Elaprase

Mucopolysaccharidosis (MPS) Agents

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

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.

ventricular tachycardia / Early / 9.0-9.0
bronchospasm / Rapid / Incidence not known
cyanosis / Early / Incidence not known
seizures / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
respiratory arrest / Rapid / Incidence not known
pulmonary embolism / Delayed / Incidence not known

antibody formation / Delayed / 53.0-53.0
erythema / Early / 7.0-7.0
edema / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
wheezing / Rapid / Incidence not known
hypoxia / Early / Incidence not known
infusion-related reactions / Rapid / Incidence not known

fever / Early / 9.0-36.0
rash / Early / 16.0-32.0
arthralgia / Delayed / 31.0-31.0
headache / Early / 28.0-28.0
pruritus / Rapid / 25.0-25.0
infection / Delayed / 0-18.0
flushing / Rapid / 7.0-16.0
urticaria / Rapid / 16.0-16.0
vomiting / Early / 5.0-14.0
fatigue / Early / 13.0-13.0
chills / Rapid / 9.0-9.0
cough / Delayed / 9.0-9.0
diarrhea / Early / 9.0-9.0
dizziness / Early / 5.0-5.0
nausea / Early / 5.0-5.0

Elaprase

Rx

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.

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.

Safety and efficacy have not been established.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

There are no drug interactions associated with Idursulfase products.

Elaprase Intravenous Inj Sol: 3mL, 6mg

0.5 mg/kg IV infused every week.

0.5 mg/kg IV infused every week.

0.5 mg/kg IV infused every week.

>= 16 months: 0.5 mg/kg IV infused every week.
< 16 months: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.

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.

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.[49603]

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.[49603] 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.