ratio for TAC compared to FAC. The TAC regimen was demonstrated a statistically significant improvement over the FAC regimen for the primary efficacy endpoint of DFS as well as the secondary endpoint of OS in the ITT population. The greater benefit of TAC over FAC applied irrespective of nodal or hormone receptor status.
Patient subsets according to prospectively defined major prognostic factors were analyzed (see table as follows): See Table 1.

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Patients with operable node negative breast cancer with one or more high risk factors (GEICAM 9805): Data from a multicenter open label randomized trial (GEICAM 9805) support the use of Docetaxel (Taxotere) for the adjuvant treatment of patients with operable node negative breast cancer with one or more high risk factors (tumour size >2 cm, age <35 years, hormone receptor status negative, tumour grade 2 or 3). Among the 1060 patients with node-negative disease, 35.6% (192) were estrogen and progesterone receptors negative (ER- and PgR-), and 63.8% (344) were estrogen and/or progesterone receptors positive (ER and/or PgR+). 1060 patients were randomized to receive either Docetaxel (Taxotere) 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (539 patients in TAC arm), or doxorubicin 50 mg/m2 followed by 5-fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (521 patients in FAC arm). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel (Taxotere) was administered as a 1 hour infusion, all other drugs were given as IV bolus on day 1 every three weeks. Primary prophylactic G-CSF was made mandatory in TAC arm after 230 patients were randomized. The incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis (see Overdosage). In both arms, after the last cycle of chemotherapy, patients with ER+ and/or PgR + tumours received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was administered according to guidelines in place at participating institutions and was given to 57.3% of patients who received TAC and 51.2% of patients who received FAC.
One primary analysis and one updated analysis were performed. The primary analysis was done when all patients had a follow-up of greater than 5 years (median follow-up time of 77 months). The updated analysis was performed when all patients had reached their 10-year (median follow up time of 10 years and 5 months) follow-up visit (unless they had a DFS event or were lost to follow-up previously). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint.
At the median follow-up time of 77 months, significantly longer DFS for the TAC arm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in the risk of relapse compared to those treated with FAC [hazard ratio = 0.68, 95% CI (0.49-0.93), p = 0.01]. At the median follow up time of 10 years and 5 months, TAC-treated patients had a 16.5% reduction in the risk of relapse compared to those treated with FAC [hazard ratio = 0.84, 95% CI (0.65-1.08), p = 0.1646]. DFS data were not statistically significant but were still associated with a positive trend in favor of TAC.
At the median follow-up time of 77 months, OS was longer in the TAC arm with TAC-treated patients having a 24% reduction in the risk of death compared to FAC [hazard ratio = 0.76, 95% CI (0.46-1.26), p = 0.29]. However, the distribution of OS was not significantly different between the 2 groups. At the median follow up time of 10 years and 5 months, TAC-treated patients had a 9% reduction in the risk of death compared to FAC-treated patients [hazard ratio = 0.91, 95% CI (0.63-1.32)]. The survival rate was 93.7% in the TAC arm and 91.4% in the FAC arm, at the 8-year follow-up timepoint, and 91.3% in the TAC arm and 89% in the FAC arm, at the 10-year follow-up timepoint.
The positive benefit risk ratio for TAC compared to FAC remained unchanged.
TAC-treated patient subsets according to prospectively defined major prognostic factors were analyzed in the primary analysis (median follow-up time of 77 months) (see table as follows): See Table 2.

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Doxorubicin and cyclophosphamide followed by Docetaxel (Taxotere) in combination with trastuzumab, or Docetaxel (Taxotere) in combination with trastuzumab, and carboplatin.
The efficacy and safety of Docetaxel (Taxotere) in combination with trastuzumab was studied for the adjuvant treatment of patients with operable breast cancer whose tumors overexpress HER2 (with node positive and high risk node negative). A total of 3,222 women were randomized in the study, and 3,174 were treated with either: AC T, AC TH, or TCH.
AC T (control arm): Doxorubicin 60 mg/m2 IV in combination with cyclophosphamide 600 mg/m2 IV on an every 3 week basis for 4 cycles, followed by Docetaxel (Taxotere) 100 mg/m2 as a 1 hour IV infusion on an every 3 week basis for 4 cycles.
AC TH: Doxorubicin 60 mg/m2 IV in combination with cyclophosphamide 600 mg/m2 IV on an every 3 week basis for 4 cycles. Three weeks after the last cycle of AC, trastuzumab 4 mg/kg loading dose by IV infusion over 90 minutes on day 1 of cycle 5 was administered, followed by trastuzumab 2 mg/kg by IV infusion over 30 minutes weekly starting day 8 of cycle 5; and Docetaxel (Taxotere) 100 mg/m2 administered by IV infusion over 1 hour on day 2 of cycle 5, then on day 1 on an every 3 week basis for all subsequent cycles (total 4 cycles of Docetaxel (Taxotere)). Beginning three weeks after the last cycle of chemotherapy, trastuzumab 6 mg/kg by IV infusion over 30 minutes was given every 3 weeks (for 1 year from the date of first administration).
TCH: Trastuzumab 4 mg/kg loading dose by IV infusion over 90 minutes on day 1 of cycle 1 only, followed by trastuzumab 2 mg/kg by IV infusion over 30 minutes weekly starting on day 8 until three weeks after the last cycle of chemotherapy. Docetaxel (Taxotere) 75 mg/m2 was administered on day 2 of cycle 1, then on day 1 of all subsequent cycles by IV infusion over 1 hour followed by carboplatin (AUC 6 mg/mL/min) as a 30 to 60 minute IV infusion, for a total of six cycles of Docetaxel (Taxotere) and carboplatin. Beginning three weeks after the last cycle of chemotherapy, trastuzumab 6 mg/kg by IV infusion over 30 minutes was given every 3 weeks (for 1 year from the date of first administration).
The patients and disease characteristics at baseline were well balanced between the 3 treatment arms.
Disease Free Survival (DFS) was the primary endpoint, and Overall Survival (OS) was the secondary endpoint.
Results of the second interim analysis, performed with a median follow-up of 36 months, demonstrated that Docetaxel (Taxotere) and trastuzumab given concurrently as part of either an anthracycline-based (AC TH) or non-anthracycline-based (TCH) adjuvant treatment regimens, for patients with HER2-positive operable breast cancer, statistically significantly prolonged both DFS and OS compared with the control arm (AC T). The relative reduction in the risk of relapse was 39% (p <0.0001) and 33% (p = 0.0003) for the AC TH and TCH arms, respectively, compared with the AC T arm. The relative reduction in the risk of death was 42% (p = 0.0024) and 34% (p = 0.0182) for the AC TH and TCH arms, respectively, compared with the AC T arm. There was no statistically significant difference between the two trastuzumab-containing arms AC TH and TCH for DFS and OS. Efficacy results are summarized in the following table: See Table 3.

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There were 29% of patients with high risk node negative disease included in the study. The benefit observed for the overall population was irrespective of the nodal status. (See Table 4.)

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Metastatic breast cancer: Docetaxel (Taxotere) in combination with doxorubicin: One large randomized phase III study, involving 429 previously untreated patients with metastatic disease, has been performed with doxorubicin (50 mg/m2) in combination with docetaxel (75 mg/m2) (AT arm) versus doxorubicin (60 mg/m2) in combination with cyclophosphamide (600 mg/m2) (AC arm). Both regimens were administered once every 3 weeks.
Time to progression was significantly longer in the docetaxel arm versus in the control arm, p = 0.0138; Overall response rate observed was significantly higher in the docetaxel arm (59.3%) versus in the control arm (46.5%), p = 0.009; Time to treatment failure was significantly longer in the docetaxel arm versus in the control arm, p = 0.0479.
In this trial, the AT arm showed a higher incidence of severe neutropenia (90% versus 68.6%), febrile neutropenia (33.3% versus 10%), infection (8% versus 2.4%), diarrhea (7.5% versus 1.4%), asthenia (8.5% versus 2.4%), and pain (2.8% versus 0%) than the AC arm. On the other hand, the AC arm showed a higher incidence of severe anemia (15.8% versus 8.5%) than the AT arm, and, in addition, a higher incidence of severe cardiac toxicity without reaching the statistically significant level: congestive heart failure (3.8% versus 2.8%), absolute LVEF decrease ≥20% (13.1% versus 6.1%), absolute LVEF decrease ≥30% (6.2% versus 1.1%). Toxic deaths occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1 due to septic shock and 3 due to congestive heart failure).
In both arms, quality of life measured by the EORTC questionnaire was comparable and stable during treatment and follow-up.
Docetaxel (Taxotere) in combination with trastuzumab: Docetaxel (Taxotere) in combination with trastuzumab was studied for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2, and who previously had not received chemotherapy for metastatic disease. One hundred eighty six patients received TM (100 mg/m2) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant chemotherapy. Docetaxel (Taxotere) plus trastuzumab was efficacious in patients whether or not they had received prior adjuvant anthracyclines. The main test used to determine HER2 positivity in this pivotal trial was immunohistochemistry (IHC). A minority of patients were tested using fluorescence in-situ hybridization (FISH). In this trial, 87% of patients had disease that was IHC 3+, and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are summarized in the following table: (See Table 5.)

