Agalsidase Beta (3594)
[ a-gal'-si-daze bay'-tah ]
| Ingredients: |
Agalsidase Beta |
| Indications: |
Fabry disease |
| Pregnancy Category: |
B |
| FDA Approved: |
2003- 04- 01 |
| Classes: |
Enzymes, metabolic; WHO Formulary |
| HCFA Jcodes: |
C9208 |
| Brand Names: |
Fabrazyme
-
EUROPE, US; Canada, Israel
;
Replagal
-
EUROPE; Israel
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$20,000.00
(
Fabry Disease ;
Fabrazyme ;
35 mg/vial ;
1 infusion (approx. 2 vials)/2 weeks ;
1 vial
)
|
DESCRIPTION
|
| |
Agalsidase beta is a recombinant human a- galactosidase A enzyme with the same amino acid sequence as the native enzyme. Purified
agalsidase beta is a homodimeric glycoprotein with a molecular weight of approximately 100 KD. The mature protein is comprised
of 2 subunits of 398 amino acids (approximately51 KD), each of which contains 3 N- linked glycosylation sites. α- galactosidase
A catalyzes the hydrolysis of globotriaosylceramide (GL- 3) and other α- galactyl- terminated neutral glycosphingolipids,
such as galabiosylceramide and blood group B substances to ceramide dihexoside and galactose. The specificactivity of agalsidase
beta is approximately 70 U/ mg (1 unit is defined as the amount of activity that results in the hydrolysis of 1 μmole of a
synthetic substrate, p- nitrophenyl- α- D- galactopyranoside, per minute under the assay conditions).
Agalsidase beta is produced by recombinant DNA technology in a Chinese Hamster Ovary mammalian cell expression system.
Fabrazyme is intended for intravenous (IV) infusion. It is supplied as a sterile, nonpyrogenic, white to off- white, lyophilized
cake or powder for reconstitution with sterile water for injection. Each vial contains 37 mg of agalsidase beta as well as
222 mg mannitol, 20.4 mg sodium phosphate monobasicmonohydrate, and 59.2 mg sodium phosphate dibasic heptahydrate. Following
reconstitution as directed, 35 mg of agalsidase beta (7 ml) may be extracted from each vial.
|
CLINICAL PHARMACOLOGY
|
| |
Mechanism of Action
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Fabry disease is an X- linked genetic disorder of glycosphingolipid metabolism. Deficiency of the lysosomal enzyme α- galactosidase
A leads to progressive accumulation of glycosphingolipids, predominantly GL- 3, in many body tissues, occurring over a period
of years or decades. Clinical manifestationsof Fabry disease include renal failure, cardiomyopathy, and cerebrovascular accidents.
Accumulation of GL- 3 in renal endothelial cells may play a role in renal failure.
Agalsidase beta is intended to provide an exogenous source of α- galactosidase A in Fabry disease patients. Preclinical and
clinical studies evaluating a limited number of cell types indicate that agalsidase beta will catalyze the hydrolysis of glycosphingolipids
including GL- 3.
|
Pharmacokinetics
|
| |
Plasma profiles of agalsidase beta were studied at 0.3, 1.0 and 3.0 mg/ kg in 15 patients with Fabry disease. The area under
the plasma concentration- time curve (AUC∞) and the clearance did not increase proportionately with increasing doses, demonstrating
that the enzyme follows non- linear pharmacokinetics. Terminal half- life was dose independent with a range of 45- 102 minutes.
In 11 patients with Fabry disease given 1.0 mg/ kg agalsidase beta every 14 days for a total of 11 infusions, the pharmacokinetic
responses following repeated dosing fell into 3 categories. In some patients, pharmacokinetic responses were maintained with
repeated dosing, whereas in other patients, pharmacokineticvalues decreased at infusion 7 relative to baseline and returned
to baseline values by infusion 11. In the remaining patients, AUC declined and failed to return to baseline by infusion 11.
