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US/ELA-00548(1)-Aug13 

 

 

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ELAPRASE
safely and effectively. See full prescribing information for ELAPRASE.

ELAPRASE® (idursulfase) injection, for intravenous use
Initial U.S. Approval: 2006

WARNING: RISK OF ANAPHYLAXIS

See full prescribing information for complete boxed warning

Life-threatening anaphylactic reactions, presenting as
respiratory distress, hypoxia, hypotension, urticaria and/or
angioedema of throat or tongue have occurred in some
patients during and up to 24 hours after ELAPRASE
infusions. Closely observe patients during and after
ELAPRASE administration and be prepared to manage
anaphylaxis. Inform patients of the signs and symptoms of
anaphylaxis and have them seek immediate medical care
should symptoms occur. Patients with compromised
respiratory function or acute respiratory disease may be at
risk of serious acute exacerbation of their respiratory
compromise due to hypersensitivity reactions, and require additional monitoring. (5.1, 5.3, 6)

------------------------------RECENT MAJOR CHANGES------------------------------

Boxed Warning 06/2013
Indication and Usage (1) 06/2013
Warnings and Precautions  
    Hypersensitivity Reactions Including Anaphylaxis (5.1) 06/2013
    Risk of Hypersensitivity Reactions, Serious Adverse
    Reactions and Antibody Development in Hunter Syndrome
 
    Patients with Severe Genetic Mutations (5.2) 06/2013
    Risk of Acute Cardiorespiratory Failure (5.4) 06/2013

------------------------------INDICATIONS AND USAGE------------------------------

ELAPRASE is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme
indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II).
ELAPRASE has been shown to improve walking capacity in patients 5 years and
older. In 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 ELAPRASE has reduced spleen volume similarly to that of adults
and children 5 years of age and older. The safety and efficacy of ELAPRASE have
not been established in pediatric patients less than 16 months of age (1).

-------------------------DOSAGE AND ADMINISTRATION----------------------------

  • 0.5 mg per kg of body weight administered once every week as an intravenous
    infusion (2).

------------------DOSAGE FORMS AND STRENGTHS-------------------

  • Injection: 6 mg/3 mL (2 mg/mL) in single-use vial (3)

---------------------------CONTRAINDICATIONS--------------------------

  • None (4)

--------------------WARNINGS AND PRECAUTIONS--------------------

  • Hypersensitivity Reactions Including Anaphylaxis: Ensure that
    personnel administering product are adequately trained in cardio-
    pulmonary resuscitative measures, and have ready access to
    emergency medical services (EMS) (5.1).
  • Risk of Hypersensitivity, Serious Adverse Reactions, and
    Antibody Development in Hunter Syndrome Patients with Severe
    Genetic Mutations:
    Hunter syndrome patients aged 7 years and
    younger 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 (5.2).
  • Risk of Acute Respiratory Complications: Patients with
    compromised respiratory function or acute febrile or respiratory
    illness may be at higher risk of life-threatening complications from
    hypersensitivity reactions. Careful consideration should be given
    to the patient’s clinical status prior to administration of
    ELAPRASE and consider delaying the ELAPRASE infusion (5.3)

--------------------------ADVERSE REACTIONS---------------------------

The most common adverse reactions occurring in at least three patients
(≥9%) aged five years and older were headache, pruritus,
musculoskeletal pain, urticaria, diarrhea, and cough. The most common
adverse reactions occurring in at least three patients (≥10%) aged seven
years and younger were pyrexia, rash, vomiting, and urticaria. In all
clinical trials, the most common adverse reactions requiring medical
intervention were hypersensitivity reactions, and included rash, urticaria,
pruritus, flushing, pyrexia, and headache (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Shire
Medical Information at 1-866-888-0660 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 06/2013


FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: RISK OF ANAPHYLAXIS
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
   2.1 Recommended Dose
   2.2 Preparation Instructions
   2.3 Administration Instructions
   2.4 Storage and Stability
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
   5.1 Hypersensitivity Reactions Including Anaphylaxis
   5.2 Risk of Hypersensitivity, Serious Adverse Reactions, and Antibody
         Development in Hunter Syndrome Patients with Severe Genetic
         Mutations
   5.3 Risk of Acute Respiratory Complications
   5.4 Risk of Acute Cardiorespiratory Failure
6 ADVERSE REACTIONS
   6.1 Clinical Trials Experience
   6.2 Immunogenicity
   6.3 Postmarketing Experience

8  USE IN SPECIFIC POPULATIONS
    8.1 Pregnancy
    8.3 Nursing Mothers
    8.4 Pediatric Use
    8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
    12.1 Mechanism of Action
    12.2 Pharmacodynamics
    12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
    14.1 Clinical Trials in Patients 5 Years and Older
    14.2 Clinical Trial in Patients 7 Years and Younger
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are
not listed.


FULL PRESCRIBING INFORMATION

WARNING: RISK OF ANAPHYLAXIS

Life-threatening anaphylactic reactions have occurred in some patients during and up to
24 hours after ELAPRASE infusions. Anaphylaxis, presenting as respiratory distress,
hypoxia, hypotension, urticaria and/or angioedema of throat or tongue have been
reported to occur during and after ELAPRASE infusions, regardless of duration of the
course of treatment. Closely observe patients during and after ELAPRASE
administration and be prepared to manage anaphylaxis. Inform patients of the signs
and symptoms of anaphylaxis and have them seek immediate medical care should
symptoms occur. Patients with compromised respiratory function or acute respiratory
disease may be at risk of serious acute exacerbation of their respiratory compromise due
to hypersensitivity reactions, and require additional monitoring [see Warnings and
Precautions (5.1, 5.3) and Adverse Reactions (6)
].

1 INDICATIONS AND USAGE

ELAPRASE is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II).
ELAPRASE has been shown to improve walking capacity in patients 5 years and older.

In 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 ELAPRASE
has reduced spleen volume similarly to that of adults and children 5 years of age and older.

The safety and efficacy of ELAPRASE have not been established in pediatric patients less than
16 months of age [see Use in Specific Populations (8.4)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dosage regimen of ELAPRASE is 0.5 mg per kg of body weight administered
once weekly as an intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.

2.2 Preparation Instructions

Prepare and use ELAPRASE according to the following steps using aseptic technique:

  1. Determine the total volume of ELAPRASE to be administered and the number of vials
    needed based on the patient’s weight and the recommended dose of 0.5 mg/kg.
    Patient’s weight (kg) x 0.5 mg per kg of ELAPRASE ÷ 2 mg per mL =
    Total mL of ELAPRASE

    Total mL of ELAPRASE ÷ 3 mL per vial = Total number of vials
    Round up to the next whole vial to determine the total number of vials needed. Remove
    the required number of vials from the refrigerator to allow them to reach room
    temperature.
  2. Before withdrawing the ELAPRASE solution from the vial, visually inspect each vial for
    particulate matter and discoloration. The ELAPRASE solution should be clear to slightly
    opalescent and colorless. Do not use if the solution is discolored or if there is particulate
    matter in the solution. Do not shake the ELAPRASE solution.
  3. Withdraw the calculated volume of ELAPRASE from the appropriate number of vials.
  4. Add the calculated volume of ELAPRASE solution to a 100 mL bag of 0.9% Sodium
    Chloride Injection, USP for intravenous infusion.
  5. Mix gently. Do not shake the solution.

2.3 Administration Instructions

Administer the diluted ELAPRASE solution to patients using a low-protein-binding infusion set
equipped with a low-protein-binding 0.2 micrometer (μm) in-line filter.

The total volume of infusion should be administered over a period of 3 hours, which may be
gradually reduced to 1 hour if no hypersensitivity reactions are observed. Patients may require
longer infusion times if hypersensitivity reactions occur; however, infusion times should not
exceed 8 hours. The initial infusion rate should be 8 mL per hour for the first 15 minutes. If the
infusion is well tolerated, the rate of infusion may be increased by 8 mL per hour increments
every 15 minutes. The infusion rate should not exceed 100 mL per hour. The infusion rate may
be slowed, temporarily stopped, or discontinued for that visit in the event of hypersensitivity
reactions [see Warnings and Precautions (5.1)]. ELAPRASE should not be infused with other
products in the infusion tubing.