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Comment: Figures based on the 12 month analysis. Data from JCO 2005, 23 (19), page 4265, based on 24 month analysis.
Comment: CCDS version 13. Based on study M77001 (Roche study) with cut off analysis at 12 months. Submitted in 2004 in EU only. Publication from Journal of Clinical Oncology, Volume 23 _ number 19 _ july 1 2005 Randomized Phase II Trial of the Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Administered As First-Line Treatment: The M77001 Study Group" showed results with cut off at 24 months.
Docetaxel (Taxotere) as single agent: Six phase II studies were conducted in patients with locally advanced or metastatic breast carcinoma. A total of 117 patients had received no prior chemotherapy (previously untreated) and 111 patients had received prior chemotherapy (previously treated) which included 83 patients who had progressive disease during anthracycline therapy (anthracycline resistant). In these clinical trials, docetaxel was administered at a 100 mg/m2 dose given as a one-hour infusion every 3 weeks.
Overall response rate (ORR) was 56% in the anthracycline resistant patients with a 4.4% complete response rate (CR); A 46% ORR was observed in the anthracycline refractory patients with 7.3% CR; Median duration of response was 27 weeks in the anthracycline resistant patients and 28 weeks in the anthracycline refractory patients; Median survival time was 11 months in the anthracycline-resistant patients; There was a high response rate in patients with visceral metastases, 53.1% in the 49 anthracycline resistant patients; In anthracycline resistant patients, a significant response rate of 40% was seen in patients with liver metastases; A 63.2% response rate was observed in patients with soft tissue disease.
Comment: CCDS version 1.
Two randomized phase III comparative studies, involving a total of 326 alkylating or 392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the recommended dose and regimen of 100 mg/m2 administered every 3 weeks.
In alkylating failure patients, docetaxel was compared to doxorubicin (75 mg/m2 every 3 weeks): Overall survival time: docetaxel 15 months versus 14 months, p = 0.38; Time to progression: docetaxel 27 weeks versus 23 weeks, p = 0.54; Response rate: docetaxel 52% versus 37%, p = 0.01; Time to response: docetaxel 12 weeks versus 23 weeks, p = 0.007.
Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas 15 doxorubicin patients (9%) discontinued due to cardiac toxicity (three fatal congestive heart failure).
In anthracycline failure patients, docetaxel was compared to the combination of mitomycin C and vinblastine (12 mg/m2 every 6 weeks and 6 mg/m2 every 3 weeks): Overall survival time: docetaxel 11 months versus 9 months, p = 0.01; Time to progression: docetaxel 19 weeks versus 11 weeks, p = 0.0004; Response rate: docetaxel 33% versus 12%, p = 0.0001.
An open-label, multicenter, randomized phase III study was conducted to compare Docetaxel (Taxotere) and paclitaxel in the treatment of advanced breast cancer in patients whose previous therapy should have included an anthracycline. A total of 449 patients were randomized to receive either Docetaxel (Taxotere) 100 mg/m2 as a 1 hour infusion or paclitaxel 175 mg/m2 as a 3 hour infusion. Both regimens were administered every 3 weeks. Efficacy results are described in the following table. (See Table 6.)

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The most frequent adverse events reported for Docetaxel (Taxotere) were neutropenia, febrile neutropenia, gastrointestinal disorders, neurologic disorders, asthenia and fluid retention. More grade 3/4 events were observed for Docetaxel (Taxotere) (55.4%) compared to paclitaxel (23.0%). No unexpected toxicities were reported for Docetaxel (Taxotere).
During these phase III studies, the safety profile of docetaxel was consistent with the safety profile observed in phase II studies (see Overdosage).
Docetaxel (Taxotere) in combination with capecitabine: Data from one multicenter, randomised, controlled phase III clinical trial support the use of Docetaxel (Taxotere) in combination with capecitabine for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this trial, 255 patients were randomized to treatment with Docetaxel (Taxotere) (75 mg/m2 as a 1-hour intravenous infusion every 3 weeks) and capecitabine (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period). 256 patients were randomized to treatment with Docetaxel (Taxotere) alone (100 mg/m2 as a 1-hour intravenous infusion every 3 weeks). Survival was superior in the Docetaxel (Taxotere)+capecitabine combination arm (p = 0.0126). Median survival was 442 days (Docetaxel (Taxotere)+capecitabine) vs. 352 days (Docetaxel (Taxotere) alone). The overall objective response rates in the all randomized population (investigator assessment) were 41.6% (Docetaxel (Taxotere)+capecitabine) vs. 29.7% (Docetaxel (Taxotere) alone); p = 0.0058. Time to disease progression or death was superior in the Docetaxel (Taxotere)+capecitabine combination arm (p<0.0001). The median time to progression was 186 days (Docetaxel (Taxotere)+capecitabine) vs. 128 days (Docetaxel (Taxotere) alone).
Non-small cell lung cancer: The efficacy and safety of Docetaxel (Taxotere) administered in chemotherapy naïve patients or in patients who have failed prior platinum-based chemotherapy have been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer.
Chemotherapy naïve patients: Docetaxel (Taxotere) as single agent: One phase III study comparing docetaxel (at a dose of 100 mg/m2 as a 1-hour intravenous infusion, once every 3 weeks) plus best supportive care (BSC) versus best supportive care has been conducted. This global multicenter trial enrolled 207 randomised patients stratified according to the extent of the disease: unresectable locally advanced disease (stage IIIb) versus metastatic disease (stage IV).
The overall survival was significantly longer in patients in the docetaxel arm (p = 0.026) compared to patients of the BSC arm. The 1-year survival rate was 25% for docetaxel versus 16% for BSC.
The overall response rate in the evaluable patients was 19.6% with a median duration of response of 37.1 weeks. The overall time to progression was significantly longer (p<0.001) in favour of docetaxel (median: 12.7 weeks) versus BSC (median: 8.9 weeks).
Other clinical benefit parameters: There was a significant improvement of clinical benefit in the docetaxel-treated patients demonstrated by less use of radiotherapy (p<0.01), disease-related medications other than for pain (p<0.01), morphinic analgesics (p<0.001) and non-morphinic analgesics (p<0.001).
Quality of life assessed on the EORTC QLQ C30 questionnaire showed significant trends favouring docetaxel compared to BSC in emotional functioning (p = 0.01), pain (p<0.001) and dyspnea (p<0.01).
Combination Therapy with Docetaxel (Taxotere) in NSCLC: In a phase III trial, 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive either Docetaxel (Taxotere) 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m2 over 30-60 minutes every 3 weeks, Docetaxel (Taxotere) 75 mg/m2 as a 1 hour infusion immediately followed by carboplatin (Cb) (AUC 6 mg/mL•min) over 30 to 60 minutes every 3 weeks or vinorelbine (V) 25 mg/m2 administered over 6-10 minutes on days 1, 8, 15, 22 followed by Cis 100 mg/m2 administered on day 1 of cycles repeated every 4 weeks. Outcome measures included survival, response rate and quality of life assessments.
Median survival in the Docetaxel (Taxotere) + Cis group was 11.3 months compared to 10.1 months in the V + Cis group, the 2-year survival rate was 21% and 14% respectively. The hazard ratio was 1.183, in favor of Docetaxel (Taxotere) + Cis (95% CI = 1.008 1.388). There was non-overlapping separation of the survival curves that started at 4 months post randomization and remained throughout the study. The overall response rate was higher in the Docetaxel (Taxotere) + Cis group compared with the vinorelbine + cisplatin group (31.6% vs. 24.5%). The median duration of response was comparable between the 2 groups (32 weeks vs. 34 weeks), as was the median time to progression (22.0 weeks vs. 23.0 weeks).
Survival data, median time to progression, response rates, Quality of life (QoL) and clinical benefit for all three arms of the study are illustrated in the following table: See Table 7.

