Consumer medicine information

Aldurazyme

Laronidase

BRAND INFORMATION

Brand name

Aldurazyme

Active ingredient

Laronidase

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Aldurazyme.

What is in this leaflet

This leaflet answers some common questions about ALDURAZYME.

It does not contain all the available information.

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

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

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

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

What ALDURAZYME is used for

ALDURAZYME is used as enzyme replacement therapy in Mucopolysaccharidosis I (MPS I) storage disorder, a disease in which the level of α-L-iduronidase is absent or lower than normal.

How it works

Patients with MPS I disease do not produce enough of their own enzyme, α-L-iduronidase. The reduced or absent α-L-iduronidase activity in patients results in the accumulation of substances called glycosaminoglycans (GAGs) in most cell types and tissues.

ALDURAZYME is an enzyme replacement therapy that is intended to restore a level of enzyme activity sufficient to remove the accumulated GAGs and to prevent further accumulation.

Before you are given ALDURAZYME

When you or your child must not be given it

Do not take ALDURAZYME if you or your child have a known, severe, life-threatening allergic reaction to any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • skin rash, itching or hives

If you are not sure whether you or your child should have ALDURAZYME, talk to your treating physician or nurse.

Before you or your child are given it

Tell your treating physician if you or your child have reacted to previous treatments with any of the following:

  • life-threatening allergic reaction
  • difficulty breathing

Tell your treating physician if you or your child have allergies to:

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

Tell your treating physician if you are pregnant or intend to become pregnant. There is no information available regarding the use of ALDURAZYME in pregnant women. Your treating physician will discuss the possible risks and benefits of having ALDURAZYME during pregnancy.

Tell your treating physician if you are breast-feeding. It is not known whether ALDURAZYME passes into breast milk. Your treating physician will discuss the possible risks and benefits of having ALDURAZYME during breast-feeding.

Tell your treating physician if you or your child have difficulty breathing or suffer from acute breathing problems. Your treating physician will discuss the possible risks and benefits of treatment with ALDURAZYME.

Tell your treating physician if your child is under 5 years of age and has been prescribed ALDURAZYME. If your child has been prescribed ALDURAZYME, you may wish to discuss this with your child's treating physician.

Patients with an acute illness at the time of ALDURAZYME infusion may be at greater risk for infusion-associated reactions. Your treating physician may recommend you receive pre-treatment to minimise your risk of an infusion-associated reaction.

Taking other medicines

Tell your treating physician or nurse if you or your child is taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and ALDURAZYME may interfere with each other. No studies have been carried out on drug interactions.

Tell your treating physician or nurse if you or your child are using medicines with chloroquine (a medicine that is used as an antimalarial) or procaine (a medicine used as local anaesthetic) as these medicines may be affected by ALDURAZYME, or may affect how well it works (different amounts of these medicines may be needed or different medicines may need to be taken). Your treating physician or nurse will advise you and decide whether or not to give you or your child ALDURAZYME.

How ALDURAZYME is given

How much to use

The recommended dosage for ALDURAZYME is 100 U/kg (0.58 mg/kg) of body weight once every week. ALDURAZYME will be given to you or your child directly into the vein (intravenously) by a trained health care professional in a hospital or a clinic.

If you are given too much (overdose)

There have been no reported overdoses of ALDURAZYME.

Your treating physician 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.

Things you or your child must do

Keep appointments with your treating physician or clinic.

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

After having ALDURAZYME

Have any tests when your treating physician says to.

Your treating physician may recommend to perform blood tests to monitor your or your child's body's response to ALDURAZYME to make sure that it is working, and to check your or your child's immune reaction to ALDURAZYME's active ingredient.

Things to be careful of

Be careful driving or operating machinery until you know how ALDURAZYME affects you. The effect of ALDURAZYME on your ability to drive a car or operate machinery has not been studied. Make sure that you know how you react to ALDURAZYME 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 treating physician or nurse as soon as possible if you or your child do not feel well after having ALDURAZYME.

ALDURAZYME may have unwanted side effects. Sometimes the side effects are serious, most of the time they are not. You or your child may need urgent medical treatment if you experience a serious reaction.

Pre-existing upper airway obstruction may contribute to the severity of some reactions.

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

Tell your treating physician or pharmacist if you notice any of the following and they worry you:

  • local reaction around the injection site such as redness, itchiness, tenderness, pain or discomfort, warmth, burning or stinging, swelling or the formation of hard lumps or scars
  • flushing or redness of the skin
  • headaches
  • chest pain
  • soreness, aching muscles, muscle tenderness or weakness (not caused by exercise)
  • chest infection
  • stomach ache

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • sudden signs of allergy such as rash, itching or hives on the skin,
  • swelling of the face, lips, tongue or other parts of the body,
  • shortness of breath, wheezing or trouble breathing

The above list includes side effects which may be very serious. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Storing ALDURAZYME

ALDURAZYME will be stored in the hospital or clinic pharmacy.

Product Description

What it looks like

ALDURAZYME is a colourless to pale yellow, clear to slightly opalescent solution.

Ingredients

Active ingredient:
laronidase

Other ingredients:
sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, polysorbate 80 and water for injections.

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park, NSW 2113
Australia
Toll Free Number: 1800 818 806

sanofi-aventis new zealand limited
56 Cawley Street Ellerslie
Auckland
New Zealand
Tell Free Number: 0800 283 684

Email: [email protected]

AUST R 100847

ALDURAZYME® is manufactured by BioMarin Pharmaceutical Inc, USA.

ALDURAZYME® is a registered trademark of BioMarin/Genzyme LLC.

This leaflet was prepared in September 2019

aldu-ccdsv2011-12-28-cmiv3-18sep19

Published by MIMS November 2019

BRAND INFORMATION

Brand name

Aldurazyme

Active ingredient

Laronidase

Schedule

S4

 

1 Name of Medicine

Laronidase-rch.

2 Qualitative and Quantitative Composition

The extractable volume of 5.0 mL from each vial provides 2.9 mg (500 U) laronidase, 43.9 mg sodium chloride, 63.5 mg monobasic sodium phosphate monohydrate, 10.7 mg dibasic sodium phosphate heptahydrate, and 0.05 mg polysorbate 80. Aldurazyme does not contain preservatives; vials are for single use only. See Section 6.1 List of Excipients.

3 Pharmaceutical Form

Aldurazyme is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, colourless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration.

4 Clinical Particulars

4.1 Therapeutic Indications

Aldurazyme is indicated as long-term enzyme replacement therapy in patients with mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency) to treat the non-neurological manifestations of the disease.

4.2 Dose and Method of Administration

Aldurazyme treatment should be supervised by a physician experienced in the management of patients with MPS I or other inherited metabolic diseases. Administration of Aldurazyme should be carried out in an appropriate clinical setting where resuscitation equipment to manage clinical emergencies would be readily available.
The recommended dosage regimen of Aldurazyme is 100 U/kg (0.58 mg/kg) of actual bodyweight administered once weekly as an intravenous infusion.
Pretreatment with antipyretics and/or antihistamines is recommended 60 minutes prior to the start of the infusion. In the phase 3 studies, all patients were pretreated prior to each infusion with age appropriate dosages of antihistamines and antipyretics, such as diphenhydramine or hydroxyzine and paracetamol or ibuprofen, respectively (see Section 4.4 Special Warnings and Precautions for Use, General).
The total volume of the infusion is determined by the patient's actual bodyweight and should be delivered over approximately 3 to 4 hours. Patients with an actual bodyweight of 20 kg or less should receive a total volume of 100 mL. Patients with an actual bodyweight of greater than 20 kg should receive a total volume of 250 mL. The initial infusion rate of 2 U/kg/hr (equivalent to 2 mL/hr in patients with an actual bodyweight of 20 kg or less or 5 mL/hr in patients with an actual bodyweight of greater than 20 kg) may be incrementally increased (doubled) every 15 minutes during the first hour, as tolerated, until a maximum infusion rate of 43 U/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hours).
Each vial of Aldurazyme contains 500 U (100 U/mL; 0.58 mg/mL) of laronidase and is intended for single use only. The concentrate for solution for infusion must be diluted with 0.9% sodium chloride for injection, using aseptic techniques. In the absence of stability studies using glass containers, it is recommended that Aldurazyme be prepared and administered using PVC containers. It is recommended that the Aldurazyme solution be administered with a PVC infusion set equipped with an inline, low protein binding 0.2 micrometre filter.
Studies in patients with hepatic or renal insufficiency have not been performed.

Instructions for reconstitution and use (aseptic techniques).

The Aldurazyme solution should not be shaken, as this may cause a decrease in the potency of the product.
1. Prepare an infusion bag of 0.9% sodium chloride for injection. Determine the total volume of the infusion to be used based on the patient's bodyweight. The total final volume should be either 100 mL (if weight is less than or equal to 20 kg) or 250 mL (if weight is greater than 20 kg).
2. Determine the number of vials to be diluted based on the individual patient's weight and the recommended dose of 100 U/kg. (Patient's weight (kg) x 1 mL/kg Aldurazyme = number mL of Aldurazyme.) Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat or microwave vials.
3. Before dilution, visually inspect each vial for particulate matter and discolouration. The Aldurazyme solution should be clear to slightly opalescent and colourless to pale yellow. A few translucent particles may be present. Do not use if the solution is discoloured.
4. Withdraw and discard a volume of the 0.9% sodium chloride for injection from the infusion bag, equal to the volume of Aldurazyme concentrate to be added.
5. Slowly withdraw the calculated volume of Aldurazyme (laronidase) from the appropriate number of vials using caution to avoid excessive agitation.
6. Slowly add the Aldurazyme solution to the 0.9% sodium chloride for injection, using care to avoid agitation of the solutions.
7. Gently rotate the infusion bag to ensure proper distribution of Aldurazyme. Prior to use, visually inspect the solution for particulate matter. Only clear and colourless solutions, practically free of visible particles, should be used. Do not shake the solution.
8. It is recommended that the diluted solution be filtered through an in-line low protein-binding 0.2 micrometre filter during administration.
Aldurazyme does not contain any preservatives, therefore, after dilution with saline in the infusion bags, any unused product or waste material should be disposed of in accordance with local requirements.
Aldurazyme must not be mixed with other medicinal products in the same infusion.

Home infusion.

Infusion of Aldurazyme at home may be considered for patients who are tolerating their infusions well and have no history of moderate or severe IARs for a few months. The decision to have a patient move to home infusion should be made after evaluation and upon recommendation by the treating physician.
Home infusion infrastructure, resources, and procedures, including training, must be established and available to the healthcare professional. Home infusion must be administered by a suitably trained and qualified healthcare professional who should be always available during the home infusion and for a specified time after infusion. Appropriate information should be given by the treating physician and/or nurse to the patient and/or caregiver prior to initiation of home infusion.
Dose and infusion rate should remain constant while at home, and not be changed without supervision of a treating physician.
If the patient experiences adverse reactions during the home infusion, the infusion process should be stopped immediately, and appropriate medical treatment should be initiated (see Section 4.4). Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient care until no such adverse reaction is present.
A home infusion guide for HCPs and patients/carers is available to provide home infusion information related to Aldurazyme.

4.3 Contraindications

Aldurazyme is contraindicated in patients with known, severe, life threatening hypersensitivity (anaphylactic reaction) to laronidase or any of the components of the formulation.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions/risk of anaphylaxis.

Life threatening anaphylactic reactions have been observed in some patients during Aldurazyme infusions. Therefore, appropriate medical support should be readily available when Aldurazyme is administered. 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.
Patients treated with Aldurazyme may develop infusion associated hypersensitivity reactions (including anaphylaxis). Some of these reactions were life threatening and included respiratory failure, respiratory distress. stridor, tachypnea, bronchospasm, obstructive airways disorder, hypoxia, hypotension, bradycardia, and urticaria.
If severe allergic or anaphylactic reactions occur, immediate discontinuation of the administration of Aldurazyme should be considered and an appropriate treatment initiated (see Section 4.8 Adverse Effects (Undesirable Effects)). The risks and benefits of readministering Aldurazyme following a severe hypersensitivity or anaphylactic reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to readminister the product.
Caution should be used if considering the administration of adrenaline to MPS I patients due to the increased prevalence of coronary artery disease in these patients.

General.

Patients with an acute illness at the time of Aldurazyme infusion appear to be at greater risk for infusion related reactions. Careful consideration should be given to the patient's clinical status prior to administration of Aldurazyme. One patient with acute bronchitis and hypoxia experienced increased tachypnoea during the first Aldurazyme infusion that resolved without intervention. The patient's respiratory symptoms returned within 30 minutes of completing the infusion and responded to bronchodilator therapy. Approximately 6 hours after the infusion, the patient experienced coughing, then respiratory arrest and died.
The diagnosis, assessment and management of MPS I should only be undertaken by physicians with experience and training in the treatment of inherited diseases of metabolism. Aldurazyme therapy should be initiated by a physician with experience in the management of patients with MPS I.
As with any intravenously administered protein product, patients may develop reactions associated with the administration of the protein (infusion associated reactions (IARs)) (see Section 4.8 Adverse Effects (Undesirable Effects)). These patients should be treated with caution when readministering Aldurazyme. In the phase 3 clinical studies with Aldurazyme, most IARs were successfully treated by slowing the rate of infusion and by administering antihistamines and antipyretics, thus enabling the continuation of treatment (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration).

Immunogenicity.

Almost all patients treated with Aldurazyme developed IgG antibodies to Aldurazyme during the clinical studies. The onset of anti-drug antibodies (ADA) positivity in most patients occurred within 3 months after starting Aldurazyme treatment and generally declined over time. Higher ADA titres were observed in patients with more severe forms of MPS I. Patients with persistently high ADA titres tended to have less reduction in urinary GAG. In patients with clinical decline, consider assessing urinary GAGs, ADA and neutralising antibodies.
Overall, a small number of patients have tested positive for IgE antibodies. The development of IgE antibodies may be associated with hypersensitivity or anaphylactic reactions (see Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity reactions/risk of anaphylaxis).
In the phase 3 double blind study and the open label extension study, almost all of the patients developed Aldurazyme specific IgG antibodies; thus, seroconversion is expected to occur in the majority of patients treated with Aldurazyme. In the phase 3 double blind study, the safety profiles for Aldurazyme and placebo were similar. In the open label extension study, 2 of the patients who received a total of 50 weeks of Aldurazyme treatment no longer had detectable IgG antibodies to Aldurazyme. Patients who have developed antibodies or symptoms of IARs should be treated with caution when administering Aldurazyme.
It is suggested that patients be monitored as clinically indicated for Aldurazyme specific IgG antibody formation.

Use in the elderly.

Clinical studies of Aldurazyme did not include patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

Safety and effectiveness of Aldurazyme in paediatric patients from ages 5 to 16 have been studied in the 3 clinical studies. Safety and effectiveness in patients below the age of 5 have not been established.

Effect on laboratory tests.

No effects on laboratory tests have been identified.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interaction studies have been conducted. Based on its metabolism, laronidase is an unlikely candidate for cytochrome P450 mediated drug-drug interactions. Interaction studies with food and drinks have not been performed; interactions are unlikely given the mechanism of action and the IV route of administration.
Aldurazyme should not be administered simultaneously with chloroquine or procaine due to a theoretical risk of interference with the intracellular uptake of laronidase.
Aldurazyme must not be mixed with other medicinal products in the same infusion.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no clinical data on the effects of laronidase on fertility.
Reproductive studies showed no impairment of mating or fertility after rats received daily IV doses of 0, 0.036, 0.36, or 3.6 mg/kg/day Aldurazyme from 28 days before cohabitation until sacrifice after 7 days of cohabitation (males) or from 15 days before cohabitation until gestation day 7 (females; sacrificed at gestation day 21). There were no treatment related effects on sperm parameters, litter parameters, or foetal gross external development at exposure levels equivalent to ca. 9 times the proposed human weekly dose on a body surface area basis.
(Category B2)
Studies in rats at IV doses of 1.3 times the proposed human doses on a body surface area basis (9.3 times when calculated on a weekly basis) did not indicate direct or indirect harmful effects on embryofoetal development. However, there are no data for the use of Aldurazyme in pregnant women and Aldurazyme should not be used during pregnancy unless clearly necessary.
 It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aldurazyme is administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

The most serious adverse reactions reported with Aldurazyme during clinical trials and the postmarketing period were anaphylactic and allergic reactions (see Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity reactions/risk of anaphylaxis). In the clinical studies, one patient developed a severe anaphylactic reaction approximately 3 hours after the initiation of the infusion (at week 62 of treatment) which consisted of urticaria and airway obstruction. Resuscitation required emergency tracheostomy. The patient's pre-existing upper airway obstruction may have contributed to the severity of the reaction. In addition, a 3-year old, severely affected patient who was treated in the postmarketing setting experienced an anaphylactic reaction and respiratory arrest during an Aldurazyme infusion requiring ventilatory support, adrenaline and corticosteroids. Both patients subsequently discontinued Aldurazyme treatment.
The most common adverse reactions associated with Aldurazyme treatment in the clinical studies were upper respiratory tract infection, rash, and injection site reaction.
The most common adverse reactions requiring intervention were infusion related reactions, particularly flushing. Most infusion related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion and/or administering additional antipyretics and/or antihistamines.
Overall infusion site reactions with laronidase administration are very common. During clinical trials and postmarketing experience, infusion/injection site reactions included: extravasation, swelling, pain, erythema, edema, discomfort, urticaria, pallor, macule, and warmth.
The data described below reflect exposure to 100 U/kg (0.58 mg/kg) of Aldurazyme for 26 weeks in a placebo controlled double blind study in 45 patients with MPS I (n = 22 Aldurazyme, and n = 23 placebo). All 45 patients continued into an open label study of Aldurazyme treatment for an additional 36 weeks. An additional 10 patients participated in a phase 1 open label study with continued infusions for up to 3 years. The population in the placebo controlled study was evenly distributed for gender (n = 23 females and n = 22 males) and ranged in ages from 6 to 43 years. Of the 45 patients in the placebo controlled study, 1 was clinically assessed as having Hurler form, 37 Hurler-Scheie and 7 Scheie. All patients were treated with antipyretics and antihistamines prior to the infusions.
Because clinical trials are conducted under widely varying and controlled conditions, the observed adverse reaction rates may not predict the rates observed in patients in clinical practice.
Table 1 enumerates adverse events and selected laboratory abnormalities that occurred during the placebo controlled trial in at least 2 patients more in the Aldurazyme group than was observed in the placebo group. Reported adverse events have been classified using standard WHOART terms. Observed adverse events in the phase 1 study and the open label treatment period following the controlled study were not different in nature or severity.
In the postmarketing experience, the most frequently reported adverse reactions (using MedDRA terminology) included chills, vomiting, nausea, arthralgia, diarrhoea, tachycardia, abdominal pain, blood pressure increase and oxygen saturation decrease. Additional significant adverse drug reactions included serious reports of infusion related bronchospasm that required treatment adrenaline, corticosteroids and/or oxygen therapy. Some of these patients were successfully rechallenged with Aldurazyme.

Infusion-associated reactions.

In a clinical study, infusion associated reactions (IARs) were reported in 7 of 22 patients treated with Aldurazyme. IARs were not significantly different between the Aldurazyme treatment group and the placebo group who received infusions of diluent and all components of Aldurazyme except the laronidase enzyme. The most common IARs included flushing, fever, headache and rash. Flushing occurred in 5 patients (23%) receiving Aldurazyme; other reactions were less frequent. There was one case of anaphylaxis during the open label extension setting and one additional case received for a patient treated in the postmarketing setting. Less common IARs include cough, bronchospasm, dyspnoea, urticaria, angioedema and pruritus.
All reactions were mild to moderate in severity. The frequency of IARs decreased with continued use during the open label extension use.

Post marketing experience.

In addition to the infusion reactions reported in clinical trials, the following infusion reactions have been reported in patients during postmarketing use of Aldurazyme: cough, dyspnoea, oxygen saturation decreased/hypoxia, tachypnoea, cyanosis, respiratory failure, drug specific antibody, neutralising antibodies, hypersensitivity, bradycardia, and manifestations of angioedema such as facial oedema and laryngeal oedema. Additional significant adverse drug reactions (ADRs) have included serious reports of infusion associated bronchospasm that required treatment with adrenaline, corticosteroids and/or oxygen therapy. Some patients were successfully rechallenged.
Other infusion reactions reported patients during postmarketing experience include: pallor, fatigue, erythema, oedema peripheral, paresthesia, feeling hot, and feeling cold.
There have been a small number of reports of extravasation in patients treated with Aldurazyme. There have been no reports of tissue necrosis associated with extravasation.

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.

4.9 Overdose

Inappropriate administration of laronidase (overdose and/or infusion rate higher than recommended) may be associated with adverse drug reactions. An excessively fast administration of laronidase may result in nausea, abdominal pain, headache, dizziness and dyspnea.
If signs or symptoms occur associated with overdose or an infusion rate higher than recommended, the infusion must be stopped immediately. If medically appropriate, further intervention may be indicated.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). Mucopolysaccharidosis I (MPS I) is characterised by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAG substrates dermatan sulfate and heparan sulfate throughout the body and leads to widespread cellular, tissue and organ dysfunction.
The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyse the accumulated substrate and to prevent further accumulation. After intravenous infusion, laronidase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely by the mannose-6 phosphate receptors.

Clinical trials.

Three clinical studies have assessed the somatic manifestations of MPS I during treatment with Aldurazyme. No clinical data exist demonstrating a benefit on the neurological manifestations of the disorder.
The safety and efficacy of Aldurazyme were assessed in a randomised, double blind, placebo controlled, multicentre phase 3 study of 45 MPS I patients. Patients received either 100 U/kg (0.58 mg/kg) of Aldurazyme or placebo once weekly for a total of 26 consecutive weeks. All patients were pretreated with antipyretics and antihistamines.
The 2 primary efficacy variables were forced vital capacity (FVC) and the 6 minute walk test (6MWT). After 26 weeks of treatment, Aldurazyme treated patients showed a significant improvement in lung function as measured by the change in percent of predicted normal FVC (mean difference from placebo 5.9 percentage points; median difference from placebo 3.0 percentage points, p = 0.016). Patients who received Aldurazyme (n = 22) improved from a mean of 48.4 to 53.7 percent of predicted normal FVC, whereas patients receiving placebo (n = 23) declined from a mean of 54.2 to 53.6 percent of predicted normal FVC (Figure 1). In Aldurazyme treated patients there was an improvement in walking ability, as measured by the distance traveled in the 6MWT (mean difference from placebo 38.1 metres; median difference from placebo 38.5 metres, p = 0.066). Patients who received Aldurazyme (n = 22) improved from a mean of 319.1 to 338.8 metres, whereas patients receiving placebo (n = 23) showed a mean decline from 366.7 to 348.3 metres (Figure 2).
In addition, a significant reduction in liver size, as measured by MRI, was observed when compared to placebo (p = 0.001). Normalisation of liver volume occurred in 72% of the Aldurazyme treated patients who had hepatomegaly at baseline. Urinary GAG excretion showed a rapid decline in Aldurazyme treated patients that was maintained through the remainder of the study (p < 0.001). No significant improvement was captured in the course of the study with the quality of life instruments used. These instruments were not specifically adapted for patients with MPS I. Apnoea/hypopnoea index and joint range of motion did not show statistically significant improvement in the intent to treat population. However, the study was not powered for these secondary variables and many patients had normal values at baseline.
All 45 patients who participated in the phase 3 double blind study were enrolled in an open label extension study. For patients previously treated with Aldurazyme, after an additional 24 weeks of treatment the mean increase from baseline in distance walked during the 6MWT was 42.9 metres (an additional 23.2 metres from start of the phase 3 open label extension study). Improvements seen in percent of predicted FVC and GAG excretion during the phase 3 double blind study were maintained. Reductions in liver size continued to be observed through week 24 of the open label extension study and normalisation of liver volume occurred in 80% of the patients who had hepatomegaly at baseline.
For patients previously treated with placebo, after 24 weeks of Aldurazyme treatment the increase in the mean distance walked during the 6MWT (23.8 m), and the improvements seen in GAG excretion were similar to those noted in the Aldurazyme group in the phase 3 double blind study. Reductions in liver size were observed after 24 weeks of treatment and normalisation of liver volume occurred in 50% of the patients who had hepatomegaly at entry into the open label extension study. The change in percent of predicted FVC was not significant after 24 weeks of treatment.
In a phase 1/2 open label study, 10 MPS I patients received 100 U/kg of Aldurazyme every week for up to 1 year. Subsequently, through a continuation of the study, patients received treatment for up to 3 years. The primary endpoints for this study were reductions in hepatosplenomegaly and urinary GAG excretion. After 1 year of treatment with Aldurazyme, the mean reductions in liver and spleen size were 26% and 21%, respectively, resulting in the normalisation of liver size in 9 of 10 patients. The mean reductions in liver and spleen size were maintained over the additional year of follow-up treatment. Urinary GAG excretion showed a mean decrease of 63% after 1 year, which decreased further with continued treatment; there was a 74% reduction at week 104 and a 79% reduction at week 152.

5.2 Pharmacokinetic Properties

Pharmacokinetics of laronidase were evaluated in 12 MPS I patients following the 1st, 12th and 26th infusions. After intravenous administration of laronidase with a mean infusion time of 4 hours and at a dose of 100 U/kg (0.58 mg/kg) bodyweight, once weekly, the mean maximum plasma concentrations (Cmax) ranged from 0.20 to 0.30 U/mL for the 3 time points. The mean area under the plasma concentration time curve (AUC∞) ranged from 0.93 to 1.19 h.U/mL. The mean volume of distribution (Vz) ranged from 0.24 to 0.60 L/kg, and the mean volume of distribution at steady state (Vss) ranged from 0.22 to 0.44 L/kg. Mean plasma clearance (CL) ranged from 1.7 to 2.3 mL/min/kg, and the mean elimination half-life (t1/2) ranged from 1.94 to 3.61 hours. Cmax showed an increase over time. The volume of distribution decreased with continued treatment, possibly related to antibody formation and/or decreased liver volume.
Laronidase is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of laronidase in a clinically significant way. Renal elimination of laronidase is considered to be a minor pathway for clearance.

5.3 Preclinical Safety Data

Genotoxicity.

No data is available.

Carcinogenicity.

Studies to assess the mutagenic and carcinogenic potential of laronidase have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride 43.9 mg, monobasic sodium phosphate, monohydrate 63.5 mg, dibasic sodium phosphate, heptahydrate 10.7 mg, polysorbate 80 0.05 mg.

6.2 Incompatibilities

Aldurazyme must not be mixed with other medicinal products in the same infusion except those mentioned in Section 4.2 Dose and Method of Administration.

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.
From a microbiological point of view, the diluted solution should be used immediately. If not used immediately, in-use storage and conditions prior to use are the responsibility of the user and should not be longer than 24 hours when refrigerated (2°C to 8°C).

6.4 Special Precautions for Storage

Store Aldurazyme under refrigeration at 2°C to 8°C. Do not freeze or shake. Protect from light. Do not use Aldurazyme after the expiration date on the vial. This product contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.

6.5 Nature and Contents of Container

Aldurazyme is supplied in a sterile solution in clear Type I glass 5 mL vials. The closure consists of a siliconised butyl stopper and an aluminium seal with a plastic flip-off cap.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
Aldurazyme does not contain any preservatives, therefore, after dilution with saline in the infusion bags, any unused product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Aldurazyme is produced by recombinant DNA technology and is a replacement therapy for the human enzyme, α-L-iduronidase. Purified laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N terminus and contains 6 N linked oligosaccharide modification sites. Laronidase is produced by a genetically engineered Chinese hamster ovary cell line. The protein is purified by a column chromatography process that includes steps to inactivate and remove potential viruses, resulting in a highly purified, active protein.
The Aldurazyme solution has a nominal laronidase concentration of 100 U/mL (0.58 mg/mL) and a pH of approximately 5.5.

CAS number.

210589-09-6.

7 Medicine Schedule (Poisons Standard)

S4, Prescription only medicine.

Summary Table of Changes