Consumer medicine information

Elaprase

Idursulfase

BRAND INFORMATION

Brand name

Elaprase

Active ingredient

Idursulfase

Schedule

What is in this leaflet

This leaflet answers some common questions about Elaprase.

It does not contain all the available information about Elaprase.

It does not take the place of talking to your doctor or a trained health care professional.

All medicines have risks and benefits. Your doctor has weighed the risks of you or your child having Elaprase against the benefits they expect it will have.

If you have any concerns about this medicine, ask your doctor or nurse.

Keep this leaflet. You may need to read it again.

What Elaprase is used for

Elaprase is used as enzyme replacement therapy to treat Hunter syndrome (Mucopolysaccharidosis II), a rare genetic disease in which an enzyme called iduronate-2-sulfatase is missing or the level of the enzyme is lower than normal.

Hunter syndrome generally occurs in males and rarely in females.

Elaprase is available only with a doctor's prescription. Only your or your child’s treating doctor can start the treatment and supervise the ongoing treatment.

Elaprase is to be given only to the person for whom it has been prescribed.

How it works

Patients with Hunter syndrome do not produce enough of their own enzyme, iduronate-2-sulfatase. The reduced iduronate-2-sulfatase levels in patients result in the accumulation of substances called glycosaminoglycans (GAG) in a number of cells and tissues. This causes the affected cells and tissues to function abnormally, thereby causing problems for various organs in the body.

Elaprase is an enzyme replacement therapy that is intended to restore sufficient levels of enzyme to assist in the removal of the accumulated substances and to reduce further accumulation.

Ask your treating doctor if you have any questions about why it has been prescribed for you or your child.

Before you are given Elaprase

When you or your child must not be given it

Do not take Elaprase if you or your child have a known, severe, life-threatening allergic reaction to:

idursulfase
any of the ingredients listed at the end of this leaflet

Symptoms of an allergic reaction may include:

shortness of breath
faintness or dizziness
headaches
skin rash, itching or hives
swelling

If you are not sure whether you or your child should have Elaprase, talk to your doctor or nurse.

Before you or your child are given it

Tell your doctor if you or your child have had reactions to any previous treatments, including any of the following reactions:

allergic reaction
difficulty breathing

Tell your doctor if you or your child have allergies to:

any other medicines
any other substances, such as foods, preservatives or dyes

Tell your doctor if you or your child is suffering from any of the following:

Respiratory condition
Airway disease
Flu-like symptoms and fever
Heart condition

Tell your doctor if you are pregnant or intend to become pregnant. There is no information available regarding the use of Elaprase in pregnant women.

Your doctor will discuss the possible risks and benefits of having Elaprase during pregnancy.

Tell your doctor if you are breast-feeding. It is not known whether Elaprase passes into breast milk. If there is a need to consider using Elaprase while you are breastfeeding, your doctor will discuss with you the benefits and risks of using it.

Tell your doctor if your child is under 16 months of age and has been prescribed Elaprase. Safety in children below the age of 16 months has not been studied. If your child has been prescribed Elaprase, you may wish to discuss this with your child’s doctor.

Taking other medicines

Tell your doctor or nurse if you or your child are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. It is not known whether there are interactions between Elaprase and other medicines.

Your doctor or nurse will advise you and decide whether or not to give you or your child Elaprase.

How Elaprase is given

How much to use

The recommended dosage for Elaprase is 0.5 mg (half a milligram) for every kg you weigh, once every week.

Your doctor will decide on the dose that is most suitable.

How to use it

Elaprase will be prepared and given to you or your child by a trained health care professional who is knowledgeable in the treatment of Hunter syndrome or other inherited metabolic disorders.

Treatment with Elaprase may be given in the clinic or in certain cases, at home.

Treatment at home must be administered by a healthcare professional. Your doctor will determine if home treatment is appropriate for you or your child.

Elaprase will be diluted in 0.9% (9 mg/mL) Sodium Chloride for Injection before use. After dilution Elaprase is given directly into the vein (intravenously). The infusion will normally last for 1 to 3 hours and will be given every week.

Infusion with Elaprase should start as soon as possible after the medicine has been diluted. If not used immediately, the solution must be stored at 2°C - 8°C and infused within 24 hours. It should be protected from light before it is given to you or your child.

If you are given too much (overdose)

There is limited information regarding overdose with Elaprase. Evidence suggests that patients may experience severe allergic reactions due to overdose.

Your doctor is trained to work out the correct dose and to contact the Australian Poisons Information Centre (telephone 13 11 26), or the New Zealand National Poisons Centre (telephone 0800 POISON or 0800 764 766) in case of an overdose.

After having Elaprase

Things you or your child must do

Keep appointments with your doctor or clinic.

It is important to have the infusion with Elaprase at the appropriate times to make sure the medicine has the best chance of providing treatment for the condition.

Have any tests when your doctor says to.

Your doctor may wish to test your or your child’s body’s response to Elaprase to make sure that it is working.

Your doctor may wish to test for allergic reactions some time after the infusion or continue to monitor after infusion.

Things to be careful of

Allergic reactions may occur approximately 24 hours after infusion.

Tell your health care professional immediately if you experience any allergic reactions.

Be careful driving or operating machinery until you know how Elaprase affects you. The effect of Elaprase on your ability to drive a car or operate machinery has not been studied.

Make sure that you know how you react to Elaprase before you drive a car or operate machinery or do anything else that may be dangerous if you are dizzy, light-headed, tired or drowsy.

Side effects

Tell your doctor or nurse as soon as possible if you or your child do not feel well after having Elaprase.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You or your child may need medical treatment if you get some of the side effects. Side effects can happen even if you or your child have been receiving treatment with Elaprase for some time.

Ask your doctor or nurse to answer any questions you may have.

Tell your doctor or nurse if you notice any of the following and they worry you:

Faintness or dizziness
Headaches
Stomach ache
Redness of skin, itching
Anxiety
Vomiting

If you notice any of the following side effects tell your treating doctor immediately or go to Emergency at your nearest hospital:

Shortness of breath
Wheezing
Difficulty breathing
Inflammation of the back of the throat
Joint pain or swelling itching with or without a rash
Local reaction around the injection site such as swelling
Hives
An uncomfortable feeling in the stomach or indigestion
Chest pain
Fever or high temperature
Seizure
Loss of consciousness
Low blood pressure

Other side effects not listed above may occur in some patients. Tell your doctor if you notice anything making you feel unwell when you are taking, or soon after you have finished taking Elaprase.

Storing Elaprase

Store Elaprase in a refrigerator at 2°C - 8°C. Do not freeze or shake.

Diluted Elaprase should be protected from light.

If not used immediately, the solution must be stored at 2°C - 8°C and infused within 24 hours.

Product Description

What it looks like

Elaprase is a clear to slightly opalescent, colourless solution.

Ingredients

Active ingredient:
idursulfase

Other ingredients:
sodium chloride, sodium phosphate - monobasic monohydrate, dibasic sodium phosphate heptahydrate, polysorbate 20.

Supplied by

In Australia this product is registered by:

sanofi-aventis australia pty ltd.
12-24 Talavera Road
Macquarie Park NSW 2113
AUSTRALIA
Toll Free Number (medical information): 1800 818 806
Email: medinfo.australia@sanofi.com

AUST R 129481

In New Zealand this product is registered by:

Sanofi-aventis New Zealand Limited
Level 8
56 Cawley Street, Ellerslie,
Auckland
New Zealand
New Zealand Free Call: 0800 283 684
Email: medinfo.australia@sanofi.com

Elaprase® is a registered trademark of Shire Human Genetic Therapies, Inc., USA.

This leaflet was prepared in December 2020

elap-ccdsv14-cmiv5-11dec20

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Elaprase

Active ingredient

Idursulfase

Schedule

1 Name of Medicine

Idursulfase.

2 Qualitative and Quantitative Composition

6 mg/3 mL concentrate for intravenous solution for infusion.
The solution in each vial contains an idursulfase¹ concentration of 2 mg/mL at a pH of approximately 6. The extractable volume of 3 mL from each vial provides 6 mg idursulfase. Elaprase does not contain preservatives; vials are for single use only.
¹ Idursulfase is produced by recombinant DNA technology in a continuous human cell line.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Elaprase, for intravenous infusion, is supplied as a sterile, aqueous, clear to slightly opalescent colourless solution that must be diluted prior to administration in 0.9% sodium chloride for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Elaprase is indicated for the long-term treatment of patients with Hunter syndrome (mucopolysaccharidosis II, MPS II).

4.2 Dose and Method of Administration

Treatment should be supervised by a physician or healthcare professional experienced in the management of patients with MPS II or other inherited metabolic disorders.
The recommended dosage regimen of Elaprase is 0.5 mg/kg of bodyweight administered every week as an intravenous infusion.
Infusion of Elaprase at home may be considered after the most careful consideration of the risks and benefits in patients who:
a) are tolerating their infusions well;
b) have received a minimum of 6 months of treatment in the clinic;
c) have been free of infusion related reactions for a period of 6 months;
d) have stable airway disease.
Home infusions must be administered by a healthcare professional.
Health professionals administering the product must be:
a) adequately trained in cardiopulmonary resuscitative measures;
b) have ready access to emergency medical services;
c) trained in recognising and managing serious infusion related reactions, hypersensitivity reactions and medical emergencies, including measures appropriate for the age of the patient, under the direction of a practicing physician.
The necessary equipment, treatments and protocols sufficient to initiate the management of acute hypersensitivity reactions including anaphylaxis are to be in place.
Elaprase is a concentrated solution for intravenous infusion and must be diluted in 100 mL of 0.9% sodium chloride for injection. Each vial of Elaprase contains 3 mL (6 mg) of idursulfase. Vials are for single use only. Use of an infusion set equipped with a 0.2 micrometre filter is recommended.
The total volume of infusion should be delivered over a 3 hour period which may be gradually reduced to periods no shorter than 1 hour provided the infusions are well tolerated and no infusion related reactions are observed. Infusions of less than three hours duration are not recommended in children less than 5 years of age. 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 minutes 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, or discontinued for that visit, based on clinical judgement, if infusion reactions were to occur (see Section 4.4 Special Warnings and Precautions for Use). Elaprase should not be infused with other products in the infusion tubing.

Preparation and administration instructions: use aseptic techniques.

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) x 0.5 mg/kg of Elaprase ÷ 2 mg/mL/vial = total # mL of Elaprase.
Total # mL of Elaprase ÷ 3 mL/vial = total # of vials.
If the number of vials calculated indicates that a partial vial is required, 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, colourless solution. Do not use if the solution in the vials is discoloured or particulate matter is present. Elaprase should not be shaken.
3. Withdraw the calculated volume of Elaprase from the appropriate number of vials.
4. Dilute the total calculated volume of Elaprase in 100 mL of 0.9% sodium chloride for injection. Once diluted into normal saline, the solution in the infusion bag should be mixed gently, but not shaken. To reduce microbial hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°-8°C for no more than 24 hours.
5. 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.

4.3 Contraindications

Hypersensitivity (anaphylactic reaction) to the active substance or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Serious hypersensitivity reactions including life threatening anaphylactoid/ anaphylactic reactions have been observed in some patients during Elaprase infusions. Reactions have included respiratory distress, hypoxia, hypotension, seizure, loss of consciousness, urticaria and/or angioedema of the throat or tongue.
Late emergent or biphasic anaphylactoid/ anaphylactic reactions have also been reported to occur after administration of Elaprase approximately 24 hours after treatment and recovery from an initial anaphylactoid/ anaphylactic reaction that occurred during Elaprase infusion. Patients who have experienced initial anaphylactoid/ anaphylactic reactions may require prolonged observation.
Interventions for biphasic reactions have included hospitalisation, and treatment with adrenaline, inhaled beta-adrenergic agonists, and corticosteroids.
Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.

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.

Infusion/ hypersensitivity reactions.

