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Mechanism of Action
US Drug Names
NOTE: The needed dosage should be calculated for the patient, then the appropriate number of vials needed to administer that dose should be reconstituted on the day of administration.
NOTE: To avoid drug wastage, the manufacturer states that small dosage adjustments may be made occasionally to the calculated dosage in order to fully utilize a reconstituted vial. Thus, the dosage of each infusion may be increased or decreased to fully utilize each vial as long as the monthly administered dosage remains substantially unaltered.
Initial doses range from 2.5 units/kg IV infused 3 times per week to 60 units/kg IV infused once every 2 weeks. Individualize initial and maintenance dosages according to patient goals and response. The ideal maintenance dosage schedule has not been determined. Although every-2-week dosing is the most commonly studied schedule, some data suggest that the dosage interval may be extended to every 3 or 4 weeks for certain patients with non-severe GD1.  However, when using an extended schedule, the overall monthly dosage typically remains approximately the same. The authors of one randomized trial of 95 patients with GD1 concluded that an every-4-week regimen at the same total monthly dose may be considered for clinically stable adult patients who have been on imiglucerase therapy for 2 years or more at 20 to 60 units/kg every 2 weeks; however, long-term follow-up data are needed for extended-interval regimens. Long-term data from adult and pediatric patients with GD1 who received imiglucerase every 2 weeks showed a continued favorable response. After 10 years, the majority of patients were receiving 15 to 45 units/kg every 2 weeks. Although a maximum dosage of imiglucerase has not been clearly determined, the FDA-approved product labeling states that dosages of up to 240 units/kg IV administered once every 2 weeks have been reported without obvious signs of toxicity.
Initial doses range from 2.5 units/kg IV infused 3 times per week to 60 units/kg IV infused once every 2 weeks.  Consensus guidelines recommend an initial dosage of 30 to 60 units/kg IV every 2 weeks; children at highest risk for complications should receive 60 units/kg IV every 2 weeks initially. Individualize maintenance dosages according to patient goals and response; doses more than 60 units/kg every 2 weeks are rarely needed. Assess the need for dosage adjustments frequently to maintain a constant dose/kg body weight. All children with physical signs or manifestations of Gaucher disease should be treated with enzyme replacement therapy; all children with GD1 will respond to enzyme replacement therapy with appropriate doses.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Imiglucerase is parenteral enzyme used in the treatment of patients with Gaucher's disease. Imiglucerase replaces the endogenous enzyme beta-glucocerebrosidase. Imiglucerase is produced by recombinant DNA technology using Chinese hamster ovary cell cultures and differs from the endogenous enzyme by one amino acid at position 495 where histidine is substituted for arginine. Imiglucerase was approved by the FDA in March 1994. A related product, alglucerase (Ceredase®), produced from pooled human placental tissue from selected donors, was approved April 1991.
For storage information, see the specific product information within the How Supplied section.
Preparation of IV infusion:
Reported adverse reactions with imiglucerase have generally not been considered serious or have usually not warranted medical intervention or discontinuation of therapy. Approximately 13.8% of patients report adverse events thought to be causally related to imiglucerase. Some of the adverse events are related to the route of administration. An injection site reaction may occur, presenting as discomfort, pruritus, burning, swelling, or sterile abscess; each of these reactions are reported in less than 1% of patients.
Roughly 15% of patients receiving imiglucerase develop IgG antibody formation to the medication. In most patients, the development of antibodies does not prohibit continued drug administration. Antibodies are most likely to develop within the first 6—12 months of treatment. While patients with IgG antibodies are at higher risk of developing imiglucerase hypersensitivity, the development of antibodies is not necessary for a hypersensitivity reaction to occur. Symptoms suggestive of hypersensitivity occur in roughly 6.6% of all patients treated. Hypersensitivity reactions manifest during or shortly after the completion of imiglucerase infusion as pruritus, flushing, chest pain (unspecified), dyspnea or other respiratory symptoms, cough, cyanosis, hypotension and, rarely, urticaria or angioedema. Serious symptoms occur in less than 1.5% of patients treated. Pretreatment with antihistamines and/or corticosteroids and a reduced rate of infusion has allowed for continued treatment in most patients. If a serious hypersensitivity reaction occurs, continued treatment with imiglucerase should be re-evaluated. Cross-sensitivity between alglucerase and imiglucerase may not always occur. In one case report, a patient exhibited anaphylactoid reactions to recombinant-derived imiglucerase but not to placental-derived alglucerase.
Approximately 6.5% of patients receiving imiglucerase reported nausea and vomiting, abdominal pain, diarrhea, rash (unspecified), fatigue, headache, fever or chills, dizziness, backache, transient peripheral edema, or sinus tachycardia. Each of these events individually occurs in less than 1.5% of the patient population treated. In some cases, these events are related to the infusion rate. Spontaneously reported post-marketing adverse reactions in children ages 2—12 years have included dyspnea, fever, nausea, vomiting, flushing, and cough; in adults (age > 16 years) and adolescents (age > 12—16 years), the most commonly reported post-marketing adverse effects included headache, pruritus, and rash.
