CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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

ADVERSE REACTIONS SECTION.

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)] 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.. Adverse reactions reported in adults and pediatric patients include back pain, chills, dizziness, fatigue, headache, hypersensitivity reactions, nausea, pyrexia, and vomiting. (6.1). 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.See Table 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 ReactionsNervous system disordersdizziness, headacheCardiac disorderstachycardiaVascular disorderscyanosis,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 disorderscough, dyspnea, pneumonia, pulmonary hypertension Gastrointestinal disordersabdominal pain, diarrhea, nausea, vomitingImmune system disordersanaphylaxis, hypersensitivitySkin and subcutaneous tissue disordersangioedema, pruritus, rash, urticaria Musculoskeletal and connective tissue disordersback painGeneral disorders and administration site conditionschest 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 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)].

BOXED WARNING SECTION.

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 healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If 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 ANAPHYLAXISSee 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 healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. (5.1)If severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment, including use of epinephrine. (5.1). Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. (5.1). Initiate CEREZYME in healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. (5.1). If severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment, including use of epinephrine. (5.1).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Gaucher disease is characterized by deficiency of -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 PharmacokineticsIn 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)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Study was randomized, double-blind, active-controlled clinical trial that enrolled 30 patients (17 male and 13 female) with Type Gaucher disease. Patient ages ranged from 12 to 69 years, with mean age of 38 years in the CEREZYME treatment group and mean age of 28 years in the alglucerase treatment group at baseline. The inclusion criteria required patients to have hemoglobin level of at least g/dL below the lower limit of the normal range for their respective age and sex. Patients were randomized 1:1 to receive either CEREZYME 60 units/kg administered intravenously every other week or alglucerase for months.In Study 1, the primary efficacy parameters were an increase in hemoglobin concentration (at least g/dL) and platelet count and decrease in spleen and liver volume at months. Efficacy results are shown in Table 3.In Study 1, bone x-rays showed improvements in cortical thickness and lucencies in of 11 CEREZYME-treated patients.Table 3: Change from Baseline to Month in Clinical Efficacy Parameters in Randomized, Double-Blind Active-Controlled Trial of CEREZYME Compared to Alglucerase in Patients 12 Years of Age and Older with Gaucher Disease Type (Study 1)Clinical ParameterCEREZYME (N=15)Alglucerase (N=15)Difference (CEREZYME Alglucerase) [95% CI]Confidence intervals were calculated using the 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)Baseline10.710.9-Absolute Change from Baseline1.91.60.3 [-0.6, 1.3]Platelet count (x 103/mm3)Baseline68.574.2-Absolute Change from Baseline22.715.86.9 [-10.4, 24.1]Liver volume (mL)Baseline25212788-Absolute Change from Baseline-310-307-3 [-246, 240]Percent Change from Baseline (%)-11-10-1 [-9, 7]Spleen volume (mL)Baseline23692603-Absolute Change from Baseline-902-874-28 [-652, 596]Percent Change from Baseline (%)-35-30-5 [-14, 4]In Study 2, an open-label extension study of Study 1, 29 patients with Type Gaucher disease continued their assigned treatment for an additional 18 months. Patients were unblinded months into Study and those on alglucerase were allowed to cross-over to CEREZYME treatment. After total treatment duration of CEREZYME for 18-24 months, mean increase from baseline of Study in hemoglobin was 2.4 g/dL, mean increase in platelet count was 40 x103/mm3, mean change in liver volume was -20%, and mean change in spleen volume was -57%.The efficacy of CEREZYME for the treatment of non-CNS manifestations of Type and Type Gaucher disease was assessed in Study 3, an observational study, using data from the International Collaborative Gaucher Group (ICGG) Gaucher Disease Registry (NCT00358943). Study included patients with Type or Type Gaucher disease who were treated with CEREZYME as initial therapy with an index clinical assessment and one or more follow-up clinical assessments. Study was baseline-controlled analysis in patients with Type Gaucher disease (19 weeks to 87 years of age) and patients with Type Gaucher disease (7 weeks to 54 years of age) who received CEREZYME intravenously as prescribed by their physicians (initiated treatment between 1992-2021). After approximately two years (1 to years) of CEREZYME treatment in patients with Type and Gaucher disease, mean changes from baseline in the following measures showed improvement: hemoglobin, platelet count, liver volume, spleen volume, and height Z-score. Among 1,052 Type Gaucher disease patients, mean baseline hemoglobin was 11.8 g/dL and mean increase from baseline was 1.5 g/dL (95% CI: 1.4, 1.5). Among 1,053 Type Gaucher disease patients, mean baseline platelet count was 128x103/mm3 and mean increase from baseline was 64x103/mm3 (95% CI: 59.6, 67.9).Among 118 Type Gaucher disease patients, mean baseline hemoglobin levels were 10 g/dL and mean increase from baseline was 1.8 g/dL (95% CI: 1.5, 2.1).Among 116 Type Gaucher disease patients, mean baseline platelet count was 149x103/mm3 and mean increase from baseline was 105x103/mm3 (95% CI: 87.4, 122.4).The 2-year summaries include measurements within to years after treatment initiation due to the lack of predefined data collection timepoints in the registry. Among 1,052 Type Gaucher disease patients, mean baseline hemoglobin was 11.8 g/dL and mean increase from baseline was 1.5 g/dL (95% CI: 1.4, 1.5). Among 1,053 Type Gaucher disease patients, mean baseline platelet count was 128x103/mm3 and mean increase from baseline was 64x103/mm3 (95% CI: 59.6, 67.9).. Among 118 Type Gaucher disease patients, mean baseline hemoglobin levels were 10 g/dL and mean increase from baseline was 1.8 g/dL (95% CI: 1.5, 2.1).. Among 116 Type Gaucher disease patients, mean baseline platelet count was 149x103/mm3 and mean increase from baseline was 105x103/mm3 (95% CI: 87.4, 122.4).

