AXOTERE® (docetaxel) 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 as a single agent at a dose of 100 mg/m2.
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 x ULN concomitant with alkaline phosphatase > 2.5 x 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 x 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/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.
Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received the recommended 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the TAXOTERE infusion and 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.
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).
|
Drug Warning Insert |
,4,7ß,10ß,13
-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 C43H53NO14• 3H2O, and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water. TAXOTERE (docetaxel) 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 mL) docetaxel (anhydrous). Each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80. TAXOTERE 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 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/m2 in phase I studies. The area under the curve (AUC) was dose proportional following doses of 70-115 mg/m2 with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the
,
ß, and 
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/m2
and 113 L, respectively. Mean total body clearance for
Japanese patients dosed at the range of 10-90
mg/m2
was similar to that of European/American populations
dosed at 100 mg/m2,
suggesting no significant difference in the elimination
of docetaxel in the two populations.
A study of
14C-docetaxel
was conducted in three cancer patients. Docetaxel was
eliminated in both the urine and feces following
oxidative metabolism of the tert-butyl ester group, but
fecal excretion was the main elimination route. Within 7
days, urinary and fecal excretion accounted for
approximately 6% and 75% of the administered
radioactivity, respectively. About 80% of the
radioactivity recovered in feces is excreted during the
first 48 hours as 1 major and 3 minor metabolites with
very small amounts (less than 8%) of unchanged drug.
A
population pharmacokinetic analysis was carried out after
TAXOTERE treatment of 535 patients dosed at 100
mg/m2.
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.
Clearance of docetaxel in combination therapy
with cisplatin was similar to that previously observed
following monotherapy with docetaxel. The pharmacokinetic
profile of cisplatin in combination therapy with
docetaxel was similar to that observed with cisplatin
alone.
The combined administration of docetaxel,
cisplatin and fluorouracil in 12 patients with solid
tumors had no influence on the pharmacokinetics of each
individual drug.
A population pharmacokinetic analysis
of plasma data from 40 patients with hormone-refractory
metastatic prostate cancer indicated that docetaxel
systemic clearance in combination with prednisone is
similar to that observed following administration of
docetaxel alone.
A study was conducted in 30 patients
with advanced breast cancer to determine the potential
for drug-drug-interactions between docetaxel (75
mg/m2),
doxorubicin (50 mg/m2),
and cyclophosphamide (500 mg/m2)
when administered in combination. The coadministration of
docetaxel had no effect on the pharmacokinetics of
doxorubicin and cyclophosphamide when the three drugs
were given in combination compared to coadministration of
doxorubicin and cyclophosphamide only. In addition,
doxorubicin and cyclophosphamide had no effect on
docetaxel plasma clearance when the three drugs were
given in combination compared to historical data for
docetaxel monotherapy.
In vitro studies showed that
docetaxel is about 94% protein bound, mainly to
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 .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). Randomized Trials In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with TAXOTERE (100 mg/m2 every 3 weeks) or the combination of mitomycin (12 mg/m2 every 6 weeks) and vinblastine (6 mg/m2 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 (See Table 1).
Table 1 - Efficacy of TAXOTERE in the Treatment of Breast
Cancer
Patients
Previously Treated with an Anthracycline-Containing
Regimen
(Intent-to-Treat
Analysis)
(n=203)
Vinblastine (n=189)
p=0.01 Log Rank
|
Efficacy Parameter |
Docetaxel |
Mitomycin/ | p-value | |||
|
Median Survival |
11.4 months |
8.7 months | ||||
|
Risk Ratio*, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) |
0.73
0.58-0.93 |
Median Time to Progression |
4.3 months |
2.5 months | p=0.01 Log Rank | |
|
Risk Ratio*, Progression (Docetaxel: Control) 95% CI (Risk Ratio) |
0.75
0.61-0.94 |
Overall Response Rate Complete Response Rate |
28.1% 3.4% |
9.5% 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 (100
mg/m2)
or doxorubicin (75 mg/m2)
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 (See Table
2).
Table 2 - Efficacy of TAXOTERE in the Treatment of Breast
Cancer Patients
Previously
Treated with an Alkylating-Containing
Regimen
(Intent-to-Treat
Analysis)
(n=161)
(n=165)
|
Efficacy Parameter |
Docetaxel |
Doxorubicin | p-value | |||
|
Median Survival |
14.7 months |
14.3 months | p=0.39 Log Rank | |||
|
Risk Ratio*, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) |
0.89
0.68-1.16 |
Median Time to Progression |
6.5 months |
5.3 months | p=0.45 Log Rank | |
|
Risk Ratio*, Progression (Docetaxel: Control) 95% CI (Risk Ratio) |
0.93
0.71-1.16 |
Overall Response Rate Complete Response Rate |
45.3% 6.8% |
29.7% 4.2% | p=0.004 Chi Square | |
*For the risk ratio, a value less than 1.00 favors
docetaxel.
In
another multicenter open-label, randomized trial
(TAX313), in the treatment of patients with advanced
breast cancer who progressed or relapsed after one prior
chemotherapy regimen, 527 patients were randomized to
receive TAXOTERE monotherapy 60 mg/m2
(n=151), 75 mg/m2
(n=188) or 100 mg/m2
(n=188). In this trial, 94% of patients had metastatic
disease and 79% had received prior anthracycline therapy.
Response rate was the primary endpoint. Response rates
increased with TAXOTERE dose: 19.9% for the 60
mg/m2
group compared to 22.3% for the 75
mg/m2
and 29.8% for the 100 mg/m2
group; pair-wise comparison between the 60
mg/m2
and 100 mg/m2
groups was statistically significant, (p=0.037).
Single
Arm Studies
TAXOTERE at a dose of 100
mg/m2
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/m2,
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/m2.
Adjuvant
Treatment of Breast Cancer
A multicenter, open-label,
randomized trial (TAX316) evaluated the efficacy and
safety of TAXOTERE for the adjuvant treatment of patients
with axillary-node-positive breast cancer and no evidence
of distant metastatic disease. After stratification
according to the number of positive lymph nodes (1-3,
4+), 1491 patients were randomized to receive either
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 every 3 weeks
for 6 cycles. TAXOTERE was administered as a 1-hour
infusion; all other drugs were given as IV bolus on day
1. 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.
Results from a second interim analysis (median
follow-up 55 months) are as follows: In study TAX 316,
the docetaxel-containing combination regimen TAC showed
significantly longer disease-free survival (DFS) than FAC
(hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified
log rank p=0.0047). The primary endpoint, disease-free
survival, included local and distant recurrences,
contralateral breast cancer and deaths from any cause.
The overall reduction in risk of relapse was 25.7% for
TAC-treated patients. (See Figure 1).
At the time of
this interim analysis, based on 219 deaths, overall
survival was longer for TAC than FAC (hazard ratio=0.69,
2-sided 95% CI=0.53, 0.90). (See Figure 2). There will be
further analysis at the time survival data
mature.
Figure 1 - TAX 316 Disease Free Survival K-M
curve
Figure 2 - TAX 316 Overall Survival K-M
Curve
The following table describes the results of subgroup
analyses for DFS and OS (See Table 3).
