Elaprase: Indications, Dosage, Precautions, Adverse Effects
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Elaprase - Product Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Mucopolysaccharidosis Type II
Class: Lysosomal enzymes
Form: Liquid solution, Intravenous (IV)
Ingredients: idursulfase, polysorbate 20, sodium chloride, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, water for injection

idursulfase

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
Intravenous (IV)2 mg/mL concentrate for solution for infusionNone

Indications and Clinical Use

ELAPRASE (idursulfase) is indicated for:

  • long-term enzyme replacement therapy in patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II).

Contraindications

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For complete listing, see the Dosage Forms, Compositionand Packaging section of the product monograph.
  • Any ELAPRASE re-treatment of patients who developed hypersensitivity reactions is at the discretion of the healthcare provider upon successful management of the symptoms.

Warnings and Precautions

Serious Warnings and Precautions

  • Risk of hypersensitivity reactions: Anaphylactoid/anaphylactic reactions, which have the potential to be life threatening, have been observed in some patients treated with ELAPRASE up to several years after initiating treatment.
  • Patients with compromised respiratory function or acute respiratory disease may be at risk of serious exacerbation of their respiratory dysfunction due to infusion related reactions. These patients require additional monitoring. Late-emergent symptoms and signs of anaphylactoid/anaphylactic reactions have been observed after ELAPRASE administration as long as 24 hours after an initial reaction. If an anaphylactoid/anaphylactic reaction occurs, the infusion of ELAPRASE should be immediately suspended and appropriate treatment and observation initiated. The current medical standards for emergency treatment are to be followed. Patients experiencing severe or refractory anaphylactoid/anaphylactic reactions may require prolonged observation times.
  • Due to the potential for severe infusion reactions appropriate medical support measures should be readily available when ELAPRASE is administered.

General

ELAPRASE is not expected to affect the ability to drive or use machines.

A registry for patients with Hunter syndrome (the Hunter Outcome Survey) has been established in order to better understand the variability and progression of the disease and monitoring and evaluation of treatments. Patients should be encouraged to participate in the process and advised that their participation may involve a long-term follow-up. Information on the registry program may be obtained by calling 1-888-867-7426.

Carcinogenesis and Mutagenesis

For animal data.

Cardiovascular

Caution should be exercised when administering ELAPRASE to patients susceptible to fluid overload, or patients with underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbations of their cardiac or respiratory status during infusion.

Hepatic

No studies have been performed in patients with hepatic impairment.

Immune

Hypersensitivity

Allergic reactions have included respiratory distress, hypoxia, decreased blood pressure, angioedema, or seizure. If severe allergic or anaphylactoid reactions occur, it is recommended that the administration of ELAPRASE be discontinued immediately and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed.

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 reaction during 19 of 8,274 infusions (0.2%) with symptoms of bronchospasm, cyanosis, dyspnea, erythema, edema (facial and peripheral), flushing, rash, respiratory distress, urticarial, vomiting, and wheezing.

Infusion Reactions

In clinical trials with ELAPRASE, the most common infusion-related reactions included cutaneous reactions (rash, pruritus, and urticaria), flushing, hypertension, pyrexia, wheezing, hypoxia, dyspnea, headache, abdominal pain, nausea, dyspepsia, chest pain, and infusion site swelling. Infusion-related reactions were treated or ameliorated by slowing the infusion rate, interrupting the infusion, or by administration of medicines, such as antihistamines, antipyretics, low-dose corticosteroids (prednisone and methylprednisolone), or beta-agonist nebulization. Reactions were more severe in patients with compromised respiratory function or respiratory illnesses. No patient discontinued treatment with ELAPRASE due to an infusion reaction during clinical studies.

Patients using supplemental oxygen should have this treatment readily available during infusion in the event of an infusion-related reaction.

Renal

No studies have been conducted in patients with renal impairment.

Respiratory

Special care should be taken when administering an infusion in patients with severe underlying airway disease. These patients should be closely monitored and infused in an appropriate clinical setting. Caution must be exercised in the management and treatment of such patients by limitation or careful monitoring of antihistamine and other sedative medicinal product use. Institution of positive-airway pressure may be necessary in some cases.

Delaying the infusion in patients who present with an acute febrile respiratory illness should be considered. Patients using supplemental oxygen should have this treatment readily available during infusion in the event of an infusion-related reaction.

Special Populations

Pregnant Women

There is no experience with ELAPRASE treatment in pregnant women. Reproduction studies in pregnant female animals have not been conducted with ELAPRASE. It is not known whether idursulfase crosses the placenta.

Nursing Women

It is not known whether ELAPRASE is excreted in human milk.

Pediatrics

Patients in the clinical studies were age 16 months and older. Children, adolescents, and adults responded similarly to treatment with ELAPRASE.

Geriatrics

Studies in patients over the age of 65 have not been performed.

Patients with the Complete Deletion, Large Rearrangement Genotype

Pediatric patients with complete deletion, large gene rearrangement genotype have a high probability of developing antibodies, including neutralizing antibodies in response to exposure to ELAPRASE. Patients with this genotype have a higher probability of developing infusion-related events and tend to show a muted response as assessed by decrease in urine output of glycosaminoglycans, liver size and spleen volume compared to patients with the missense genotype. Management of patients must be decided on an individual basis.

Monitoring and Laboratory Tests

No special laboratory tests are required for patients receiving ELAPRASE, other than the usual tests that are required for monitoring patients with Hunter syndrome.

Adverse Reactions

Adverse Drug Reaction Overview

Adverse reactions were commonly reported in association with infusions. The most common infusion-related reactions were cutaneous reactions (rash, pruritus, and urticaria), flushing, hypertension, pyrexia, wheezing, dyspnea, headache, abdominal pain, nausea, dyspepsia, chest pain, and infusion site swelling. The frequency of infusion-related reactions decreased over time with continued ELAPRASE treatment. Adverse drug reactions (ADRs) that were reported during the 53-week placebo-controlled study were almost all mild to moderate in severity.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1 lists those adverse drug reactions observed during the 53-week placebo-controlled study in the patients 5 years and older treated with 0.5 mg/kg weekly ELAPRASE compared to patients receiving placebo. Information is presented by system organ class and frequency. Frequency is given as very common (>1/10) or common (>1/100, <1/10). The occurrence of an event in a single patient is defined as common in view of the small number of patients treated in the trial.

Adverse drug reactions were defined in Table 1 as treatment-emergent events with suspected causality and excluded non-serious events that were reported only once in a single patient; treatment emergent events with an excess incidence of at least 9% compared with placebo were also considered as adverse drug reactions. Adverse reactions occurring only in placebo-treated patients are excluded. Note: All types of rash and all types of urticaria have been combined.

Table 1: Adverse Drug Reactions in the 53-week Placebo-controlled Clinical Trial (5 Years and Older) (n(%))
System Organ ClassAdverse Drug Reaction
(Preferred Term)
ELAPRASE
0.5 mg/kg Weekly
(n=32)
Placebo
(n=32)
Cardiac disorders
Common:Arrhythmia*1 (3.1)0
Cyanosis1 (3.1)0
Eye disorders
Common:Lacrimation increased2 (6.3)0
Gastrointestinal disorders
Very common:Dyspepsia4 (12.5)0
Common:Nausea3 (9.4)3 (9.4)
Abdominal pain2 (6.3)2 (6.3)
Diarrhea2 (6.3)1 (3.1)
Swollen tongue2 (6.3)0
General disorders and administration site conditions
Very Common:Pyrexia7 (21.9)8 (25.0)
Infusion site swelling4 (12.5)1 (3.1)
Common:Edema peripheral2 (6.3)0
Musculoskeletal and connective tissue disorders
Very Common:Chest pain7 (21.9)0
Common:Arthralgia1(3.1)1(3.1)
Nervous system disorders
Very Common:Headache9 (28.1)8 (25.0)
Common:Dizziness2 (6.3)2 (6.3)
Tremor2 (6.3)0
Respiratory, thoracic and mediastinal disorders
Common:Cough3 (9.4)1 (3.1)
Tachypnoea2 (6.3)1 (3.1)
Wheezing2 (6.3)0
Bronchospasm1 (3.1)0
Dyspnoea1 (3.1)1 (3.1)
Pulmonary embolism*1 (3.1)0
Skin and subcutaneous tissue disorders
Very Common:Rash8 (25.0)6 (18.8)
Pruritus7 (21.9)3 (9.4)
Urticaria5 (15.6)0
Common:Erythema2 (6.3)0
Eczema1 (3.1)0
Face edema1 (3.1)0
Vascular disorders
Very Common:Hypertension6 (18.8)6 (18.8)
Common:Flushing3 (9.4)3 (9.4)
Hypotension2 (6.3)3 (9.4)

* see serious adverse reactions below

In clinical studies, serious adverse reactions were reported in a total of 5 patients who received 0.5 mg/kg of ELAPRASE weekly or every other week. Four patients experienced a hypoxic episode during one or several infusions, which necessitated oxygen therapy in 3 patients with severe underlying obstructive airway disease (2 with a tracheostomy). The most severe episode, which was associated with a short seizure, occurred in a patient who received his infusion while he had a febrile respiratory exacerbation. In this patient, who had less severe underlying disease, spontaneous resolution occurred shortly after the infusion was interrupted. These events did not recur with subsequent infusions using a slower infusion rate and administration of pre-infusion medication, usually with low-dose steroids, antihistamine, and beta-agonist nebulization. The fifth patient, who had pre-existing cardiopathy, was diagnosed with ventricular premature complexes and pulmonary embolism during the study.

Adverse drug reactions that occurred in the 0.5 mg/kg weekly ELAPRASE group with a frequency of a single event reported are listed here by MedDRA SYSTEM ORGAN CLASS and preferred term:

Blood and Lymphatic System Disorders

anemia, lymphadenitis, thrombocytopenia

Psychiatric Disorders

anxiety

Nervous System Disorders

depressed level of consciousness, hyperaesthesia

Eye Disorders

conjunctivitis allergic, vision blurred

Ear and Labyrinth Disorders

vertigo

Cardiac Disorders

palpitations

Respiratory, Thoracic and Mediastinal Disorders

nasal congestion, pharyngitis, rhinorrhea

Gastrointestinal Disorders

abdominal pain upper, gastroenteritis, loose stools

Musculoskeletal and Connective Tissue Disorders

back pain, bone pain, muscle cramp, myalgia, neck pain

Renal and Urinary Disorders

enuresis, nocturia

General Disorders and Administration Site Conditions

feeling cold, inflammation localized, injection site joint swelling, malaise, pain, rigors, sensation of foreign body

Investigations

blood alkaline phosphatase increased, blood bilirubin increased, blood lactate dehydrogenase increased, blood uric acid increased, hemoglobin decreased, heart rate decreased, heart rate increased

Table 2 enumerates treatment emergent adverse events (TEAEs) (regardless of investigator causality assessment) that occurred in the 53-week placebo-controlled clinical trial in patients 5 years and older, with a difference of more than 2 patients between the 0.5 mg/kg weekly ELAPRASE and placebo treatment groups. Reported frequencies of adverse events have been classified by MedDRA terms.

Table 2: Treatment Emergent Adverse Events with a Difference of More Than 2 Patients Between 0.5 mg/kg Elaprase Weekly and Placebo Treatment Groups (5 years and older) (n(%))
System Organ ClassAdverse Event
(Preferred Term)
ELAPRASE
0.5 mg/kg Weekly
(n=32)
Placebo
(n=32)
Ear and labyrinth disordersEar disorder3(9.4)0
Hypoacusis1(3.1)4(12.5)
Gastrointestinal disordersDiarrhea11(34.4)15(46.9)
Vomiting8(25.0)16(50.0)
Abdominal pain upper5(15.6)2(6.3)
Dyspepsia4(12.5)0
General disorders and administration site conditionsInfusion site swelling4(12.5)1(3.1)
Asthenia3(9.4)0
Fall04(12.5)
Catheter site pain03(9.4)
Infections and infestationsHordeolum03(9.4)
Injury, poisoning, and
 procedural complications
Arthropod bite3(9.4)0
Abrasion03(9.4)
InvestigationsAlanine aminotransferase increased04(12.5)
Aspartate aminotransferase increased03(9.4)
Musculoskeletal and connective tissue disordersChest pain7(21.9)0
Nervous system disordersHeadache19(59.4)14(43.8)
Dizziness4(12.5)8(25.0)
Psychiatric disordersDepression3(9.4)0
Respiratory, thoracic, and mediastinal disordersCough16(50.0)19(59.4)
Pharyngitis13(40.6)10(31.3)
Dyspnea4(12.5)9(28.1)
Epistaxis2(6.3)5(15.6)
Skin and subcutaneous tissue disordersRash14 (43.8)11 (34.4)
Pruritus10 (31.3)5 (15.6)
Urticaria5 (15.6)0
Acne3 (9.4)0

Table 3 enumerates TEAEs (regardless of investigator causality assessment) that occurred in an open-label trial (patients aged 7 years and younger, administered ELAPRASE 0.5 mg/kg weekly) in more than 2 patients. Reported frequencies of adverse events have been classified by MedDRA terms.

Table 3 Treatment Emergent Adverse Events Occurring in More Than 2 Patients by System Organ Class and Preferred Term (7 years and younger) (Safety Population, N=28)
System Organ ClassAdverse Events
Preferred Term
Patients
n (%)
Cardiac disordersLeft ventricular hypertrophy4(14.3)
Ear and labyrinth disordersDeafness4(14.3)
Gastrointestinal disordersVomiting10(35.7)
Diarrhea7(25.0)
General disorders and administration site conditionsPyrexia25(89.3)
Infections and infestationsUpper respiratory tract infection18(64.3)
Respiratory tract infection12(42.9)
Rhinitis11(39.3)
Viral upper respiratory tract infection9(32.1)
Otitis media acute7(25.0)
Pharyngitis7(25.0)
Gastroenteritis6(21.4)
Upper respiratory tract infection bacterial6(21.4)
Pneumonia5(17.9)
Sinusitis5(17.9)
Bronchitis4(14.3)
Bronchopneumonia4(14.3)
Otitis media4(14.3)
Gastrointestinal infection3(10.7)
Otitis externa3(10.7)
Viral infection3(10.7)
Viral pharyngitis3(10.7)
Psychiatric disordersAgitation4(14.3)
Sleep disorder3(10.7)
Respiratory, thoracic and mediastinal disordersCough16(57.1)
Nasal congestion6(21.4)
Allergic cough3(10.7)
Asthma3(10.7)
Rhinorrhea3(10.7)
Sleep apnea syndrome3(10.7)
Skin and subcutaneous tissue disordersRash7(25.0)
Urticaria4(14.3)

Immunogenicity

Across 4 clinical studies (TKT008, TKT018, TKT024, TKT024EXT) assessing immunogenicity, 53/107 (50%) patients exposed to ELAPRASE developed anti-idursulfase IgG antibodies. All IgG-positive serum samples were tested for neutralizing antibodies (NAb) activity. A maximum of 26 of 107 patients (24.3%) tested positive for any NAb at some time during treatment with idursulfase.

In a post-hoc analysis of immunogenicity in TKT024/024EXT, approximately half (51%) of the patients exposed to weekly ELAPRASE 0.5 mg/kg for 2 years developed an antibody response and 13% developed a persistent neutralizing response defined as 3 consecutive samples positive for NAb. There was no statistically significant association between antibody status and the effect of ELAPRASE on the clinical endpoints (6MWT or %FVC). All antibody status groups showed improvement on ELAPRASE, although the magnitude of the effect was less pronounced in antibody-positive patients. Similarly, urine GAG (glycosaminoglycans) levels decreased in all antibody status groups, but there was a mild to moderate decrease in the magnitude of the ELAPRASE-induced urine GAG response in patients with antibodies, NAb and those who tested positive for antibodies on at least three consecutive visits. Thus, regardless of antibody status, ELAPRASE treatment resulted in pharmacodynamic and clinical effects.

Another clinical study (HGT-ELA-038) evaluated immunogenicity in children 16 months to 7.5 years of age. During the 53-week study, 67.9% (19 of 28) of patients had at least one blood sample that tested positive for anti-ELAPRASE antibodies, and 57.1% (16 of 28) tested positive for antibodies on at least three consecutive study visits. Fifty-four percent of these patients tested positive for NAb at least once and half of the patients tested positive for NAb on at least three consecutive study visits. There was a clear link between genotype and immunogenicity. All patients with the complete deletion/large rearrangement genotype developed antibodies, and the majority of them (7/8) also tested positive for NAb on at least 3 consecutive occasions. All patients with the frameshift/splice site mutation genotype developed antibodies and 4/6 also tested positive for NAb on at least 3 consecutive study visits. Antibody negative patients were found exclusively in the missense mutation genotype group.

Post-Market Adverse Drug Reactions

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 anaphylactoid/anaphylactic reactions have occurred up to 24 hours after treatment and recovery from an initial reaction. In addition, some patients experienced repeated anaphylaxis over a two- to four-month period, up to several years after initiating ELAPRASE treatment (see Warnings and Precautions).

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 was withdrawn.

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

Drug Interactions

Overview

Based on its metabolism in cellular lysosomes, idursulfase would not be a candidate for cytochrome P450 mediated drug-drug interactions.

Drug-Drug Interactions

No formal drug interaction studies have been conducted with ELAPRASE.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

  • ELAPRASE is intended for use under the supervision of a physician or other experienced health care provider.
  • The infusion rate may be slowed and/or temporarily stopped, based on clinical judgement, when infusion-related reactions occur (see Administration)

Recommended Dose and Dosage Adjustment

ELAPRASE is administered at a dose of 0.5 mg/kg body weight every week by intravenous infusion.

Administration

The total volume of infusion may be administered over a period of 3 hours, which may be gradually reduced to 1 hour if no infusion-related reactions are observed. Patients may require longer infusion times due to infusion reactions; however, infusion times should not exceed 8 hours. The initial infusion rate should be 8 mL/hr for the first 15 minutes. If the infusion is well tolerated, the rate may be increased by 8 mL/hr increments at 15 minute intervals in order to administer the full volume within the desired period of time. However, at no time should the infusion rate exceed 100 mL/hr. The infusion rate may be slowed and/or temporarily stopped, based on clinical judgment, when infusion-related reactions occur.

See Special Handling Instructions for method of dilution.

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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

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 hydrolyzes the 2-sulfate esters of terminal iduronate sufate residues from the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate in the lysosomes of various cell types. 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 progressive organ system dysfunction.

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.

Pharmacodynamics

In the pivotal TKT024 study, urine GAG levels decreased in patients treated with ELAPRASE weekly compared to placebo patients (p<0.0001). Among all 32 weekly ELAPRASE treated patients, 16 (50%) had normalized urine GAG levels below the upper limit of normal (defined as 126.6 µg GAG/mg creatinine) at Week 53. None of the placebo patients had normalized urine GAG levels that fell below the upper limit of normal by Week 53.

Treatment of Hunter syndrome patients with ELAPRASE provides exogenous enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the external oligosaccharide chains of the ELAPRASE molecule allow specific 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. The pharmacodynamic effect of ELAPRASE treatment as measured by urine GAG, was less pronounced in subjects who developed an immune response to ELAPRASE.

In the extension Study (TKT024EXT) in which all patients received weekly idursulfase, reductions in mean urine GAG levels were maintained in the TKT024 Weekly group, and the TKT024EOW (every other week) dose group experienced further mean reductions in urine GAG levels following transition to the weekly dose. At the completion of TKT024EXT, mean urine GAG levels fell below the upper limit of normal in the TKT024 Weekly and EOW dose groups and were near normal in the TKT024 placebo group. Changes in the urine GAG levels were the earliest signs of clinical improvement with idursulfase treatment and the greatest decreases in urine GAG were seen in the first 4 months of treatment in all treatment groups. In those patients whose urine GAG levels fell to within the normal range, this fall was regardless of patient age, disease severity at baseline, and residual IS activity category. The higher the urine GAG levels at baseline the greater the magnitude of decreases in urine GAG with idursulfase treatment.

Pharmacodynamic effects of ELAPRASE treatment were assessed in children ≤5 years old in Study HGT-ELA-038. In this study the age range of enrolled patients at baseline was 16 months to 7.5 years and they were analyzed in three age groups (one year old, two to four year old and five year old or more). In Study HGT-ELA -038 ELAPRASE treatment resulted in a mean decrease from baseline of approximately 40 to 60% in urine GAG levels at Week 53 depending on the age group. The magnitude of decreases was comparable to the previous registration Study TKT024, which reported an approximately 60% decrease for the same weekly ELAPRASE dose at Week 53. Decreases in urine GAG levels were evident in all age groups and appeared as early as the Week 18 time point and continued through Week 53. The pharmacodynamic effect of ELAPRASE treatment as measured by urine GAG, was less pronounced in subjects who developed an immune response to ELAPRASE.

Pharmacokinetics

Idursulfase is taken up by selective receptor-mediated mechanisms involving binding to mannose-6-phosphate receptors. Upon internalization by cells, it is localized within cellular lysosomes, thereby limiting distribution of the protein. Degradation of idursulfase is achieved by generally well understood protein hydrolysis mechanisms to produce small peptides and amino acids. Since metabolic degradation of this product is expected to occur in cells via normal proteolytic mechanisms, no metabolism studies were conducted in humans.

The pharmacokinetic (PK) characteristics of idursulfase were evaluated in several studies in patients with Hunter syndrome (see Table 4). 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.

