Taxotere (docetaxel) - Letter to Health Professionals

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Health Canada posts safety alerts, public health advisories, press releases and other notices from industry as a service to health professionals, consumers, and other interested parties. Although Health Canada approves therapeutic products, Health Canada does not endorse either the product or the company. Any questions regarding product information should be discussed with your health professional.

This is duplicated text of a letter from sanofi-aventis Canada Inc.
Contact sanofi-aventis for a copy of any references, attachments or enclosures.

APPROVAL WITH CONDITIONS OF TAXOTERE® FOR USE IN COMBINATION WITH DOXORUBICIN AND CYCLOPHOSPHAMIDE IN ADJUVANT TREATMENT OF PATIENTS WITH OPERABLE NODE-POSITIVE BREAST CANCER.

DEAR HEALTH CARE PROFESSIONAL LETTER

December 5, 2006

Dear Health Care Professional(s):

Sanofi-aventis Canada Inc. is pleased to announce that Health Canada has granted a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Policy to TAXOTERE (docetaxel) for use in combination with doxorubicin and cyclophosphamide in adjuvant treatment of patients with operable node-positive breast cancer.

Health Canada has issued a marketing authorization with conditions under the Notice of Compliance with Conditions Policy for TAXOTERE to reflect the promising nature of the clinical efficacy and safety of TAXOTERE in patients with this serious disease, and the need for further follow up to verify the clinical benefit.

This NOC/c is based on results of a single, multinational, randomized, unblinded, Phase III study in which 1491 patients were randomized. The primary objective of the study was to compare disease free survival (DFS) after treatment of TAXOTERE in combination with doxorubicin and cyclophosphamide (TAC), to 5-fluorouracil in combination with doxorubicin and cyclophosphamide (FAC) in operable breast cancer subjects with positive axillary lymph nodes. Prophylactic antibiotic therapy with ciprofloxacin was compulsory for subjects treated with TAC. DFS was defined as time from randomization to relapse, second primary cancer or death from any cause. Further to the Independent Data Monitoring Committee (IDMC) recommendation, subjects who received additional antitumor therapy without evidence of relapse for whatever reason (e.g., intolerance to randomized therapy, withdrawal of consent after randomization) were not counted as DFS events. Secondary endpoints included comparing overall survival. At inclusion, subjects had a median age of 49 years (range 23-70), 49% of subjects were pre-menopausal, and 76% had positive estrogen and/or progesterone receptors. The six cycles of treatment were completed as per protocol in 91.1% and 95.3% of TAC and FAC-treated subjects, respectively.

An interim analysis had been prospectively planned 3 years after recruitment of 50% of the subjects. This first interim analysis showed that TAC was associated with a 32% relapse risk reduction (hazard ratio=0.68, 95% CI 0.54 -0.86) but the corresponding p-value of 0.0011 did not meet the Peto's stopping rule of 0.001. Based on these results, IDMC recommended that an additional interim analysis be conducted on more mature data. This second interim analysis was to be conducted after a total of 400 DFS events were observed in the combined study population. The treatment comparison was to be performed at the p=0.001 level for the primary efficacy endpoint of DFS.

The second interim analysis was performed at 399 DFS events, with a median follow up of 55 months. Significantly longer DFS for the TAC arm compared to the FAC arm was demonstrated. TAC-treated patients had a 28% relative reduction in the risk of relapse compared to those treated with FAC (hazard ratio=0.72, 95% CI (0.59-0.88) p=0.001, stopping boundary 0.001). This corresponds to an absolute difference in risk of relapse of 8.5% at 4 years. Overall survival was also significantly longer in the TAC arm with TAC-treated patients having a 30% relative reduction in the risk of death compared to FAC (hazard ratio= 0.70, 95% CI (0.53-0.91), p=0.008). This corresponds to an absolute difference in risk of death of 4.0% at 4 years.

The beneficial effect of TAC was seen in both hormone receptor positive and negative patients, and in patients with 1 to 3 positive nodes. However, a beneficial effect of TAC in patients with 4 or more positive lymph nodes was not observed with a median follow-up of 55 months. Long-term follow-up of patients in this study is ongoing.

INDICATIONS AND CLINICAL USE

TAXOTERE in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.

