TAXOTERE

Sanofi-Aventis U.S. LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use TAXOTERE safely and effectively. See full prescribing information for TAXOTERE.  TAXOTERE (docetaxel) Injection Concentrate, Intravenous Infusion (IV). Initial U.S. Approval: 1996 BOXED WARNING WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving TAXOTERE at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of TAXOTERE and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to TAXOTERE or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5) RECENT MAJOR CHANGES Warnings and Precautions (5.9) 12/2013 INDICATIONS AND USAGETAXOTERE is a microtubule inhibitor indicated for: Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC (1.1) Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC (1.2) Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer (1.3) Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction (1.4) Squamous Cell Carcinoma of the Head and Neck Cancer (SCCHN): with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN (1.5) DOSAGE AND ADMINISTRATIONAdminister in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over 1 hr every 3 weeks. PVC equipment is not recommended. Use only a 21 gauge needle to withdraw TAXOTERE from the vial. BC locally advanced or metastatic: 60 mg/m2 to 100 mg/m2 single agent (2.1) BC adjuvant: 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles (2.1) NSCLC: after platinum therapy failure: 75 mg/m2 single agent (2.2) NSCLC: chemotherapy-naive: 75 mg/m2 followed by cisplatin 75 mg/m2 (2.2) HRPC: 75 mg/m2 with 5 mg prednisone twice a day continuously (2.3) GC: 75 mg/m2 followed by cisplatin 75 mg/m2 (both on day 1 only) followed by fluorouracil 750 mg/m2 per day as a 24-hr IV (days 1–5), starting at end of cisplatin infusion (2.4) SCCHN: 75 mg/m2 followed by cisplatin 75 mg/m2 IV (day 1), followed by fluorouracil 750 mg/m2 per day as a 24-hr IV (days 1–5), starting at end of cisplatin infusion; for 4 cycles (2.5) SCCHN: 75 mg/m2 followed by cisplatin 100 mg/m2 IV (day 1), followed by fluorouracil 1000 mg/m2 per day as a 24-hr IV (days 1–4); for 3 cycles (2.5) For all patients: Premedicate with oral corticosteroids (2.6) Adjust dose as needed (2.7) DOSAGE FORMS AND STRENGTHS One vial TAXOTERE: Single use vials 20 mg/mL, 80 mg/4 mL, and 160 mg/8 mL (3) CONTRAINDICATIONS Hypersensitivity to docetaxel or polysorbate 80 (4) Neutrophil counts of

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1. TAXOTERE INDICATIONS AND USAGE
  • 1.1 Breast Cancer
  • 1.2 Non-Small Cell Lung Cancer
  • 1.3 Prostate Cancer
  • 1.4 Gastric Adenocarcinoma
  • 1.5 Head and Neck Cancer
• 2. TAXOTERE DOSAGE AND ADMINISTRATION
  • 2.1 Breast Cancer
  • 2.2 Non-Small Cell Lung Cancer
  • 2.3 Prostate Cancer
  • 2.4 Gastric Adenocarcinoma
  • 2.5 Head and Neck Cancer
  • 2.6 Premedication Regimen
  • 2.7 Dosage Adjustments During Treatment
  • 2.8 Administration Precautions
  • 2.9 Preparation and Administration
  • 2.10 Stability
• 3. DOSAGE FORMS AND STRENGTHS
• 4. TAXOTERE CONTRAINDICATIONS
• 5. WARNINGS AND PRECAUTIONS
  • 5.1 Toxic Deaths
  • 5.2 Hepatic Impairment
  • 5.3 Hematologic Effects
  • 5.4 Hypersensitivity Reactions
  • 5.5 Fluid Retention
  • 5.6 Acute Myeloid Leukemia
  • 5.7 Cutaneous Reactions
  • 5.8 Neurologic Reactions
  • 5.9 Eye Disorders
  • 5.10 Asthenia
  • 5.11 Use in Pregnancy
• 6. TAXOTERE ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience
  • 6.2 Post-Marketing Experiences
• 7. DRUG INTERACTIONS
• 8. USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
• 10. OVERDOSAGE
• 11. TAXOTERE DESCRIPTION
• 12. CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Human Pharmacokinetics
• 13. NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14. CLINICAL STUDIES
  • 14.1 Locally Advanced or Metastatic Breast Cancer
  • 14.2 Adjuvant Treatment of Breast Cancer
  • 14.3 Non-Small Cell Lung Cancer (NSCLC)
  • 14.4 Hormone Refractory Prostate Cancer
  • 14.5 Gastric Adenocarcinoma
  • 14.6 Head and Neck Cancer
• 15. REFERENCES
• 16. HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage
  • 16.3 Handling and Disposal
• 17. PATIENT COUNSELING INFORMATION
• PRINCIPAL DISPLAY PANEL - 1 mL Vial Carton
• PRINCIPAL DISPLAY PANEL - 4 mL Vial Carton

FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

1.1 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.

1.2 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.

1.3 Prostate Cancer

TAXOTERE in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.

1.4 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.

1.5 Head and Neck Cancer

TAXOTERE in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

2. DOSAGE AND ADMINISTRATION

For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7)].

Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).

2.1 Breast Cancer

• For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of TAXOTERE is 60 mg/m² to 100 mg/m² administered intravenously over 1 hour every 3 weeks.
• For the adjuvant treatment of operable node-positive breast cancer, the recommended TAXOTERE dose is 75 mg/m² administered 1 hour after doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7)].

2.2 Non-Small Cell Lung Cancer

• For treatment after failure of prior platinum-based chemotherapy, TAXOTERE was evaluated as monotherapy, and the recommended dose is 75 mg/m² administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m² in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5), Clinical Studies (14)].
• For chemotherapy-naïve patients, TAXOTERE was evaluated in combination with cisplatin. The recommended dose of TAXOTERE is 75 mg/m² administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m² over 30–60 minutes every 3 weeks [see Dosage and Administration (2.7)].

2.3 Prostate Cancer

• For hormone-refractory metastatic prostate cancer, the recommended dose of TAXOTERE is 75 mg/m² every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration (2.7)].

2.4 Gastric Adenocarcinoma

• For gastric adenocarcinoma, the recommended dose of TAXOTERE is 75 mg/m² as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m², as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m² per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)].

2.5 Head and Neck Cancer

Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the TAXOTERE containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

• Induction chemotherapy followed by radiotherapy (TAX323)
  For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of TAXOTERE is 75 mg/m² as a 1 hour intravenous infusion followed by cisplatin 75 mg/m² intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m² per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. [see Dosage and Administration (2.7)].
• Induction chemotherapy followed by chemoradiotherapy (TAX324)
  For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of TAXOTERE is 75 mg/m² as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m² administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m²/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)].

2.6 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 twice daily) for 3 days starting 1 day prior to TAXOTERE administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.4)].

