Idursulfase, a purified form of human iduronate-2-sulfatase, is for the treatment of Hunter syndrome, which is also called mucopolysaccharidosis (MPS) II. Patients with the syndrome do not produce enough of a functional lysosomal enzyme called iduronate-2-sulfatase because of a a genetic defect. The deficiency of iduronate-2-sulfatase production causes an accumulation of glycosaminoglycans in cells throughout the body. The buildup of these carbohydrates produces a variety of physical and neurological problems including abnormal bone and joint growth, respiratory problems, learning disabilities, and hearing loss. Many people with severe MPS II die during early adolescence, but people with milder forms of the disorder can live well into adulthood. Idursulfase serves as a replacement for the deficient enzyme in people with MPS II. Idursulfase is produced by recombinant DNA technology in a human cell line and is the first treatment for Hunter syndrome. A Hunter outcome survey has been established in order to understand better the variability and progression of Hunter syndrome in the population as a whole and to monitor and evaluate long-term treatment effects of idursulfase. Patients and their physicians are encouraged to participate in this program. For more information, visit the official Elaprase website or call 1-866-888-0660. Idursulfase was FDA-approved in July 2006.
General Administration Information
For storage information, see the 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
-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.
Serious hypersensitivity reactions or anaphylaxis, including life-threatening reactions, has been reported with idursulfase therapy. Reactions included respiratory distress, hypoxia, hypotension, urticaria, and angioedema. During 26 of 8,274 infusions (0.3%) in clinical trials, 16 of 108 (15%) patients experienced infusion-related reactions that involved adverse events in at least two of the following three body systems: cutaneous, respiratory, or cardiovascular. Of these 16 patients, 11 experienced significant hypersensitivity reactions during 19 of 8,274 infusions (0.2%) with symptoms of bronchospasm, cyanosis, dyspnea, erythema, edema (facial and peripheral), flushing, rash, respiratory distress, urticaria, vomiting, and wheezing. One of these episodes occurred in a patient with a tracheostomy and severe airway disease who received an infusion while he had a pre-existing febrile illness and then experienced respiratory distress, hypoxia, cyanosis, and seizures with loss of consciousness. As hypersensitivity reactions may be life threatening, appropriate medical support should be readily available when idursulfase is administered. 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 treatment. If a severe infusion reaction occurs, immediately suspend the infusion, and initiate appropriate treatment. Consider resuming the infusion at a slower rate or discontinuing the infusion for that visit. During clinical studies, subsequent infusions were managed by use of antihistamines and/or corticosteroids before or during infusions, a slower rate of administration, and/or early discontinuation of the idursulfase infusion if serious symptoms developed. With these measures, no patient discontinued treatment permanently due to a hypersensitivity reaction. One patient with Hunter syndrome, who received idursulfase at twice the recommended dosage for 1.5 years, experienced 2 anaphylactic reactions over a 3-month period 4.5 years after the initiation of idursulfase. In postmarketing reports, patients receiving idursulfase experienced anaphylactic reactions up to several years after initiating treatment. Some patients were reported to have repeated anaphylactic events over a two- to four-month time period. Medical management included treatment with antihistamines, inhaled beta-adrenergic agonists, corticosteroids, oxygen, and vasopressors. Treatment was discontinued for some patients, while others continued treatment with premedication and a slower infusion rate. The most common hypersensitivity and infusion-related reactions reported with idursulfase were headache, fever, flushing, and cutaneous reactions such as rash, pruritus, and urticaria. Among 64 patients who received idursulfase 0.5 mg/kg weekly for 53 weeks, the following adverse reactions were reported: headache (28% vs. 25% placebo), pruritus (25% vs. 9% placebo), and urticaria (16% vs. 0% placebo). Additional adverse reactions that were reported with a higher incidence in the idursulfase 0.5 mg/kg every other week group than in the placebo group included rash (16%), flushing (16%), fatigue (13%), ventricular tachycardia (9%), and chills (9%). In an open-label extension trial in 94 patients receiving idursulfase 0.5 mg/kg once weekly for 24 months, the following reactions were reported: hypersensitivity reaction (53%), rash (23%), fever (9%), flushing (7%), erythema (7%), and dizziness (5%). Additionally, hypersensitivity reactions (57%), fever (36%), and rash (32%) were reported in pediatric patients (16 months to 4 years (n = 20); 5 to 7.5 years (n = 8)), who received idursulfase 0.5 mg/kg weekly for 53 weeks.
