PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Fabry Disease Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Only FDA-approved disease-specific therapy for Fabry disease; provides exogenous source of a-galactosidase A; given by IV infusion; reduces glycolipid concentrations; may positively impact clinical manifestations of Fabry disease.

    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.
    NOTE: When to start treatment and the optimal duration of treatment is unknown. Recent guidelines recommend that enzyme replacement therapy be started in all patients with Fabry disease with clinical signs and symptoms and in carriers with substantial disease manifestations.
    Intravenous dosage
    Adults

    The recommended dosage is 1 mg/kg IV infused every 2 weeks. The initial dose should be reduced to 0.5 mg/kg 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 IV once tolerance has been established. As compared with placebo, agalsidase beta 1 mg/kg IV every 2 weeks for 20 weeks significantly reduced kidney, heart, and skin endothelial deposits of globotriaosylceramide (GL-3). Complete or almost complete clearance of renal microvascular endothelial deposits were found in 20 of 29 patients; 8 patients had a single endothelial inclusion in most vessels, and 1 patient had a missing biopsy. Plasma concentrations of GL-3 were directly correlated with clearance of the microvascular deposits. The number of patients with no microvascular endothelial deposits of GL-3 or only trace amounts (score of 0) in the kidney, skin, and heart after 6 months of open-label therapy were 42 of 43, 45 of 47, and 24 of 32, respectively. Analysis of patients that only received agalsidase beta for the open-label period yielded similar results for the kidney and skin. Receipt of 11 months of agalsidase beta resulted in a score of 0 for the heart in 14 of 17 patients versus 10 of 15 patients that received only 6 months of therapy. NOTE: In clinical trials, patients received doses up to 3 mg/kg IV every 2 weeks. The optimal dose for the reversal, maintenance, and prevention of globotriaosylceramide accumulation is unknown. Higher doses or prolonged treatment time may be needed to clear globotriaosylceramide accumulation in podocytes, cardiomyocytes, and renal tubular epithelial cells. No data are available for the use of agalsidase beta in patients with the cardiac variant of Fabry disease; these patients have residual a-galactosidase A activity, and their only symptom is myocardial dysfunction during middle age.

    Children > = 8 years and Adolescents

    1 mg/kg IV infused every 2 weeks. The initial dose should be reduced to 0.5 mg/kg 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 IV once tolerance has been established. Normalization of elevated plasma globotriaosylceramide (GL-3) concentrations and clearance of GL-3 inclusions in the capillary endothelium occurred in all pediatric patients receiving agalsidase beta in a clinical trial by week 24 of treatment.

    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 8—12 years: No maximum dosage information is available.
    Children 1—7 years: 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:
    - Reconstituted product should be refrigerated and used within 24 hours if not used immediately
    - Refrigerate (between 36 and 46 degrees F)

    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

    Most patients develop IgG antibodies to the agalsidase beta. Some patients developed 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. 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 mg of mannitol per vial.

    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.

    Children, infants, neonates

    The safety and effectiveness of agalsidase beta in neonates, infants, and children younger than 8 years of age have not been established. Although enzyme replacement has not been evaluated in younger children affected with Fabry disease, clinically it is expected that treatment with enzyme replacement is likely to begin when the clinical signs and symptoms of the disease are first detected.

    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

    Agalsidase beta is a FDA pregnancy risk category B drug. Clinical data concerning use during pregnancy is absent. Since there are no adequate and well-controlled studies in pregnant women, its use is only recommended if clearly needed. A registry is available for pregnant women who receive the drug. Participation is voluntary. Information regarding the pregnancy registry may be obtained by visiting the manufacturer's website or by calling 800—745—4447.

    Breast-feeding

    Data are limited regarding use of agalsidase beta during breast-feeding, and its excretion in human milk is unknown. The manufacturer recommends caution when administering to lactating women. However, because of its large molecular weight and short elimination half life, the probability of significant excretion in breast milk is unlikely. Additionally, because the drug is an enzyme and would likely be digested in the infants gastrointestinal tract, toxicity risk may be limited. A registry is available for lactating women who receive the drug. Participation is voluntary. Information regarding the registry may be obtained by visiting the manufacturer's website or by calling (800)—745—4447.

    ADVERSE REACTIONS

    Severe

    hearing loss / Delayed / 5.0-5.0
    anaphylactoid reactions / Rapid / 0-1.0
    bradycardia / Rapid / 5.0
    nephrotic syndrome / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    stroke / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    angioedema / Rapid / 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
    hypoxia / Early / Incidence not known
    lymphadenopathy / Delayed / Incidence not known

    Mild

    infection / Delayed / 4.0-44.0
    chills / Rapid / 43.0-43.0
    headache / Early / 39.0-39.0
    fever / 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 (unspecified) / 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
    xerostomia / Early / 4.0-4.0
    nausea / Early / 5.0
    pallor / Early / 5.0
    vomiting / Early / 5.0
    abdominal pain / Early / 5.0
    diarrhea / Early / 5.0
    urticaria / Rapid / 5.0
    asthenia / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    lacrimation / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Amiodarone: (Minor) There are no known drug interactions with agalsidase beta; drug interactions studies were not performed. Theoretically, there is a possible drug interaction between agalsidase beta and amiodarone due to a risk of decreased intracellular alpha galactosidase A activity induced by amiodarone; coadministration of amiodarone with agalsidase beta is not recommended because a decreased response to agalsidase beta therapy could result.
    Chloroquine: (Moderate) Theoretically, there is a possible drug interaction between agalsidase beta and chloroquine due to a risk of decreased intracellular alpha galactosidase A activity induced by chloroquine.
    Gentamicin: (Moderate) Theoretically, there is a possible drug interaction between agalsidase beta and gentamicin due to a risk of decreased intracellular alpha galactosidase A activity induced by gentamicin.
    Hydroxychloroquine: (Moderate) Theoretically, there is a possible drug interaction between agalsidase beta and hydroxychloroquine due to a risk of decreased intracellular alpha galactosidase A activity induced by hydroxychloroquine.

    PREGNANCY AND LACTATION

    Pregnancy

    Agalsidase beta is a FDA pregnancy risk category B drug. Clinical data concerning use during pregnancy is absent. Since there are no adequate and well-controlled studies in pregnant women, its use is only recommended if clearly needed. A registry is available for pregnant women who receive the drug. Participation is voluntary. Information regarding the pregnancy registry may be obtained by visiting the manufacturer's website or by calling 800—745—4447.

    Data are limited regarding use of agalsidase beta during breast-feeding, and its excretion in human milk is unknown. The manufacturer recommends caution when administering to lactating women. However, because of its large molecular weight and short elimination half life, the probability of significant excretion in breast milk is unlikely. Additionally, because the drug is an enzyme and would likely be digested in the infants gastrointestinal tract, toxicity risk may be limited. A registry is available for lactating women who receive the drug. Participation is voluntary. Information regarding the registry may be obtained by visiting the manufacturer's website or by calling (800)—745—4447.

    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—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—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.