For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the TAXOTERE infusion [see Warnings and Precautions (5.4)].

2.7 Dosage Adjustments During Treatment

Breast Cancer

Patients who are dosed initially at 100 mg/m² and who experience either febrile neutropenia, neutrophils <500 cells/mm³ for more than 1 week, or severe or cumulative cutaneous reactions during TAXOTERE therapy should have the dosage adjusted from 100 mg/m² to 75 mg/m². If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m² to 55 mg/m² or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m² and who do not experience febrile neutropenia, neutrophils <500 cells/mm³ for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during TAXOTERE therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have TAXOTERE treatment discontinued entirely.

Combination Therapy with TAXOTERE in the Adjuvant Treatment of Breast Cancer

TAXOTERE in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm³. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their TAXOTERE dose reduced to 60 mg/m². Patients who experience grade 3 or 4 stomatitis should have their TAXOTERE dose decreased to 60 mg/m². Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during TAXOTERE therapy should have their dosage of TAXOTERE reduced from 75 mg/m² to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², treatment should be discontinued.

Non-Small Cell Lung Cancer

Monotherapy with TAXOTERE for NSCLC treatment after failure of prior platinum-based chemotherapy

Patients who are dosed initially at 75 mg/m² and who experience either febrile neutropenia, neutrophils <500 cells/mm³ for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during TAXOTERE treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m². Patients who develop ≥grade 3 peripheral neuropathy should have TAXOTERE treatment discontinued entirely.

Combination therapy with TAXOTERE for chemotherapy-naïve NSCLC

For patients who are dosed initially at TAXOTERE 75 mg/m² in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm³, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the TAXOTERE dosage in subsequent cycles should be reduced to 65 mg/m². In patients who require a further dose reduction, a dose of 50 mg/m² is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.

Prostate Cancer

Combination therapy with TAXOTERE for hormone-refractory metastatic prostate cancer

TAXOTERE should be administered when the neutrophil count is ≥1,500 cells/mm³. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm³ for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during TAXOTERE therapy should have the dosage of TAXOTERE reduced from 75 mg/m² to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued.

Gastric or Head and Neck Cancer

TAXOTERE in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer

Patients treated with TAXOTERE in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the TAXOTERE dose should be reduced from 75 mg/m² to 60 mg/m². If subsequent episodes of complicated neutropenia occur the TAXOTERE dose should be reduced from 60 mg/m² to 45 mg/m². In case of grade 4 thrombocytopenia the TAXOTERE dose should be reduced from 75 mg/m² to 60 mg/m². Patients should not be retreated with subsequent cycles of TAXOTERE until neutrophils recover to a level >1,500 cells/mm³ and platelets recover to a level >100,000 cells/mm³. Discontinue treatment if these toxicities persist. [see Warnings and Precautions (5.3)].

Recommended dose modifications for toxicities in patients treated with TAXOTERE in combination with cisplatin and fluorouracil are shown in Table 1.

Liver dysfunction:

In case of AST/ALT >2.5 to ≤5 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 × ULN and AP >2.5 to ≤5 × ULN, TAXOTERE should be reduced by 20%.

In case of AST/ALT >5 × ULN and/or AP >5 × ULN TAXOTERE should be stopped.

The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:

Cisplatin dose modifications and delays

Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:

• Grade 2: Reduce cisplatin dose by 20%.
• Grade 3: Discontinue treatment.

Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

For other cisplatin dosage adjustments, also refer to the manufacturers' prescribing information.

Fluorouracil dose modifications and treatment delays

For diarrhea and stomatitis, see Table 1.

In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.

For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.

For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information.

Combination Therapy with Strong CYP3A4 inhibitors:

Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor. [see Drug Interactions (7), Clinical Pharmacology (12.3)].

2.8 Administration Precautions

TAXOTERE is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing TAXOTERE solutions. The use of gloves is recommended. Please refer to [see How Supplied/ Storage and Handling (16.3)].

If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.

Contact of the TAXOTERE concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final TAXOTERE dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

One-vial TAXOTERE (Injection Concentrate)

TAXOTERE Injection Concentrate requires NO prior dilution with a diluent and is ready to add to the infusion solution.

Please follow the preparation instructions provided below.

2.9 Preparation and Administration

DO NOT use the two-vial formulation (Injection Concentrate and diluent) with the one-vial formulation.

One-vial TAXOTERE (Injection Concentrate)

TAXOTERE Injection Concentrate (20 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution. Use only a 21 gauge needle to withdraw TAXOTERE from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates.

• TAXOTERE vials should be stored between 2 and 25°C (36 and 77°F). If the vials are stored under refrigeration, allow the appropriate number of vials of TAXOTERE Injection Concentrate vials to stand at room temperature for approximately 5 minutes before use.
• Using only a 21 gauge needle, aseptically withdraw the required amount of TAXOTERE injection concentrate (20 mg docetaxel/mL) with a calibrated syringe and inject via a single injection (one shot) into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 mg/mL to 0.74 mg/mL.
  If a dose greater than 200 mg of TAXOTERE is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL TAXOTERE is not exceeded.
• Thoroughly mix the infusion by gentle manual rotation.
• As with all parenteral products, TAXOTERE should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the TAXOTERE dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded.
• TAXOTERE infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

The TAXOTERE dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.

2.10 Stability

TAXOTERE final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 6 hours. TAXOTERE final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 6 hours (including the 1 hour intravenous administration).

In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C (36 and 46°F).

3. DOSAGE FORMS AND STRENGTHS

One-vial TAXOTERE (Injection Concentrate)

TAXOTERE 20 mg/mL

TAXOTERE (docetaxel) Injection Concentrate 20 mg/1 mL: 20 mg docetaxel in 1 mL in 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol.

TAXOTERE 80 mg/4 mL

TAXOTERE (docetaxel) Injection Concentrate 80 mg/4 mL: 80 mg docetaxel in 4 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol.

TAXOTERE 160 mg/8 mL

TAXOTERE (docetaxel) Injection Concentrate 160 mg/8 mL: 160 mg docetaxel in 8 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol.

4. CONTRAINDICATIONS

• TAXOTERE is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions (5.4)].
• TAXOTERE should not be used in patients with neutrophil counts of <1500 cells/mm³.

5. WARNINGS AND PRECAUTIONS

5.1 Toxic Deaths

Breast Cancer

TAXOTERE administered at 100 mg/m² was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m², mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.

Non-Small Cell Lung Cancer

TAXOTERE administered at a dose of 100 mg/m² in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m² dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m² dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see Dosage and Administration (2.2), Clinical Studies (14)].

5.2 Hepatic Impairment

Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with TAXOTERE [see Boxed Warning, Use in Specific Populations (8.6), Clinical studies (14)].