2.4 Storage and Stability

ELAPRASE does not contain preservatives; therefore, after dilution with saline, the infusion
bags should be used immediately. If immediate use is not possible, the diluted solution should be
stored refrigerated at 2°C to 8°C (36°F to 46 °F) for up to 24 hours. Other than during infusion,
do not store the diluted ELAPRASE solution at room temperature. Any unused product or waste
material should be discarded and disposed of in accordance with local requirements.

3 DOSAGE FORMS AND STRENGTHS

Injection: 6 mg/3 mL (2 mg/mL) in single-use vials

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions Including Anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, have occurred during and up to 24
hours after infusion. Some of these reactions were life-threatening and included respiratory
distress, hypoxia, hypotension, urticaria, and angioedema of the throat or tongue, regardless of
duration of the course of treatment.

If anaphylactic or other acute reactions occur, immediately discontinue the infusion of
ELAPRASE and initiate appropriate medical treatment. When severe reactions have occurred
during clinical trials, subsequent infusions were managed with antihistamine and/or
corticosteroids prior to or during infusions, a slower rate of ELAPRASE infusion, and/or early
discontinuation of the ELAPRASE infusion [see Adverse Reactions (6)].

In clinical trials with ELAPRASE, 16 of 108 (15%) patients experienced hypersensitivity
reactions during 26 of 8,274 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 anaphylactic 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.

In postmarketing reports, patients receiving ELAPRASE 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.

Due to the potential for severe reactions, appropriate medical support should be readily available
when ELAPRASE is administered. Observe patients closely for an appropriate period of time
after administration of ELAPRASE, taking into account the time to onset of anaphylaxis seen in
premarketing clinical trials and postmarketing reports. Inform patients of the signs and
symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and
symptoms occur.

5.2 Risk of Hypersensitivity, Serious Adverse Reactions, and Antibody Development in
Hunter Syndrome Patients with Severe Genetic Mutations

In the clinical trial of Hunter syndrome patients aged 7 years and younger, 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.
Eleven of 15 (73%) patients with complete gene deletion, large gene rearrangement, nonsense,
frameshift or splice site mutations and five of 12 (42%) patients with missense mutations
experienced hypersensitivity reactions. Nine of 15 (60%) patients with complete gene deletion,
large gene rearrangement, nonsense, frameshift or splice site mutations and two of 12 (17%)
patients with missense mutations had serious adverse reactions. All 15 patients with complete
gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations developed
anti-idursulfase (ELAPRASE) antibodies, compared to only 3 patients with missense mutations
(Table 2). Thirteen patients with these mutations developed neutralizing antibodies, which
interfere with ELAPRASE uptake into the cell or ELAPRASE enzyme activity, compared to
only one patient with missense mutation [see Warnings and Precautions (5.1), Adverse
Reactions (6.1, 6.2) and Use in Specific Populations (8.4)]
.

5.3 Risk of Acute Respiratory Complications

Patients with compromised respiratory function or acute febrile or respiratory illness at the time
of ELAPRASE infusion may be at higher risk of life-threatening complications from
hypersensitivity reactions. Careful consideration should be given to the patient’s clinical status
prior to administration of ELAPRASE and consider delaying the ELAPRASE infusion. One
patient with a tracheostomy, severe airway disease and acute febrile illness experienced
respiratory distress, hypoxia, cyanosis, and seizure with a loss of consciousness during
ELAPRASE infusion.

5.4 Risk of Acute Cardiorespiratory Failure

Caution should be exercised when administering ELAPRASE to patients susceptible to fluid
overload, or patients with acute underlying respiratory illness or compromised cardiac and/or
respiratory function for whom fluid restriction is indicated. 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 ELAPRASE infusion, and
some patients may require prolonged observation times that should be based on the individual
needs of the patient [see Adverse Reactions (6.1, 6.3)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.