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The combination Docetaxel (Taxotere) + Cb shows similar activity in survival as V+Cis, and is tolerable with limited incidences of nausea, vomiting, anemia, neurotoxicity, renal dysfunction and low incidence in discontinuation due to adverse events.
Other clinical benefit parameters such as changes of pain scores, global rating of QOL by EuroQoL 5D (EQ5D), Lung Cancer Symptom Scale (LCSS), and changes in performance status and body weight consistently indicated benefit for the Docetaxel (Taxotere)+Cis group.
Global quality of life and clinical benefit parameters were improved in the Docetaxel (Taxotere)+Cb treatment group. Patients receiving Docetaxel (Taxotere)+Cb experienced less severe weight loss (p<0.001), and had better performance status (p<0.001), than patients on the control therapy, V+Cis. The patients with Docetaxel (Taxotere)+Cb showed a significantly better response on the LCSS global and EQ5D global compared to the V+Cis patients (longitudinal analysis p = 0.016 and p<0.001, respectively).
Docetaxel (Taxotere) treatment after failure of platinum-based therapy: Six phase II studies were conducted in patients with locally advanced or metastatic non-small cell lung cancer. A total of 160 patients had received no prior chemotherapy (previously untreated), and 88 patients had received prior platinum-based therapy (previously treated), which included 37 patients who had progressive disease with platinum therapy (platinum refractory). In these clinical trials, Docetaxel (Taxotere) was administered at a 100 mg/m2 dose given as a one-hour infusion every 3 weeks.
Overall response rate (ORR) for evaluable previously untreated patients was 31%. For the evaluable previously treated patients the ORR was 19%.
Median survival time for all previously untreated patients or previously treated patients was 9 and 8 months, respectively.
Median duration of response for previously untreated patients or previously treated patients was 25 and 29 weeks, respectively.
Median time to progression for previously both untreated patients or previously treated patients was 14 weeks.
Phase III studies: In a Phase III multicenter study conducted in the United States, 373 locally advanced or metastatic NSCLC patients in whom prior chemotherapy has failed were randomized into three treatment groups: docetaxel 100 mg/m2 (D/100) [n = 125] as a 1-hour I.V. infusion every 3 weeks or; docetaxel 75 mg/m2 (D/75) [n = 125] as a 1-hour I.V. infusion every 3 weeks or; according to physicians choice, either vinorelbine (30 mg/m2 [n = 89] as an I.V. infusion on day 1, 8, and 15 repeated every 3 weeks) or ifosfamide (2 g/m2 [n = 34] on day 1, 2, and 3 of repeated every 3 weeks).
Comment: FSR Tax 320 p.35.
Survival analysis including all patients but excluding survival time after subsequent chemotherapy, shows that the 1 year survival rate is higher in each docetaxel group (32%) compared to 10% in vinorelbine (V) or isofosfamide (I) control group. Among patients followed up at least one year before subsequent chemotherapy, the 1-year survival was significantly different in favor of the docetaxel group (16% alive) compared to the V or I group (5% alive) [p = 0.023]. Comment: FSR Tax 320 p.86.
Response rate for the D/100 group was statistically significantly higher than the V/I control group in the evaluable patient analysis (11.9% versus 1%; p = 0.001). In the D/75 group, the response rate was also statistically significantly higher than the V/I control group (7.5% versus 1.0%; p = 0.036). These results were both confirmed in the ITT population. The combined docetaxel groups had a statistically significant higher response rate than the V/I control group (p = 0.003) and it was confirmed in the ITT population. Comment: FSR Tax 320 p.90.
The overall time to progression (TTP) was significantly longer for the D/100 group compared to the V/I control group in evaluable patients (8.4 versus 7.6 weeks, p = 0.020). TTP was longer in the D/75 population versus the V/I control group (8.1 versus 7.6 weeks, p = 0.09). TTP of the combined docetaxel groups was significantly longer compared to the V/I treatment group in the evaluable population (p = 0.031). These results were confirmed in the ITT population.
Quality of Life (QoL): The Lung Cancer Symptom Scale (LCSS), a lung cancer specific Quality of Life instrument, was used to assess QoL of patients in this study. There was a significant difference in QoL in the D/100 group compared to the V/I treatment group (p<0.05) with respect to patient total score, fatigue, lung cancer symptoms and observer total score. For responders or patients with disease stabilization while on treatment, there is a clear improvement in QoL with both D/100 and D75.
In a second multicenter phase III study, 204 locally advanced or metastatic NSCLC patients in whom prior chemotherapy failed were randomized into two treatment groups: Docetaxel 100 [n = 49] or 75 [n = 55] mg/m2 as a 1-hour intravenous infusion every 3 weeks versus; Best Supportive Care (BSC) [n = 100].
The median survival was 7.2 months for the combined docetaxel patients versus 4.6 months for the supportive care patients (p = 0.14). However, in patients treated with docetaxel at 75 mg/m2, overall survival was significantly longer (p = 0.016) in favour of docetaxel versus BSC with median survival of 9 months versus 4.6 months, respectively. The 1-year survival was also significantly longer (p = 0.016) in docetaxel (40%) versus BSC (16%).
The median time to progression was significantly longer (p<0.001) in the combined docetaxel patients (median: 10.6 weeks) versus BSC (median: 6.7 weeks), and was also significantly longer in sub-group of patients treated with docetaxel at 75 or 100 mg/m2.
The overall response rate was 7.6% in the evaluable patients, and the median duration of response was 26.1 weeks.
Other clinical benefit parameters: There was less use of morphinic analgesic (p<0.01), non-morphinic analgesics (p<0.01), other disease-related medications (p = 0.06) and radiotherapy (p<0.01) in patients treated with docetaxel at 75 mg/m2 compared to those with BSC. Similar results were also seen in the combined docetaxel doses versus BSC.
Quality of life assessed on the LCSS, showed a trend in favour of docetaxel, especially in the patient-rated pain and observer-rated fatigue and pain scores. Comment: TAX 317.
Prostate Cancer: The safety and efficacy of Docetaxel (Taxotere) in combination with prednisone or prednisolone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter Phase III trial. A total of 1006 patients with KPS≥60 were randomized to the following treatment groups: Docetaxel (Taxotere) 75 mg/m2 every 3 weeks for 10 cycles; Docetaxel (Taxotere) 30 mg/m2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles; Mitoxantrone 12 mg/m2 every 3 weeks for 10 cycles.
All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily, continuously. Patients who received docetaxel every three weeks demonstrated significantly longer overall survival compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for the Docetaxel (Taxotere) arms versus the control arm are summarized in the following table: See Table 8.

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Other clinical benefit parameters: No statistical differences were observed between treatment groups for Global Quality of Life.
Gastric Adenocarcinoma: A multicenter, open-label, randomized trial, was conducted to evaluate the safety and efficacy of Docetaxel (Taxotere) for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either Docetaxel (Taxotere) (T) (75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and 5-fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The median number of cycles administered per patient was 6 (with a range of 1 16) for the TCF arm compared to 4 (with a range of 1 12) for the CF arm. Time to progression (TTP) was the primary endpoint. The risk reduction of progression was 32.1% and was associated with a significantly longer TTP (p = 0.0004) in favor of the TCF arm. Overall survival was also significantly longer (p = 0.0201) in favor of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized in the following table: See Table 9.

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Subgroup analyses across age, gender and race consistently favored the TCF arm compared to the CF arm.
Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favor of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global health status on the QLQ-C30 questionnaire (p = 0.0121) and a longer time to definitive worsening of Karnofsky performance status (p = 0.0088).
Head and neck cancer: Induction chemotherapy followed by radiotherapy (TAX323): The safety and efficacy of Docetaxel (Taxotere) in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with locally advanced inoperable SCCHN, and WHO perfomance status 0 or 1, were randomized to one of two treatment arms. Patients on the Docetaxel (Taxotere) arm received Docetaxel (Taxotere) (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 on Day 1, followed by 5-fluorouracil (F) 750 mg/m2 per day as a continuous infusion on Days 1 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 on Day 1, followed by 5-fluorouracil (F) 1000 mg/m2 as a continuous infusion on Days 1 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction (1.8 Gy 2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed following chemotherapy, before or after radiotherapy. The primary endpoint in this study, progression free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.5 months respectively) with a 28% risk reduction of mortality, p = 0.0128. (See Table 10.)