5.3 Hematologic Effects

Perform frequent peripheral blood cell counts on all patients receiving TAXOTERE. Patients should not be retreated with subsequent cycles of TAXOTERE until neutrophils recover to a level >1500 cells/mm³ and platelets recover to a level > 100,000 cells/mm³.

A 25% reduction in the dose of TAXOTERE is recommended during subsequent cycles following severe neutropenia (<500 cells/mm³) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a TAXOTERE cycle [see Dosage and Administration (2.7)].

Neutropenia (<2000 neutrophils/mm³) occurs in virtually all patients given 60 mg/m² to 100 mg/m² of TAXOTERE and grade 4 neutropenia (<500 cells/mm³) occurs in 85% of patients given 100 mg/m² and 75% of patients given 60 mg/m². Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. TAXOTERE should not be administered to patients with neutrophils <1500 cells/mm³.

Febrile neutropenia occurred in about 12% of patients given 100 mg/m² but was very uncommon in patients given 60 mg/m². Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see Adverse Reactions (6.1), Clinical Studies (14)].

Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection [see Dosage and Administration (2.7), Adverse Reactions (6)].

5.4 Hypersensitivity Reactions

Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the TAXOTERE infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with TAXOTERE.

Hypersensitivity reactions may occur within a few minutes following initiation of a TAXOTERE infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of TAXOTERE [see Dosage and Administration (2.6)].

5.5 Fluid Retention

Severe fluid retention has been reported following TAXOTERE therapy. Patients should be premedicated with oral corticosteroids prior to each TAXOTERE administration to reduce the incidence and severity of fluid retention [see Dosage and Administration (2.6)]. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.

When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.

Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m². Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m². Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of TAXOTERE to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

5.6 Acute Myeloid Leukemia

Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received TAXOTERE, doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin and cyclophosphamide [see Clinical Studies (14.2)]. In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up.

5.7 Cutaneous Reactions

Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended [see Dosage and Administration (2.7)]. The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued TAXOTERE due to skin toxicity.

5.8 Neurologic Reactions

Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued [see Dosage and Administration (2.7)]. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).

5.9 Eye Disorders

Cystoid macular edema (CME) has been reported in patients treated with TAXOTERE. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, TAXOTERE treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.

5.10 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.

5.11 Use in Pregnancy

TAXOTERE can cause fetal harm when administered to a pregnant woman. Docetaxel caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis.

There are no adequate and well-controlled studies in pregnant women using TAXOTERE. If TAXOTERE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with TAXOTERE [see Use in Specific Populations (8.1)].

6. ADVERSE REACTIONS

The most serious adverse reactions from TAXOTERE are:

• Toxic Deaths [see Boxed Warning, Warnings and Precautions (5.1)]
• Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.2)]
• Neutropenia [see Boxed Warning, Warnings and Precautions (5.3)]
• Hypersensitivity [see Boxed Warning, Warnings and Precautions (5.4)]
• Fluid Retention [see Boxed Warning, Warnings and Precautions (5.5)]

The most common adverse reactions across all TAXOTERE indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.

Adverse reactions are described according to indication. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established.

6.1 Clinical Trial Experience

Breast Cancer

Monotherapy with TAXOTERE for locally advanced or metastatic breast cancer after failure of prior chemotherapy

TAXOTERE 100 mg/m²: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received TAXOTERE administered at 100 mg/m² as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to TAXOTERE. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving TAXOTERE for the treatment of breast cancer and in patients with other tumor types (See Table 3).

Table 3 - Summary of Adverse Reactions in Patients Receiving TAXOTERE at 100 mg/m²

Adverse Reaction	All Tumor Types Normal LFTsNormal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN n=2045 %	All Tumor Types Elevated LFTsElevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN n=61 %	Breast Cancer Normal LFTsNormal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN n=965 %
Hematologic
Neutropenia
<2000 cells/mm3	96	96	99
<500 cells/mm3	75	88	86
Leukopenia
<4000 cells/mm3	96	98	99
<1000 cells/mm3	32	47	44
Thrombocytopenia
<100,000 cells/mm3	8	25	9
Anemia
<11 g/dL	90	92	94
<8 g/dL	9	31	8
Febrile NeutropeniaFebrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization	11	26	12
Septic Death	2	5	1
Non-Septic Death	1	7	1
Infections
Any	22	33	22
Severe	6	16	6
Fever in Absence of Infection
Any	31	41	35
Severe	2	8	2
Hypersensitivity Reactions
Regardless of Premedication
Any	21	20	18
Severe	4	10	3
With 3-day Premedication	n=92	n=3	n=92
Any	15	33	15
Severe	2	0	2
Fluid Retention
Regardless of Premedication
Any	47	39	60
Severe	7	8	9
With 3-day Premedication	n=92	n=3	n=92
Any	64	67	64
Severe	7	33	7
Neurosensory
Any	49	34	58
Severe	4	0	6
Cutaneous
Any	48	54	47
Severe	5	10	5
Nail Changes
Any	31	23	41
Severe	3	5	4
Gastrointestinal
Nausea	39	38	42
Vomiting	22	23	23
Diarrhea	39	33	43
Severe	5	5	6
Stomatitis
Any	42	49	52
Severe	6	13	7
Alopecia	76	62	74
Asthenia
Any	62	53	66
Severe	13	25	15
Myalgia
Any	19	16	21
Severe	2	2	2
Arthralgia	9	7	8
Infusion Site Reactions	4	3	4

Hematologic Reactions

Reversible marrow suppression was the major dose-limiting toxicity of TAXOTERE [see Warnings and Precautions (5.3)]. 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 intravenous 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 have been reported [see Boxed Warning, Warnings and Precautions (5.4)]. 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 instituting appropriate therapy.

Fluid Retention.

Fluid retention can occur with the use of TAXOTERE [see Boxed Warning, Dosage and Administration (2.6), Warnings and Precautions (5.5)].

Cutaneous Reactions

Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.7)]. 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 Reactions

Neurologic reactions are discussed elsewhere in the label [see Warnings and Precautions (5.8)]

Gastrointestinal Reactions

Nausea, vomiting, and 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 Reactions

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. Seven of 86 (8.1%) 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 Reactions

In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT >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 AST and/or ALT >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 AST and/or ALT >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 4 and 5).

