Cerezyme

WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate CEREZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1) ] . WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS See full prescribing information for complete boxed warning . Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. ( 5.1 ) Initiate CEREZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. ( 5.1 ) If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment, including use of epinephrine. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Infusion-Associated Reactions (IARs) : If a severe IAR occurs, discontinue CEREZYME immediately and initiate appropriate medical treatment. ( 5.2 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies, including CEREZYME. In addition, other hypersensitivity reactions have included pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, cough, cyanosis, tachycardia, and hypotension [see Adverse Reactions (6.1) ] . Patients with antibody to imiglucerase have a higher risk of hypersensitivity reactions. Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody. Consider periodic monitoring of patients during the first year of treatment for IgG antibody formation [see Adverse Reactions (6.2) ] . Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administer CEREZYME under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate CEREZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment, including use of epinephrine. Consider the risks and benefits of re-administering CEREZYME following severe hypersensitivity reactions (including anaphylaxis). If the decision is made to re-administer CEREZYME, consider decreasing the infusion rate and administering antihistamines, antipyretics, and/or corticosteroids. Monitor patients for the occurrence of new signs and symptoms of a severe hypersensitivity reaction. If a mild or moderate hypersensitivity reaction occurs, consider decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines, antipyretics, and/or corticosteroids. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur. 5.2 Infusion-Associated Reactions Infusion-associated reactions (IARs) such as angioedema, pruritus, rash, urticaria, chest discomfort, chills, fatigue, infusion-site burning, infusion-site discomfort, infusion-site swelling, pyrexia and hypertension have been observed in patients treated with CEREZYME [see Adverse Reactions (6.1) ] . If a severe IAR occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment. Consider the risks and benefits of re-administering CEREZYME following a severe IAR. If a mild or moderate IAR occurs, consider decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines, antipyretics, and/or corticosteroids.

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) ] .

<table width="85%"><caption>Table 2: Adverse Reactions in Adults and Pediatric Patients Treated with CEREZYME </caption><col width="40%" align="left" valign="top"/><col width="60%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Adverse Reactions</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nervous system disorders</td><td styleCode="Rrule">dizziness, headache</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cardiac disorders</td><td styleCode="Rrule">tachycardia</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vascular disorders</td><td styleCode="Rrule">cyanosis,<footnote ID="fn1">Signs and symptoms suggestive of hypersensitivity reactions including anaphylaxis <content styleCode="italics">[see <linkHtml href="#S5.1">Warnings and Precautions (5.1)</linkHtml>]</content> and other infusion-associated reactions <content styleCode="italics">[see <linkHtml href="#S5.2">Warnings and Precautions (5.2)</linkHtml>]</content>.</footnote> flushing,<footnoteRef IDREF="fn1"/> hypotension,<footnoteRef IDREF="fn1"/> hypertension<footnoteRef IDREF="fn1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Respiratory, thoracic and mediastinal disorders</td><td styleCode="Rrule">cough,<footnoteRef IDREF="fn1"/> dyspnea,<footnoteRef IDREF="fn1"/> pneumonia, pulmonary hypertension </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gastrointestinal disorders</td><td styleCode="Rrule">abdominal pain, diarrhea, nausea, vomiting</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Immune system disorders</td><td styleCode="Rrule">anaphylaxis,<footnoteRef IDREF="fn1"/> hypersensitivity</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Skin and subcutaneous tissue disorders</td><td styleCode="Rrule">angioedema,<footnoteRef IDREF="fn1"/> pruritus,<footnoteRef IDREF="fn1"/> rash, urticaria<footnoteRef IDREF="fn1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal and connective tissue disorders</td><td styleCode="Rrule">back pain</td></tr><tr><td styleCode="Lrule Rrule">General disorders and administration site conditions</td><td styleCode="Rrule">chest discomfort,<footnoteRef IDREF="fn1"/> chills, fatigue, infusion-site burning, infusion-site discomfort, infusion-site swelling, pyrexia</td></tr></tbody></table>