The following serious adverse reactions are described below and elsewhere in the labeling:

In clinical trials, the most common adverse reactions (>10%) following ELAPRASE treatment
were hypersensitivity reactions, and included rash, urticaria, pruritus, flushing, pyrexia, and
headache. Most hypersensitivity reactions requiring intervention were ameliorated with slowing
of the infusion rate, temporarily stopping the infusion, with or without administering additional
treatments including antihistamines, corticosteroids or both prior to or during infusions.

In clinical trials, the most frequent serious adverse reactions following ELAPRASE treatment were
hypoxic episodes. Other notable serious adverse reactions that occurred in the ELAPRASE-treated
patients but not in the placebo-treated patients included one case each of: cardiac arrhythmia,
pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia.

Clinical Trials in Patients 5 Years and Older

A 53-week, double-blind, placebo-controlled clinical trial of ELAPRASE was conducted in 96
male patients with Hunter syndrome, ages 5-31 years old. Of the 96 patients, 83% were White,
non-Hispanic. Patients were randomized to three treatment groups, each with 32 patients:
ELAPRASE 0.5 mg/kg once weekly, ELAPRASE 0.5 mg/kg every other week, or placebo.
Hypersensitivity reactions were reported in 69% (22 of 32) of patients who received once-weekly
treatment of ELAPRASE.

Table 1 summarizes the adverse reactions that occurred in at least 9% of patients (≥3 patients) in
the ELAPRASE 0.5 mg/kg once weekly group and with a higher incidence than in the placebo
group.

Table 1. Adverse Reactions that Occurred in the Placebo-Controlled Trial in At Least
9% of Patients in the ELAPRASE 0.5 mg/kg Once Weekly Group and with a Higher
Incidence than in the Placebo Group (5 Years and Older)

Additional adverse reactions that occurred in at least 9% of patients (≥3 patients) in the
ELAPRASE 0.5 mg/kg every other week group and with a higher incidence than in the placebo
group included: rash (19%), flushing (16%), fatigue (13%), tachycardia (9%), and chills (9%).

Extension Trial

An open-label extension trial was conducted in patients who completed the placebo-controlled
trial. Ninety-four of the 96 patients who were enrolled in the placebo-controlled trial consented
to participate in the extension trial. All 94 patients received ELAPRASE 0.5 mg/kg once weekly
for 24 months. No new serious adverse reactions were reported. Approximately half (53%) of
patients experienced hypersensitivity reactions during the 24-month extension trial. In addition
to the adverse reactions listed in Table 1, common hypersensitivity reactions occurring in at least
5% of patients (≥ 5 patients) in the extension trial included: rash (23%), pyrexia (9%), flushing
(7%), erythema (7%), nausea (5%), dizziness (5%), vomiting (5%), and hypotension (5%).

Clinical Trial in Patients 7 Years and Younger

A 53-week, open-label, single-arm, safety trial of once weekly ELAPRASE 0.5 mg/kg treatment
was conducted in patients with Hunter syndrome, ages 16 months to 4 years old (n=20) and ages
5 to 7.5 years old (n=8) at enrollment. Patients experienced similar adverse reactions as those
observed in clinical trials in patients 5 years and older, with the most common adverse reactions
following ELAPRASE treatment being hypersensitivity reactions (57%). A higher incidence of
the following common hypersensitivity reactions were reported in this younger age group:
pyrexia (36%), rash (32%) and vomiting (14%). The most common serious adverse reactions
occurring in at least 10% of patients (≥ 3 patients) included: bronchopneumonia/pneumonia
(18%), ear infection (11%), and pyrexia (11%).

Twenty-seven patients had results of genotype analysis: 15 patients had complete gene deletion,
large gene rearrangement, nonsense, frameshift or splice site mutations and 12 patients had
missense mutations.

Safety results demonstrated that patients with complete gene deletion, large gene rearrangement,
nonsense, frameshift, or splice site mutations are more likely to experience hypersensitivity
reactions and have serious adverse reactions following ELAPRASE administration, compared to
patients with missense mutations. Table 2 summarizes these findings.

