Cerezyme

Imiglucerase.

Each 400-U vial contains imiglucerase (total amount)* 424 units, mannitol 340 mg, sodium citrates 140 mg (trisodium citrate 104 mg and disodium hydrogen citrate 36 mg), polysorbate 80 NF 1.06 mg.
Citric acid and/or sodium hydroxide may have been added at the time of manufacture to adjust pH.
*This provides a respective withdrawal dose of imiglucerase 400 U.
Cerezyme is an analogue of the human enzyme β-glucocerebrosides, produced by recombinant DNA technology. β-glucocerebrosides (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysomal glycoprotein enzyme which catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide.
Cerezyme is produced by recombinant DNA technology using mammalian cell culture (Chinese hamster ovary). Purified imiglucerase is a monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites (Mr=60,430). Imiglucerase differs from placental glucocerebrosidase by 1 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. These mannose-terminated oligosaccharide chains of imiglucerase are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease.
An enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate ρ-nitrophenyl-β-D-glucopyranoside (pNP-Glc)/min at 37°C.
After reconstitution with sterile water for injection, USP, the imiglucerase concentration is 40 U/mL. Reconstituted solutions have a pH of approximately 6.1.

Pharmacology: Pharmacodynamics: Mechanism of Action: Gaucher disease is characterized by a deficiency of β-glucocerebrosidase activity, resulting in accumulation of glucocerebroside in tissue macrophages which become engorged and are typically found in the liver, spleen and bone marrow, and occasionally 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. Cerezyme catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. In clinical trials, Cerezyme improved anemia and thrombocytopenia, reduced spleen and liver size, and decreased cachexia to a degree similar to that observed with Ceredase (alglucerase injection).
Pharmacokinetics: During 1-hr IV infusions of 4 doses (7.5, 15, 30, 60 U/kg) of Cerezyme, steady-state enzymatic activity was achieved by 30 min. Following infusion, plasma enzymatic activity declined rapidly with a half-life (t_½) ranging from 3.6-10.4 min. Plasma clearance ranged from 9.8-20.3 mL/min/kg (mean±SD, 14.5±4 mL/min/kg). The volume of distribution corrected for weight ranged from 0.09-0.15 L/kg (0.12±0.02 L/kg). These variables do not appear to be influenced by dose or duration of infusion. However, only 1 or 2 patients were studied at each dose level and infusion rate. The pharmacokinetics of Cerezyme do not appear to be different from placental-derived alglucerase (Ceredase).
In patients who developed immunoglobulin G (IgG) antibody to Cerezyme, an apparent effect on serum enzyme levels resulted in diminished volume of distribution and clearance, and increased elimination (t_½) compared to patients without antibody (see Warnings).

Long-term enzyme replacement therapy in patients with a confirmed diagnosis of non-neuronopathic (type 1) or chronic neuronopathic (type 3) Gaucher disease and who exhibit clinically significant non-neurological manifestations of the disease.
The non-neurological manifestations include ≥1 of the following conditions: anemia, after exclusion of other causes eg, iron deficiency; thrombocytopenia; bone disease, after exclusion of other causes eg, vitamin D deficiency; hepatomegaly or splenomegaly.

Cerezyme is administered by IV infusion >1-2 hrs. Dosage should be individualized to each patient. Initial dosages range from 2.5 U/kg of body weight 3 times weekly to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that treatment be initiated at a relatively high dose or relatively frequent administration. Dosage adjustments should be made on an individual basis, and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient's clinical manifestations.

Experience with doses up to 240 U/kg every 2 weeks have been reported. At that dose, there have been no reports of obvious toxicity.

There are no known contraindications to the use of Cerezyme.
Treatment with Cerezyme should be carefully reevaluated if there is significant clinical evidence of hypersensitivity.

Approximately 15% of patients treated and tested to date have developed IgG antibody to Cerezyme during the 1st 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 a higher risk of hypersensitivity reaction. Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody. It is suggested that patients should be monitored periodically for IgG antibody formation during the 1st year of treatment.
Treatment with Cerezyme should be approached with caution in patients who have exhibited symptoms of hypersensitivity to the product.
Anaphylactoid reaction has been reported in <1% of the patient population. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in rate of infusion and pretreatment with antihistamines and/or corticosteroids.