In these patients, the average AUC was 25% of its initial level. Some patients with elevated titers of antibody to agalsidasewere
among those with decreased AUC. The development of antibodies to agalsidase did not influence half- life, but reduced both
apparent Cmax and AUC. The long- term consequence of antibody development to the pharmacokinetics of agalsidase has not been established.
|
|
CLINICAL STUDIES
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The safety and efficacy of agalsidase beta were assessed in a randomized, double- blind, placebo- controlled, multinational,
multicenter study of 58 Fabry patients (56 males and 2 females), ages 16- 61 years, all naïve to enzyme replacement therapy.
Patients received either 1.0 mg/ kg of agalsidasebeta or placebo every 2 weeks for 5 months (20 weeks) for a total of 11 infusions.
All patients were pretreated with acetaminophen and an antihistamine to decrease or prevent infusion associated reactions.
Oral steroids were an additional option to the pretreatment regimen for patients who exhibited severeor recurrent infusion
reactions. The primary efficacy endpoint of GL- 3 inclusions in renal interstitial capillary endothelial cells, was assessed
by light microscopy and was graded on an inclusion severity score ranging from 0 (normal or near normal) to 3 (severe inclusions).
A GL- 3 inclusion score of 0 was achieved in 20 of 29 (69%) patients treated with agalsidase beta compared to 0 of 29 treated
with placebo (p <0.001). Similar reductions in GL- 3 inclusions were observed in the capillary endothelium of the heart and
skin (see TABLE 1 ).No differences between groups in symptoms or renal function were observed during this 5 month study.
| TABLE 1
Reduction of GL- 3 Inclusions to Normal or Near Normal Levels (0 Score) in the Capillary Endothelium of the Kidney, Heart
and Skin
|
| |
5 Months of the Controlled Study |
6 Months of the Open- Label Extension Study |
| |
Placebo |
Agalsidase Beta |
Placebo/ Agalsidase Beta |
Agalsidase Beta/ Agalsidase Beta |
| |
(n=29) |
(n=29) |
(n=29)* |
(n=29)* |
| Kidney |
0/ 29 |
20/ 29 |
24/ 24 |
23/ 25 |
| Heart |
1/ 29 |
21/ 29 |
13/ 18 |
19/ 22 |
| Skin |
1/ 29 |
29/ 29 |
25/ 26 |
26/ 27 |
|
| *
|
Results reported where biopsies were available. |
|
All 58 patients in the randomized study participated in an open- label extension study of agalsidase beta at 1.0 mg/ kg every
2 weeks indefinitely. At the end of 6 months of open- label treatment, most patients achieved a GL- 3 inclusion score of 0
in capillary endothelium (see TABLE 1 ). GL- 3 was decreased to normal or near normal levels in mesangial cells, glomerular capillary endothelium, interstitial
cells and non- capillary endothelium. GL- 3 deposition was still present in vascular smooth muscle cells, tubular epithelium
and podocytes, at variably reduced levels. PlasmaGL- 3 levels were reduced to levels below the limit of detection and remained
so up to 18 months of treatment.
The reduction of GL- 3 inclusions suggests that agalsidase beta may ameliorate disease expression; however, the relationship
of GL- 3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.
|
INDICATIONS AND USAGE
|
| |
Agalsidase beta is indicated for use in patients with Fabry disease. Agalsidase beta reduces globotriaosylceramide (GL- 3)
deposition in capillary endothelium of the kidney and certain other cell types (see CLINICAL STUDIES ).
|
CONTRAINDICATIONS
|
| |
No known contraindications.
|
WARNINGS
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Infusion Reactions
|
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Infusion reactions occurred in many patients treated with agalsidase beta (see ADVERSE REACTIONS ). Some of the reactions were severe. Infusion reactions included fever, rigors, chest tightness, hypertension, hypotension,
pruritus, myalgia, dyspnea, urticaria, abdominal pain, andheadache. All patients were pretreated with acetaminophen and an
antihistamine. Infusion reactions occurred in some patients after receiving antipyretics, antihistamines and oral steroids.
Patients should be given antipyretics prior to infusion. If an infusion reaction occurs, regardless of pre- treatment, decreasing
the infusion rate, temporarily stopping the infusion, and/ or administration of additional antipyretics, antihistamines and/
or steroids may ameliorate the symptoms. Becauseof the potential for severe infusion reactions, appropriate medical support
measures should be readily available when agalsidase beta is administered.
|
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PRECAUTIONS
|
| |
General
|
| |
Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of
severe complications from infusion reactions (see WARNINGS ). Patients with compromised cardiac function should be monitored closely if the decisionis made to administer agalsidase
beta.
