Adverse Event Reporting

It is the responsibility of Genzyme Corporation to collect, review, and communicate all relevant information regarding adverse events (AEs) for patients receiving Cerezyme^® (imiglucerase for injection)and Ceredase^® (alglucerase injection) to the US Food and Drug Administration and the regulatory authorities in countries where these drugs are in clinical investigation or are approved for marketing.

Definitions
An adverse experience or adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. This includes any untoward signs or symptoms experienced by the patient or subject from the time of first infusion.

Adverse events may include, but are not limited to:

• Subjective or objective symptoms spontaneously offered by the patient or subject and/or observed by the physician or medical staff.
• Laboratory abnormalities of clinical significance.

Disease signs, symptoms and/or laboratory abnormalities already existing prior to the use of the product are not considered adverse experiences unless they re-occur after the patient has recovered from the pre-existing condition, or represent an exacerbation in intensity or frequency.

Adverse events considered serious, as defined below, should be reported on the Adverse Event Report Form and faxed to Genzyme within 24 hours.

A serious adverse event involves an occurrence that at any dose:

• Results in death
• Is life-threatening (Any event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.)
• Requires inpatient hospitalization or prolongation of an existing hospitalization
• Results in persistent or significant disability/incapacity (Any adverse event that resulted in a substantial disruption of a person’s ability to conduct normal life functions.)
• Is a congenital anomaly/birth defect
• Is an important medical event (Any event that, based upon appropriate medical judgment, may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed above.)

The physician will be asked to provide an assessment of the severity of the AE using the following categories: mild, moderate and severe. This assessment is subjective and the physician should use medical judgment to compare the reported AE to similar types of events observed in clinical practice. It is important to recognize that severity is not equivalent to event seriousness. Guidelines for severity assessments are listed below:

• Mild: Symptom(s) barely noticeable to the patient or does not make the patient uncomfortable. The AE does not influence performance or functioning. Prescription drugs are not ordinarily needed for relief of symptom(s).
• Moderate: Symptom(s) of a sufficient severity to make the patient uncomfortable. Performance of daily activities is influenced. Treatment of symptom(s) may be needed.
• Severe: Symptom(s) of a sufficient severity to cause the patient severe discomfort. Severity may cause cessation of treatment with the drug. Treatment for symptom(s) may be given.

Reporting of Adverse Events
All adverse events should be reported to Genzyme, even if the event does not appear to be related to the product. Such communications should be directed to:

United States & Other Non-European Countries
Genzyme Corporation
Medical Affairs
500 Kendall Street
Cambridge, MA 02142 USA

Phone: 800-745-4447 option 2 or + 617-768-9000 option 2
Fax: + 617-761-8506

Europe
Genzyme Europe BV
Pharmacovigilance Department
Gooimeer 10
1411 DD Naarden
The Netherlands

Phone: + 31-35-699-1299
Fax: + 31-35-694-8756

Serious adverse event (SAE) reports should be reported to the Genzyme Pharmacovigilance department within 24 hours. A detailed written description that includes copies of relevant patient records, autopsy reports and other documents as appropriate should also be forwarded. SAEs will be reported by Genzyme in accordance with the requirements of Regulatory Agencies.

Non-serious adverse events should also be reported to the Genzyme Pharmacovigilance department in a timely manner by faxing a completed AE Report Form (PDF).

Antibody Monitoring
Treatment of patients with protein drugs may result in possible immunological reactions directed against the protein. After several years of experience with Ceredase^® (alglucerase injection) and Cerezyme^® (imiglucerase for injection), the immune response rates are well established. Approximately 15% of patients treated with Cerezyme^® develop IgG antibodies to Cerezyme^®.

Antibody monitoring is a service provided by the Genzyme Corporation. The primary objective of the Cerezyme^® antibody monitoring service is to better understand the formation of antibodies within the Gaucher patient population receiving ERT. Physicians who utilize this service benefit by collecting important antibody results data for managing the care of their patients who are receiving Cerezyme^®.

Recommended Antibody Monitoring Schedule
Antibody monitoring is recommended for all patients receiving Cerezyme^® therapy according to the following schedule:

• Baseline (drawn but not tested unless clinically indicated)
• A sample drawn after 6 months is tested and results reported (optional)

Additional testing as clinically indicated, such as:

• Suspected immune-mediated adverse event
• Prior to switch to home therapy
• Suspected loss of ERT effectiveness

Ordering Sample Collection Boxes
Genzyme provides complimentary boxes and supplies for the collection and shipping of samples for antibody testing. To order antibody testing collection boxes in the U.S. and Canada, call Genzyme 800.745.4447, option 1 or in Europe and rest of world, contact the Genzyme office/representative in the respective country or contact Genzyme in the U.S. at 617.768.9000, option 1.

Click links below to download the applicable sample collection, preparation, and shipment instructions for your area, as well as a sample requisition form.

• Sample Requisition Form (PDF)
• Antibody Instructions for USA and Canada Sites (PDF)
• Antibody Instructions for EU Sites (PDF)
• Antibody Instructions for non-USA, EU or Canada Sites (PDF)

Obtaining Results
Test results will be reported as hard copy within approximately 4-6 weeks. From the US, Canada, and internationally except the European Union, any questions regarding the assay tests or results of the testing should be directed to the Medical Information department at 800.745.4447, option 2. From the European Union countries, contact Genzyme BV at +31.35.699.1431.