Dosage Form: injection, solution, concentrate
FULL PRESCRIBING INFORMATION
The incidence of treatment-related mortality associated with Taxotere therapy is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive Taxotere as a single agent at a dose of 100 mg/m2 [see Warnings and Precautions (5.1)].
Taxotere should not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 × ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of Taxotere therapy [see Warnings and Precautions (5.2)].
Taxotere therapy should not be given to patients with neutrophil counts of <1500 cells/mm3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving Taxotere [see Warnings and Precautions (5.3)].
Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received a 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Taxotere infusion and administration of appropriate therapy [see Warnings and Precautions (5.4)]. Taxotere must not be given to patients who have a history of severe hypersensitivity reactions to Taxotere or to other drugs formulated with polysorbate 80 [see Contraindications (4)].
Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites) [see Warnings and Precautions (5.5)].
1. INDICATIONS AND USAGE
Breast Cancer
- Taxotere is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.
- Taxotere in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.
Non-Small Cell Lung Cancer
- Taxotere as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.
- Taxotere in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.
Prostate Cancer
- Taxotere in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.
Gastric Adenocarcinoma
- Taxotere in combination with cisplatin and 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
- Taxotere in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
2. DOSAGE AND ADMINISTRATION
For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7)].
Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).
Breast Cancer
- For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Taxotere is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.
- For the adjuvant treatment of operable node-positive breast cancer, the recommended 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. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7)].
Non-Small Cell Lung Cancer
- For treatment after failure of prior platinum-based chemotherapy, Taxotere was evaluated as monotherapy, and the recommended dose is 75 mg/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5), Clinical Studies (14)].
- For chemotherapy-naïve patients, Taxotere was evaluated in combination with cisplatin. The recommended dose of Taxotere is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30–60 minutes every 3 weeks [see Dosage and Administration (2.7)].
Prostate Cancer
- For hormone-refractory metastatic prostate cancer, the recommended dose of Taxotere is 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration (2.7)].
Gastric Adenocarcinoma
- For gastric adenocarcinoma, the recommended dose of Taxotere is 75 mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous intravenous 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 [see Dosage and Administration (2.7)].
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 treated on the Taxotere containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.
- Induction chemotherapy followed by radiotherapy (TAX323)
For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Taxotere is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous 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. [see Dosage and Administration (2.7)].
- Induction chemotherapy followed by chemoradiotherapy (TAX324)
For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of 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 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 [see Dosage and Administration (2.7)].
Premedication Regimen
- All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to Taxotere administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.4)].
- For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the Taxotere infusion [see Warnings and Precautions (5.4)].
Dosage Adjustments During Treatment
Breast Cancer
Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during Taxotere therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Taxotere therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Taxotere treatment discontinued entirely.
Combination Therapy with Taxotere in the Adjuvant Treatment of Breast Cancer
Taxotere in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their Taxotere dose reduced to 60 mg/m2. Patients who experience grade 3 or 4 stomatitis should have their Taxotere dose decreased to 60 mg/m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Taxotere therapy should have their dosage of Taxotere reduced from 75 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, treatment should be discontinued.
Non-Small Cell Lung Cancer
Monotherapy with Taxotere for NSCLC treatment after failure of prior platinum-based chemotherapy
Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Taxotere treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Taxotere treatment discontinued entirely.
Combination therapy with Taxotere for chemotherapy-naïve NSCLC
For patients who are dosed initially at Taxotere 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the Taxotere dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.
Prostate Cancer
Combination therapy with Taxotere for hormone-refractory metastatic prostate cancer
Taxotere should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Taxotere therapy should have the dosage of Taxotere reduced from 75 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.
Gastric or Head and Neck Cancer
Taxotere in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer
Patients treated with Taxotere in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the Taxotere dose should be reduced from 75 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Taxotere dose should be reduced from 60 to 45 mg/m2. In case of grade 4 thrombocytopenia the Taxotere dose should be reduced from 75 to 60 mg/m2. Patients should not be retreated with subsequent cycles of 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 Warnings and Precautions (5.3)].
Recommended dose modifications for toxicities in patients treated with Taxotere in combination with cisplatin and fluorouracil are shown in Table 1.
| Toxicity | Dosage adjustment |
|---|---|
| Diarrhea grade 3 | First episode: reduce fluorouracil dose by 20%. Second episode: then reduce Taxotere dose by 20%. |
| Diarrhea grade 4 | First episode: reduce Taxotere and fluorouracil doses by 20%. Second episode: discontinue treatment. |
| Stomatitis/mucositis grade 3 | First episode: reduce fluorouracil dose by 20%. Second episode: stop fluorouracil only, at all subsequent cycles. Third episode: reduce Taxotere dose by 20%. |
| Stomatitis/mucositis grade 4 | First episode: stop fluorouracil only, at all subsequent cycles. Second episode: reduce Taxotere dose by 20%. |
Liver dysfunction:
In case of AST/ALT >2.5 to ≤5 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 × ULN and AP >2.5 to ≤5 × ULN, Taxotere should be reduced by 20%.