Most patients develop IgG antibodies to agalsidase beta (see ADVERSE REACTIONS, Immunogenicity ). Some patients developed IgE or skin test reactivity specific to agalsidase beta. Physicians should consider testing for
IgE (see Laboratory Tests ) inpatients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients
with anti- agalsidase beta IgE.
|
Information for the Patient
|
| |
Patients should be informed that a Registry has been established in order to better understand the variability and progression
of Fabry disease in the population as a whole and in women (see Responses in Women ), and to monitor and evaluate long- term treatment effectsof agalsidase beta. The Registry will also monitor the effect of
agalsidase beta on pregnant women and their offspring, and determine if agalsidase beta is excreted in breast milk. Patients
should be encouraged to participate and advised that their participation is voluntary and may involve longterm follow- up.
For more information visit www.fabryregistry.com or call (800) 745- 4447.
|
Laboratory Tests
|
| |
There are no marketed tests for antibodies against agalsidase beta. If testing is warranted, contact your local Genzyme representative
or Genzyme Corporation at 800- 745- 4447.
|
Carcinogenesis, Mutagenesis, and Impairment of Fertility
|
| |
There are no animal or human studies to assess the carcinogenic or mutagenic potential of agalsidase beta. There are no studies
assessing the potential effect of agalsidase beta on fertility in humans.
|
Pregnancy Category B
|
| |
Reproduction studies have been performed in rats at doses up to 30 times the human dose and have revealed no evidence of impaired
fertility or negative effects on embryo fetal development due to agalsidase beta. There are, however, no adequate and well-
controlled studies in pregnant women. Because animalreproduction studies are not always predictive of human response, this
drug should be used during pregnancy only if clearly needed.
Women of childbearing potential should be encouraged to enroll in the Fabry patient registry (see Information for the Patient ).
|
Nursing Mothers
|
| |
It is not known whether agalsidase beta is excreted in human milk. Because many drugs are excreted in human milk, caution
should be exercised when agalsidase beta is administered to a nursing woman.
Nursing mothers should be encouraged to enroll in the Fabry registry (see Information for the Patient ).
|
Responses in Women
|
| |
Fabry disease is an X- linked genetic disorder. However, some heterozygous women will develop signs and symptoms of Fabry
disease due to the variability of the X chromosome inactivation within cells. Generally, the rates of progression of organ
impairment are slower than in male Fabry disease patientsand severity of signs and symptoms is variable.
Two women were enrolled in the clinical studies with agalsidase beta. Therefore, no determination can be made whether symptomatic
women respond to agalsidase beta differently than men. There is also insufficient information to determine whether the relationship
between cellular histologic evaluationsof biopsies and clinical manifestations differ between women and men.
|
Pediatric Use
|
| |
The safety and effectiveness of agalsidase beta in pediatric patients have not been established.
|
Geriatric Use
|
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Clinical studies of agalsidase beta did not include sufficient numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects.
|
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DRUG INTERACTIONS
|
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No drug interaction studies were performed.
No in vitro metabolism studies were performed.
|
ADVERSE REACTIONS
|
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The most serious and most common adverse reactions reported with agalsidase beta are infusion reactions. Serious and/ or frequently
occurring infusion reactions consisted of one or more of the following: tachycardia, hypertension, throat tightness, chest
pain/ tightness, dyspnea, fever, chills/ rigors, abdominal pain, pruritus, urticaria, nausea, vomiting, lip or ear edema,
and rash (see WARNINGS, Infusion Reactions ). Infusion reactions declined in frequency with continued use of agalsidase beta. However, serious infusion reactions may
occur after extended durationsof agalsidase beta treatment.
Other reported serious adverse events included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased
cardiac output, vertigo, hypoacousia, and nephrotic syndrome. These adverse events also occur as manifestations of Fabry disease;
an alteration in frequency or severity cannotbe determined from the small numbers of patients studied.