CLINICAL TRIALS EXPERIENCE SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.See Table 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 ReactionsNervous system disordersdizziness, headacheCardiac disorderstachycardiaVascular disorderscyanosis,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 disorderscough, dyspnea, pneumonia, pulmonary hypertension Gastrointestinal disordersabdominal pain, diarrhea, nausea, vomitingImmune system disordersanaphylaxis, hypersensitivitySkin and subcutaneous tissue disordersangioedema, pruritus, rash, urticaria Musculoskeletal and connective tissue disordersback painGeneral disorders and administration site conditionschest discomfort, chills, fatigue, infusion-site burning, infusion-site discomfort, infusion-site swelling, pyrexia.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Imiglucerase is 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 monomeric glycoprotein of 497 amino acids, containing 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 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 micromole of the synthetic substrate para-nitrophenyl-b-D-glucopyranoside (pNP-Glc) per minute at 37C. Reconstituted solutions have pH of approximately 6.1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer CEREZYME under the supervision of healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. (2.1)The recommended dosage is 2.5 units/kg three times 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). Administer CEREZYME under the supervision of healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. (2.1). The recommended dosage is 2.5 units/kg three times 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 healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1)].Initiate CEREZYME in 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)].. 2.2Recommended 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 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 to hours [see Dosage and Administration (2.5)].For pediatric patients weighing 20 kg or less, infuse the diluted CEREZYME solution over hours [see Dosage and Administration (2.5)].. 2.3Dosage and Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions. If severe hypersensitivity reaction (e.g., anaphylaxis) or severe infusion-associated reaction (IAR) occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment [see Warnings and Precautions (5.1, 5.2) ].If mild or moderate hypersensitivity reaction or 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) ].. 2.4Preparation Instructions. Use aseptic technique during preparation.Reconstitution1. Determine the number of CEREZYME vials to be reconstituted based on the individual patients 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 concentration of 40 units/mL.4.Withdraw the required volume of CEREZYME from the vial(s). DilutionDilute the CEREZYME solution for infusion promptly with 0.9% Sodium Chloride Injection to final volume that is calculated based on prescribed dose.For CEREZYME administered at dose of 60 units/kg, use the following final volumes (see Table 1).For patients weighing between 1.5 kg and less than kg, dilute CEREZYME to final volume of 12 mL in syringe for infusion.For patients weighing between kg and less than 13 kg, dilute CEREZYME to final volume of 26 mL in syringe for infusion.For patients weighing between 13 kg and less than or equal to 20 kg, dilute CEREZYME to 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 final volume of 200 mL in an infusion bag.For patients weighing greater than 100 kg, dilute CEREZYME to final volume of 400 mL in an infusion bag.If CEREZYME is prescribed at dose lower than 60 units/kg, dilute the required total units of reconstituted CEREZYME (at concentration of 40 units/mL) with 0.9% Sodium Chloride Injection to final concentration between units/mL and 30 units/mL inclusive. If the determined dose of CEREZYME translates into total volume of 26 mL or less, administer using syringe for infusion via syringe pump.For accuracy of dilution, if less than mL of reconstituted CEREZYME (40 units/mL) is needed for the preparation of the determined dose, prepare larger final volume of CEREZYME for infusion initially maintaining the final concentration of the diluted CEREZYME solution between units/mL to 30 units/mL. Subsequently, discard the excess volume and administer only the volume of CEREZYME solution corresponding to the prescribed dose.Gently invert the syringe for infusion or the infusion bag to mix the solution. Throughout CEREZYME preparation, avoid vigorous shaking, agitation and foaming.Vials are for single dose only. Discard any unused solution.. 