Fabrazyme

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Fabrazyme

Classes

Fabry Disease Agents

Administration

For storage information, see specific product information within the How Supplied section.

Injectable Administration

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

Intravenous Administration

Agalsidase beta is only given intravenously as an IV infusion.
 
Reconstitution of Vials and Preparation of Infusion
The drug vial and diluent need to reach room temperature before reconstitution. The number of needed drug vials is based on the patient's weight in kg times the recommended dose of 1 mg/kg.
Slowly inject 1.1 mL (5-mg vial) or 7.2 mL (35-mg vial) of Sterile Water for Injection down the side of each drug vial. Roll and tilt the vial to produce a clear solution. Do not shake or agitate the product. If the solution is not colorless or has particulate matter, discard the vial.
After vial reconstitution, the 5-mg vial will contain 1 mL of solution and the 35-mg vial will contain 7 mL of solution for a concentration of 5 mg/mL. Agalsidase beta does not contain any preservatives. Vials are for single-use only and any unused product should be discarded.
The reconstituted vial solution should be further diluted with 0.9% NaCl Injection to a total volume based on patient weight:
weight 35 kg or less: minimum total volume of 50 mL
weight 35.1 to 70 kg: minimum total volume of 100 mL
weight 70.1 to 100 kg: minimum total volume of 250 mL
weight more than 100 kg: minimum total volume of 500 mL
Withdraw the needed amount of drug solution from the vial; do not use a filter needle. Prior to adding the volume of reconstituted drug, withdraw an equal volume of 0.9% NaCl from the bag. Inject the drug solution directly into the 0.9% NaCl bag. Do not inject the drug solution into the airspace within the infusion bag. Gently invert the bag to mix the solution. Do not vigorously shake or agitate the bag.
Storage: Prepared infusion solutions should be used immediately. If immediate use is not possible, the infusion solution can be stored for up to 24 hours at 2 to 8 degrees C (36 to 46 degrees F).
 
Intravenous infusion
Administer antipyretics (e.g., acetaminophen) prior to the start of infusion. Patients in clinical trials also received antihistamines (or steroids). Appropriate medical support measures need to be readily available during the infusion, as a severe infusion reaction may occur.
Administer using an in-line low protein binding 0.2 micron filter. Do not infuse through the same intravenous line used for other products.
Infuse no faster than 0.25 mg/minute (15 mg/hour) initially. For patients weighing less than 30 kg, the infusion rate should not be increased above 0.25 mg/minute. For patients weighing 30 kg or more, increases in the infusion rate of 0.05 to 0.08 mg/minute (increments of 3 to 5 mg/hour) with each subsequent infusion is reasonable after patient tolerance to agalsidase beta has been established. For patients weighing 30 kg or more, the duration of infusion should not be less than 1.5 hours (based on patient tolerance). In the event of infusion-associated reactions, infusion rates may be slowed or temporarily stopped.
The initial infusion rate should not exceed 0.01 mg/minute in patients being rechallenged with agalsidase beta after having a positive skin test or testing positive for anti-agalsidase beta IgE. The infusion rate can be doubled every 30 minutes to a maximum of 0.25 mg/minute after patient tolerance has been established.

Adverse Reactions
Severe

hearing loss / Delayed / 5.0-5.0
anaphylactoid reactions / Rapid / 0-1.0
bradycardia / Rapid / 5.0
cardiac arrest / Early / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
stroke / Early / Incidence not known
myocardial infarction / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known

Moderate

infusion-related reactions / Rapid / 50.0-55.0
edema / Delayed / 21.0-21.0
hypertension / Early / 14.0-14.0
sinus tachycardia / Rapid / 9.0-9.0
dyspnea / Early / 8.0-8.0
wheezing / Rapid / 6.0-6.0
depression / Delayed / 6.0-6.0
chest pain (unspecified) / Early / 5.0-5.0
hypotension / Rapid / 5.0
palpitations / Early / Incidence not known
ataxia / Delayed / Incidence not known
antibody formation / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
erythema / Early / Incidence not known
hypoxia / Early / Incidence not known
lymphadenopathy / Delayed / Incidence not known

Mild

infection / Delayed / 4.0-44.0
chills / Rapid / 43.0-43.0
fever / Early / 39.0-39.0
headache / Early / 39.0-39.0
cough / Delayed / 33.0-33.0
paresthesias / Delayed / 31.0-31.0
fatigue / Early / 24.0-24.0
dizziness / Early / 21.0-21.0
rash / Early / 20.0-20.0
nasal congestion / Early / 19.0-19.0
back pain / Delayed / 16.0-16.0
myalgia / Early / 14.0-14.0
pruritus / Rapid / 10.0-10.0
sinusitis / Delayed / 9.0-9.0
tinnitus / Delayed / 8.0-8.0
pharyngitis / Delayed / 6.0-6.0
anxiety / Delayed / 6.0-6.0
flushing / Rapid / 5.0-5.0
muscle cramps / Delayed / 5.0-5.0
xerostomia / Early / 4.0-4.0
abdominal pain / Early / 5.0
nausea / Early / 5.0
urticaria / Rapid / 5.0
vomiting / Early / 5.0
diarrhea / Early / 5.0
pallor / Early / 5.0
arthralgia / Delayed / Incidence not known
asthenia / Delayed / Incidence not known
vertigo / Early / Incidence not known
rhinorrhea / Early / Incidence not known
lacrimation / Early / Incidence not known
hypoesthesia / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known

