Dear Health Care Professional Letter DOCETAXEL for Injection

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Contact: Bureau of Metabolism, Oncology and Reproductive Sciences

February 17, 2011

Dear Health Care Professional(s):

Hospira Healthcare Corporation is pleased to announce that Health Canada has issued a Notice of Compliance with conditions (NOC/C) under the Notice of Compliance with Conditions Policy for DOCETAXEL for Injection for use in combination with doxorubicin and cyclophosphamide in adjuvant treatment of patients with operable node-positive breast cancer. Marketing authorization with conditions was issued based on the promising nature of the clinical efficacy and the need for confirmatory studies to verify the longterm clinical benefit.

This NOC/c is based on results of a single, multinational, randomized, unblinded, Phase III study in which 1,491 patients were randomized. The primary objective of the study was to compare disease free survival (DFS) after treatment of DOCETAXEL 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 (for example [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 premenopausal, 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% confidence interval 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% confidence interval (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% confidence interval (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 followup of 55 months. Long-term follow-up of patients in this study is ongoing.

Indications And Clinical Use

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

The effectiveness of DOCETAXEL for Injection 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 DOCETAXEL for Injection as adjuvant treatment.

Other Uses of DOCETAXEL for Injection

DOCETAXEL for Injection has received non-conditional approvals for the treatment of:

• locally advanced or metastatic breast cancer in monotherapy, or in combination with doxorubicin as first line therapy (should be reserved for patients with potentially life threatening diseases such as visceral or lung metastatic cancer), or in combination with capecitabine after failure of prior anthracycline containing chemotherapy;
• locally advanced or metastatic non-small cell lung cancer in monotherapy or in combination with platinum derivatives;
• metastatic carcinoma of the ovary after failure of first-line or subsequent chemotherapy;
• androgen-independent (hormone refractory) metastatic prostate cancer in combination with prednisone or prednisolone;
• recurrent or metastatic squamous cell carcinoma of the head and neck in monotherapy 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.

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

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% versus [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 DOCETAXEL for Injection 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 DOCETAXEL for Injection dose is 75 milligrams per meter squared (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.

Availability And Preparation

Hospira's DOCETAXEL for Injection contains the same active ingredient, is of the same dosage form (sterile solution for infusion), is to be used for the same indications, in the same dosage regimen and via the same routes of administration as the innovator product, Taxotere^®1.

However, there are important differences in the product concentration and preparation procedures between DOCETAXEL for Injection and Taxotere:

• DOCETAXEL for Injection is available as a 10 milligram per millilitre (mg/mL) solution, in a single dose vial (20 mg/2 mL) and in multi-dose vials (80 mg/8 mL and 160 mg/16 mL).
• DOCETAXEL for Injection must be diluted directly into the infusion solution (0.9% Sodium chloride solution or 5% Dextrose solution) prior to administration.

Should you have medical enquiries regarding DOCETAXEL for Injection, please contact Hospira Clinical Support team: Telephone: 1-866-488-6088 option #4, or email mail-ClinSupport@hospira.com

Original Signed by:

Beryl Chan
Scientific Affairs Director, Quality and Regulatory
Hospira Healthcare Corporation
1111 Dr. Frederik-Philips Blvd. Suite 600
Saint Laurent (Québec)
H4M 2X6