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) × 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.

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)].

6.1 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:

• Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1)]

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.

6.2 Immunogenicity

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.

8.1 Pregnancy

8.2 Lactation

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.

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

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.

14.1 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).

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.

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)].

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.

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 Takeda Pharmaceuticals at 1-866-888-0660.