Table 4 - Hematologic Adverse Reactions 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

	TAXOTERE 100 mg/m2		TAXOTERE 60 mg/m2
	Normal LFTsNormal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN	Elevated LFTsElevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN	Normal LFTsNormal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Adverse Reaction	n=730	n=18	n=174
	%	%	%
Neutropenia
Any         <2000 cells/mm3	98	100	95
Grade 4   <500 cells/mm3	84	94	75
Thrombocytopenia
Any        <100,000 cells/mm3	11	44	14
Grade 4  <20,000 cells/mm3	1	17	1
Anemia   <11 g/dL	95	94	65
InfectionIncidence 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.
Any	23	39	1
Grade 3 and 4	7	33	0
Febrile NeutropeniaFebrile Neutropenia: For 100 mg/m2, ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever >38.1°C
By Patient	12	33	0
By Course	2	9	0
Septic Death	2	6	1
Non-Septic Death	1	11	0

Table 5 - Non-Hematologic Adverse Reactions 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

	TAXOTERE 100 mg/m2		TAXOTERE 60 mg/m2
	Normal LFTsNormal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN	Elevated LFTsElevated Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN	Normal LFTsNormal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
Adverse Reaction	n=730	n=18	n=174
	%	%	%
NA = not available
Acute Hypersensitivity   Reaction Regardless of Premedication
Any	13	6	1
Severe	1	0	0
Fluid RetentionFluid 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/m2 dose   Regardless of Premedication
Any	56	61	13
Severe	8	17	0
Neurosensory
Any	57	50	20
Severe	6	0	0
Myalgia	23	33	3
Cutaneous
Any	45	61	31
Severe	5	17	0
Asthenia
Any	65	44	66
Severe	17	22	0
Diarrhea
Any	42	28	NA
Severe	6	11
Stomatitis
Any	53	67	19
Severe	8	39	1

In the three-arm monotherapy trial, TAX313, which compared TAXOTERE 60 mg/m², 75 mg/m² and 100 mg/m² in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with TAXOTERE 60 mg/m² compared to 55.3% and 65.9% treated with 75 mg/m² and 100 mg/m² respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m² vs. 6.9% and 16.5% for patients treated at 75 mg/m² and 100 mg/m² respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m² compared to 5.3% and 1.6% for patients treated at 75 and 100 mg/m² respectively.

The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m², 75 mg/m², and 100 mg/m² 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 reactions observed in 744 patients, who were treated with TAXOTERE 75 mg/m² every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 6).

Table 6- Clinically Important Treatment Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving TAXOTERE in Combination with Doxorubicin and Cyclophosphamide (TAX316).

	TAXOTERE 75 mg/m2+ Doxorubicin 50 mg/m2+ Cyclophosphamide 500 mg/m2 (TAC) n=744 %		Fluorouracil 500 mg/m2+ Doxorubicin 50 mg/m2+ Cyclophosphamide 500 mg/m2 (FAC) n=736 %
Adverse Reaction	Any	Grade 3/4	Any	Grade 3/4
Anemia	92	4	72	2
Neutropenia	71	66	82	49
Fever in absence of infection	47	1	17	0
Infection	39	4	36	2
Thrombocytopenia	39	2	28	1
Febrile neutropenia	25	N/A	3	N/A
Neutropenic infection	12	N/A	6	N/A
Hypersensitivity reactions	13	1	4	0
Lymphedema	4	0	1	0
Fluid RetentionCOSTART term and grading system for events related to treatment.	35	1	15	0
Peripheral edema	27	0	7	0
Weight gain	13	0	9	0
Neuropathy sensory	26	0	10	0
Neuro-cortical	5	1	6	1
Neuropathy motor	4	0	2	0
Neuro-cerebellar	2	0	2	0
Syncope	2	1	1	0
Alopecia	98	N/A	97	N/A
Skin toxicity	27	1	18	0
Nail disorders	19	0	14	0
Nausea	81	5	88	10
Stomatitis	69	7	53	2
Vomiting	45	4	59	7
Diarrhea	35	4	28	2
Constipation	34	1	32	1
Taste perversion	28	1	15	0
Anorexia	22	2	18	1
Abdominal Pain	11	1	5	0
Amenorrhea	62	N/A	52	N/A
Cough	14	0	10	0
Cardiac dysrhythmias	8	0	6	0
Vasodilatation	27	1	21	1
Hypotension	2	0	1	0
Phlebitis	1	0	1	0
Asthenia	81	11	71	6
Myalgia	27	1	10	0
Arthralgia	19	1	9	0
Lacrimation disorder	11	0	7	0
Conjunctivitis	5	0	7	0

Of the 744 patients treated with TAC, 36.3% experienced severe treatment emergent adverse reactions 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 reactions, 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 Reactions

In addition to gastrointestinal reactions 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 Reactions

More cardiovascular reactions 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 (2.3% vs. 0.9%, at 70 months median follow-up). One patient in each arm died due to heart failure.

Acute Myeloid Leukemia (AML)

Treatment-related acute myeloid leukemia or myelodysplasia 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.

Lung Cancer

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 7. 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 where otherwise noted.

Table 7 - Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving TAXOTERE as Monotherapy for Non-Small Cell Lung Cancer Previously Treated with Platinum-Based ChemotherapyNormal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN

Adverse Reaction	TAXOTERE 75 mg/m2 n=176 %	Best Supportive Care n=49 %	Vinorelbine/Ifosfamide n=119 %
Neutropenia
Any	84	14	83
Grade 3/4	65	12	57
Leukopenia
Any	84	6	89
Grade 3/4	49	0	43
Thrombocytopenia
Any	8	0	8
Grade 3/4	3	0	2
Anemia
Any	91	55	91
Grade 3/4	9	12	14
Febrile Neutropenia Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization	6	NANot Applicable	1
Infection
Any	34	29	30
Grade 3/4	10	6	9
Treatment Related Mortality	3	NANot Applicable	3
Hypersensitivity Reactions
Any	6	0	1
Grade 3/4	3	0	0
Fluid Retention
Any	34	NDNot Done	23
Severe	3		3
Neurosensory
Any	23	14	29
Grade 3/4	2	6	5
Neuromotor
Any	16	8	10
Grade 3/4	5	6	3
Skin
Any	20	6	17
Grade 3/4	1	2	1
Gastrointestinal
Nausea
Any	34	31	31
Grade 3/4	5	4	8
Vomiting
Any	22	27	22
Grade 3/4	3	2	6
Diarrhea
Any	23	6	12
Grade 3/4	3	0	4
Alopecia	56	35	50
Asthenia
Any	53	57	54
SevereCOSTART term and grading system	18	39	23
Stomatitis
Any	26	6	8
Grade 3/4	2	0	1
Pulmonary
Any	41	49	45
Grade 3/4	21	29	19
Nail Disorder
Any	11	0	2
SevereCOSTART term and grading system	1	0	0
Myalgia
Any	6	0	3
SevereCOSTART term and grading system	0	0	0
Arthralgia
Any	3	2	2
SevereCOSTART term and grading system	0	0	1
Taste Perversion
Any	6	0	0
SevereCOSTART term and grading system	1	0	0

Combination therapy with TAXOTERE in chemotherapy-naïve advanced unresectable or metastatic NSCLC

Table 8 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.

