Docetaxel
Indications: Carcinoma, breast
Taxotere for Injection Concentrate(Aventis)
Prescribing information as of November 2001
WARNING
TAXOTERE(r) (docetaxel) for Injection Concentrate should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
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 at a dose of 100 mg/m 2 (see WARNINGS ).
TAXOTERE should generally not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with SGOT and/or SGPT >1.5 Γ ULN concomitant with alkaline phosphatase > 2.5 Γ 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 Γ ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, SGOT or SGPT, and alkaline phosphatase values should be obtained prior to each cycle of TAXOTERE therapy and reviewed by the treating physician.
TAXOTERE therapy should not be given to patients with neutrophil counts of < 1500 cells/mm 3 . 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.
Severe hypersensitivity reactions characterized by hypotension and/or bronchospasm, or generalized rash/erythema occurred in 2.2% (2/92) of patients who received the recommended 3-day dexamethasone premedication. Hypersensitivity reactions requiring discontinuation of the TAXOTERE infusion were reported in five patients who did not receive premedication. These reactions resolved after discontinuation of the infusion and the administration of appropriate therapy. 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 WARNINGS ).
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 PRECAUTIONS ).
DESCRIPTION
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3- phenylisoserine,N- tert -butyl ester, 13-ester with 5(beta)-20-epoxy-1,2(alpha),4,7(beta),10(beta),13(alpha)-hexahydroxytax- 11-en-9-one 4-acetate 2- benzoate, trihydrate. Docetaxel has the following structural formula:
Docetaxel is a white to almost-white powder with an empirical formula of C 43 H 53 NO 14 Β·3H 2 O, and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water. TAXOTERE (docetaxel) for Injection Concentrate is a clear yellow to brownish-yellow viscous solution. TAXOTERE is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg (0.5 mL) or 80 mg (2.0 mL) docetaxel (anhydrous). Each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80.
TAXOTERE for Injection Concentrate requires dilution prior to use. A sterile, non-pyrogenic, single-dose diluent is supplied for that purpose. The diluent for TAXOTERE contains 13% ethanol in Water for Injection, and is supplied in 1.5 mL (to be used with 20 mg TAXOTERE for Injection Concentrate) and 6.0 mL (to be used with 80 mg TAXOTERE for Injection Concentrate) vials.
CLINICAL PHARMACOLOGY
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use.
HUMAN PHARMACOKINETICS
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-115 mg/m 2 in phase I studies. The area under the curve (AUC) was dose proportional following doses of 70-115 mg/m 2 with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the (alpha), (beta), and (gamma) phases of 4 min, 36 min, and 11.1 hr, respectively. The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean values for total body clearance and steady state volume of distribution were 21 L/h/m 2 and 113 L, respectively. Mean total body clearance for Japanese patients dosed at the range of 10-90 mg/m 2 was similar to that of European/American populations dosed at 100 mg/m 2 , suggesting no significant difference in the elimination of docetaxel in the two populations.
A study of 14 C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert -butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.
A population pharmacokinetic analysis was carried out after TAXOTERE treatment of 535 patients dosed at 100 mg/m 2 . Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase I studies. The pharmacokinetics of docetaxel were not influenced by age or gender and docetaxel total body clearance was not modified by pretreatment with dexamethasone. In patients with clinical chemistry data suggestive of mild to moderate liver function impairment (SGOT and/or SGPT >1.5 times the upper limit of normal [ULN] concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should, in general, not be treated with TAXOTERE.
In vitro studies showed that docetaxel is about 94% protein bound, mainly to (alpha) 1 -acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.
In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism can be inhibited by CYP3A4 inhibitors, such as ketoconazole, erythromycin, troleandomycin, and nifedipine. Based on in vitro findings, it is likely that CYP3A4 inhibitors and/or substrates may lead to substantial increases in docetaxel blood concentrations. No clinical studies have been performed to evaluate this finding (see PRECAUTIONS ).
CLINICAL STUDIES
Breast Cancer: The efficacy and safety of TAXOTERE have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens), primarily at a dose of 100 mg/m 2 given as a 1-hour infusion every 3 weeks, but with some experience at 60 mg/m 2 , in two large randomized trials and a number of smaller single arm studies.
Randomized Trials: In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with TAXOTERE or the combination of mitomycin (12 mg/m 2 every 6 weeks) and vinblastine (6 mg/m 2 every 3 weeks). 203 patients were randomized to TAXOTERE and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the TAXOTERE arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results:
Efficacy of TAXOTERE in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen
(Intent-to-Treat Analysis)
Efficacy Parameter Docetaxel (n=203) Mitomycin/ Vinblastine (n=189) p-value
Median Survival 11.4 months 8.7 months p=0.01
Log Rank
Risk Ratio * , Mortality (Docetaxel: Control) 0.73
95% CI (Risk Ratio) 0.58-0.93
Median Time to Progression 4.3 months 2.5 months p=0.01
Log Rank
Risk Ratio * , Progression (Docetaxel: Control) 0.75
95% CI (Risk Ratio) 0.61- 0.94
Overall Response Rate 28.1% 9.5%
Complete Response Rate 3.4% 1.6% p<0.0001
Chi Square
*For the risk ratio, a value less than 1.00 favors docetaxel.