Table 3 - Subset Analyses-Adjuvant Breast Cancer
Study
744
467
277
0.74
0.64
0.84
(0.60, 0.92)
(0.47, 0.87)
(0.63, 1.12)
0.69
0.45
0.93
(0.53, 0.90)
(0.29, 0.70)
(0.66, 1.32)
566 178
0.76 0.68
(0.59, 0.98) (0.48, 0.97)
0.69 0.66
(0.48, 0.99) (0.44, 0.98)
|
|
Disease Free Survival |
Overall Survival |
Patient subset | Number of patients | Hazard ratio* | 95% CI | Hazard ratio* | 95% CI | |||
|
No. of positive nodes Overall 1-3 4+ |
|
|
|
|
|
||||||
|
Receptor status Positive Negative |
|
|
|
|
|
||||||
*a hazard ratio of less than 1 indicates that TAC is
associated with a longer disease free survival or overall
survival compared to FAC.
Non-Small
Cell Lung Cancer (NSCLC)
The efficacy and safety of
TAXOTERE has been evaluated in patients with
unresectable, locally advanced or metastatic non-small
cell lung cancer whose disease has failed prior
platinum-based chemotherapy or in patients who are
chemotherapy-naïve.
Monotherapy with TAXOTERE for NSCLC
Previously Treated with Platinum-Based Chemotherapy
Two
randomized, controlled trials established that a TAXOTERE
dose of 75 mg/m2
was tolerable and yielded a favorable outcome in patients
previously treated with platinum-based chemotherapy (see
below). TAXOTERE at a dose of 100 mg/m2,
however, was associated with unacceptable hematologic
toxicity, infections, and treatment-related mortality and
this dose should not be used.
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
<</u>2
to TAXOTERE or best supportive care. The primary endpoint
of the study was survival. Patients were initially
randomized to TAXOTERE 100 mg/m2
or best supportive care, but early toxic deaths at this
dose led to a dose reduction to TAXOTERE 75
mg/m2.
A total of 104 patients were randomized in this amended
study to either TAXOTERE 75 mg/m2
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
<</u>2
were randomized to TAXOTERE 75 mg/m2,
TAXOTERE 100 mg/m2
and a treatment in which the investigator chose either
vinorelbine 30 mg/m2
days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2
g/m2
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/m2
arm and the comparator arms are summarized in Table 4 and
Figures 3 and 4 showing the survival curves for the two
studies.
Table 4 - Efficacy of TAXOTERE in the Treatment of
Non-Small Cell Lung Cancer
Patients
Previously Treated with a Platinum-Based Chemotherapy
Regimen
(Intent-to-Treat
Analysis)
Supportive Care/75 n=49
75 mg/m2 n=125
(V/I) n=123
††, Mortality (Docetaxel: Control) 95% CI (Risk Ratio)
† (24, 50)
† (22, 39)
|
|
TAX317 |
TAX320 |
Docetaxel | Best | Docetaxel | Control | ||||||||
|
Overall Survival Log-rank Test |
p=0.01 |
p=0.13 |
Risk Ratio |
0.56
(0.35, 0.88) |
0.82
(0.63, 1.06) |
Median Survival 95% CI |
7.5 months* (5.5, 12.8) |
4.6 months (3.7, 6.1) | 5.7 months (5.1, 7.1) | 5.6 months (4.4, 7.9) | ||||
|
% 1-year Survival 95% CI |
37%* |
12% (2, 23) | 30%** | 20% (13, 27) | ||||||||||
|
Time to Progression 95% CI |
12.3 weeks* (9.0, 18.3) |
7.0 weeks (6.0, 9.3) | 8.3 weeks (7.0, 11.7) | 7.6 weeks (6.7, 10.1) | ||||||||||
|
Response Rate 95% CI |
5.5% (1.1, 15.1) |
Not Applicable | 5.7% (2.3, 11.3) | 0.8% (0.0, 4.5) | ||||||||||
|
* p |
Only one of the two trials (TAX317) showed a clear effect
on survival, the primary endpoint; that trial also showed
an increased rate of survival to one year. In the second
study (TAX320) the rate of survival at one year favored
TAXOTERE 75 mg/m2.
Figure 3 - TAX317 Survival K-M Curves - TAXOTERE 75
mg/m2
vs.
Best Supportive Care
Figure 4 - TAX320 Survival K-M Curves - TAXOTERE 75
mg/m2
vs.
Vinorelbine or Ifosfamide Control
Patients
treated with TAXOTERE at a dose of 75
mg/m2
experienced no deterioration in performance status and
body weight relative to the comparator arms used in these
trials.
Combination Therapy with TAXOTERE for
Chemotherapy-Naïve NSCLC
In a randomized controlled
trial (TAX326), 1218 patients with unresectable stage
IIIB or IV NSCLC and no prior chemotherapy were
randomized to receive one of three treatments:
TAXOTERE
75 mg/m2
as a 1 hour infusion immediately followed by cisplatin 75
mg/m2
over 30-60 minutes every 3 weeks; vinorelbine 25
mg/m2
administered over 6-10 minutes on days 1, 8, 15, 22
followed by cisplatin 100 mg/m2
administered on day 1 of cycles repeated every 4 weeks;
or a combination of TAXOTERE and carboplatin.
The
primary efficacy endpoint was overall survival. Treatment
with TAXOTERE+cisplatin did not result in a statistically
significantly superior survival compared to
vinorelbine+cisplatin (see table below). The 95%
confidence interval of the hazard ratio (adjusted for
interim analysis and multiple comparisons) shows that the
addition of TAXOTERE to cisplatin results in an outcome
ranging from a 6% inferior to a 26% superior survival
compared to the addition of vinorelbine to cisplatin. The
results of a further statistical analysis showed that at
least (the lower bound of the 95% confidence interval)
62% of the known survival effect of vinorelbine when
added to cisplatin (about a 2-month increase in median
survival; Wozniak et al. JCO, 1998) was maintained. The
efficacy data for the TAXOTERE+cisplatin arm and the
comparator arm are summarized in Table
5.
Table 5 - Survival Analysis of TAXOTERE in Combination
Therapy for Chemotherapy-Naïve NSCLC
a
b
c
|
Comparison |
Taxotere+Cisplatin n=408 |
Vinorelbine+Cisplatin n=405 | ||||||
|
Kaplan-Meier Estimate of Median Survival |
10.9 months |
10.0 months | ||||||
|
p-value |
0.122 |
Estimated Hazard Ratio |
0.88 |
Adjusted 95% CI |
(0.74, 1.06) |
|||
|
a |
From the superiority test (stratified log rank) comparing TAXOTERE+cisplatin to vinorelbine+cisplatin |
| b | Hazard ratio of TAXOTERE+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that TAXOTERE+cisplatin is associated with a longer survival. |
| c | Adjusted for interim analysis and multiple comparisons. |
The second comparison in the study, vinorelbine+cisplatin versus TAXOTERE+carboplatin, did not demonstrate superior survival associated with the TAXOTERE arm (Kaplan-Meier estimate of median survival was 9.1 months for TAXOTERE+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the TAXOTERE+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between TAXOTERE+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 6).
