Cerezyme

6 ADVERSE REACTIONS Adverse reactions reported in adults include back pain, chills, dizziness, fatigue, headache, hypersensitivity reactions, nausea, pyrexia, and vomiting. ( 6.1 ) Adverse reactions reported in pediatric patients 2 years of age and older are similar to adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-745-4447 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. System Organ Class Adverse Reactions Nervous system disorders dizziness, headache Cardiac disorders tachycardia Vascular disorders cyanosis, Signs and symptoms suggestive of hypersensitivity and other infusion-associated reactions [see Warnings and Precautions (5.1)] . flushing, hypotension 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 Adverse reactions reported in pediatric patients 2 years of age and older were similar to adults. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other imiglucerase products may be misleading. 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) ] .

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Imiglucerase is a hydrolytic lysosomal glucocerebrosidase-specific enzyme. It is an analogue of the human enzyme b-glucocerebrosidase (b-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45), produced by recombinant DNA technology using mammalian cell culture (Chinese hamster ovary). Purified imiglucerase is a monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites (Mr=60,430). Imiglucerase differs from placental glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine. The oligosaccharide chains at the glycosylation sites have been modified to terminate in mannose sugars. The modified carbohydrate structures on imiglucerase are somewhat different from those on placental glucocerebrosidase. Cerezyme (imiglucerase) for injection is intended for intravenous use. It is supplied as a sterile, nonpyrogenic, white to off-white lyophilized powder for reconstitution with Sterile Water for Injection, USP. Each single-dose vial contains 424 units imiglucerase, mannitol (340 mg), polysorbate 80, NF (1.06 mg), and sodium citrates: disodium hydrogen citrate (36 mg) and trisodium citrate (104 mg). An enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-b-D-glucopyranoside (pNP-Glc) per minute at 37°C. Reconstituted solutions have a pH of approximately 6.1.

2 DOSAGE AND ADMINISTRATION The recommended dosage ranges from 2.5 units/kg three times a week to 60 units/kg once every two weeks. ( 2.1 ) Cerezyme is administered by intravenous infusion over 1 to 2 hours. ( 2.1 ) Titrate the dosage based on clinical manifestations of disease and therapeutic goals for the patient. ( 2.1 ) See the full prescribing information for preparation and administration instructions. ( 2.2 ) 2.1 Recommended Dosage Therapy with Cerezyme should be directed by physicians knowledgeable in the management of patients with Gaucher disease. The recommended dosage of Cerezyme based upon disease severity ranges from 2.5 units/kg three times a week to 60 units/kg once every two weeks. For patients weighing 18 kg and greater, infuse the diluted Cerezyme solution over 1 to 2 hours. For patients weighing less than 18 kg, infuse the diluted Cerezyme solution over 2 hours [see Dosage and Administration (2.2) ] . Titrate the dosage based on clinical manifestations of disease and therapeutic goals for the patient. 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 Preparation and Administration Instructions Cerezyme does not contain preservatives. Reconstitution and Dilution Using Aseptic Technique Determine the number of Cerezyme vials to be reconstituted based on the individual patient's dosage regimen and remove vial(s) from the refrigerator. Reconstitute each 400 unit vial of Cerezyme by slowly injecting 10.2 mL of Sterile Water for Injection, USP, down the inside wall of each vial. Roll and tilt the vial to allow the powder to dissolve completely. Each vial will yield a concentration of Cerezyme after reconstitution of 40 units/mL. Visually inspect the solution after reconstitution for particulate matter and discoloration. Discard if opaque particles or discoloration are observed. Withdraw up to 10 mL per vial. Discard unused portion. Dilute the Cerezyme solution promptly with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 to 200 mL. For patients weighing less than 18 kg, dilute Cerezyme to a final volume of 100 mL. Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation. Visually inspect the solution prior to administration of the final product for particulate matter and discoloration. Slight flocculation of protein particles (described as thin translucent fibers) may occur after dilution and does not affect the quality of the product. For patients weighing 18 kg and greater, infuse the diluted Cerezyme solution over 1 to 2 hours. For patients weighing less than 18 kg, infuse the diluted Cerezyme solution over 2 hours. The diluted solution may be filtered through an in-line low protein-binding 0.2 µm filter during administration. Storage and Handling If the reconstituted Cerezyme vial is not used immediately, store at room temperature at 68°F to 77°F (20°C to 25°C) or refrigerated at 36°F to 46°F (2°C to 8°C) for up to 12 hours. After dilution, Cerezyme is stable for up to 24 hours when stored refrigerated at 36°F to 46°F (2°C to 8°C).

