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Fabrazyme (agalsidase beta) – Summary of product characteristics - A16AB04

Updated on site: 06-Oct-2017

Medication nameFabrazyme
ATC CodeA16AB04
Substanceagalsidase beta
ManufacturerGenzyme Europe B.V.

1.NAME OF THE MEDICINAL PRODUCT

Fabrazyme 35 mg powder for concentrate for solution for infusion

Fabrazyme 5 mg powder for concentrate for solution for infusion

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Fabrazyme 35 mg powder for concentrate for solution for infusion

Each vial of Fabrazyme contains a nominal value of 35 mg of agalsidase beta. After reconstitution with 7.2 ml water for injections, each vial of Fabrazyme contains 5 mg/ml (35 mg/7 ml) of agalsidase beta. The reconstituted solution must be diluted further (see section 6.6).

Fabrazyme 5 mg powder for concentrate for solution for infusion

Each vial of Fabrazyme contains a nominal value of 5 mg of agalsidase beta. After reconstitution with 1.1 ml water for injections, each vial of Fabrazyme contains 5 mg/ml of agalsidase beta. The reconstituted solution must be diluted further (see section 6.6).

Agalsidase beta is a recombinant form of human -galactosidase A and is produced by recombinant DNA technology using a mammalian Chinese Hamster Ovary (CHO) cell culture. The amino acid sequence of the recombinant form, as well as the nucleotide sequence which encoded it, are identical to the natural form of -galactosidase A.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

White to off-white lyophilised cake or powder.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

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

Fabrazyme is indicated in adults, children and adolescents aged 8 years and older.

4.2Posology and method of administration

Fabrazyme treatment should be supervised by a physician experienced in the management of patients with Fabry disease or other inherited metabolic diseases.

Posology

The recommended dose of Fabrazyme is 1 mg/kg body weight administered once every 2 weeks as an intravenous infusion.

Lower dosing regimens have been used in clinical studies. In one of these studies, performed in adult male patients, after an initial dose of 1.0 mg/kg every 2 weeks for 6 months, 0.3 mg/kg every 2 weeks may maintain clearance of GL-3 in certain cell types in some patients; however, the long term clinical relevance of these findings has not been established (see section 5.1).

The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise the potential occurrence of infusion-associated reactions. After patient tolerance is established, the infusion rate may be increased gradually with subsequent infusions.

Infusion of Fabrazyme at home may be considered for patients who are tolerating their infusions well. The decision to have a patient move to home infusion should be made after evaluation and recommendation by the treating physician. Patients experiencing adverse events during the home infusion need to immediately stop the infusion process and seek the attention of a healthcare professional. Subsequent infusions may need to occur in a clinical setting. Dose and infusion rate should remain constant while at home, and not be changed without supervision of a healthcare professional.

Special populations

Renal impairment

No dose adjustment is necessary for patients with renal insufficiency.

Hepatic impairment

Studies in patients with hepatic insufficiency have not been performed.

Elderly

The safety and efficacy of Fabrazyme in patients older than 65 years have not been established and no dosage regimen can presently be recommended in these patients.

Paediatric population

The safety and efficacy of Fabrazyme in children aged 0 to7 years have not yet been established. Currently available data are described in sections 5.1 and 5.2 but no recommendation on posology can be made in children aged 5 to 7 years. No data are available in children 0 to 4 years

No dose adjustment is necessary for children 8-16 years

Method of administration

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3Contraindications

Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients listed in section 6.1.

4.4Special warnings and precautions for use

Immunogenicity

Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. The majority of patients developed IgG antibodies to r-hαGAL, typically within 3 months of the first infusion with Fabrazyme. Over time, the majority of seropositive patients in clinical trials demonstrated either a downward trend in titers (based on a ≥ 4-fold reduction in titer from the peak measurement to the last measurement) (40% of the patients), tolerised (no detectable antibodies confirmed by 2 consecutive radioimmuno- precipitation (RIP) assays) (14% of the patients) or demonstrated a plateau (35% of the patients).

Infusion associated reactions

Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs), which are defined as any related adverse event occurring on the infusion day. These patients should be treated with caution when re-administering agalsidase beta (see section 4.8). Antibody status should be regularly monitored.

