Health Canada
Symbol of the Government of Canada

Common menu bar links

Drugs and Health Products

Dear Health Care Professional Letter for AVASTIN

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Contact: Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate

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 Hoffmann-La Roche Limited.
Contact the company for a copy of any references, attachments or enclosures.

Authorization with Conditions of AVASTIN« (bevacizumab)

For Use as a Single Agent, for the Treatment of Patients with Glioblastoma After Relapse or Disease Progression, Following Prior Therapy

March 2010

Dear Health Care Professional:

Hoffmann-La Roche Limited is pleased to announce that Health Canada has issued a Notice of Compliance with Conditions (NOC/c) for AVASTIN (bevacizumab) for use as a single agent, for the treatment of patients with glioblastoma after relapse or disease progression, following prior therapy. AVASTIN is a monoclonal antibody targeted against vascular endothelial growth factor (VEGF). AVASTIN received full approval for the treatment of metastatic colorectal cancer in September 2005, and for the treatment of unresectable, advanced, metastatic or recurrent non-squamous non-small cell lung cancer in March 2009. AVASTIN received marketing authorization with conditions for the treatment of metastatic HER2-negative breast cancer (ECOG Class 0-1) in February 2009.

Marketing authorization with conditions was issued based on the promising nature of the clinical evidence in patients with glioblastoma after relapse or disease progression. This NOC/c is based on the results of study AVF3708g, an open-label, multicenter, randomized, non-comparative study conducted in 167 patients, and study NCI 06-C-0064E, a single-arm, single institution trial with 56 patients.

Products authorized under Health Canada's NOC/c policy, have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. To support the NOC/c to extend the indication of AVASTIN for the treatment of patients with glioblastoma, Roche committed to submit to Health Canada an additional confirmatory study, BO21990. BO21990 is a randomized, double-blind, placebo-controlled, multicenter Phase III trial of bevacizumab, temozolomide and radiotherapy, followed by bevacizumab and temozolomide versus placebo, temozolomide and radiotherapy followed by placebo and temozolomide in patients with newly diagnosed glioblastoma. Roche also committed to safety monitoring and other requirements relevant to submissions considered under the NOC/c policy.

Study AVF3708g
The efficacy and safety of AVASTIN as treatment for patients with glioblastoma was studied in an open-label, multicentre, randomised, non-comparative study (study AVF3708g).

Glioblastoma patients in first or second relapse after prior radiotherapy (completed at least 8 weeks prior to receiving AVASTIN) and temozolomide, were randomised (1:1) to receive AVASTIN (10milligram/kilogram [mg/kg] intravenous [IV] infusion every 2 weeks) or AVASTIN plus irinotecan until disease progression or until unacceptable toxicity.

Of the 85 patients randomized to the AVASTIN arm, the median age was 54 years, 32% were female, 81% were in first relapse, Karnofsky performance status was 90-100 for 45% and 70-80 for 55%.

The efficacy of AVASTIN was demonstrated using response assessment based on both World Health Organization (WHO) radiographic criteria and by stable or decreasing corticosteroid use, which occurred in 25.9% (95% Confidence Interval 17%, 36.1%) of the patients. Median duration of response was 4.2 months (95% CI 3.0, 5.7). Radiologic assessment was based on magnetic resonance imaging (MRI) (using T1 and T2/FLAIR), collected every 6 weeks. MRI does not necessarily distinguish between tumor, edema, and radiation necrosis.

Study NCI 06-C-0064E
Study NCI 06-C-0064E was a single-arm, single institution trial with 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received AVASTIN 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity.

The median age was 54, 54% were male, 98% Caucasian, and 68% had a Karnofsky performance status of 90-100.

The efficacy of AVASTIN was supported by an objective response rate of 19.6% (95% confidence interval (CI) 10.9%, 31.3%) using the modified WHO response criteria taking corticosteroid dose into consideration. Median duration of response was 3.9 months (95% CI 2.4, 17.4).

AVASTIN used as a single agent, provided promising clinical benefit in patients with this serious disease, who relapsed or progressed following prior therapy.

New Indication and Clinical Use2

AVASTIN, as a single agent, is indicated for the treatment of patients with glioblastoma after relapse or disease progression, following prior therapy.