1. Determine the number of CEREZYME vials to be reconstituted based on the individual patients 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 concentration of 40 units/mL.. 4.Withdraw the required volume of CEREZYME from the vial(s). Dilute the CEREZYME solution for infusion promptly with 0.9% Sodium Chloride Injection to final volume that is calculated based on prescribed dose.. For CEREZYME administered at dose of 60 units/kg, use the following final volumes (see Table 1).For patients weighing between 1.5 kg and less than kg, dilute CEREZYME to final volume of 12 mL in syringe for infusion.For patients weighing between kg and less than 13 kg, dilute CEREZYME to final volume of 26 mL in syringe for infusion.For patients weighing between 13 kg and less than or equal to 20 kg, dilute CEREZYME to 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 final volume of 200 mL in an infusion bag.For patients weighing greater than 100 kg, dilute CEREZYME to final volume of 400 mL in an infusion bag.. For patients weighing between 1.5 kg and less than kg, dilute CEREZYME to final volume of 12 mL in syringe for infusion.. For patients weighing between kg and less than 13 kg, dilute CEREZYME to final volume of 26 mL in syringe for infusion.. For patients weighing between 13 kg and less than or equal to 20 kg, dilute CEREZYME to 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 final volume of 200 mL in an infusion bag.. For patients weighing greater than 100 kg, dilute CEREZYME to final volume of 400 mL in an infusion bag.. If CEREZYME is prescribed at dose lower than 60 units/kg, dilute the required total units of reconstituted CEREZYME (at concentration of 40 units/mL) with 0.9% Sodium Chloride Injection to final concentration between units/mL and 30 units/mL inclusive. If the determined dose of CEREZYME translates into total volume of 26 mL or less, administer using syringe for infusion via syringe pump.. For accuracy of dilution, if less than mL of reconstituted CEREZYME (40 units/mL) is needed for the preparation of the determined dose, prepare larger final volume of CEREZYME for infusion initially maintaining the final concentration of the diluted CEREZYME solution between units/mL to 30 units/mL. Subsequently, discard the excess volume and administer only the volume of CEREZYME solution corresponding to the prescribed dose.. Gently invert the syringe for infusion or the infusion bag to mix the solution. Throughout CEREZYME preparation, avoid vigorous shaking, agitation and foaming.. 2.5 Administration Instructions Visually inspect the diluted 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.Administer CEREZYME as an intravenous infusion with 0.2 micron in-line low protein-binding filter.Table 1: Total Infusion Volumes and Infusion Time for CEREZYMEPatient WeightTotal Infusion VolumeFinal concentration of diluted CEREZYME solution is between units/mL and 30 units/mL. Infusion TimeMaximum Infusion Rate1.5 kg to 6 kg12 mL2 hours6 mL/hour6 kg to 13 kg26 mL2 hours13 mL/hour13 kg to <= 20 kg100 mL2 hours50 mL/hour> 20 kg to <= 100 kg200 mL1 to hours200 mL/hour> 100 kg400 mL1 to hours400 mL/hour. 2.6Storage and Handling. If the reconstituted CEREZYME vial is not used immediately:Refrigerate the reconstituted solution at 2C to 8C (36F to 46F) or store at room temperature at 20C to 25C (68F to 77F) for up to 12 hours. Refrigerate the diluted solution at 2C to 8C (36F to 46F) for up to 24 hours. If the reconstituted CEREZYME vial is not used immediately:Refrigerate the reconstituted solution at 2C to 8C (36F to 46F) or store at room temperature at 20C to 25C (68F to 77F) for up to 12 hours. Refrigerate the reconstituted solution at 2C to 8C (36F to 46F) or store at room temperature at 20C to 25C (68F to 77F) for up to 12 hours.. Refrigerate the diluted solution at 2C to 8C (36F to 46F) for up to 24 hours.

DOSAGE FORMS & STRENGTHS SECTION.

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

GERIATRIC USE SECTION.

8.5 Geriatric Use. Among the patients with Type Gaucher disease in Study [see Clinical Studies (14)] who had hemoglobin or platelet count measurements to 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 Gaucher disease. The safety evaluation for patients 65 years of age and older with Type Gaucher disease was conducted using data from 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 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 Gaucher disease.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. CEREZYME (imiglucerase) for injection is supplied as white to off-white lyophilized powder in carton containing one single-dose vial: NDC 58468-4663-1. Each vial contains 400 units of imiglucerase. CEREZYME does not contain any preservatives.. Store refrigerated at 2C to 8C (36F to 46F). For storage of reconstituted and diluted solution [see Dosage and Administration (2.2)].

IMMUNOGENICITY.

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 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)].

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hypersensitivity Reactions Including Anaphylaxis and Infusion-Associated Reactions Advise patients and caregivers that life-threatening hypersensitivity reactions, including anaphylaxis, and IARs may occur with CEREZYME treatment.Advise patients and caregivers that anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.Inform patients and caregivers of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and IARs and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1, 5.2)].Patient RegistryInform 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. 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.

LACTATION SECTION.

8.2 Lactation. Risk SummaryAvailable published literature suggests 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 mothers 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)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Gaucher disease is characterized by deficiency of -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.

NONCLINICAL TOXICOLOGY SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 400 Unit Vial Carton. NDC 58468-4663-1Rx onlyCerezyme(R) (imiglucerase) for injection400 units per vialFor intravenous infusion after reconstitution and dilutionsanofi. PRINCIPAL DISPLAY PANEL 400 Unit Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of CEREZYME for the treatment of non-CNS manifestations of Type or Type Gaucher disease have been established in pediatric patients. Use of CEREZYME for the treatment of non-CNS manifestations of Type 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 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 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 Gaucher disease and additional safety and efficacy data from an observational study of Type Gaucher disease in adults and pediatric patients [see Adverse Reactions (6.1) and Clinical Studies (14)].

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

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 PharmacokineticsIn 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)].

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryAvailable 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 drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks associated with symptomatic Type 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 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 RiskPregnancy may exacerbate existing Type Gaucher disease symptoms or result in new disease manifestations. Untreated symptomatic Type Gaucher disease may lead to complications during pregnancy, including hepatosplenomegaly, which can interfere with the normal growth of pregnancy and thrombocytopenia, which can lead to excessive bleeding.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)1/2026Dosage and Administration (2.3, 2.4, 2.5)1/2026Warnings and Precautions (5.1, 5.2)1/2026.

SPL UNCLASSIFIED SECTION.

2.1 Recommendations Prior to CEREZYME Treatment Administer CEREZYME under the supervision of healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1)].Initiate CEREZYME in 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)].

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryAvailable 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 drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks associated with symptomatic Type 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 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 RiskPregnancy may exacerbate existing Type Gaucher disease symptoms or result in new disease manifestations. Untreated symptomatic Type Gaucher disease may lead to complications during pregnancy, including hepatosplenomegaly, which can interfere with the normal growth of pregnancy and thrombocytopenia, which can lead to excessive bleeding.. 8.2 Lactation. Risk SummaryAvailable published literature suggests 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 mothers 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 or Type Gaucher disease have been established in pediatric patients. Use of CEREZYME for the treatment of non-CNS manifestations of Type 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 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 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 Gaucher disease and additional safety and efficacy data from an observational study of Type 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 Gaucher disease in Study [see Clinical Studies (14)] who had hemoglobin or platelet count measurements to 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 Gaucher disease. The safety evaluation for patients 65 years of age and older with Type Gaucher disease was conducted using data from 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 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 Gaucher disease.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infusion-Associated Reactions (IARs): If severe IAR occurs, discontinue CEREZYME immediately and initiate appropriate medical treatment. (5.2). 5.1Hypersensitivity 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 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 healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate CEREZYME in healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment.If 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 severe hypersensitivity reaction. If 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.. 5.2Infusion-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 severe IAR occurs, discontinue CEREZYME and immediately initiate appropriate medical treatment. Consider the risks and benefits of re-administering CEREZYME following severe IAR.If mild or moderate IAR occurs, consider decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines, antipyretics, and/or corticosteroids.