The effectiveness of TAXOTERE in combination with doxorubicin and cyclophosphamide is based on improved disease free survival and overall survival in comparison to the combination of 5-fluorouracil, doxorubicin and cyclophosphamide at a median follow up of 55 months. However long-term data are not yet available.

Patients should be advised about the conditional nature of the market authorization for TAXOTERE as adjuvant treatment.

Other Uses of TAXOTERE

TAXOTERE has received non-conditional approvals for the treatment of:

  • advanced or metastatic breast cancer, as a single agent, or in combination with doxorubicin; or in combination with capecitabine after failure of previous chemotherapy;
  • advanced or metastatic non small cell lung cancer, as a single agent or in combination with platinum derivatives;
  • metastatic ovarian cancer after failure of previous chemotherapy;
  • androgen independent metastatic prostate cancer in combination with prednisone or prednisolone;
  • recurrent or metastatic squamous cell carcinoma of the head and neck after failure of previous chemotherapy.

SERIOUS WARNINGS AND PRECAUTIONS

The following list is a summary of the most serious warnings and precautions. For a complete list and for further details on this list, please refer to the Product Monograph.

  • TAXOTERE should be administered under the supervision of a physician experienced in the use of antineoplastic agents.
  • TAXOTERE therapy should not be given to patients with neutrophil counts of less than 1,500 cells/mm3.
  • Severe hypersensitivity reactions requiring immediate discontinuation of TAXOTERE may occur.
  • Treatment related acute myeloid leukemia may occur. No studies have been conducted to assess the carcinogenic potential of TAXOTERE.

ADVERSE REACTIONS

Of the 744 patients treated with TAC in the adjuvant breast cancer trial, 33.1% experienced severe treatment-emergent adverse events possibly or probably related to treatment compared to 22.1% of the 736 patients treated with FAC.

Adverse events related to study treatment that occurred more frequently in the TAC arm than in the FAC arm with a greater than 10% difference were: fever in absence of infection (43% vs. 13%), peripheral edema (27% vs. 7%), stomatitis (69% vs. 53%), neuro-sensory (24% vs. 8%), myalgia (23% vs. 8%), taste perversion (27% vs. 15%), asthenia (79% vs. 69%), anemia (92% vs. 72%), febrile neutropenia (25% vs. 3%), thrombocytopenia (39% vs. 28%) and infection (27% vs. 17%).

G-CSF was used as treatment or secondary prophylaxis in 29.2% of TAC-treated patients compared to 5.6% of FAC-treated patients.

Four patients in the TAC treatment arm and 1 patient in the FAC treatment arm were reported to have treatment related colitis/enteritis/large intestine perforation

More cardiovascular events were reported in the TAC arm than in the FAC arm: treatment related dysrythmias, all grades (3.9% vs 2.9%), treatment related hypotension, all grades (1.5% vs 0.5%) and clinically significant treatment-emergent congestive heart failure (CHF), cardiac function grade 3-4 (1.6% vs 0.5%). One TAC-treated patient died due to heart failure.

The following events were observed to be ongoing at the median follow-up time of 55 months: neurosensory (9/73) and peripheral edema (18/112).

DRUG INTERACTION

The pharmacokinetics of TAXOTERE given in combination with doxorubicin and cyclophosphamide, have been studied in 30 patients treated for advanced breast cancer. There was no evidence of a pharmacokinetic interaction between the three drugs.

DOSAGE AND ADMINISTRATION

For the adjuvant treatment of patients with operable node-positive breast cancer, the 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. In addition to G-CSF, the prophylactic use of antibiotics may provide additional benefit.

Should you have medical enquiries regarding TAXOTERE, please contact our Medical Information department at 1-800-265-7927.

Original Signed by:

Franca Mancino, M. Sc.
Senior Director, Regulatory Affairs & Pharmacovigilance

sanofi-aventis Canada Inc.
2150 St. Elzear Blvd. West
Laval, Quebec, H7L 4A8
1-800-265-7927

Any suspected adverse drug reactions can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Health Product Safety Information Division
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701C
OTTAWA, Ontario, K1A 0K9
Tel: (613) 957-0337 or Fax: (613) 957-0335
Toll free for consumers and health professionals:
Tel: 866 234-2345, Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

The Adverse Reaction Reporting Form and the Adverse Reaction Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at:
Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS)
E-mail: bmors_enquiries@hc-sc.gc.ca
Tel:  613-941-3171
Fax: 613-941-1365

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