ELAPRASE
商品名：idursulfase
黏多醣症第二型患者用藥
ELAPRASE is a formulation of idursulfase, a purified form of human iduronate-2-
sulfatase, a lysosomal enzyme. Idursulfase is produced by recombinant DNA technology
in a human cell line. Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of
terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and
heparan sulfate in the lysosomes of various cell types.
Idursulfase is a 525-amino acid glycoprotein with a molecular weight of approximately
76 kilodaltons. The enzyme contains eight asparagine-linked glycosylation sites occupied
by complex oligosaccharide structures. The enzyme activity of idursulfase is dependent
on the post-translational modification of a specific cysteine to formylglycine. Idursulfase
has a specific activity ranging from 41 to 77 U/mg of protein (one unit is defined as
the amount of enzyme required to hydrolyze 1 μmole of heparin disaccharide substrate
per hour under the specified assay conditions).
ELAPRASE is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic,
clear to slightly opalescent, colorless solution that must be diluted prior to administration
in 0.9% Sodium Chloride Injection, USP. Each vial contains an extractable volume of
3.0 mL with an idursulfase concentration of 2.0 mg/mL at a pH of approximately 6,
providing 6.0 mg idursulfase, 24.0 mg sodium chloride, 6.75 mg sodium phosphate
monobasic monohydrate, 2.97 mg sodium phosphate dibasic heptahydrate, and 0.66 mg
polysorbate 20. ELAPRASE does not contain preservatives; vials are for single use only.
CLINICAL PHARMACOLOGY
Mechanism of Action
Hunter syndrome (Mucopolysaccharidosis II, MPS II) is an X-linked recessive disease
caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme
cleaves the terminal 2-0-sulfate moieties from the glycosaminoglycans (GAG) dermatan
sulfate and heparan sulfate. Due to the missing or defective iduronate-2-sulfatase
enzyme in patients with Hunter syndrome, GAG progressively accumulate in the lysosomes
of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction,
and organ system dysfunction.
Treatment of Hunter syndrome patients with ELAPRASE provides exogenous enzyme
for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the
oligosaccharide chains allow specific binding of the enzyme to the M6P receptors on
the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular
lysosomes and subsequent catabolism of accumulated GAG.
Pharmacokinetics
The pharmacokinetic characteristics of idursulfase were evaluated in several studies in
patients with Hunter syndrome. The serum concentration of idursulfase was quantified
using an antigen-specific ELISA assay. The area under the concentration-time curve
(AUC) increased in a greater than dose proportional manner as the dose increased
from 0.15 mg/kg to 1.5 mg/kg following a single 1-hour infusion of ELAPRASE. The
pharmacokinetic parameters at the recommended dose regimen (0.5 mg/kg ELAPRASE
administered weekly as a 3-hour infusion) were determined at Week 1 and Week 27 in
10 patients ages 7.7 to 27 years (Table 1). There were no apparent differences in PK
parameter values between Week 1 and Week 27.
INDICATIONS AND USAGE
ELAPRASE is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II,
MPS II). ELAPRASE has been shown to improve walking capacity in these patients.
CONTRAINDICATIONS
None.
WARNINGS
Hypersensitivity Reactions (see BOXED WARNING)
Hypersensitivity reactions, which may be life-threatening, have been observed in some
patients during ELAPRASE infusions. Reactions have included respiratory distress,
hypoxia, hypotension, angioedema, or seizure. In clinical trials with ELAPRASE, 16/108
patients (15%) experienced infusion reactions during 26 of 8274 infusions (0.3%) 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 8274 infusions (0.2%). One of these episodesoccurred in a patient with a tracheostomy and severe airway disease, who received
an ELAPRASE infusion while he had a pre-existing febrile illness, and then experienced
respiratory distress, hypoxia, cyanosis, and seizure with loss of consciousness.
Because of the potential for severe infusion reactions, appropriate medical support
should be readily available when ELAPRASE is administered.
