Consumer medicine information

Fabrazyme

Agalsidase beta

BRAND INFORMATION

Brand name

Fabrazyme

Active ingredient

Agalsidase beta

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fabrazyme.

SUMMARY CMI

FABRAZYME®

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 FABRAZYME?

FABRAZYME contains the active ingredient agalsidase beta-rch. FABRAZYME is used as enzyme replacement therapy in Fabry Disease. For more information, see Section 1. Why am I using FABRAZYME? in the full CMI.

2. What should I know before I am given FABRAZYME?

You or your child should not be given FABRAZYME if you or your child have ever had an allergic reaction to agalsidase beta or any of the ingredients listed at the end of the CMI.

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

For more information, see Section 2. What should I know before I am given FABRAZYME? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FABRAZYME and affect how it works. Check with your doctor if you are not sure about what medicines, vitamins or supplements you or your child are taking and if these affect FABRAZYME.

For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How is FABRAZYME given?

  • The recommended dosage for FABRAZYME is 1 mg/kg of body weight given once every two weeks.
  • FABRAZYME 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 information can be found in Section 4. How is FABRAZYME given? in the full CMI.

5. What should I know while being given FABRAZYME?

Things you should do
  • Remind any doctor, dentist or pharmacist you or your child visit that you or your child are being given FABRAZYME.
  • Attend appointments with your treating doctor or clinic.
  • Have any tests when your treating doctor says to.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how FABRAZYME affects you.
  • Children should be careful when undertaking activities requiring attention such as riding bicycles or climbing.
  • FABRAZYME may cause dizziness, lightheadedness, tiredness and sleepiness in some people.
Looking after your medicine
  • FABRAZYME will be stored in the hospital or clinic pharmacy.
  • FABRAZYME will be used immediately after it has been prepared for infusion.

For more information, see Section 5. What should I know while being given FABRAZYME? in the full CMI.

6. Are there any side effects?

Common and less serious side effects include headaches, dizziness and lightheadedness, sleepiness, 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, runny nose, flushing or redness of the skin, pale skin, soreness, aching muscles, muscle tenderness, weakness (not caused by exercise), shaking or pins and needles, nausea, vomiting, and stomach-ache.
Serious side effects include signs of allergic reaction (shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, skin rash, itching or hives), difficulty swallowing, changes in your heartbeat (increase or decrease), and chest pain.
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

FABRAZYME® (fab-ra-ZIME)

Active ingredient(s): agalsidase beta-rch (ag-al-SI-daze bee-ta R.C.H)

Consumer Medicine Information (CMI)

This leaflet provides important information about using FABRAZYME. 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 FABRAZYME.

Where to find information in this leaflet:

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

1. Why am I using FABRAZYME?

FABRAZYME contains the active ingredient agalsidase beta-rch. FABRAZYME is a recombinant human α-galactosidase. Patients with Fabry Disease do not produce enough of their own α-galactosidase enzyme. Reduced levels of α-galactosidase enzyme results in the accumulation of substances called glycosphingolipids in a number of cell types and tissues.

FABRAZYME is used as enzyme replacement therapy in Fabry Disease. It is intended to restore a level of enzyme activity sufficient to remove the accumulated substances and to prevent further accumulation.

2. What should I know before I am given FABRAZYME?

Warnings

You/your child should not be given FABRAZYME if:

  • you are allergic to agalsidase-beta, agalsidase, 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/your child:

  • have any other medical conditions
  • take any medicines for any other condition.

During treatment, you or your child 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 no information available regarding the use of FABRAZYME in pregnant women.

Your treating doctor will discuss the possible risks and benefits of receiving FABRAZYME during pregnancy.

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

FABRAZYME is not recommended for use when breast-feeding as it is not known whether FABRAZYME passes into breast milk. If there is a need to consider using FABRAZYME while you are breast-feeding, your treating doctor will discuss with you the benefits and risks of using it.

Children under 8 years of age

Tell your doctor if your child is under 8 years of age and has been prescribed FABRAZYME.

Safety in children below the age of 8 years has not been studied. If your child has been prescribed FABRAZYME, you may wish to discuss this with your child's treating doctor.

