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  • CLASSES

    Mucopolysaccharidosis (MPS) Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Purified form of human iduronate-2- sulfatase for the treatment of mucopolysaccharidosis II (Hunter syndrome).
    Serves as a replacement for the deficient enzyme in people with Hunter syndrome; first FDA-approved treatment for Hunter syndrome.
    Produced by recombinant DNA technology in a human cell line.

    COMMON BRAND NAMES

    Elaprase

    HOW SUPPLIED

    Elaprase Intravenous Inj Sol: 3mL, 6mg

    DOSAGE & INDICATIONS

    For the treatment of mucopolysaccharidosis II (Hunter syndrome).
    NOTE: Idursulfase has been designated as an orphan drug for this indication by the FDA.
    Intravenous infusion dosage
    Adults, Adolescents, and Children >= 16 months

    0.5 mg/kg/dose IV infusion once weekly, given over at least 1 hour. Among 96 patients 5 to 31 years of age with a documented deficiency in iduronate-2-sulfatase enzyme activity and a percent predicted forced vital capacity (FVC) less than 80%, greater improvement in the distance walked during a 6-minute walk test and in the percent predicted FVC from baseline to week 53 occurred in idursulfase recipients. Specifically, idursulfase recipients experienced a 35 meter greater mean increase in the distance walked as compared with placebo recipients. The mean percent predicted FVC improved 3.4% with idursulfase and 0.8% with placebo. The best time to initiate treatment and the optimal duration of treatment are unknown. Among patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long-term clinical outcome; however, treatment with idursulfase has reduced spleen volume similarly to that of adults and children aged 5 years or older.

    Neonates, Infants, and Children younger than 16 months

    Safety and efficacy have not been established.

    MAXIMUM DOSAGE

    Adults

    0.5 mg/kg IV infused every week.

    Geriatric

    0.5 mg/kg IV infused every week.

    Adolescents

    0.5 mg/kg IV infused every week.

    Children

    >= 16 months: 0.5 mg/kg IV infused every week.
    < 16 months: 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.

    ADMINISTRATION

    Injectable Administration

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

    Intravenous Administration

    Idursulfase is only given intravenously as an IV infusion by a health care professional.
    Question each recipient about any past reaction to idursulfase. When severe infusion reactions occurred during clinical studies, subsequent infusions were managed by use of antihistamines and/or corticosteroids before or during infusions, a slower rate administration, and/or early discontinuation of the infusion if serious symptoms developed. With these measures, no patient discontinued treatment permanently due to a hypersensitivity reaction.
     
    IV Infusion preparation
    Idursulfase is a clear to slightly opalescent, colorless solution that must be diluted in 0.9% Sodium Chloride Injection, USP before administration. Do not use if the solution in the vials is discolored or if particulate matter is present. Do not shake the solution.
    Determine the amount of drug solution needed to provide the dose. The number of needed drug vials is based on the patient's weight in kg times the recommended dose of 0.5 mg/kg. There are 6 mg of idursulfase per vial at a concentration of 2 mg/mL. Round up to determine the number of whole vials needed to provide the dose.
    Using aseptic technique, withdraw the calculated volume from the appropriate number of vials. Idursulfase does not contain preservatives; vials are for single use only. Discard any remaining drug left in a vial after withdrawing the patient's calculated dose.
    Slowly add the total calculated volume of idursulfase to the bag containing 100 mL of 0.9% Sodium Chloride Injection, USP. Mix gently, but do not shake.
    Storage of diluted injection: Diluted solutions should be used immediately. Idursulfase does not contain any preservatives. If immediate use is not possible, the diluted solution should be stored refrigerated for up to 24 hours at 2—8 degrees C (36—46 degrees F). Other than during infusion, do not store idursulfase at room temperature. Discard any unused product.
     
    IV Infusion administration
    Appropriate medical support measures need to be readily available during the infusion, as a severe infusion reaction may occur.
    Use of an infusion set equipped with a 0.2 mcm filter is recommended. Infuse in a dedicated line.
    Infuse at 8 mL/hour for the first 15 minutes. If the infusion is well tolerated, the rate may be increased by 8 mL/hour increments at 15 minute intervals in order to administer the full volume within the desired period of time. However, at no time should the infusion rate exceed 100 mL/hour. The total volume of the infusion may be administered over a period of 1—3 hours; infusion times should not exceed 8 hours.
    If the patient appears to be exhibiting any unusual reaction to the infusion such as flushing, fever, hives, irritability, rash, respiratory difficulty, and pulse or blood pressure alterations, immediately stop the infusion, and consult the prescribing physician. If infusion reactions occur, the infusion rate may be slowed, temporarily stopped, or discontinued for that visit. Base the decision on clinical judgment.
    After the drug solution has been infused, remove the bag from the IV administration set and replace with a bag containing 50 mL of 0.9% Sodium Chloride Injection, USP. Flush through the volume of drug remaining in the IV tubing to ensure full dosing.