Common Brand Names

Fabrazyme

Dea Class

Rx

Description

Enzyme replacement therapy; recombinant human alpha-galactosidase A enzyme
Used for pediatric and adult patients 2 years of age and older with confirmed Fabry disease
Anaphylaxis and severe infusion-associated reactions have been reported

Dosage And Indications
For the treatment of Fabry disease.
NOTE: Agalsidase beta has been designated as an orphan drug for this indication by the FDA.
Intravenous dosage Adults

1 mg/kg/dose IV every 2 weeks. Reduce the initial dose to 0.5 mg/kg/dose IV in patients being rechallenged after a positive skin test or who have tested positive for anti-agalsidase beta IgE. The dose may be increased to 1 mg/kg/dose IV once tolerance has been established.

Children and Adolescents 2 to 17 years

1 mg/kg/dose IV every 2 weeks. Reduce the initial dose to 0.5 mg/kg/dose IV in patients being rechallenged after a positive skin test or who have tested positive for anti-agalsidase beta IgE. The dose may be increased to 1 mg/kg/dose IV once tolerance has been established.

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. It is common for patients with advanced Fabry disease to undergo kidney dialysis and transplantation. To date, there are no data regarding these patient populations, but there is no theoretical reason that these patients should have any dosage adjustment.

Drug Interactions

There are no drug interactions associated with Agalsidase Beta products.

How Supplied

Fabrazyme Intravenous Inj Pwd F/Sol: 5mg, 35mg

Maximum Dosage
Adults

No maximum dosage information is available.

Geriatric

No maximum dosage information is available.

Adolescents

No maximum dosage information is available.

Children

Children 2 to 12 years: No maximum dosage information is available.
Children 1 year: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Mechanism of Action: Agalsidase beta, by providing an exogenous source of a-galactosidase A, catalyzes the hydrolysis of glycosphingolipids, including globotriaosylceramide. Specifically, this enzyme removes the third sugar molecule, a galactose, attached to ceramide. Without a-galactosidase A, globotriaosylceramide accumulates in the lysosomes. Prolonged elevated concentrations of glycosphingolipids, especially globotriaosylceramide, in many body tissues promote the clinical manifestations of Fabry disease, such as renal failure, cardiomyopathy and cerebrovascular accidents. Agalsidase beta reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types.In clinical trials, GL-3 was decreased to normal or near normal levels in mesangial cells, glomerular capillary endothelium, interstitial cells and non-capillary endothelium following use of agalsidase beta. GL-3 deposition was still present in vascular smooth muscle cells, tubular epithelium and podocytes, at variably reduced levels. Plasma GL-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.

Pharmacokinetics

Agalsidase beta is given by intravenous infusion. Agalsidase beta is rapidly removed from the circulation and taken up by vascular endothelial and parenchymal cells into lysosomes. The protein is likely taken into cells by mannose-6-phosphate, mannose, and asialoglycoprotein receptors. The protein is highly sialyated; the ratio of sialic acid to galactose residues is 0.88. The non-specific removal of agalsidase beta by hepatic asialoglycoprotein receptors is minimal due to the low number of exposed galactose residues. Agalsidase beta displays non-linear kinetics over the dose range of 0.3, 1 and 3 mg/kg, as the plasma concentration-time curve and clearance do not increase proportionately with increasing dose. Clearance appears to be biphasic; the most rapid elimination phase is 1 to 2 hours after the infusion. As a protein, agalsidase beta is expected to be metabolically degraded through peptide hydrolysis. Renal elimination is expected to be a minor pathway. The terminal half-life is dose independent with a range of 45 to 102 minutes.
 
Reduction in plasma globotriaosylceramide (GL-3) concentrations is dose-dependent. Of 3 patients that received 1 mg/kg every 2 weeks, 2 had complete elimination of GL-3 from their plasma after the first infusion. The other patient had a reduction in their GL-3 concentration after the first infusion but did not have total clearance during the treatment period of 10 weeks. More frequent administration of agalsidase beta (every 48 hours) does not appear to result in greater tissue GL-3 concentration reduction. However, the small number of patients in each group and the short study duration (total of 5 infusions per group) limits this observation.

Pregnancy And Lactation
Pregnancy

Available data from postmarketing case reports and case series with agalsidase beta use in human pregnancy have not revealed a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to agalsidase beta; information about the registry can be obtained at www.registrynxt.com or by calling 1-800-745-4447 (ext 15500) or 1-800-633-1610.

There is no information regarding the presence of agalsidase beta in human milk, the effects of agalsidase beta on the breastfed infant, or the effects of agalsidase beta on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for agalsidase beta and any potential adverse effects on the breastfed child from agalsidase beta or the underlying maternal condition. A registry is available for lactating women who receive the drug. Participation is voluntary. Information regarding the registry may be obtained by visiting www.registrynxt.com or by calling (800)-745-4447 (ext 15500).[49184]