Table 8 - Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naïve Advanced Non-Small Cell Lung Cancer Patients Receiving TAXOTERE in Combination with Cisplatin

Adverse Reaction	TAXOTERE 75 mg/m2 + Cisplatin 75 mg/m2 n=406 %	Vinorelbine 25 mg/m2 + Cisplatin 100 mg/m2 n=396 %
Neutropenia
Any	91	90
Grade 3/4	74	78
Febrile Neutropenia	5	5
Thrombocytopenia
Any	15	15
Grade 3/4	3	4
Anemia
Any	89	94
Grade 3/4	7	25
Infection
Any	35	37
Grade 3/4	8	8
Fever in absence of infection
Any	33	29
Grade 3/4	< 1	1
Hypersensitivity ReactionReplaces NCI term "Allergy"
Any	12	4
Grade 3/4	3	< 1
Fluid RetentionCOSTART term and grading system
Any	54	42
All severe or life-threatening events	2	2
Pleural effusion
Any	23	22
All severe or life-threatening events	2	2
Peripheral edema
Any	34	18
All severe or life-threatening events	<1	<1
Weight gain
Any	15	9
All severe or life-threatening events	<1	<1
Neurosensory
Any	47	42
Grade 3/4	4	4
Neuromotor
Any	19	17
Grade 3/4	3	6
Skin
Any	16	14
Grade 3/4	<1	1
Nausea
Any	72	76
Grade 3/4	10	17
Vomiting
Any	55	61
Grade 3/4	8	16
Diarrhea
Any	47	25
Grade 3/4	7	3
AnorexiaCOSTART term and grading system
Any	42	40
All severe or life-threatening events	5	5
Stomatitis
Any	24	21
Grade 3/4	2	1
Alopecia
Any	75	42
Grade 3	<1	0
AstheniaCOSTART term and grading system
Any	74	75
All severe or life-threatening events	12	14
Nail DisorderCOSTART term and grading system
Any	14	<1
All severe events	<1	0
MyalgiaCOSTART term and grading system
Any	18	12
All severe events	<1	<1

Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2.0%) in the vinorelbine+cisplatin arm.

The second comparison in the study, vinorelbine+cisplatin versus TAXOTERE+carboplatin (which did not demonstrate a superior survival associated with TAXOTERE, [see Clinical Studies (14.3)]) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the TAXOTERE+carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm.

Prostate Cancer

Combination therapy with TAXOTERE in patients with prostate cancer

The following data are based on the experience of 332 patients, who were treated with TAXOTERE 75 mg/m² every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 9).

Table 9 - Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received TAXOTERE in Combination with Prednisone (TAX327)

	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 Reaction	Any	Grade 3/4	Any	Grade 3/4
Anemia	67	5	58	2
Neutropenia	41	32	48	22
Thrombocytopenia	3	1	8	1
Febrile neutropenia	3	N/A	2	N/A
Infection	32	6	20	4
Epistaxis	6	0	2	0
Allergic Reactions	8	1	1	0
Fluid RetentionRelated to treatment	24	1	5	0
Weight GainRelated to treatment	8	0	3	0
Peripheral EdemaRelated to treatment	18	0	2	0
Neuropathy Sensory	30	2	7	0
Neuropathy Motor	7	2	3	1
Rash/Desquamation	6	0	3	1
Alopecia	65	N/A	13	N/A
Nail Changes	30	0	8	0
Nausea	41	3	36	2
Diarrhea	32	2	10	1
Stomatitis/Pharyngitis	20	1	8	0
Taste Disturbance	18	0	7	0
Vomiting	17	2	14	2
Anorexia	17	1	14	0
Cough	12	0	8	0
Dyspnea	15	3	9	1
Cardiac left ventricular function	10	0	22	1
Fatigue	53	5	35	5
Myalgia	15	0	13	1
Tearing	10	1	2	0
Arthralgia	8	1	5	1

Gastric Cancer

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 10).

Table 10 - Clinically Important Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study

	TAXOTERE 75 mg/m2 + cisplatin 75 mg/m2 + fluorouracil 750 mg/m2 n=221		Cisplatin 100 mg/m2 + fluorouracil 1000 mg/m2 n=224
Adverse Reaction	Any %	Grade 3/4 %	Any %	Grade 3/4 %
Clinically important treatment emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.
Anemia	97	18	93	26
Neutropenia	96	82	83	57
Fever in the absence of infection	36	2	23	1
Thrombocytopenia	26	8	39	14
Infection	29	16	23	10
Febrile neutropenia	16	N/A	5	N/A
Neutropenic infection	16	N/A	10	N/A
Allergic reactions	10	2	6	0
Fluid retentionRelated to treatment	15	0	4	0
Edema Related to treatment	13	0	3	0
Lethargy	63	21	58	18
Neurosensory	38	8	25	3
Neuromotor	9	3	8	3
Dizziness	16	5	8	2
Alopecia	67	5	41	1
Rash/itch	12	1	9	0
Nail changes	8	0	0	0
Skin desquamation	2	0	0	0
Nausea	73	16	76	19
Vomiting	67	15	73	19
Anorexia	51	13	54	12
Stomatitis	59	21	61	27
Diarrhea	78	20	50	8
Constipation	25	2	34	3
Esophagitis/dysphagia/odynophagia	16	2	14	5
Gastrointestinal pain/cramping	11	2	7	3
Cardiac dysrhythmias	5	2	2	1
Myocardial ischemia	1	0	3	2
Tearing	8	0	2	0
Altered hearing	6	0	13	2

Head and Neck Cancer

Combination therapy with TAXOTERE in head and neck cancer

Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with TAXOTERE 75 mg/m² in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients). The treatment regimens are described in Section 14.6.

6.2 Post-Marketing Experiences

The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Body as a whole: diffuse pain, chest pain, radiation recall phenomenon.

Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.

Cutaneous: very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported.

Gastrointestinal: abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.

Hematologic: bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with TAXOTERE when used in combination with other chemotherapy agents and/or radiotherapy.

Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.

Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.

Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.

Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of cystoid macular edema (CME) have been reported in patients treated with TAXOTERE.

Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.

Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Renal: renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.

Metabolism and nutrition disorders: cases of hyponatremia have been reported.

7. DRUG INTERACTIONS

Docetaxel is a CYP3A4 substrate. 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.

In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of TAXOTERE and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with TAXOTERE, close monitoring for toxicity and a TAXOTERE dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see 'Warnings and Precautions' section ]

Based on its mechanism of action and findings in animals, TAXOTERE can cause fetal harm when administered to a pregnant woman. If TAXOTERE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with TAXOTERE.

TAXOTERE can cause fetal harm when administered to a pregnant woman. 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.

8.3 Nursing Mothers

It is not known whether docetaxel 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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The efficacy of TAXOTERE in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of TAXOTERE in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.

TAXOTERE has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluoruracil (TCF).

TAXOTERE Monotherapy

TAXOTERE monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1–22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m² as a 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia.