The data described below reflect exposure of 29 patients to 1.0 mg/ kg agalsidase beta every 2 weeks for 5 months in a placebo-
controlled study. All 58 patients continued into an open- label extension study of agalsidase beta treatment for up to 30
additional months. An additional 28 patients receivedopen- label treatment. All patients were treated with antipyretics and
antihistamines prior to the infusions.
Because clinical trials are conducted under widely varying and controlled conditions, the observed adverse reaction rates
may not predict the rates observed in patients in clinical practice.
TABLE 2 enumerates adverse events and selected laboratory abnormalities that occurred during the placebo- controlled trial in at least
2 patients more in the agalsidase beta group than was observed in the placebo group. Reported adverse events have been classifiedby
organ system. Observed adverse events in the Phase 1/ 2 study and the open- label treatment period following the controlled
study were not different in nature or severity.
| TABLE 2
Incidence (%) of Adverse Events Occurring in the Placebo- Controlled Study
|
| |
Placebo |
Agalsidase Beta |
| Adverse Event |
(n=29) |
(n=29) |
| Body as a Whole
|
| |
Chest pain |
3 (10%) |
5 (17%) |
| |
Fever |
5 (17%) |
14 (48%) |
| |
Pain |
3 (10%) |
6 (21%) |
| |
Pallor |
1 (3%) |
4 (14%) |
| |
Rigors |
4 (14%) |
15 (52%) |
| |
Temperature changed sensation |
1 (3%) |
5 (17%) |
| Cardiovascular
|
| |
Cardiomegaly |
1 (3%) |
3 (10%) |
| |
Hypertension |
0 |
3 (10%) |
| |
Hypotension |
2 (7%) |
4 (14%) |
| |
Edema dependent |
1 (3%) |
6 (21%) |
| Central and Peripheral Nervous System
|
| |
Dizziness |
2 (7%) |
4 (14%) |
| |
Headache |
11 (38%) |
13 (45%) |
| |
Paraesthesia |
2 (7%) |
4 (14%) |
| Gastrointestinal System
|
| |
Dyspepsia |
1 (3%) |
3 (10%) |
| |
Nausea |
4 (14%) |
8 (28%) |
| Musculoskeletal System
|
| |
Arthrosis |
0 |
3 (10%) |
| |
Skeletal pain |
0 |
6 (21%) |
| Psychiatric
|
| |
Anxiety |
5 (17%) |
8 (28%) |
| |
Depression |
1 (3%) |
3 (10%) |
| Reproductive, Male
|
| |
Testicular pain |
0 |
2 (7%) |
| Respiratory System
|
| |
Bronchitis |
1 (3%) |
3 (10%) |
| |
Bronchospasm |
0 |
2 (7%) |
| |
Laryngitis |
0 |
2 (7%) |
| |
Pharyngitis |
2 (7%) |
8 (28%) |
| |
Rhinitis |
7 (24%) |
11 (38%) |
| |
Sinusitis |
0 |
2 (7%) |
|
Immunogenicity
|
| |
Sixty- three of 71 (89%) patients in the clinical studies treated with agalsidase beta have developed antibodies to agalsidase
beta. Most patients who develop antibodies do so within the first 3 months of exposure. Antibodies to agalsidase beta were
purified from 15 patients with high antibody titers(=12, 800) and studied for inhibition of in vitro enzyme activity. Under the conditions of this assay, most of these 15 patients had inhibition of in vitro enzyme activity ranging between 14- 74% at one or more timepoints during the study. No general pattern was seen in individual
patient reactivity over time. The clinical significance of binding and/ or inhibitory antibodies to agalsidase beta is not
known. In patients followed in the open- label study, reduction of GL- 3 in plasma and GL- 3 inclusions in superficial skin
capillaries was maintained after antibody formation.
The data reflect the percentage of patients whose test results were considered positive for antibodies to agalsidase beta
using an ELISA and radioimmunoprecipitation (RIP) assay for antibodies. These results are highly dependent on the sensitivity
and specificity of the assay. Additionally, the observedincidence of antibodies in an assay may be influenced by several factors
including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons,
comparison of the incidence of antibodies to agalsidase beta with the incidence of antibodies to other productsmay be misleading.
|
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OVERDOSAGE
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There have been no reports of overdose with agalsidase beta. In clinical trials, patients received doses up to 3.0 mg/ kg
body weight.
|
DOSAGE AND ADMINISTRATION
|
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The recommended dosage of agalsidase beta is 1.0 mg/ kg body weight infused every 2 weeks as an IV infusion.