Table 6 - Response and TTP Analysis of TAXOTERE in
Combination Therapy for Chemotherapy-Naïve
NSCLC
a
b (95% CI)a
|
Endpoint |
TAXOTERE+Cisplatin |
Vinorelbine+Cisplatin | p-value |
|
Objective Response Rate (95% CI) |
31.6% (26.5%, 36.8%) |
24.4% (19.8%, 29.2%) | Not Significant |
|
Median Time to Progression |
21.4 weeks (19.3, 24.6) |
22.1 weeks (18.1, 25.6) | Not Significant |
|
a |
Adjusted for multiple comparisons. |
| b | Kaplan-Meier estimates. |
2 every 3 weeks for 10 cycles.
2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
2 every 3 weeks for 10 cycles.
| •
|
TAXOTERE 75 mg/m |
| •
|
TAXOTERE 30 mg/m |
| •
|
Mitoxantrone 12 mg/m |
Table 7 - Efficacy of TAXOTERE in the Treatment of
Patients with Androgen Independent (Hormone Refractory)
Metastatic Prostate Cancer (Intent-to-Treat
Analysis)
every 3 weeks
335 18.9 (17.0-21.2) 0.761 (0.619-0.936) 0.0094
|
|
TAXOTERE |
Mitoxantrone |
|
Number of patients Median survival (months) 95% CI Hazard ratio 95% CI p-value* |
|
337 16.5 (14.4-18.6) -- -- -- |
*Stratified log rank test. Threshold for statistical
significance = 0.0175 because of 3
arms.
Figure 5 - TAX327 Survival K-M Curves
Gastric Adenocarcinoma
A multicenter, open-label,
randomized trial was conducted to evaluate the safety and
efficacy of 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 TAXOTERE
(T) (75 mg/m2
on day 1) in combination with cisplatin (C) (75
mg/m2
on day 1) and fluorouracil (F) (750
mg/m2
per day for 5 days) or cisplatin (100
mg/m2
on day 1) and 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
demographic characteristics were balanced between the two
treatment arms. The median age was 55 years, 71% were
male, 71% were Caucasian, 24% were 65 years of age or
older, 19% had a prior curative surgery and 12% had
palliative surgery. 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 and was defined as time from randomization to
disease progression or death from any cause within 12
weeks of the last evaluable tumor assessment or within 12
weeks of the first infusion of study drugs for patients
with no evaluable tumor assessment after randomization.
The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI:
1.19-1.83) with a significantly longer TTP (p=0.0004) in
the TCF arm. Approximately 75% of patients had died at
the time of this analysis. Overall survival was
significantly longer (p=0.0201) in the TCF arm with a HR
of 1.29 (95% CI: 1.04-1.61). Efficacy results are
summarized in Table 8 and Figures 6 and
7.
Table
8 - Efficacy of TAXOTERE in the treatment of patients
with gastric adenocarcinoma
n=221
n=224
† (95%CI) *p-value
† (95%CI) *p-value
| Endpoint |
TCF |
CF |
|
Median TTP (months) (95%CI) Hazard ratio |
5.6 (4.86-5.91) |
3.7 (3.45-4.47) |
|
1.47
(1.19-1.83)
0.0004 |
||
|
Median survival (months) (95%CI) Hazard ratio |
9.2 (8.38-10.58) |
8.6 (7.16-9.46) |
|
1.29
(1.04-1.61)
0.0201 |
||
|
Overall Response Rate (CR+PR) (%)
|
36.7 |
25.4 |
|
0.0106 |
||
|
* |
Unstratified logrank test |
| † | For the hazard ratio (CF/TCF), values greater than 1.00 favor the TAXOTERE arm. |
Figure 6 - Gastric Cancer Study (TAX325) Time to
Progression K-M Curve
Figure 7 - Gastric Cancer Study (TAX325) Survival K-M
Curve
Head
and Neck Cancer
The safety and efficacy of TAXOTERE
in the induction treatment of patients with squamous
cell carcinoma of the head and neck (SCCHN) was
evaluated in a multicenter, open-label, randomized
trial (TAX323). In this study, 358 patients with
inoperable locally advanced SCCHN, and WHO
performance status 0 or 1, received either TAXOTERE
75 mg/m2
followed by cisplatin 75 mg/m2
on Day 1, followed by fluorouracil 750
mg/m2
per day as a continuous infusion on Days 1-5 (TPF) or
cisplatin 100 mg/m2
on Day 1, followed by fluorouracil 1000
mg/m2/day
as a continuous infusion on Days 1-5 (PF). These regimens
were administered every three weeks for 4 cycles. 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 regimen (1.8 Gy-2.0 Gy once a day, 5 days per
week for a total dose of 66 to 70 Gy) or with an
accelerated/hyperfractionated regimen (twice a day, with
a minimum interfraction interval of 6 hours, 5 days per
week, for a total dose of 70 to 74 Gy, respectively).
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=0.0077 (median PFS: 11.4 vs. 8.3 months
respectively) with an overall median follow up time of
33.7 months. Median overall survival with a median
follow-up of 51.2 months was also significantly longer in
favor of the TPF arm compared to the PF arm (median OS:
18.6 vs. 14.2 months respectively). Efficacy results are
presented in Table 9 and Figures 8 and
9.
Table 9 - Efficacy of TAXOTERE in the induction treatment
of patients with inoperable locally advanced SCCHN
(Intent-to-Treat Analysis)
|
Endpoint |
TAXOTERE+
|
Cisplatin+ Fluorouracil n=181 |
|
Median progression free survival (months)
|
11.4
|
8.3
(7.4-9.1) |
|
0.71
(0.56-0.91) 0.0077 |
||
|
Median survival (months)
|
18.6
|
14.2
(11.5-18.7) |
|
0.71
(0.56-0.90) 0.0055 |
||
|
Best overall response (CR + PR) to
|
|
53.6 (46.0-61.0) |
|
0.006 |
||
|
Best overall response (CR + PR) to study
|
|
58.6 (51.0-65.8) |
|
0.006 |
||
A Hazard ratio of less than 1 favors
TAXOTERE+Cisplatin+Fluorouracil
* Stratified log-rank test based on primary tumor site
** Stratified log-rank test, not adjusted for multiple
comparisons
*** Chi square test, not adjusted for multiple
comparisons
Figure 8 - TAX323 Progression-Free Survival K-M
Curve
Figure 9 - TAX323 Overall Survival K-M
Curve
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 inoperable locally advanced squamous cell
carcinoma of the head and neck
(SCCHN).
CONTRAINDICATIONS
TAXOTERE
is contraindicated in patients who have a history of
severe hypersensitivity reactions to docetaxel or to
other drugs formulated with polysorbate 80.
TAXOTERE
should not be used in patients with neutrophil counts of
<1500 cells/mm3.
WARNINGS
TAXOTERE
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.
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
(SGOT and/or SGPT > 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 a PS of 2 at study entry
.
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 to reduce the severity
of fluid retention and hypersensitivity reactions. This
regimen was evaluated in 92 patients with metastatic
breast cancer previously treated with chemotherapy given
TAXOTERE at a dose of 100 mg/m2
every 3 weeks.
The pretreatment regimen for
hormone-refractory metastatic prostate cancer is oral
dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour
before the TAXOTERE infusion section).
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. Hypersensitivity reactions require
immediate discontinuation of the TAXOTERE infusion.
Patients with a history of severe hypersensitivity
reactions should not be rechallenged with
TAXOTERE.
