Cerezyme

Gauchers Disease Agents

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Administer via intravenous infusion. Do not administer by any other route.
Do not use vials that are not yet reconstituted if discoloration or particulate matter are present.
Reconstitution:
Reconstitute each 200 unit vial with 5.1 mL of Sterile Water for Injection, USP. This gives a reconstituted volume of roughly 5.3 mL and a final concentration of 40 units/mL.
Reconstitute each 400 unit vial with 10.2 mL of Sterile Water for Injection, USP. This gives a reconstituted volume of roughly 10.6 ml and a final concentration of 40 units/mL.
After reconstitution, the solution in the vial is stable for up to 12 hours at controlled room temperature or under refrigeration.
Preparation of IV infusion:
Any vials exhibiting opaque particles or discoloration should not be used to prepare the infusion.
Withdraw the appropriate calculated dosage from the reconstituted vial(s) and further dilute with NS injection to a final volume of 100—200 mL.
Being a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after preparing the infusion.
Solution should be used promptly after dilution and not stored for later use. The infusion is stable up to 24 hours if stored under refrigeration at 2—8 degrees C (36—46 degrees F).
Intravenous infusion:
Infuse dosage over 1—2 hours.
Administer separately from other IV fluids and medications. Use aseptic technique.
During administration, the diluted solution may be filtered through an in-line low protein-binding 0.2 micron filter.

angioedema / Rapid / 6.6-6.6
cyanosis / Early / 6.6-6.6
anaphylactoid reactions / Rapid / 0-1.0

antibody formation / Delayed / 15.0-15.0
chest pain (unspecified) / Early / 6.6-6.6
hypotension / Rapid / 6.6-6.6
dyspnea / Early / 6.6-6.6
sinus tachycardia / Rapid / 1.5-1.5
peripheral edema / Delayed / 1.5-1.5

flushing / Rapid / 6.6-6.6
cough / Delayed / 6.6-6.6
urticaria / Rapid / 6.6-6.6
fatigue / Early / 1.5-1.5
rash / Early / 1.5-1.5
headache / Early / 1.5-1.5
diarrhea / Early / 1.5-1.5
nausea / Early / 1.5-1.5
fever / Early / 1.5-1.5
vomiting / Early / 1.5-1.5
dizziness / Early / 1.5-1.5
abdominal pain / Early / 1.5-1.5
chills / Rapid / 1.5-1.5
pruritus / Rapid / 0-1.0
injection site reaction / Rapid / 0-1.0

Cerezyme

Rx

Parenteral enzyme used for Gaucher's disease; replaces the endogenous enzyme beta-glucocerebrosidase.

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.

Miglustat: (Major) Combination therapy with miglustat and imiglucerase is not indicated for Gaucher disease. Miglustat may increase the clearance of imiglucerase, although the clinical significance of this interaction is not yet known.

Cerezyme Intravenous Inj Pwd F/Sol: 200U, 424U

Dosage is based on disease severity and patient response. A specific maximum dosage is not available, however, consensus guidelines state that doses > 60 units/kg IV once every 2 weeks are rarely necessary.

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.

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.