The initial IV infusion rate should be no more than 0.25 mg/ min (15 mg/ h). The infusion rate may be slowed in the event
of infusion- associated reactions. After patient tolerance to the infusion is well established, the infusion rate may be increased
in increments of 0.05- 0.08 mg/ min (increments of 3- 5mg/ h) each subsequent infusion. Thirty- one of 58 (53%) patients have
received infusions at rates = 33 mg/ h.
Patients should receive antipyretics prior to infusion (see WARNINGS ).
Instructions for Use
|
| |
Agalsidase beta does not contain any preservatives. Vials are for single- use only. Any unused product should be discarded.
Shaking or agitation of this product should be avoided. Do not use filter needles during the preparation of the infusion.
|
Reconstitution and Dilution (using aseptic technique)
- Agalsidase beta vials and diluent should be allowed to reach room temperature prior to reconstitution (approximately 30 minutes).
The number of vials needed is based on the patient's body weight (kg) and the recommended dose of 1.0 mg/ kg.
- Patient weight (in kg) = Patient dose (in mg)
-
- Patient dose (in mg) ÷ 35 mg/ vial = Number of vials to reconstitute (if the number of vials includes a fraction, round up
to the next whole number)
- Example: Patient weight (80 kg) = Patient dose (80 mg)
- 80 mg ÷ 35 mg/ vial = 2.29 vials, therefore, 3 vials should be reconstituted
- Reconstitute each vial of agalsidase beta by slowly injecting 7.2 ml of sterile water for injection down the inside wall of
each vial. Roll and tilt each vial gently. Each vial will yield a 5.0 mg/ ml clear, colorless solution (total extractable
amount per vial is 35 mg, 7.0 ml).
- Visually inspect the reconstituted vials for particulate matter and discoloration. Do not use the reconstituted solution if
there is particulate matter or if it is discolored.
- The reconstituted solution should be further diluted with 0.9% sodium chloride injection to a final total volume of 500 ml.
Prior to adding the volume of reconstituted agalsidase beta required for the patient dose, remove an equal volume of 0.9%
sodium chloride for injection from the 500ml infusion bag.
- Patient dose (in mg) ÷ 5 mg/ ml = Number of ml of reconstituted agalsidase beta required for patient dose
-
- Example: Patient dose = 80 mg
- 80 mg ÷ 5 mg/ ml = 16 ml of agalsidase beta
- Slowly withdraw the reconstituted solution from each vial up to the total volume required for the patient dose. Inject the
reconstituted agalsidase beta solution directly into the sodium chloride solution. Do not inject in the airspace within the
infusion bag. Discard any vial with unusedreconstituted solution.
- Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation.
- Agalsidase beta should not be infused in the same IV line with other products.
- The diluted solution may be filtered through an in- line low protein- binding 0.2 μm filter during administration.
|
HOW SUPPLIED
|
| |
Fabrazyme is supplied as a sterile, nonpyrogenic, white to off- white lyophilized cake or powder. Fabrazyme is supplied in
single- use, clear Type I glass 20 ml (cc) vials. The closure consists of a siliconized butyl stopper and an aluminum seal
with a plastic purple flip- off cap.
Storage
|
| |
Store agalsidase beta under refrigeration between 2- 8°C (36- 46°F). DO NOT USE agalsidase beta after the expiration date
on the vial.
Reconstituted and diluted solutions of agalsidase beta should be used immediately. This product contains no preservatives.
If immediate use is not possible, the reconstituted and diluted solution may be stored for up to 24 hours at 2- 8°C (36- 46°F).
|
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PRODUCT IDENTIFICATION
|
| |
None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| powder for injection - intravenous - 35 mg -
|
| 1.0 |
$4750.00 |
Fabrazyme
Genzyme Corporation
|
58468004001 |
|
|