    STORAGE

    Elaprase:
    - 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
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema, hypotension, infusion-related reactions, risk of serious hypersensitivity reactions or anaphylaxis

    Due to the risk of serious hypersensitivity reactions or anaphylaxis or infusion reactions, appropriate medical support and monitoring measures should be readily available during idursulfase infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. Life-threatening hypersensitivity reactions including respiratory distress, hypoxia, hypotension, angioedema, anaphylaxis, or urticaria have occurred during idursulfase infusions. Patients who developed IgG antibodies at any time had an increased incidence of infusion reactions including allergic reactions. Biphasic anaphylactic reactions have also been observed after drug administration, and patients who have experienced anaphylactic reactions may require prolonged observation. Anaphylactic reactions have been reported to occur during and up to 24 hours after idursulfase infusion. Immediately suspend the infusion and administer appropriate treatment if a severe reaction occurs. If appropriate, discontinue the infusion for that visit, or consider resuming the infusion at a slower rate. In clinical trials, when severe infusion-related reactions occurred, subsequent infusions were managed by pre-treatment with antihistamines and/or corticosteroids, a slower rate of administration, and/or early discontinuation of the infusion if serious symptoms developed. With these measures, no patient discontinued treatment permanently due to a hypersensitivity reaction. In the clinical trial of Hunter syndrome patients aged <= 7 years, those patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations experienced a higher incidence of hypersensitivity reactions, serious adverse reactions and antiidursulfase antibody development than Hunter syndrome patients with missense mutations.

    Acute bronchospasm, asthma, fever, respiratory depression, respiratory infection, respiratory insufficiency

    Life-threatening anaphylactic reactions, presenting as respiratory distress, hypoxia, and other events have occurred in some patients during and up to 24 hours after idursulfase infusions. Closely observe patients during and after administration and be prepared to manage these events. Patients with compromised respiratory function (e.g., asthma, acute bronchospasm) or acute illness with fever or acute respiratory illness may be at higher risk of life-threatening complications from hypersensitivity reactions, and require additional monitoring. Careful consideration should be given to the patient’s clinical status prior to administration and consider delaying the infusion. Administer idursulfase with extreme caution to patients with respiratory depression, respiratory insufficiency, or a respiratory infection. Appropriate medical support and monitoring measures should be readily available during idursulfase infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.

    Cardiac disease, heart failure, pulmonary edema

    Caution should be exercised when administering idursulfase to patients susceptible to fluid overload or patients with cardiac disease or respiratory disease for whom fluid restriction is indicated (e.g., heart failure, pulmonary edema). These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during idursulfase infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.

    Pregnancy

    Idursulfase is a FDA pregnancy risk category C drug. Clinical data concerning use during pregnancy is absent. The potential for idursulfase to cause fetal harm or to affect reproduction capacity is unknown. According to the manufacturer, idursulfase should be given to pregnant women only if clearly needed.

    Breast-feeding

    According to the manufacturer, it is not known whether idursulfase is excreted in human milk and caution should be exercised when the drug is administered to a breast-feeding woman. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and effectiveness of idursulfase in neonates, infants, or children < 16 months of age have not been established.

    Geriatric

    Clinical studies of idursulfase did not include patients older than 31 years of age. It is not known whether geriatric patients would respond differently from younger adult patients.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 22.0-22.0
    anaphylactic shock / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    cyanosis / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    pulmonary embolism / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 51.0-51.0
    hypertension / Early / 25.0-25.0
    wheezing / Rapid / 19.0-19.0
    infusion-related reactions / Rapid / 15.0-15.0
    edema / Delayed / 13.0-13.0
    hypotension / Rapid / Incidence not known
    hypoxia / Early / Incidence not known
    erythema / Early / Incidence not known

    Mild

    fever / Early / 63.0-63.0
    headache / Early / 59.0-59.0
    arthralgia / Delayed / 31.0-31.0
    pruritus / Rapid / 28.0-28.0
    malaise / Early / 22.0-22.0
    urticaria / Rapid / 16.0-16.0
    myalgia / Early / 16.0-16.0
    rash (unspecified) / Early / 13.0-13.0
    anxiety / Delayed / 13.0-13.0
    irritability / Delayed / 13.0-13.0
    dyspepsia / Early / 13.0-13.0
    infection / Delayed / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Idursulfase products.