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Clinical benefit parameters: Patients treated with TPF experienced significantly less deterioration of their Global health score compared to those treated with PF (p = 0.01, using the EORTC QLQ-C30). The performance status scale, for head and neck subscales designed to measure disturbances of speech and eating, was also significantly in favor of TPF. Median time to first deterioration of WHO performance status was longer in the TPF arm compared to PF, with a 30.5% deterioration of PSWHO risk reduction (p = 0.0158) in favor of the TPF arm.
Induction chemotherapy followed by chemoradiotherapy (TAX324): The safety and efficacy of Docetaxel (Taxotere) in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label, phase III, trial (TAX324).
In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two arms. Patients on the Docetaxel (Taxotere) arm received Docetaxel (Taxotere) (T) 75 mg/m2 by IV infusion on day 1 followed by cisplatin (P) 100 mg/m2 administered as a 30 minute to three hour IV infusion, followed by the continuous IV infusion of fluorouracil (F) 1000 mg/m2/day from day 1 to day 4. The cycles wersee repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receive chemoradiotherapy (CRT) as per protocol (TPF/CRT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 as a 30 minute to three hour IV infusion on day 1 followed by the continuous IV infusion of fluorouracil (F) 1000 mg/m2/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receive CRT as per protocol (PF/CRT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 as a 30 minute to three-hour IV infusion on day 1 followed by the continuous IV infusion of fluorouracil (F) 1000 mg/m2/day from 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receive CRT as per protocol (PF/CRT).
Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapy with a minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 to day 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one hour IV infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks, for a total dose of 70 to 72 Gy).
Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT.
The primary efficacy endpoint in this study, overall survival (OS) was significantly longer (log-rank test, p = 0.0058) with the Docetaxel (Taxotere)-containing regimen compared to PF (median OS: 70.6 versus 30.1 months respectively), with a 30% risk reduction in mortality compared to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54 0.90). The secondary endpoint, PFS, demonstrated a 29% risk reduction of progression or death and a 22 month improvement in median PFS (35.5 months for TPF and 13.1 for PF). This was also statistically significant with an HR of 0.71; 95% CI 0.56-0.90; log-rank test p = 0.004. Efficacy results are presented in the table as follows: (See Table 11.)

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Pediatrics: Docetaxel (Taxotere) has been tested in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluoruracil (TCF) (see as follows).
Monotherapy: Docetaxel (Taxotere) 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 TAXOTERE 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 tumours. Enrolled patients were 61.8% male, 61.8% Caucasian, 18% Hispanic, 13.5% Black and 6.7% other. Efficacy was not established.
Overall, the safety profile of Docetaxel (Taxotere) monotherapy from these 2 trials in pediatric patients was consistent with the known safety profile observed in adults.
Docetaxel (Taxotere) in combination: Docetaxel (Taxotere) was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Fifty patients (median age 16 years, range 9-21 years); 70% male, 64% Caucasian, 26% Asian, 4% Black, 6% other received Docetaxel (Taxotere) (75 mg/m2) in combination with cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2) (TCF) versus 25 patients who received cisplatin (80 mg/m2) and 5-fluorouracil (1000 mg/m2/day) (CF).
Overall complete response rate after induction treatment of NPC showed 1 patient out of 50 in the TCF group (2.0%) had a complete response while none of the 25 patients in the CF group had a complete response212. The safety findings with TCF in pediatric patients were similar to those with TCF in adults.
In conclusion, the overall safety profile of Docetaxel (Taxotere) in pediatric patients was consistent with the known safety profile in adults.
Pharmacokinetics: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-115 mg/m2 in phase I studies.
The kinetic profile of docetaxel is dose independent and 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 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment.
Following the administration of a 100 mg/m2 dose given as a one-hour infusion a mean peak plasma level of 3.7 μg/mL was obtained with a corresponding AUC of 4.6 h•μg/mL. Mean values for total body clearance and steady-state volume of distribution were 21 L/h/m2 and 113 L, respectively. Interindividual variation in total body clearance was approximately 50%.
Docetaxel is more than 95% bound to plasma proteins.
A study of 14C-docetaxel has been conducted in three cancer patients. Within seven days, docetaxel was eliminated in both the urine and faeces following cytochrome P450 mediated oxidative metabolism of the tert-butyl ester group. The urinary and faecal excretion accounted for about 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces is excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites and very low amounts of unchanged drug.
A population pharmacokinetic analysis has been performed with docetaxel in 577 patients. Pharmacokinetic parameters estimated by the model were very close to those estimated from Phase I studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient.
In a small number of patients (n = 23) with clinical chemistry data suggestive of mild to moderate liver function impairment (ALT, AST ≥1.5 times the ULN associated with alkaline phosphatase ≥2.5 times the ULN), total clearance was lowered by 27% on average. Docetaxel clearance was not modified in patients with mild to moderate fluid retention and there is no data available in patients with severe fluid retention.
When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite).
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide, studied in 30 patients with breast cancer, were not influenced by their coadministration.
Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and the effect of docetaxel on the pharmacokinetics of capecitabine showed no effect by capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC) and no effect by docetaxel on the pharmacokinetics of 5'DFUR (the most important metabolite of capecitabine).
Clearance of docetaxel in combination therapy with cisplatin or carboplatin was similar to that observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is similar to that observed with cisplatin alone.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the pharmacokinetics of docetaxel was observed.
The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug.
Pediatric: Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials.
Following docetaxel administration at 55 235 mg/m2 in a 1-h infusion every 3 weeks in 26 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 20.3±10.9 L/h/m2.
In combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m2 IV day 1 in 26 patients aged 10 to 21 years (median 16 years), docetaxel clearance was 27.1±11.4 L/h/m2, corresponding to an AUC of 3.43±2.05 (range: 1.64 8.82) μg.h/mL.
In summary, the pharmacokinetic parameters of docetaxel monotherapy and TCF combination in children were comparable to those in adults.
Toxicology: Non-Clinical Safety Data: Carcinogenicity: The carcinogenic potential of docetaxel has not been studied.
Mutagenicity: Docetaxel has been shown to be mutagenic in the in vitro micronucleus and chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in the mouse. However, it did not induce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent with the pharmacological activity of docetaxel.
Impairment of Fertility: Adverse effects on the testis observed in rodent toxicity studies suggest that docetaxel may impair male fertility.
Indications/Uses
Breast Cancer: Adjuvant breast cancer: Docetaxel (Taxotere) in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with: operable node-positive breast cancer; operable node-negative breast cancer (with one or more high risk factors [see Pharmacology: Pharmacodynamics under Actions]).
Doxorubicin and cyclophosphamide followed by Docetaxel (Taxotere) in combination with trastuzumab (AC TH) is indicated for the adjuvant treatment of patients with operable breast cancer whose tumors overexpress HER2.
Metastatic breast cancer: Docetaxel (Taxotere) in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition.
Docetaxel (Taxotere) in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2 and who previously have not received chemotherapy for metastatic disease.
Docetaxel (Taxotere) in monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent.
Docetaxel (Taxotere) in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.
Non-Small Cell Lung Cancer: Docetaxel (Taxotere) in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not previously received chemotherapy for this condition. Docetaxel (Taxotere) in combination with carboplatin represents a treatment option to cisplatin-based therapy (see Overdosage and Pharmacology: Pharmacodynamics under Actions).
Docetaxel (Taxotere) is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.
Prostate Cancer: Docetaxel (Taxotere) in combination with prednisone or prednisolone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.
Gastric Adenocarcinoma: Docetaxel (Taxotere) in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.
Head and Neck Cancer: Docetaxel (Taxotere) in combination with cisplatin and 5-fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck.
Dosage/Direction for Use
General: Premedication consisting of a corticosteroid (see Prostate cancer as follows), such as oral dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can be used (see Precautions).
For prostate cancer, given the concurrent use of prednisone or prednisolone, the recommended premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the Docetaxel (Taxotere) infusion (see Precautions).
Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities.
Docetaxel is administered as a one-hour infusion every three weeks.
Breast Cancer: Adjuvant breast cancer: In the adjuvant treatment of operable node positive and node negative breast cancer, the recommended Docetaxel (Taxotere) dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses (TAC regimen) (see also Dosage adjustments as follows).
In the adjuvant treatment of patients with operable breast cancer whose tumors overexpress HER2 the recommended Docetaxel (Taxotere) dose is as follows: AC TH: AC (cycles 1-4): doxorubicin (A) 60 mg/m2 followed by cyclophosphamide (C) 600 mg/m2 administered every three weeks for 4 cycles.
TH (cycles 5-8): docetaxel (T) 100 mg/m2 administered every three weeks for 4 cycles, and trastuzumab (H) administered weekly according the following schedule: Cycle 5 (starting three weeks after the last cycle of AC): Day 1: trastuzumab 4 mg/kg (loading dose); Day 2: docetaxel 100 mg/m2; Days 8 and 15: trastuzumab 2 mg/kg.
Cycles 6-8: Day 1: docetaxel 100 mg/m2 and trastuzumab 2 mg/kg; Days 8 and 15: trastuzumab 2 mg/kg.
Three weeks after day 1 of cycle 8: trastuzumab 6 mg/kg is given every three weeks.
Trastuzumab is administered for a total duration of 1 year.
TCH: TCH (cycles 1-6): docetaxel (T) 75 mg/m2 and carboplatin (C) at AUC of 6 mg/mL/min administered every three weeks and trastuzumab (H) administered weekly according the following schedule: Cycle 1: Day 1: trastuzumab 4 mg/kg (loading dose); Day 2: docetaxel 75 mg/m2 and carboplatin at AUC of 6 mg/mL/min; Days 8 and 15: trastuzumab 2 mg/kg.
Cycles 2-6: Day 1: docetaxel 75 mg/m2 followed by carboplatin at AUC of 6 mg/mL/min and trastuzumab 2 mg/kg; Days 8 and 15: trastuzumab 2 mg/kg.
Three weeks after day 1 of cycle 6: trastuzumab 6 mg/kg is given every three weeks.
Trastuzumab is administered for a total duration of 1 year.
Metastatic breast cancer: In first-line treatment of breast cancer, docetaxel 75 mg/m2 is administered in combination therapy with doxorubicin 50 mg/m2.
For the Docetaxel (Taxotere) plus trastuzumab combination the recommended Docetaxel (Taxotere) dose is 100 mg/m2 every three weeks, with trastuzumab administered weekly. For trastuzumab dosage and administration, see local package insert.
For the second line treatment of breast cancer, the recommended dosage of docetaxel is 100 mg/m2 as a single agent.
The recommended dosage of docetaxel is 75 mg/m2 every three weeks, when combined with capecitabine administered orally at 1250 mg/m2 twice daily (within 30 minutes after a meal) for 2 weeks followed by a 1-week rest period. For capecitabine dose calculation according to body surface area, see local package insert (see Preparation and Handling under Cautions for Usage).
Non-small cell lung cancer: In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen is docetaxel 75 mg/m2 immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes or carboplatin (AUC 6 mg/mL/min) over 30 to 60 minutes.
For treatment after failure of prior platinum-based chemotherapy, the recommended dose is docetaxel 75 mg/m2 as a single agent. (See Preparation and Handling under Cautions for Usage).
Prostate cancer: For prostate cancer, the recommended dose of Docetaxel (Taxotere) is 75 mg/m2 every 3 weeks. Prednisone or prednisolone 5 mg orally twice daily is administered continuously.
Gastric adenocarcinoma: For gastric adenocarcinoma, the recommended dose of Docetaxel (Taxotere) is 75 mg/m2 as a 1 hour infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/m2 per day given as a 24 hour continuous infusion for 5 days, starting at the end of the cisplatin infusion.
Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate the risk of hematological toxicities. (See Dosage adjustments as follows).
Head and neck cancer: Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients on the Docetaxel (Taxotere) containing arm of the TAX 323 and TAX 324 studies received prophylactic antibiotics.
Induction chemotherapy followed by radiotherapy (TAX 323): For the induction treatment of locally advanced inoperable squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of Docetaxel (Taxotere) is 75 mg/m2 as a 1 hour infusion followed by cisplatin 75 mg/m2 over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.
Induction chemotherapy followed by chemoradiotherapy (TAX 324): For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel (Taxotere) is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30 minute to 3 hour infusion, followed by 5-fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.
For cisplatin and 5-fluorouracil dose modifications, see local package insert.
Dosage adjustments: General: Docetaxel should be administered when the neutrophil count is ≥1,500/mm3. Patients who experienced either febrile neutropenia, neutrophils <500/mm3 for more than one week, severe or cumulative cutaneous reactions or severe neurosensory signs and/or symptoms during docetaxel therapy should have the dosage of docetaxel reduced from 100 to 75 mg/m2, and/or from 75 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.
Combination therapy with Docetaxel (Taxotere) for Breast Cancer: Primary G-CSF prophylaxis should be considered in patients who receive Docetaxel (Taxotere), doxorubicin, and cyclophosphamide (TAC) adjuvant therapy for breast cancer (see Precautions and Adverse Reactions). Patients who experience febrile neutropenia and/or neutropenic infection should have their Docetaxel (Taxotere) dose reduced to 60 mg/m2 in all subsequent cycles. Patients who experience Grade 3 or 4 stomatitis should have their dose decreased to 60 mg/m2.
Patients who received AC TH or TCH adjuvant therapy for operable breast cancer whose tumors overexpress HER2 and who experience an episode of febrile neutropenia or infection should receive prophylactic G-CSF in all subsequent cycles. For a second episode of febrile neutropenia or infection, patients should continue prophylactic G-CSF, and Docetaxel (Taxotere) will be reduced from 100 mg/m2 to 75 mg/m2 (in the AC TH regimen); Docetaxel (Taxotere) will be reduced from 75 mg/m2 to 60 mg/m2 (in the TCH regimen).
However, in clinical practice neutropenia could occur in cycle 1. Thus, G-CSF should be used in consideration of the neutropenic risk of the patient and current recommendations. Depending on the treatment regimen, patients who experience Grade 3 or 4 stomatitis should have their dose decreased from 100 mg/m2 to 75 mg/m2 (in the AC TH regimen) or from 75 mg/m2 to 60 mg/m2 (in the TCH regimen).
For capecitabine dose modifications when combined with docetaxel, see local package insert. For patients developing the first appearance of a Grade 2 toxicity which persists at the time of the next Docetaxel (Taxotere)/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume at 100% of the original dose.
For patients developing the second appearance of a Grade 2 toxicity, or the first appearance of a Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0-1, then resume treatment with Docetaxel (Taxotere) 55 mg/m2. For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the Docetaxel (Taxotere) dose.
For Docetaxel (Taxotere) dose modifications due to hepatic impairment, (see Precautions).
Combination therapy with Docetaxel (Taxotere) for NSCLC: For patients who are dosed initially with docetaxel 75 mg/m2 in combination with cisplatin or carboplatin, and whose nadir platelet count during the previous course of therapy is <25,000/mm3 (with cisplatin) and <75,000/mm3 (with carboplatin) or in patients who experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the docetaxel dosage in subsequent cycles should be reduced to 65 mg/m2. For cisplatin dosage adjustments, see local package insert.
Docetaxel (Taxotere) in combination with cisplatin and 5-fluorouracil in gastric cancer or head and neck cancer.
Patients treated with Docetaxel (Taxotere) in combination with cispatin and 5-fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. G-CSF should be administered to mitigate the risk of complicated neutropenia.
If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the Docetaxel (Taxotere) dose should be reduced from 75 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel (Taxotere) dose should be reduced from 60 to 45 mg/m2. In case of Grade 4 thrombocytopenia the Docetaxel (Taxotere) dose should be reduced from 75 to 60 mg/m2. Patients should not be retreated with subsequent cycles of Docetaxel (Taxotere) until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist. (See Precautions). (See Table 12.)

