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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT Myozyme 50 mg, powder for concentrate for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One vial contains 50 mg of alglucosidase alfa. After reconstitution, the solution contains 5 mg of alglucosidase alfa-/ml and after dilution, the concentration varies from 0.5 mg to 4 mg/ml. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for concentrate for solution for infusion. White to off-white powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Myozyme is indicated for long-term enzyme replacement therapy (ERT) in patients with a confirmed diagnosis of Pompe disease (acid α-glucosidase deficiency). The benefits of Myozyme in patients with late-onset Pompe disease have not been established (see section 5.1). 4.2 Posology and method of administration Myozyme treatment should be supervised by a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular diseases. The recommended dosage regimen of alglucosidase alfa is 20 mg/kg of body weight administered once every 2 weeks as an intravenous infusion. Infusions should be administered incrementally. It is recommended that the infusion begin at an initial rate of 1 mg/kg/hr and be gradually increased by 2 mg/kg/hr every 30 minutes if there are no signs of infusion associated reactions (IARs) until a maximum rate of 7 mg/kg/hr is reached. IARs are described in section 4.8. Posology for children, adolescents, adults and elderly: The safety and efficacy of Myozyme have been primarily evaluated in children with ages ranging from infancy to adolescence. There is no evidence for special considerations when Myozyme is administered to children, adolescents, adults or elderly patients. The safety and efficacy of Myozyme in patients with renal or hepatic insufficiency have not been evaluated and no specific dosage regimen can be recommended for these patients.

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Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease. 4.3 Contraindications Hypersensitivity (anaphylactic reaction) to the active substance or to any of the excipients. 4.4 Special warnings and precautions for use Approximately 39% of patients treated with Myozyme developed IARs, defined as any related adverse event occurring during the infusion or during the 2 hours following infusion (see section 4.8). A tendency was observed in patients treated with a higher dose (40 mg/kg) to experience more symptoms when developing IARs. Patients should be closely monitored and all cases of IARs, delayed reactions and possible immunological reactions should be reported. Patients with an acute illness (e.g. pneumonia, sepsis) at the time of Myozyme infusion appear to be at greater risk for IARs. Careful consideration should be given to the patient’s clinical status prior to administration of Myozyme. Patients who have experienced IARs should be treated with caution when re-administering Myozyme (see section 4.3 and 4.8). Mild and transient effects may not require medical treatment or discontinuation of the infusion. Reduction of the infusion rate, temporary interruption of the infusion, or pre-treatment, generally with oral antihistamine and/or antipyretics, has effectively managed reactions. Infusion reactions may occur at any time during the infusion of Myozyme, especially with higher infusion rates. Allergic-type reactions may occur with the administration of an intravenous protein product. If severe or anaphylactic reactions occur, immediate discontinuation of Myozyme infusion should be considered and appropriate medical treatment should be initiated. The current medical standards for emergency treatment of anaphylactic reactions are to be observed. In clinical studies, the majority of patients developed IgG antibodies to rhGAA typically within 3 months of treatment. Thus seroconversion is expected to occur in most patients treated with Myozyme. A tendency was observed for patients treated with a higher dose (40 mg/kg) to develop higher titers of antibodies. There does not appear to be a correlation between the onset of IARs and the time of antibody formation. One of the IgG positive patients evaluated tested positive for inhibitory effects on in vitro testing. Due to the rarity of the condition and the limited experience to date, the effect of antibody formation on safety and efficacy is currently not fully established. Antibody titers should be regularly monitored. Transient nephrotic syndrome which resolved following temporary interruption of ERT was observed in one patient with infantile-onset Pompe disease who received very frequent dosing of rhGAA (10 mg/kg 5 times weekly) over an extended period. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug-drug interactions studies have been carried out with alglucosidase alfa. Because it is a recombinant human protein, alglucosidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions. 4.6 Pregnancy and lactation Myozyme should not be used during pregnancy unless clearly necessary. Alglucosidase alfa may be excreted in milk. Because there are no data available on effects in neonates exposed to alglucosidase alfa via breast milk, it is recommended to stop breast-feeding when Myozyme is used. 4.7 Effects on ability to drive and use machines