When severe infusion reactions occurred during clinical studies, subsequent infusions
were managed by use of antihistamines and/or corticosteroids prior to or during infusions,
a slower rate of ELAPRASE administration, and/or early discontinuation of the ELAPRASE
infusion if serious symptoms developed. With these measures, no patient discontinued
treatment permanently due to a hypersensitivity reaction.
Patients with compromised respiratory function or acute respiratory disease may be at
higher risk of life-threatening complications from infusion reactions. Consider delaying
the ELAPRASE infusion in patients with concomitant acute respiratory and/or febrile illness.
If a severe infusion reaction occurs, immediately suspend the infusion of ELAPRASE and
initiate appropriate treatment, depending on the severity of the symptoms. Consider
resuming the infusion at a slower rate, or, if the reaction is serious enough to warrant it,
discontinue the ELAPRASE infusion for that visit.
PRECAUTIONS
Information for Patients
A Hunter Outcome Survey has been established in order to understand better the variability
and progression of Hunter syndrome (MPS II) in the population as a whole, and to monitor
and evaluate long-term treatment effects of ELAPRASE. Patients and their physicians are
encouraged to participate in this program. For more information, visit www.elaprase.com or
call OnePathSM at 1-866-888-0660 .
Drug Interactions
No formal drug interaction studies have been conducted with ELAPRASE.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate
mutagenic potential have not been performed with ELAPRASE.
ELAPRASE at intravenous doses up to 5 mg/kg, administered twice weekly (about 1.6 times
the recommended human weekly dose based on body surface area) had no effect on fertility
and reproductive performance in male rats.
Pregnancy: Teratogenic Effects: Category C
Reproduction studies in pregnant female animals have not been conducted with ELAPRASE.
It is also not known whether ELAPRASE can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. ELAPRASE should be given to
pregnant women only if clearly needed.
Nursing Mothers
It is not known whether this product is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when ELAPRASE is administered
to a nursing woman.
Pediatric Use
Patients in the clinical studies were age 5 and older (see CLINICAL STUDIES). Children,
adolescents, and adults responded similarly to treatment with ELAPRASE. Safety and
efficacy have not been established in pediatric patients less than 5 years of age.
Geriatric Use
Clinical studies of ELAPRASE did not include patients aged 65 or over. It is not known
whether geriatric patients respond differently from younger patients.
ADVERSE REACTIONS
The most common adverse reactions requiring intervention were infusion-related reactions
(see BOXED WARNING and WARNINGS).
In clinical studies, the most frequent serious adverse events related to the use of ELAPRASE
were hypoxic episodes. Other notable serious adverse reactions that occurred in the
ELAPRASE treated patients but not in the placebo patients included one case each of:
cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection,
and arthralgia.
Adverse reactions were commonly reported in association with infusions. The most common
infusion-related reactions were headache, fever, cutaneous reactions (rash, pruritus,
erythema, and urticaria), and hypertension. The frequency of infusion-related reactions
decreased over time with continued ELAPRASE treatment.
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a product cannot be directly compared to rates in
the clinical trials of another product and may not reflect the rates observed in practice.
Table 3 enumerates those adverse reactions that were reported during the 53-week,
placebo-controlled study that occurred in at least 10% of patients treated with
ELAPRASE weekly administration, and that occurred more frequently than in the
placebo patients. The most common (>30%) adverse reactions were pyrexia, headache,
and arthralgia.
OVERDOSAGE
There is no experience with overdosage of ELAPRASE in humans. Single intravenous
doses of idursulfase up to 20 mg/kg were not lethal in male rats and cynomolgus
monkeys (approximately 6.5 and 13 times, respectively, of the recommended human
dose based on body surface area) and there were no clinical signs of toxicity.
DOSAGE AND ADMINISTRATION
The recommended dosage regimen of ELAPRASE is 0.5 mg/kg of body weight administered
every week as an intravenous infusion.
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