Patients treated with Elaprase may develop infusion related reactions (see Section 4.8 Adverse Effects (Undesirable Effects)). The most common infusion related reactions included cutaneous reactions (rash, pruritus, urticaria), pyrexia, headache, hypertension and flushing. Infusion related reactions were treated or ameliorated by slowing the infusion rate, interrupting the infusion or by administration of medications, such as antihistamines, antipyretics, low dose corticosteroids (prednisone and methylprednisolone) or beta-agonist nebulisation.
No patient discontinued treatment with Elaprase due to an infusion reaction during clinical studies.
Severe infusion related reactions were reported occasionally in patients with severe underlying obstructive airway disease. These patients should therefore be closely monitored and infused with Elaprase in an appropriate clinical setting. Delaying Elaprase infusion should be considered in patients who present with an acute febrile respiratory illness. Patients using supplemental oxygen should have this treatment readily available during infusion in the event of an infusion related reaction.
The most serious infusion related reactions include anaphylactoid/ anaphylactic reactions. Biphasic anaphylactoid/ anaphylactic reactions have also been reported with Elaprase. The most common infusion related reactions include cutaneous reactions (rash, pruritis, urticaria), flushing, hypertension, pyrexia, wheezing, hypoxia, dyspnoea, headache, abdominal pain, nausea, dyspepsia, chest pain, and infusion site swelling. If severe allergic or anaphylactoid/ anaphylactic type reactions occur, it is recommended that the administration of Elaprase be discontinued immediately and appropriate medical treatment and observation initiated. The current medical standards for emergency treatment are to be observed. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when Elaprase is administered because of the potential for severe infusion reactions.
Late emergent anaphylactoid/ anaphylactic reactions have been observed in some patients treated with Elaprase up to several years after initiating treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing surveillance). With appropriate pretreatment and monitoring, patients continued weekly Elaprase treatments. Because of the potential for late emergent anaphylactoid reactions, patients who experience initial severe or refractory reactions may require prolonged observation dependent on the clinical needs.

Patients with the complete deletion/ large rearrangement genotype.

Patients with complete deletion are more likely to manifest a severe form of MPS II disease compared to other known genotypes. Paediatric patients with the complete deletion/ large rearrangement genotype have a high probability of developing antibodies, including neutralising antibodies, in response to exposure to Elaprase. Patients with this genotype have a higher probability of developing infusion related adverse events and tend to show a muted response assessed by decrease in uGAG levels, liver size and spleen volume compared to the patients with the missense genotype. In general, patients with the frameshift/ splice site mutation genotype develop antibody responses between those seen in patients with complete deletion/ large rearrangement or missense genotypes. However, individual patients with a complete deletion genotype and high titer antibodies experienced a therapeutic response similar or better than some patients with a missense mutation genotype and no antibody response.

Use in renal/ hepatic impairment.

Because Elaprase is not cleared through renal or hepatic mechanisms, it is believed that patients with renal or hepatic insufficiency would not respond differently to treatment with Elaprase and therefore would not require a dose adjustment.

Use in the elderly.

Clinical studies of Elaprase did not include patients aged 65 and over therefore it has not been determined whether they would respond differently from younger patients.

Paediatric use.

The safety and efficacy of Elaprase have not been established in paediatric patients less than 16 months of age. Patients in the clinical studies were aged 16 months to 18 years of age. Children, adolescents and adults responded similarly to treatment with Elaprase.

Effects on laboratory tests.

Across studies there were no clinical meaningful changes in clinical laboratory parameters.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been conducted with Elaprase. As Elaprase is an enzyme, it would be an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A fertility study was performed in male rats at intravenous doses up to 5 mg/kg, administered twice weekly, and has not revealed evidence of impaired male fertility due to Elaprase.
(Category B2)
There are no adequate and well controlled studies in pregnant women, and no relevant reproductive toxicity studies have been conducted with idursulfase in animals. It is not known whether Elaprase can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Elaprase should not be administered during pregnancy except when the indication and need are clear and the potential benefit is judged by the physician to substantially justify the risk.
It is not known whether Elaprase is excreted in human milk. Therefore, it is recommended that the patient should not breastfeed whilst treated with Elaprase.
Animal studies show that Elaprase is excreted in breast milk and is present in the foetal circulation in utero. Caution should be used when giving Elaprase to pregnant or lactating women after consideration of risks and benefits.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

TKT024.

The most common adverse reactions observed in the 53 week, placebo controlled study were infusion related reactions. In the weekly Elaprase treatment group 202 infusion related reactions were reported in 22 of 32 patients following administration of 1580 weekly infusions.
In the every other week Elaprase treatment group 145 infusion related reactions were reported in 22 of 32 patients following administration of 1629 biweekly infusions. In the placebo treatment group 128 infusion related reactions were reported in 21 of 32 patients. Infusion related reactions reported in the placebo group were similar in nature and severity to those in the Elaprase treated groups.
Table 1 presents adverse drug reactions for Elaprase in a placebo controlled clinical trial and represents a subset of the data presented in Table 2.

In clinical studies, the most frequent serious adverse events related to the use of Elaprase were hypoxic episodes, which necessitated oxygen therapy in three patients with severe underlying obstructive airway disease. 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 one 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 preinfusion medication, usually with low dose corticosteroids, antihistamine and beta-agonist nebulisation.
The most common adverse drug reactions are listed in Table 2. Information is presented by system organ class and frequency (very common > 1/10; common > 1/100, < 1/10). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most serious infusion related reactions include anaphylactoid/ anaphylactic reactions. Biphasic anaphylactoid/ anaphylactic reactions have also been reported with Elaprase. The most common infusion related reactions include cutaneous reactions (rash, pruritus, urticaria and erythema), flushing, hypertension, pyrexia, wheezing, hypoxia, dyspnoea, headache, vomiting, abdominal pain, nausea, dyspepsia, chest pain, and infusion site swelling. An infusion related reaction was defined as an AE that occurred on the day of the infusion (i.e. within 24 hours after receiving an infusion), began either during or after the infusion, was judged as possibly or probably related to study drug, and was not associated with protocol defined testing or assessments. Infusion related reactions were treated or ameliorated by slowing the infusion rate, interrupting the infusion or by administration of medications such as antihistamines, antipyretics, low dose corticosteroids (prednisone and methylprednisolone) or beta-agonist nebulisation. The frequency of infusion related reactions decreased over time with continued Elaprase treatment.
The most common adverse reactions requiring intervention were infusion related reactions, as described above.

Note that clinical trials are conducted under widely varying conditions therefore the observed adverse reaction rates may not predict the rates observed in patients in clinical practice.

Safety in young children.

In a 53 week open label safety study (HGT-ELA-038) including 20 children aged 16 months to 4 years and 8 children aged 5 to 7 years at study entry, the safety profile of weekly Elaprase 0.5 mg/kg doses was similar to that observed in previous clinical studies with almost all adverse reactions being infusion related reactions.

Immunogenicity.

Across 4 clinical studies (TKT08, 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 neutralising 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 neutralising response defined as 3 consecutive samples positive 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, uGAG levels decreased in all antibody status groups, but there was a mild to moderate decrease in the magnitude of the Elaprase induced uGAG response in patients with antibodies, neutralising antibodies 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.
A fifth 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 neutralising antibodies at least once and half of the patients tested positive for neutralising antibodies 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 neutralising antibodies on at least 3 consecutive occasions. All patients with the frameshift/ splice site mutation genotype developed antibodies and 4/6 also tested positive for neutralising antibodies on at least 3 consecutive study visits. Antibody negative patients were found exclusively in the missense mutation genotype group.

Post-marketing surveillance.

Rare cases have been reported of patients who have had symptoms and signs suggestive of late emergent anaphylactoid/ anaphylactic reactions approximately 24 hours after treatment and recovery from an initial reaction. These symptoms required treatment with inhaled beta-adrenergic agonists, adrenaline, antihistamines, corticosteroids and hospitalisation. With appropriate pretreatment and monitoring, patients continued weekly Elaprase treatments. Because of the potential for late emergent anaphylactoid/ anaphylactic reactions, patients who experience initial severe or refractory reactions may require prolonged observation dependent on the clinical needs.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

There is limited information regarding overdose with Elaprase. Evidence suggests the patients may experience an anaphylactoid reaction due to overdose.
Single dose studies of idursulfase have been performed in male rats and cynomolgus monkeys at doses up to 40 times the human dose with no signs of toxicity.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) or the New Zealand National Poisons Information Centre (telephone 0800 POISON or 0800 764 766).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, ATC code: A16AB09.

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 (I2S). I2S functions to catabolise the glycosaminoglycans (GAG) dermatan sulphate and heparan sulphate by cleavage of oligosaccharide linked sulphate moieties. Due to the missing or defective I2S 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.
Treatment of Hunter syndrome patients with Elaprase provides exogenous enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow specific binding of the enzyme to the M6P receptors on the cell surface, leading to cellular internalisation of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.

Clinical trials.

A total of 108 male Hunter syndrome patients with a broad spectrum of symptoms were enrolled in two randomised, placebo controlled clinical studies; 106 continued treatment in two open label, extension studies.
Safety of Elaprase infusions has been assessed in children less than 7.5 years of age in an open label, multicentre, single arm study of 28 male patients.

TKT024.

In a 53 week, randomised, double blind, placebo controlled clinical study (TKT024), 96 patients between the ages of 5 and 31 years received Elaprase 0.5 mg/kg every week (n = 32) or 0.5 mg/kg every other week (n = 32) or placebo (n = 32). The study included patients with a documented deficiency in iduronate-2-sulfatase enzyme activity, a percent predicted forced vital capacity (FVC) < 80% and a broad spectrum of disease severity (see Table 3).
The primary efficacy endpoint was a two component composite score based on the sum of the ranks of the change from baseline to the end of the study in the distance walked during six minutes (6 minute walk test or 6MWT) as a measure of endurance, and % predicted FVC as a measure of pulmonary function. This endpoint differed significantly from placebo for patients treated with Elaprase weekly (p = 0.0049) (see Table 3).
Additional clinical benefit analyses were performed on individual components of the primary endpoint composite score, absolute changes in FVC, changes in urine GAG levels, liver and spleen volumes, measurement of forced expiratory volume in 1 second (FEV₁) and changes in left ventricular mass (LVM).
Urine GAG levels were normalised below the upper limit of normal (defined as 126.6 microgram GAG/mg creatinine) in 50% of the patients receiving Elaprase weekly. None of the placebo patients had normalised urine GAG levels that fell to below the upper limit of normal by week 53.
Of the 25 patients with abnormally large livers at baseline in the Elaprase weekly group, 80% (20 patients) had reductions in liver volume to within the normal range by the end of the study. 4.3% of the patients in the placebo group who had hepatomegaly at baseline improved to normal by week 53.
Of the 9 patients in the Elaprase weekly group with abnormally large spleens at baseline, 3 had spleen volumes that normalised by the end of the study. Among the patients with enlarged spleens at baseline, 18.18% of the placebo patients normalised by week 53.
Approximately half of the patients in the Elaprase weekly group (15 of 32; 47%) had left ventricular hypertrophy (LVH) at baseline, defined as LVM index > 103 g/m². Of these, 6 (40%) had normalised LVM by the end of the study. 22.22% of the placebo patients with LVH at baseline had normal LVM by week 53.

TKT024EXT.

In the extension study (TKT024EXT) in which all patients received weekly idursulfase, statistically significant mean increases from treatment baseline were seen in the distance walked in the 6MWT at the majority of time points tested, with significant mean and percent increases ranging from 13.7 m to 41.5 m and from 6.4% to 11.7%, respectively, (maximum at month 20). At most time points tested, patients in the original TKT024 weekly group improved their walking distance to a greater extent than patients in the other 2 treatment groups.
Percentage predicted FVC remained stable in all Hunter syndrome patients treated for 2 to 3 years with idursulfase 0.5 mg/kg weekly.
At the completion of TKT024EXT, mean urinary 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 mine 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.
The decrease in liver and spleen volumes at week 53 were maintained during the extension study (TKT024EXT) in all patients regardless of prior TKT024 treatment assignment. Seventy one out of 94 patients had hepatomegaly at baseline. Liver volume normalised by month 24 for 73% (52 out of 71) of these patients. In addition, mean liver volume decreased to a near maximum extent by month 8 in all TKT024 treatment groups, increasing slightly from this nadir at month 36. Decreases in mean liver volume were seen regardless of age, disease severity, antibody status, or neutralising antibody status. For the study population as a whole, mean spleen volume also decreased rapidly after the initiation of idursulfase and remained well below mean baseline volume for the duration of the extension study.
In the extension study (TKT024EXT) the mean left ventricular mass index returned to baseline.

HGT-ELA-038.

In an open label, multicentre, single arm study HGT-ELA-038, 28 male patients between the ages of 16 months and 7.5 years received Elaprase 0.5 mg/kg every week.
The study was designed to assess the safety of Elaprase infusions for male patients with Hunter syndrome who are ≤ 5 years old. In addition, this study was to evaluate efficacy, clinical outcomes and Elaprase pharmacokinetics in this patient population.
The primary pharmacodynamic endpoint of this study was measurement of urinary GAG clearance. Exploratory efficacy endpoints included mean change in liver size and spleen volume as measured by ultrasound.
All patient groups experienced a decrease in urinary uGAG levels, liver size and spleen volume after initiation of Elaprase treatment. Patients with the complete deletion/ large rearrangement genotype had a less pronounced decrease in uGAG levels than patients with the missense mutation genotype. In the patients with the complete deletion/ large rearrangement genotype the initial response was followed by an increase in the liver size to approximately baseline values at 53 weeks and spleen volume also increased but remained below baseline values at 53 weeks. Patients with frameshift/ splice genotype had the least pronounced response to Elaprase. These genotype based results are consistent with the antibody based analysis, which showed that patients with antibodies and neutralising antibodies had a slightly less pronounced decrease in uGAG, liver size and spleen volume. It is not possible to predict the individual clinical outcome based on antibody response or genotype.
No data are available on the effect of Elaprase on the neurological or skeletal manifestations of Hunter syndrome.

5.2 Pharmacokinetic Properties

The pharmacokinetic characteristics of idursulfase were evaluated in several studies in patients with Hunter syndrome. 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. The pharmacokinetic parameters at the recommended dose regimen (0.5 mg/kg Elaprase administered weekly as a 3 hour infusion) were determined at week 1 and week 27 in 10 patients ages 7.7 to 27 years (Table 4). There were no apparent differences in pharmacokinetic parameter values between week 1 and week 27.
PK was also evaluated in study HGT-ELA-038 in patients aged 16 months to 7.5 years who received 0.5 mg/ Elaprase as a 3 hour infusion. PK was evaluated at week 1 (n = 27) and week 27 (n = 11) (see Table 5). 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.
The systemic exposure (C_max and AUC_0-∞) and clearance (Cl and V_ss) of Elaprase observed at week 1 in studies TKT024 and HGT-ELA-038 are summarised in Table 4 and Table 5. In the analysis, the patients in TKT024 and HGT-ELA-038 were segmented by age into paediatric (5 to 11 years; n = 11), adolescent (12 to 18 years; n = 8) and adult populations (> 18 years; n = 9) (see Table 6).
At week 1, a higher t_1/2 value for Elaprase was observed in patients 1.4 to 7.5 years, however comparable systemic exposure (i.e. C_max and AUC) and clearance rates (i.e. Cl) behaviours across the age range 1.4 to > 18 years, indicating no appreciable correlation between systemic exposure levels of Elaprase and the patient's age.
The systemic exposure (C_max and AUC_0-∞) and clearance (Cl and V_ss) of Elaprase observed at week 1 for the TKT024 and HGT-ELA-038 studies are summarised in Table 7. In the analysis, patients in the TKT024 and HGT-ELA-038 studies were stratified across five weight categories; < 20 kg, ≥ 20 and < 30 kg, ≥ 30 and < 40 kg, ≥ 40 and < 50 kg and ≥ 50 kg.
A higher volume of distribution at steady state (V_ss) 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 bodyweight.

5.3 Preclinical Safety Data

Genotoxicity.

Studies with idursulfase have not been performed to evaluate genotoxic potential.

Carcinogenicity.

Studies with idursulfase have not been performed to evaluate carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

24.0 mg sodium chloride, 6.75 mg monobasic sodium phosphate monohydrate, 2.97 mg dibasic sodium phosphate heptahydrate, 0.66 mg polysorbate 20.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

Diluted solution.

Elaprase is for single use in one patient only. This product contains no preservatives. To reduce microbial hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°-8°C for no more than 24 hours.

6.4 Special Precautions for Storage

Store Elaprase under refrigeration at 2°C-8°C. Do not freeze or shake. Protect from light. Do not use Elaprase after the expiration date on the vial.
For storage conditions of the diluted medicinal product, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Elaprase is a sterile, aqueous, clear to slightly opalescent colourless solution supplied in a 5 mL Type I glass vial. The vials are closed with a butyl rubber stopper with fluororesin coating and an aluminium overseal with a blue flip-off plastic cap.
Elaprase is supplied as a pack of 1 vial.

6.6 Special Precautions for Disposal

Any unused medicine should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Elaprase (idursulfase) is a purified form of the lysosomal enzyme, iduronate-2-sulfatase. Idursulfase is produced by recombinant DNA technology in a human cell line providing a human glycosylation profile. Idursulfase is a 525 amino acid glycoprotein with 8 N-linked glycosylation sites that are occupied by complex, hybrid and high-mannose type oligosaccharide chains. Idursulfase has a molecular weight of approximately 76 kD.

CAS number.

50936-59-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

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