Although there are no known contraindications, imiglucerase should be used with caution in patients with a known hypersensitivity to imiglucerase or alglucerase. Patients receiving imiglucerase have developed IgG antibodies to the product. In roughly 4% of patients, symptoms suggestive of hypersensitivity occur during the infusion. Anaphylactoid-type reactions have occurred in less than 1%. Pretreatment with antihistamines and/or corticosteroids and a slower rate of infusion has allowed for continued treatment in most patients. If a serious hypersensitivity reaction occurs, continued treatment with imiglucerase should be re-evaluated. Cross-sensitivity between alglucerase and imiglucerase may not always occur. In one case report, a patient exhibited an anaphylactoid reaction to recombinant-derived imiglucerase but not to placental-derived alglucerase.
The safe and effective use of imiglucerase has been established in children and adolescents age 2 to 16 years. Use in this age group is supported by adequate and well-controlled studies of imiglucerase and alglucerase (Ceredase) in adults and pediatric patients. Additional data from the medical literature and long term postmarketing experience also support imiglucerase use in children. Imiglucerase has been administered to patients younger than 2 years, however safe and effective use in infants younger than 2 years has not been established.
The use of imiglucerase should be directed by a qualified health care professional knowledgeable in the management of Gaucher's disease. In < 1% of patients, pulmonary hypertension has been observed during treatment with imiglucerase. Pulmonary hypertension is a known complication of Gaucher's disease in patients receiving and not receiving imiglucerase. No causal relationship to imiglucerase has been established. Patients with respiratory symptoms should be evaluated for the presence of pulmonary hypertension.
Previously, the imiglucerase product may have contained small amounts of Haemaccel, a gelatin polypeptide, from the manufacturing process. Products that have an expiration date before April 2007 still contain Haemaccel, and should be use cautiously in patients with an immediate gelatin hypersensitivity. However, this warning is not applicable to products that have an expiration date of April 2007 or later as they do not contain Haemaccel.
Imiglucerase is classified in FDA pregnancy risk category C. Animal reproduction and human reproduction data are not available. According to the manufacturer, it should be used during pregnancy with caution and only when the benefit to the mother outweighs the potential, unknown risk to the fetus. However, a report from a panel of clinicians that treat Gaucher's disease indicated that treatment with enzyme replacement therapy during pregnancy led to a reduced risk of spontaneous abortion and a reduced risk of Gaucher-related complications during delivery and during the postpartum period. No adverse effects on the fetus have been reported secondary to imiglucerase therapy. Imiglucerase has thus been suggested, based on the data available, as an agent for consideration for the treatment of Gaucher's disease during pregnancy. There is also a published case report of the successful use of imiglucerase in a pregnant, and subsequently lactating, patient.
It is not known if imiglucerase is distributed into breast milk. According to the manufacturer, it should be used with caution in breast-feeding women. Enzymes such as imiglucerase are likely to be degraded by the infant's digestive sytem and unlikely to reach the systemic circulation of a nursing infant. Limited data in a report from a panel of clinicians that treat Gaucher's disease indicated that breast-feeding complications were reduced in women treated with enzyme replacement therapy postpartum. No adverse effects on the nursing infant were reported secondary to imiglucerase therapy. Consider reducing the duration of breast-feeding to avoid excessive bone loss in the mother. There are published reports of the successful use of imiglucerase in a pregnant, and subsequently lactating, patient. The case report stated a small amount of imiglucerase was found to be excreted into human breast milk, but only in the first milk produced after infusion, and the patient was able to successfully breast-feed the infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Imiglucerase substitutes for the deficient enzyme glucocerebrosidase in patients with Gaucher's disease. Gaucher's disease is a congenital disorder of lipid metabolism. The disease is characterized by a deficiency of glucocerebrosidase, a necessary catalyst for the hydrolysis of glucosylceramide, an endogenous, very insoluble glycolipid. Patients with this condition have a build-up of glucosylceramide in lysosomes of phagocytic cells, which are found in storage cells of the liver, spleen, and bone marrow as well as in the lung, kidney, and intestine. Clinically, this build-up is associated with splenomegaly, hepatomegaly, increased skin pigmentation, and bone lesions.
Imiglucerase is designed to be preferentially taken up by macrophages, the drug's site of action. Treatment with imiglucerase results in hydrolysis of the accumulated glucosylceramide within macrophages and improvement in hemoglobin, hematocrit, and platelet counts, and a decrease in hepatomegaly and splenomegaly. Reductions in size of an enlarged liver and spleen correspond to hematological improvement and patients' subjective improvement. A decrease in cachexia is also seen. Treatment with imiglucerase does not cure the underlying condition, but it does reverse the disease process and provide symptomatic improvement. Continued use is required to maintain suppression of symptoms.
Imiglucerase is administered by IV infusion. The clearance of imiglucerase from plasma is reported to range from 10—20 ml/minute per kilogram. The enzymatic activity has a plasma half-life of approximately 4—11 minutes. Imiglucerase has been demonstrated to be taken up by the liver in a manner similar to placental-derived aglucerase, although the exact metabolic fate is unknown. Patients who develop IgG antibodies to imiglucerase exhibit decreased volumes of distribution, decreased imiglucerase clearance, and increased imiglucerase half-life compared to patients who do not develop these antibodies.
Because glycoproteins are destroyed in the GI tract and therefore are not orally absorbed, imiglucerase is administered by IV infusion. Plasma enzymatic activity achieves steady-state in about 30 minutes.
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