Imiglucerase

12.1 Mechanism of Action Gaucher disease is characterized by a deficiency of β-glucocerebrosidase activity, which results in accumulation of glucocerebroside in various tissues including liver, spleen, and bone marrow. The mannose sugars on imiglucerase mediate binding to and internalization by cells including macrophages. CEREZYME catalyzes the hydrolysis of glucocerebroside to glucose and ceramide.

1 INDICATIONS AND USAGE CEREZYME is indicated for the treatment of non-central nervous system (CNS) manifestations of Type 1 or Type 3 Gaucher disease in adults and pediatric patients. CEREZYME is a hydrolytic lysosomal glucocerebrosidase-specific enzyme indicated for the treatment of non-central nervous system (CNS) manifestations of Type 1 or Type 3 Gaucher disease in adults and pediatric patients. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer CEREZYME under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) The recommended dosage is 2.5 units/kg three times a week to 60 units/kg once every two weeks administered intravenously. ( 2.2 ) Titrate the dosage based on disease severity and therapeutic goals for the patient. ( 2.2 ) See the full prescribing information for dosage modifications due to hypersensitivity reactions and/or IARs. ( 2.3 ) See the full prescribing information for preparation and administration instructions. ( 2.4 , 2.5 ) 2.1 Recommendations Prior to CEREZYME Treatment Administer CEREZYME under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ] . Initiate CEREZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ] . For patients who experience hypersensitivity reactions to CEREZYME, premedicate with antihistamines and/or corticosteroids. Monitor patients for the occurrence of new hypersensitivity reactions [see Warnings and Precautions (5.1) ] . 2.2 Recommended Dosage and Administration Ensure physicians knowledgeable in the management of patients with Gaucher disease direct therapy with CEREZYME. The recommended dosage of CEREZYME is 2.5 units/kg three times a week to 60 units/kg once every two weeks administered intravenously. Titrate the dosage based on disease severity and therapeutic goals for the patient. For adults and pediatric patients weighing greater than 20 kg, infuse the diluted CEREZYME solution over 1 to 2 hours [see Dosage and Administration (2.5) ] . For pediatric patients weighing 20 kg or less, infuse the diluted CEREZYME solution over 2 hours [see Dosage and Administration (2.5) ] . 2.3 Dosage and Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions If a severe hypersensitivity reaction (e.g., anaphylaxis) or a severe infusion-associated reaction (IAR) occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment [see Warnings and Precautions (5.1 , 5.2) ]. If a mild or moderate hypersensitivity reaction or a mild or moderate IAR occurs, consider decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines, antipyretics, and/or corticosteroids [ see Warnings and Precautions (5.1 , 5.2) ]. 2.4 Preparation Instructions Use aseptic technique during preparation. Reconstitution 1. Determine the number of CEREZYME vials to be reconstituted based on the individual patient's dosage regimen and remove vial(s) from the refrigerator [see Dosage and Administration (2.1) ] . 2. Reconstitute each vial of CEREZYME by slowly injecting 10.2 mL of Sterile Water for Injection, down the inside wall of each vial. 3. Roll and tilt the vial to allow the powder to dissolve completely. Visually inspect the reconstituted solution for particulate matter and discoloration. Discard if opaque particles or discoloration are observed. After reconstitution, each vial will yield CEREZYME at a concentration of 40 units/mL. 4. Withdraw the required volume of CEREZYME from the vial(s). Dilution Dilute the CEREZYME solution for infusion promptly with 0.9% Sodium Chloride Injection to a final volume that is calculated based on prescribed dose. For CEREZYME administered at a dose of 60 units/kg, use the following final volumes (see Table 1 ). For patients weighing between 1.5 kg and less than 6 kg, dilute CEREZYME to a final volume of 12 mL in a syringe for infusion. For patients weighing between 6 kg and less than 13 kg, dilute CEREZYME to a final volume of 26 mL in a syringe for infusion. For patients weighing between 13 kg and less than or equal to 20 kg, dilute CEREZYME to a final volume of 100 mL in an infusion bag. For patients weighing greater than 20 kg and less than or equal to 100 kg, dilute CEREZYME to a final volume of 200 mL in an infusion bag. For patients weighing greater than 100 kg, dilute CEREZYME to a final volume of 400 mL in an infusion bag. If CEREZYME is prescribed at a dose lower than 60 units/kg, dilute the required total units of reconstituted CEREZYME (at a concentration of 40 units/mL) with 0.9% Sodium Chloride Injection to a final concentration between 6 units/mL and 30 units/mL inclusive. If the determined dose of CEREZYME translates into a total volume of 26 mL or less, administer using a syringe for infusion via a syringe pump. For accuracy of dilution, if less than 2 mL of reconstituted CEREZYME (40 units/mL) is needed for the preparation of the determined dose, prepare a larger final volume of CEREZYME for infusion initially maintaining the final concentration of the diluted CEREZYME solution between 6 units/mL to 30 units/mL. Subsequently, discard the

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Infusion-Associated Reactions [see Warnings and Precautions (5.2) ] Adverse reactions reported in adults and pediatric patients include back pain, chills, dizziness, fatigue, headache, hypersensitivity reactions, nausea, pyrexia, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials and Postmarketing Experience The following adverse reactions associated with the use of imiglucerase were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. See Table 2 for adverse reactions occurring in adults and pediatric patients treated with CEREZYME in clinical trials and the postmarketing setting. Table 2: Adverse Reactions in Adults and Pediatric Patients Treated with CEREZYME Adverse Reactions Nervous system disorders dizziness, headache Cardiac disorders tachycardia Vascular disorders cyanosis, Signs and symptoms suggestive of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ] and other infusion-associated reactions [see Warnings and Precautions (5.2) ] . flushing, hypotension, hypertension Respiratory, thoracic and mediastinal disorders cough, dyspnea, pneumonia, pulmonary hypertension Gastrointestinal disorders abdominal pain, diarrhea, nausea, vomiting Immune system disorders anaphylaxis, hypersensitivity Skin and subcutaneous tissue disorders angioedema, pruritus, rash, urticaria Musculoskeletal and connective tissue disorders back pain General disorders and administration site conditions chest discomfort, chills, fatigue, infusion-site burning, infusion-site discomfort, infusion-site swelling, pyrexia 6.2 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of CEREZYME or of other imiglucerase products. Approximately 15% of patients treated and tested to date have developed IgG antibody to CEREZYME during the first year of therapy. Patients who developed IgG antibody did so largely within 6 months of treatment and rarely developed antibodies to CEREZYME after 12 months of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity. Patients with antibody to CEREZYME have higher risk of hypersensitivity reaction [see Warnings and Precautions (5.1) ] . Patients who developed IgG antibody to CEREZYME had increased elimination half-life compared to patients without antibody [see Clinical Pharmacology (12.3) ] .