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No studies on the ability to drive and use machines have been conducted with Myozyme. 4.8 Undesirable effects Most adverse events reported in 39 infantile-onset patients (see section 5.1) treated with Myozyme up to more than one year (76 weeks) during two clinical studies were due to manifestations of Pompe disease and not related to the administration of Myozyme. Adverse Drug Reactions (ADRs) are listed in Table 1 by System Organ Class. The ADRs listed are reported in more than 1 patient and shown as percentage of patients experiencing the ADR with the absolute number of patients in brackets. ADRs were mostly mild to moderate in intensity and almost all occurred during the infusion or during the 2 hours following the infusion (IARs). Serious infusion reactions included urticaria, rales, tachycardia, decreased oxygen saturation, bronchospasm, tachypnea, periorbital edema, and hypertension all of which occurred in a single patient, except urticaria (2 patients). Table 1. System Organ Class Preferred term Frequency

(no. of patients) N = 39

Psychiatric disorders Agitation 5% (2 pts) Nervous system disorders Tremor 5% (2 pts) Cardiac disorders Tachycardia 8% (3 pts) Cyanosis 5% (2 pts) Vascular disorders Flushing 13% (5 pts) Hypertension 5% (2 pts) Pallor 5% (2 pts) Respiratory, thoracic and mediastinal disorders

Cough 8% (3 pts)

Tachypnoea 8% (3 pts) Gastrointestinal disorders Vomiting 5% (2 pts) Skin and subcutaneous tissue disorders

Urticaria 13% (5 pts)

Rash 10% (4 pts) Rash macular 5% (2 pts) Erythema 5% (2 pts) Rash maculo-papular 5% (2 pts) General disorders and administration site conditions

Pyrexia 15% (6 pts)

Rigors 5% (2 pts) Investigations Oxygen saturation decreased 8% (3 pts) Blood creatine phosphokinase MB

increased 5% (2 pts)

Blood pressure increased 5% (2 pts) A limited number of patients with late-onset Pompe disease (see section 5.1) have been treated with Myzozyme. ADRs reported in 2 of 9 late-onset patients treated with Myozyme for up to 1 year in 3 different studies included increased heart rate, hypertension, headache, peripheral coldness, paresthesia, flushing, infusion site pain, infusion site reaction, increased blood pressure and dizziness. The 2 late onset patients did not experience the same ADRs. The ADRs were, mild in intensity and assessed as an IAR.

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4.9 Overdose No case of overdose has been reported. In clinical studies doses up to 40 mg/kg body weight were used. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Alimentary tract and metabolism products – enzymes. ATC code: A16AB07 alglucosidase alfa . Alglucosidase alfa is a recombinant form of human acid α-glucosidase and is produced by recombinant DNA technology using Chinese Hamster Ovary (CHO) cell culture. Pompe disease Pompe disease is a rare, progressive and fatal metabolic myopathy with an estimated global incidence of 1 in 40,000 births. Other names for Pompe disease include glycogen storage disease type II (GSD-II), acid maltase deficiency (AMD) and glycogenosis type II. Pompe disease belongs to the lysosomal storage disorders as it is caused by a deficiency of a naturally-occurring lysosomal hydrolase, acid α-glucosidase (GAA) that degrades lysosomal glycogen to glucose. Deficiency of this enzyme leads to glycogen accumulation in various tissues, particularly cardiac, respiratory and skeletal muscle, leading to the development of hypertrophic cardiomyopathy and progressive muscle weakness, including impairment of respiratory function. The clinical presentation of Pompe disease can be described as a spectrum of disease which ranges from a rapidly-progressing infantile-onset form (onset of symptoms of Pompe disease typically within the first year of life and a very short expected life-span) to a less rapidly-progressing late-onset form. The infantile-onset form of Pompe disease is characterised by massive deposition of glycogen in the heart, and skeletal muscle always resulting in rapidly progressive cardiomyopathy, generalised muscle weakness and hypotonia. Motor development is often completely arrested, or if motor milestones are achieved, they are subsequently lost. Death typically occurs due to cardiac and/or respiratory failure before the age of one year. In a retrospective natural history study in patients with infantile-onset Pompe disease (n=168), the median age at onset of symptoms was 2.0 months and the median age of death was 9.0 months. Kaplan-Meier survival rates at 12, 24 and 36 months of age were 26%, 9% and 7%, respectively. A non-typical, more slowly progressive form of infantile-onset Pompe disease has been described which is characterised by a less severe cardiomyopathy and consequently a more prolonged survival. The late-onset form of Pompe disease manifests during infancy, childhood, adolescence or even adulthood and is much less rapidly progressive than the infantile-onset form. Usually, it is characterised by the presence of sufficient residual GAA activity to preclude the development of cardiomyopathy, however some cardiac involvement has been reported in up to approximately 4% of patients with late-onset Pompe disease. Patients with late-onset Pompe disease typically present with progressive myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, and varying degrees of respiratory involvement, ultimately progressing to profound disability and/or the need for ventilatory support. The time course of disease progression is extremely variable and not predictable, with some patients experiencing a rapid deterioration in skeletal and respiratory muscle function leading to loss of ambulation and respiratory failure, others progressing less rapidly, and yet others presenting with a dissociation in the progression of skeletal and respiratory muscle involvement.

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It is postulated that Myozyme will restore lysosomal GAA activity resulting in stabilisation or restoration of cardiac and skeletal muscle function (including respiratory muscles). Due to the blood-brain barrier effect and the enzyme’s size, uptake of alglucosidase alfa in the central nervous system is unlikely. Infantile-onset Pompe disease The safety and efficacy of Myozyme was assessed in a pivotal, randomised, open-label, historically-controlled clinical trial of 18 non-ventilated infantile-onset patients aged 6 months or less at the onset of treatment. The untreated historical cohort was matched to the pivotal study population and was derived from a retrospective natural history study (n=42) in patients with infantile-onset Pompe disease. Patients were randomized to receive either 20 mg/kg or 40 mg/kg every two weeks for a period of 52 weeks. The primary endpoint of the pivotal trial was the time to event (death and/or invasive ventilation) from diagnosis. However, the invasive ventilator-free survival was not recorded in the historical population and a comparison of this endpoint is not possible. After 52 weeks of treatment, all 18 patients treated with Myozyme were alive and 15 of these 18 patients were alive and free of invasive ventilatory support whereas 1 of 42 patients in the historical cohort group was alive at 18 months of age. Comparison of survival curves from time of diagnosis versus the historical control population was made using a Cox proportional hazards regression analysis. After 52 weeks, patients treated with Myozyme demonstrated prolonged survival as compared to survival in an untreated historical cohort (see Table 2). Table 2: Results for study endpoints using the Cox regression model Treated Patients

Historical Reference Comparator

Endpoint

Treatment Effect Hazard Ratio

95% Confidence Interval

p-value

N=18

N=42

Survival

0.01

(0.00, 0.10)

<0.0001

Note: Results are from a Cox proportional hazards regression analysis which includes treatment as a time-varying covariate, and also includes age of diagnosis and age at symptom onset. Subjects in the historical reference group were born in 1993 or later.

Echocardiographic indices of cardiomyopathy improved as measured by a decrease in left ventricular mass (LVM). All 12 patients with available data showed decreases in LVM as compared to baseline values (mean decrease 57.6%). Thirteen patients (72.2%) made gains in motor function over baseline as measured by motor performance age-equivalent scores of the Alberta Infant Motor Scale (AIMS). Maintenance or improvement in growth from baseline after 26 weeks treatment with Myozyme was evidenced in 72.2-93.8% of patients. Analyses of efficacy did not reveal any differences between the 2 dose groups with respect to survival, invasive ventilator-free survival, any ventilator-free survival, decrease in LVM, gains in growth parameters and acquisition of motor milestones. Based on these results the 20 mg/kg qow dose is recommended. A second open-label clinical trial also assessed the safety and efficacy of Myozyme in 21 patients with predominantly a non-typical form of infantile-onset Pompe disease who ranged in age from 6 months to 3.5 years at initiation of treatment. Patients received 20 mg/kg Myozyme every other week for 52 weeks. Survival in the treated patients was compared to survival in a similar cohort of untreated historical subjects using a Cox proportional hazards regression analysis (See Table 3).