Table 2. Impact of Antibody Status and Genetic Mutations on Occurrence of Serious
Adverse Reactions and Hypersensitivity in Patients 7 Years and Younger Treated with
ELAPRASE

* Serious adverse reactions included: bronchopneumonia/pneumonia, ear infection, and pyrexia [see Adverse
Reactions (6.1)]
.

6.2 Immunogenicity

Clinical Trials in Patients 5 Years and Older

As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials in
patients 5 years and older, 63 of the 64 patients treated with ELAPRASE 0.5 mg/kg once weekly
or placebo for 53 weeks, followed by ELAPRASE 0.5 mg/kg once weekly in the extension trial,
had immunogenicity data available for analysis. Of the 63 patients, 32 (51%) patients tested
positive for anti-idursulfase IgG antibodies (Ab) at least one time (Table 2). Of the 32 Ab-positive
patients, 23 (72%) tested positive for Ab at three 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.

Thirteen of 32 (41%) Ab-positive patients also tested 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. There
was no clear relationship between the presence of either Ab or NAb and therapeutic response.

Clinical Trial in Patients 7 Years and Younger

In the clinical trial in patients 7 years and younger, 19 of 28 (68%) patients treated with
ELAPRASE 0.5 mg/kg once weekly tested Ab-positive. Of the 19 Ab-positive patients, 16
(84%) tested positive for Ab at three or more different time points (persistent Ab). In addition, 15
of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) NAb-positive
patients having persistent NAb.

All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or
splice site mutations tested positive for Ab (Table 2). Of these 15 patients, neutralizing
antibodies were observed in 13 (87%) patients. The NAbs in these patients developed earlier
(most reported to be positive at Week 9 rather than at Week 27, as reported in clinical trials in
patients older than 5 years of age) and were associated with higher titers and greater in vitro
neutralizing activity than in patients older than 5 years of age. The presence of Ab was
associated with reduced systemic idursulfase exposure [see Clinical Pharmacology (12.3)].

The immunogenicity 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. The observed incidence of positive antibody 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.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of ELAPRASE.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.

In post-marketing experience, late-emergent symptoms and signs of anaphylactic reactions have
occurred up to 24 hours after initial treatment and recovery from an initial anaphylactic reaction.
In addition, patients experienced repeated anaphylaxis over a two- to four-month period, up to
several years after initiating ELAPRASE treatment [see Warnings and Precautions (5.1)].

A seven year-old male patient with Hunter syndrome, who received ELAPRASE at twice the
recommended dosage (1 mg/kg weekly) for 1.5 years, experienced two anaphylactic events after
4.5 years of treatment. Treatment has been withdrawn [see Overdosage (10)].

Serious adverse reactions that resulted in death included cardiorespiratory arrest, respiratory
failure, respiratory distress, cardiac failure, and pneumonia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy category C.

Teratogenicity studies have not been conducted with ELAPRASE. A pre- and postnatal
development study in rats showed no evidence of adverse effects on pre- and postnatal
development at intravenous doses up to 12.5 mg/kg, administered twice weekly (about 4 times
the recommended human weekly dose of 0.5 mg/kg based on body surface area). There are no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during pregnancy only if
clearly needed.

8.3 Nursing Mothers

ELAPRASE was excreted in breast milk of lactating rats at a concentration higher (4 to 5-fold)
than that of the plasma. It is not known whether ELAPRASE 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.

8.4 Pediatric Use

Clinical trials with ELAPRASE were conducted in 96 patients with Hunter syndrome, ages 5 to
31 years old, with the majority of the patients in the pediatric age group (median age 15 years
old). In addition, an open-label, uncontrolled clinical trial was conducted in 28 patients with
Hunter syndrome, ages 16 months to 7.5 years old. Patients 16 months to 5 years of age
demonstrated reduction in spleen volume that was similar to that of adults and children 5 years
and older. However, there are no data to support improvement in disease-related symptoms or
long term clinical outcome in patients 16 months to 5 years of age. [see Clinical Studies (14)].