3. What if I am taking other medicines?

Tell your doctor or nurse if you or your child 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.

  • No studies have been carried out between FABRAZYME and other medicines. However, some medicines and FABRAZYME may interfere with each other.
  • Tell your doctor or nurse if you or your child are taking other medicines as these medicines may be affected by FABRAZYME, or may affect how well it works.
  • You or your child may need different amounts of these medicines or different medicines may need to be taken. Your doctor or nurse will advise you and decide whether or not to give you or your child the medicine.

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

4. How is FABRAZYME given?

How much is given

  • The recommended dosage for FABRAZYME is 1 mg/kg of body weight given once every two weeks. FABRAZYME 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.
  • The treating doctor will decide on the dose that is most suitable. They will also tell you how long it will take to give the medicine. It may take several hours.

If you are given too much FABRAZYME

Your treating doctor is trained to work out the correct dose and to phone the Poisons Information Centre (by calling 13 11 26), in case of an overdose. There have been no reported overdoses of FABRAZYME.

If you think that you or your child have been given too much FABRAZYME, you may need urgent medical attention.

5. What should I know while being given FABRAZYME?

Things you should do

Keep appointments with your treating doctor or clinic.

It is important for you or your child to receive FABRAZYME infusions 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 doctor says to.

Your treating doctor may wish to test you or your child's body's response to FABRAZYME to make sure that it is working.

Remind any doctor, dentist or pharmacist you or your child visit that you or your child are being treated with FABRAZYME.

Driving or using machines

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

FABRAZYME may cause dizziness, lightheadedness, tiredness and sleepiness in some people.

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

Children should be careful when undertaking activities requiring attention such as riding bicycles or climbing.

The effect of FABRAZYME on your ability to drive a car or operate machinery has not been studied.

Looking after your medicine

FABRAZYME will be stored in the hospital or clinic pharmacy.

FABRAZYME will be used immediately after it has been prepared for infusion.

6. Are there any side effects?

All medicines can have side effects. If you or your child 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, nurse or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Alertness and sleep-related:
  • headaches
  • dizziness and lightheadedness
  • sleepiness.
Injection site-related:
  • 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.
Sight, hearing, smell, taste or touch-related:
  • runny nose.
Skin and muscle-related:
  • flushing or redness of the skin
  • pale skin
  • soreness, aching muscles, muscle tenderness, weakness (not caused by exercise), shaking or pins and needles.
Stomach and gut-related:
  • nausea, vomiting
  • stomach-ache.
Speak to your doctor or nurse if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergy-related:
  • itchy rash, hives, itching or rash
  • shortness of breath, wheezing or coughing, difficulty breathing
  • swelling of the face, lips, mouth, tongue or throat
  • difficulty swallowing.
Heart-related:
  • increase or decrease in your heartbeat
  • chest pain.
Tell your doctor or nurse straight away, if you notice any of these serious side effects.

Tell your doctor or nurse if you notice anything else that may be making you or your child feel unwell while you or your child are being given FABRAZYME, or soon after having finished being given FABRAZYME.

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

Reporting side effects

After you or your child have received medical advice for any side effects you or your child 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 FABRAZYME contains

Active ingredient
(main ingredient)		agalsidase beta
Other ingredients
(inactive ingredients)
  • mannitol
  • monobasic sodium phosphate monohydrate
  • dibasic sodium phosphate heptahydrate

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

What FABRAZYME looks like

FABRAZYME is a white to off-white powder before it is prepared for infusion and a clear, colourless solution after it has been prepared for infusion.

FABRAZYME 5 mg is supplied in clear 5 mL glass vials (Aust R 94000).

FABRAZYME 35 mg is supplied in clear 20 mL glass vials (Aust R 82755).

Each pack contains 1 vial.

Who distributes FABRAZYME

Distributed by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Freecall: 1800 818 806
Email: [email protected]

This leaflet was prepared in November 2024.

fabr-ccdsv4-cmiv6-15nov24

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

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Fabrazyme

Active ingredient

Agalsidase beta

Schedule

S4

 

1 Name of Medicine

Fabrazyme, agalsidase beta-rch mg powder for injection.

