Agalsidase beta is a recombinant human alpha-galactosidase A enzyme given by intravenous infusion in adult and pediatric patients 2 years and older. Patients with Fabry disease have a deficiency of the lysosomal enzyme, ceramidetrihexosidase or alpha-galactosidase A, which breaks down glycosphingolipids (predominantly globotriaosylceramide or GL-3). Glycosphingolipids accumulate in the lining of blood vessels in the heart, kidney, and other organs in patients without an adequate presence of alpha-galactosidase A. Crises of severe pain in the extremities (acroparesthesias), hypohidrosis, corneal opacities, and dysfunction of several organs (kidney, brain, heart) are the primary manifestations, and patients often have decreased life expectancy and experience renal failure, cardiomyopathy, and cerebrovascular accidents. Replacement of the deficient enzyme may reduce concentrations of the accumulated glycolipids in various tissues and attenuate disease symptoms. Anaphylaxis and severe infusion-associated reactions have been reported with agalsidase beta. The most common adverse drug reactions are upper respiratory tract infection, chills, fever, headache, cough, paresthesia, fatigue, peripheral edema, dizziness, and rash.
General Administration Information
For storage information, see specific product information within the How Supplied section.
Route-Specific Administration
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 Injection from the bag. Inject the drug solution directly into the 0.9% NaCl Injection 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).
IV Infusion
-Consider pretreatment with antihistamines, antipyretics, and/or corticosteroids prior to the start of infusion. Appropriate medical support measures (including cardiopulmonary resuscitation equipment) needs 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.
A registry has been established to help monitor and evaluate the long-term treatment effects of agalsidase beta. Information may be obtained by visiting www.registrynxt.com or calling 1-800-745-4447 (extension 15500) in the United States.
Infusion-related reactions to agalsidase beta occurred in 59% of patients in clinical trials; some infusion reactions were severe. Infusion-related reactions are defined as adverse reactions occurring on the same day as the infusion. Severe infusion-related reactions included chills, vomiting, hypotension, and paresthesias (31%). Other infusion-related reactions included fever (39%), rash (20%), flushing (5%), chills (49%), dyspnea (8%), headache (39%), fatigue (24%), pain in extremity (19%), hypertension (14%), chest pain (unspecified) or discomfort (5%), dizziness (21%), sinus tachycardia (9%), peripheral edema (21%), myalgia (18%), somnolence, pruritus (10%), throat tightness, nausea, abdominal pain, bradycardia, nasal congestion, diarrhea, urticaria, and feeling hot or cold. In a clinical trial of pediatric patients (8 to 16 years), vomiting, fever, headache, dizziness, nausea, abdominal pain, and diarrhea were reported at a rate of more than 20%. The incidence of infusion-related reactions was higher in patients who were positive for anti-agalsidase beta antibodies compared to patients who were negative for anti-agalsidase beta antibodies. Closely observe patients during and after drug administration and be prepared to manage hypersensitivity or infusion-related reactions; appropriate medical support, including cardiopulmonary resuscitation equipment, should be readily available. Symptoms of infusion-related reactions may be lessened by decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines, antipyretics, and/or corticosteroids. Patients pretreated with antihistamines, antipyretics, and/or corticosteroids may still experience reactions. If severe infusion-related or hypersensitivity reactions occur, immediately discontinue the agalsidase beta infusion and initiate appropriate medical treatment.
In clinical trials of patients 16 to 61 years, back pain (16%) was reported more frequently in patients receiving agalsidase beta than placebo. Arthralgia was reported in more than 20% of pediatric patients (8 to 16 years) who received agalsidase beta during a clinical trial. Asthenia has also been reported with postmarketing use of agalsidase beta; however, a causal relationship to the drug has not been established.
More patients receiving agalsidase beta vs. placebo experienced pain (16%), tinnitus (8%), burning sensation (6%), and hypoacousia or hearing loss (5%). Cardiorespiratory arrest, heart failure, cerebrovascular accident (stroke), myocardial infarction, and palpitations have also been reported with postmarketing use of agalsidase beta; however, a causal relationship to the drug has not been established.
Antibody formation occurred in approximately 83% (110/133) of adult patients receiving agalsidase beta; 77% (102/133) of patients developed neutralizing antibody (NAb) that inhibited in vitro agalsidase beta catalytic activity, which declined over time, and 6% (8/133) of patients developed NAb that inhibited cellular uptake. In pediatric patients (8 to 15 years), antibodies to agalsidase beta were detected in approximately 69% (11/16) of patients. Most patients developed antibodies within the first 3 months of treatment; antibody titers generally declined over time. Approximately 18% of adult patients who developed antibodies became antibody-negative by 74 weeks from the time of seroconversion; however, none of the pediatric patients became antibody-negative. Female patients generally had lower incidence of antibodies and lower antibody titers compared to male patients. Patients with truncating GLA mutations, had higher incidence of antibodies and higher antibody titers compared to patients with nontruncating GLA mutations. Patients with plasma alpha-galactosidase A activity of 1.5 nmol/hour/mL or less had a higher incidence of antibodies and higher antibody titers compared to patients with plasma alpha-galactosidase A activity of more than 1.5 nmol/hour/mL. Over 90% of adult and pediatric patients treated with agalsidase beta achieved and maintained normalization of plasma globotriaosylceramide (GL-3) concentrations irrespective of developing antibodies to agalsidase beta.
Anaphylactoid reactions or severe allergic reactions have been reported in approximately 1% of patients receiving agalsidase beta. Reactions have included localized angioedema (swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, erythema, pruritus, and nasal congestion. In clinical trials, 10 of 238 patients developed IgE antibodies or skin test reactivity to agalsidase beta; 2 of 6 patients in the rechallenge study discontinued treatment with agalsidase beta early due to recurrent infusion-associated reactions. Three patients experienced a total of 4 serious infusion-associated reactions during infusion, including bronchospasm, urticaria, hypotension, and development of agalsidase beta antibodies. Other infusion-associated reactions occurring in more than 1 patient included rigors, hypertension, nausea, vomiting, and pruritus. Hypersensitivity reactions were observed more often in adult patients with persistent anti-agalsidase beta antibodies and in adult patients with high antibody titer compared to that in antibody-negative adult patients. Appropriate medical support including cardiopulmonary resuscitation equipment should be readily available upon agalsidase beta administration. If a severe anaphylactic or allergic reaction occurs, discontinue administration of agalsidase beta immediately and initiate emergency treatment. Consider the risks and benefits of further treatment in patients with suspected allergic reactions to agalsidase beta. Some patients have been rechallenged and have continued to receive the drug under close clinical supervision. Consider testing for IgE antibodies if a patient develops a severe hypersensitivity reaction, including anaphylaxis; patients who develop IgE antibodies to agalsidase beta appear to be at higher risk for hypersensitivity and therefore should be monitored closely during administration. There are currently no marketed tests for antibodies against agalsidase beta; however, a testing service is provided by Genzyme. Call 1-800-745-4447 for information on testing and to obtain a sample collection box.
During clinical trials, the following respiratory effects, infections, and related symptoms were reported more frequently in patients receiving agalsidase beta than with placebo: upper respiratory tract infection, including nasal congestion, sinusitis, pharyngitis, and respiratory tract congestion (53%), cough (33%), lower respiratory tract infection (18%), wheezing (6%), fungal infection (5%), and viral infection (5%). During a clinical trial, rhinitis and pharyngitis were each reported in greater than 20% of pediatric patients (8 to 16 years) who received agalsidase beta. Hypoxia and respiratory failure have also been reported with postmarketing use of agalsidase beta; however, a causal relationship to the drug has not been established.
During clinical trials, the following general effects were reported more frequently in patients receiving agalsidase beta than placebo: excoriation (9%), increased serum creatine (9%), and fall (6%). Hyperhidrosis, hypoesthesia, lymphadenopathy, leukocytoclastic vasculitis, and renal failure (unspecified) have also been reported with postmarketing use of agalsidase beta; however, a causal relationship to the drug has not been established.
Anxiety and depression were each reported in 6% of patients receiving agalsidase beta in clinical trials compared to 3% and 2% of patients receiving placebo, respectively.
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.
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.
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.
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.
Available data from a pregnancy sub-study within the Fabry Disease registry, 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. There is a registry that monitors outcomes in lactating persons 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.
Infusion-related reactions may occur during agalsidase beta administration; monitor patients carefully during the infusion. Consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids prior to the start of infusion. 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, including cardiopulmonary resuscitation equipment, 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.
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 Limits:
-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.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Agalsidase Beta products.
Agalsidase beta, by providing an exogenous source of alpha-galactosidase A, catalyzes the hydrolysis of glycosphingolipids, including globotriaosylceramide (GL-3). Specifically, this enzyme removes the third sugar molecule, a galactose, attached to ceramide. Without alpha-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 GL-3 deposition in capillary endothelium of the kidney and certain other cell types.
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.
-Special Populations
Pediatrics
The pharmacokinetics of agalsidase beta have been evaluated in 15 pediatric patients 8 to 16 years of age after receiving doses of 1 mg/kg IV every 14 days. Concentrations of the drug were elevated and the half-life was prolonged after IgG seroconversion; however, this elevation did not impact clearance of globotriaosylceramide (GL-3). Mean Cmax and half-life after 1, 12, and 24 infusions in pediatric patients were 2.2, 4.9, and 7.1 mcg/mL and 86, 130, and 151 minutes, respectively. Mean Cmax and half life in adult patients receiving 1 mg/kg IV every 14 days ranged from 2.1 to 3.1 mcg/mL and 89 to 119 minutes, respectively.