In case of AST/ALT >5 × ULN and/or AP >5 × ULN Taxotere should be stopped.
The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:
Cisplatin dose modifications and delays
Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:
• Grade 2: Reduce cisplatin dose by 20%.
• Grade 3: Discontinue treatment.
Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.
Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 × normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).
For other cisplatin dosage adjustments, also refer to the manufacturers' prescribing information.
| Creatinine clearance result before next cycle | Cisplatin dose next cycle |
|---|---|
| CrCl = Creatinine clearance | |
| CrCl ≥60 mL/min | Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle. |
| Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was reinstituted at the next cycle. | |
| CrCl between 40 and 59 mL/min | |
| If no recovery was observed, then cisplatin was omitted from the next treatment cycle. | |
| Dose of cisplatin was omitted in that treatment cycle only. | |
| If CrCl was still <40 mL/min at the end of cycle, cisplatin was discontinued. | |
| CrCl <40 mL/min | |
| If CrCl was >40 and <60 mL/min at end of cycle, a 50% cisplatin dose was given at the next cycle. | |
| If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle. | |
Fluorouracil dose modifications and treatment delays
For diarrhea and stomatitis, see Table 1.
In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.
For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.
For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information.
Combination Therapy with Strong CYP3A4 inhibitors:
Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor. [see Drug Interactions (7), Clinical Pharmacology (12.3)].
Administration Precautions
Taxotere is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Taxotere solutions. The use of gloves is recommended. Please refer to [see How Supplied/ Storage and Handling (16.3)].
If Taxotere Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Taxotere Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.
Contact of the Taxotere concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final Taxotere dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
Two-vial formulation (Injection Concentrate and Diluent)
Taxotere Injection Concentrate requires two dilutions prior to administration. Please follow the preparation instructions provided below. Note: Both the Taxotere Injection Concentrate and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL docetaxel.
The table below provides the fill range of the Diluent, the approximate extractable volume of Diluent when the entire contents of the diluent vial are withdrawn, and the concentration of the initial diluted solution for Taxotere 20 mg and Taxotere 80 mg (see Table 3).
| Product | Diluent 13% (w/w) ethanol in water for injection Fill Range (mL) | Approximate extractable volume of Diluent when entire contents are withdrawn (mL) | Concentration of the initial diluted solution (mg/mL docetaxel) |
|---|---|---|---|
| Taxotere® 20 mg/0.5 mL | 1.88 – 2.08 mL | 1.8 mL | 10 mg/mL |
| Taxotere® 80 mg/2 mL | 6.96 – 7.70 mL | 7.1 mL | 10 mg/mL |
Preparation and Administration
DO NOT use the two-vial formulation (Injection Concentrate and diluent) with the one-vial formulation.
Two-vial formulation (Injection Concentrate and Diluent)
A. Initial Diluted Solution
- Taxotere vials should be stored between 2°C and 25°C (36°F and 77°F). If the vials are stored under refrigeration, allow the appropriate number of vials of Taxotere Injection Concentrate and diluent (13% ethanol in water for injection) vials to stand at room temperature for approximately 5 minutes.
- Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 1.8 mL for Taxotere 20 mg and approximately 7.1 mL for Taxotere 80 mg) into a syringe by partially inverting the vial, and transfer it to the appropriate vial of Taxotere Injection Concentrate. If the procedure is followed as described, an initial diluted solution of 10 mg docetaxel/mL will result.
- Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixture of the concentrate and diluent. Do not shake.
- The initial diluted Taxotere solution (10 mg docetaxel/mL) should be clear; however, there may be some foam on top of the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any foam to dissipate. It is not required that all foam dissipate prior to continuing the preparation process.
The initial diluted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours.
B. Final Dilution for Infusion
- Aseptically withdraw the required amount of initial diluted Taxotere solution (10 mg docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/mL.
If a dose greater than 200 mg of Taxotere is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL Taxotere is not exceeded. - Thoroughly mix the infusion by manual rotation.
- As with all parenteral products, Taxotere should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Taxotere initial diluted solution or final dilution for intravenous infusion is not clear or appears to have precipitation, these should be discarded.
The final Taxotere dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature and lighting conditions.
Stability
Taxotere final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours. Taxotere final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).
3. DOSAGE FORMS AND STRENGTHS
Two-vial formulation (Injection Concentrate and Diluent)
Taxotere 80 mg/2 mL
Taxotere (docetaxel) Injection Concentrate 80 mg/2 mL: 80 mg docetaxel in 2 mL polysorbate 80 and Diluent for Taxotere 80 mg (13% (w/w) ethanol in water for injection). Both items are in a blister pack in one carton.
Taxotere 20 mg/0.5 mL
Taxotere (docetaxel) Injection Concentrate 20 mg/0.5 mL: 20 mg docetaxel in 0.5 mL polysorbate 80 and Diluent for Taxotere 20 mg (13% (w/w) ethanol in water for injection). Both items are in a blister pack in one carton.
4. CONTRAINDICATIONS
- Taxotere is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions (5.4)].