In clinical trials, sixty seven percent (67 %) of the patients experienced at least one infusion- associated reaction (see section 4.8). The frequency of IARs decreased over time. Patients experiencing mild or moderate infusion-associated reactions when treated with agalsidase beta during clinical trials have continued therapy after a reduction in the infusion rate (~0.15 mg/min; 10 mg/hr) and/or pre-treatment with antihistamines, paracetamol, ibuprofen and/or corticosteroids.

Hypersensitivity

As with any intravenous protein medicinal product, allergic-type hypersensitivity reactions are possible.

A small number of patients have experienced reactions suggestive of immediate (Type I) hypersensitivity. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed. With careful rechallenge Fabrazyme has been re-administered to all 6 patients who tested positive for IgE antibodies or had a positive skin test to Fabrazyme in a clinical trial. In this trial, the initial rechallenge administration was at a low dose and a lower infusion rate (1/2 the therapeutic dose at 1/25 the initial standard recommended rate). 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.

Patients with advanced renal disease

The effect of Fabrazyme treatment on the kidneys may be limited in patients with advanced renal disease.

4.5Interaction with other medicinal products and other forms of interaction

No interaction studies and no in vitro metabolism studies have been performed. Based on its metabolism, agalsidase beta is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

Fabrazyme should not be administered with chloroquine, amiodarone, benoquin or gentamycin due to a theoretical risk of inhibition of intra-cellular -galactosidase A activity.

4.6Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of agalsidase beta in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal development (see section 5.3).

Fabrazyme should not be used during pregnancy unless clearly necessary.

Breast-feeding

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 breast-feeding when Fabrazyme is used.

Fertility

Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility.

4.7Effects on ability to drive and use machines

Fabrazyme may have a minor influence on the ability to drive or use machines on the day of Fabrazyme administration because dizziness, somnolence, vertigo and syncope may occur (see section 4.8).

4.8Undesirable effects

Summary of the safety profile

Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs). Reactions suggestive of

immediate (Type I) hypersensitivity have been reported in a small number of patients (see section 4.4).

Very common adverse reactions included chills, pyrexia, feeling cold, nausea, vomiting, headache and paraesthesia. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. Anaphylactoid reactions have been reported in the postmarketing setting.

Tabulated list of adverse reactions

Adverse reactions reported from clinical trials with a total of 168 patients (154 males and 14 females) treated with Fabrazyme administered at a dose of 1 mg/kg every 2 weeks for a minimum of one infusion up to a maximum of 5 years are listed by System Organ Class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10 and uncommon ≥ 1/1000 to < 1/100) in the table below. The occurrence of an adverse reaction in a single patient is defined as uncommon in light of the relatively small number of patients treated. Adverse reactions only reported during the Post Marketing period are also included in the table below at a frequency category of “not known” (cannot be estimated from the available data). Adverse reactions were mostly mild to moderate in severity:

Incidence of adverse reactions with Fabrazyme treatment

System organ

Very common

Common

Uncommon

Not known

class

 

 

 

 

Infections and

---

nasopharyngitis

rhinitis

 

infestations

 

 

 

 

Immune system

---

---

---

anaphylactoid

disorders

 

 

 

reaction

Nervous system

headache,

dizziness, somnolence,

hyperaesthesia,

---

disorders

paraesthesia

hypoaesthesia, burning

tremor

 

 

 

sensation, lethargy,

 

 

 

 

syncope

 

 

Eye disorders

---

lacrimation increased

eye pruritus, ocular

---

 

 

 

hyperaemia

 

Ear and

---

tinnitus, vertigo

auricular swelling,

---

labyrinth

 

 

ear pain

 

disorders

 

 

 

 

Cardiac

---

tachycardia,

sinus bradycardia

---

Disorders

 

palpitations, bradycardia

 

 

Vascular

---

flushing, hypertension,

peripheral coldness

---

disorders

 

pallor, hypotension, hot

 

 

 

 

flush

 

 

Respiratory,

---

dyspnoea, nasal

bronchospasm,

hypoxia

thoracic and

 

congestion, throat

pharyngolaryngeal

 

mediastinal

 

tightness, wheezing,

pain, rhinnorhoea,

 

disorders

 

cough, dyspnoea

tachypnoea, upper

 

 