The recommended dose for TAXOTERE monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1–26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma.

TAXOTERE in Combination

TAXOTERE was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to TAXOTERE (75 mg/m²) in combination with cisplatin (75 mg/m²) and 5-fluorouracil (750 mg/m²) (TCF) or to cisplatin (80 mg/m²) and 5-fluorouracil (1000 mg/m²/day) (CF). The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response.

Pharmacokinetics:

Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m² to 235 mg/m² in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m² .

Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m² in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9±8.75 L/h/m², corresponding to an AUC of 4.20±2.57 μg.h/mL.

In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.

Non-Small Cell Lung Cancer

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.

Prostate Cancer

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 treatment emergent adverse reactions 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.

Breast Cancer

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.

Gastric Cancer

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 reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): 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.

Head and Neck Cancer

Among the 174 and 251 patients who received the induction treatment with TAXOTERE in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively.

These clinical studies of TAXOTERE in combination with cisplatin and fluorouracil in patients with SCCHN 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.

8.6 Hepatic Impairment

Patients with bilirubin >ULN should not receive TAXOTERE. Also, patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN should not receive TAXOTERE [see Boxed Warning, Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

10. OVERDOSAGE

There is no known antidote for TAXOTERE overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

In two reports of overdose, one patient received 150 mg/m² and the other received 200 mg/m² as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.

In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m² on a mg/m² basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m² basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m² on a mg/m² basis) and was associated with abnormal mitosis and necrosis of multiple organs.

11. 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 5β-20-epoxy-1,2α,4,7β,10β,13α-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.

One-vial TAXOTERE (Injection Concentrate)

TAXOTERE (docetaxel) Injection Concentrate is a sterile, non-pyrogenic, pale yellow to brownish-yellow solution at 20 mg/mL concentration.

Each mL contains 20 mg docetaxel (anhydrous) in 0.54 grams polysorbate 80 and 0.395 grams dehydrated alcohol solution.

TAXOTERE is available in single use vials containing 20 mg (1 mL), 80 mg (4 mL) or 160 mg (8 mL) docetaxel (anhydrous).

TAXOTERE Injection Concentrate requires NO prior dilution with a diluent and is ready to add to the infusion solution.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Human Pharmacokinetics

Absorption: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m² to 115 mg/m² in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m² to 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 α, β, and γ phases of 4 min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m².

Distribution: 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 steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α₁-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.

Metabolism: In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 [see Drug Interactions (7)] .

Elimination: 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.

Effect of Age: 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 1 studies. The pharmacokinetics of docetaxel were not influenced by age.

Effect of Gender: The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel.

Hepatic Impairment: The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1.5 times 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 not be treated with TAXOTERE. Patients with severe hepatic impairment have not been studied. [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]

Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m² to 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.

Effect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m² intravenous) alone or docetaxel (10 mg/m² intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was co-administration with ketoconazole [see Dosage and Administration (2.7) and Drug-Drug Interactions (7)].

Effect of Combination Therapies:

• Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone.
• Cisplatin: 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.
• Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug.
• Prednisone: 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.
• Cyclophosphamide and Doxorubicin: 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.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with docetaxel have not been performed.

Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K₁ cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60^th to 1/15^th the recommended human dose on a mg/m² basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.

Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50^th 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 intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3^rd and 1/15^th the recommended human dose on a mg/m² basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

14. CLINICAL STUDIES

14.1 Locally Advanced or Metastatic 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). Two hundred three 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 12).

Table 12 - Efficacy of TAXOTERE in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis)

Efficacy Parameter	Docetaxel (n=203)	Mitomycin/Vinblastine (n=189)	p-value
Median Survival	11.4 months	8.7 months
Risk RatioFor the risk ratio, a value less than 1.00 favors docetaxel., Mortality (Docetaxel: Control)	0.73		p=0.01 Log Rank
95% CI (Risk Ratio)	0.58–0.93
Median Time to Progression	4.3 months	2.5 months
Risk RatioFor the risk ratio, a value less than 1.00 favors docetaxel., Progression (Docetaxel: Control)	0.75		p=0.01 Log Rank
95% CI (Risk Ratio)	0.61–0.94
Overall Response Rate	28.1%	9.5%	p<0.0001
Complete Response Rate	3.4%	1.6%	Chi Square

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. One hundred sixty-one 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 13).

Table 13 - Efficacy of TAXOTERE in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis)

Efficacy Parameter	Docetaxel (n=161)	Doxorubicin (n=165)	p-value
Median Survival	14.7 months	14.3 months
Risk RatioFor the risk ratio, a value less than 1.00 favors docetaxel., Mortality (Docetaxel: Control)	0.89		p=0.39 Log Rank
95% CI (Risk Ratio)	0.68–1.16
Median Time to Progression	6.5 months	5.3 months
Risk RatioFor the risk ratio, a value less than 1.00 favors docetaxel., Progression (Docetaxel: Control)	0.93		p=0.45 Log Rank
95% CI (Risk Ratio)	0.71–1.16
Overall Response Rate	45.3%	29.7%	p=0.004
Complete Response Rate	6.8%	4.2%	Chi Square

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.

14.2 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/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 intravenous 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 TAX316, 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 (See Table 14).

Table 14 - Subset Analyses-Adjuvant Breast Cancer Study

		Disease Free Survival		Overall Survival
Patient subset	Number of patients	Hazard ratioa hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.	95% CI	Hazard ratioa hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.	95% CI
No. of positive nodes
Overall	744	0.74	(0.60, 0.92)	0.69	(0.53, 0.90)
1–3	467	0.64	(0.47, 0.87)	0.45	(0.29, 0.70)
4+	277	0.84	(0.63, 1.12)	0.93	(0.66, 1.32)
Receptor status
Positive	566	0.76	(0.59, 0.98)	0.69	(0.48, 0.99)
Negative	178	0.68	(0.48, 0.97)	0.66	(0.44, 0.98)

14.3 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 [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5.3)].

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/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 ≤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 15 and Figures 3 and 4 showing the survival curves for the two studies.

Table 15 - 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)

	TAX317		TAX320
	Docetaxel 75 mg/m2 n=55	Best Supportive Care n=49	Docetaxel 75 mg/m2 n=125	Control (V/IVinorelbine/Ifosfamide) n=123
Overall Survival
Log-rank Test	p=0.01		p=0.13
Risk Ratioa value less than 1.00 favors docetaxel, Mortality
(Docetaxel: Control)	0.56		0.82
95% CI (Risk Ratio)	(0.35, 0.88)		(0.63, 1.06)
Median Survival	7.5 monthsp≤0.05	4.6 months	5.7 months	5.6 months
95% CI	(5.5, 12.8)	(3.7, 6.1)	(5.1, 7.1)	(4.4, 7.9)
% 1-year Survival	37%p≤0.05 uncorrected for multiple comparisons	12%	30%Vinorelbine/Ifosfamide uncorrected for multiple comparisons	20%
95% CI	(24, 50)	(2, 23)	(22, 39)	(13, 27)
Time to Progression	12.3 weeksp≤0.05	7.0 weeks	8.3 weeks	7.6 weeks
95% CI	(9.0, 18.3)	(6.0, 9.3)	(7.0, 11.7)	(6.7, 10.1)
Response Rate	5.5%	Not Applicable	5.7%	0.8%
95% CI	(1.1, 15.1)		(2.3, 11.3)	(0.0, 4.5)

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.