General: In <1% of the patient population, pulmonary hypertension and pneumonia have also been observed during treatment with Cerezyme. Pulmonary hypertension and pneumonia are known complications of Gaucher disease and have been observed both in patients receiving and not receiving Cerezyme. No causal relationship with Cerezyme has been established. Patients with respiratory symptoms in the absence of fever should be evaluated for the presence of pulmonary hypertension.
Therapy with Cerezyme should be directed by physicians knowledgeable in the management of patients with Gaucher disease.
Caution is advised in administration of Cerezyme to patients previously treated with Ceredase and who have developed antibody to Ceredase or who have exhibited symptoms of hypersensitivity to Ceredase.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Studies have not been conducted in either animals or humans to assess the potential effects of Cerezyme on carcinogenesis, mutagenesis, or impairment of fertility.
Use in pregnancy & lactation: Teratogenic Effects: Pregnancy category C.
Animal reproduction studies have not been conducted with Cerezyme. It is also not known whether Cerezyme can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cerezyme should not be administered during pregnancy except when the indication and need are clear, and the potential benefit is judged by the physician to substantially justify the risk.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cerezyme is administered to a nursing woman.
Use in children: The safety and effectiveness of Cerezyme have been established in patients between 2 and 16 years. Use of Cerezyme in this age group is supported by evidence from adequate and well-controlled studies of Cerezyme and Ceredase in adults and pediatric patients, with additional data obtained from the medical literature and from long-term post-marketing experience. Cerezyme has been administered to patients <2 years; however, the safety and effectiveness in patients <2 years have not been established.

Teratogenic Effects: Pregnancy category C.
Animal reproduction studies have not been conducted with Cerezyme. It is also not known whether Cerezyme can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cerezyme should not be administered during pregnancy except when the indication and need are clear, and the potential benefit is judged by the physician to substantially justify the risk.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cerezyme is administered to a nursing woman.

Since the approval of Cerezyme in May 1994, Genzyme has maintained a worldwide post-marketing database of spontaneously reported adverse events and adverse events discussed in the medical literature. The percentage of events for each reported adverse reaction term has been calculated using the number of patients from these sources as the denominator for total patient exposure to Cerezyme since 1994. Actual patient exposure is difficult to obtain due to the voluntary nature of the database, and the continuous accrual and loss of patients over that span of time. The actual number of patients exposed to Cerezyme since 1994 is likely to be greater than estimated from these voluntary sources and therefore, the percentages calculated for the frequencies of adverse reactions are most likely greater than the actual incidences.
Experience in patients treated with Cerezyme has revealed that approximately 13.8% of patients experienced adverse events which were judged to be related to Cerezyme administration and which occurred with an increase in frequency. Some of the adverse events were related to the route of administration. These include discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture. Each of these events was found to occur in <1% of the total patient population.
Symptoms suggestive of hypersensitivity have been noted in approximately 6.6% of patients. Onset of such symptoms has occurred during or shortly after infusions; these symptoms include pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Anaphylactoid reaction has also been reported (see Warnings). Each of these events was found to occur in <1.5% of the total patient population. Pre-treatment with antihistamines and/or corticosteroids and reduced rate of infusion have allowed continued use of Cerezyme in most patients.
Additional adverse reactions that have been reported in approximately 6.5% of patients treated with Cerezyme include: Nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Each of these events was found to occur in <1.5% of the total patient population.
Incidence rates cannot be calculated from the spontaneously reported adverse events in the post-marketing database. From this database, the most commonly reported adverse events in children (defined as 2-12 years) included dyspnea, fever, nausea, flushing, vomiting and coughing, whereas in adolescents (>12-16 years) and in adults (>16 years) the most commonly reported events included headache, pruritus and rash.
In addition to the adverse reactions that have been observed in patients treated with Cerezyme, transient peripheral edema has been reported for this therapeutic class of drug.

Interaction between Cerezyme and other medicinal products have not been studied. Other forms of interactions eg, with food, are unlikely.
Incompatibilities: In the absence of incompatibility studies, Cerezyme must not be mixed with other products.

After reconstitution, Cerezyme should be inspected visually before use. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. The diluted solution may be filtered through an in-line low protein-binding 0.2 micrometer filter during administration. Any vials exhibiting opaque particles or discoloration should not be used.
On the day of use, after the correct amount of Cerezyme to be administered to the patient has been determined, the appropriate number of vials are each reconstituted with sterile water for injection, USP. The final concentrations and administration volumes are provided in the following table (see table)

Click on icon to see table/diagram/image

A nominal (10 mL for the 400 unit vial) is withdrawn from each vial. The appropriate amount of Cerezyme for each patient is diluted with 0.9% sodium chloride injection, USP, to a final volume of 100-200 mL. Cerezyme is administered by IV infusion over 1-2 hrs. Aseptic techniques should be used when diluting the dose. Since Cerezyme does not contain any preservative, after reconstitution, vials should be promptly diluted and not stored for subsequent use. Cerezyme, after reconstitution, has been shown to be stable for up to 12 hrs when stored at room temperature (25°C) and at 2°-8°C. Cerezyme, when diluted, has been shown to be stable for up to 24 hrs when stored at 2°-8°C.
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 vial as long as the monthly administered dosage remains substantially unaltered.

Store at 2°-8°C (36°-46°F).

Other Agents Affecting Metabolism

A16AB02 - imiglucerase ; Belongs to the class of enzymes. Used in the treatment of alimentary tract and metabolism problems.

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