ELAPRASE

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) ]. 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 ).

2 DOSAGE AND ADMINISTRATION The recommended dosage is 0.5 mg per kg of body weight administered once every week as an intravenous infusion ( 2 ). 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: 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. 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. Withdraw the calculated volume of ELAPRASE from the appropriate number of vials. Add the calculated volume of ELAPRASE solution to a 100 mL bag of 0.9% Sodium Chloride Injection, USP for intravenous infusion. 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 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 ). 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 mu…

4 CONTRAINDICATIONS None. None. ( 4 )

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with ELAPRASE use in pregnant women. Available data from a small number of postmarketing cases with ELAPRASE use in pregnancy are insufficient to inform drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In an animal reproduction study, no evidence of adverse effects on pre- and post-natal development was observed with twice weekly intravenous administration of idursulfase to pregnant rats from gestation day 6 through lactation day 19 at about 4 times the recommended human weekly dose of 0.5 mg/kg based on body surface area ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a pre- and post-natal development study, idursulfase was administered to pregnant rats twice weekly, intravenously, from gestation day 6 through lactation day 19. No significant adverse effects on pre- and post-natal development of the offspring were observed at twice weekly intravenous doses up to 12.5 mg/kg (about 4 times the recommended human weekly dose of 0.5 mg/kg based on body surface area).

6 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 Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. 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) System Organ Class Adverse Reaction ELAPRASE (0.5 mg/kg weekly) N=32 n (%) Placebo N=32 n (%) Gastrointestinal disorder Diarrhea 3 (9%) 1 (3%) Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain 4 (13%) 1 (3%) Nervous system disorders Headache 9 (28%) 8 (25%) Respiratory, thoracic and mediastinal disorders Cough 3 (9%) 1 (3%) Skin and subcutaneous tissue disorders Pruritus 8 (25%) 3 (9%) Urticaria 5 (16%) 0 (0%) 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…