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Table 3: Results for survival using the Cox regression model Treated Patients

Historical Reference Comparator

Endpoint

Treatment Effect Hazard Ratio

95% Confidence Interval

p-value

N=21

N=48

Survival

0.29

(0.11, 0.81)

0.018

Note: Results are from a Cox proportional hazards regression analysis which includes treatment as a time-varying covariate, and also includes age of diagnosis and age at symptom onset. Subjects in the historical reference group were born in 1995 or later.

Additional efficacy data were available in the first 15 patients. In 10 patients who were free of invasive-ventilator support at baseline, 50% remained so after 52 weeks of treatment, whereas all 5 patients who were receiving invasive ventilation at baseline continued to require ventilation throughout the study (one had died before week 26). Thirteen of 15 patients (86.6%) with follow up data showed improvement in echocardiographic indices of cardiomyopathy over baseline as measured by a decrease in LVM. Eighty percent to 93.3% showed maintenance or improvement in growth parameters. Six patients (40 %) had measurable gains in motor function as determined by increases in age-equivalent scores from baseline in the AIMS and/or Peabody Development Motor Scale (PDMS-2). The vast majority of patients with infantile-onset Pompe disease treated with Myozyme demonstrate improvement in cardiac function as well as stabilisation or improvements in growth parameters. However, motor and respiratory responses to treatment have been more variable. Patients with infantile-onset Pompe disease who demonstrated motor gains, had greater preservation of motor function and lower glycogen content in the quadriceps muscle at baseline. It is noteworthy that a higher proportion of patients with better motor outcomes show stability or improvement in growth parameters (weight), while the large majority of patients, regardless of their motor outcomes or baseline features, show reversal of cardiomyopathy as measured by changes in LVM z score. The totality of the data suggests that early diagnosis and treatment may be critical to achieve the best outcomes in these infantile onset patients. Late-onset Pompe disease An open-label clinical trial assessed the safety and efficacy of Myozyme in 5 patients with late-onset Pompe disease who ranged in age from 5 to 15 years at initiation of treatment. Patients received 20 mg/kg Myozyme every other week for 26 weeks. All patients were freely ambulatory and all but one patient did not require any form of ventilator support (1 patient required nocturnal non-invasive ventilation). Of the 3 patients with significant pulmonary involvement at screening/baseline (percentage predicted forced vital capacity in the sitting position ranging from 58-67%), two demonstrated clinically meaningful improvements in FVC (+11.5% and +16.0%) in the sitting position by Week 26. Evaluation of motor function gave disparate results. Ten patients with advanced late-onset Pompe disease (i.e. wheelchair-bound for 10/10 and ventilator-dependent for 9/10) aged 9-54 years were treated in expanded access programs with alglucosidase alfa 20-40 mg/kg every 2 weeks for various periods of time between 6 months and 2.5 years. The pulmonary benefits observed in patients included a clinically meaningful improvement in FVC of 35% in one patient, and significant reductions in the number of hours of ventilator support needed in 2 patients. Benefits of treatment on motor function including the regaining of lost motor skills were observed in some patients. Only one patient became wheelchair-free. In this group of patients a variable response has also been seen with respect to motor function. Pompe Registry Medical or healthcare professionals are encouraged to register patients who are diagnosed with Pompe disease at www.PompeRegistry.com. Patient data will be anonymously collected in this Registry. The objectives of the “Pompe Registry” are to enhance the understanding of Pompe disease and to monitor

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patients and their response to enzyme replacement therapy over time, with the ultimate goal of improving clinical outcomes for these patients. 5.2 Pharmacokinetic properties In a pivotal trial including 18 patients, the pharmacokinetics of Myozyme were evaluated in 15 patients with infantile-onset Pompe disease (all aged less than 6 months at treatment-onset) who received doses of 20 mg/kg or 40 mg/kg alglucosidase alfa as an approximate 4 to 6.5-hour infusion, respectively. Pharmacokinetics were dose proportional and did not change over time. After the first and sixth infusion of Myozyme, mean maximum plasma concentrations (Cmax) ranged from 178.2 to 263.7 µg/ml for the 20 mg/kg and 40 mg/kg dose groups respectively. The mean area under the plasma concentration-time curve (AUC∞) ranged from 977.5 to 1,872.5 µg•hr/mL for the 20 mg/kg and 40 mg/kg dose groups. Mean plasma clearance (CL) was 21.9 mL/hr/kg and mean volume of distribution at steady state (Vss) was 66.2 mL/kg for both dose groups with small between-subject variability of 15% and 11%, respectively. Mean plasma elimination half-life (t1/2) was 2.75 hours for the two dose groups. The pharmacokinetics of Myozyme were also evaluated in a separate trial in 21 patients with infantile-onset Pompe disease (all aged between 6 months and 3.5 years at treatment-onset) who received doses of 20 mg/kg of alglucosidase alfa. In 12 patients with available data the AUC∞ and Cmax were approximately equivalent to those observed for the 20 mg/kg dose group in the pivotal trial. The t½ of approximately 2-3 hours was also similar in this group of patients. The pharmacokinetics of Myozyme were evaluated in a trial in 5 patients with late-onset Pompe disease aged 6-15 years who received 20 mg/kg alglucosidase alfa every 2 weeks. There was no difference in the pharmacokinetic profile of Myozyme in late-onset patients compared to infantile-onset patients. 5.3 Preclinical safety data Preclinical data reveal no special hazards for humans based on studies of safety pharmacology, single and repeat dose toxicity. No significant adverse findings were observed in a mouse embryofoetal study. Data from a mouse fertility and early embryonic development study were not conclusive. The potential effects on reproductive and developmental functions have not been fully characterised. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Mannitol Sodium phosphate monobasic monohydrate Sodium phosphate dibasic heptahydrate Polysorbate 80 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 18 months After dilution, an immediate use is recommended. However, chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8°C when stored under protection from light.

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6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). 6.5 Nature and contents of container 50 mg of powder in a vial (Clear Type 1 glass) with a stopper (siliconised butyl) and a seal (aluminium) with a flip-off cap (plastic). Pack sizes of 1, 10 or 25 vials. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Myozyme has to be reconstituted with water for injections, then diluted with 9 mg/ml (0.9%) sodium chloride solution and then administered by intravenous infusion. Reconstitution and dilution should be performed in accordance with good practice rules, particularly for the respect of asepsis. Due to the proteinaceous nature of the product, particle formation may occur in the reconstituted solution and final infusion bags. Therefore, a 0.2 micron low protein binding in-line filter should be used for administration. It was demonstrated that the use of a 0.2 micron in-line filter removes visible particles and does not result in an apparent loss of protein or activity. Determine the number of vials to be reconstituted based on the individual patient’s dose regimen (mg/kg) and remove the required vials from the refrigerator in order to allow them to reach room temperature (approximately 30 minutes). As Myozyme does not contain a preservative, each vial of Myozyme is for single use only. Use Aseptic Technique Reconstitution Reconstitute each 50 mg vial of Myozyme with 10.3 ml water for injections. Add the water for injections by slow drop-wise addition down the side of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl or shake the vial. The reconstituted volume is 10.5 ml containing 5 mg/ml, and appears as a clear, colourless to pale yellow solution which may contain particles in the form of thin white strands or translucent fibres. Perform an immediate inspection of the reconstituted vials for particulate matter and discoloration. If upon immediate inspection foreign particles other than those described above are observed, or if the solution is discoloured, do not use. The pH of the reconstituted solution is approximately 6.2. After reconstitution, it is recommended to promptly dilute the vials (see below). Dilution When reconstituted as above, the reconstituted solution in the vial contains 5 mg alglucosidase alfa per ml. The reconstituted volume allows accurate withdrawal of 10.0 ml (equal to 50 mg) from each vial. This should then be further diluted as follows: Slowly withdraw the reconstituted solution from each vial until the volume for the patient’s dose is obtained. The recommended final concentration of alglucosidase in the infusion bags ranges from 0.5 mg/ml to 4 mg/ml. Remove airspace within the infusion bag. Also remove an equal volume of 0.9% sodium chloride, that will be replaced with reconstituted Myozyme. Slowly inject the reconstituted Myozyme directly into the 0.9% sodium chloride solution. Gently invert or massage the infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion bag. The final infusion solution should be administered as close to preparation time as possible.

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Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD/MM/YYYY} 10. DATE OF REVISION OF THE TEXT {MM/YYYY}

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ANNEX II

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

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A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers of the biological active substance Genzyme Corp., 500 Soldiers Field Road, Allston, MA 02134, USA Genzyme Corp. 45, 51, 76 and 80 New York Avenue, Framingham, MA 01701, USA Name and address of the manufacturer responsible for batch release Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom B. CONDITIONS OF THE MARKETING AUTHORISATION • CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON

THE MARKETING AUTHORISATION HOLDER Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). • CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT The Marketing Authorisation Holder (MAH) must provide educational material to physicians on infusion-associated reactions, development of antibodies and pregnancy. • OTHER CONDITIONS The MAH must ensure that the system of pharmacovigilance is in place and functioning before the product is placed on the market. The MAH commits to performing the pharmacovigilance activities detailed in the Pharmacovigilance Plan. An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk Management Systems for medicinal products for human use.

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE PACKAGING 1. NAME OF THE MEDICINAL PRODUCT Myozyme 50 mg powder for concentrate for solution for infusion Alglucosidase alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 50 mg of alglucosidase alfa After reconstitution, the solution contains 5 mg of alglucosidase alfa/ml and after dilution, the concentration varies from 0.5 mg to 4 mg/ml. 3. LIST OF EXCIPIENTS Mannitol Sodium phosphate monobasic monohydrate Sodium phosphate dibasic heptahydrate Polysorbate 80 4. PHARMACEUTICAL FORM AND CONTENTS powder for concentrate for solution for infusion (50 mg in a vial- pack size of 1 , 10 or 25 ) 1 vial (10, 25 vials) of 50 mg alglucosidase alfa 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use Read the package leaflet before use. For single use only 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP {MM/YYYY}

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9. SPECIAL STORAGE CONDITIONS Store at 2°C-8°C (in a refrigerator) 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused product should be discarded 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Genzyme Europe B.V. Gooimeer 10 NL-1411 DD Naarden The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/0/00/000/000 13. BATCH NUMBER Batch {number} 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS {NATURE/TYPE} 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Myozyme 50 mg powder for concentrate for solution for infusion Alglucosidase alfa 2. METHOD OF ADMINISTRATION Intravenous use 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER Batch {number} 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 50 mg per vial 6. OTHER Store at 2°C-8°C (in a refrigerator) Genzyme Europe B.V.-NL

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B. PACKAGE LEAFLET

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Myozyme 50 mg powder for concentrate for solution for infusion Alglucosidase alfa

Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if

their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist. In this leaflet: 1. What Myozyme is and what it is used for 2. Before you use Myozyme 3. How to use Myozyme 4. Possible side effects 5. How to store Myozyme 6. Further information 1. WHAT MYOZYME IS AND WHAT IT IS USED FOR Alglucosidase alfa is a form of the human enzyme acid α-glucosidase which has been produced by recombinant DNA technology. Alglucosidase alfa is used as enzyme replacement therapy in Pompe disease, where the level of acid α-glucosidase enzyme activity is absent or lower than normal. If you suffer from Pompe disease, glycogen is not removed from the cells of your body and starts to build up in the cells. Myozyme is indicated for use as long-term enzyme replacement therapy in patients with a confirmed diagnosis of Pompe disease. The benefits of Myozyme in patients with late-onset Pompe disease have not been established. 2. BEFORE YOU USE MYOZYME Do not use Myozyme: If you are allergic (hypersensitive) to alglucosidase alfa or any of the other ingredients of Myozyme. Take special care with Myozyme If you are treated with Myozyme you may develop infusion-associated reactions. An infusion associated reaction is defined as any related side effect occurring during the infusion or during the 2 hours following infusion. (See 4 “Possible Side Effects”). When you experience such a reaction following the administration of Myozyme, you should immediately contact your doctor. You may be given additional medication such as antihistamines and paracetamol to help prevent allergic-type reactions. Different groups of patients using Myozyme There is no evidence for special considerations for the treatment of different patient groups such as children, adolescents, adults or elderly patients with Myozyme.

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Using other medicines Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Pregnancy and breast-feeding There is no experience of the use of Myozyme in pregnant women. Myozyme should not be used during pregnancy unless clearly necessary. Ask you doctor or pharmacist for advice before taking any medicine. 3. HOW TO USE MYOZYME Instructions for proper use The powder for concentrate for solution for infusion has to be reconstituted and diluted prior to administration by intravenous infusion. The use of this medicinal product will be supervised by a specialized physician knowledgeable in the management of Pompe disease. The recommended dosage regimen of Myozyme is 20 mg/kg body weight administered once every 2 weeks, administered as an intravenous infusion. If you use more Myozyme than you should There are no cases of overdose reported. If you forget use Myozyme If you have missed a infusion, please contact your doctor. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Myozyme can cause side effects, although not everybody gets them. Side effects reported in a total of 39 patients with infantile-onset Pompe disease treated for more than one year (76 weeks) were mild to moderate in intensity and almost all were experienced during the infusion or shortly (within 2 hours) thereafter (infusion associated reactions). Side effects reported in two patients or more (5% or more) included hives, rash, redness of the skin, face flushing, increased/high blood pressure, paleness, decreased oxygen concentration in blood, elevated creatinine phosphokinase MB in blood, fever, chills, cough, elevated respiration, vomiting, elevated heart rate, bluish discoloration of the skin caused by lack of oxygen in the blood, agitation, tremor. Some infusion-associated reactions reported did get serious. Serious reactions included hives, abnormal breathing sounds, elevated heart rate, decreased oxygen concentration in blood, difficulty in breathing, elevated respiration, swelling around the eyes, and high blood pressure. All were reported by one patient except hives (2 patients). Side effects reported in 9 late onset Pompe patients treated for up to 1 year included increased heart rate, increased blood pressure, headache, peripheral coldness, tingling, face flushing, infusion site pain, infusion site effect and dizziness. All side effects were reported by one patient and reported during the infusion or shortly (within 2 hours) thereafter. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE MYOZYME

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Keep out of the reach and sight of children Store in a refrigerator (2°C – 8°C). Do not use after the expiry date stated on the labelling after the letters ‘EXP’. “After dilution, an immediate use is recommended. However chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8°C when stored under protection from light Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Myozyme contains - The active substance is alglucosidase alfa 50 mg. One vial contains 50 mg of alglucosidase alfa.

After reconstitution, the solution contains 5 mg of alglucosidase alfa/ml and after dilution, the concentration varies from 0.5 mg to 4 mg/ml.