- Taxotere should not be used in patients with neutrophil counts of <1500 cells/mm3.
5. WARNINGS AND PRECAUTIONS
Toxic Deaths
Breast Cancer
Taxotere administered at 100 mg/m2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m2, mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.
Non-Small Cell Lung Cancer
Taxotere administered at a dose of 100 mg/m2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see Dosage and Administration (2.2), Clinical Studies (14)].
Hepatic Impairment
Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Taxotere [see Boxed Warning, Use in Specific Populations (8.6), Clinical studies (14)].
Hematologic Effects
Perform frequent peripheral blood cell counts on all patients receiving Taxotere. Patients should not be retreated with subsequent cycles of Taxotere until neutrophils recover to a level >1500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3.
A 25% reduction in the dose of Taxotere is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Taxotere cycle [see Dosage and Administration (2.7)].
Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 100 mg/m2 of Taxotere and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Taxotere should not be administered to patients with neutrophils <1500 cells/mm3.
Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was very uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see Adverse Reactions (6.1), Clinical Studies (14)].
Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection [see Dosage and Administration (2.7), Adverse Reactions (6)].
Hypersensitivity Reactions
Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Taxotere infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with Taxotere.
Hypersensitivity reactions may occur within a few minutes following initiation of a Taxotere infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Taxotere [see Dosage and Administration (2.6)].
Fluid Retention
Severe fluid retention has been reported following Taxotere therapy. Patients should be premedicated with oral corticosteroids prior to each Taxotere administration to reduce the incidence and severity of fluid retention [see Dosage and Administration (2.6)]. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.
When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.
Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2. Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m2. Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of Taxotere to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).
Acute Myeloid Leukemia
Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received Taxotere, doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin and cyclophosphamide [see Clinical Studies (14.2)]. In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up.
Cutaneous Reactions
Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended [see Dosage and Administration (2.7)]. The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued Taxotere due to skin toxicity.
Neurologic Reactions
Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued [see Dosage and Administration (2.7)]. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).
Asthenia
Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.
Use in Pregnancy
Taxotere can cause fetal harm when administered to a pregnant woman. Docetaxel caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis.
There are no adequate and well-controlled studies in pregnant women using Taxotere. If Taxotere is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Taxotere [see Use in Specific Populations (8.1)].
6. ADVERSE REACTIONS
The most serious adverse reactions from Taxotere are:
- Toxic Deaths [see Boxed Warning, Warning and Precautions (5.1)]
- Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.2)]
- Neutropenia [see Boxed Warning, Warnings and Precautions (5.3)]
- Hypersensitivity [see Boxed Warning, Warnings and Precautions (5.4)]
- Fluid Retention [see Boxed Warning, Warnings and Precautions (5.5)]
The most common adverse reactions across all Taxotere indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.
Adverse reactions are described according to indication. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established.
Clinical Trial Experience
Breast Cancer
Monotherapy with Taxotere for locally advanced or metastatic breast cancer after failure of prior chemotherapy
Taxotere 100 mg/m2: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received Taxotere administered at 100 mg/m2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to Taxotere. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving Taxotere for the treatment of breast cancer and in patients with other tumor types (See Table 4).
| Adverse Reaction | All Tumor Types Normal LFTs* n=2045 % | All Tumor Types Elevated LFTs† n=61 % | Breast Cancer Normal LFTs* n=965 % |
|---|---|---|---|
| |||
| Hematologic | |||
| Neutropenia | |||
| <2000 cells/mm3 | 96 | 96 | 99 |
| <500 cells/mm3 | 75 | 88 | 86 |
| Leukopenia | |||
| <4000 cells/mm3 | 96 | 98 | 99 |
| <1000 cells/mm3 | 32 | 47 | 44 |
| Thrombocytopenia | |||
| <100,000 cells/mm3 | 8 | 25 | 9 |
| Anemia | |||
| <11 g/dL | 90 | 92 | 94 |
| <8 g/dL | 9 | 31 | 8 |
| Febrile Neutropenia‡ | 11 | 26 | 12 |
| Septic Death | 2 | 5 | 1 |
| Non-Septic Death | 1 | 7 | 1 |
| Infections | |||
| Any | 22 | 33 | 22 |
| Severe | 6 | 16 | 6 |
| Fever in Absence of Infection | |||
| Any | 31 | 41 | 35 |
| Severe | 2 | 8 | 2 |
| Hypersensitivity Reactions | |||
| Regardless of Premedication | |||
| Any | 21 | 20 | 18 |
| Severe | 4 | 10 | 3 |
| With 3-day Premedication | n=92 | n=3 | n=92 |
| Any | 15 | 33 | 15 |
| Severe | 2 | 0 | 2 |
| Fluid Retention | |||
| Regardless of Premedication | |||
| Any | 47 | 39 | 60 |
| Severe | 7 | 8 | 9 |
| With 3-day Premedication | n=92 | n=3 | n=92 |
| Any | 64 | 67 | 64 |
| Severe | 7 | 33 | 7 |
| Neurosensory | |||
| Any | 49 | 34 | 58 |
| Severe | 4 | ||
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