CLASSES
Mucopolysaccharidosis (MPS) Agents
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
- Discard unused portion. Do not store for later use.
- Protect from freezing
- Protect from light
- Refrigerate (between 36 and 46 degrees F)
- Store in carton
CONTRAINDICATIONS / PRECAUTIONS
Angioedema, hypotension, infusion-related reactions, serious hypersensitivity reactions or anaphylaxis
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.
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
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]
Breast-feeding
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.
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
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
Moderate
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
Mild
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
DRUG INTERACTIONS
There are no drug interactions associated with Idursulfase products.
PREGNANCY AND LACTATION
Pregnancy
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.
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.