Hematologic Effects
Neutropenia (< 2000
neutrophils/mm3)
occurs in virtually all patients given 60-100
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 and are described in clinical studies.
Three
breast cancer patients with severe liver impairment
(bilirubin > 1.7 times ULN) developed fatal
gastrointestinal bleeding associated with severe
drug-induced thrombocytopenia.
In gastric cancer
patients treated with TAXOTERE 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.
Hepatic Impairment
Fluid
Retention
Acute Myeloid Leukemia
Treatment-related
acute myeloid leukemia (AML) has occurred in patients
given anthracyclines and/or cyclophosphamide, including
use in adjuvant therapy for breast cancer. In the
adjuvant breast cancer trial AML occurred in 3 of 744
patients who received TAXOTERE, doxorubicin and
cyclophosphamide and in 1 of 736 patients who received
fluorouracil, doxorubicin and
cyclophosphamide.
Pregnancy
TAXOTERE can cause fetal
harm when administered to pregnant women. Studies in both
rats and rabbits at doses
>
0.3 and 0.03 mg/kg/day, respectively (about 1/50 and
1/300 the daily maximum recommended human dose on a
mg/m2
basis), administered during the period of organogenesis,
have shown that TAXOTERE is embryotoxic and fetotoxic
(characterized by intrauterine mortality, increased
resorption, reduced fetal weight, and fetal ossification
delay). The doses indicated above also caused maternal
toxicity.
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 or potential risk
for loss of the pregnancy. Women of childbearing
potential should be advised to avoid becoming pregnant
during therapy with TAXOTERE.
PRECAUTIONS
General
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.
Hematologic Effects
In order
to monitor the occurrence of myelotoxicity, it is
recommended that frequent peripheral blood cell counts be
performed 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.
Hypersensitivity
Reactions
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.
More severe reactions, however, require the immediate
discontinuation of TAXOTERE and aggressive therapy. All
patients should be premedicated with an oral
corticosteroid prior to the initiation of the infusion of
TAXOTERE.
Cutaneous
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. 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.
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. 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.
9.8% (9/92) 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).
Neurologic
Severe neurosensory
symptoms (paresthesia, dysesthesia, pain) were observed
in 5.5% (53/965) of metastatic breast cancer patients,
and resulted in treatment discontinuation in 6.1%. When
these symptoms occur, dosage must be adjusted. If
symptoms persist, treatment should be discontinued.
Patients who experienced neurotoxicity in clinical trials
and for whom follow-up information on the complete
resolution of the event was available had spontaneous
reversal of symptoms with a median of 9 weeks from onset
(range: 0 to 106 weeks). Severe peripheral motor
neuropathy mainly manifested as distal extremity weakness
occurred in 4.4% (42/965).
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.
Information for Patients
For
additional information, see the accompanying.
Drug
Interactions
There have been no formal clinical studies
to evaluate the drug interactions of TAXOTERE with other
medications. In vitro studies have shown that the
metabolism of docetaxel may be modified by the
concomitant administration of compounds that induce,
inhibit, or are metabolized by cytochrome P450 3A4, such
as cyclosporine, terfenadine, ketoconazole, erythromycin,
and troleandomycin. Caution should be exercised with
these drugs when treating patients receiving TAXOTERE as
there is a potential for a significant
interaction.
Carcinogenicity, Mutagenicity, Impairment
of Fertility
No studies have been conducted to assess
the carcinogenic potential of TAXOTERE. TAXOTERE has been
shown to be clastogenic in the in vitro chromosome
aberration test in CHO-K1
cells and in the in vivo micronucleus test in the mouse,
but it did not induce mutagenicity in the Ames test or
the CHO/HGPRT gene mutation assays. TAXOTERE produced no
impairment of fertility in rats when administered in
multiple IV doses of up to 0.3 mg/kg (about 1/50 the
recommended human dose on a mg/m2
basis), but decreased testicular weights were reported.
This correlates with findings of a 10-cycle toxicity
study (dosing once every 21 days for 6 months) in rats
and dogs in which testicular atrophy or degeneration was
observed at IV doses of 5 mg/kg in rats and 0.375 mg/kg
in dogs (about 1/3 and 1/15 the recommended human dose on
a mg/m2
basis, respectively). An increased frequency of dosing in
rats produced similar effects at lower dose
levels.
Pregnancy
Pregnancy Category D.
Nursing
Mothers
It is not known whether TAXOTERE is excreted in
human milk. Because many drugs are excreted in human
milk, and because of the potential for serious adverse
reactions in nursing infants from TAXOTERE, mothers
should discontinue nursing prior to taking the
drug.
Pediatric Use
The safety and effectiveness of
TAXOTERE in pediatric patients have not been
established.
Geriatric
Use
In a study conducted in chemotherapy-naïve patients
with NSCLC (TAX326), 148 patients (36%) in the
TAXOTERE+cisplatin group were 65 years of age or greater.
There were 128 patients (32%) in the
vinorelbine+cisplatin group 65 years of age or greater.
In the TAXOTERE+cisplatin group, patients less than 65
years of age had a median survival of 10.3 months (95% CI
: 9.1 months, 11.8 months) and patients 65 years or older
had a median survival of 12.1 months (95% CI : 9.3
months, 14 months). In patients 65 years of age or
greater treated with TAXOTERE+cisplatin, diarrhea (55%),
peripheral edema (39%) and stomatitis (28%) were observed
more frequently than in the vinorelbine+cisplatin group
(diarrhea 24%, peripheral edema 20%, stomatitis 20%).
Patients treated with TAXOTERE+cisplatin who were 65
years of age or greater were more likely to experience
diarrhea (55%), infections (42%), peripheral edema (39%)
and stomatitis (28%) compared to patients less than the
age of 65 administered the same treatment (43%, 31%, 31%
and 21%, respectively).
When TAXOTERE was combined with
carboplatin for the treatment of chemotherapy-naïve,
advanced non-small cell lung carcinoma, patients 65 years
of age or greater (28%) experienced higher frequency of
infection compared to similar patients treated with
TAXOTERE+cisplatin, and a higher frequency of diarrhea,
infection and peripheral edema than elderly patients
treated with vinorelbine+cisplatin.
Of the 333 patients
treated with TAXOTERE every three weeks plus prednisone
in the prostate cancer study (TAX327), 209 patients were
65 years of age or greater and 68 patients were older
than 75 years. In patients treated with TAXOTERE every
three weeks, the following TEAEs occurred at rates
>
10% higher in patients 65 years of age or greater
compared to younger patients: anemia (71% vs. 59%),
infection (37% vs. 24%), nail changes (34% vs. 23%),
anorexia (21% vs. 10%), weight loss (15% vs. 5%)
respectively.
In the adjuvant breast cancer trial
(TAX316), TAXOTERE in combination with doxorubicin and
cyclophosphamide was administered to 744 patients of whom
48 (6%) were 65 years of age or greater. The number of
elderly patients who received this regimen was not
sufficient to determine whether there were differences in
safety and efficacy between elderly and younger
patients.
Among the 221 patients treated with TAXOTERE
in combination with cisplatin and fluorouracil in the
gastric cancer study, 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, dizziness, edema, 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.
Of the 174
patients who received the induction treatment with
TAXOTERE in combination with cisplatin and fluorouracil
for SCCHN (TAX323), 18 (10%) patients were 65 years of
age or older.