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 to 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 16.

Table 16 - Survival Analysis of TAXOTERE in Combination Therapy for Chemotherapy-Naïve NSCLC

Comparison	Taxotere+Cisplatin n=408	Vinorelbine+Cisplatin n=405
Kaplan-Meier Estimate of Median Survival	10.9 months	10.0 months
p-valueFrom the superiority test (stratified log rank) comparing TAXOTERE+cisplatin to vinorelbine+cisplatin	0.122
Estimated Hazard RatioHazard ratio of TAXOTERE+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that TAXOTERE+cisplatin is associated with a longer survival.	0.88
Adjusted 95% CIAdjusted for interim analysis and multiple comparisons.	(0.74, 1.06)

The second comparison in the same three-arm 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 17).

Table 17 - Response and TTP Analysis of TAXOTERE in Combination Therapy for Chemotherapy-Naïve NSCLC

Endpoint	TAXOTERE+Cisplatin	Vinorelbine+Cisplatin	p-value
Objective Response Rate	31.6%	24.4%	Not Significant
(95% CI)Adjusted for multiple comparisons.	(26.5%, 36.8%)	(19.8%, 29.2%)
Median Time to ProgressionKaplan-Meier estimates.	21.4 weeks	22.1 weeks	Not Significant
(95% CI)Adjusted for multiple comparisons.	(19.3, 24.6)	(18.1, 25.6)

14.4 Hormone Refractory 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/m² every 3 weeks for 10 cycles.
• TAXOTERE 30 mg/m² administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
• Mitoxantrone 12 mg/m² every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone 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 Table 18 and Figure 5.

Table 18 - Efficacy of TAXOTERE in the Treatment of Patients with Androgen Independent (Hormone Refractory) Metastatic Prostate Cancer (Intent-to-Treat Analysis)

	TAXOTERE+ Prednisone every 3 weeks	Mitoxantrone+ Prednisone every 3 weeks
Number of patients	335	337
Median survival (months)	18.9	16.5
95% CI	(17.0–21.2)	(14.4–18.6)
Hazard ratio	0.761	--
95% CI	(0.619–0.936)	--
p-valueStratified log rank test. Threshold for statistical significance = 0.0175 because of 3 arms.	0.0094	--

14.5 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 19 and Figures 6 and 7.

Table 19 - Efficacy of TAXOTERE in the treatment of patients with gastric adenocarcinoma

Endpoint	TCF n=221	CF n=224
Median TTP (months)	5.6	3.7
(95%CI)	(4.86–5.91)	(3.45–4.47)
Hazard ratioFor the hazard ratio (TCF/CF), values less than 1.00 favor the TAXOTERE arm.	0.68
(95%CI)	(0.55–0.84)
Unstratified log-rank testp-value	0.0004
Median survival (months)	9.2	8.6
(95%CI)	(8.38–10.58)	(7.16–9.46)
Hazard ratioFor the hazard ratio (TCF/CF), values less than 1.00 favor the TAXOTERE arm.	0.77
(95%CI)	(0.62–0.96)
Unstratified log-rank testp-value	0.0201
Overall Response Rate (CR+PR) (%)	36.7	25.4
p-value	0.0106

Subgroup analyses were consistent with the overall results across age, gender and race.

14.6 Head and Neck Cancer

Induction chemotherapy followed by radiotherapy (TAX323)

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, were randomized to one of two treatment arms. Patients on the TAXOTERE arm received TAXOTERE (T) 75 mg/m² followed by cisplatin (P) 75 mg/m² on Day 1, followed by fluorouracil (F) 750 mg/m² per day as a continuous infusion on Days 1–5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m² on Day 1, followed by fluorouracil (F) 1000 mg/m²/day as a continuous infusion on Days 1–5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction 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 20 and Figures 8 and 9.

Table 20 - Efficacy of TAXOTERE in the induction treatment of patients with inoperable locally advanced SCCHN (Intent-to-Treat Analysis)

ENDPOINT	TAXOTERE+ Cisplatin+ Fluorouracil n=177	Cisplatin+ Fluorouracil n=181
A Hazard ratio of less than 1 favors TAXOTERE+Cisplatin+Fluorouracil
Median progression free survival (months) (95%CI)	11.4 (10.1–14.0)	8.3 (7.4–9.1)
Adjusted Hazard ratio (95%CI) Stratified log-rank test based on primary tumor sitep-value	0.71 (0.56–0.91) 0.0077
Median survival (months) (95%CI)	18.6 (15.7–24.0)	14.2 (11.5–18.7)
Hazard ratio (95%CI) Stratified log-rank test, not adjusted for multiple comparisonsp-value	0.71 (0.56–0.90) 0.0055
Best overall response (CR + PR) to chemotherapy (%) (95%CI)	67.8 (60.4–74.6)	53.6 (46.0–61.0)
Chi square test, not adjusted for multiple comparisonsp-value	0.006
Best overall response (CR + PR) to study treatment [chemotherapy +/- radiotherapy] (%) (95%CI)	72.3 (65.1–78.8)	58.6 (51.0–65.8)
Chi square test, not adjusted for multiple comparisonsp-value	0.006

Induction chemotherapy followed by chemoradiotherapy (TAX324)

The safety and efficacy of TAXOTERE in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the TAXOTERE arm received TAXOTERE (T) 75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m² administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m²/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m² as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m²/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles.

All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70–72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT.

The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the TAXOTERE-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 – 0.90]. Overall survival results are presented in Table 21 and Figure 10.

15. REFERENCES

• NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
• OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.
• American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006;63:1172–1193
• Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

16. HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

One-vial TAXOTERE (Injection Concentrate)

TAXOTERE Injection Concentrate is supplied in a single use vial as a sterile, pyrogen-free, non-aqueous solution.

TAXOTERE 20 mg/mL           (NDC 0075-8003-01)

TAXOTERE (docetaxel) Injection Concentrate 20 mg/1 mL: 20 mg docetaxel in 1 mL in 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol.

The vial is in a blister pack in one carton.

TAXOTERE 80 mg/4 mL           (NDC 0075-8004-04)

TAXOTERE (docetaxel) Injection Concentrate 80 mg/4 mL: 80 mg docetaxel in 4 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol.

The vial is in a blister pack in one carton.