In clinical studies, the most frequent serious adverse events were hypoxic episodes. Other serious adverse reactions that occurred in idursulfase recipients but not in placebo recipients included one case each of cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory arrest, infection, and arthralgia. Serious adverse reactions that resulted in death included cardiorespiratory arrest, respiratory failure, respiratory distress, cardiac failure, and pneumonia. Musculoskeletal pain (13% vs. 3% placebo), cough (9% vs. 3% placebo), bronchopneumonia/pneumonia (18%), and ear infection (11%) were reported during idursulfase clinical trials.
Gastrointestinal adverse events reported with idursulfase treatment during clinical trials include nausea, vomiting, and diarrhea. Diarrhea occurred in 9% (vs. 3% placebo) of patients (n = 64) who received idursulfase 0.5 mg/kg weekly for 53 weeks. Nausea (5%) and vomiting (5%) were reported in an open-label extension trial involving 94 patients receiving idursulfase 0.5 mg/kg once weekly for 24 months. Vomiting (14%) was also reported in pediatric patients (16 months to 4 years (n = 20); 5 to 7.5 years (n = 8)), who received idursulfase 0.5 mg/kg weekly for 53 weeks.
Anti-idursulfase IgG antibody formation occurred in 32 (53%) of 63 patients 5 years and older who received idursulfase 0.5 mg/kg weekly. Of the 32 antibody (Ab)-positive patients, 23 (72%) tested positive for Ab at 3 or more different time points (persistent Ab). The incidence of hypersensitivity reactions was higher in patients who tested positive for Ab than those who tested negative. Sera from 13 (41%) out of 32 anti-idursulfase antibody positive patients were positive for antibodies that neutralize idursulfase uptake into cells (uptake neutralizing antibodies, uptake NAb) or enzymatic activity (activity NAb) at least one time, and 8 (25%) of Ab-positive patients had persistent NAb. In pediatric patients 7 years and younger with Hunter syndrome, all 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations developed anti-idursulfase antibodies, compared to only 3 (out of 13) patients with the missense mutation. Thirteen patients with these mutations developed NAb, compared to only one patient with the missense mutation. The presence of Ab was associated with reduced systemic idursulfase exposure. The relationship between the presence of anti-idursulfase antibodies and clinical efficacy outcomes is unknown. The data reflect the percentage of patients whose test results were positive for antibodies to idursulfase in specific assays and are highly dependent on the sensitivity and specificity of these assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to idursulfase with the incidence of antibodies to other products may be misleading.
Due to the risk of infusion-related reactions, including serious hypersensitivity reactions or anaphylaxis, 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 or younger, 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 anti-idursulfase antibody development than Hunter syndrome patients with missense mutations.
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.
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.
There are no adequate and well-controlled studies with idursulfase use in pregnant women. Data available from a small number of postmarketing cases with idursulfase use in pregnancy are insufficient to inform a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal data in pregnant rats did not reveal evidence of adverse effects on pre- and post-natal development from gestation day 6 through lactation day 19 with twice weekly intravenous administration of idursulfase doses up to 12.5 mg/kg, about 4 times the recommended human weekly dose.
There are no data on the presence of idursulfase in human milk, the effects on a breast-fed infant, or the effects on milk production. Idursulfase was excreted in the breast milk of lactating rats. 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.
The safety and effectiveness of idursulfase in neonates, infants, or children < 16 months of age have not been established.
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.
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 Limits:
-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.
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 Idursulfase products.
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.
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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Geriatric
Clinical studies of idursulfase did not include patients older than 31 years of age. It is not known whether older adults respond differently from younger patients.