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For cisplatin and 5-fluorouracil dosage adjustments, see local package insert.
Special Populations: Children: Efficacy has not been established in children (see Pharmacology: Pharmacodynamics: Pediatrics and Pharmacokinetics: Pediatric under Actions).
Elderly: Based on a population pharmacokinetic analysis, there are no special instructions for the use of Docetaxel (Taxotere) in elderly.
For capecitabine dosage reduction when combined with docetaxel, see capecitabine local package insert.
Hepatic impairment: Patients with hepatic impairment: based on pharmacokinetic data obtained with Docetaxel (Taxotere) at 100 mg/m2 as a single agent, patients who have elevations of both transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel is 75 mg/m2. For those patients with serum bilirubin >ULN and/or ALT and AST >3.5 times the ULN associated with alkaline phosphatase >6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by Docetaxel (Taxotere) in combination.
Renal impairment: Administration: Intravenous infusion.
Overdosage
Signs and Symptoms: There have been a few reports of overdose.
Management: In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. There is no known antidote for docetaxel overdose. The primary anticipated complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.
Contraindications
Docetaxel (Taxotere) is contraindicated: in patients who have a history of severe hypersensitivity reactions to the drug or polysorbate 80; in patients with baseline neutrophil counts of <1,500/mm3; in pregnant women; in patients with severe liver impairment.
Contraindications for other drugs also apply when combined with Docetaxel (Taxotere).
Special Precautions
An oral corticosteroid (see prostate cancer as follows) such as dexamethasone 16 mg per day (e.g, 8 mg BID) for 3 days starting one day prior to docetaxel administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.
The pretreatment regimen for prostate cancer is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the Docetaxel (Taxotere) infusion.
Neutropenia: Neutrophil nadirs occurred at a median of 7 days but this interval may be shorter in heavily pretreated patients. Frequent monitoring of complete blood counts should be conducted in all patients receiving docetaxel. Patients should be retreated with docetaxel only when neutrophils recover to a level ≥1,500/mm3 (see Dosage & Administration).
In patients treated with Docetaxel (Taxotere) in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received prophylactic G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF should be closely monitored (see Dosage & Administration and Adverse Reactions).
In patients treated with Docetaxel (Taxotere) in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received primary prophylactic G-CSF.
Primary G-CSF prophylaxis should be considered in patients who receive adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be closely monitored (see Dosage & Administration and Adverse Reactions).
Gastrointestinal reactions: Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Enterocolitis could develop at any time, and could lead to death as early as on the first day of onset. Patients should be closely monitored for early manifestations of serious gastrointestinal toxicity. (See Dosage & Administration, Neutropenia as previously mentioned and Adverse Reactions).
Hypersensitivity Reactions: Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. Severe reactions, such as generalised rash/erythema, severe hypotension, bronchospasm or very rarely fatal anaphylaxis, have been reported in patients who received premedication. Hypersensitivity reactions require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with docetaxel.
Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a potentially fatal hypersensitivity reaction to docetaxel.
Cutaneous reactions: Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema followed by desquamation has been observed.
Fluid retention: Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely.
Patients with liver impairment: In patients treated with docetaxel at 100 mg/m2 as a single agent who have serum transaminase levels (ALT and /or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia.
The recommended dose of docetaxel in patients with elevated liver function tests (LFTs) is 75 mg/m2. LFTs should be measured at baseline and before each cycle.
For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 times the ULN concurrent with serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.
No data are available in patients with hepatic impairment treated with docetaxel in combination.
The amount of ethanol in Docetaxel (Taxotere) should be taken into account when given to patients with hepatic impairment (see Excipients as follows).
Nervous System: The development of severe neurosensory signs and/or symptoms has been observed and requires a reduction of dose.
Cardiac toxicity: Heart failure has been observed in patients receiving Docetaxel (Taxotere) in combination with trastuzumab, particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy. This may be moderate to severe and has been associated with death (see Adverse Reactions).
Ventricular arrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide (see Adverse Reactions).
Baseline cardiac assessment is recommended.
Eye disorders: Cystoid macular oedema (CMO) has been reported in patients treated with docetaxel, as well as with other taxanes. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is diagnosed, docetaxel treatment should be discontinued and appropriate treatment initiated (see Adverse Reactions).
Second primary malignancies: Second primary malignancies have been reported when docetaxel was given in combination with anticancer treatments known to be associated with second primary malignancies. Second primary malignancies (including acute myeloid leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma and renal cancer) may occur several months or years after docetaxel-containing therapy. Patients should be monitored for second primary malignancies (see Adverse Reactions).
Interactions: The concomitant use of Docetaxel (Taxotere) with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided (see Interactions).
Excipients: polysorbate 80; ethanol (anhydrous) (395 mg/mL).
For 20 mg/1 mL concentrate vial: Each vial contains 395 mg of ethanol anhydrous.
For 80 mg/4 mL concentrate vial: Each vial contains 1.58 g of ethanol anhydrous.
The amount of ethanol in Docetaxel (Taxotere) may be harmful in patients suffering from alcoholism and should also be taken into account in pregnant or breast-feeding women, in children and in high-risk groups such as patients with liver disease or epilepsy.
Consideration should be given to possible effects on the central nervous system.
The amount of ethanol in Docetaxel (Taxotere) may alter the effects of other medicinal products.
The amount of ethanol in Docetaxel (Taxotere) may impair the ability to drive or use machines (see Driving a Vehicle or Performing Other Hazardous Tasks as follows).
Driving a Vehicle or Performing Other Hazardous Tasks: No studies on the effects on the ability to drive and use machines have been performed.
The amount of ethanol in Docetaxel (Taxotere) and the side effects of the product may impair the ability to drive or use machines (See Precautions and Adverse Reactions). Therefore, patients should be warned of the potential impact of the side effects of the product on the ability to drive or use machines, and be advised not to drive or use machines if they experience these side effects during treatment.
Use in Elderly: An analysis of safety data in patients equal to or greater than 60 years of age treated with Docetaxel (Taxotere) + capecitabine combination therapy showed an increase in the incidence of treatment-related Grade 3 and 4 adverse events, treatment-related serious adverse events and early withdrawals from treatment due to adverse events compared to patients less than 60 years of age.
The proportion of elderly patients was 5.5% and 6.6% in the AC TH and TCH regimens, respectively and is too limited to allow for conclusions regarding the adverse events occurring by age (<65 years versus ≥65 years).
In a study conducted in chemotherapy-naïve patients with NSCLC (TAX 326), 148 patients in the Docetaxel (Taxotere) + cisplatin group were 65 years of age or greater, and 15 patients were 75 years of age and greater; no overall differences in effectiveness were observed when older patients were compared to younger patients. In elderly patients in the Docetaxel (Taxotere) + cisplatin group, there was a trend toward more diarrhea and Grade 3/4 neurotoxicity (both more frequent and severe) in comparison to the vinorelbine + cisplatin group.
In the Docetaxel (Taxotere) + carboplatin group, 114 patients were 65 years of age or greater, and 15 patients were 75 years of age and greater. In this group, there was a trend toward more diarrhea, and Grade 3/4 infection, and a trend toward less nausea/vomiting, neurotoxicity and neuro-sensory events in comparison to the vinorelbine + cisplatin group.
Of the 333 patients treated with Docetaxel (Taxotere) every three weeks in the prostate cancer study (TAX 327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. Differences in efficacy were not identified between elderly patients and younger patients. In patients treated with Docetaxel (Taxotere) every three weeks, the incidence of anemia, infection, nail changes, anorexia, weight loss occurred at rates ≥10% higher in patients who were 65 years of age or greater compared to younger patients.
Among the 221 patients treated with Docetaxel (Taxotere) in combination with cisplatin and 5-fluorouracil in the gastric cancer study (TAX325), 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse events was higher in the elderly patients compared to younger patients. The incidence of the following adverse events (all grades): lethargy, stomatitis, diarrhea, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored.
Among the 174 and 251 patients who received the induction treatment with Docetaxel (Taxotere) in combination with cisplatin and 5-fluorouracil (TPF) for SCCHN in the TAX 323 and TAX 324 studies, only 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. The number of elderly patients who received this regimen was not sufficient to determine whether geriatric patients responded differently from younger patients.
Use In Pregnancy & Lactation
Pregnancy: Docetaxel has been shown to be both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats.
Docetaxel may cause foetal harm when administered to pregnant women. Therefore, docetaxel must not be used during pregnancy.
Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.
Lactation: It is not known whether docetaxel is excreted in human milk.
Because of the potential for adverse reactions in nursing infants, breast feeding must be discontinued for the duration of docetaxel therapy.
Adverse Reactions
The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data).
Clinical Studies: The adverse reactions considered to be possibly or probably related to the administration of docetaxel have been obtained from patients treated with docetaxel as a single agent or in combination; these patients had normal LFTs at baseline. The following narrative describes the adverse reactions experienced by patients treated with docetaxel as a single agent at 100 mg/m2, in clinical trials and postmarketing studies.
Unless otherwise noted, the tables present a summary of the following groups: among the patients who received docetaxel as monotherapy, 1312 patients received 100 mg/m2 and 121 patients received 75 mg/m2 of Docetaxel (Taxotere), 258 patients received 75 mg/m2 of Docetaxel (Taxotere) with 50 mg/m2 of doxorubicin. These reactions were described using the NCI Common Toxicity Criteria and the COSTART terms.
Haematology: Bone marrow suppression and other haematologic adverse reactions to docetaxel include: Neutropenia (in patients who did not receive G-CSF) (96.6%), the most frequent adverse reaction, was reversible and not cumulative. The median day to nadir was 7 days and the median duration of severe neutropenia (<500 cells/mm3) (76.4%) was 7 days.
Febrile neutropenia (11.8%) and severe infections (4.6%) associated with neutrophil counts <500/mm3, infectious episodes (20%) (5.7% severe including sepsis and pneumonia, fatal in 1.7%) occurred. Thrombocytopenia <100,000/mm3 (7.8%), (0.2% severe), bleeding episodes (2.4%) (rarely associated with severe thrombocytopenia (<50,000/mm3) and anemia ((<11 g/dl): 90.4% (8.9% severe (<8 g/dl)) were also reported. (See Table 13.)

