FABRAZYME 35mg powder for concentrate infusion solution medication leaflet

Fabrazyme 35 mg powder for concentrate for solution for infusion

Fabrazyme 5 mg powder for concentrate for solution for infusion

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 reconstitutionwith 7.2 ml water for injections, each vial of Fabrazyme contains 5 mg/ml (35 mg/7 ml) of agalsidasebeta. 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 with1.1 ml water for injections, each vial of Fabrazyme contains 5 mg/ml of agalsidase beta. Thereconstituted 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 acidsequence of the recombinant form, as well as the nucleotide sequence which encoded it, are identicalto the natural form of -galactosidase A.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white lyophilisate or powder.

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

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

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

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

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 andrecommendation by the treating physician. Patients experiencing adverse events during the homeinfusion need to immediately stop the infusion process and seek the attention of a healthcareprofessional. Subsequent infusions may need to occur in a clinical setting. Dose and infusion rateshould remain constant while at home, and not be changed without supervision of a healthcareprofessional.

No dose adjustment is necessary for patients with renal insufficiency.

Studies in patients with hepatic insufficiency have not been performed.

The safety and efficacy of Fabrazyme in patients older than 65 years have not been established and nodosage regimen can presently be recommended in these patients.

The safety and efficacy of Fabrazyme in children aged 0 to 7 years have not yet been established.

Currently available data are described in sections 5.1 and 5.2 but no recommendation on posology canbe made in children aged 5 to 7 years. No data are available in children 0 to 4 years. No doseadjustment is necessary for children 8-16 years.

For patients weighing < 30 kg, the maximum infusion rate should remain at 0.25 mg/min (15 mg/hr).

Fabrazyme should be administered as an intravenous (IV) infusion.

The initial IV infusion rate should be no more than 0.25 mg/min (15 mg/hour). The infusion rate maybe slowed in the event of infusion-associated reactions.

After patient tolerance is well established, the infusion rate may be increased in increments of 0.05 to0.083 mg/min (increments of 3 to 5 mg/hr) with each subsequent infusion. In clinical trials withclassic patients, the infusion rate was increased incrementally to reach a minimum duration of 2 hours.

This was achieved after 8 initial infusions at 0.25 mg/min (15 mg/hr), without any IARs, change ininfusion rate, or infusion interruption. A further decrease of infusion time to 1.5 hours was allowed forpatients without new IARs during the last 10 infusions or reported serious adverse events within thelast 5 infusions. Each rate increment of 0.083 mg/min (~5 mg/hr) was maintained for 3 consecutiveinfusions, without any new IARs, change in infusion rate, or infusion interruption, before subsequentrate increases.

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

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

Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies isexpected in patients with little or no residual enzyme activity. The majority of patients developed IgGantibodies to r-hαGAL, typically within 3 months of the first infusion with Fabrazyme. Over time, themajority of seropositive 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) (40% ofthe 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-associatedreactions (IARs), which are defined as any related adverse event occurring on the infusion day. Thesepatients 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. Patientsexperiencing mild or moderate infusion-associated reactions when treated with agalsidase beta duringclinical 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.

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

A small number of patients have experienced reactions suggestive of immediate (Type I)hypersensitivity. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation ofthe administration of Fabrazyme should be considered and appropriate treatment initiated. The currentmedical standards for emergency treatment are to be observed. With careful rechallenge Fabrazymehas been re-administered to all 6 patients who tested positive for IgE antibodies or had a positive skintest to Fabrazyme in a clinical trial. In this trial, the initial rechallenge administration was at a lowdose 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 of1 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 renaldisease.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially‘sodium-free’.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered medicinal product should be clearly recorded.

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

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

There are limited data from the use of agalsidase beta in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3). As a precautionary measure, it is preferable to avoid the use of Fabrazyme duringpregnancy.

Agalsidase beta is excreted in human milk. The effect of agalsidase beta on newborns/infants isunknown. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom Fabrazyme therapy taking into account the benefit of breast feeding for the child and the benefitof therapy for the woman.