The safety and effectiveness of ELAPRASE have not been established in pediatric patients less
than 16 months of age.

8.5 Geriatric Use

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

10 OVERDOSAGE

One patient with Hunter syndrome, who received ELAPRASE at twice the recommended dosage
for one and a half years, experienced two anaphylactic reactions over a 3-month period 4.5 years
after initiating ELAPRASE treatment.

11 DESCRIPTION

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 46 to 74 units/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 administered as an intravenous infusion and 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 mL with
an idursulfase concentration of 2 mg/mL at a pH of approximately 6. Each vial contains 6 mg
idursulfase, sodium chloride (24 mg), sodium phosphate monobasic monohydrate (6.75 mg),
sodium phosphate dibasic heptahydrate (2.97 mg), and polysorbate 20 (0.66 mg). ELAPRASE
does not contain preservatives. Each vial is for single use only.

12 CLINICAL PHARMACOLOGY

12.1 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-O-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.

ELAPRASE is intended to provide exogenous enzyme for uptake into cellular lysosomes.
Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow 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.

12.2 Pharmacodynamics

Decreases in urinary GAG levels were observed following treatment with ELAPRASE. The
responsiveness of urinary GAG to dosage alterations of ELAPRASE 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 [see Adverse Reactions (6.2) and Clinical Studies (14.1, 14.2)].

12.3 Pharmacokinetics

Clinical Trials in Patients 5 Years and Older

The pharmacokinetic characteristics of idursulfase were evaluated in 59 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 7.7 to 27 years of age (Table 3). There were no apparent
differences in PK parameter values between Week 1 and Week 27 regardless of the antibody
status in these patients.

Table 3. Pharmacokinetic Parameters in Patients 7.7 to 27 Years of Age

Clinical Trial in Patients 7 Years and Younger

Idursulfase pharmacokinetics was evaluated in 27 patients with Hunter syndrome 16 months to
7.5 years of age who received ELAPRASE 0.5 mg/kg once weekly as a 3-hour infusion. The
presence of anti-idursulfase antibody (Ab) was associated with a reduced systemic exposure of
idursulfase. Eight of the 18 Ab-positive patients had no measurable idursulfase concentrations.
An additional 9 Ab-positive patients had decreased Cmax, AUC, and t1/2 at Week 27 compared to
Week 1 (Table 4). Idursulfase pharmacokinetics was similar between Week 1 and Week 27 in
Ab-negative patients (Table 4).

Table 4. Pharmacokinetic Parameters in Patients 16 months to 7.5 Years of Age

*Positive anti-idursulfase antibody (Ab) is defined as having at least one serum specimen with measurable
  antibody during study duration.
Eight of 18 patients with positive Ab had no measurable concentrations at Week 27.
#N = 26
$N = 9

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.

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

14.1 Clinical Trials in Patients 5 Years and Older

The safety and efficacy of ELAPRASE were evaluated in a 53-week, randomized, double-blind,
placebo-controlled clinical trial of 96 patients with Hunter syndrome. The trial included patients
with deficiency in iduronate-2-sulfatase enzyme activity and a percent predicted forced vital
capacity (% predicted FVC) less than 80%. The age of patients ranged from 5 to 31 years.
Patients received ELAPRASE 0.5 mg/kg once per week (n=32), ELAPRASE 0.5 mg/kg once
every other week (n=32), or placebo (n=32).

The primary efficacy outcome assessment was a two-component composite score based on the
sum of the ranks of the change from baseline to Week 53 in distance walked in six minutes (6-
minute walk test) and the ranks of the change in % predicted FVC. This two-component
composite primary endpoint differed statistically significantly between the three groups, and the
difference was greatest between the placebo group and the once weekly treatment group (once
weekly ELAPRASE vs. placebo, p=0.0049).

Examination of the individual components of the composite score showed that, in the adjusted
analysis, the weekly ELAPRASE-treated group experienced a 35 meter greater mean increase in
the distance walked in six minutes compared to placebo. The changes in %-predicted FVC were
not statistically significant (Table 5).

