Aglucerase (Ceredase) for the Treatment of Gaucher Disease (Enzyme Replacement Therapy)

Ceredase® (alglucerase injection)

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, glucocerebroside, 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® (alglucerase injection) catalyzes the hydrolysis of the glycolipid, glucocerebroside, to glucose and ceramide as part of the normal degradation pathway for membrane lipids. Glucocerebroside is primarily derived from hematologic cell turnover. Gaucher disease is characterized by a functional deficiency in ß-glucocerebrosidase enzymatic activity and the resultant accumulation of lipid glucocerebroside in tissue macrophages which become engorged and are termed Gaucher cells. Gaucher cells are typically found in liver, spleen and bone marrow and occasionally, as well, in lung, kidney and intestine. Secondary hematologic sequelae include severe anemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly. Skeletal complications, including osteonecrosis and osteopenia with secondary pathological fractures, are a common feature of Gaucher disease.

INDICATIONS AND USAGE 

Ceredase® (alglucerase injection) is indicated for use as long-term enzyme replacement therapy for children, adolescents, and adult patients with a confirmed diagnosis of Type I Gaucher disease who exhibit signs and symptoms that are severe enough to result in one or more of the following conditions

a) moderate-to-severe anemia;

b) thrombocytopenia with bleeding tendency; 

c) bone disease; 

d) significant hepatomegaly or splenomegaly. 

DOSAGE AND ADMINISTRATION 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 the drug be initiated with relatively high doses or relatively frequent administration. After the 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.

CONTRAINDICATIONS There are no known contraindications to the use of Ceredase® (alglucerase injection). 

WARNINGS 

• 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®. 

PRECAUTIONS 

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 full prescribing information)

ADVERSE REACTIONS

• Experience in over 1000 patients treated with Ceredase® has revealed a small number of adverse events. Some of these events were related to the route of administration including discomfort, pruritus, burning and swelling or sterile abscess at the site of venipuncture. The remaining experiences consisted of slight fever, chills, abdominal discomfort, nausea, or vomiting. None of these events were judged to require medical intervention. 
• Symptoms suggestive of hypersensitivity have been noted in a limited number of patients. Onset of such symptoms has occurred during or shortly after infusions; these symptoms have included pruritus, flushing, urticaria/angioedema (a small number of patients have had upper airway involvement), chest discomfort, respiratory symptoms, nausea and abdominal cramping. Hypotension has been reported to occur during a few of these events. 
• Pretreatment with antihistamines and reduced rate of infusion has allowed continued use of Ceredase® in most patients. Additional adverse symptoms which have been reported include: fatigue, vasomotor irritability or hot flash, weakness, headache, light headedness, dysosmia, oral ulcerations, backache and transient peripheral edema, and diarrhea. Menstrual abnormalities and false positive pregnancy tests have previously been reported, but due to the introduction of manufacturing steps designed to reduce the level of hCG in Ceredase®, the likelihood of these occurrences is reduced.

OVERDOSE 

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