The effectiveness of AVASTIN in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with AVASTIN.

Patients should be advised about the conditional nature of the market authorization for AVASTIN in glioblastoma.

Pharmacology

AVASTIN is a recombinant humanised monoclonal antibody that selectively binds to and neutralises the biologic activity of VEGF. AVASTIN inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralising the biologic activity of VEGF reduces the vascularisation of tumours, thereby inhibiting tumour growth.

Contraindications

AVASTIN is contraindicated in patients with known hypersensitivity to any components of the product and to Chinese hamster ovary cell products or other recombinant human or humanised antibodies. AVASTIN is contraindicated in patients with untreated Central Nervous System (CNS) metastases.

Serious Warnings and Precautions

AVASTIN administration can result in the development of gastrointestinal perforation and wound dehiscence, in some instances resulting in fatality. Gastrointestinal perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with AVASTIN (that is [i.e.] was not correlated to duration of exposure). The incidence of gastrointestinal perforation in patients receiving irinotecan/bolus 5-fluorouracil/leucovorin with AVASTIN was 2%. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting. Gastrointestinal perforation should be included in the differential diagnosis of patients on AVASTIN presenting with abdominal pain. AVASTIN therapy should be permanently discontinued in patients with gastrointestinal perforation or wound dehiscence requiring medical intervention. AVASTIN therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed.

Adverse Events

The most serious AEs previously described in the Product Monograph1 include gastrointestinal perforations, hemorrhage, arterial thromboembolism, non-gastrointestinal fistula, hypertensive crises, reversible posterior leukoencephalopathy syndrome, neutropenia and infections, nephrotic syndrome and congestive heart failure. The most frequently observed AEs in patients with glioblastoma receiving AVASTIN, as a single agent, were infection, fatigue, headache, hypertension, diarrhea, and epistaxis.

Dosage and Administration

The recommended dose of AVASTIN for glioblastoma treatment is 10 mg/kg of body weight given once every 2 weeks as an intravenous infusion. It is recommended that AVASTIN treatment be continued until disease progression of the underlying disease.

Other Indications of AVASTIN Authorized Under a Notice of Compliance Metastatic Colorectal Cancer (mCRC): AVASTIN in combination with fluoropyrimidine-based chemotherapy is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.

Locally Advanced, Metastatic or Recurrent Non Small Cell Lung Cancer (NSCLC): AVASTIN, in combination with carboplatin/paclitaxel chemotherapy regimen, is indicated for treatment of patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer.

Other Indications of AVASTIN Authorized Under a Notice of Compliance with Conditions Metastatic Breast Cancer (mBC): AVASTIN in combination with paclitaxel is indicated for the treatment of patients with metastatic HER2-negative breast cancer who are ECOG Class 0-1.

The effectiveness of AVASTIN in metastatic breast cancer (mBC) is based on an improvement in progression-free survival. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with AVASTIN in breast cancer.

Please refer to Product Monograph for full prescribing and safety information1. Should you have any questions or require additional information regarding the use of AVASTIN, please contact the Drug Information Department at Hoffmann-La Roche Limited at 1-888-762-4388 from 8:30 a.m. to 4:30 p.m. Monday to Friday Eastern Standard Time.

Original Signed by:

Lorenzo Biondi, M.Sc.Phm.
Vice President, Medical and Regulatory Affairs

Hoffmann-La Roche Limited
Drug Safety Department
2455 Meadowpine Boulevard
Mississauga, Ontario, L5N 6L7
or call toll free at: 1-888-762-4388
or Fax at: 905-542-5864
or email to: mississauga.drug_safety@roche.com

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, Address Locator 0701C
Ottawa, Ontario
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 (BGTD)
E-mail: BGTD_RAD_Enquiries@hc-sc.gc.ca
Tel: (613) 957-1722
Fax: (613) 946-9520

The AR Reporting Form and the ADR Guidelines can be found on the Health Canada website or in The Canadian Compendium of Pharmaceuticals and Specialties.

References:

1. AVASTIN Product Monograph, available at Next link will take you to another Web site rochecanada

2. Kreisl TN, Kim L, Moore K et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740-5.