Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 24 July 2018

Indication(s)

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).

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None ( 4)
Adverse reactions

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 Shire Medical Information at 1-866-888-0660 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 can not 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.

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.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION 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.

Use in special populations

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.

Pregnancy and lactation
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.

More information

Category Value
Authorisation number BLA125151
Agency product number 5W8JGG2651
Orphan designation No
Product NDC 54092-700
Date First Approved 24-07-2006
Date Last Revised 10-03-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 644104
Storage and handling 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.
Marketing authorisation holder Shire US Manufacturing Inc.
Warnings

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)].

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)