Ceredase

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

This medicine has been tested in a limited number of children. In effective doses, the medicine has not been shown to cause different side effects or problems than it does in adults.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of alglucerase in the elderly with use in other age groups.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

It is important that your doctor check your progress while you are receiving alglucerase to make sure that the dosage is correct for you.

Ceredase® (alglucerase injection) is a modified form of the enzyme, ß-glucocerebrosidase (ß-D-glucosyl-N-acylsphingosine glucohydrolase, EC 3.2.1.45). Alglucerase is a monomeric glycoprotein of 497 amino acids with carbohydrates making up approximately 6% of the molecule (Mr=59,300 as determined by SDS-PAGE). The unmodified enzyme (ß-glucocerebrosidase) also contains 497 amino acids and contains approximately 12% carbohydrate (Mr=67,000). The carbohydrates on the unmodified enzyme consist of N-linked carbohydrate chains of the complex and high mannose type. Glucocerebrosidase and alglucerase catalyze the hydrolysis of the glycolipid, glucocerebrosidase, within the lysosomes of the reticuloendothelial system.

Alglucerase is prepared by modification of the oligosaccharide chains of human ß-glucocerebrosidase. The modification alters the sugar residues at the non-reducing ends of the oligosaccharide chains of the glycoprotein so that they are predominantly terminated with mannose residues which are specifically recognized by carbohydrate receptors on macrophage cells.

Ceredase® is supplied as a clear sterile non-pyrogenic solution of alglucerase in a citrate buffered solution (53 mM citrate, 143 mM sodium) containing 1% albumin human USP. The enzyme is supplied in one concentration, 400 units per bottle (80 units/mL) with a fill volume of 5 mL per bottle. An enzyme unit (U) is defined as the amount of enzyme required to hydrolyze in one minute one micromole of the synthetic substrate, p-nitrophenyl-ß-D-glucopyranoside.

Ceredase® is purified from a large pool of human placental tissue collected from selected donors. Steps have been introduced into the manufacturing process to reduce further the risk of viral contamination. However, no procedure has been shown to be totally effective in removing viral infectivity (see PRECAUTIONS). Each lot of product has been tested and found negative for hepatitis B surface antigen (HBsAg) and for human immunodeficiency virus antigen (HIV-1) and antibody (HIV-1/2).

Human chorionic gonadotropin (hCG) is a naturally occurring hormone in human placenta. It is likely the hCG is partially deglycosylated. In vitro studies have previously demonstrated biological activity of approximately 3 units of hCG activity per unit Ceredase®, as determined by an in vitro cell based assay. New process steps have since been introduced into the manufacturing process that significantly reduce the amount of hCG present in the Ceredase® product. Initial manufacturing data indicate that the resulting level of hCG in the product is less than 1 μg hCG per mg Ceredase® protein, as determined by the ELISA assay. These data indicate that the level of hCG in the product has been reduced about 15 fold as a result of the new process steps.

Approximately 13% of patients treated clinically and tested to date have developed IgG antibody to Ceredase® during the first year of therapy. It appears that patients who will develop IgG antibody are most likely to do so within 6 months of treatment and will rarely develop antibodies to Ceredase® after 12 months of therapy. Approximately 25% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity.

Thus, patients with antibody to Ceredase® have a higher risk of hypersensitivity reaction. Conversely, not all patients with symptoms of hypersensitivity have detectable antibody and further evaluation of their antibody isotypes and mechanisms is continuing. It is suggested that patients be monitored periodically for IgG antibody formation.

At present, should a patient experience a reaction with symptoms suggestive of hypersensitivity, it is recommended that a serum sample for tryptase levels and complement activation be drawn within two hours of the event after appropriate treatment of the symptoms. Subsequent serum for testing antibody to Ceredase® would be helpful. Decreased efficacy has been noted in less than 0.5% of treated patients due to antibodies to Ceredase®.

General

Therapy with Ceredase® (alglucerase injection) should be directed by physicians knowledgeable in the management of patients with Gaucher disease. Treatment with Ceredase® should be approached with caution in patients who have exhibited symptoms of hypersensitivity to the product. Pretreatment with antihistamines has allowed continued use of Ceredase® in some patients (see ADVERSE REACTIONS). Ceredase® should also be used with caution in patients with androgen sensitive malignancies, e.g., prostate cancer and patients with known prior allergies to hCG.