The clinical study of TAXOTERE in
combination with cisplatin and fluorouracil in patients
with SCCHN (TAX323) did not include sufficient numbers of
patients aged 65 and over to determine whether they
respond differently from younger patients. Other reported
clinical experience with this treatment regimen has not
identified differences in responses between elderly and
younger patients.
ADVERSE
REACTIONS
Adverse reactions are described for TAXOTERE
according to indication:
-in the treatment of breast
cancer, at the maximum dose of 100
mg/m2
-in
the treatment of advanced breast cancer at doses of 60,
75, and 100 mg/m2
-in
the adjuvant therapy of breast cancer at a dose of 75
mg/m2,
in combination with doxorubicin and cyclophosphamide
-in
the treatment of advanced non-small cell lung cancer
after prior platinum-based chemotherapy, at a dose of 75
mg/m2
-in
the treatment of non-small cell lung cancer in patients
who have not previously received chemotherapy for this
condition, at a dose of 75 mg/m2,
in combination with cisplatin
-in the treatment of
androgen independent (hormone refractory) metastatic
prostate cancer, at a dose of 75 mg/m2
every three weeks in combination with prednisone
-in the
treatment of advanced gastric adenocarcinoma in patients
who have not received prior chemotherapy for advanced
disease, at a dose of 75 mg/m2
in combination with cisplatin and fluorouracil
-in the
induction treatment of SCCHN, at a dose of 75
mg/m2
every three weeks in combination with cisplatin and
fluorouracil.
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 10).
Table 10 - Summary of Adverse Events in Patients
Receiving TAXOTERE at 100 mg/m2
3 <500 cells/mm3 Leukopenia <4000 cells/mm3 <1000 cells/mm3 Thrombocytopenia <100,000 cells/mm3 Anemia <11 g/dL <8 g/dL Febrile Neutropenia***
95.5 75.4 95.6 31.6 8.0 90.4 8.8 11.0
96.4 87.5 98.3 46.6 24.6 91.8 31.1 26.2
98.5 85.9 98.6 43.7 9.2 93.6 7.7 12.3
Non-Septic Death
1.6 0.6
4.9 6.6
1.4 0.6
21.0 4.2 n=92 15.2 2.2
19.7 9.8 n=3 33.3 0
17.6 2.6 n=92 15.2 2.2
47.0 6.9 n=92 64.1 6.5
39.3 8.2 n=3 66.7 33.3
75.8
62.3
74.2
9.2
6.6
8.2
4.4
3.3
4.0
|
Adverse Event |
All Tumor Types
|
All Tumor Types
Elevated LFTs** n=61 % |
Breast Cancer
Normal LFTs* n=965 % |
|
Hematologic Neutropenia <2000 cells/mm |
|
||
|
Septic Death |
|
||
|
Infections Any Severe |
21.6 6.1 |
32.8 16.4 | 22.2 6.4 |
|
Fever in Absence of Infection Any Severe |
31.2 2.1 |
41.0 8.2 | 35.1 2.2 |
|
Hypersensitivity Reactions Regardless of Premedication Any Severe With 3-day Premedication Any Severe |
|
||
|
Fluid Retention Regardless of Premedication Any Severe With 3-day Premedication Any Severe |
|
59.7 8.9 n=92 64.1 6.5 | |
|
Neurosensory Any Severe |
49.3 4.3 |
34.4 0 | 58.3 5.5 |
|
Cutaneous Any Severe |
47.6 4.8 |
54.1 9.8 | 47.0 5.2 |
|
Nail Changes Any Severe |
30.6 2.5 |
23.0 4.9 | 40.5 3.7 |
|
Gastrointestinal Nausea Vomiting Diarrhea Severe |
38.8 22.3 38.7 4.7 |
37.7 23.0 32.8 4.9 | 42.1 23.4 42.6 5.5 |
|
Stomatitis Any Severe |
41.7 5.5 |
49.2 13.0 | 51.7 7.4 |
|
Alopecia |
|
||
|
Asthenia Any Severe |
61.8 12.8 |
52.5 24.6 | 66.3 14.9 |
|
Myalgia Any Severe |
18.9 1.5 |
16.4 1.6 | 21.1 1.8 |
|
Arthralgia |
|
||
|
Infusion Site Reactions |
|
|
*Normal Baseline LFTs: Transaminases |
| **Elevated Baseline LFTs: SGOT and/or SGPT > 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN |
| ***Febrile Neutropenia: ANC grade 4 with fever > 38°C with IV antibiotics and/or hospitalization |
Reversible marrow suppression was the major dose-limiting toxicity of TAXOTERE. The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm3) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles. Febrile neutropenia (<500 cells/mm3 with fever > 38°C with IV antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids. Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids. Thrombocytopenia (<100,000 cells/mm3) associated with fatal gastrointestinal hemorrhage has been reported. Hypersensitivity Reactions Severe hypersensitivity reactions are discussed in the precautions section. Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and appropriate therapy. Cutaneous Severe skin toxicity is discussed in precautions. Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after TAXOTERE infusion, recovered before the next infusion, and were not disabling. Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain. Neurologic:.
Gastrointestinal Gastrointestinal reactions (nausea and/or vomiting and/or diarrhea) were generally mild to moderate. Severe reactions occurred in 3-5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. Cardiovascular Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely. 8.1% (7/86) of metastatic breast cancer patients receiving TAXOTERE 100 mg/m2 in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by > 10% associated with a drop below the institutional lower limit of normal. Infusion Site Reactions Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein. Hepatic In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients. Increases in SGOT or SGPT > 1.5 times the ULN, or alkaline phosphatase > 2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on TAXOTERE, increases in SGOT and/or SGPT > 1.5 times ULN concomitant with alkaline phosphatase > 2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. (Whether these changes were related to the drug or underlying disease has not been established.) Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry 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/m2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as 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/m2 who had normal LFTs (see Tables 11 and 12).
Table 11 - Hematologic Adverse Events in Breast Cancer
Patients Previously Treated
with
Chemotherapy Treated at TAXOTERE 100
mg/m2
with Normal
or
Elevated Liver Function Tests or 60
mg/m2
with Normal Liver Function Tests
Adverse Event
60 mg/m2
LFTs* n=730 %
LFTs** n=18 %
LFTs* n=174 %
Neutropenia
Any Grade 4
<2000 cells/mm3 <500 cells/mm3
Thrombocytopenia
Any Grade 4
<100,000 cells/mm3 <20,000 cells/mm3
Infection***
Any Grade 3 and 4
Febrile Neutropenia****
By Patient By Course
|
|
TAXOTERE
100
mg/m2 |
TAXOTERE | |
| Normal | Elevated | Normal | |
|
|
98.4 84.4 |
100 93.8 | 95.4 74.9 |
|
|
10.8 0.6 |
44.4 16.7 | 14.4 1.1 |
|
Anemia <11 g/dL |
94.6 |
94.4 | 64.9 |
|
|
22.5 7.1 |
38.9 33.3 | 1.1 0 |
|
|
11.8 2.4 |
33.3 8.6 | 0 0 |
|
Septic Death |
1.5 |
5.6 | 1.1 |
|
Non-Septic Death |
1.1 |
11.1 | 0 |
2, ANC grade 4 and fever > 38°C with IV antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever > 38.1°C
|
*Normal Baseline LFTs: Transaminases |
| **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 |
Table 12 - Non-Hematologic Adverse Events in Breast
Cancer Patients Previously Treated
with
Chemotherapy Treated at TAXOTERE 100
mg/m2
with Normal
or
Elevated Liver Function Tests or 60
mg/m2
with Normal Liver Function Tests
Adverse Event
60 mg/m2
LFTs* n=730 %
LFTs** n=18 %
LFTs* n=174 %
Acute Hypersensitivity
Reaction Regardless of
Premedication
Any Severe
Fluid Retention***
Regardless of Premedication
Any Severe
Neurosensory
Any Severe
Cutaneous
Any Severe
Asthenia
Any Severe
Diarrhea
Any Severe
Stomatitis
Any Severe
|
|
TAXOTERE
100
mg/m2 |
TAXOTERE | |
| Normal | Elevated | Normal | |
|
|
13.0 1.2 |
5.6 0 | 0.6 0 |
|
|
56.2 7.9 |
61.1 16.7 | 12.6 0 |
|
|
56.8 5.8 |
50 0 | 19.5 0 |
|
Myalgia |
22.7 |
33.3 | 3.4 |
|
|
44.8 4.8 |
61.1 16.7 | 30.5 0 |
|
|
65.2 16.6 |
44.4 22.2 | 65.5 0 |
|
|
42.2 6.3 |
27.8 11.1 | NA |
|
|
53.3 7.8 |
66.7 38.9 | 19.0 0.6 |
2 dose
|
*Normal Baseline LFTs: Transaminases |
| ** 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 |
| NA = not available |
|
|
TAXOTERE 75 mg/m2+
|
Fluorouracil 500 mg/m2+
Doxorubicin 50 mg/m2+ Cyclophosphamide 500 mg/m2 (FAC) n=736 % |
Adverse Event |
Any |
G 3/4 | Any | G 3/4 | ||
|
Anemia |
91.5 |
4.3 | 71.7 | 1.6 | |||||
|
Neutropenia |
71.4 |
65.5 | 82.0 | 49.3 | |||||
|
Fever in absence of infection |
46.5 |
1.3 | 17.1 | 0.0 | |||||
|
Infection |
39.4 |
3.9 | 36.3 | 2.2 | |||||
|
Thrombocytopenia |
39.4 |
2.0 | 27.7 | 1.2 | |||||
|
Febrile neutropenia |
24.7 |
N/A | 2.5 | N/A | |||||
|
Neutropenic infection |
12.1 |
N/A | 6.3 | N/A | |||||
|
Hypersensitivity reactions |
13.4 |
1.3 | 3.7 | 0.1 | |||||
|
Lymphedema |
4.4 |
0.0 | 1.2 | 0.0 | |||||
|
Fluid Retention*
|
35.1
|
0.9
0.4 0.3 |
14.7
7.3 8.6 |
0.1
0.0 0.3 |
|||||
|
Neuropathy sensory |
25.5 |
0.0 | 10.2 | 0.0 | |||||
|
Neuro-cortical |
5.1 |
0.5 | 6.4 | 0.7 | |||||
|
Neuropathy motor |
3.8 |
0.1 | 2.2 | 0.0 | |||||
|
Neuro-cerebellar |
2.4 |
0.1 | 2.0 | 0.0 | |||||
|
Syncope |
1.6 |
0.5 | 1.2 | 0.3 | |||||
|
Alopecia |
97.8 |
N/A | 97.1 | N/A | |||||
|
Skin toxicity |
26.5 |
0.8 | 17.7 | 0.4 | |||||
|
Nail disorders |
18.5 |
0.4 | 14.4 | 0.1 | |||||
|
Nausea |
80.5 |
5.1 | 88.0 | 9.5 | |||||
|
Stomatitis |
69.4 |
7.1 | 52.9 | 2.0 | |||||
|
Vomiting |
44.5 |
4.3 | 59.2 | 7.3 | |||||
|
Diarrhea |
35.2 |
3.8 | 27.9 | 1.8 | |||||
|
Constipation |
33.9 |
1.1 | 31.8 | 1.4 | |||||
|
Taste perversion |
27.8 |
0.7 | 15.1 | 0.0 | |||||
|
Anorexia |
21.6 |
2.2 | 17.7 | 1.2 | |||||
|
Abdominal Pain |
10.9 |
0.7 | 5.3 | 0.0 | |||||
|
Amenorrhea |
61.7 |
N/A | 52.4 | N/A | |||||
|
Cough |
13.7 |
0.0 | 9.8 | 0.1 | |||||
|
Cardiac dysrhythmias |
7.9 |
0.3 | 6.0 | 0.3 | |||||
|
Vasodilatation |
27.0 |
1.1 | 21.2 | 0.5 | |||||
|
Hypotension |
2.6 |
0.0 | 1.1 | 0.1 | |||||
|
Phlebitis |
1.2 |
0.0 | 0.8 | 0.0 | |||||
|
Asthenia |
80.8 |
11.2 | 71.2 | 5.6 | |||||
|
Myalgia |
26.7 |
0.8 | 9.9 | 0.0 | |||||
|
Arthralgia |
19.4 |
0.5 | 9.0 | 0.3 | |||||
|
Lacrimation disorder |
11.3 |
0.1 | 7.1 | 0.0 | |||||
|
Conjunctivitis |
5.1 |
0.3 | 6.9 | 0.1 | |||||
* COSTART term and grading system for events related to
treatment.
Of
the 744 patients treated with TAC, 36.3% experienced
severe TEAEs compared to 26.6% of the 736 patients
treated with FAC. Dose reductions due to hematologic
toxicity occurred in 1% of cycles in the TAC arm versus
0.1% of cycles in the FAC arm. Six percent of patients
treated with TAC discontinued treatment due to adverse
events, compared to 1.1% treated with FAC; fever in the
absence of infection and allergy being the most common
reasons for withdrawal among TAC-treated patients. Two
patients died in each arm within 30 days of their last
study treatment; 1 death per arm was attributed to study
drugs.
Fever and Infection
Fever in the absence of
infection was seen in 46.5% of TAC-treated patients and
in 17.1% of FAC-treated patients. Grade 3/4 fever in the
absence of infection was seen in 1.3% and 0% of TAC- and
FAC-treated patients respectively. Infection was seen in
39.4% of TAC-treated patients compared to 36.3% of
FAC-treated patients. Grade 3/4 infection was seen in
3.9% and 2.2% of TAC-treated and FAC-treated patients
respectively. There were no septic deaths in either
treatment arm.
Gastrointestinal events
In addition to
gastrointestinal events reflected in the table above, 7
patients in the TAC arm were reported to have
colitis/enteritis/large intestine perforation vs. one
patient in the FAC arm. Five of the 7 TAC-treated
patients required treatment discontinuation; no deaths
due to these events occurred.
Cardiovascular
events
More cardiovascular events were reported in the
TAC arm vs. the FAC arm; dysrhythmias, all grades (7.9%
vs. 6.0%), hypotension, all grades (2.6% vs. 1.1%) and
CHF (1.6% vs. 0.5%). One patient in each arm died due to
heart failure.
Acute Myeloid Leukemia
Treatment-related
acute myeloid leukemia (AML) is known to occur in
patients treated with anthracyclines and/or
cyclophosphamide, including use in adjuvant therapy for
breast cancer. AML occurs at a higher frequency when
these agents are given in combination with radiation
therapy. AML occurred in the adjuvant breast cancer trial
(TAX316). The cumulative risk of developing
treatment-related AML at 5 years in TAX316 was 0.4% for
TAC-treated patients and 0.1% for FAC-treated patients.
This risk of AML is comparable to the risk observed for
other anthracyclines/cyclophosphamide containing adjuvant
breast chemotherapy regimens.
Monotherapy with TAXOTERE
for Unresectable, Locally Advanced or Metastatic NSCLC
Previously Treated with Platinum-Based
Chemotherapy
TAXOTERE 75 mg/m2:
Treatment emergent adverse drug reactions are shown in
Table 14. Included in this table are safety data for a
total of 176 patients with non-small cell lung carcinoma
and a history of prior treatment with platinum-based
chemotherapy who were treated in two randomized,
controlled trials. These reactions were described using
NCI Common Toxicity Criteria regardless of relationship
to study treatment, except for the hematologic toxicities
or otherwise noted.
Table 14 - Treatment Emergent Adverse Events Regardless
of Relationship to Treatment
in
Patients Receiving TAXOTERE as Monotherapy for Non-Small
Cell Lung Cancer
Previously
Treated with Platinum-Based
Chemotherapy*
2
n=176
%
†
†
††
0.6
|
|
TAXOTERE
|
Best
Supportive Care n=49 % |
Vinorelbine/
Ifosfamide n=119 % |
|
Neutropenia Any Grade 3/4 |
84.1 65.3 |
14.3 12.2 | 83.2 57.1 |
|
Leukopenia Any Grade 3/4 |
83.5 49.4 |
6.1 0 | 89.1 42.9 |
|
Thrombocytopenia Any Grade 3/4 |
8.0 2.8 |
0 0 | 7.6 1.7 |
|
Anemia Any Grade 3/4 |
91.0 9.1 |
55.1 12.2 | 90.8 14.3 |
|
Febrile Neutropenia** |
6.3 |
NA | 0.8 |
|
Infection Any Grade 3/4 |
33.5 10.2 |
28.6 6.1 | 30.3 9.2 |
|
Treatment Related Mortality |
2.8 |
NA | 3.4 |
|
Hypersensitivity Reactions Any Grade 3/4 |
5.7 2.8 |
0 0 | 0.8 0 |
|
Fluid Retention Any Severe |
33.5 2.8 |
ND | 22.7 3.4 |
|
Neurosensory Any Grade 3/4 |
23.3 1.7 |
14.3 6.1 | 28.6 5.0 |
|
Neuromotor Any Grade 3/4 |
15.9 4.5 |
8.2 6.1 | 10.1 3.4 |
|
Skin Any Grade 3/4 |
19.9 0.6 |
6.1 2.0 | 16.8 0.8 |
|
Gastrointestinal Nausea Any Grade 3/4 Vomiting Any Grade 3/4 Diarrhea Any Grade 3/4 |
33.5 5.1 21.6 2.8 22.7 2.8 |
30.6 4.1 26.5 2.0 6.1 0 | 31.1 7.6 21.8 5.9 11.8 4.2 |
|
Alopecia |
56.3 |
34.7 | 49.6 |
|
Asthenia Any Severe*** |
52.8 18.2 |
57.1 38.8 | 53.8 22.7 |
|
Stomatitis Any Grade 3/4 |
26.1 1.7 |
6.1 0 | 7.6 0.8 |
|
Pulmonary Any Grade 3/4 |
40.9 21.0 |
49.0 28.6 | 45.4 18.5 |
|
Nail Disorder Any Severe*** |
11.4 1.1 |
0 0 | 1.7 0 |
|
Myalgia Any Severe*** |
6.3 0 |
0 0 | 2.5 0 |
|
Arthralgia Any Severe*** |
3.4 0 |
2.0 0 | 1.7 0.8 |
|
Taste Perversion Any Severe*** |
5.7 |
0 0 | 0 0 |
Not Applicable;††Not Done
|
*Normal Baseline LFTs: Transaminases |
| **Febrile Neutropenia: ANC grade 4 with fever > 38°C with IV antibiotics and/or hospitalization |
| ***COSTART term and grading system |
| † |
Table 15 - Adverse Events Regardless of Relationship to
Treatment in
Chemotherapy-Naïve
Advanced Non-Small Cell Lung Cancer
Patients
Receiving TAXOTERE in Combination with
Cisplatin
2 + Cisplatin 75 mg/m2 n=406 %
2 + Cisplatin 100 mg/m2 n=396 %
Any
Grade 3/4
91
74
90
78
Any
Grade 3/4
15
3
15
4
Any
Grade 3/4
89
7
94
25
Any
Grade 3/4
35
8
37
8
Any
Grade 3/4
33
< 1
29
1
Any
Grade 3/4
12
3
4
< 1
Any
All severe or life-threatening events
Pleural effusion
Any
All severe or life-threatening events
Peripheral edema
Any
All severe or life-threatening events
Weight gain
Any
All severe or life-threatening events
54
2
23
2
34
<1
15
<1
42
2
22
2
18
<1
9
<1
Any
Grade 3/4
47
4
42
4
Any
Grade 3/4
19
3
17
6
Any
Grade 3/4
16
<1
14
1
Any
Grade 3/4
72
10
76
17
Any
Grade 3/4
55
8
61
16
Any
Grade 3/4
47
7
25
3
Any
All severe or life-threatening events
5
5
Any
Grade 3/4
24
2
21
1
Any
Grade 3
75
< 1
42
0
Any
All severe or life-threatening events
12
14
Any
All severe events
14
< 1
<1
0
Any
All severe events
18
< 1
12
< 1
|
Adverse Event |
TAXOTERE 75 mg/m |
Vinorelbine 25 mg/m |
|
Neutropenia |
|
|
|
Febrile Neutropenia |
5 |
5 |
|
Thrombocytopenia |
|
|
|
Anemia |
|
|
|
Infection |
|
|
|
Fever in absence of infection |
|
|
|
Hypersensitivity Reaction* |
|
|
|
Fluid Retention** |
|
|
|
Neurosensory |
|
|
|
Neuromotor |
|
|
|
Skin |
|
|
|
Nausea |
|
|
|
Vomiting |
|
|
|
Diarrhea |
|
|
|
Anorexia** |
42 |
40 |
|
Stomatitis |
|
|
|
Alopecia |
|
|
|
Asthenia** |
74 |
75 |
|
Nail Disorder** |
|
|
|
Myalgia** |
|
|
* |
Replaces NCI term "Allergy" |
|
** |
COSTART term and grading system |
