Prescribing Information as of February 2005

Rx only

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 · 3H ₂ O, 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/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.

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.

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/m ² ), doxorubicin (50 mg/m ² ), and cyclophosphamide (500 mg/m ² ) 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 (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).

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/m ² every 3 weeks) 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:

In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with TAXOTERE (100 mg/m ² ) 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:

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/m ² (n=151), 75 mg/m ² (n=188) or 100 mg/m ² (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/m ² group compared to 22.3% for the 75 mg/m ² and 29.8% for the 100 mg/m ² group; pair-wise comparison between the 60 mg/m ² and 100 mg/m ² groups was statistically significant, (p=0.037).

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 .

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/m ² administered 1-hour after doxorubicin 50 mg/m ² and cyclophosphamide 500 mg/m ² (TAC arm), or doxorubicin 50 mg/m ² followed by fluorouracil 500 mg/m ² and cyclosphosphamide 500 mg/m ² (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.

The following table describes the results of subgroup analyses for DFS and OS.

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-na[iuml ]ve.

Monotherapy with TAXOTERE for NSCLC Previously Treated with Platinum-Based Chemotherapy

Two randomized, controlled trials established that a TAXOTERE dose of 75 mg/m ² was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (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 3 and 4 showing the survival curves for the two studies.

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/m ² .

Patients treated with TAXOTERE at a dose of 75 mg/m ² experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.

Combination Therapy with TAXOTERE for Chemotherapy-Na[iuml ]ve 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/m ² as a 1 hour infusion immediately followed by cisplatin 75 mg/m ² over 30-60 minutes every 3 weeks; vinorelbine 25 mg/m ² administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m ² 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 the table below.

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 below).

Prostate Cancer

The safety and efficacy of TAXOTERE in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) >/=60 were randomized to the following treatment groups:

• TAXOTERE 75 mg/m ² every 3 weeks for 10 cycles.
• TAXOTERE 30 mg/m ² administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
• Mitoxantrone 12 mg/m ² every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.

In the TAXOTERE every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the TAXOTERE weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the TAXOTERE every 3 week arm versus the control arm are summarized in the following table and figure 5:

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 treat-ment 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.

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/mm ³ .

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/m ² 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/m ² , 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/m ² 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/m ² dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m ² dose level, 3 of 5 patients had a PS of 2 at study entry (see BOXED WARNING, CLINICAL STUDIES , and DOSAGE AND ADMINISTRATION sections).

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 (see DOSAGE AND ADMINISTRATION section). This regimen was evaluated in 92 patients with metastatic breast cancer previously treated with chemotherapy given TAXOTERE at a dose of 100 mg/m ² 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 (see DOSAGE AND ADMINISTRATION section).

Hypersensitivity Reactions

Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by hypotension and/or bronchospasm, or generalized rash/erythema occurred in 2.2% of the 92 patients premedicated with 3-day corticosteroids. Hypersensitivity reactions requiring discontinuation of the TAXOTERE infusion were reported in 5 out of 1260 patients with various tumor types who did not receive premedication, but in 0/92 patients premedicated with 3-day corticosteroids. Patients with a history of severe hypersensitivity reactions should not be rechallenged with TAXOTERE.

Hematologic Effects

Neutropenia (< 2000 neutrophils/mm ³ ) occurs in virtually all patients given 60-100 mg/m ² of TAXOTERE and grade 4 neutropenia (<500 cells/mm ³ ) occurs in 85% of patients given 100 mg/m ² and 75% of patients given 60 mg/m ² . 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/mm ³ .

Febrile neutropenia occurred in about 12% of patients given 100 mg/m ² but was very uncommon in patients given 60 mg/m ² . 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 impair-ment (bilirubin > 1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia.

Hepatic Impairment

(see BOXED WARNING ).

Fluid Retention

(see BOXED WARNING ).

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 (TAX316, see CLINICAL STUDIES ) 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 (see ADVERSE REACTIONS ).

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/m ² 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/mm ³ and platelets recover to a level > 100,000 cells/mm ³ .

A 25% reduction in the dose of TAXOTERE is recommended during subsequent cycles following severe neutropenia (<500 cells/mm ³ ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a TAXOTERE cycle (see DOSAGE AND ADMINISTRATION section).

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 (see BOXED WARNING and WARNINGS: Premedication Regimen ).

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 (see DOSAGE AND ADMINISTRATION section). 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 (see BOXED WARNING and WARNINGS: Premedication Regimen ). 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 section). 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/m ² . 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/m ² . 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 (see DOSAGE AND ADMINISTRATION section). 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 Patient Information Leaflet.

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-K ₁ 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/m ² 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/m ² basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

Pregnancy

Pregnancy Category D (see WARNINGS section).

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-na[iuml ]ve 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-na[iuml ]ve, 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.

ADVERSE REACTIONS

Adverse reactions are described for TAXOTERE according to indication:

• in the treatment of breast cancer, at the maximum dose of 100 mg/m ²
• in the treatment of advanced breast cancer at doses of 60, 75 and 100 mg/m ²
• in the adjuvant therapy of breast cancer at a dose of 75 mg/m ² , 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/m ²
• 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/m ² , in combination with cisplatin
• in the treatment of androgen independent (hormone refractory) metastatic prostate cancer, at a dose of 75 mg/m ² every three weeks in combination with prednisone

Monotherapy with TAXOTERE for Locally Advanced or Metastatic Breast Cancer After Failure of Prior Chemotherapy

TAXOTERE 100 mg/m ² :    Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received TAXOTERE administered at 100 mg/m ² 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.

Hematologic: (see WARNINGS ).

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/mm ³ ) 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/mm ³ 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/mm ³ ) associated with fatal gastrointestinal hemorrhage has been reported.

Hypersensitivity Reactions

Severe hypersensitivity reactions are discussed in the BOXED WARNING , WARNINGS , and PRECAUTIONS sections. 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.

Fluid Retention:   (see BOXED WARNING , WARNINGS: Premedication Regimen , and PRECAUTIONS sections).

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:   (see PRECAUTIONS ).

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/m ² 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/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.

In the three-arm monotherapy trial, TAX313, which compared TAXOTERE 60, 75 and 100 mg/m ² in advanced breast cancer, the overall safety profile was consistent with the safety profile observed in previous TAXOTERE trials. Grade 3/4 or severe adverse events occurred in 49.0% of patients treated with TAXOTERE 60 mg/m ² compared to 55.3% and 65.9% treated with 75 and 100 mg/m ² respectively. Discontinuation due to adverse events was reported in 5.3% of patients treated with 60 mg/m ² vs. 6.9% and 16.5% for patients treated at 75 and 100 mg/m ² respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m ² compared to 5.3% and 1.6% for patients treated at 75 and 100 mg/m ² respectively.

The following adverse events were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60, 75, and 100 mg/m ² respectively), thrombocytopenia (7%, 11% and 12% respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14% respectively), treatment-related grade 3/ 4 infection (2%, 3%, and 7% respectively) and anemia (87%, 94%, and 97% respectively).

Combination Therapy with TAXOTERE in the Adjuvant Treatment of Breast Cancer

The following table presents treatment emergent adverse events (TEAEs) observed in 744 patients, who were treated with TAXOTERE 75 mg/m ² every 3 weeks in combination with doxorubicin and cyclophosphamide.

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/m ² :    Treatment emergent adverse drug reactions are shown below. 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.

Combination Therapy with TAXOTERE in Chemotherapy-Naive Advanced Unresectable or Metastatic NSCLC

The table below presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted.