Consumer medicine information

Myozyme

Alglucosidase alfa

BRAND INFORMATION

Brand name

Myozyme

Active ingredient

Alglucosidase alfa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Myozyme.

SUMMARY CMI

MYOZYME®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Myozyme?

Myozyme contains the active ingredient alglucosidase alfa-rch. Alglucosidase alfa-rch is a type of protein. Myozyme is used to treat Pompe disease, a rare genetic disease in which the level of an enzyme called acid alfa-glucosidase is missing or is lower than in healthy individuals. Myozyme is used as a replacement to the lack of or low levels of the enzyme.

For more information, see Section 1. Why am I using Myozyme? in the full CMI.

2. What should I know before I use Myozyme?

Do not use if you have ever had an allergic reaction to alglucosidase alfa-rch or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Myozyme? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Myozyme and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Myozyme?

  • The recommended dosage for Myozyme is 20 mg/kg of body weight once every two weeks. Myozyme 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.

More instructions can be found in Section 4. How do I use Myozyme? in the full CMI.

5. What should I know while using Myozyme?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Myozyme.
  • Keep appointments with your treating physician or clinic.
  • Have any tests when your treating physician says to.
  • Call your doctor straight away if you or your child have experienced loss in mobility since the last Myozyme infusion.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Myozyme affects you.
  • Make sure that you know how you react to Myozyme before you do anything else that may be dangerous if you are dizzy, light-headed, tired or drowsy.
Looking after your medicine
  • Myozyme should be stored in the hospital or clinic pharmacy under refrigeration at 2°C - 8°C.
  • After reconstitution and dilution, Myozyme should be protected from light.

For more information, see Section 5. What should I know while using Myozyme? in the full CMI.

6. Are there any side effects?

  • Common side effects include nausea, feeling hot, headache, sleepiness, fainting, burning sensation and increased tear production. Serious side effects include dizziness and lightheadedness, bluish tinged skin, fast heart beat/rate, fever or high temperature, itchy rash, hives, itching or rash, flushing or redness of skin, pale skin, redness, swelling or pain around infusion site, severe skin reactions, difficulty breathing, wheezing or coughing, fast breathing, vomiting or retching, cramps, irritability or agitation, increased sweating and swelling of the face.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

MYOZYME® [my-oh-ZIME]

Active ingredient(s): Alglucosidase alfa-rch [al-glue-co-SIDE-aze al-fa R.C.H]

Consumer Medicine Information (CMI)

This leaflet provides important information about using Myozyme. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Myozyme.

Where to find information in this leaflet:

1. Why am I using Myozyme?
2. What should I know before I use Myozyme?
3. What if I am taking other medicines?
4. How do I use Myozyme?
5. What should I know while using Myozyme?
6. Are there any side effects?
7. Product details

1. Why am I using Myozyme?

Myozyme contains the active ingredient alglucosidase alfa-rch. Alglucosidase alfa-rch is a type of protein.

Myozyme is used to treat Pompe disease, a rare genetic disease in which the level of an enzyme called acid alfa-glucosidase is missing or is lower than in healthy individuals. Myozyme is used as a replacement to the lack of or low levels of the enzyme.

Myozyme is available only with a doctor's prescription. Only the treating physician can start the treatment and supervise the ongoing treatment.

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

How Myozyme works

Patients with Pompe disease do not produce enough of their own enzyme, acid alfa-glucosidase. The reduced acid alfa-glucosidase activity in patients results in the build up of glycogen in many parts of the body. Myozyme is an enzyme replacement therapy that is intended to restore a level of enzyme activity sufficient to remove the accumulated glycogen and to prevent further accumulation.

Pompe disease has been described under 2 forms: early-onset and late-onset. Your physician is in the best position to determine the risks and benefits of treatment with Myozyme and he will discuss it with you or your child.

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

This medicine is only available with a physician's prescription.

It is not addictive.

2. What should I know before I use Myozyme?

Warnings

Do not use Myozyme if:

  • you are allergic to alglucosidase alfa-rch, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition
  • or your child have allergies to: any other medicines and/or any other substances, such as foods, preservatives or dyes
  • or your child have experienced loss in mobility since the last Myozyme infusion.

Your treating physician may recommend to perform blood tests to monitor your or your child's body's response to Myozyme to make sure that it is working, especially if you or your child have experienced a loss of mobility since the last Myozyme infusion, to check your or your child's immune reaction to Myozyme active ingredient or if you have experienced certain side effects.

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

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

There is limited experience of the use of Myozyme in pregnant women. Your treating physician will discuss the possible risks and benefits of having Myozyme during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

There is limited information available regarding the use of Myozyme in breastfeeding women. Myozyme may be found in breast milk. The continuation of treatment for Pompe disease during pregnancy and breast-feeding should be individualised. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

If you have not told your treating physician about any of the above, tell them before you or your child are given Myozyme.

Tell your treating physician if you or your child have received Myozyme or another drug, and experienced any of the following conditions:

  • life-threatening allergic reaction
  • difficulty breathing

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Tell your treating physician or nurse if you or your child are receiving treatment with medicines that suppress your immune system, because you or your child have Pompe disease, there is a risk that you get a severe infection of your airways or lungs. Using these medicines to suppress the immune system may further increase this risk.

Some medicines may interfere with Myozyme and affect how it works.

Tell your treating physician or nurse if you or your child are using other medicines as these medicines may be affected by Myozyme 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 Myozyme.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Myozyme.

4. How do I use Myozyme?

How much to use

  • The recommended dosage for Myozyme is 20 mg/kg of body weight once every two weeks. Myozyme 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.
  • Follow the instructions provided and use Myozyme until your doctor tells you to stop.

When to use Myozyme

  • Myozyme is given by infusion once every 2 weeks.

How to use Myozyme

  • Myozyme will be prepared and given to you or your child by a treating physician or a nurse.
  • Myozyme will be reconstituted, diluted and should be protected from light before it is given to you or your child. It is given as a drip through a needle placed into a vein (intravenous infusion), usually in the arm. This takes approximately 4 hours.
  • A few patients have had an allergic reaction to Myozyme. Your or your child's treating physician or nurse will check for allergic reactions during the infusion. Your or your child's treating physician may decide to check for allergic reactions some time after the infusion. You may need to be given pre-treatment medicines to prevent an allergic reaction (e.g. antihistamines and/or corticosteroids) or to reduce fever (antipyretics).
  • In studies, doctors have used medicines to suppress the immune system to reduce the production of antibodies. Because you or your child have Pompe disease, there is a risk that you could get a severe infection of your airways or lungs. Using these medicines to suppress the immune system may further increase this risk.
  • Infusion with Myozyme should start as soon as possible after the medicine has been reconstituted and diluted. If not used immediately, the solution must be stored at 2°C - 8°C and infused within 24 hours of reconstitution and dilution.
  • You may be at an increased risk of an infusion associated reaction (IAR), if you are given Myozyme at a higher dose or infusion rate than recommended. If you experience IARs you should tell your doctor immediately.

How long to use it

  • It is important to continue treatment with Myozyme unless your treating physician tells you or your child to stop.

If you miss a dose of Myozyme

If have any concerns, talk to your doctor and arrange another visit as soon as possible.

If you received too much Myozyme

Overdose is most unlikely because your physician gives the infusions. If you have any concerns, ask your doctor.

5. What should I know while using Myozyme?

Things you should do

Keep appointments with your treating physician or clinic.

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

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 Myozyme to make sure that it is working, especially if you or your child have experienced a loss of mobility since the last Myozyme infusion and to check your or your child's immune reaction to Myozyme active ingredient.

Call your doctor straight away if you:

  • or your child have experienced loss in mobility since the last Myozyme infusion.

Remind any doctor, dentist or pharmacist you visit that you are using Myozyme.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Myozyme affects you.

The effect of Myozyme on your ability to drive a car or operate machinery has not been studied. Make sure that you know how you react to Myozyme 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.

Looking after your medicine

  • Myozyme should be stored in the hospital or clinic pharmacy under refrigeration at 2°C - 8°C.
  • After reconstitution and dilution, Myozyme should be protected from light.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
General:
  • headache
  • nausea
  • sleepiness
  • fainting
  • burning sensation
Other:
  • increased tear production
  • feeling hot
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reaction-related:
  • difficulty breathing, wheezing or coughing
  • fast breathing
  • itchy rash, hives, itching or rash
  • swelling of the face
  • increased sweating
  • fever or high temperature
  • flushing or redness of skin
Heart-related:
  • fast heart beat/rate
Infusion site-related:
  • redness, swelling or pain around infusion site
Skin-related:
  • bluish tinged skin
  • pale skin
  • severe skin reactions
Other:
  • dizziness and lightheadedness
  • vomiting or retching, cramps
  • irritability or agitation
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Myozyme contains

Active ingredient
(main ingredient)
  • alglucosidase alfa
Other ingredients
(inactive ingredients)
  • mannitol
  • monobasic sodium phosphate monohydrate
  • dibasic sodium phosphate heptahydrate
  • polysorbate 80
Potential allergensNo

Do not take this medicine if you are allergic to any of these ingredients.

What Myozyme looks like

Myozyme is supplied in a clear glass vial and is a white to off-white powder before it is prepared for infusion and a clear, colourless to pale yellow solution when it is prepared for infusion, which may contain particles. (Aust R 136005).

Who distributes Myozyme

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: [email protected]

Myozyme® is a registered trademark of Genzyme Corporation, USA.

This leaflet was prepared in November 2023.

myoz-ccdsv11-cmi6-09nov23

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Myozyme

Active ingredient

Alglucosidase alfa

Schedule

S4

 

1 Name of Medicine

Alglucosidase alfa.

2 Qualitative and Quantitative Composition

Each 50 mg vial contains 52.5 mg alglucosidase alfa.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for concentrate for solution for infusion. Following reconstitution as directed, each vial contains 10.5 mL reconstituted solution and a total extractable volume of 10 mL at 5.0 mg/mL alglucosidase alfa. Myozyme does not contain preservatives.
Each vial is for single use only.
Each reconstituted vial must be diluted prior to administration in 0.9% sodium chloride for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Myozyme is indicated for the long-term treatment of patients with a confirmed diagnosis of Pompe disease (acid alfa-glucosidase deficiency).

4.2 Dose and Method of Administration

Dose.

The recommended dosage regimen of Myozyme is 20 mg/kg of bodyweight administered once every 2 weeks as an intravenous infusion.

Elderly population.

Clinical studies did not include any subjects aged 65 years and older. It is not known whether they respond differently than younger subjects.

Paediatric population.

There is no evidence for special considerations when Myozyme is administered to paediatric patients of all ages.

Method of administration.

Each reconstituted vial must be diluted prior to administration in 0.9% sodium chloride for injection.
For instructions on reconstitution and dilution of the medicine before administration, see Section 6.6 Special Precautions for Disposal.
Infusions should be administered incrementally. Myozyme should be administered at an initial infusion rate of no more than 1 mg/kg/hr. The infusion rate may be increased by 2 mg/kg/hr every 30 minutes, after patient tolerance to the infusion rate is established, until a maximum rate of 7 mg/kg/hr is reached. Appropriate medical support measures should be readily available when Myozyme is administered because of the potential for severe infusion reactions. The infusion rate may be slowed and/or temporarily stopped in the event of Infusion Associated Reactions (IARs).

4.3 Contraindications

Hypersensitivity (anaphylactic reaction) to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Risk of hypersensitivity reactions.

Serious hypersensitivity reactions, including life threatening anaphylactic reactions, have been observed in infantile and late onset Pompe patients during Myozyme infusion, some of which were IgE mediated. A small number of patients (< 1%) in clinical trials and in the commercial setting developed anaphylactic shock and/or cardiac arrest during Myozyme infusion that required life support measures. Reactions included bronchospasm, wheezing, respiratory arrest, respiratory distress, apnoea, stridor, dyspnoea, oxygen saturation decreased, cardiac arrest, hypotension, bradycardia, tachycardia, cyanosis, vasoconstriction, flushing, chest pain, chest discomfort, throat tightness, angioedema, pharyngeal oedema, face oedema, peripheral oedema, urticaria, and rash.
If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of the administration of Myozyme should be considered and appropriate medical treatment should be initiated. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when Myozyme is administered because of the potential for severe infusion reactions.
The risks and benefits of re-administering alglucosidase alfa following an anaphylactic or severe hypersensitivity reaction should be considered. Some patients have been rechallenged and have continued to receive alglucosidase alfa under close clinical supervision. Extreme caution should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.

Immunogenicity.

There are no marketed tests for antibodies against alglucosidase alfa. It is recommended that patients be monitored for IgG antibody formation every 3 months. If testing is warranted, contact Sanofi Genzyme at 1800 818 806 for information on testing and to obtain a sample collection box.
In clinical studies, the majority of patients, i.e. 89% (34/38) developed IgG antibodies to alglucosidase alfa, typically within 3 months of treatment. Patients treated with higher doses of Myozyme tended to develop a more robust antibody response and experienced more IARs. It is recommended that patients be monitored for IgG antibody formation periodically. The effect of antibody development on the long term efficacy of alglucosidase alfa is not fully understood. There does not appear to be a correlation between the onset of IARs and the time of antibody formation.
There is an observation that some patients who develop high and sustained IgG antibody titres, including Cross Reactive Immunologic Material (CRIM)-negative patients (i.e. patients in whom no endogenous GAA protein was detected by Western blot analysis and/or predicted based on the genotype), may experience reduced clinical alglucosidase alfa treatment efficacy. The cause of a poor clinical response in some of these patients is thought to be multi-factorial.
A small number of patients who were IgG positive also tested positive for inhibition of enzyme effects in an in vitro assay. There is evidence to suggest that patients developing sustained titres ≥ 12,800 of anti-alglucosidase alfa antibodies may have a poorer clinical response to treatment, or may lose motor function as antibody titres increase. Treated patients who experience a decrease in motor function should be tested for neutralisation of enzyme uptake or activity.
A small number of patients tested positive for alglucosidase alfa specific IgE antibodies, 1 of whom experienced an anaphylactic reaction. Testing was typically performed for IARs, especially moderate to severe or recurrent reactions. Some patients have been successfully re-challenged using slower rates and/or lower initial doses and continued to receive treatment with alglucosidase alfa under close clinical supervision.
The effect of antibody development on the long-term efficacy of Myozyme is not fully understood.
Some IgG positive patients in clinical trials and on commercial therapy who were evaluated for the presence of inhibitory antibodies tested positive for inhibition of enzyme activity and/or uptake in in vitro assays.
Infusion reactions were reported in 20 of 39 patients (51%) treated with Myozyme in clinical studies and appear to be more common in antibody positive patients: 8 of 15 patients with high antibody titres experienced infusion reactions whereas none of 3 antibody negative patients experienced infusion reactions.
Patients in clinical trials, expanded access programs and on commercial therapy have undergone testing for Myozyme specific IgE antibodies. Testing was performed for infusion reactions, especially moderate to severe or recurrent reactions, for which mast cell activation was suspected. A small number of these patients tested positive for Myozyme specific IgE binding antibodies, some of whom experienced an anaphylactic reaction (see Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity reactions).
Some patients have been successfully rechallenged using a slower infusion rate at lower initial doses and have continued to receive treatment with Myozyme under close clinical supervision.
Severe cutaneous and possibly immune mediated reactions have been reported with alglucosidase alfa including ulcerative and necrotizing skin lesions. Skin biopsy in one patient demonstrated deposition of anti-rhGAA antibodies in the lesion.
Nephrotic syndrome was observed in a few Pompe patients treated with alglucosidase alfa and who had high IgG antibody titres (≥ 102,400). In these patients renal biopsy was consistent with immune complex deposition. Patients improved following treatment interruption. It is therefore recommended to perform periodic urinalysis among patients with high IgG antibody titres.
Patients should be monitored for signs and symptoms of systemic immune complex mediated reactions involving skin and other organs while receiving alglucosidase alfa. If immune mediated reactions occur, discontinuation of the administration of alglucosidase alfa should be considered, and appropriate medical treatment initiated. The risks and benefits of readministering alglucosidase alfa following an immune mediated reaction should be considered. Some patients have been successfully rechallenged and continued to receive alglucosidase alfa under close clinical supervision.

Immunomodulation.

Immunogenicity data from clinical trials and published literature in CRIM-negative infantile-onset patients (IOPD) suggests that the administration of immune tolerance induction (ITI) regimens given to alglucosidase alfa naive patients (prophylactic ITI) may be effective in preventing or reducing the development of High Sustained Antibody Titre (HSAT) against alglucosidase alfa. Data from a small number of patients who developed HSAT with or without inhibitory activity following treatment with Myozyme showed limited treatment effect of ITI. Data from a limited number of patients from clinical studies suggest that prophylactic ITI, younger age at treatment (before the development of HSAT), and less advanced disease may contribute to better responses to Myozyme, which suggests that early initiation of ITI can result in improved clinical outcomes. ITI regimens may need to be tailored to individual patient needs. (See Section 5.1 Pharmacodynamic Properties, Clinical trials).
Pompe patients are at increased risk of respiratory infections due to the progressive effects of the disease on the respiratory muscles. Pompe patients treated with immunosuppressive agents may be at further increased risk of developing severe infections and vigilance is recommended. Fatal and life-threatening respiratory infections have been observed in some of these patients.

Risk of cardiac arrhythmia and sudden cardiac death during general anaesthesia for central venous catheter placement.

Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in infantile onset Pompe disease patients with cardiac hypertrophy, associated with the use of general anaesthesia for the placement of a central venous catheter intended for Myozyme infusion. Caution should be used when administering general anaesthesia for the placement of a central venous catheter in infantile onset Pompe disease patients with cardiac hypertrophy.

Risk of acute cardiorespiratory failure.

Acute cardiorespiratory failure requiring intubation and inotropic support has been observed after infusion with Myozyme in a few infantile onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of Myozyme. (See Section 6.6, Preparation and administration instructions: use aseptic techniques).

Infusion associated reactions (IARs).

In clinical trials and expanded access programs with Myozyme, 38 of 280 (approximately 14%) patients treated with Myozyme have developed infusion reactions that involved at least 2 of 3 body systems: cutaneous, respiratory or cardiovascular systems. These events included: Cardiovascular: hypotension, cyanosis, hypertension, tachycardia, ventricular extrasystoles, bradycardia, pallor, flushing, nodal rhythm, peripheral coldness; Respiratory: tachypnoea, wheezing/bronchospasm, rales, throat tightness, hypoxia, dyspnoea, cough, respiratory tract irritation, oxygen saturation decreased; Cutaneous: angioneurotic oedema, urticaria, rash, erythema, periorbital oedema, pruritus, hyperhidrosis, cold sweat, livedo reticularis (see Section 4.8 Adverse Effects (Undesirable Effects)). Of these cases, 8 patients experienced severe or significant hypersensitivity reactions.
Additional IARs reported from worldwide post-marketing sources after marketing approval (including ongoing clinical programs) included: cardiac arrest, bradycardia, angioneurotic oedema, pharyngeal oedema, oedema peripheral, chest pain, chest discomfort, dyspnoea, muscle spasm, fatigue and conjunctivitis. Those IARs assessed as severe included cardiac arrest, bradycardia, chest pain, and dyspnoea.
Infusion associated reactions (IARs) occurred in 51% (20/39) of patients treated with Myozyme in two infantile onset clinical studies for 52 weeks. In a randomized, double-blind, placebo-controlled trial of patients with late-onset Pompe disease, 28% of patients in the alglucosidase alfa treatment group experienced IARs. IARs occur at any time during and mostly up to 2 hours after the infusion of Myozyme. They are more likely to occur with higher infusion rates. The majority of reactions were assessed as mild to moderate, some reactions were severe. Some patients were pretreated with antihistamines, antipyretics and/or steroids. IARs may occur in patients after receiving antipyretics, antihistamines or steroids.
If an IAR occurs, regardless of pretreatment, decreasing the infusion rate, temporarily stopping the infusion and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. If severe infusion reactions occur, immediate discontinuation of the administration of Myozyme should be considered and appropriate medical treatment should be initiated. Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. In some cases of anaphylactic reaction and cardiac arrest, epinephrine and/or cardiopulmonary resuscitation measures have been administered. Early detection of signs and symptoms of hypersensitivity or anaphylactic reactions may assist in effective management of patients and prevent possible significant or irreversible outcomes. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when Myozyme is administered because of the potential for severe hypersensitivity reactions. Patients who have experienced IARs should be treated with caution when readministered Myozyme.
Severe infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included pyrexia, decreased oxygen saturation, tachycardia, cyanosis, and hypotension. Other infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included rash, flushing, urticaria, pyrexia, cough, tachycardia, decreased oxygen saturation, vomiting, tachypnoea, agitation, increased blood pressure, cyanosis, hypertension, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face oedema, feeling hot, headache, hyperhidrosis, lacrimation increased, livedo reticularis, nausea, periorbital oedema, restlessness, and wheezing.
Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from infusion reactions. These patients should be monitored more closely when administering Myozyme.
There were no differences between the 20 mg/kg and 40 mg/kg doses in any of the studied endpoints; however there was an increase in infusion related reaction with the 40 mg/kg dose (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients who experience IARs suggestive of hypersensitivity reactions may also be tested for IgE antibodies to alglucosidase alfa.

Paediatric use.

Paediatric patients from 1 month up to 3.5 years of age at time of first infusion have been treated with Myozyme in clinical trials. Other open label clinical trials of Myozyme have been performed in older paediatric patients ranging from 2 to 16 years at the initiation of treatment. Two of the 3 major trials investigating the efficacy of Myozyme have focused on infantile-onset Pompe disease. AGLU1602 included 18 patients (mean age 4.6 months with a range of 1.2 - 6.1 months) and AGLU17012 included 21 patients (mean age 15.7 months with a range of 3.7 - 43.1 months. Two paediatric patients (< 18 years old) have also been included in Study AGLU02704 in late-onset Pompe patients. In addition, paediatric patients have been included in the following trials: AGLU02203 (33 patients commenced, 20 patients completed), AGLU03707 (4 patients in an immune tolerance induction study) and AGLU3807 (4 patients in a study to evaluate a prophylactic immunomodulatory regimen given prior to Myozyme).

Use in the elderly.

Clinical studies did not include any subjects aged 65 years and older. It is not known whether they respond differently than younger subjects.

Use in renal impairment.

The safety and efficacy of Myozyme in patients with renal impairment has not been evaluated and no specific dose regimen can be recommended for these patients.

Use in hepatic impairment.

The safety and efficacy of Myozyme in patients with hepatic impairment has not been evaluated and no specific dose regimen can be recommended for these patients.

Effects on laboratory tests.

Overall, there were few clinically significant abnormal clinical laboratory evaluations in patients treated with Myozyme. However, assessment of clinical significance varied across investigators based upon individual standards of clinical practice. In general, changes in laboratory parameters during the conduct of the studies of patients treated with Myozyme were consistent with the evolving clinical status of individual patients and were not considered treatment related.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interaction studies have been conducted with Myozyme.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The limited data from clinical studies, post-marketing reports and published case reports with the use of Myozyme in male and female patients have not identified a Myozyme - associated risk on fertility and reproductive performance.
Alglucosidase alfa at intravenous doses up to 40 mg/kg, administered every other day (plasma AUC 5 times the human steady-state exposure at the recommended biweekly dose) had no effect on fertility or reproductive performance in mice.
(Category B1)
The limited data from post-marketing reports and published case reports with the use of alglucosidase alfa in pregnant women have not identified a Myozyme - associated risk of miscarriage, or adverse maternal or fetal outcomes. There have been reports of diaphragmatic hernia, atrial septal defect and truncus arteriosus persistent in post-marketing experience, however the relationship of Myozyme to these events is unknown.
Myozyme should not be used during pregnancy unless clearly necessary. The continuation of treatment for Pompe disease during pregnancy should be individualised to the pregnant woman. Untreated Pompe disease may result in worsening disease symptoms in pregnant women.
Developmental studies performed in pregnant mice and rabbits at IV doses up to 40 mg/kg/day during the period of organogenesis (9.5 and 13 times the expected human exposure, based on AUC values) revealed no evidence of embryofetal developmental toxicity due to alglucosidase alfa.
 Alglucosidase alfa may be excreted in breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Myozyme and any potential adverse effects on the breastfed child from Myozyme or from the underlying maternal condition.
A lactating woman may consider interrupting breastfeeding, pumping and discarding breast milk during Myozyme administration and for 24 hours thereafter in order to minimise drug exposure to a breastfed infant.
In a pre- and postnatal study in mice, survival of the offspring was reduced during days 15-21 of lactation at the highest dose evaluated (40 mg/kg IV every other day; 5 times the expected human exposure based on AUC values). However, the relationship of this finding to Myozyme was unclear since this observation was not dose or time dependent, and there were no other effects on any other parameter evaluated in the high dose group. Furthermore, when the data was analysed on a per litter basis, the litter loss was not significantly different between the control group and the highest dose tested. Myozyme should be given to a breastfeeding woman only if clearly needed and after a careful risk/ benefit analysis has been conducted for both the mother and child.

4.7 Effects on Ability to Drive and Use Machines

No studies on the ability to drive and handle machines have been conducted with alglucosidase alfa. Because dizziness has been reported as an infusion associated reaction, this may affect the ability to drive and use machines on the day of the infusion.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Infantile-onset Pompe disease.

The most common serious treatment emergent adverse events (regardless of relationship) observed in clinical studies with Myozyme were pneumonia, respiratory failure, respiratory distress, catheter related infection, respiratory syncytial virus infection, gastroenteritis, and fever. The most common treatment emergent adverse events (regardless of relationship) were fever, diarrhoea, rash, vomiting, cough, pneumonia, otitis media, upper respiratory tract infection, gastroenteritis and decreased oxygen saturation.
Five additional juvenile onset Pompe disease patients were evaluated in a single centre, open label, nonrandomised, uncontrolled clinical trial. Patients were aged 5 to 15 years, ambulatory (able to walk at least 10 metres in 6 minutes), and not receiving invasive ventilatory support at study entry. All 5 patients received treatment with 20 mg/kg Myozyme for 26 weeks. The most common treatment emergent adverse events (regardless of causality) observed with Myozyme treatment in this study were headache, pharyngitis, upper abdominal pain, malaise, and rhinitis.

Adverse drug reactions.

The most common adverse drug reactions (ADRs) were infusion associated reactions (IARs). Infusion reactions occurred in approximately 50% of patients treated with Myozyme in two infantile onset clinical studies for 52 weeks. The majority of these reactions were mild to moderate. IARs which were reported in more than 1 patient in clinical studies and the expanded access program included rash, flushing, urticaria, pyrexia, cough, tachycardia, decreased oxygen saturation, vomiting, tachypnoea, agitation, increased blood pressure, interrupi, hypertension, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face oedema, feeling hot, headache, hyperhidrosis, lacrimation increased, livedo reticularis, nausea, periorbital oedema, restlessness and wheezing. Severe infusion reactions reported in more than 1 patient included pyrexia, decreased oxygen saturation, tachycardia, cyanosis and hypotension.
If severe infusion reactions occur, immediate discontinuation of the administration of Myozyme should be considered, and appropriate medical treatment should be initiated. Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Myozyme is administered. Most infusion related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion and/or administration of antipyretics, antihistamines or steroids.

Late-onset Pompe disease.

The most common adverse reactions observed in a randomized, double-blind, placebo controlled study of 90 patients with late-onset Pompe disease (aged 10 to 70 years) were infusion reactions. Patients were treated with 20 mg/kg alglucosidase alfa or placebo (randomized in a 2:1 ratio) once every two weeks for 78 weeks. Infusion reactions occurred in approximately 28% of patients treated with alglucosidase alfa, compared to 23% of placebo-treated patients. The majority of these reactions was mild to moderate and resolved spontaneously. Infusion reactions which were reported in ≥ 5% of alglucosidase alfa-treated patients included headache, nausea, dizziness, urticaria, rash, chest discomfort, anaphylaxis, vomiting, hyperhidrosis, flushing and blood pressure increased.
Serious adverse reactions reported in 4 patients treated with alglucosidase alfa were: angioedema, chest discomfort, throat tightness, non-cardiac chest pain and supraventricular tachycardia. Reactions in 2 of these patients were IgE-mediated anaphylactic reactions.
Adverse Events reported in at least 5% of patients treated with alglucosidase alfa or placebo in a clinical study of patients with late onset Pompe disease are listed in Table 2.

Adverse drug reactions - IOPD and LOPD.

Of the serious ADRs reported with Myozyme, the most significant were cardiorespiratory failure, anaphylactic reactions and cardiac arrest. Cardiorespiratory failure, possibly associated with fluid overload, was reported in a few infantile onset Pompe disease patient and pre-existing cardiac hypertrophy likely contributed to the severity of the reaction (see Section 4.4, Risk of acute cardiorespiratory failure).
Other ADRs, listed by System Organ Class are listed below:

Immune system disorders.

Hypersensitivity.

Psychiatric disorders.

Agitation, restlessness.

Nervous system disorders.

Tremor, dizziness, paraesthesia, headache.

Eye disorders.

Conjunctivitis.

Cardiac disorders.

Tachycardia, cyanosis, cardiac arrest, bradycardia.

Vascular disorders.

Flushing, hypertension, flushing, pallor, hypotension, vasoconstriction.

Respiratory, thoracic and mediastinal disorders.

Tachypnoea, cough, throat tightness, respiratory arrest, apnea, respiratory distress, bronchospasm, wheezing, pharyngeal oedema, dyspnoea, stridor.

Gastrointestinal disorders.

Vomiting, retching, nausea, diarrhoea, nausea, abdominal pain.

Skin and subcutaneous tissue disorders.

Urticaria, rash, erythema, rash-maculopapular, rash-papular, pruritus, hyperhidrosis, periorbital edema, livedo reticularis, lacrimation increased.

Musculoskeletal and connective tissue disorders.

Muscle spasms, muscle twitching, myalgia, arthralgia.

Renal and urinary disorders.

Nephrotic syndrome, proteinuria.

General disorders and administration site conditions.

Pyrexia, irritability, chills, chest discomfort, peripheral oedema, local swelling, fatigue, feeling hot, peripheral coldness, infusion site pain, infusion site reaction, infusion site swelling, infusion site induration, infusion site extravasation.

Investigations.

Oxygen saturation decreased, heart rate increased, blood pressure increased, body temperature increased.

Post-marketing experience.

Infusion-associated reactions (IARs) reported from worldwide post-marketing sources have included cardiac arrest, bradycardia, angioneurotic oedema, pharyngeal oedema, oedema peripheral, chest pain, chest discomfort, dyspnoea, muscle spasm, fatigue, respiratory distress, throat tightness and conjunctivitis. Those IARs assessed as severe included cardiac arrest, bradycardia, chest pain, and dyspnoea. The majority of patients continued to receive treatment with Myozyme, some under close clinical supervision.
A review of the safety information revealed a total of 5 patients experienced significant infusion associated reactions. In addition, a patient who experienced nonserious recurrent generalised urticaria was IgE positive. In total, 11 patients treated in either clinical studies or with commercial Myozyme have tested positive for IgE antibodies. In total, (up until March 2008) 178 patients treated with Myozyme in clinical trials and/or the commercial setting were evaluated for in vitro inhibition of enzyme activity. Of these, 137 patients were also evaluated for inhibition of uptake. A total of 32 of 178 (18.0%) patients tested positive for in vitro inhibition by inhibition of enzyme activity and/or inhibition of uptake assay at one or more time points.
Four of the 32 patients tested for inhibition of enzyme activity and all 32 patients tested positive for inhibition of uptake at one or more time points. Nineteen of the 32 (59%) patients were classified as positive for uptake inhibition and 13 (41%) patients were classified as borderline. The majority of infantile onset patients who developed inhibitory antibodies were Cross Reactive Immunologic Material (CRIM) negative, developed peak antibody titres ≥ 102,400 and showed signs of clinical decline. In late onset patients who tested positive for inhibition of cellular uptake in study AGLU02704 there was no clear effect of IgG antibodies or inhibitory antibodies on safety or efficacy endpoints at study conclusion.
In addition to infusion reactions reported in clinical trials and expanded access program, the following infusion reactions have been reported from worldwide sources after marketing approval, including ongoing clinical programs: peripheral/ local edema, abdominal pain, arthralgia, syncope and somnolence. Additional adverse drug reactions included proteinuria and nephrotic syndrome in patients with high IgG antibody titres (≥ 102,400).
Recurrent reactions consisting of flu-like illness or a combination of events such as fever, chills, myalgia, arthralgia, pain, or fatigue occurring after completion of infusions and lasting usually for a few days have been observed in some patients treated with alglucosidase alfa. The majority of patients were successfully rechallenged with alglucosidase alfa using lower doses and/or pretreatment with anti-inflammatory drugs and/or corticosteroids and have continued to receive treatment under close clinical supervision.
Significant skin lesions (necrotising inflammation) were reported in 1 patient following Myozyme treatment in a post-marketing setting. After temporary discontinuation of Myozyme treatment, lesions resolved and the patient was able to continue on therapy.
Severe cutaneous and possibly immune mediated reactions have been reported with alglucosidase alfa including ulcerative and necrotizing skin lesions. Skin biopsy in one patient demonstrated deposition of anti-rhGAA antibodies in the lesion.
Nephrotic syndrome was observed in a few Pompe patients treated with alglucosidase alfa and who had high IgG antibody titres (≥ 102,400). In these patients renal biopsy was consistent with immune complex deposition. Patients improved following treatment interruption. It is therefore recommended to perform periodic urinalysis among patients with high IgG antibody titres.

Hypersensitivity.

Significant hypersensitivity reactions have been reported from worldwide post-marketing sources in patients treated with Myozyme. Some of these patients experienced life-threatening anaphylactic reactions, including anaphylactic shock, some of which were IgE-mediated. Reactions generally occurred shortly after initiation of the infusion. Patients presented with a constellation of signs and symptoms, primarily respiratory, cardiovascular, oedematous and/or cutaneous in nature. Reactions included bronchospasm, wheezing, respiratory arrest, respiratory distress, apnea, stridor, dyspnea, oxygen saturation decreased, cardiac arrest, hypotension, bradycardia, tachycardia, cyanosis, vasoconstriction, flushing, chest pain, chest discomfort, throat tightness, angioedema, pharyngeal edema, face edema, peripheral edema, urticaria, and rash.
In approximately 280 patients treated with Myozyme, some patients experienced severe or significant hypersensitivity reactions, including a life threatening anaphylactic shock (see Section 4.4, Risk of hypersensitivity reactions). One patient developed an anaphylactic shock, which consisted of bronchoconstriction, hypotension, cyanosis, hypoxia, pallor and oxygen desaturation, during Myozyme infusion that required life support measures.
The majority of adverse reactions received during the current reporting period were consistent with the manifestation of the underlying Pompe disease or disease progression.
Physicians should monitor hypersensitivity reactions, drug-induced skin reactions, clinical decline or plateau of treatment and consider the risks and benefits of continued treatment.

Reporting of suspected adverse reactions.

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

In clinical trials, patients received doses up to 40 mg/kg of bodyweight. IARs are more likely to occur with higher doses or infusion rates, than recommended. See Section 4.4 Special Warnings and Precautions for Use, Infusion associated reactions (IARs).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code: A16AB07.
Myozyme is a purified form of the lysosomal enzyme acid alfa-glucosidase (GAA). Alglucosidase alfa-rch is produced by recombinant DNA technology in a Chinese hamster ovary cell line. Alglucosidase alfa-rch is a 896 amino acid glycoprotein with 7 asparagine linked glycosylation sites that are occupied by a mixture of complex, oligomannose and phosphorylated oligomannose structures. Alglucosidase alfa-rch has a molecular weight of approximately 110 kD.

Mechanism of action.

Pompe disease (glycogen storage disease type II, GSD II, glycogenosis type II, acid maltase deficiency) is a rare autosomal recessive disease caused by the deficiency of lysosomal acid alfa-glucosidase (GAA). GAA degrades lysosomal glycogen by catalysing the hydrolysis of the α1, 4- and α1,6-glycosidic linkages. Pompe disease results in intralysosomal accumulation of glycogen in various tissues, particularly cardiac and skeletal muscles, leading to the development of cardiomyopathy, progressive muscle weakness, and impairment of respiratory function.
Treatment of Pompe disease with Myozyme provides an exogenous source of GAA.
Intracellular trafficking of the 110 kD form of rhGAA to the lysosome occurs via a cation independent mannose-6-phosphate receptor dependent mechanism. This receptor is present on the surface of many cell types and may play a role in uptake of exogenous lysosomal enzymes. During internalisation and trafficking to the lysosome, rhGAA undergoes proteolytic and N-glycan processing resulting in the formation of a mature form, which degrades lysosomal glycogen at low pH.

Clinical trials.

The efficacy of Myozyme has been evaluated in 3 clinical trials of patient's naïve to enzyme replacement therapy (ERT) at the initiation of treatment and are detailed below. In addition, several other studies and expanded access programs were conducted.
In a retrospective natural history study in patients with infantile onset Pompe disease (n = 168), the median age at onset of symptoms was 2.0 months and the median age of death was 9.0 months. Kaplan-Meier survival rates at 12, 24 and 36 months of age were 26%, 9% and 7%, respectively.
Paediatric population.

Infantile onset Pompe disease.

The pivotal study, AGLU01602, was an international, multicentre, historically controlled clinical trial of 18 nonventilated infantile onset Pompe disease patients aged 7 months or less at first infusion.
Patients were randomised equally to receive either 20 mg/kg or 40 mg/kg Myozyme every 2 weeks for the duration of the study. The primary endpoint was the proportion of patients alive and/or free of invasive ventilation at 18 months of age (time to event). An untreated historical cohort (n = 42), derived from a retrospective natural history study discussed above, served as a comparator group for assessment of the primary endpoint. Given the limited data on invasive ventilator use in the historical population, a comparison to overall survival in the historical cohort was made.
The primary efficacy endpoint for pivotal study AGLU01602 was achieved. At the 18 month milestone, 13 of the 18 patients in AGLU01602 were alive and invasive ventilator free, 3 were receiving invasive ventilator support, and 2 patients who had not reached the age of 18 months by the end of the study were censored from the analysis, though they were alive and free of invasive ventilator support at that time. By contrast only one of 42 patients in the historical cohort group was alive at 18 months of age. Comparison of survival curves from time of diagnosis versus the historical control population was made using a Cox proportional hazards regression analysis. After 52 weeks, patients treated with Myozyme demonstrated prolonged survival as compared to survival in an untreated historical cohort (see Table 3). Results from the Cox analysis indicate that in this study Myozyme reduced the risk of death and/or allowed the patient to be free of invasive ventilation at 18 months of age by 99% (hazard ratio 0.01), which is also highly significant. Results for the primary endpoint are detailed in Table 3.
Treatment with Myozyme greatly increased patient survival as assessed at 18 months of age.
Cardiac status and motor function were assessed as secondary endpoints.
Changes from baseline to month 12 in left ventricular mass index (LVMI) were measured by echocardiography. For the 14 patients with both baseline and month 12 echocardiograms, all had decreases from baseline in LVMI (mean decrease 118 g/m2, range 45 to 193 g/m2). 13 patients (72%, 13/18) made gains in motor function over baseline as measured by motor performance age equivalent scores of the Alberta Infant Motor Scale (AIMS).
There were no differences between the 20 mg/kg and 40 mg/kg doses in any of the studied endpoints; however there was an increase in infusion related reactions with the 40 mg/kg dose (see Section 4.8 Adverse Effects (Undesirable Effects)).
Sixteen of the 18 patients who participated in Study AGLU01602 were enrolled in an extension study (AGLU02403) for up to 150 weeks. One patient died and did not enter into the extension study. A second patient continued treatment under an international expanded access program. At the end of the study, 14 of 16 patients (87.5%) were alive and 9 of 16 patients (56.3%) were alive and free of invasive ventilatory support. The two patients were aged 2 years 6 months and 3 years 5 months, respectively. One additional patient died after study end and another one after withdrawal from the study. See Table 4.
At their last evaluation, 7 patients (38.9%) had a left ventricular mass within normal limits, and mean LVMI had decreased 40%. By the end of the extension study, a total of 11 patients (61%) acquired new motor skills while on treatment with alglucosidase alfa, including the achievement of independent ambulation, as assessed by AIMS and motor milestone scores. The remaining 7 patients (38.9%) were classified as motor non responders at the end of study and had minimal or no significant gross motor skills. Three patients made significant motor gains during the study that were not maintained by the end of the study. See Figure 1.
Study AGLU01702 was an international, multicentre, open label clinical trial of 21 infantile onset patients who were 3 months to 3.5 years old at first treatment. All patients received 20 mg Myozyme every other week for up to 168 weeks. Five of 21 patients were receiving invasive ventilatory support at the time of first infusion.
The primary outcome measure was the proportion of patients alive at the conclusion of treatment. At the end of the study, 15 (71.4%) of 21 patients were alive. None of the deaths were assessed as related to alglucosidase alfa treatment. The effect of Myozyme treatment on survival was further assessed using a Cox proportional hazards model to fit time to event from time of disease diagnosis. Survival data were compared firstly to these observed in a subgroup of the natural history study population (called the historical reference subgroup) (n = 86) and secondly to a subset of 16 patients belonging to the historical reference subgroup who had survived past 15 months. Results from the Cox analysis (Table 5) indicate that in this study Myozyme reduced the risk of death by 78% (hazard ratio 0.209), which is also highly significant.
16 patients were free of invasive ventilatory support at the time of first infusion. At the end of the study, 7 (43.8%) patients remained free of invasive ventilation, 5 patients died, and 4 patients were invasive ventilator dependent.
Fifteen of 21 patients (71%) showed improvement in cardiomyopathy as measured by a decrease in left ventricular mass (LMV) from first to last study evaluation. Two additional patients maintained normal LVM throughout the study. Thirteen of 21 patients (61.9%) had measurable gains in motor function as determined by increases in age-equivalent scores from baseline in the AIMS and/or Peabody Development Motor Scale. The remaining patients (8 of 21, 38.9%) did not demonstrate measurable gains across these motor assessments.

Late onset Pompe disease.

AGLU02804 was a single centre, open label clinical trial which assessed the efficacy of Myozyme in 5 patients with late onset Pompe disease who ranged in age from 5 to 15 years at initiation of treatment. Patients received 20 mg/kg Myozyme every other week for 26 weeks. All patients were freely ambulatory and all but 1 patient did not require any form of ventilator support. Of the 3 patients with significant pulmonary involvement at baseline (percentage predicted forced vital capacity (FVC) in the sitting position ranging from 58-67%), 2 demonstrated clinically meaningful improvements in FVC (+11.5 and +16%) in the sitting position by week 26. Motor function was evaluated using the 6 minute walk test (6MWT). Three of the patients demonstrated a clinically meaningful improvement (ranging from 41-118 m) in 6MWT at fast speed by week 26. 1 patient experienced a clinically meaningful improvement in the 6MWT at comfortable speed.
Study AGLU02704 was a randomized, double-blind, placebo-controlled study of 90 patients (45 male, 45 female) with late-onset Pompe disease who ranged in age from 10 to 70 years at initiation of treatment. All patients were naïve to enzyme replacement therapy. Patients were randomized in a 2:1 ratio and received 20 mg/kg alglucosidase alfa (n=60) or placebo (n=30) every other week for 78 weeks (18 months). At baseline, all patients were ambulatory (some required assistive walking devices), did not require invasive ventilator support or non-invasive ventilation while awake and sitting upright and had a forced vital capacity (FVC) between 30 and 79% of predicted in the sitting position. Patients who could not walk 40 metres in 6 minutes or were unable to perform appropriate pulmonary and muscle function testing were excluded from the study.
The co-primary efficacy outcome assessments were distance walked (metres) in 6 minutes (6-Minute Walk Test, 6MWT) and FVC % predicted in the sitting position. After 78 weeks, patients treated with alglucosidase alfa showed improvement in distance walked as measured by 6MWT and stabilization of pulmonary function as measured by FVC % predicted as compared to placebo-treated patients. The estimated mean distance walked in 6 minutes increased by 25.13 metres for alglucosidase alfa-treated patients and decreased by 2.99 metres for placebo-treated patients, indicating a statistically significant alglucosidase alfa treatment effect compared to placebo of + 28.12 metres (p = 0.0347). The estimated mean % predicted FVC increased by 1.20% for alglucosidase alfa patients and decreased by 2.20% for placebo-treated patients, for a statistically significant treatment effect of 3.40% (p=0.0055). The results are shown in Table 6.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of Myozyme was evaluated in studies AGLU01602 and AGLU01702 as part of the clinical development program. In both studies, plasma GAA levels obtained before and after Myozyme infusions on day 0 and week 12 were evaluated via a GAA activity assay and these data were used to determine various pharmacokinetic parameters. The pharmacokinetic profile of Myozyme was also evaluated in AGLU02804 on day 0 and at weeks 12 and 26. Pharmacokinetic parameters from these 3 clinical studies are summarised in Table 7.
Pharmacokinetic data were available from 15 of the 18 patients with infantile onset Pompe disease treated with Myozyme in study AGLU01602 at a dosage of 20 mg/kg or 40 mg/kg every 2 weeks. The 20 mg/kg dose was infused over a period of approximately 4 hours and the 40 mg/kg dose was infused over approximately 6.5 hours. The pharmacokinetics of rhGAA were dose proportional and did not change over time.
The pharmacokinetics of Myozyme were also evaluated in 12 patients with infantile onset Pompe disease in study AGLU01702 at a dosage of 20 mg/kg. Patients received 20 mg/kg of Myozyme as an approximate 4 hour infusion every 2 weeks. The pharmacokinetic parameters were similar to those observed for the 20 mg/kg dose group in AGLU01602 study (see Table 7).
The pharmacokinetics of Myozyme were evaluated in clinical study AGLU02804 in 5 patients with late onset Pompe disease who received 20 mg/kg Myozyme every 2 weeks. There was no difference in the pharmacokinetic profile of Myozyme in late-onset patients compared to infantile onset patients (see Table 7).
19 of 21 patients who received treatment with Myozyme and had pharmacokinetics and antibody titre data available at week 12 developed antibodies to alglucosidase alfa. 5 patients with antibody titres ≥ 12,800 at week 12 had an average increase in clearance of 50% (range 5% to 90%) from week 1 to week 12. The other 14 patients with antibody titres < 12,800 at week 12 had similar average clearance values at week 1 and week 12.

5.3 Preclinical Safety Data

Genotoxicity.

No studies have been conducted to assess the genotoxic potential of Myozyme.

Carcinogenicity.

No studies have been conducted to assess the carcinogenic potential of Myozyme.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, polysorbate 80, dibasic sodium phosphate heptahydrate, monobasic sodium phosphate monohydrate.

6.2 Incompatibilities

Myozyme should not be infused in the same intravenous line with other products.

6.3 Shelf Life

3 years.
If storage is necessary after reconstitution hold at 2°C - 8°C for no more than 24 hours.

6.4 Special Precautions for Storage

Store Myozyme under refrigeration at 2°C - 8°C. Do not freeze or shake.
Do not use Myozyme after the expiration date on the vial.
This product contains no preservatives. To reduce microbial hazard, use as soon as practicable after dilution. For storage conditions after dilution of the medicinal product, see Section 6.3 Shelf Life.
The reconstituted and diluted infusion solution should be protected from light.

6.5 Nature and Contents of Container

It is supplied in single-use, clear Type I glass 20 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

Preparation and administration instructions: use aseptic techniques.

1. Determine the number of vials to be reconstituted based on the individual patient's weight and the recommended dose of 20 mg/kg.
Patient weight (kg) x dose (mg/kg) = patient dose (in mg).
Patient dose (in mg) divided by 50 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number for vials needed to withdraw the calculated volume of Myozyme required.
Patient dose (in mg) divided by 5 mg/mL = total number of mL required of reconstitution Myozyme solution.
Example: Patient weight (16 kg) x dose (20 mg/kg) = patient dose (320 mg). 320 mg divided by 50 mg/vial = 6.4 vials therefore, 7 vials should be reconstituted.
2. Remove the required number of vials from the refrigerator and allow them to reach room temperature prior to reconstitution (approximately 30 minutes). Reconstitute each vial by slowly injecting 10.3 mL of sterile water for injection to the inside wall of each vial. Each vial will yield 5 mg/mL. The total extractable dose per vial is 50 mg per 10 mL. Avoid forceful impact of the water for injection on the powder and avoid foaming. This is done by slow drop wise addition of the water for injection down the inside of the vial and not directly onto the lyophilised cake. Tilt and roll each vial gently. Do not invert, swirl, or shake.
3. The reconstituted Myozyme solution should be protected from light.
4. Perform an immediate visual inspection on the reconstituted vials for particulate matter and discolouration. If upon immediate inspection opaque particles are observed or if the solution is discoloured do not use. The reconstituted solution may occasionally contain some alglucosidase alfa-rch particles in the form of thin white strands or translucent fibres subsequent to the initial inspection. This may also happen following dilution for infusion. These particles have been shown to contain alglucosidase alfa-rch and may appear after the initial reconstitution step and increase over time. Studies have shown that these particles are removed via in line filtration without having a detectable effect on the purity or strength.
5. Withdraw the calculated volume of Myozyme from the appropriate number of vials.
6. Myozyme should be diluted in 0.9% sodium chloride for injection immediately after reconstitution to a final concentration of 0.5 to 4 mg/mL.
7. Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe.
8. Remove airspace from the infusion bag to minimise particle formation due to the sensitivity of Myozyme to air-liquid interfaces.
9. Add the reconstituted Myozyme solution slowly and directly into the sodium chloride solution. Do not add directly into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag.
10. Gently invert or massage the infusion bag to mix. Do not shake. To reduce microbial hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°C-8°C for no more than 24 hours. Protect from light.
The diluted solution should be filtered through a 0.2 micrometre, low protein binding, inline filter during administration to remove any visible particles.
After reconstitution: Myozyme is for single use in one patient only. Remaining Myozyme left in a vial after withdrawing the patient's calculated dose should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

No data available.

7 Medicine Schedule (Poisons Standard)

S4, Prescription Only Medicine.

Summary Table of Changes