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.

5.1 Hypersensitivity and Infusion-Associated Reactions

Hypersensitivity reactions, some of which are serious and include anaphylaxis, have been reported. In addition, hypersensitivity and other infusion-associated reactions have been reported during or shortly after infusion and include 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)].

If a severe hypersensitivity reaction occurs, discontinue Cerezyme treatment and initiate appropriate medical treatment. Consider the risks and benefits of readministering Cerezyme to individual patients following a severe reaction. If the decision is made to readminister the product, consider reducing the rate of infusion and pretreat with antihistamines and/or corticosteroids and monitor patients for the occurrence of new signs and symptoms of a severe hypersensitivity reaction.

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.

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)].

8.1 Pregnancy

8.2 Lactation

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.

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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)].

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.