Dear Health Care Professional Letter - VECTIBIX

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Amgen
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Authorization With Conditions Of VECTIBIX™ (panitumumab)

Marketingauthorization with conditions has been issued for VECTIBIX™ for the following indication:
VECTIBIX™ is indicated as monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma with non-mutated (wild-type)
KRAS
after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

July 14, 2008

Dear Health Care Professional:

Amgen Canada Inc. is pleased to announce that Health Canada has issued a Notice of Compliance with Conditions (NOC/c) for VECTIBIX™ as monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Marketing authorization with conditions was issued based on the promising nature of the clinical efficacy and the need for confirmatory studies to verify the long-term clinical benefit.

VECTIBIX™ (panitumumab) is a recombinant, fully human IgG2 monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR).

KRAS plays an important role in cell growth regulation and oncogenesis. Anti-EGFR therapies work by blocking the activation of EGFR, thereby inhibiting downstream events that lead to malignant signalling. However, in patients with tumours harbouring a mutated or activated KRAS gene, the KRAS protein is always turned "on" regardless of whether EGFR has been activated or therapeutically inhibited. Thus, in patients with mutated KRAS genes, signalling continues despite anti-EGFR therapy. Mutant KRAS genes are detected in approximately 40 percent of colorectal cancer (CRC) tumours.

Authorization with conditions for VECTIBIX was based on progression-free survival (PFS) in KRAS wild-type mCRC patients in a pivotal phase 3 study. The relationship between KRAS mutation status was determined in archived paraffin embedded tumour tissue. The tumour samples obtained from the primary resection of colorectal cancer were analyzed for the presence of the seven most common activating mutations in codon 12 and 13 of the KRAS gene by using an allele-specific polymerase chain reaction. The hazard ratio for PFS was 0.45 (95% CI: 0.34- 0.59) in favour of VECTIBIXTM in the KRAS wild-type group and 0.99 (95% CI: 0.73-1.36) in the KRAS mutant group. The difference in median PFS in the KRAS wild-type group was 5 weeks. The progression-free survival rates at the first scheduled visit (week 8) in the KRAS wildtype group were 61.9% on VECTIBIX™ plus Best Supportive Care (BSC) and 28.1% on BSC alone, a difference of 33.8% [95% CI: 21.9, 45.8]. There were no differences in overall survival seen in either group. In the KRAS wild-type group the response rate was 17% for VECTIBIX™ and 0% for BSC. In the KRAS mutant group there were no responses in either treatment arm. Stable disease rates in the KRAS wild-type group were 34% for VECTIBIX™ and 12% for BSC. The stable disease rates in the KRAS mutant group were 12% for VECTIBIX™ and 8% for BSC.

Indications and Clinical Use

VECTIBIX™ (panitumumab) is indicated as monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of VECTIBIX™ as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival. Currently no data are available that demonstrate an increased survival with VECTIBIX™.

Contraindications

VECTIBIX™ (panitumumab) is contraindicated in patients with known hypersensitivity reactions to panitumumab or any other component of the product.

Serious Warnings and Precautions

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

  • Dermatological toxicity
  • Infusion reactions
  • VECTIBIX™ is not indicated for use in combination with chemotherapy with or without bevacizumab
  • Administration of VECTIBIX™ in combination with IFL (Irinotecan, bolus 5FU/Leucovorin) should be avoided

Dosage and Administration

The VECTIBIX™ (panitumumab) infusion should be prepared using appropriate aseptic technique. Do not administer VECTIBIX™ as an IV push or bolus. VECTIBIX™ must be administered using an IV infusion pump and a low protein binding 0.2 µm or 0.22 µm inline filter.

The recommended dose of VECTIBIX™ is 6 mg/kg of body weight given once every 2 weeks. VECTIBIX™ should not be mixed with, or administered as an infusion with other medicinal products.

Adverse Drug Reactions by KRAS Status in the Pivotal Clinical Trial

The safety profile of VECTIBIX™ in patients whose tumors express KRAS wild-type (n=123) was generally consistent with overall mCRC monotherapy set.

In the randomized controlled trial, all 123 patients (100%), with non-mutated (wild-type) KRAS status, treated with VECTIBIX™ experienced adverse reactions, of which 62% reported grade 3-4 events.

The most frequently(>20% patients) reported adverse reactions were erythema (71%), pruritus (69%), dermatitis acneiform (60%), paronychia (33%), fatigue (33%), anorexia (30%), abdominal pain (27%), exfoliative rash (25%), constipation (24%), diarrhea (24%), skin fissures (24%), rash (20%) and cough (20%) of which the grade 3-4 reactions included dermatitis acneiform (9%), erythema (8%), abdominal pain (7%), anorexia (6%), constipation (5%), fatigue (5%), pruritus (4%) paronychia (3%), exfoliative rash (3%), rash (2%), and diarrhea (2%).

Two percent of patients permanently discontinued treatment due to gastrointestinal disorders [abdominal pain, intestinal obstruction (1% each)], and general disorders [asthenia, general physical health deterioration, pelvic mass (1% each)] One percent of subjects discontinued treatment due to skin and subcutaneous tissue disorders [dermatitis acneiform (1%)].

Serious adverse drug reactions reported with VECTIBIX™ treatment were dehydration (2%), diarrhea, paronychia, and hypomagnesemia (1% each).

For further details, see the VECTIBIX™ Product Monograph.

Availability of Dosage Forms

VECTIBIX™ is supplied as a preservative-free solution (20 mg/mL) containing 100, 200 or 400 mg of panitumumab in 5, 10 and 20 mL single-use vials, respectively.

VECTIBIX™ is provided in a dispensing pack containing one vial.

Amgen Canada Inc.
6775 Financial Drive, Suite 100
Mississauga, Ontario
L5N 0A4

Reporting Suspected Side Effects

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance

By toll-free telephone: 866-234-2345
By toll-free fax: 866-678-6789
Online: www.healthcanada.gc.ca/medeffect
By email: CanadaVigilance@hc-sc.gc.ca

By regular mail:
Canada Vigilance National Office
Marketed Health Products Safety and
Effectiveness Information Bureau
Marketed Health Products Directorate
Health Products and Food Branch
Health Canada
Tunney's Pasture, AL 0701C
Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

For other inquiries at Health Canada, please refer to contact information:
Biologics and Genetic Therapies Directorate:E-mail: bcans_enquiries@hc-sc.gc.ca
Email: BGTD_RAD_Enquiries@hc-sc.gc.ca
Tel: (613) 957-1722
Fax: (613) 946-9520

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.

Should you have any questions or require further information regarding the use of VECTIBIX™, please contact Amgen Medical Information at 1-866-502-6436.

Sincerely,

Original Signed by

Clive Ward-Able, B. Pharm., M.D.
Executive Director, Medical
Amgen Canada Inc.

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