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Metastatic Breast Cancer
Early-Stage Breast Cancer
Advanced NSCLC
Metastatic Androgen Independent Prostate Cancer
IMPORTANT SAFETY INFORMATION including BOXED WARNING

WARNING
The incidence of treatment-related mortality associated with Taxotere® therapy is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive Taxotere® as a single agent at a dose of 100 mg/m2 (see WARNINGS section of the prescribing information)

Continued below

Taxotere® (docetaxel) Injection Concentrate: Drug Interactions1

Taxotere® is a CYP3A4 substrate.

In vitro studies have shown that the metabolism of Taxotere® 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 Taxotere® increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of Taxotere®. 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.

A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between Taxotere® (docetaxel) Injection Concentrate (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) when administered in combination.

The coadministration of Taxotere® had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the 3 drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on Taxotere® plasma clearance when the 3 drugs were given in combination compared to historical data for Taxotere® monotherapy.

Important Safety Information

  • Taxotere® should not be given to patients with hepatic impairment. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle.

Preclinical synergy with doxorubicin1-3

Clinical significance of these in vitro observations has not been established

  • Taxotere® is approved in combination with doxorubicin and cyclophosphamide as adjuvant treatment for operable, node-positive breast cancer
  • In vitro, Taxotere® + doxorubicin demonstrated synergistic cytotoxicity in multiple human breast cancer cell lines (MCF7AD+, BT 474, and R-27)2,3
  • In vitro, pretreatment with Taxotere® increased the intracellular concentrations of doxorubicin in the R-27 breast cancer cell line
    • The intracellular concentration of doxorubicin increased from 10 to
      44.5 ng/105 in 60 minutes2
  • In an R-27 human breast cancer xenograft model, the combination of Taxotere® + doxorubicin was synergistic, resulting in increased antitumor activity2

    Tumor response over time4

IMPORTANT SAFETY INFORMATION

WARNINGS:

  • The incidence of treatment-related mortality associated with Taxotere® therapy is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive Taxotere® as a single agent at a dose of 100 mg/m2
  • Taxotere® should not be given to patients with bilirubin >upper limit of normal (ULN), or to patients with AST and/or ALT>1.5 X ULN concomitant with alkaline phosphatase >2.5 X ULN
    • Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death
    • Patients with isolated elevations of transaminase >1.5 X ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death
    • Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of Taxotere® therapy
  • Taxotere® therapy should not be given to patients with neutrophil counts of <1500 cells/mm3
    • In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving Taxotere®
  • Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received the recommended 3-day dexamethasone premedication
    • Hypersensitivity reactions require immediate discontinuation of Taxotere® infusion and administration of appropriate therapy
  • Taxotere® must not be given to patients who have a history of severe hypersensitivity reactions to Taxotere® or to other drugs formulated with polysorbate 80
  • Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites)
  • Neutropenia (<2,000 neutrophils/mm3) occurs in virtually all patients given 60-100 mg/m2 of Taxotere® and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 and 75% of patients given
    60 mg/m2
  • Patients should be premedicated with oral corticosteroids prior to each Taxotere® administration to reduce the incidence and severity of fluid retention. Patients with pre-existing effusions should be closely monitored from the first dose for possible exacerbation of the effusions
  • Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use with Taxotere® in adjuvant therapy of breast cancer
  • 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
  • Severe neurosensory symptoms (paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%
    • When these symptoms occur, dosage must be adjusted; if symptoms persist, treatment should be discontinued
  • Severe asthenia was reported in 14.9% (144/965) of metastatic breast cancer patients, but 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
  • Taxotere® can cause fetal harm when administered to pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Taxotere®
  • 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
  • In patients treated with TCF for gastric cancer, the incidence of serious adverse events was higher in patients ≥65 years than in younger patients. Adverse events (all grades) occurring at rates ≥10% higher in elderly patients included lethargy, stomatitis, diarrhea, dizziness, edema, and febrile neutropenia/neutropenic infection.
  • Taxotere® should be administered in a facility equipped to manage possible complications (e.g. anaphylaxis)

Please click here for Taxotere full prescribing information, including boxed WARNING.

Taxotere® (docetaxel) Injection Concentrate Indications

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

Advanced 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 (NSCLC) 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 NSCLC who have not previously received chemotherapy for this condition.

Metastatic Androgen-Independent Prostate Cancer
TAXOTERE® in combination with prednisone is indicated for the treatment of patients with androgen-independent (hormone-refractory) metastatic prostate cancer.

Advanced Gastric/GE Junction Cancer
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.

Locally Advanced 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).



References

  1. Taxotere® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; May 2010.
  2. Egawa T, Kubota T, Suto A, et al. Docetaxel enhances the cytotoxicity of anthracyclines by increasing intracellular drug accumulation. Oncol Rep. 2002;9(4):777-781.
  3. Budman DR, Calabro A. In vitro search for synergy and antagonism: evaluation of docetaxel combinations in breast cancer cell lines. Breast Cancer Res Treat. 2002;74(1):41-46.
  4. Egawa T, Kubota T, Suto A, et al. Antitumor activity of doxorubicin in combination with docetaxel against human breast cancer xenografts. In Vivo. 2003;17(1):23-28.
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US.DOC.10.05.001  Last update:  June 2010