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Hypersensitivity reactions: Hypersensitivity reactions (25.9%), occurring generally within a few minutes following the start of the infusion, were usually mild to moderate. Frequently reported symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and drug fever or chills. Severe reactions (5.3%) resolved after discontinuing the infusion and appropriate therapy. (See Table 14.)

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Cutaneous: Reversible cutaneous reactions (56.6%) were generally mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on feet, hands, (including severe hand and foot syndrome), but also on arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion. Less frequently (5.9%), severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were reported. Nail disorders (27.9%) were characterised by hypo- or hyperpigmentation, pain and onycholysis.
In some cases multiple factors such as concomitant infections, concomitant medications and underlying disease may have contributed to the development of these effects. (See Table 15.)

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Fluid retention: Fluid retention adverse reactions have been obtained from a retrospective analysis of 92 patients treated with docetaxel as single agent, 100 mg/m2, who were also given the 3 day premedication regimen.
Fluid retention was observed in 64.1% (6.5% severe) of patients who received 3 days of premedication. Events such as peripheral edema and less frequently pleural effusion, pericardial effusion, ascites and weight gain have been reported. The peripheral edema usually starts at the lower extremities and may become generalized with a weight gain of 3 kgs or more. Fluid retention is cumulative in incidence and severity (see Precautions). (See Table 16.)

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In patients treated by docetaxel as single agent, at 100 mg/m2, the median cumulative dose to treatment discontinuation was more than 1,000 mg/m2 and the median time to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks). The onset of moderate and severe retention is delayed (median cumulative dose: 818.9 mg/m2) in patients with premedication compared with patients without premedication (median cumulative dose: 489.7 mg/m2); however, it has been reported in some patients during early courses of therapy. Fluid retention has not been accompanied by acute episodes of oliguria or hypotension.
Gastrointestinal: The following gastrointestinal effects have been reported: Nausea: 40.5% (4% severe); Vomiting: 24.5% (3% severe); Diarrhoea: 40.6% (4% severe); Abdominal pain: 7.3% (1% severe); Anorexia: 16.8%; Constipation: 9.8% (0.2% severe); Stomatitis: 41.8% (5.3% severe); Esophagitis: 1% (0.4% severe); Taste perversion: 10.1% (0.07% severe); Gastrointestinal bleeding: 1.4% (0.3% severe). (See Table 17.)

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Neurologic: Mild to moderate neuro-sensory signs and/or symptoms occurred in 50% of the patients. Severe neurosensory symptoms (paresthesia, dysesthesia, pain including burning) were observed in 4.1% of metastatic breast cancer patients, and resulted in treatment discontinuation in 2%. Neuro-motor events (13.8% with 4% severe) mainly characterised by weakness. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued (see Dosage & 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 81 days from onset (range: 0 to 741 days). (See Table 18.)

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Cardiovascular: Cardiovascular events consisted of: Hypotension (3.8%); Dysrhythmia (4.1%); Hypertension (2.4%); Heart failure (0.5%). (See Table 19.)

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Hepatic: In patients treated at 100 mg/m2 as a single agent, increases in serum levels of AST, ALT, bilirubin and alkaline phosphatase greater than 2.5 times the ULN were observed in less than 5% of the patients. (See Table 20.)

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Others: Alopecia (79% with 0.5% severe); Asthenia (62.6% with 11.2% severe); Arthralgias (8.6%); Myalgias (20%); Dyspnea (16.1% with 2.7% severe); Generalized or localized pain (16.5% with 0.8% severe), including chest pain (4.5% with 0.4% severe) without any cardiac or respiratory involvement; Infusion site reactions, generally mild occurred in 5.6% of the patients and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein. (See Table 21.)

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Overall, the adverse events pattern observed in patients treated with Docetaxel (Taxotere) in combination with doxorubicin is similar to those treated with Docetaxel (Taxotere) as monotherapy.
Combination therapy with Docetaxel (Taxotere) in the adjuvant treatment of operable node-positive and high risk node negative breast cancer: The following table presents treatment emergent adverse events (TEAEs) observed during the treatment period in 744 patients with node positive breast canceprr, who were treated with Docetaxel (Taxotere) 75 mg/m2 every 3 weeks in combination with doxorubicin and cyclophosphamide.
Of the 744 patients treated with TAC, 36.7% experienced severe adverse events during the treatment period compared to 13.8% during the follow-up period. Dose reductions due to hematologic toxicity occurred in 1% of cycles during the treatment period. Six percent of patients discontinued treatment due to adverse events; fever in the absence of infection and allergy being the most common reasons for withdrawal. Two patients treated with TAC died within 30 days of their last study treatment; 1 death was considered to be related to study drug. (See Table 22.)

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Fever and Infection: Fever in the absence of infection was seen in 36.6% of patients and infection was seen in 29.2% (G3/4: 3.2%) of TAC patients during the study period. There were no deaths due to sepsis during the study period.
Gastrointestinal events: In addition to gastrointestinal events reflected in the previous table, 7 patients were reported to have colitis/enteritis/large intestine perforation. Two of these patients required treatment discontinuation; no deaths due to these events occurred during the treatment period.
Cardiovascular events: The following treatment emergent cardiovascular events were reported during the study period: arrhythmias, all grades (6.2%), hypotension, all grades (1.9%) and CHF (3.5%). Twenty-six patients in the TAC group developed CHF during the study period, with most cases reported in the follow-up period. CHF lead to death in 2 TAC patients and to 4 FAC patients. The risk of CHF is higher in the TAC group in the first year.
Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome: After 10 years of follow up in study TAX316, AML occurred in 3 of 744 (0.4%) patients who received Docetaxel (Taxotere), doxorubicin, and cyclophosphamide and in 1 of 736 (0.1%) patients who received fluorouracil, doxorubicin and cyclophosphamide. One TAC patient died due to AML during the follow up period (median follow-up time of 8 years). Myelodysplastic syndrome occurred in 2 of 744 (0.3%) patients who received Docetaxel (Taxotere), doxorubicin, and cyclophosphamide and in 1 of 736 (0.1%) patients who received fluorouracil, doxorubicin and cyclophosphamide.
Other persistent reactions: In Study TAX316 the most common adverse events that started during the treatment period and persisted into the follow-up period in TAC patients are described in Table 23 (median follow-up time of 8 years). The majority of the events that had persisted resolved during the follow-up period. (See Table 23.)

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The following table presents treatment emergent adverse events (TEAEs) observed during the treatment period in 532 patients with node negative breast cancer, who were treated with Docetaxel (Taxotere) 75 mg/m2 every 3 weeks. (See Table 24.)

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Table as follows shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis after it was made mandatory in the TAC arm. (See Table 25.)

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Of the 532 patients treated with TAC, 28.2% experienced severe and TEAEs. Dose reductions due to hematologic toxicity occurred in 1.5% of cycles. 4.7 percent of patients discontinued treatment due to adverse events; fever in the absence of infection and neutropenia being the most common reasons for withdrawal. No patients died within 30 days of their last study treatment. No death was considered to be related to TM.
Fever and Infection: There were no deaths due to sepsis.
Gastrointestinal events: No cases of colitis/enteritis/large intestine perforation were reported. Other gastrointestinal events are reflected in the previous table.
Cardiovascular events: Three patients (0.6%) developed congestive heart failure during the follow-up period. At the end of the follow-up period (median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient died because of dilated cardiomyopathy.
Acute Leukemia/Myelodysplastic Syndrome: During the follow-up period (median follow-up time of 10 years and 5 months), acute leukemia occurred in 1 of 532 (0.2%) patients in TAC arm. No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.
Persistent reactions: In Study GEICAM 9805 the most common adverse events that started during the treatment period and persisted into the follow-up period in TAC patients are described in Table 26 (median follow-up time of 10 years and 5 months). The majority of the events that had persisted resolved during the follow-up period. (See Table 26.)

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Alopecia related to study drug started or worsened during the follow-up period in 42 patients (7.9%).
Combination Therapy with Docetaxel (Taxotere) and capecitabine for Breast cancer: For the Docetaxel (Taxotere) + capecitabine combination therapy the most frequent treatment-related undesirable effects (≥5%) reported in a phase III trial in breast cancer patients failing anthracycline treatment are presented in the following table. (See Table 27 and Table 28.)

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Combination therapy with Docetaxel (Taxotere) and trastuzumab for breast cancer: The following table displays adverse events (all grades), which were reported in ≥10% of patients treated with Docetaxel (Taxotere) with trastuzumab for metastatic breast cancer: See Table 29.