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

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 (seesection 4.8).

Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies isexpected in patients with little or no residual enzyme activity. Patients with antibodies to r-hαGALhave a greater potential to experience infusion-associated reactions (IARs). Reactions suggestive ofimmediate (Type I) hypersensitivity have been reported in a small number of patients (see section4.4).

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

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 oneinfusion 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 ≥ 1/1,000 to < 1/100) in the table below. Theoccurrence of an adverse reaction in a single patient is defined as uncommon in light of the relativelysmall number of patients treated. Adverse reactions only reported during the Post Marketing periodare also included in the table below at a frequency category of “not known” (cannot be estimated fromthe 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 knownclass

Infections and --- nasopharyngitis rhinitisinfestations

Immune system --- --- --- anaphylactoiddisorders reaction

Nervous system headache, dizziness, somnolence, hyperaesthesia, ---disorders paraesthesia hypoaesthesia, burning tremorsensation, lethargy,syncope

Eye disorders --- lacrimation increased eye pruritus, ocular ---hyperaemia

Ear and --- tinnitus, vertigo auricular swelling, ---labyrinth ear paindisorders

Cardiac --- tachycardia, sinus bradycardia ---

Disorders palpitations, bradycardia

Vascular --- flushing, hypertension, peripheral coldness ---disorders pallor, hypotension, hotflush

Respiratory, --- dyspnoea, nasal bronchospasm, hypoxiathoracic and congestion, throat pharyngolaryngealmediastinal tightness, wheezing, pain, rhinorrhoea,disorders cough, dyspnoea tachypnoea, upperexacerbated respiratory tractcongestion

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, leukocytoclasticsubcutaneous erythema, pruritus rash erythematous, vasculitistissue disorders generalised, rash pruritic, skinangioneurotic oedema, discolouration, skinswelling face, rash discomfortmaculo-papular

Musculoskeletal --- pain in extremity, musculoskeletal pain ---and connective myalgia, back pain,tissue disorders muscle spasms,arthralgia, muscletightness,musculoskeletalstiffness

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 sitethrombosis, malaise,oedema

Investigations oxygen saturationdecreased

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)

Infusion associated reactions

Infusion associated reactions consisted most often of fever and chills. Additional symptoms includedmild 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 theadministration of non-steroidal anti-inflammatory medicinal products, antihistamines and/orcorticosteroids. Sixty seven percent (67%) of the patients experienced at least one infusion-associatedreaction. The frequency of these reactions decreased over time. The majority of these reactions can beattributed to the formation of IgG antibodies and/or complement activation. In a limited number ofpatients IgE antibodies were demonstrated (see section 4.4).

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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 bothmales and females. It is characterised by the deficiency of -galactosidase. Reduced or absent -galactosidase activity results in the presence of elevated concentrations of GL-3 and its associatedsoluble form lyso-GL-3 in plasma and in accumulation of GL-3 in the lysosomes of many cell typesincluding the endothelial and parenchymal cells, ultimately leading to life-threatening clinicaldeteriorations as a result of renal, cardiac and cerebrovascular complications.

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient toclear the accumulating substrate in the organ tissues; thereby, preventing, stabilizing or reversing theprogressive 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 byvascular endothelial and parenchymal cells into lysosomes, likely through the mannose-6 phosphate,mannose and asialoglycoprotein receptors.

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

In the dose finding study, the effects of 0.3, 1.0 and 3.0 mg/kg once every 2 weeks and 1.0 and3.0 mg/kg once every 2 days were evaluated. A reduction in GL-3 was observed in kidney, heart, skinand plasma at all doses. Plasma GL-3 was cleared in a dose dependent manner but was less consistentat the dose of 0.3 mg/kg. In addition, infusion-associated reactions were dose dependent.

In the first placebo-controlled clinical trial of 58 Fabry patients with classic phenotype (56 males and2 females), Fabrazyme was effective in clearing GL-3 from the vascular endothelium of the kidneyafter 20 weeks of treatment. This clearance was achieved in 69% (20/29) of the Fabrazyme treatedpatients, but in none of the placebo patients (p<0.001). This finding was further supported by astatistically significant decrease in GL-3 inclusions in kidney, heart and skin combined and in theindividual 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 wasdemonstrated further in the open label extension of this trial. This was achieved in 47 of the 49patients (96%) with available information at month 6, and in 8 of the 8 patients (100%) with availableinformation at the end of the study (up to a total of 5 years of treatment). Clearance of GL-3 was alsoachieved in several other cell types from the kidney. Plasma GL-3 levels rapidly normalised withtreatment 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 thekidney 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 andsymptoms, the results also indicate that patients may achieve reduced pain and enhanced quality oflife upon enzyme replacement therapy.

Another double-blind, placebo-controlled study of 82 Fabry patients with classic phenotype (72 malesand 10 females) was performed to determine whether Fabrazyme would reduce the rate of occurrenceof renal, cardiac, or cerebrovascular disease or death. The rate of clinical events was substantiallylower 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)). Thisresult was consistent across renal, cardiac and cerebrovascular events.

Two large observational studies followed a group of patients (n=89 to 105) who were maintained onstandard-dose Fabrazyme (1.0 mg/kg every 2 weeks) or assigned to a reduced dose of Fabrazyme(0.3-0.5 mg/kg every 2 weeks) followed by a switch to agalsidase alfa (0.2 mg/kg every 2 weeks) ordirectly switched to agalsidase alfa (0.2 mg/kg every 2 weeks). Due to the observational, multi-centredesign of these studies based in a real-world clinical setting, there are confounding factors affectingthe interpretation of the results, including the selection of patients and assignment of treatment groupsand available parameters between centres over time. Due to the rarity of Fabry disease, the studypopulations of the observational studies overlapped and the treatment groups in respective studieswere small. Moreover, most patients with more severe disease, especially men, remained on standarddose Fabrazyme, whereas a treatment switch occurred more frequently in patients with less severedisease and women. Comparisons between the groups should therefore be cautiously interpreted.

The Fabrazyme standard-dose group demonstrated no significant changes in cardiac, renal, orneurologic organ function or in symptoms related to Fabry disease. Similarly, no significant changesin cardiac or neurologic function were observed in patients in the Fabrazyme dose-reduction group.

However, deterioration in renal parameters, as measured by estimated glomerular filtration rate(eGFR), was observed in patients treated with a lower dose (p<0.05). The annual decreases in eGFRwere attenuated in patients who re-switched back to standard dose Fabrazyme. These results areconsistent with 10-year follow-up evidence from the Canadian Fabry Disease Initiative Registry.

In the observational studies an increase in symptoms related to Fabry disease (e.g., gastrointestinalpain, diarrhoea) was observed in patients who had received a dose reduction of agalsidase beta.

Also, in the postmarketing setting, experience was gained in patients who initiated Fabrazymetreatment at a dose of 1 mg/kg every 2 weeks and subsequently received a reduced dose for anextended period. In some of these patients, an increase of some of the following symptoms wasspontaneously reported: pain, paraesthesia and diarrhoea, as well as cardiac, central nervous systemand renal manifestations. These reported symptoms resemble the natural course of Fabry disease.

In an analysis conducted in the Fabry Registry, the incidence rates (95% confidence interval) of thefirst severe clinical event in Classic male Fabrazyme-treated patients with sustained anti-agalsidasebeta IgG antibodies were 43.98 (18.99, 86.66), 48.60 (32.03, 70.70), and 56.07 (30.65, 94.07) per1000 person-years in the low, medium, and high peak titre groups, respectively. These observeddifferences were not statistically significant.

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 thesuperficial skin vascular endothelium was achieved in all patients who had accumulated GL-3 atbaseline. The 2 female patients had little or no GL-3 accumulation in the superficial skin vascularendothelium 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 wererandomised prior to the onset of clinical symptoms involving major organs and treated with two lowerdose regimens of agalsidase beta, 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks. Results weresimilar between the two treatment groups. Superficial skin capillary endothelium GL-3 scores werereduced to zero or maintained at zero at all time points post-baseline upon treatment in 19/27 patientscompleting the study without a dose increase. Both baseline and 5-year kidney biopsies were obtainedin a subset of 6 patients: in all, kidney capillary endothelium GL-3 scores were reduced to zero, buthighly 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 doseof 1.0 mg/kg every 2 weeks.

Following an intravenous administration of agalsidase beta to adults at doses of 0.3 mg, 1 mg and3 mg/kg body weight, the AUC values increased more than dose proportional, due to a decrease inclearance, indicating a saturated clearance. The elimination half-life was dose independent and rangedfrom 45 to 100 minutes.

After intravenous administration of agalsidase beta to adults with an infusion time of approximately300 minutes and at a dose of 1 mg/kg body weight, biweekly, mean Cmax plasma concentrationsranged from 2000-3500 ng/ml, while the AUCinf ranged from 370-780 g min/ml. Vss ranged from8.3-40.8 l, plasma clearance from 119-345 ml/min and the mean elimination half-life from80-120 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 agalsidasebeta in a clinically significant way. Renal elimination of agalsidase beta is considered to be a minorpathway for clearance.

Fabrazyme pharmacokinetics was also evaluated in two paediatric studies. In one of these studies, 15paediatric patients with available pharmacokinetics data, aged 8.5 to 16 years weighing 27.1 to 64.9kg were treated with 1.0 mg/kg every 2 weeks. Agalsidase beta clearance was not influenced byweight 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 240min. The net effect of these changes after seroconversion was an increase in exposure of 2- to 3-foldbased on AUC and Cmax. No unexpected safety issues were encountered in patients with an increase inexposure 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 meanelimination half-life was 88 and 107 minutes, respectively. After IgG seroconversion, there was noapparent change in CL (+24% and +6%, resp.), while Vss was 1.8 and 2.2-fold higher, with the neteffect being a small decrease in Cmax (up to -34% and -11%, resp.) and no change in AUC (-19% and -6%, resp.).

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

Mannitol (E421)

Sodium dihydrogen phosphate monohydrate (E339)

Disodium phosphate heptahydrate (E339)

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

3 years.

Reconstituted and diluted solutions

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

Store in a refrigerator (2°C - 8°C).

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

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 siliconisedbutyl 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 siliconisedbutyl 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.

The powder for concentrate for solution for infusion has to be reconstituted with water for injections,diluted with 0.9% sodium chloride solution for injection and then administered by intravenousinfusion. Aseptic technique should be used.

The number of vials should be determined to be reconstituted based on the individual patient’s weightand the required vials should be removed from the refrigerator in order to allow them to reach roomtemperature (in approximately 30 minutes). Each vial of Fabrazyme is intended for single use only.

Fabrazyme 35 mg powder for concentrate for solution for infusion

Each vial of Fabrazyme 35 mg has to be reconstituted with 7.2 ml water for injections. Forcefulimpact of the water for injections on the powder and foaming should be avoided. This is done by slowdrop-wise addition of the water for injection down the inside of the vial and not directly onto thelyophilisate. Each vial should be rolled and tilted gently. The vial should not be inverted, swirled orshaken.

Fabrazyme 5 mg powder for concentrate for solution for infusion

Each vial of Fabrazyme 5 mg has to be reconstituted with 1.1 ml water for injections. Forceful impactof the water for injections on the powder and foaming should be avoided. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto thelyophilisate. Each vial should be rolled and tilted gently. The vial should not be inverted, swirled orshaken.