    PREGNANCY AND LACTATION

    Pregnancy

    Idursulfase is a FDA pregnancy risk category C drug. Clinical data concerning use during pregnancy is absent. The potential for idursulfase to cause fetal harm or to affect reproduction capacity is unknown. According to the manufacturer, idursulfase should be given to pregnant women only if clearly needed.

    According to the manufacturer, it is not known whether idursulfase is excreted in human milk and caution should be exercised when the drug is administered to a breast-feeding woman. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Idursulfase is a recombinant, exogenous form of iduronate-2-sulfatase that breaks down accumulated glycosaminoglycans (GAG). Normally, iduronate-2-sulfatase hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the GAG dermatan sulfate and heparan sulfate in the lysosomes of various cell types. The exogenous enzyme, idursulfase, enters cells through mannose-6-phosphate (M6P) residues on the oligosaccharide chains. Specific binding of idursulfase to the M6P receptors on the cell surface leads to cellular internalization of the enzyme and uptake into cellular lysosomes. The enzyme activity of idursulfase is dependent on the post-translational modification of a specific cysteine to formylglycine. Idursulfase has a specific activity of 46 units/mg to 74 units/mg of protein, and one unit is defined as the amount of enzyme required to hydrolyze 1 micromole of heparin disaccharide substrate per hour under the specified assay conditions.

    PHARMACOKINETICS

    Idursulfase is administered as an intravenous infusion. The pharmacokinetic characteristics of idursulfase were evaluated in patients with Hunter syndrome. The serum concentration of idursulfase was quantified using an antigen-specific ELISA assay.
     
    Decreases in urinary GAG levels were observed following treatment with idursulfase. The responsiveness of urinary GAG to dosage alterations of idursulfase is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. Patients who tested positive for anti-idursulfase antibodies (Ab) experienced a less pronounced decrease in urinary GAG levels. In patients who remained Ab negative, sustained reductions in both liver and spleen volumes were observed following treatment with idursulfase.

    Intravenous Route

    The pharmacokinetics (PK) of intravenous idursulfase were evaluated in two separate studies.
     
    In the first study, PK values were reported for older children and adult patients 7.7 to 27 years of age (n = 10). The PK parameters at the recommended dose regimen (0.5 mg/kg administered weekly as a 3-hour infusion) were determined at Week 1 and 27, respectively, as follows: Cmax = 1.5 mcg/mL and 1.1 mcg/mL, AUC = 206 minute x mcg/mL and 169 minute x mcg/mL, T1/2 = 44 min and 48 min, Clearance = 3 mL/minute/kg and 3.4 mL/minute/kg. There were no apparent differences in PK parameter values between Week 1 and Week 27 regardless of the antibody status in these patients.
     
    In the second study, younger pediatric patients aged 16 months to 7.5 years (n = 27) were evaluated. The presence of anti-idursulfase antibody (Ab), defined as having at least one serum specimen with measurable antibody during study duration, was associated with a reduced systemic exposure of idursulfase. At the above recommended dose, the PK parameters were as follows at Week 1: Cmax = 1.33 mcg/mL, AUC = 224 minute x mcg/mL, T1/2 = 160 min, Clearance = 2.4 mL/minute/kg. At Week 27, Negative Ab (n = 9) and Positive Ab (n = 10) PK parameters, respectively, were as follows: Cmax = 1.4 mcg/mL and 0.706 mcg/mL, AUC = 281 minute x mcg/mL and 122 minute x mcg/mL, T1/2 = 134 min and 84 min, Clearance = 2 mL/minute/kg and 7.4 mL/minute/kg. All patients with the complete gene deletion or large gene rearrangement genotype (n = 8) developed Ab at Week 27. Five of these eight patients had no measurable idursulfase concentrations at Week 27, and three had a lower systemic exposure at Week 27 compared to Week 1.