1 INDICATIONS AND USAGE Cerezyme is indicated for treatment of adults and pediatric patients 2 years of age and older with Type 1 Gaucher disease that results in one or more of the following conditions: anemia thrombocytopenia bone disease hepatomegaly or splenomegaly Cerezyme is a hydrolytic lysosomal glucocerebrosidase-specific enzyme indicated for treatment of adults and pediatric patients 2 years of age and older with Type 1 Gaucher disease that results in one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly or splenomegaly. ( 1 )

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics No formal pharmacodynamic studies have been conducted with Cerezyme. 12.3 Pharmacokinetics During one-hour intravenous infusions of four doses (7.5, 15, 30, 60 units/kg) of Cerezyme, steady-state enzymatic activity was achieved by 30 minutes. Following infusion, the half-life of plasma enzymatic activity ranged from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 mL/min/kg (mean ± SD, 14.5 ± 4.0 mL/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 L/kg (mean ± SD, 0.12 ± 0.02 L/kg). These variables do not appear to be influenced by dose or duration of infusion. However, only one or two patients were studied at each dose level and infusion rate. Antidrug Antibody Effects on Pharmacokinetics In patients who developed IgG antibody to Cerezyme, an apparent effect on serum enzyme levels resulted in diminished volume of distribution and clearance and increased elimination half-life compared to patients without antibody [see Adverse Reactions (6.2) ] .

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.

12.2 Pharmacodynamics No formal pharmacodynamic studies have been conducted with Cerezyme.

12.3 Pharmacokinetics During one-hour intravenous infusions of four doses (7.5, 15, 30, 60 units/kg) of Cerezyme, steady-state enzymatic activity was achieved by 30 minutes. Following infusion, the half-life of plasma enzymatic activity ranged from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 mL/min/kg (mean ± SD, 14.5 ± 4.0 mL/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 L/kg (mean ± SD, 0.12 ± 0.02 L/kg). These variables do not appear to be influenced by dose or duration of infusion. However, only one or two patients were studied at each dose level and infusion rate. Antidrug Antibody Effects on Pharmacokinetics In patients who developed IgG antibody to Cerezyme, an apparent effect on serum enzyme levels resulted in diminished volume of distribution and clearance and increased elimination half-life compared to patients without antibody [see Adverse Reactions (6.2) ] .

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3 DOSAGE FORMS AND STRENGTHS 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 )

Cerezyme IMIGLUCERASE IMIGLUCERASE IMIGLUCERASE MANNITOL TRISODIUM CITRATE DIHYDRATE DISODIUM HYDROGEN CITRATE POLYSORBATE 80

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate carcinogenic potential have not been performed with imiglucerase. Mutagenesis Imiglucerase was negative in the Ames test. Impairment of Fertility An animal fertility study was not performed. No histopathological findings on reproductive organs were observed in 13-week toxicity studies conducted in rats and monkeys.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate carcinogenic potential have not been performed with imiglucerase. Mutagenesis Imiglucerase was negative in the Ames test. Impairment of Fertility An animal fertility study was not performed. No histopathological findings on reproductive organs were observed in 13-week toxicity studies conducted in rats and monkeys.

BLA020367

Cerezyme

IMIGLUCERASE

58468-4663

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 400 Unit Vial Carton NDC 58468-4663-1 Rx only Cerezyme ® (imiglucerase) for injection 400 units per vial For intravenous infusion after reconstitution and dilution SANOFI GENZYME PRINCIPAL DISPLAY PANEL - 400 Unit Vial Carton

Manufactured by: Genzyme Corporation Cambridge, MA 02141 A SANOFI COMPANY U.S. License Number: 1596 Cerezyme is a registered trademark of Genzyme Corporation.

17 PATIENT COUNSELING INFORMATION Hypersensitivity and Infusion-Associated Reactions Advise patients and caregivers that hypersensitivity and other infusion-associated reactions may occur during and after Cerezyme treatment, including anaphylaxis and other serious or severe reactions. Inform patients of the signs and symptoms of these reactions and have them seek medical care should signs and symptoms occur [see Warnings and Precautions (5.1) ] . Patient Registry Inform patients and caregivers that the Gaucher patient registry has been established in order to better understand the variability and progression of Gaucher disease and to continue to monitor and evaluate long-term treatment effects of Cerezyme. A pregnancy sub-registry will also monitor the effects of Cerezyme on pregnant women and their offspring [see Use in Specific Populations (8.1) ] . Encourage patients and caregivers to participate in the Gaucher patient registry. Advise patients that their participation is voluntary and may involve long-term follow-up. For information regarding the registry program, visit www.registrynxt.com or call 1-800-745-4447, extension 15500.