The reconstituted solution contains 5 mg agalsidase beta per ml and appears as a clear colourlesssolution. The pH of the reconstituted solution is approximately 7.0. Before further dilution, thereconstituted solution in each vial should be visually inspected for particulate matter anddiscolouration. The solution should not be used if foreign particles are observed or if the solution isdiscoloured.

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

Fabrazyme 35 mg powder for concentrate for solution for infusion

Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it isrecommended to remove an equal volume of 0.9% sodium chloride solution for injection, from theinfusion bag.

The airspace within the infusion bag should be removed to minimise the air/liquid interface.

7.0 ml (equal to 35 mg) of the reconstituted solution from each vial up to the total volume requiredshould be slowly withdrawn for the patient dose. Filter needles should not be used and foamingshould be avoided.

The reconstituted solution should slowly be injected directly into the 0.9% sodium chloride solutionfor injection (not in any remaining airspace) to a final concentration between 0.05 mg/ml and0.7 mg/ml. The total volume of sodium chloride 0.9% solution for infusion (between 50 and 500 ml)should be determined based on the individual dose. For doses lower than 35 mg a minimum of 50 mlshould be used, for doses 35 to 70 mg a minimum of 100 ml should be used, for doses 70 to 100 mg aminimum of 250 ml should be used and for doses greater than 100 mg only 500 ml should be used.

The infusion bag should be gently inverted or lightly massaged to mix the diluted solution. Theinfusion bag should not be shaken or excessively agitated.

Fabrazyme 5 mg powder for concentrate for solution for infusion

Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it isrecommended to remove an equal volume of 0.9% sodium chloride solution for injection, from theinfusion bag.

The airspace within the infusion bag should be removed to minimise the air/liquid interface.

1.0 ml (equal to 5 mg) of the reconstituted solution from each vial up to the total volume requiredshould be slowly withdrawn for the patient dose. Filter needles should not be used and foamingshould be avoided.

The reconstituted solution should slowly be injected directly into the 0.9% sodium chloride solutionfor injection (not in any remaining airspace) to a final concentration between 0.05 mg/ml and0.7 mg/ml. The total volume of sodium chloride 0.9% solution for infusion (between 50 and 500 ml)should be determined based on the individual dose. For doses lower than 35 mg a minimum of 50 mlshould be used, for doses 35 to 70 mg a minimum of 100 ml should be used, for doses 70 to 100 mg aminimum of 250 ml should be used and for doses greater than 100 mg only 500 ml should be used.

The infusion bag should be gently inverted or lightly massaged to mix the diluted solution. Theinfusion bag should not be shaken or excessively agitated.

It is recommended to administer the diluted solution through an in-line low protein-binding 0.2 µmfilter to remove any protein particles which will not lead to any loss of agalsidase beta activity. Theinitial IV infusion rate should be no more than 0.25 mg/min (15 mg/hour). The infusion rate may beslowed in the event of infusion-associated reactions.

After patient tolerance is well established, the infusion rate may be increased in increments of 0.05 to0.083 mg/min (increments of 3 to 5 mg/hr) with each subsequent infusion. In clinical trials withclassic patients, the infusion rate was increased incrementally to reach a minimum duration of 2 hours.

This was achieved after 8 initial infusions at 0.25 mg/min (15 mg/hr), without any IARs, change ininfusion rate, or infusion interruption. A further decrease of infusion time to 1.5 hours was allowed forpatients without new IARs during the last 10 infusions or reported serious adverse events within thelast 5 infusions. Each rate increment of 0.083 mg/min (~5 mg/hr) was maintained for 3 consecutiveinfusions, without any new IARs, change in infusion rate, or infusion interruption, before subsequentrate increases.

For patients weighing < 30 kg, the maximum infusion rate should remain at 0.25 mg/min (15 mg/hr).

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

Sanofi B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands

EU/1/01/188/001

EU/1/01/188/002

EU/1/01/188/003

EU/1/01/188/004

EU/1/01/188/005

EU/1/01/188/006

Date of first authorisation: 03 August 2001

Date of last renewal: 28 July 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.