Ceredase® is prepared from pooled human placental tissue that may contain the causative agents of some viral diseases. Manufacturing steps have been designed to reduce the risk of transmitting viral infectious agents. These steps have demonstrated in vitro inactivation of a panel of model viruses, including human immunodeficiency virus (HIV-1). The risk of contamination from slowly acting or latent viruses, including the Creutzfeldt-Jacob disease agent, is believed to be remote but has not been tested. Accordingly, the benefits and the risks of treatment with this product should be assessed prior to use.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been conducted to assess the potential effects of Ceredase® on carcinogenesis or mutagenesis. Histopathology studies using hCG-reduced Ceredase® to detect effects on spermatogenesis in rats have revealed no testicular changes.

Pregnancy Category C

Animal reproductive studies have not been conducted with Ceredase®. It is also not known whether Ceredase® can cause fetal harm when administered to a pregnant woman, or can affect reproductive capacity. Ceredase® should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Since Ceredase® may be excreted in human milk, caution should be exercised when Ceredase® is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Ceredase® (alglucerase injection) have been established in patients between 2 and 16 years of age. Use of Ceredase® in this age group is supported by evidence from adequate and well-controlled studies of Ceredase® and Cerezyme® (imiglucerase for injection) in adults and pediatric patients, with additional data obtained from the medical literature and from long-term postmarketing experience. Ceredase® has been administered to patients younger than 2 years of age, however the safety and effectiveness in patients younger than 2 have not been established.

As hCG has been detected in Ceredase®, physicians should be alert for signs of early virilization in males under the age of ten. One case of precocious puberty has been reported to date, however due to the recent introduction of manufacturing steps designed to reduce the level of hCG in Ceredase®, the likelihood of this occurrence is reduced.

No obvious toxicity was detected after single doses up to 234 units/kg. There is no experience with larger doses.

Ceredase® (alglucerase injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized for each patient. Initial dosage may be as little as 2.5 units/kg of body weight 3 times a week up to as much as 60 units/kg administered as frequently as once a week or as infrequently as every 4 weeks. 60 units/kg every 2 weeks is the dose for which the most data are available. Disease severity may dictate that drug be initiated with relatively high doses or relatively frequent administration. After patient response is well-established, a reduction in dosage may be attempted for maintenance therapy. Progressive reductions can be made at intervals of 3-6 months while carefully monitoring response parameters.

Ceredase® should not be shaken. Each bottle should be inspected visually for particulate matter and discoloration before use. Any bottles exhibiting particulate matter or discoloration should not be used. DO NOT USE Ceredase® after the expiration date on the bottle.

On the day of use, the appropriate amount of Ceredase® for each patient is diluted with 0.9% sodium chloride IV solution to a final volume not to exceed 200 mL. Aseptic techniques should be used when diluting the dose. Ceredase®, when diluted to 100 to 200 mL, has been shown to be stable for up to 18 hours when stored at 2-8°C. The use of an in-line particulate filter is recommended for the infusion apparatus. Since Ceredase® does not contain any preservative, after opening, bottles should not be stored for subsequent use.

Relatively low toxicity, combined with the extended time course of response, allows small dosage adjustments to be made occasionally to avoid discarding partially used bottles. Thus, the dosage administered in individual infusions may be slightly increased or decreased to utilize fully each bottle as long as the monthly administered dosage remains substantially unaltered.

Ceredase® (alglucerase injection) is supplied as a clear sterile citrate buffered solution (53 mM citrate, 143 mM sodium) containing 1% albumin human USP. The following package is available:

-The 400 unit bottle contains 5 mL in a 10 mL glass bottle. NDC 58468-1060-1.

Store at 2-8°C.

Ceredase® (alglucerase injection) is manufactured by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142

Certain manufacturing operations have been performed by other firms.

NDC  58468-1060-1

Ceredase®
(alglucerase injection)

5 mL

Concentration:

80 U/mL

For
intravenous
infusion only

Genzyme Corporation

500 Kendall Street
Cambridge, MA 02142