Table 4: Comparison of Initial and Repeat-Dose PK Parameters for All Evaluable Patient Samples – Based on Idursulfase Concentration Data (Mean (SD))
WeekPK Parameter
Cmax
(Mg/mL)
AUC
(min* Mg/mL)

(min)
Cl
(mL/min/kg)
Vss (% BW)
TKT024
Week 1
(n=28)
1.64
(0.55)
234
(82)
50
(36)
2.55
(0.97)
19.2%
(7.5%)
TKT024
Week 27
(n=30)
1.17
(0.41)
165
(48)
39
(17)
3.45
(1.03)
23.3%
(10.8%)
TKT024EXT
Week 1
(n= 44)
1.20
(0.65)
192
(70)
60
(16)
2.95
(0.93)
24.3%
(12.3%)

In Study TKT024EXT, in which patients received idursulfase 0.5mg/kg weekly as a 3-hour infusion, there were no changes in pharmacokinetic parameters with repeat dosing (Week 18, n=68) and pharmacokinetic parameters were similar to those in Study TKT024. There was no effect of anti-idursulfase IgG antibodies on the PK of idursulfase.

PK was also evaluated in Study HGT-ELA-038 in patients aged 16 months to 7.5 years who received 0.5 mg/kg ELAPRASE as a 3-hour infusion. PK was evaluated at Week 1 (n=27) and Week 27 (n=19). Serum concentrations were less than the lower limit of quantification (LLOQ) at all time points in 8 of 27 subjects (30%) at Week 27 and measurable only at some sampling times in the remaining 19 subjects (70%). The PK profiles of all 11 antibody-negative subjects at Week 27 were similar to those at Week 1. The 8 antibody-positive subjects with measurable serum concentration levels, exhibited significantly higher clearance rates at Week 27 compared to Week 1.

Key PK parameters for ELAPRASE were comparable across the different weight groups. These results indicate that the total systemic exposure and clearance rate of ELAPRASE are not affected by body weight. However, a higher volume of distribution at steady state (Vss) was observed in the lowest weight groups.

Overall, there was no apparent trend in either systemic exposure or clearance rate of ELAPRASE with respect to either age or body weight.

Storage and Stability

Store at 2°C to 8°C (in a refrigerator), and protect from light.

Do not freeze or shake.

Do not use ELAPRASE after the expiration date on the vial.

This product contains no preservatives. The product should be diluted in an infusion bag using strict aseptic technique. The diluted solution should be used immediately. If immediate use is not possible, the diluted solution can be stored refrigerated at 2°C to 8°C for up to 24 hours, or must be administered within 8 hours if held at room temperature.

Special Handling Instructions

ELAPRASE should be prepared and administered by a healthcare professional.

  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 # of vials 
    Round up to determine the number of whole vials needed from which to withdraw the calculated volume of ELAPRASE to be administered.
  2. Perform a visual inspection of each vial. ELAPRASE is a clear to slightly opalescent, colorless solution. Do not use if the solution in the vials is discolored or particulate matter is present. ELAPRASE should not be shaken.
  3. Withdraw the calculated volume of ELAPRASE from the appropriate number of vials.
  4. Using strict aseptic technique, dilute the total calculated volume of ELAPRASE in 100 mL of 0.9% Sodium Chloride Injection, USP. Once diluted into normal saline, the solution in the infusion bag should be mixed gently, but not shaken. Diluted solution stored at room temperature should be discarded if not administered within 8 hours of preparation. Diluted solution may be stored refrigerated for up to 24 hours.
  5. Use of an infusion set equipped with a 0.2 micrometer (μm) filter is recommended. ELAPRASE should not be infused with other products in the infusion tubing.
  6. ELAPRASE is supplied in single-use vials. Remaining ELAPRASE left in a vial after withdrawing the patient’s calculated dose should be disposed of in accordance with local requirements.

Dosage Forms, Composition and Packaging

ELAPRASE is a sterile, aqueous, clear to slightly opalescent, colorless solution supplied 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 vial of ELAPRASE contains a 2.0 mg/mL solution of idursulfase protein (6.0 mg) in an extractable volume of 3.0 mL, and is for single use only.

The concentrate must be further diluted; see Special Handling Instructions.

ELAPRASE is available in a pack size of 1 vial per carton.

The following is a list of excipients used in the ELAPRASE formulation:

Polysorbate 20; 
Sodium chloride; 
Sodium phosphate dibasic, heptahydrate; 
Sodium phosphate monobasic, monohydrate; 
Water for Injection.