Table 5. Clinical Trial Results

Pharmacodynamic assessments included urinary GAG levels and changes in liver and spleen
size. Urinary GAG levels were elevated in all patients at baseline. Following 53 weeks of
treatment, mean urinary GAG levels were reduced in the ELAPRASE once weekly group,
although GAG levels still remained above the upper limit of normal in half of the ELAPRASE-
treated patients. Urinary GAG levels remained elevated and essentially unchanged in the
placebo group. Sustained reductions in both liver and spleen volumes were observed in the
ELAPRASE once weekly group through Week 53 compared to placebo. There were essentially
no changes in liver and spleen volumes in the placebo group.

Extension Trial

Patients who participated in the placebo-controlled trial were eligible to continue treatment in an
open-label extension trial. During the extension trial, all patients received ELAPRASE
0.5mg/kg once weekly for 24 months.

Patients who were treated with ELAPRASE once weekly and every other week in the placebo-
controlled trial demonstrated improvement in distance walked in the 6-minute walk test for an
additional 8 months of treatment in the extension trial. There was no change in mean %-
predicted FVC in all Hunter syndrome patients after 6 months of treatment in the extension trial;
however, a slight decrease in mean %-predicted FVC was demonstrated through to month 24 of
the extension trial. The long-term effect of ELAPRASE on pulmonary function in Hunter
syndrome patients is unclear.

There were no further reductions in mean urinary GAG levels in patients initially treated with
ELAPRASE once weekly; however, the patients treated with ELAPRASE every other week
during the placebo-controlled trial experienced further reductions in mean urinary GAG levels
after changing to a more frequent dosing regimen during the extension trial. The persistence of
reduced urinary GAG levels did not correlate with the long term effect demonstrated by the 6-
minute walk test distance or %-predicted FVC.

14.2 Clinical Trial in Patients 7 Years and Younger

A 53-week, open-label, multicenter, single-arm trial was conducted to assess the safety,
pharmacokinetics, and pharmacodynamics of ELAPRASE 0.5 mg/kg once weekly in male
Hunter syndrome patients aged 7 years and younger. Safety results demonstrated that patients
with complete gene deletion or large gene rearrangement mutations are more likely to develop
antibodies, including neutralizing antibodies, and to experience hypersensitivity reactions with
ELAPRASE administration [see Adverse Reactions (6.1, 6.2)]. In patients who remained
antibody negative, the pharmacokinetic profile, reduction in urinary GAG excretion levels, and
reduction in spleen volume were similar to those of adults and children 5 years and older. In
patients who were persistently antibody positive, the presence of anti-idursulfase antibody was
associated with reduced systemic exposure of idursulfase and a less pronounced decrease in
urinary GAG levels [see Clinical Pharmacology (12.2, 12.3)].

16 HOW SUPPLIED/STORAGE AND HANDLING

ELAPRASE is supplied as a sterile injection in a 5 mL Type I glass vial. The vials are closed
with a butyl rubber stopper with fluororesin coating and an aluminum overseal with a blue flip-
off plastic cap.

Each carton contains a single vial            NDC 54092-700-01

Store ELAPRASE vials in the carton at 2°C to 8°C (36°F to 46°F) to protect from light. Do not
freeze or shake. Do not use ELAPRASE after the expiration date on the vial.

17 PATIENT COUNSELING INFORMATION

Information for Patients

Patients should be advised that life-threatening anaphylactic reactions have occurred in some
patients during and up to 24 hours after ELAPRASE therapy. Patients who have experienced
anaphylactic reactions may require prolonged observation. Patients with compromised
respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of
their respiratory compromise due to hypersensitivity reactions.

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, call Shire Human Genetic
Therapies, Inc. at 1-866-888-0660.

 

ELAPRASE is manufactured by:

Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421
US License Number 1593
Phone # 1-866-888-0660

ELAPRASE is a registered trademark of Shire Human Genetic Therapies, Inc.

©2013 Shire Human Genetic Therapies, Inc.