Table 16 - Clinically Important Treatment Emergent
Adverse Events (Regardless of
Relationship)
in Patients with Prostate Cancer who Received TAXOTERE
in
Combination
with Prednisone (TAX 327)
|
|
TAXOTERE 75 mg/m2
every
3 weeks
+
prednisone
5
mg twice daily
n=332
% |
Mitoxantrone 12 mg/m2
every
3 weeks
+
prednisone
5
mg twice daily
n=335
% |
Adverse Event |
Any |
G 3/4 | Any | G 3/4 | ||
|
Anemia |
66.5 |
4.9 | 57.8 | 1.8 | |||||
|
Neutropenia |
40.9 |
32.0 | 48.2 | 21.7 | |||||
|
Thrombocytopenia |
3.4 |
0.6 | 7.8 | 1.2 | |||||
|
Febrile neutropenia |
2.7 |
N/A | 1.8 | N/A | |||||
|
Infection |
32.2 |
5.7 | 20.3 | 4.2 | |||||
|
Epistaxis |
5.7 |
0.3 | 1.8 | 0.0 | |||||
|
Allergic Reactions |
8.4 |
0.6 | 0.6 | 0.0 | |||||
|
Fluid Retention* Weight Gain* Peripheral Edema* |
24.4 7.5 18.1 |
0.6 0.3 0.3 | 4.5 3.0 1.5 | 0.3 0.0 0.0 | |||||
|
Neuropathy Sensory |
30.4 |
1.8 | 7.2 | 0.3 | |||||
|
Neuropathy Motor |
7.2 |
1.5 | 3.0 | 0.9 | |||||
|
Rash/Desquamation |
6.0 |
0.3 | 3.3 | 0.6 | |||||
|
Alopecia |
65.1 |
N/A | 12.8 | N/A | |||||
|
Nail Changes |
29.5 |
0.0 | 7.5 | 0.0 | |||||
|
Nausea |
41.0 |
2.7 | 35.5 | 1.5 | |||||
|
Diarrhea |
31.6 |
2.1 | 9.6 | 1.2 | |||||
|
Stomatitis/Pharyngitis |
19.6 |
0.9 | 8.4 | 0.0 | |||||
|
Taste Disturbance |
18.4 |
0.0 | 6.6 | 0.0 | |||||
|
Vomiting |
16.9 |
1.5 | 14.0 | 1.5 | |||||
|
Anorexia |
16.6 |
1.2 | 14.3 | 0.3 | |||||
|
Cough |
12.3 |
0.0 | 7.8 | 0.0 | |||||
|
Dyspnea |
15.1 |
2.7 | 8.7 | 0.9 | |||||
|
Cardiac left ventricular function |
9.6 |
0.3 | 22.1 | 1.2 | |||||
|
Fatigue |
53.3 |
4.5 | 34.6 | 5.1 | |||||
|
Myalgia |
14.5 |
0.3 | 12.8 | 0.9 | |||||
|
Tearing |
9.9 |
0.6 | 1.5 | 0.0 | |||||
|
Arthralgia |
8.1 |
0.6 | 5.1 | 1.2 | |||||
* Related to treatment
Combination
therapy with 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 TAXOTERE 75 mg/m2
in combination with cisplatin and fluorouracil (see Table
17).
Table 17 - Clinically Important Treatment Emergent
Adverse Events Regardless of Relationship to Treatment in
the Gastric Cancer Study
|
|
TAXOTERE 75 mg/m2
+
|
Cisplatin 100 mg/m2
+
|
Adverse Event |
Any
|
G3/4
% |
Any
% |
G3/4
% |
||
|
Anemia |
96.8 |
18.2 | 93.3 | 25.6 | |||||
|
Neutropenia |
95.5 |
82.3 | 83.3 | 56.8 | |||||
|
Fever in the absence of infection |
35.7 |
1.8 | 22.8 | 1.3 | |||||
|
Thrombocytopenia |
25.5 |
7.7 | 39.0 | 13.5 | |||||
|
Infection |
29.4 |
16.3 | 22.8 | 10.3 | |||||
|
Febrile neutropenia |
16.4 |
N/A | 4.5 | N/A | |||||
|
Neutropenic infection |
15.9 |
N/A | 10.4 | N/A | |||||
|
Allergic reactions |
10.4 |
1.8 | 5.8 | 0 | |||||
|
Fluid retention* |
14.9 |
0 | 4.0 | 0.4 | |||||
|
Edema* |
13.1 |
0 | 3.1 | 0.4 | |||||
|
Lethargy |
62.9 |
21.3 | 58.0 | 17.9 | |||||
|
Neurosensory |
38.0 |
7.7 | 24.6 | 3.1 | |||||
|
Neuromotor |
8.6 |
3.2 | 7.6 | 2.7 | |||||
|
Dizziness |
15.8 |
4.5 | 8.0 | 1.8 | |||||
|
Alopecia |
66.5 |
5.0 | 41.1 | 1.3 | |||||
|
Rash/itch |
11.8 |
0.9 | 8.5 | 0.0 | |||||
|
Nail changes |
8.1 |
0.0 | 0.0 | 0.0 | |||||
|
Skin desquamation |
1.8 |
0.0 | 0.4 | 0.0 | |||||
|
Nausea |
73.3 |
15.8 | 76.3 | 18.8 | |||||
|
Vomiting |
66.5 |
14.9 | 73.2 | 18.8 | |||||
|
Anorexia |
50.7 |
13.1 | 54.0 | 11.6 | |||||
|
Stomatitis |
59.3 |
20.8 | 61.2 | 27.2 | |||||
|
Diarrhea |
77.8 |
20.4 | 49.6 | 8.0 | |||||
|
Constipation |
25.3 |
1.8 | 33.9 | 3.1 | |||||
|
Esophagitis/dysphagia/odynophagia |
16.3 |
1.8 | 13.8 | 4.9 | |||||
|
Gastrointestinal pain/cramping |
11.3 |
1.8 | 7.1 | 2.7 | |||||
|
Cardiac dysrhythmias |
4.5 |
2.3 | 2.2 | 0.9 | |||||
|
Myocardial ischemia |
0.9 |
0.0 | 2.7 | 2.2 | |||||
|
Tearing |
8.1 |
0 | 2.2 | 0.4 | |||||
|
Altered hearing |
6.3 |
0 | 12.5 | 1.8 | |||||
Clinically important TEAEs were determined based upon
frequency, severity, and clinical impact of the adverse
event.
*Related to treatment
Combination
Therapy with TAXOTERE in Head and Neck Cancer
The
following table summarizes the safety data obtained in
174 patients with locally advanced inoperable SCCHN, who
were treated with TAXOTERE 75 mg/m2
in combination with cisplatin and fluorouracil (Table
18).
Table
18 - Clinically Important Treatment Emergent Adverse
Events (Regardless of Relationship) in Patients with
SCCHN Receiving TAXOTERE in Combination with Cisplatin
and fluorouracil (TAX 323).
|
|
TAXOTERE 75 mg/m2
+
|
Cisplatin 100 mg/m2 + fluorouracil 1000 mg/m2 n=181 |
Adverse Event |
Any
|
G3/4
% |
Any
% |
G3/4
% |
||
|
Neutropenia |
93.1 |
76.3 | 86.7 | 52.8 | |||||
|
Anemias |
89.1 |
9.2 | 87.8 | 13.8 | |||||
|
Thrombocytopenia |
23.6 |
5.2 | 47.0 | 18.2 | |||||
|
Infection |
27.0 |
8.6 | 26.0 | 7.7
|
|||||
|
Fever in the absence of infection |
31.6 |
0.6 | 36.5 | 0 | |||||
|
Febrile neutropenia* |
5.2 |
N/A | 2.2 | N/A | |||||
|
Neutropenic infect | |||||||||