In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with TAXOTERE or doxorubicin (75 mg/m 2 every 3 weeks). 161 patients were randomized to TAXOTERE and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below:
Efficacy of TAXOTERE in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen
(Intent-to-Treat Analysis)
Efficacy Parameter Docetaxel (n=161) Doxorubicin (n=165) p-value
Median Survival 14.7 months 14.3 months p=0.39
Log Rank
Risk Ratio * , Mortality (Docetaxel: Control) 0.89
95% CI (Risk Ratio) 0.68-1.16
Median Time to Progression 6.5 months 5.3 months p=0.45
Log Rank
Risk Ratio * , Progression (Docetaxel: Control) 0.93
95% CI (Risk Ratio) 0.71-1.16
Overall Response Rate 45.3% 29.7%
Complete Response Rate 6.8% 4.2% p=0.004
Chi Square
*For the risk ratio, a value less than 1.00 favors docetaxel.
Single Arm Studies: TAXOTERE at a dose of 100 mg/m 2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0-44.8) and the complete response rate was 2.1%.
TAXOTERE was also studied in three single arm Japanese studies at a dose of 60 mg/m 2 , in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2-55.7), similar to the response rate in single arm studies of 100 mg/m 2 .
Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry abnormalities. Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given TAXOTERE at 100 mg/m 2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as SGOT and/or SGPT > 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN); and 174 patients in Japanese studies given TAXOTERE at 60 mg/m 2 who had normal LFTs.
Hematologic Adverse Events in Breast Cancer Patients Previously Treated with Chemotherapy Treated at TAXOTERE 100 mg/m 2
with Normal or Elevated Liver Function Tests or 60 mg/m 2 with Normal Liver Function Tests
TAXOTERE 100 mg/m 2 TAXOTERE 60 mg/m 2
Adverse Event Normal LFTs * n=730 % Elevated LFTs ** n=18 % Normal LFTs * n=174 %
Neutropenia
Any <2000 cells/mm 3 98.4 100 95.4
Grade 4 <500 cells/mm 3 84.4 93.8 74.9
Thrombocytopenia
Any <100,000 cells/mm 3 10.8 44.4 14.4
Grade 4 <20,000 cells/mm 3 0.6 16.7 1.1
Anemia <11 g/dL 94.6 94.4 64.9
Infection ***
Any 22.5 38.9 1.1
Grade 3 and 4 7.1 33.3 0
Febrile Neutropenia ****
By Patient 11.8 33.3 0
By Course 2.4 8.6 0
Septic Death 1.5 5.6 1.1
Non-Septic Death 1.1 11.1 0
*Normal Baseline LFTs: Transaminases = 1.5 times ULN or alkaline phosphatase = 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
**Elevated Baseline LFTs: SGOT and/or SGPT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
***Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia.
****Febrile Neutropenia: For 100 mg/m 2 , ANC grade 4 and fever > 38Β°C with IV antibiotics and/or hospitalization; for 60 mg/m 2 , ANC grade 3/4 and fever > 38.1Β°C
Non-Hematologic Adverse Events in Breast Cancer Patients Previously Treated with Chemotherapy Treated at TAXOTERE
100 mg/m 2 with Normal or Elevated Liver Function Tests or 60 mg/m 2 with Normal Liver Function Tests
TAXOTERE 100 mg/m 2 TAXOTERE 60 mg/m 2
Adverse Event Normal LFTs * n=730 % Elevated LFTs ** n=18 % Normal LFTs * n=174 %
Acute Hypersensitivity
Reaction Regardless of Premedication
Any 13.0 5.6 0.6
Severe 1.2 0 0
Fluid Retention *** Regardless of Premedication
Any 56.2 61.1 12.6
Severe 7.9 16.7 0
Neurosensory
Any 56.8 50 19.5
Severe 5.8 0 0
Myalgia 22.7 33.3 3.4
Cutaneous
Any 44.8 61.1 30.5
Severe 4.8 16.7 0
Asthenia
Any 65.2 44.4 65.5
Severe 16.6 22.2 0
Diarrhea
Any 42.2 27.8 NA
Severe 6.3 11.1
Stomatitis
Any 53.3 66.7 19.0
Severe 7.8 38.9 0.6
*Normal Baseline LFTs: Transaminases = 1.5 times ULN or alkaline phosphatase = 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
**Elevated Baseline Liver Function: SGOT and/or SGPT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
***Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m 2 dose
NA = not available
Non-Small Cell Lung Cancer (NSCLC): The efficacy and safety of TAXOTERE in non-small cell lung cancer have been evaluated in patients with locally advanced or metastatic disease and a history of prior treatment with a platinum-based chemotherapy regimen. Two randomized, controlled trials established that a TAXOTERE dose of 75 mg/m 2 was tolerable and yielded a favorable outcome (see below). TAXOTERE at a dose of 100 mg/m 2 , however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used (see BOXED WARNING , WARNINGS , and DOSAGE AND ADMINISTRATION sections).
One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status =2 to TAXOTERE or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to TAXOTERE 100 mg/m 2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to TAXOTERE 75 mg/m 2 . A total of 104 patients were randomized in this amended study to either TAXOTERE 75 mg/m 2 or best supportive care.
In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status =2 were randomized to TAXOTERE 75 mg/m 2 , TAXOTERE 100 mg/m 2 and a treatment in which the investigator chose either vinorelbine 30 mg/m 2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m 2 days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the TAXOTERE 75 mg/m 2 arm and the comparator arms are summarized in the table below and in figures 1 and 2 showing the survival curves for the two studies.