Idursulfase

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 ).

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

None. None. ( 4 )

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 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) ] .

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 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 Anti-idursulfase antibodies (Ab) Anti-idursulfase neutralizing antibodies (Nab) Total Positive Negative Positive Negative Antibody Status Reported (patients) 28 19 9 15 13 Serious Adverse Reactions Serious adverse reactions included: bronchopneumonia/pneumonia, ear infection, and pyrexia [see Adverse Reactions (6.1) ] . (patients) 13 11 2 9 4 Hypersensitivity (patients) 16 12 4 10 6 Patients with genotype data 27 M U T A T I O N S Missense Mutation (n=12) Antibody status 12 3 9 1 11 Serious Adverse Reactions 2 0 2 0 2 Hypersensitivity Reactions 5 1 4 0 5 Complete Gene Deletion, Large Gene Rearrangement, Nonsense, Frameshift, Splice Site Mutations (n=15) Antibody Status 15 15 0 13 2 Serious Adverse Reactions 9 9 0 7 2 Hypersensitivity Reactions 11 11 0 10 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. […]

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).

8.2 Lactation Risk Summary There are no data on the presence of idursulfase in human milk, the effects on the breastfed infant, or the effects on milk production. Idursulfase was excreted in breast milk of lactating rats ( see Data ). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ELAPRASE and any potential adverse effects on the breastfed child from ELAPRASE or from the underlying maternal condition. Data Idursulfase was excreted in breast milk of lactating rats at a concentration higher (4- to 5-fold) than the maximum blood concentration, when administered as a single intravenous dose up to 2.5 mg/kg. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

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.

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.