TAXOTERE 160 mg/8 mL           (NDC 0075-8005-01)

TAXOTERE (docetaxel) Injection Concentrate 160 mg/8 mL: 160 mg docetaxel in 8 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol.

The vial is in a blister pack in one carton.

16.2 Storage

Store between 2°C and 25°C (36°F and 77°F). Retain in the original package to protect from light. Freezing does not adversely affect the product.

16.3 Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)].

17. PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

• TAXOTERE may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives if receiving TAXOTERE [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].
• Obtain detailed allergy and concomitant drug information from the patient prior to TAXOTERE administration.
• Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report if they were not compliant with oral corticosteroid regimen.
• Instruct patients to immediately report signs of a hypersensitivity reaction.
• Tell patients to watch for signs of fluid retention such as peripheral edema in the lower extremities, weight gain and dyspnea.
• Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.
• Instruct patients to report myalgia, cutaneous, or neurologic reactions.
• Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, fatigue, excessive tearing, infusion site reactions, and hair loss are associated with docetaxel administration.

Patient Information

TAXOTERE (TAX-O-TEER)
(docetaxel Injection Concentrate)
Intravenous Infusion

Read this Patient Information before you receive your first treatment with TAXOTERE and each time before you are treated. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about TAXOTERE?

TAXOTERE can cause serious side effects, including death.

• The chance of death in people who receive TAXOTERE is higher if you:
  • have liver problems
  • receive high doses of TAXOTERE
  • have non-small cell lung cancer and have been treated with chemotherapy medicines that contain platinum
• TAXOTERE can affect your blood cells. Your doctor should do routine blood tests during treatment with TAXOTERE. This will include regular checks of your white blood cell counts. If your white blood cells are too low, your doctor may not treat you with TAXOTERE until you have enough white blood cells. People with low white blood counts can develop life-threatening infections. The earliest sign of infection may be fever. Follow your doctor's instructions for how often to take your temperature while taking TAXOTERE. Call your doctor right away if you have a fever.
• Serious allergic reactions can happen in people who take TAXOTERE. Serious allergic reactions are medical emergencies that can lead to death and must be treated right away.

  Tell your doctor right away if you have any of these signs of a serious allergic reaction:

  • trouble breathing
  • sudden swelling of your face, lips, tongue, throat, or trouble swallowing
  • hives (raised bumps), rash, or redness all over your body
• Your body may hold too much fluid (severe fluid retention) during treatment with TAXOTERE. This can be life threatening. To decrease the chance of this happening, you must take another medicine, a corticosteroid, before each TAXOTERE treatment. You must take the corticosteroid exactly as your doctor tells you. Tell your doctor or nurse before your TAXOTERE treatment if you forget to take the corticosteroid dose or do not take it as your doctor tells you.

What is TAXOTERE?

TAXOTERE is a prescription anti-cancer medicine used to treat certain people with:

• breast cancer
• non-small cell lung cancer
• prostate cancer
• stomach cancer
• head and neck cancer

It is not known if TAXOTERE is effective in children.

Who should not receive TAXOTERE?

Do not receive TAXOTERE if you:

• have had a severe allergic reaction to:
  • docetaxel, the active ingredient in TAXOTERE, or
  • any other medicines that contain polysorbate 80. Ask your doctor or pharmacist if you are not sure.

  See "What is the most important information I should know about TAXOTERE?" for the signs and symptoms of a severe allergic reaction.

• have a low white blood cell count.

What should I tell my doctor before receiving TAXOTERE?

Before you receive TAXOTERE, tell your doctor if you:

• are allergic to any medicines. See "Who should not receive TAXOTERE?" Also, see the end of this leaflet for a complete list of the ingredients in TAXOTERE.
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. TAXOTERE can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if TAXOTERE passes into your breast milk. You and your doctor should decide if you will receive TAXOTERE or breastfeed.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TAXOTERE may affect the way other medicines work, and other medicines may affect the way TAXOTERE works.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How will I receive TAXOTERE?

• TAXOTERE will be given to you as an intravenous (IV) injection into your vein, usually over 1 hour.
• TAXOTERE is usually given every 3 weeks.
• Your doctor will decide how long you will receive treatment with TAXOTERE.
• Your doctor will check your blood cell counts and other blood tests during your treatment with TAXOTERE to check for side effects of TAXOTERE.
• Your doctor may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving TAXOTERE.

What are the possible side effects of TAXOTERE?

TAXOTERE may cause serious side effects including death.

• See "What is the most important information I should know about TAXOTERE?"
• Acute Myeloid Leukemia (AML), a type of blood cancer, can happen in people who take TAXOTERE along with certain other medicines.
• Other Blood Disorders. Changes in blood counts due to leukemia and other blood disorders may occur years after treatment with TAXOTERE.
• Skin Reactions including redness and swelling of your arms and legs with peeling of your skin.
• Neurologic Symptoms including numbness, tingling, or burning in your hands and feet.
• Vision Problems including blurred vision or loss of vision.

The most common side effects of TAXOTERE include:

• changes in your sense of taste
• feeling short of breath
• constipation
• decreased appetite
• changes in your fingernails or toenails
• swelling of your hands, face or feet
• feeling weak or tired
• joint and muscle pain
• nausea and vomiting
• diarrhea
• mouth or lips sores
• hair loss
• rash
• redness of the eye, excess tearing
• skin reactions at the site of TAXOTERE administration such as increased skin pigmentation, redness, tenderness, swelling, warmth or dryness of the skin.
• tissue damage if TAXOTERE leaks out of the vein into the tissues

Tell your doctor if you have any side effect that bothers you or does not go away.

These are not all the possible side effects of TAXOTERE. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about TAXOTERE

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. This Patient Information leaflet summarizes the most important information about TAXOTERE. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about TAXOTERE that is written for health professionals.

For more information, call 1-800-633-1610

What are the ingredients in TAXOTERE?

Active ingredient: docetaxel

Inactive ingredients include: ethanol and polysorbate 80

This Patient Information has been approved by the U.S. Food and Drug Administration.

sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

Revised: 12/2013
© 2013 sanofi-aventis U.S. LLC

PRINCIPAL DISPLAY PANEL - 1 mL Vial Carton

NDC 0075-8003-01

TAXOTERE ^®
(docetaxel)
Injection Concentrate

20 mg/mL

READY TO ADD TO INFUSION SOLUTION

For Intravenous Infusion Only

Contains 1 mL

Rx ONLY

SANOFI

PRINCIPAL DISPLAY PANEL - 4 mL Vial Carton

NDC 0075-8004-04

TAXOTERE ^®
(docetaxel)
Injection Concentrate

80 mg/4 mL
(20 mg/mL)

READY TO ADD TO INFUSION SOLUTION

For Intravenous Infusion Only

Contains 4 mL

Rx ONLY

SANOFI