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There was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the combination arm compared to Docetaxel (Taxotere) monotherapy.
Cardiac toxicity: Symptomatic heart failure was reported in 2.2% of the patients who received Docetaxel (Taxotere) plus trastuzumab compared to 0% of patients given Docetaxel (Taxotere) alone. In the Docetaxel (Taxotere) plus trastuzumab arm, 64% had received a prior anthracycline as adjuvant therapy, compared with 55% in the docetaxel arm alone.
Hematological toxicity: Grade 3/4 neutropenia was reported in 32% of the patients given Docetaxel (Taxotere) plus trastuzumab.
Combination therapy with Docetaxel (Taxotere) for adjuvant treatment of patients with operable breast cancer whose tumors overexpress HER2 and who received either AC TH or TCH: See Table 30.

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The 3 year cumulative incidence of all symptomatic cardiac events was 2.36% and 1.16% in the AC TH and TCH arms, respectively (versus 0.52% in the AC T control arm, see Pharmacology: Pharmacodynamics under Actions). The 3 year cumulative incidence of CHF events (Grade 3 or 4) was 1.9% and 0.4% in the AC TH and TCH arms, respectively (versus 0.3% in the AC T control arm).
Combination therapy with Docetaxel (Taxotere) in NSCLC: Clinically important treatment related adverse events are shown as follows. Included in this table are safety data for a total of 807 patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy who were treated in the Docetaxel (Taxotere) combination arms of a randomized, open label, three arm controlled trial. These reactions were described using the NCI Common Toxicity Criteria and are considered possibly or probably related to study treatment, except for the haematologic toxicities or as otherwise noted. (See Table 31.)

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Combination therapy with Docetaxel (Taxotere) in prostate cancer patients: The following data are based on the experience of 332 patients, who were treated with Docetaxel (Taxotere) 75 mg/m2 every 3 weeks in combination with prednisone or prednisolone 5 mg orally twice daily. (See Table 32.)

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Combination therapy with Docetaxel (Taxotere) in gastric adenocarcinoma: Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease, who were treated with Docetaxel (Taxotere) 75 mg/m2 in combination with cisplatin and 5-fluorouracil. (See Table 33.)

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Febrile neutropenia or neutropenic infection: Febrile neutropenia and/or neutropenic infection occurred in 28.6% of patients, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in only 18.6% of patients (10% of cycles) for the TCF arm. Febrile neutropenia and/or neutropenic infection occurred at lower rates, 12.2% when patients received prophylactic G-CSF, and 26.9% without prophylactic G-CSF (see Dosage & Administration).
Combination therapy with Docetaxel (Taxotere) in head and neck cancer: The following table summarizes the safety data obtained in 174 patients with locally advanced inoperable squamous cell carcinoma of the head and neck (SCCHN), who were treated with Docetaxel (Taxotere) 75 mg/m2 in combination with cisplatin and 5-fluorouracil. (See Table 34.)

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The following table summarizes the safety data obtained in 251 patients with locally advanced squamous cell carcinoma of the head and neck who were treated with Docetaxel (Taxotere) 75 mg/m2 in combination with cisplatin and 5-fluorouracil. (See Table 35.)

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Post Marketing Experiences: Hypersensitivity: Rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.
Hypersensitivity reactions with potential fatal outcome (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.
Cutaneous: Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and scleroderma-like changes usually preceded by peripheral lymphedema have been reported with docetaxel. In some cases multiple factors such as concomitant infections, concomitant medications and underlying disease may have contributed to the development of these effects. Cases of permanent alopecia (frequency not known) have been reported.
Fluid retention: Dehydration and pulmonary oedema have rarely been reported.
Gastrointestinal: Enterocolitis (frequency not known), including colitis, ischemic colitis, and neutropenic enterocolitis, has been reported with a potential fatal outcome (frequency not known).
Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events including enterocolitis and gastrointestinal perforation.
Rare cases of ileus and intestinal obstruction have been reported.
Neurologic: Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel administration. These reactions sometimes appear during the infusion of the drug.
Cardiovascular: Rare occurrences of venous thromboembolic events and myocardial infarction have been reported.
Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide.
Hepatic: Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.
Ear and labyrinth disorders: Rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.
Eye Disorders: Rare cases of lacrimation with or without conjunctivitis have been reported and very rarely cases of lacrimal duct obstruction resulting in excessive tearing have been reported primarily in patients receiving other anti-tumor agents concomitantly.
Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion.
Cases of Cystoid Macular Oedema (CMO) have been reported in patients treated with docetaxel, as well as with other taxanes.
Respiratory, thoracic and mediastinal disorders: Acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease pulmonary fibrosis, respiratory failure, and radiation recall phenomena have rarely been reported, and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.
General disorders and administration site conditions: Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation (frequency not known).
Blood and lymphatic disorders: Disseminated intravascular coagulation (DIC), often in association with sepsis, or multiorgan failure, has been reported.
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Second primary malignancies (frequency not known), including non-Hodgkin lymphoma and renal cancer, have been reported in association with docetaxel when used in combination with other anticancer treatments known to be associated with second primary malignancies. Acute myeloid leukemia and myelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies in breast cancer with TAC regimen (see Pharmacology: Pharmacodynamics: Clinical Studies: Combination therapy with Docetaxel (Taxotere) in the adjuvant treatment of operable node-positive and high risk node negative breast cancer under Actions).
Renal and urinary disorders: Renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.
Metabolism and nutrition disorders: Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia, and hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular with diarrhoea.
Drug Interactions
In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds which induce, inhibit or are metabolised by cytochrome P450-3A such as ciclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with these drugs as concomitant therapy since there is a potential for a significant interaction.
In case of combination with CYP3A4 inhibitors, the occurrence of Docetaxel (Taxotere) adverse reactions may increase, as a result of reduced metabolism. If the concomitant use of a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) cannot be avoided, a close clinical surveillance is warranted and a dose-adjustment of Docetaxel (Taxotere) may be suitable during the treatment with the strong CYP3A4 inhibitor (see Precautions). In a pharmacokinetic study with 7 patients, the co-administration of docetaxel with the strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in docetaxel clearance by 49%.
Docetaxel is highly protein bound (>95%).
Although the possible in vivo interaction of docetaxel with concomitantly administered medication has not been investigated formally, in vitro tightly protein-bound drugs such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did not influence the binding of digitoxin.
Caution For Usage
Preparation and Handling: Recommendations for the safe handling: Docetaxel (Taxotere) is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when handling it and preparing Docetaxel (Taxotere) infusions.
The use of gloves is recommended.
If Docetaxel (Taxotere) concentrate, premix solution or infusion solution should come into contact with skin, wash immediately and thoroughly with soap and water.
If Docetaxel (Taxotere) concentrate, premix solution or infusion solution should come into contact with mucous membranes, wash immediately and thoroughly with water.
Preparation for the intravenous administration: DO NOT use the two vial formulation (injection concentrate and diluent) with the single vial formulation.
Preparation of the infusion solution: More than one Docetaxel (Taxotere) concentrate vial may be necessary to obtain the required dose for the patient.
Using a 21 gauge needle, aseptically withdraw the required amount of Docetaxel (Taxotere) concentrate solution (20 mg/mL) with a calibrated syringe. Inject the required concentrate volume via a single injection (one shot) into a 250 mL infusion bag or bottle containing either 5% glucose solution or 0.9% sodium chloride solution.
If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded.
Mix the infusion bag or bottle manually using a rocking motion.
The Docetaxel (Taxotere) infusion solution should be aseptically administered intravenously within 6 hours (including the 1 hour infusion) under room temperature (below 25°C) and normal lighting conditions.
Solutions containing a precipitate should be discarded.
Disposal: All materials that have been utilised for dilution and administration should be disposed of according to standard procedures.
Incompatibilities/Compatibilities:
None known.
Storage
Vials of Docetaxel (Taxotere) concentrate for infusion should be stored between +2 and +25 degrees Celsius and protected from light.
Freezing does not adversely affect the product.
Shelf-life: Unopened Vial: Respect the date indicated on the outer packaging.
After opening of the vial: Each vial is for single use and must be used immediately after opening.
Once added to the infusion bag: From a microbiological point of view reconstitution/dilution must take place in controlled and aseptic conditions.
Once added as recommended into the infusion bag, the docetaxel infusion solution, if stored below 25°C, is stable for 6 hours. It should be used within 6 hours (including the one hour infusion IV 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 to 8°C.
Docetaxel infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.
ATC Classification
L01CD02 - docetaxel ; Belongs to the class of plant alkaloids and other natural products, taxanes. Used in the treatment of cancer.
Presentation/Packing
Inj (vial) 20 mg/mL x 1's. 80 mg/4 mL x 1's.
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