2 Qualitative and Quantitative Composition

Fabrazyme 5 mg - each vial contains a nominal value of 5 mg of agalsidase beta.
Fabrazyme 35 mg - each vial contains a nominal value of 35 mg of agalsidase beta.
After reconstitution with sterile water for injection (see Section 4.2 Dose and Method of Administration, Instructions for use) the resulting solution has an agalsidase beta concentration of 5 mg/mL and a pH of approximately 7. The reconstituted solution must be diluted further. The diluted solution may be filtered through an in-line low protein binding 0.2 micrometre filter during administration.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Fabrazyme is supplied as a sterile, non-pyrogenic, white to off-white lyophilised powder in a clear glass vial. Fabrazyme is a powder for injection.
Fabrazyme is intended for intravenous infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Fabrazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase deficiency).

4.2 Dose and Method of Administration

Therapy with Fabrazyme should only be initiated or continued by a physician with expertise in the treatment of Fabry disease (see Section 4.4 Special Warnings and Precautions for Use).
If an infusion-associated reaction occurs during a Fabrazyme infusion, decreasing the infusion rate, temporarily stopping the infusion and/or administration of antipyretics, antihistamines and/or steroids may ameliorate the symptoms. Patients who experience an infusion-associated reaction during a Fabrazyme infusion should be treated with caution when Fabrazyme is re-administered. If severe allergic or anaphylactoid reactions occur, immediate discontinuation of the administration of Fabrazyme and current medical standards for emergency treatment are to be observed. See Table 1.
The recommended dosage is 1 mg/kg of Fabrazyme per dose, infused every 2 weeks. Dosage should be individualised for each patient and small adjustments can be made to avoid discarding partially used vials.
No dose adjustment is necessary for paediatric patients 8-16 years old. The safety and efficacy in patients younger than 8 years of age have not been evaluated. However, patients with Fabry disease younger than 8 years old may be treated with Fabrazyme when clearly needed and after a careful risk/ benefit analysis has been conducted by the physician.
The initial infusion rate should be no more than 0.25 mg/min (15 mg/hr) to minimise the potential occurrence of infusion-associated reactions. After patient tolerance is established, the infusion rate may be increased gradually with subsequent infusions.

Instructions for use.

1. Determine the number of vials for reconstitution based on the patient's body weight (kg) and the recommended dose of 1 mg/kg.
2. Using aseptic technique, reconstitute each vial with sterile water for injection to yield a 5 mg/mL clear, colourless solution. The final concentration and administration volumes are provided in Table 2.
3. Visually inspect the reconstituted vials for particulate matter and discolouration. Do not use vials exhibiting particulate matter or discolouration. Fabrazyme does not contain preservatives. Vials are for single use only.
4. Immediately withdraw reconstituted solution from each vial and, using aseptic technique, further dilute with 0.9% sodium chloride for injection to a total volume based on the individual dose dispensed (see Table 3). Total infusion volumes as low as 50 mL were used in the Phase 1/2 trial.
5. Administer the solution intravenously at an initial rate of no more than 0.25 mg/min. The diluted solution may be filtered through an in-line low protein-binding 0.2 micrometre filter during administration.
6. Fabrazyme should not be infused in the same intravenous line with other products.
Fabrazyme does not contain any preservatives; therefore after dilution with saline in the infusion bag, the unused product should be discarded.

4.3 Contraindications

Treatment with Fabrazyme is contraindicated if there is clinical evidence of anaphylaxis to agalsidase beta or any of the excipients.

4.4 Special Warnings and Precautions for Use

The diagnosis, assessment and management of Fabry disease should only be undertaken by physicians with experience and training in the treatment of inherited diseases of metabolism. Fabrazyme therapy should only be initiated or continued under the ongoing supervision of a physician with such expertise in the treatment of Fabry disease.
As with any intravenously administered protein product, patients may develop IgG antibodies to Fabrazyme (see Section 4.8 Adverse Effects (Undesirable Effects)). Some patients develop IgE or skin reactivity specific to Fabrazyme. Patients with antibodies to Fabrazyme have a higher risk of infusion-associated reactions (see Section 4.8 Adverse Effects (Undesirable Effects)).
Physicians should consider testing for IgE (see Section 4.4 Special Warnings and Precautions for Use, Laboratory tests) in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE.
Patients treated with Fabrazyme may develop infusion associated reactions, the majority of which are mild to moderate in intensity. If an infusion associated reaction occurs during a Fabrazyme infusion, decreasing the infusion rate, temporarily stopping the infusion and/or administration of antipyretics, antihistamines, and/or steroids may ameliorate the symptoms (see Section 4.2 Dose and Method of Administration).
Patients who experience an infusion-associated reaction during a Fabrazyme infusion should be treated with caution when Fabrazyme is re-administered. If severe allergic or anaphylactoid reactions occur, immediate discontinuation of the administration of Fabrazyme and current medical standards for emergency treatment are to be observed. The risks and benefits of re-administering Fabrazyme following a severe hypersensitivity or anaphylactoid reaction should be considered. Patients who have had a positive skin test or who have tested positive for IgE antibodies to r-hαGAL have been successfully rechallenged with Fabrazyme. The initial rechallenge administration should be at a low dose and a lower infusion rate [1/2 the therapeutic dose (0.5 mg/kg) at 1/25 the initial standard recommended rate (0.01 mg/min)]. Once a patient tolerates the infusion, the dose may be increased to reach the therapeutic dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards, as tolerated.
Studies in humans have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility.
Fabrazyme at the proposed clinical use may not produce significant hepatic toxicity, but caution should be exercised in patients with hepatic impairment.

Laboratory tests.

It is suggested that patients be monitored routinely for IgG antibody formation. The recommendation for long-term routine antibody monitoring should be as follows: samples should be drawn at baseline, every 3 months until month 18 and then every 6 months until the results are negative. Once one negative result has been obtained, an additional sample will be collected to confirm the patient has tolerised. Clinicians may submit a sample at any time for immediate testing in the event a patient experiences a reaction that is suspected to be immune-mediated.

Use in the elderly.

Clinical studies did not include any subjects aged 65 and over and therefore did not determine whether they respond differently from younger subjects.

Paediatric use.

Safety and efficacy of Fabrazyme have been investigated in children aged 8-16 years (see Section 5.2 Pharmacokinetic Properties; Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients younger than 8 years of age were not included in clinical studies. The safety and efficacy in patients younger than 8 years of age have not been evaluated. Patients younger than 8 years of age with Fabry disease may be treated with Fabrazyme when clearly needed and after a careful risk/ benefit analysis has been conducted by the physician.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug/ drug interaction studies were performed. In the absence of drug interaction studies, Fabrazyme must not be mixed with other medicinal products in the same infusion.
No in vitro metabolism studies have been carried out. Based on its metabolism, agalsidase beta is an unlikely candidate for cytochrome P450-mediated drug/drug interactions. Fabrazyme is not recommended to be administered with chloroquine, amiodarone, benoquin or gentamicin due to a theoretical risk of inhibited intracellular α-galactosidase activity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There have been no studies conducted to assess the potential effect of Fabrazyme on fertility.
(Category B2)
Category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed.
Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility. There are no adequate data from the use of agalsidase beta in pregnant women.
A study to evaluate the effects of agalsidase beta on embryo-foetal development in rats was conducted. Agalsidase beta did not affect embryo-foetal development in rats at IV doses up to 30 mg/kg/day during organogenesis, associated with maternal plasma AUC about 45 times that expected in humans.
 Fabrazyme should not be used during lactation unless clearly necessary. Agalsidase beta may be excreted in milk. Because there are no data available on effects in neonates exposed to agalsidase beta via breast milk, it is recommended to stop nursing when Fabrazyme is used.

4.7 Effects on Ability to Drive and Use Machines

No studies on the ability to drive and use machines have been conducted with Fabrazyme.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Table 4 presents the incidence of adverse drug reactions, related to Fabrazyme in a total of 181 patients treated with Fabrazyme in the Phase 1/2 Extension study, the Phase 3 Double-Blind/Open-Label Extension studies, the Phase 2 Japan Bridging study, the Phase 4 Double-Blind study/Open-Label Extension and the Phase 2 Paediatric studies for a minimum of one infusion to a maximum of 5 years. The majority of these product-related adverse events were judged to be mild to moderate in severity. Currently available data demonstrate that the total number of Fabrazyme-treated patients experiencing any related adverse event on the same day as infusion has decreased over time. Observed adverse events in the Phase 1/2 study and the open-label treatment period following the controlled study were not different in nature or severity.
In the Phase 2 paediatric study (AGA-016-01), the safety profile of Fabrazyme treatment in paediatric Fabry disease patients, ages 8 to 16 years, was found to be consistent with that seen in adults. The safety of Fabrazyme in patients younger than 8 years of age has not been evaluated.
The occurrence of somnolence can be attributed to clinical trial specified pre-treatment with antihistamines. Most of the patients had experienced one or more infusion-associated events during the long-term treatment.
One hundred and twenty eight (128) of 181 patients in the 7 clinical studies combined experienced at least one adverse event (AE) that was considered related to Fabrazyme treatment. Additional drug related AEs as assessed by the investigator seen in ≥ 1% of patients in clinical trials include (≥ 1% defined as occurring in at least one patient):

Blood and lymphatic system disorders.

Anaemia, eosinophilia, leucopoenia.

Cardiac disorders.

Aortic valve incompetence, arrhythmia, bradycardia, arrhythmia supraventricular, bundle branch block right, cardiac arrest, cardiac valve disease, dilatation atrial, dilation ventricular, mitral valve disease, mitral valve incompetence, mitral valve sclerosis, pulmonary valve incompetence, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles, ventricular hypokinesia.

Ear and labyrinth disorders.

Auricular swelling, ear discomfort, ear pain, tinnitus, vertigo.

Eye disorders.

Diplopia, eye oedema, eye pruritus, night blindness, ocular hyperaemia, vision blurred, visual acuity reduced, visual disturbance.

General disorders and administration site conditions.

Axillary pain, catheter site rash, catheter site related reaction, discomfort, feeling cold and hot, feeling jittery, gait disturbance, influenza-like illness, infusion site pain, infusion site reaction, injection site thrombosis, oedema, sluggishness, thirst.

Gastrointestinal disorders.

Dysphagia, dyspepsia, gastroenteritis, gingivitis, retching.

Immune system disorders.

Seasonal allergy.

Infections and infestations.

Gingival infection, infection, rash pustular, nasopharyngitis, rhinitis, tooth infection.

Injury, poisoning and procedural complications.

Excoriation, fall, post-procedural nausea, vascular access complication.

Musculoskeletal and connective tissue disorders.

Chest wall pain, flank pain, groin pain, joint stiffness, musculoskeletal chest pain, musculoskeletal pain, pain in jaw, shoulder pain.

Investigations.

Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, cardiac imaging procedure abnormal, cardiac output decreased, creatinine renal clearance decreased, cystatin C increased, ejection fraction decreased, electrocardiogram PR shortened, electrocardiogram ST segment abnormal, electrocardiogram T wave abnormal, haematocrit decreased, haemoglobin decreased, heart rate irregular, hepatic enzyme increased, prostate examination abnormal, intraocular pressure increased, right ventricular systolic pressure increased, albumin urine present/ protein urine present, skin test positive.

Metabolism and nutrition disorders.

Hypocalcaemia.

Nervous system disorders.

Cerebrovascular accident/ischaemic stroke, migraine, psychomotor hyperactivity, sinus headache, syncope/syncope vasovagal, restless legs syndrome, tremor, balance disorder, dyskinesia, hyperaesthesia.

Psychiatric disorders.

Agitation, anxiety, confusional state, depression, hallucination visual, flat effect, restlessness.

Renal and urinary disorders.

Dysuria, haematuria, renal failure, renal impairment, benign prostatic hyperplasia, proteinuria.

Reproductive system and breast disorders.

Dysmenorrhoea, nipple pain, erectile dysfunction.

Respiratory, thoracic and mediastinal disorders.

Bronchospasm, productive cough, pharyngolaryngeal pain, pulmonary oedema, respiratory distress, rhinitis allergic, rhinorrhea, rhonchi, tachypnoea, throat irritation, upper respiratory tract congestion.

Skin and subcutaneous tissue disorders.

Acne, eczema, generalised erythema, hair growth abnormal, rash erythematous, rash maculo-papular, rash pruritic, livedo reticularis, skin discolouration, skin discomfort, urticaria localised.

Vascular disorders.

Orthostatic hypotension, peripheral coldness, poor peripheral circulation, poor venous access, vasoconstriction and vasospasm.
The safety profile of Fabrazyme treatment in paediatric patients was consistent with that seen in adults.
Infusion-associated reactions (IARs) (defined as product-related adverse events occurring on the same day as the infusion) were the most frequently reported related adverse events in the 7 clinical studies discussed in Table 4. The majority (65%) of patients ever on Fabrazyme experienced at least one infusion associated event during the long-term treatment. These IARs included events of chills, fever (pyrexia/ body temperature increased/ hyperthermia), temperature change sensation (feeling cold/feeling hot), hypertension (blood pressure increased), nausea, vomiting, flushing (hot flush), paraesthesia (burning sensation), fatigue (lethargy/ malaise/ asthenia), pain (pain in extremity), headache, chest pain (chest discomfort), pruritus (pruritus generalised), urticaria, dyspnoea (dyspnoea exacerbated), dizziness, pallor, somnolence and tachycardia.
In the majority of patients, the adverse events associated with Fabrazyme infusions have been successfully managed using standard medical practices, such as reduction in infusion rate and/or pre-medication with, or additional administration of non-steroidal anti-inflammatory drugs, antipyretics, antihistamines and/or corticosteroids.
The majority of these IARs are thought to be associated with the formation of IgG antibodies and/or complement activation. The majority of patients developed IgG antibodies to r-hαGAL, which is not unexpected (see Section 4.4 Special Warnings and Precautions for Use). The mean time to seroconversion was within three months of the first infusion of treatment with Fabrazyme. The majority of patients in clinical trials demonstrated either a downward trend in titres (based on a ≥ 4-fold reduction in titre from the peak measurement to the last measurement) or tolerised (no detectable antibody by radioimmunoprecipitation (RIP)). There was no evidence that IgG seroconversion inhibited or neutralised the activity of Fabrazyme.

Post-marketing adverse drug reactions.

During the post-marketing period, the adverse drug reaction profile was generally similar to that seen during the clinical studies. Adverse drug reactions seen during the post-marketing period included: feeling hot and cold, malaise, musculoskeletal pain, oedema, rhinitis, rhinorrhoea and oxygen saturation decreased/ hypoxia. Infusion site reaction was seen and not unexpected given the route of administration. One patient reported an event of leukocytoclastic vasculitis. One case of membranous glomerulonephritis has been reported.
A small number of patients have experienced anaphylactoid reactions which in some cases were considered life-threatening. Signs and symptoms of possible anaphylactoid reactions have included events of localised angioedema, generalised urticaria, bronchospasm and hypotension (see Section 4.4 Special Warnings and Precautions for Use).

4.9 Overdose

There have been no reported cases of overdose with Fabrazyme. In clinical trials, patients received doses up to 3 mg/kg body weight were used.
Contact the Australian Poisons Information Centre (telephone 13 11 26) for advice on management.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Alimentary tract and metabolism, ATC code: A16AB04.

Mechanism of action.