- The other ingredients are - mannitol, - sodium phosphate monobasic monohydrate - sodium phosphate dibasic heptahydrate - polysorbate 80

What Myozyme looks like and contents of the pack Myozyme, 50 mg, is presented as a powder for concentrate for solution for infusion (in a vial- pack sizes: of 1, 10 or 25) Not all pack sizes may be marketed. Myozyme is supplied as a white to off-white powder. After reconstitution it is a clear, colourless to pale yellow solution, which may contain particles. The reconstituted solution must be further diluted. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder Genzyme Europe B.V., Gooimeer 10, 1411 DD, Naarden, The Netherlands Manufacturer Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien/ Luxembourg/Luxemburg Genzyme Belgium nv/sa (Belgique/Belgien), Tél/Tel: + 32 2 714 17 11

Magyarország Genzyme Europe B.V. Képviselet, Tel: +36 1 309 6689

Česká Republika/Slovenská Republika/ Slovenija Genzyme Europe B.V. organizační složka (Česká Republika), Tel: +420 227 133 665

Nederland Genzyme Europe BV, Tel: +31 35 6991200

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Danmark/Norge/Sverige/Suomi/Finland/ Ísland

Österreich

Deutschland Genzyme GmbH, Tel: +49 610236740

Polska/Eesti/Latvija/Lietuva Genzyme Polska Sp. z o.o. (Poola/Polija/Lenkija), Tel: +48 22 516 24 30

Ελλάδα/Κύπρος Genzyme Hellas Ltd. (Ελλάδα), Τηλ: ++30 210 9949270

Portugal Genzyme Portugal, Tel: +351 21 422 0100

España Genzyme, S.L., Tel: +34 91 6591670

France Genzyme S.A.S, Tél: + 33 (0) 825 825 863

United Kingdom/Ireland Genzyme Therapeutics (United Kingdom), Tel: +44 1865 405200

Italia/Malta Genzyme Srl (Italia/Italja), Tel: +39 059 349811

This leaflet was last approved in {MM/YYYY}. Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.eu.int/. There are also links to other websites about rare diseases and treatments. <----------------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only: Instructions for use – reconstitution, dilution and administration 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. Myozyme should not be administered as a mixture with other medicinal products in the same infusion. Use Aseptic Technique • Reconstitution Reconstitute each 50 mg vial of Myozyme with 10.3 ml water for injections. Add the water for injections by slow drop-wise addition down the side of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl or shake the vial. The reconstituted volume is 10.5 ml containing 5 mg enzyme/ml, and appears as a clear, colourless to pale yellow solution which may contain particles in the form of thin white strands or translucent fibres. Perform an immediate inspection of the reconstituted vials for particulate matter and discoloration. If upon immediate inspection foreign particles other than those described above are observed, or if the solution is discoloured, do not use. The pH of the reconstituted solution is approximately 6.2.

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After reconstitution it is recommended to promptly dilute the vials (see below). • Dilution When reconstituted as above, the reconstituted solution in the vial contains 5 mg alglucosidase alfa per ml. The reconstituted volume allows accurate withdrawal of 10.0 ml (equal to 50 mg) from each vial. This should then be further diluted as follows: Slowly withdraw the reconstituted solution from each vial until the volume for the patient’s dose is obtained. The recommended final concentration in the infusion bags ranges from 0.5 mg/ml to 4 mg/ml Myozyme. Remove airspace within the infusion bag and an equal volume of 0.9% sodium chloride, that will be added of reconstituted Myozyme. Slowly inject the reconstituted Myozyme directly into the 0.9% sodium chloride solution. Gently invert or massage the infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion bag. The final infusion solution should be administered as close to preparation time as possible. The product diluted in 0.9% sodium chloride intravenous solution will retain chemical stability if stored up to 24 hours at 2°C to 8°C under protection from light; but microbiological safety will depend on the reconstitution and dilution having been performed aseptically. Myozyme contains no preservatives. Any unused product or waste material should be disposed of in accordance with local requirements • Administration It is recommended to start the administration of the diluted solution within three hours. The total time between reconstitution and completion of the infusion should not exceed 24 hours. The recommended dosage regimen of Myozyme is 20 mg/kg of body weight administered once every 2 weeks as an intravenous infusion. Infusions should be administered incrementally. It is recommended that the infusion begin at an initial rate of 1 mg/kg/hr and be gradually increased by 2 mg/kg/hr every 30 minutes if there are no signs of IARs (Infusion Associated Reactions) until a maximum rate of 7 mg/kg/hr is reached.