These highlights do not include all the information needed to use CEREZYME

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)].

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)].

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) ].

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

1. Dilute the CEREZYME solution for infusion promptly with 0.9% Sodium Chloride Injection to a final volume that is calculated based on prescribed dose.
2. 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.
3. 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.
4. 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 excess volume and administer only the volume of CEREZYME solution corresponding to the prescribed dose.
5. 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.

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 a 0.2 micron in-line low protein-binding filter.

• If the reconstituted CEREZYME vial is not used immediately:
  • Refrigerate the reconstituted solution at 2°C to 8°C (36°F to 46°F) or store at room temperature at 20°C to 25°C (68°F to 77°F) for up to 12 hours.
• Refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours.

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.

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 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.

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)].

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.

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)].

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)].

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.

No formal pharmacodynamic studies have been conducted with CEREZYME.

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)].

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.

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)].