Fabry disease is a rare genetic disorder of glycosphingolipid metabolism. Deficiency of the lysosomal enzyme α-galactosidase leads to progressive accumulation of glycosphingolipids, predominantly globotriaosylceramide (GL-3), in most body tissues and fluids. Progressive accumulation of GL-3 occurs predominantly in the lysosomes of endothelial, perithelial and smooth muscle cells of blood vessels. GL-3 accumulation also occurs in ganglion cells of the autonomic nervous system, cardiomyocytes of the heart, epithelial cells of glomeruli and tubules in the kidney, epithelial cells of the cornea and cells of many other tissues.
Excessive accumulation of GL-3 in the vascular wall results in narrowing and thrombosis of arteries and arterioles. This derangement of the vascular architecture often involves capillaries and has been implicated in the development of peripheral neuritis, angiokeratoma corporis diffusum universale, renal failure, myocardial infarction and cerebral infarction. Ultimately premature death results from renal disease, cardiac disease or cerebrovascular disease.
Fabrazyme is intended as an enzyme replacement therapy to provide an exogenous source of α-galactosidase in Fabry disease patients who are deficient or lacking endogenous enzyme. This recombinant human α-galactosidase (r-hαGAL) will catalyse the hydrolysis of glycosphingolipids including GL-3. The clinical studies conducted with Fabrazyme support this mechanism of action.
Histological analysis of tissues from patients in the Phase 1/2 trial showed that treatment with Fabrazyme at all dose regimens tested resulted in reduction of GL-3 from the vasculature of the kidney, heart and skin. GL-3 was cleared from the plasma in a dose-dependent manner (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Clinical trials.

The safety and efficacy of Fabrazyme were assessed in a randomised, double-blind, placebo-controlled, multicentre study of 58 patients (56 males and 2 females), 16 to 61 years of age. Patients received 1 mg/kg of Fabrazyme or placebo every other week for 5 months (20 weeks) for a total of 11 infusions. The primary efficacy variable, GL-3 clearance from renal vascular endothelium, was assessed by light microscopy and was graded on an inclusion severity score ranging from 0 (near normal) to 3 (severe). The prospectively defined renal efficacy endpoint (score of 0) was achieved in 20 of 29 (69%) patients treated with Fabrazyme. In contrast, no patients receiving placebo attained this efficacy endpoint (p < 0.0001). Similar results were achieved in the capillary endothelium of the heart and skin (see Table 5).
The safety and efficacy of Fabrazyme were further investigated in an open-label, multicentre extension study in which Fabrazyme therapy was administered at 1 mg/kg to all 58 participants of the original pivotal trial for an additional 54 months of treatment.
Mean plasma GL-3 levels showed a rapid decrease and return to normal levels (i.e. < 7.03 microgram/mL) within 6 months (i.e. first time point tested) of treatment with Fabrazyme. Importantly, mean plasma GL-3 levels remained normal through Month 54 (end of the study). Additionally, a retrospective histological review of other renal cell types confirmed that GL-3 is cleared to normal or near normal levels from mesangial cells, glomerular capillary endothelium, interstitial cells and non-capillary endothelium, and reduced in cell types with the highest substrate burden (vascular smooth muscle cells, tubular epithelium and podocytes).
During the extended follow-up, the kidney function, as measured by estimated GFR and serum creatinine, remained stable throughout the study.
The safety and clinical efficacy of Fabrazyme were also assessed in a randomised (2:1), Phase 4 double-blind, placebo-controlled, multinational, multicentre study of 82 Fabry patients (72 males and 10 females). Patients received either 1 mg/kg of Fabrazyme or placebo every other week for up to a maximum of 35 months. The primary efficacy endpoint was the time to clinically significant progression of the composite outcomes of renal, cardiac and cerebrovascular disease and/or death. Among the 82 patients enrolled, 13 patients (42%) in the placebo group and 14 patients (27%) in the Fabrazyme group met the pre-defined clinical endpoint (progression of clinical symptoms). The results are summarised in Table 6 and Figure 1.
While benefit was seen in patients with varying severity of disease, the most pronounced benefit was observed among patients who had less severe disease at baseline.

Paediatric use.

Efficacy and safety of Fabrazyme were studied in an open label paediatric study. In this study, sixteen patients with Fabry disease (8-16 years old; 14 males, 2 females) had been treated for one year. Clearance of GL-3 in the skin vascular endothelium was achieved in all patients who had accumulated GL-3 at baseline. Since Fabrazyme treats the underlying pathology of Fabry disease by significantly clearing GL-3 from vascular endothelium of the kidney, heart and skin, paediatric patients younger than 8 years old would be expected to benefit from treatment with Fabrazyme.