14 CLINICAL STUDIES Study RC 91-0110 was a randomized, double-blind, active-controlled study of 30 patients (17 male and 13 female), aged 12 to 69 years (mean age of 38 years in the Cerezyme group and mean age of 28 years in the alglucerase group at baseline), with Gaucher disease type 1 and a hemoglobin of at least 1 g/dL below the lower age limit for age and sex. Patients were randomized 1:1 to receive either Cerezyme 60 units/kg every other week or alglucerase for 6 months. Primary efficacy parameters were an increase in hemoglobin concentration of at least 1 g/dL, increase in platelet count and decrease in spleen and liver volume at 6 months. Efficacy results are shown in Table 1. Table 1: Change from Baseline to Month 6 in Clinical Efficacy Parameters in a Randomized, Double-Blind Active-Controlled Trial of Cerezyme Compared to Alglucerase in Patients 12 Years of Age and Older with Gaucher Disease Type 1 Clinical Parameter Cerezyme (N=15) Alglucerase (N=15) Difference (Cerezyme – Alglucerase) [95% CI] Confidence intervals were calculated using the t distribution (appropriate for small sample sizes) and the standard error of the difference in sample means (i.e. the pooled estimate of the common standard deviation, computed as the weighted average of the standard deviations in the two treatment groups); there was no evidence that the assumption of equal variances between the groups was violated. Hemoglobin concentration (g/dL) Baseline 10.7 10.9 – Absolute Change from Baseline 1.9 1.6 0.3 [-0.6, 1.3] Platelet count (× 10 3 /mL 3 ) Baseline 68.5 74.2 – Absolute Change from Baseline 22.7 15.8 6.9 [-10.4, 24.1] Liver volume (mL) Baseline 2521 2788 – Absolute Change from Baseline -310 -307 -3 [-246, 240] Percent Change from Baseline (%) -11 -10 -1 [-9, 7] Spleen volume (mL) Baseline 2369 2603 – Absolute Change from Baseline -902 -874 -28 [-652, 596] Percent Change from Baseline (%) -35 -30 -5 [-14, 4] Bone x-rays showed improvements in cortical thickness and lucencies in 7 of 11 Cerezyme treated patients. In study RC 92-0501, twenty-nine patients continued treatment for total duration of 24 months. Patients were unblinded at 9 months and allowed to cross-over to Cerezyme treatment. At 24 months, mean increase in hemoglobin was 2.4 g/dL, mean increase in platelet count was 40 ×10 3 /mL 3 , mean change in liver volume was -20%, and mean change in spleen volume was -57%.

8.4 Pediatric Use The safety and effectiveness of Cerezyme for treatment of Type 1 Gaucher disease that results in one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly or splenomegaly have been established in pediatric patients 2 years of age and older. Use of Cerezyme for this indication is supported by evidence from adequate and well-controlled studies of Cerezyme and alglucerase in adults and pediatric patients 12 years of age and older, with additional data obtained from the medical literature and from postmarketing experience in pediatric patients as young as 2 years of age [see Adverse Reactions (6.1) , Clinical Studies (14) ] . The safety and effectiveness of Cerezyme have not been established in pediatric patients younger than 2 years of age.

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 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 USE IN SPECIFIC POPULATIONS 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 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 treatment of Type 1 Gaucher disease that results in one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly or splenomegaly have been established in pediatric patients 2 years of age and older. Use of Cerezyme for this indication is supported by evidence from adequate and well-controlled studies of Cerezyme and alglucerase in adults and pediatric patients 12 years of age and older, with additional data obtained from the medical literature and from postmarketing experience in pediatric patients as young as 2 years of age [see Adverse Reactions (6.1) , Clinical Studies (14) ] . The safety and effectiveness of Cerezyme have not been established in pediatric patients younger than 2 years of age.

16 HOW SUPPLIED/STORAGE AND HANDLING Cerezyme (imiglucerase) for injection, 400 units as a white to off-white lyophilized powder in a single-dose vial: NDC 58468-4663-1 Store refrigerated at 2°C to 8°C (36°F to 46°F). For storage of reconstituted and diluted solution see [ Dosage and Administration (2.2) ] .

Store refrigerated at 2°C to 8°C (36°F to 46°F). For storage of reconstituted and diluted solution see [ Dosage and Administration (2.2) ] .