Imiglucerase

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 )

For injection: 400 units of imiglucerase as a white to off-white lyophilized powder in a single-dose vial for reconstitution. For injection: 400 units of imiglucerase as a lyophilized powder in a single-dose vial. ( 3 )

None. None. ( 4 )

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.

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) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CEREZYME during pregnancy. Pregnant women exposed to CEREZYME and health care providers are encouraged to contact the Gaucher patient registry at 1-800-745-4447, extension 15500 or visit www.registrynxt.com. Risk Summary Available data on more than 500 pregnancies from the international Gaucher Disease registry, postmarketing reports, published observational studies and case reports with CEREZYME or non–US-licensed imiglucerase use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks associated with symptomatic Type I Gaucher disease in pregnancy (see Clinical Considerations ) . No animal reproduction studies have been conducted with imiglucerase. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Untreated symptomatic Type 1 Gaucher disease may lead to complications during pregnancy, including hepatosplenomegaly, which can interfere with the normal growth of a pregnancy and thrombocytopenia, which can lead to excessive bleeding.

8.2 Lactation Risk Summary Available published literature suggests a small amount of imiglucerase is present in breast milk immediately following an infusion of imiglucerase. Published case reports and postmarketing reports of breastfed infants have not reported adverse effects due to CEREZYME exposure. There are no data available on the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CEREZYME and any potential adverse effects on the breastfed infant from imiglucerase or from the underlying maternal condition. Lactating women with Gaucher disease treated with CEREZYME should be encouraged to enroll in the Gaucher patient registry [see Use in Specific Populations (8.1) ] .

8.4 Pediatric Use The safety and effectiveness of CEREZYME for the treatment of non-CNS manifestations of Type 1 or Type 3 Gaucher disease have been established in pediatric patients. Use of CEREZYME for the treatment of non-CNS manifestations of Type 1 Gaucher disease is supported by evidence from adequate and well-controlled trials in adults and pediatric patients 12 years of age and older and additional safety and efficacy data from an observational study of Type 1 Gaucher disease in pediatric patients [see Adverse Reactions (6.1) and Clinical Studies (14) ] . Use of CEREZYME for the treatment of non-CNS manifestations of Type 3 Gaucher disease is supported by evidence from adequate and well-controlled trials in adults and pediatric patients 12 years of age and older with Type I Gaucher disease and additional safety and efficacy data from an observational study of Type 3 Gaucher disease in adults and pediatric patients [see Adverse Reactions (6.1) and Clinical Studies (14) ] .

8.5 Geriatric Use Among the patients with Type 1 Gaucher disease in Study 3 [see Clinical Studies (14) ] who had hemoglobin or platelet count measurements 1 to 3 years after initiating CEREZYME (n = 1,053), 6% of patients were 65 and over and 1% were 75 and over. No overall differences in effectiveness of CEREZYME were observed between patients 65 years of age and older and younger adult patients with Type 1 Gaucher disease. The safety evaluation for patients 65 years of age and older with Type 1 Gaucher disease was conducted using data from a pharmacovigilance database that collected individual case safety reports and did not reveal new safety findings. Clinical studies of CEREZYME did not include sufficient numbers of patients 65 years of age and older to detect differences in safety between older and younger adult patients with Type 1 Gaucher disease. Clinical studies of CEREZYME did not include sufficient numbers of patients 65 years of age and older to detect differences in efficacy and safety between older and younger adult patients with Type 3 Gaucher disease.

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.