Use in the elderly.

Clinical studies did not include any subjects aged 65 and over and therefore did not determine whether they respond differently from younger subjects.

5.2 Pharmacokinetic Properties

Plasma profiles of agalsidase beta were studied in adults at 0.3, 1 and 3 mg/kg. The area under the plasma concentration-time curve (AUC∞) did not increase proportionately with increasing dose, demonstrating that the drug displays non-linear pharmacokinetics. Terminal half-life was dose independent with a range of 45 to 102 minutes.
Pharmacokinetics of agalsidase beta were also evaluated in 11 adult Fabry patients participating in a Phase 3 pivotal clinical trial. Following an intravenous infusion of 1 mg/kg Fabrazyme over a period averaging 280 to 300 minutes, mean maximum plasma concentrations (Cmax) ranged from 2000 to 3500 nanogram/mL. The mean AUC∞ ranged from 372 to 784 min.microgram/mL. The mean volume of distribution (Vz) was 0.23 to 0.49 L/kg and the mean volume of distribution at steady state (Vss) was 0.12 to 0.57 L/kg. Mean plasma clearance ranged from 1.75 to 4.87 mL/min/kg and the mean elimination half-life (t1/2) ranged from 82.3 to 119 minutes.
Fabrazyme pharmacokinetics were also evaluated in 15 paediatric patients (8.5 to 16 years old weighing 27.1 to 64.9 kg). Weight did not influence Fabrazyme pharmacokinetics in this population. Baseline clearance was 129 mL/min with a volume of distribution at steady state (Vdss) of 21.4 L; half-life was 84 min. After seroconversion, clearance decreased to 37 mL/min, Vdss decreased to 8.6 L, and half-life increased to 156 min. The net effect of these changes after seroconversion was an increase in exposure of 2 to 4-fold based on AUC and Cmax. This increase in exposure after seroconversion was not correlated with an increased incidence of adverse events nor did it result in a change in efficacy.

5.3 Preclinical Safety Data

Genotoxicity.

There have been no studies conducted to assess the mutagenic potential of Fabrazyme.

Carcinogenicity.

There have been no studies conducted to assess the carcinogenic potential of Fabrazyme.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol; monobasic sodium phosphate monohydrate; dibasic sodium phosphate heptahydrate.
Fabrazyme does not contain preservatives. Vials are for single use only.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
To reduce microbiological hazard, use as soon as practicable after reconstitution/dilution.
Fabrazyme diluted for infusion in 0.9% sodium chloride for injection is stable for up to 24 hours when stored at 2°C to 8°C (36°F to 46°F) without microbial contamination. The diluted solution may be filtered through an in-line low protein-binding 0.2 micrometre filter during administration.

6.4 Special Precautions for Storage

Store Fabrazyme under refrigeration between 2°C to 8°C (36°F to 46°F). Do not use Fabrazyme 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

Fabrazyme 5 mg is supplied in clear Type I glass 5 mL vials. Fabrazyme 35 mg is supplied in 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.
Pack size: 1 vial per carton.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Fabrazyme is produced by recombinant DNA technology and is an enzyme replacement for the human enzyme, α-galactosidase A enzyme with the same amino acid sequence as the native enzyme. Alpha-galactosidase catalyses the hydrolysis of globotriaosylceramide (GL-3) and other α-galactyl terminated neutral glycosphingolipids, such as galabiosylceramide and blood group B substances. GL-3 is hydrolysed to ceramide dihexoside and galactose. Purified agalsidase beta is a homodimeric glycoprotein with a molecular weight of approximately 100 kD. The mature protein is comprised of two subunits of 398 amino acids (approximately 51 kD), each of which contains three N-linked glycosylation sites. Agalsidase beta is produced by recombinant DNA technology in a Chinese hamster ovary cell line. The protein is purified by a column chromatography process that includes measures to inactivate and remove potential viruses, resulting in a highly purified, active protein.

CAS number.

104138-64-9.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes