CLASSES
Fabry Disease Agents
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
COMMON BRAND NAMES
Fabrazyme
HOW SUPPLIED
Fabrazyme Intravenous Inj Pwd F/Sol: 5mg, 35mg
DOSAGE & 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.
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.
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.
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.
STORAGE
Fabrazyme:
- Diluted product if not used immediately can be stored at 36 to 46 degrees F for up to 24 hours
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion. Do not store for later use.
- Do not freeze
- Reconstituted product should be refrigerated and used within 24 hours if not used immediately
- Refrigerate (between 36 and 46 degrees F)
- Store diluted product in accordance with package insert instructions
- Store reconstituted product in accordance with package insert instructions
CONTRAINDICATIONS / PRECAUTIONS
General Information
No determination can be made whether symptomatic females with Fabry disease respond to agalsidase beta differently than males. Only 2 females were enrolled in the clinical studies with agalsidase beta. Fabry disease is an X-linked genetic disorder. However, some heterozygous females 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 patients and severity of signs and symptoms is variable. There is also insufficient information to determine whether the relationship between cellular histologic evaluations of biopsies and clinical manifestations differ between females and males.
Mannitol hypersensitivity
Some patients develop IgE or skin test reactivity specific to agalsidase beta. Consider testing for IgE in patients who experience suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-agalsidase beta IgE. There are no marketed tests for antibodies against agalsidase beta. For testing, contact Genzyme Corporation at 1-800-745-4477. Because of the potential for severe infusion reactions, appropriate treatment measures should be readily available. Use the drug with caution in patients with mannitol hypersensitivity, as the product contains 222 and 33 mg of mannitol per 35 and 5 mg vial, repectively.
Cardiac disease
Patients with cardiac disease may be at higher risk for severe complications from infusion reactions related to agalsidase beta. Possible cardiovascular adverse events associated with agalsidase-beta receipt include hypertension, hypotension, chest pain (unspecified) sometimes described as chest tightness, tachycardia, dependent edema, stroke, bradycardia, cardiac arrhythmia, cardiac arrest, and decreased cardiac output or heart failure. Patients with advanced Fabry disease often have compromised cardiac function. These patients should be monitored closely during agalsidase beta administration. Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when agalsidase beta is administered.
Geriatric
Clinical studies of agalsidase beta did not include sufficient numbers of geriatric subjects > 65 years of age to determine whether they respond to the drug differently from younger subjects in terms of efficacy or safety.
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.
Breast-feeding
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]
Infusion-related reactions
Infusion-related reactions may occur during agalsidase beta administration; monitor patients carefully during the infusion. Administer antipyretics (e.g., acetaminophen) prior to the start of infusion. Patients in clinical trials also received antihistamines (or steroids). Infusion reactions have occurred in some patients even after pretreatment with antipyretics, antihistamines, and oral steroids. If a reaction occurs, slowing the infusion rate or temporarily stopping the infusion may help. Administration of additional antipyretic and/or an antihistamine and oral steroid may help reduce the symptoms. Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available during agalsidase beta administration. The frequency of serious infusion reactions declines with continued use; however, a serious reaction may occur after extended use of agalsidase beta. Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion-related reactions; monitor cardiac function closely in these patients.[49184]
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
DRUG INTERACTIONS
There are no drug interactions associated with Agalsidase Beta products.
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]
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.