 

exacerbated

respiratory tract

 

 

 

 

congestion

 

Gastrointestinal

nausea, vomiting

abdominal pain,

dyspepsia, dysphagia

---

Disorders

 

abdominal pain upper,

 

 

 

 

abdominal discomfort,

 

 

 

 

stomach discomfort,

 

 

 

 

hypoaesthesia oral,

 

 

 

 

diarrhoea

 

 

Skin and

---

pruritus, urticaria, rash,

livedo reticularis,

leukocytoclastic

subcutaneous

 

erythema, pruritus

rash erythematous,

vasculitis

tissue disorders

 

generalized,

rash pruritic, skin

 

 

 

angioneurotic oedema,

discolouration, skin

 

 

 

swelling face, rash

discomfort

 

 

 

maculo-papular

 

 

Musculoskeletal

---

pain in extremity,

musculoskeletal pain

---

and connective

 

myalgia, back pain,

 

 

tissue disorders

 

muscle spasms,

 

 

 

 

arthralgia, muscle

 

 

 

 

tightness,

 

 

 

 

musculoskeletal

 

 

 

 

stiffness

 

 

General

chills, pyrexia,

fatigue, chest

feeling hot and cold,

---

disorders and

feeling cold

discomfort, feeling hot,

influenza-like illness,

 

administration

 

oedema peripheral, pain,

infusion site pain,

 

site conditions

 

asthenia, chest pain, face

infusion site reaction,

 

 

 

oedema, hyperthermia

injection site

 

 

 

 

thrombosis, malaise,

 

 

 

 

oedema

 

Investigations

 

 

 

oxygen saturation

 

 

 

 

decreased

For the purpose of this table, ≥1% is defined as reactions occurring in 2 or more patients.

Adverse reaction terminology is based upon the Medical Dictionary for Regulatory Activities (MedDRA)

Description of selected adverse reactions

Infusion associated reactions

Infusion associated reactions consisted most often of fever and chills. Additional symptoms included mild or moderate dyspnoea, hypoxia (oxygen saturation decreased), throat tightness, chest discomfort, flushing, pruritus, urticaria, face oedema, angioneurotic oedema, rhinitis, bronchospasm, tachypnoea, wheezing, hypertension, hypotension, tachycardia, palpitations, abdominal pain, nausea, vomiting, infusion-related pain including pain at the extremities, myalgia, and headache.

The infusion-associated reactions were managed by a reduction in the infusion rate together with the administration of non-steroidal anti-inflammatory medicinal products, antihistamines and/or corticosteroids. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. The frequency of these reactions decreased over time. The majority of these reactions can be attributed to the formation of IgG antibodies and/or complement activation. In a limited number of patients IgE antibodies were demonstrated (see section 4.4).

Paediatric population

Limited information from clinical trials suggests that the safety profile of Fabrazyme treatment in paediatric patients ages 5-7, treated with either 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks is similar to that of patients (above the age of 7) treated at 1.0 mg/kg every 2 weeks.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

4.9Overdose

In clinical trials doses up to 3 mg/kg body weight were used.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. ATC code: A16AB04.

Fabry disease

Fabry disease is an inherited heterogeneous and multisystemic progressive disease, that affects both males and females. It is characterised by the deficiency of -galactosidase. Reduced or absent - galactosidase activity results in the accumulation of GL-3 in the lysosomes of many cell types including the endothelial and parenchymal cells, ultimately leading to life-threatening clinical deteriorations as a result of renal, cardiac and cerebrovascular complications.

Mechanism of action

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to clear the accumulating substrate in the organ tissues; thereby, preventing, stabilizing or reversing the progressive decline in function of these organs before irreversible damage has occurred.

After intravenous infusion, agalsidase beta is rapidly removed from the circulation and taken up by vascular endothelial and parenchymal cells into lysosomes, likely through the mannose-6 phosphate, mannose and asialoglycoprotein receptors.

Clinical efficacy and safety

Efficacy and safety of Fabrazyme was evaluated in two studies with children, one dose-finding study, two double-blind placebo-controlled studies, and one open-label extension study in both male and female patients.

