Alglucerase (3042)
[ al-glue'-ser-ace ]
| Ingredients: |
Alglucerase |
| Indications: |
Gaucher disease |
| Pregnancy Category: |
C |
| FDA Approved: |
1991- 04- 01 |
| Classes: |
Enzymes, metabolic; WHO Formulary |
| HCFA Jcodes: |
J0205 |
| Brand Names: |
Ceredase
-
US
;
|
| DEA schedules: |
(none)
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DESCRIPTION
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Alglucerase is a modified form of the enzyme, β- glucocerebrosidase (β- 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 (b- 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 β- 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 specifically recognized by carbohydrate receptors on macrophage cells. Alglucerase
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. The enzyme is supplied as 400 international units per bottle (80 units/ ml) and 50 units
per bottle (10 units/ ml) with a fill volume 5 ml per bottle. An enzyme unit (U) is defined as the amount of enzyme required
to hydrolyze one minute one micromole of the synthetic substrate, 4- methylumbelliferyl- β- glucoside.
Alglucerase 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 (HIV- 1) and antibody (HIV- 1/ 2).
Human chorionic gonadotropin (hCG), a naturally occurring hormone in human placenta, has been detected in alglucerase. Although
it is likely the hCG is partially deglycosylated, in vitro studies demonstrate biological activity of approximately 3 units of hCG activity per unit of alglucerase. Preliminary studies
suggest that the deglycosylated hCG in alglucerase is rapidly cleared ar a rate which is approximately forty times greater
than that of native hCG.
Therefore, in vivo biological activity and clearance of the material may be different to the naturally occurring hormone and is currently under
investigation.
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CLINICAL PHARMACOLOGY
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Alglucerase 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 β- 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.
Pharmacokinetics
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Following an intravenous infusion of different doses (between 0.6 and 234 unit/ kg) of alglucerase over a 4 hour period, steady-
state enzymatic activity was achieved by 60 minutes. Individual steady- state activity and area under the curve of the activity
increased linearly with the infused dose (0.6 to 121 units/ kg). Following infusion termination, plasma enzymatic activity
declined rapidly with elimination of half- life ranging between 3.6 and 10.4 minutes. Plasma clearance of alglucerase, calculated
from its plasma enzymatic activity, was variable and ranged between 6.34 and 25.39 ml/ min/ kg, whereas the volume of distribution
ranged from 49.4 to 282.1 ml/ kg. Within the dosage range of 0.6 and 121 units/ kg, elimination half- life, plasma clearance,
and volume of distribution values appear to be independent of the infused dose.
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Pharmacologic Actions
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Chronic administration of alglucerase in 13 patients with Type 1 Gaucher disease induced the following effects:
- Splenomegaly and hepatomegaly were significantly reduced, presumably by disruption of the lysosomal storage sites and metabolism of glucocerebroside in
Gaucher cells. This effect was demonstrated within 6 months of initiation of therapy.
- Hematologic deficiencies in hemoglobin, hematocrit, erythrocyte and platelet counts were significantly improved. In most patients a change in hemoglobin
was the first observable effect. In some patients hemoglobin levels were normalized after 6 months of therapy.
- Improved mineralization of bone, as revealed by plain radiographs of long bones, occurred in 3 patients after prolonged treatment as a result of a
reduction in the osteolytic actions of lipid- laden Gaucher cells in the marrow.
- Cachexia and wasting in children were reduced.
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INDICATIONS AND USAGE
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Alglucerase is indicated for use as long- term enzyme replacement therapy for patients with a confirmed diagnosis of Type
1 Gaucher disease who exhibit signs and symptoms that are severe enough to result in one or more of the following conditions:
- Moderate- to- severe anemia
- Thrombocytopenia with bleeding tendency
- Bone disease
- Significant hepatomegaly or splenomegaly
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CONTRAINDICATIONS
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There are no known contraindications to the use of alglucerase.
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WARNINGS
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Approximately 14% of 538 patients treated clinically and tested to date have developed IgG antibody to alglucerase 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 alglucerase after 12 months of therapy. Approximately 25% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity.
Thus, patients with antibody to alglucerase 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 2 hours of the event after appropriate treatment
of the symptoms. Subsequent serum for testing antibody to alglucerase would be helpful. Decreased efficacy has been noted
in less than 0.5% of treated patients due to antibodies to alglucerase.
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PRECAUTIONS
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General
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Therapy with alglucerase should be directed by physicians knowledgeable in the management of patients with Gaucher disease.
Treatment with alglucerase should be approached with caution in patients who have exhibited symptoms of hypersensitivity to
the product. Pre- treatment with antihistamines has allowed continued use of alglucerase in some patients. (See ADVERSE REACTIONS .) As hCG has been detected in alglucerase physicians should be alert for signs of early virilization in males under the age
of 10, although no cases of precocious puberty have been reported to date. Alglucerase should also be used with caution in
patients with androgen sensitive malignancies, e.g., prostate cancer and patients with known prior allergies to hCG.
Alglucerase 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.
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Carcinogenesis, Mutagenesis, and Impairment of Fertility
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Studies have not been conducted to assess the potential effects of alglucerase on carcinogenesis, mutagenesis, or impairment
of fertility in animals or man.
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Pregnancy Category C
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Animal reproductive studies have not been conducted with alglucerase. It is also not know whether alglucerase can cause fetal
harm when administered to a pregnant woman, or can affect reproductive capacity. Alglucerase should be given to a pregnant
woman only if clearly needed.
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Nursing Mothers
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Since alglucerase may be excreted in human milk caution should be exercised when alglucerase is administered to a nursing
woman.
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ADVERSE REACTIONS
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Experience in over 1000 patients treated with alglucerase 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
was reported to occur during one of these events. (See WARNINGS .)
Pre- treatment with antihistamines and reduced rate of infusion has allowed continued use of alglucerase 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, menstrual abnormalities and diarrhea.
Because it contains human chorionic gonadotropin, alglucerase may cause a false positive pregnancy test.
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OVERDOSAGE
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No obvious toxicity was detected after single doses of up to 234 units/ kg. There is no experience with larger doses.
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DOSAGE AND ADMINISTRATION
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Alglucerase 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 is 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.
Alglucerase 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 alglucerase after the expiration
date on the bottle.
On the day of use, the appropriate amount of alglucerase 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.
Alglucerase, when diluted to 100- 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 alglucerase 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 bottle. 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.
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HOW SUPPLIED
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Ceredase is supplied as a clear sterile citrate buffered solution (53 mM citrate, 143 mM sodium) containing 1% albumin human.
Storage: Store at 2- 8°C.
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PRODUCT IDENTIFICATION
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None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
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| solution - injectable - 10 u/ ml -
|
| 5.0 ml |
$185.00 |
Ceredase
Genzyme Corporation
|
58468178101 |
| solution - injectable - 80 u/ ml -
|
| 5.0 ml |
$1480.00 |
Ceredase
Genzyme Corporation
|
58468106001 |
|
|