In the dose finding study, the effects of 0.3, 1.0 and 3.0 mg/kg once every 2 weeks and 1.0 and

3.0 mg/kg once every 2 days were evaluated. A reduction in GL-3 was observed in kidney, heart, skin and plasma at all doses. Plasma GL-3 was cleared in a dose dependent manner, but was less consistent at the dose of 0.3 mg/kg. In addition, infusion-associated reactions were dose dependent.

In the first placebo-controlled clinical trial, Fabrazyme was effective in clearing GL-3 from the vascular endothelium of the kidney after 20 weeks of treatment. This clearance was achieved in 69% (20/29) of the Fabrazyme treated patients, but in none of the placebo patients (p<0.001). This finding was further supported by a statistically significant decrease in GL-3 inclusions in kidney, heart and skin combined and in the individual organs in patients treated with agalsidase beta compared to placebo patients (p<0.001). Sustained clearance of GL-3 from kidney vascular endothelium upon agalsidase beta treatment was demonstrated further in the open label extension of this trial. This was achieved in 47 of the 49 patients (96%) with available information at month 6, and in 8 of the

8 patients (100%) with available information at the end of the study (up to a total of 5 years of treatment). Clearance of GL-3 was also achieved in several other cell types from the kidney. Plasma GL-3 levels rapidly normalised with treatment and remained normal through 5 years.

Renal function, as measured by glomerular filtration rate and serum creatinine, as well as proteinuria, remained stable in the majority of the patients. However, the effect of Fabrazyme treatment on the kidney function was limited in some patients with advanced renal disease.

Although no specific study has been conducted to assess the effect on the neurological signs and symptoms, the results also indicate that patients may achieve reduced pain and enhanced quality of life upon enzyme replacement therapy.

Another double-blind, placebo-controlled study of 82 patients was performed to determine whether Fabrazyme would reduce the rate of occurrence of renal, cardiac, or cerebrovascular disease or death. The rate of clinical events was substantially lower among Fabrazyme-treated patients compared to placebo-treated patients (risk reduction = 53% intent-to-treat population (p=0.0577); risk reduction = 61 % per-protocol population (p=0.0341)). This result was consistent across renal, cardiac and cerebrovascular events.

The results of these studies indicate that Fabrazyme treatment at 1 mg/kg every other week provides clinical benefit on key clinical outcomes in patients with early and advanced Fabry disease. Because this condition is slowly progressive, early detection and treatment is critical to achieve the best outcomes.

In an additional study, 21 male patients were enrolled to follow GL3 clearance in kidney and skin tissues at an alternative dosing regimen. Following treatment with 1 mg/kg every other week for 24 weeks, a dose regimen of 0.3 mg/kg every 2 weeks for 18 months was able to maintain the

clearance of cellular GL-3 in the capillary endothelium of the kidney, other kidney cell types and skin (superficial skin capillary endothelium) in the majority of patients. However, at the lower dose, IgG antibodies may play a role with respect to GL-3 clearance in some patients. Due to the limitations of the study design (small number of patients), no definitive conclusion regarding the dose maintenance regimen can be drawn, but these findings suggest that, after an initial debulking dose of 1.0 mg/kg every 2 weeks, 0.3 mg/kg every 2 weeks may be sufficient in some patients to maintain clearance of GL-3.

In the postmarketing setting, experience was gained in patients who initiated treatment at a dose of 1 mg/kg every 2 weeks and subsequently received a reduced dose for an extended period. In some of these patients, an increase of some of the following symptoms was spontaneously reported: pain,

paraesthesia and diarrhoea, as well as cardiac, central nervous system and renal manifestations. These reported symptoms resemble the natural course of Fabry disease.

Paediatric population

In one open-label paediatric study, sixteen patients with Fabry disease (8-16 years old; 14 males, 2 females) had been treated for one year at 1.0 mg/kg every 2 weeks. Clearance of GL-3 in the superficial skin vascular endothelium was achieved in all patients who had accumulated GL-3 at baseline. The 2 female patients had little or no GL-3 accumulation in the superficial skin vascular endothelium at baseline, making this conclusion applicable in male patients only.

In an additional 5-year open-label paediatric study, 31 male patients aged 5 to 18 years were randomized prior to the onset of clinical symptoms involving major organs and treated with two lower dose regimens of agalsidase beta, 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks. Results were similar between the two treatment groups. Superficial skin capillary endothelium GL-3 scores were reduced to zero or maintained at zero at all time points post-baseline upon treatment in 19/27 patients completing the study without a dose increase. Both baseline and 5-year kidney biopsies were obtained in a subset of 6 patients: in all, kidney capillary endothelium GL-3 scores were reduced to zero but highly variable effects were observed in podocyte GL-3, with a reduction in 3 patients. Ten (10) patients met per protocol dose increase criteria, two (2) had a dose increase to the recommended dose of 1.0 mg/kg every 2 weeks.

5.2Pharmacokinetic properties

Following an intravenous administration of agalsidase beta to adults at doses of 0.3 mg, 1 mg and 3 mg/kg body weight, the AUC values increased more than dose proportional, due to a decrease in

clearance, indicating a saturated clearance. The elimination half-life was dose independent and ranged from 45 to 100 minutes.

After intravenous administration of agalsidase beta to adults with an infusion time of approximately 300 minutes and at a dose of 1 mg/kg body weight, biweekly, mean Cmax plasma concentrations ranged from 2000-3500 ng/ml, while the AUCinf ranged from 370-780 g min/ml. Vss ranged from 8.3-40.8 l, plasma clearance from 119-345 ml/min and the mean elimination half-life from

80-120 minutes.

Agalsidase beta is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of agalsidase beta in a clinically significant way. Renal elimination of agalsidase beta is considered to be a minor pathway for clearance.

Paediatric population

Fabrazyme pharmacokinetics was also evaluated in two paediatric studies. In one of these studies, 15 paediatric patients with available pharmacokinetics data, aged 8.5 to 16 years weighing 27.1 to 64.9 kg were treated with 1.0 mg/kg every 2 weeks. Agalsidase beta clearance was not influenced by weight in this population. Baseline CL was 77 ml/min with a Vss of 2.6 l; half-life was 55 min. After IgG seroconversion, CL decreased to 35 ml/min, Vss increased to 5.4 l, and half-life increased to 240 min. The net effect of these changes after seroconversion was an increase in exposure of 2- to 3-fold based on AUC and Cmax. No unexpected safety issues were encountered in patients with an increase in exposure after seroconversion.

In another study with 30 paediatric patients with available pharmacokinetics data, aged 5 to 18 years, treated with two lower dose regimens of 0.5 mg/kg every 2 weeks and 1.0 mg/kg every 4 weeks, mean CL was 4.6 and 2.3 ml/min/kg, respectively, mean Vss was 0.27 and 0.22 l/kg, respectively, and mean elimination half-life was 88 and 107 minutes, respectively. After IgG seroconversion, there was no apparent change in CL (+24% and +6%, resp.), while Vss was 1.8 and 2.2 fold higher, with the net

effect being a small decrease in Cmax (up to -34% and -11%, resp.) and no change in AUC (-19% and - 6%, resp.).

5.3Preclinical safety data

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, single dose toxicity, repeated dose toxicity and embryonal/foetal toxicity. Studies with regard to other stages of the development have not been carried out. Genotoxic and carcinogenic potential are not expected.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Mannitol

Sodium phosphate monobasic, monohydrate

Sodium phosphate dibasic, heptahydrate

6.2Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products in the same infusion.

6.3Shelf life

3 years.

Reconstituted and diluted solutions

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage and conditions prior to use are the responsibility of the user. The reconstituted solution cannot be stored and should be promptly diluted; only the diluted solution can be held for up to 24 hours at 2 C-8 C.

6.4Special precautions for storage

Store in a refrigerator (2 C – 8 C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

6.5Nature and contents of container

Fabrazyme 35 mg powder for concentrate for solution for infusion

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.

Package sizes: 1, 5 and 10 vials per carton.

Not all pack sizes may be marketed.

Fabrazyme 5 mg powder for concentrate for solution for infusion

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

Package sizes: 1, 5 and 10 vials per carton.

Not all pack sizes may be marketed.

6.6Special precautions for disposal and other handling

The powder for concentrate for solution for infusion has to be reconstituted with water for injections, diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous infusion. Use Aseptic Technique

Determine the number of vials to be reconstituted based on the individual patient’s weight and remove the required vials from the refrigerator in order to allow them to reach room temperature (in approximately 30 minutes). Each vial of Fabrazyme is intended for single use only.

Reconstitution

Fabrazyme 35 mg powder for concentrate for solution for infusion

Reconstitute each vial of Fabrazyme 35 mg with 7.2 ml water for injections. Avoid forceful impact of the water for injections 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 lyophilized cake. Roll and tilt each vial gently. Do not invert, swirl or shake the vial.

Fabrazyme 5 mg powder for concentrate for solution for infusion

Reconstitute each vial of Fabrazyme 5 mg with 1.1 ml water for injections. Avoid forceful impact of the water for injections 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 lyophilized cake. Roll and tilt each vial gently. Do not invert, swirl or shake the vial.

The reconstituted solution contains 5 mg agalsidase beta per ml, and appears as a clear colourless solution. The pH of the reconstituted solution is approximately 7.0. Before further dilution, visually inspect the reconstituted solution in each vial for particulate matter and discoloration. Do not use the solution if foreign particles are observed or if the solution is discoloured.

After reconstitution it is recommended to promptly dilute the vials, to minimise protein particle formation over time.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Dilution

Fabrazyme 35 mg powder for concentrate for solution for infusion

Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it is recommended to remove an equal volume of 0.9% sodium chloride intravenous solution, from the infusion bag.

Remove the airspace within the infusion bag to minimize the air/liquid interface.

Slowly, withdraw 7.0 ml (equal to 35 mg) of the reconstituted solution from each vial up to the total volume required for the patient dose. Do not use filter needles and avoid foaming.

Then slowly inject the reconstituted solution directly into the 0.9% sodium chloride intravenous solution (not in any remaining airspace) to a final concentration between 0.05 mg/ml and 0.7 mg/ml. Determine the total volume of sodium chloride 0.9% solution for infusion (between 50 and 500 ml) based on the individual dose. For doses lower than 35 mg use a minimum of 50 ml, for doses 35 to 70 mg use a minimum of 100 ml, for doses 70 to 100 mg use a minimum of 250 ml and for doses greater than 100 mg use only 500 ml. Gently invert or lightly massage the infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion bag.

Fabrazyme 5 mg powder for concentrate for solution for infusion

Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it is recommended to remove an equal volume of 0.9% sodium chloride intravenous solution, from the infusion bag.

Remove the airspace within the infusion bag to minimize the air/liquid interface.

Slowly, withdraw 1.0 ml (equal to 5 mg) of the reconstituted solution from each vial up to the total volume required for the patient dose. Do not use filter needles and avoid foaming.

Then slowly inject the reconstituted solution directly into the 0.9% sodium chloride intravenous solution (not in any remaining airspace) to a final concentration between 0.05 mg/ml and 0.7 mg/ml. Determine the total volume of sodium chloride 0.9% solution for infusion (between 50 and 500 ml) based on the individual dose. For doses lower than 35 mg use a minimum of 50 ml, for doses 35 to 70 mg use a minimum of 100 ml, for doses 70 to 100 mg use a minimum of 250 ml and for doses greater than 100 mg use only 500 ml. Gently invert or lightly massage the infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion bag.

Administration

It is recommended to administer the diluted solution through an in-line low protein-binding 0.2 µm filter to remove any protein particles which will not lead to any loss of agalsidase beta activity. The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise the potential occurrence of infusion-associated reactions. After patient tolerance is established, the infusion rate may be increased gradually with subsequent infusions.

7.MARKETING AUTHORISATION HOLDER

Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands

8.MARKETING AUTHORISATION NUMBERS

EU/1/01/188/001 Fabrazyme 35 mg 1 vial of powder for concentrate for solution for infusion EU/1/01/188/002 Fabrazyme 35 mg 5 vials of powder for concentrate for solution for infusion EU/1/01/188/003 Fabrazyme 35 mg 10 vials of powder for concentrate for solution for infusion EU/1/01/188/004 Fabrazyme 5 mg 1 vial of powder for concentrate for solution for infusion EU/1/01/188/005 Fabrazyme 5 mg 5 vials of powder for concentrate for solution for infusion EU/1/01/188/006 Fabrazyme 5 mg 10 vials of powder for concentrate for solution for infusion

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 03 August 2001

Date of last renewal: 03 August 2006

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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