Myozyme

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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* per ml and after dilution, the 
concentration varies from 0.5 mg to 4 mg/ml. 
 
*Human acid α-glucosidase is produced in Chinese hamster ovary cells (CHO) by recombinant DNA 
technology. 
 
For the 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).  
 
Myozyme is indicated in adults and paediatric patients of all ages. 
 
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. 
 
Posology 
The recommended dose regimen of alglucosidase alfa is 20 mg/kg of body weight administered once 
every 2 weeks.  
 
Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of 
all clinical manifestations of the disease. 
 
Paediatric and older people  
There is no evidence for special considerations when Myozyme is administered to paediatric patients 
of all ages or older people. 
 
Patients with renal and hepatic impairment 
The safety and efficacy of Myozyme in patients with renal or hepatic impairment have not been 
evaluated and no specific dose regimen can be recommended for these patients.  
 



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Method of administration 
Myozyme should be administered as an intravenous infusion. 
 
Infusions should be administered incrementally. It is recommended that the infusion begin at an initial 
rate of 1 mg/kg/h and be gradually increased by 2 mg/kg/h every 30 minutes if there are no signs of 
infusion associated reactions (IARs) until a maximum rate of 7 mg/kg/h is reached. IARs are 
described in section 4.8. 
 
For instructions on reconstitution and dilution of the medicinal product before administration, see 
section 6.6.  
 
4.3 Contraindications 
 
Life threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of the 
excipients listed in section 6.1, when rechallenge was unsuccessful (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity/Anaphylactic reactions 
Serious and life-threatening anaphylactic reactions, including anaphylactic shock, have been reported 
in infantile- and late-onset patients during Myozyme infusions (see section 4.8). Because of the 
potential for severe infusion associated reactions, appropriate medical support measures, including 
cardiopulmonary resuscitation equipment, should be readily available when Myozyme is 
administered. If severe hypersensitivity 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.  
 
Infusion Associated Reactions 
Approximately half of the patients treated with Myozyme in infantile-onset clinical studies and 28% 
of the patients treated with Myozyme in a late-onset clinical study developed infusion associated 
reactions (IARs). IARs are defined as any related adverse event occurring during the infusion or 
during the hours following infusion. Some reactions were severe (see section 4.8). A tendency was 
observed in infantile patients treated with a higher dose (40 mg/kg) to experience more symptoms 
when developing IARs. Infantile onset patients who develop high IgG antibody titres appear to be at 
higher risk for developing more frequent IARs. 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 should be closely 
monitored and all cases of IARs, delayed reactions and possible immunological reactions should be 
reported to the marketing authorisation holder.  
 
Patients who have experienced IARs (and in particular anaphylactic reactions) should be treated with 
caution when re-administering Myozyme (see sections 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 and/or corticosteroids, has effectively managed most reactions. IARs may occur at any 
time during the infusion of Myozyme or generally up to 2 hours after, and are more likely with higher 
infusion rates.  
 
Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which 
may predispose them to a higher risk of severe complications from infusion associated reactions. 
Therefore, these patients should be monitored more closely during administration of Myozyme. 
 
Immunogenicity 
In clinical studies, the majority of patients developed IgG antibodies to alglucosidase alfa typically 
within 3 months of treatment. Thus seroconversion is expected to occur in most patients treated with 
Myozyme. A tendency was observed for infantile-onset patients treated with a higher dose (40 mg/kg) 



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to develop higher titres of IgG antibodies. There does not appear to be a correlation between the onset 
of IARs and the time of IgG antibody formation. A limited number 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 IgG antibody formation on safety and efficacy is 
currently not fully established. The probability of a poor outcome and of developing high and 
sustained IgG antibody titres appears higher among CRIM-negative patients (Cross Reactive 
Immunologic Material- negative patients in whom no endogenous GAA protein was detected by 
Western blot analysis) than among CRIM-positive patients in whom endogenous GAA protein was 
detected by Western blot analysis and/or predicted based on genotype. However, high and sustained 
IgG antibody titres also occur in some CRIM-positive patients. The cause of a poor clinical outcome 
and of developing high and sustained IgG antibody titres is thought to be multi-factorial. IgG antibody 
titres should be regularly monitored.  
 
Patients who experience hypersensitivity reactions may also be tested for IgE antibodies to 
alglucosidase alfa and other mediators of anaphylaxis. Patients who develop IgE antibodies to 
alglucosidase alfa appear to be at a higher risk for the occurrence of IARs when Myozyme is re-
administered (see section 4.8). Therefore, these patients should be monitored more closely during 
administration of Myozyme. Some IgE positive patients were successfully rechallenged with 
Myozyme using a slower infusion rate at lower initial doses and have continued to receive Myozyme 
under close clinical supervision. 
 
Immune-mediated reactions 
Severe cutaneous reactions, possibly immune mediated, have been reported with alglucosidase alfa, 
including ulcerative and necrotizing skin lesions (see section 4.8). Nephrotic syndrome was observed 
in a few patients with Pompe disease treated with alglucosidase alfa and who had high IgG antibody 
titres (≥ 102,400) (see section 4.8). In these patients renal biopsy showed immune complex 
deposition.  Patients improved following treatment interruption. It is therefore recommended to 
perform periodic urinalysis among patients with high IgG antibody titres. 
 
Patients should be monitored for signs and symptoms of systemic immune-mediated reactions 
involving skin and other organs while receiving alglucosidase alfa. If immune-mediated reactions 
occur, discontinuation of the administration of alglucosidase alfa should be considered and 
appropriate medical treatment initiated. The risks and benefits of re-administering alglucosidase alfa 
following an immune-mediated reaction should be considered. Some patients have been successfully 
rechallenged and continued to receive alglucosidase alfa under close clinical supervision. 
 
Immunomodulation 
Immunogenicity data from clinical trials and published literature in CRIM-negative infantile-onset 
patients (IOPD) suggests that the administration of immune tolerance induction (ITI) regimen given to 
alglucosidase alfa naive patients (prophylactic ITI) may be effective in preventing or reducing the 
development of High Sustained Antibody Titer (HSAT) against alglucosidase alfa. Data from a small 
number of patients with HSAT, with or without inhibitory activity, showed limited ITI treatment 
effect. Better treatment responses were observed in younger patients with less advanced disease who 
received prophylactic ITI before development of HSAT, which suggests that early initiation of ITI can 
result in improved clinical outcomes. ITI regimens may need to be tailored to individual patient needs 
(see section 5.1). 
 
Patients with Pompe disease are at increased risk of respiratory infections due to the progressive 
effects of the disease on the respiratory muscles. Patients with Pompe disease treated with 
immunosuppressive agents maybe at further increased risk of developing severe infections and 
vigilance is recommended. Fatal and life-threatening respiratory infections have been observed in 
some of these patients.  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 



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No interactions studies have been performed. Because it is a recombinant human protein, 
alglucosidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no data from the use of alglucosidase alfa in pregnant women. Studies in animals have 
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Myozyme 
should not be used during pregnancy unless clearly necessary. 
 
Breast-feeding 
Alglucosidase alfa may be excreted in breast 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. 
 
Fertility 
There are no clinical data on the effects of alglucosidase alfa on fertility. Preclinical data did not 
reveal any significant adverse findings (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. Because 
dizziness has been reported as an infusion associated reaction, this may affect the ability to drive and 
use machines on the day of the infusion.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Infantile-onset Pompe disease 
In clinical trials, 39 infantile-onset patients were treated with Myozyme for more than three years 
(168 weeks with a median of 121 weeks; see section 5.1). Adverse reactions reported in at least 
2 patients are listed in Table 1 by System Organ Class. Adverse reactions were mostly mild to 
moderate in intensity and almost all occurred during the infusion or during the 2 hours following the 
infusion (infusion associated reactions, IARs). Serious infusion reactions including urticaria, rales, 
tachycardia, decreased oxygen saturation, bronchospasm, tachypnea, periorbital edema and 
hypertension have been reported.  
 
Late-onset Pompe disease 
In a placebo-controlled study lasting 78 weeks, 90 patients with late-onset Pompe disease, aged 10 to 
70 years, were treated with Myozyme or placebo randomized in a 2:1 ratio (see section 5.1). Overall, 
the numbers of patients experiencing adverse reactions and serious adverse reactions were comparable 
between the two groups. The most common adverse reactions observed were IARs. Slightly more 
patients in the Myozyme group than in the placebo group experienced IARs (28% versus 23%). The 
majority of these reactions were non-serious, mild to moderate in intensity and resolved 
spontaneously. Adverse reactions reported in at least 2 patients are listed in Table 1. Serious adverse 
reactions reported in 4 patients treated with Myozyme were: angioedema, chest discomfort, throat 
tightness, non-cardiac chest pain and supraventricular tachycardia. Reactions in 2 of these patients 
were IgE-mediated hypersensitivity reactions.  
 
Tabulated list of adverse reactions 
 
Table 1: Adverse reactions (reported in at least 2 patients) and adverse reactions reported in post-
marketing setting, expanded access programs and non-controlled clinical trials, per System Organ 
Class, presented by frequency categories: very common (≥1/10), common (≥1/100 to<1/10), 
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known 



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(cannot be estimated from the available data). Due to the small patient population, an adverse reaction 
reported in 2 patients is classified as common. Within each frequency grouping, adverse reactions are 
presented in order of decreasing seriousness. 
 
 
System Organ 
Class 

Frequency Adverse reaction 
(Preferred Term Level) 

Additional adverse 
reactions4  

 

Infantile-onset  
Pompe disease1 

Late-onset  
Pompe disease2 

Infantile- and Late-
onset Pompe disease 

Immune system 
disorders  

common  Hypersensitivity  

Psychiatric 
disorders 

common Agitation   
not known   Agitation 

Restlessness 
Nervous system 
disorders 

common Tremor Dizziness 
Paraesthesia 
Headache3 

 

not known    Tremor 
Headache 

Eye disorders not known   Conjunctivitis 
Cardiac disorders very 

common 
Tachycardia   

common Cyanosis   
not known    Cardiac arrest 

Bradycardia 
Tachycardia 
Cyanosis 

Vascular 
disorders 

very 
common 

Flushing   

common Hypertension 
Pallor 

Flushing  

not known    Hypertension 
Hypotension 
Vasoconstriction 
Pallor 

Respiratory, 
thoracic and 
mediastinal 
disorders  

very 
common 

Tachypnoea  
Cough  

  

common  Throat tightness  
not known   Respiratory arrest 

Apnea 
Respiratory distress 
Bronchospasm 
Wheezing 
Pharyngeal oedema 
Dyspnoea 
Tachypnoea 
Throat tightness 
Stridor 
Cough 

Gastrointestinal 
disorders 

very 
common 

Vomiting   

common Retching  
Nausea 

Diarrhoea 
Vomiting  

 



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Nausea3 
not known   Abdominal pain 

Retching 
Skin and 
subcutaneous 
tissue disorders 

very 
common 

Urticaria 
Rash 

  

common Erythema 
Rash maculopapular 
Rash macular 
Rash papular 
Pruritus 

Urticaria 
Rash papular 
Pruritus 
Hyperhidrosis 
 

 

not known   Periorbital edema 
Livedo reticularis 
Lacrimation increased 
Rash 
Erythema 
Hyperhidrosis 

Musculoskeletal 
and connective 
tissue disorders 

common  Muscle spasms 
Muscle twitching  
Myalgia 

 

not known   Arthralgia 
Renal and urinary 
disorders 

not known   Nephrotic syndrome 
Proteinuria 

General disorders 
and 
administration 
site conditions 

very 
common 

Pyrexia   

common Irritability 
Chills 

Pyrexia 
Chest discomfort  
Peripheral oedema 
Local swelling 
Fatigue3 
Feeling hot 

 

not known    Chest pain 
Face edema 
Feeling hot 
Pyrexia 
Chills 
Chest discomfort 
Irritability 
Peripheral coldness 
Infusion site pain  
Infusion site reaction 
Infusion site swelling  
Infusion site 
induration 
Infusion site 
extravasation 

Investigations very 
common 

Oxygen saturation 
decreased 

  

common Heart rate increased  
Blood pressure 
increased 
Body temperature 
increased 

Blood pressure 
increased 
 

 

not known   Oxygen saturation 
decreased 
Heart rate increased 



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1 Reactions reported in 39 infantile-onset patients in 2 clinical trials. 
2 Reactions reported in 60 late-onset patients in a placebo-controlled clinical trial. 
3 Reactions reported more frequently in the placebo group than in the Myozyme group in late-onset patients. 
4 Additional adverse reactions from post-marketing, expanded access programs and non-controlled clinical trials. 
 
Description of selected adverse reactions 
 
A small number of patients (<1%) in clinical trials and in the commercial setting developed 
anaphylactic shock and/or cardiac arrest during Myozyme infusion that required life-support 
measures. Reactions generally occurred shortly after initiation of the infusion. Patients presented with 
a constellation of signs and symptoms, primarily respiratory, cardiovascular, edematous and/or 
cutaneous in nature (see section 4.4). 
 
Recurrent reactions consisting of flu-like illness or a combination of events such as fever, chills, 
myalgia, arthralgia, pain, or fatigue occurring post-infusion and lasting usually for a few days, have 
been observed in some patients treated with alglucosidase alfa. The majority of patients were 
successfully re-challenged with alglucosidase alfa using lower doses and/or pretreatment with anti-
inflammatory drugs and/or corticosteroids and have continued to receive treatment under close 
clinical supervision. 
 
Patients with moderate to severe or recurrent IARs have been evaluated for alglucosidase alfa specific 
IgE antibodies; some patients tested positive including some who experienced an anaphylactic 
reaction. 
 
Nephrotic syndrome as well as severe cutaneous reactions, possibly immune mediated, have been 
reported with alglucosidase alfa including ulcerative and necrotizing skin lesions (see section 4.4). 
 
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. 
 
4.9 Overdose 
 
There is no experience with overdose of alglucosidase alfa. In clinical studies doses up to 40 mg/kg 
body weight were used.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. 
ATC code: A16AB07. 
 



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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.  
 
Mechanism of action 
 
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.  
 
Clinical efficacy and safety 
 
Infantile-onset Pompe disease; clinical trial in patients aged 6 months or less 
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 



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disease. Patients were randomized to receive either 20 mg/kg or 40 mg/kg once every two weeks for a 
period of 52 weeks. After a minimum of 52 weeks, 16 of these 18 patients were enrolled in an 
extension study to receive continued treatment at the same dose for a total duration of up to three 
years (150 weeks).  
 
The primary endpoint was the proportion of patients who were alive and free of invasive ventilator 
support. However, the invasive ventilator-free survival was not recorded in the untreated historical 
cohort 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 untreated historical cohort was alive at 18 months 
of age. Two patients died and did not enter into the extension study. After 104 weeks of treatment, all 
16 patients who enrolled in the extension study were alive and 10 of these 16 patients were free of 
invasive ventilatory support. At the end of the study (with individual patient treatment durations 
ranging from 60 to 150 weeks; mean follow-up period of 119 weeks) 14 of 16 patients were alive and 
9 of 16 patients were alive and free of invasive ventilatory support. One additional patient died after 
study end and another one after withdrawal from the study. 
 
Comparison of survival curves from time of diagnosis versus the untreated historical cohort was made 
using a Cox proportional hazards regression analysis.  Patients treated with Myozyme demonstrated 
prolonged survival as compared to survival in an untreated historical cohort (see Table 2).  
 
Table 2: Results for endpoint survival 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 

 
0.05 

 
(0.015, 0.147) 

 
<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 were aged 6 months or less at the onset of treatment.  
Subjects in the untreated historical cohort were born in 1993 or later. 
 
Echocardiographic indices of cardiomyopathy improved as measured by a decrease in left ventricular 
mass (LVM). After 52 weeks of treatment, LVM decreased from baseline in all 14 patients with 
available data and was within normal limits in 3 of 14 patients. After the first year (64 up to 
130 weeks) of treatment LVM further decreased in 8 patients. At 104 weeks of treatment LVM 
assessments were available for 8 patients, of which 5 decreased to within normal limits. 
 
As measured by motor performance age-equivalent scores of the Alberta Infant Motor Scale (AIMS), 
seven of the 18 patients made motor development gains during the study and were walking 
independently by the last study assessment (with individual patient treatment durations ranging from 
52 to 130 weeks; mean follow-up period of 94 weeks). An additional 4 patients made motor 
development gains during the study and were sitting independently by the last study assessment (with 
individual patient treatment durations ranging from 78 to 130 weeks; mean follow-up period of 
110 weeks), although they did not have functional use of the legs. The remaining 7 patients made no 
clinically significant motor gains or were unable to sustain the motor gains made and had very limited 
motor movement by the last study assessment (with individual patient treatment durations ranging 
from 52 to 142 weeks; mean follow-up period of 103 weeks). 
 
After 52 weeks of treatment 14 of 18 patients (77.8%) had maintained or improved weight-for-age 
percentiles (above the 3rd percentile), 14 of 15 patients (93.3%) were above the 3rd percentile for 
length and 12 of 15 patients (80.0%) were above the 3rd percentile for head circumference. In the 
second year of treatment, 15 out of 17 patients had further improved weight-for-age percentiles (with 
individual patient treatment durations ranging from 78 to 142 weeks; mean follow-up period of 
111 weeks), 10 out of 16 patients had further improved length-for-age percentiles (with individual 
patient treatment durations ranging from 90 to 130 weeks; mean follow-up period of 113 weeks) and 



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11 out of 15 patients had further improved head circumference-for-age percentiles (with individual 
patient treatment durations ranging from 90 to 130 weeks; mean follow-up period of 110 weeks). At 
104 weeks of treatment, all 13 patients with available data had maintained or improved weight-for-age 
percentiles (above the 3rd percentile), all 12 patients with available data were above the 3rd percentile 
for length and all 12 patients with available data were above the 3rd percentile for head 
circumference. 
 
Analyses of efficacy did not reveal meaningful 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. 
 
Infantile-onset Pompe disease; clinical trial in patients aged 6 months to 3.5 years 
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 once every two 
weeks for 52 weeks except for 8 patients who received 40 mg/kg after at least 26 weeks of treatment. 
After 52 weeks all patients continued treatment for a total duration of more than 3 years (168 weeks 
with a median of 121 weeks). 
 
The primary endpoint of the pivotal trial was the proportion of patients who were alive. After 
52 weeks of treatment, 16 of 21 patients (76.2%) treated with Myozyme were alive. After 104 weeks 
of treatment, 14 of 21 patients (66.7%) were alive and 1 patient was alive but had discontinued from 
the study. These proportions were maintained up to the end of the study (with individual patient 
treatment durations ranging from 1 to 168 weeks; mean follow-up period of 109 weeks). In the 
untreated historical cohort 5 of 47 patients (10.6%) for whom data were available, were alive at age 
30 months (2.5 years).  
 
Survival in the treated patients was compared to survival in a similar historical cohort of untreated 
subjects using a Cox proportional hazards regression analysis (See Table 3). 
 
Table 3: Results for endpoint 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 

 
0.301 

 
(0.112,0.804) 

 
0.0166 

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 ranged in age from 6 months to 3.5 years at initiation of treatment.  
Subjects in the untreated historical cohort were born in 1995 or later.  
 
Additional efficacy data showed that of 16 patients who were free of invasive-ventilator support at 
baseline, 7 remained so after 104 weeks of treatment. The 9 remaining patients either died (5 patients) 
or became invasive-ventilator dependent (4 patients). All 5 patients who were receiving invasive 
ventilation at baseline continued to require ventilation throughout the study (4 patients survived 
beyond week 104 and one patient died).  
 
After 52 weeks of treatment, LVM decreased from baseline in all 12 patients with available data and 
was within normal limits in 6 of 12 patients. After the first year (58 up to 168 weeks) of treatment 
LVM further decreased in 9 out of 12 patients with available data. At 104 weeks of treatment LVM 
assessments were available for 10 patients, of which 9 decreased to within normal limits. 
 
After 52 weeks of treatment, 3 out of 8 patients with available data made gains in motor function over 
baseline as measured by raw scores and age-equivalent scores from baseline in the AIMS. Six of the 
11 patients with available data continued to make motor development gains beyond Week 52 (with 



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individual patient treatment durations ranging from 58 to 168 weeks; mean follow-up period of 
121 weeks), including 3 patients ambulatory and 3 patients with only functional sitting skills by the 
last study visit. The remaining 5 patients showed no significant change in motor development beyond 
Week 52 (with individual patient treatment durations ranging from 104 to 168 weeks; mean follow-up 
period of 140 weeks), including 4 patients with no significant motor skills in any of the positions 
evaluated and 1 patient with only functional sitting skills by the last study visit.  
 
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 at an early stage of disease may be 
critical to achieve the best outcomes in these infantile onset patients.  
 
IOPD Immune Tolerance Induction 
 
Use of ITI and alglucosidase alfa has been evaluated in 1 clinical trial and a retrospective chart review 
of patients naïve to ERT at the initiation of treatment and 1 clinical trial of patients already receiving 
alglucosidase alfa at time of initiating ITI. 
 
A retrospective chart review at Duke Center identified 21 CRIM-negative IOPD patients of which 19 
patients were ERT naïve at the time of ITI initiation. Of the 21 patients, 16 survived through the end 
of this study, with a median time from ERT initiation to last assessment of 44.6 months (range: 5.7 to 
105.47); 5 patients died due to respiratory failure and disease progression, all of whom were ERT-
naïve at the start of ERT+ITI treatment. Younger patients diagnosed and treated early and who 
received ITI concomitantly to ERT initiation had a trend towards better survival rate than patients 
treated with similar regimen at a later age. The study data demonstrated that prophylactic ITI prevents 
or reduces the occurrence of antibodies against alglucosidase alfa over time, which may maintain 
clinical benefit of ERT and improve survival in CRIM-negative IOPD patients. 
 
 
Late-onset Pompe disease; pivotal clinical trial 
The safety and efficacy of Myozyme was assessed in a randomized, double-blind, placebo-controlled 
study in 90 patients with late-onset Pompe disease who ranged in age from 10 to 70 years at initiation 
of treatment and were all naive to enzyme replacement therapy.  Patients were randomized in a 2:1 
ratio and received 20 mg/kg Myozyme (n=60) or placebo (n=30) once every two weeks for 78 weeks 
(18 months).  
 
The co-primary efficacy outcome assessments were distance walked (meters) in 6 minutes (6-Minute 
Walk Test, 6MWT) and FVC (Forced Vital Capacity) % predicted in the sitting position. After 
78 weeks, patients treated with Myozyme showed improvement in distance walked as measured by 
6MWT and stabilization of pulmonary function as measured by FVC % predicted as compared to 
placebo-treated patients.  The distance walked in 6 minutes increased by a median of 15.0 meters for 
Myozyme-treated patients and decreased by a median of 7.5 meters for placebo-treated patients, 
indicating a statistically significant Myozyme treatment effect compared to placebo (p=0.0283).  The 
% predicted FVC changed by a median of 0.0 for Myozyme-treated patients and decreased by a 
median of 3% for placebo-treated patients, indicating a statistically significant treatment effect 
(p=0.0026). The results are shown in Table 4. 
 
Table 4: Change from baseline: efficacy outcomes in the placebo-controlled study 



13 

 Myozyme (N = 60) 
Placebo 
(N = 30) 

6-Minute Walk Test Distance (meters) 
Pre-treatment Baseline 
 

Mean  ±  s.d. 
Median 

332.20 ± 126.69  
360.0 

317.93 ± 132.29 
339.0 

Week 78/Last Observation 
 

Mean  ±  s.d. 
Median 

357.85 ± 141.32 
367.5 

313.07 ± 144.69 
307.0 

Change from Baseline to 
Week 78/Last Observation* 

Mean  ±  s.d 
Median 

26.08 ± 64.41 
15.0  

-4.87 ± 45.24 
-7.5 

Wilcoxon-Mann-Whitney Test p-value 0.0283 

Forced Vital Capacity (Percent of predicted normal) 
Pre-treatment Baseline 
 

Mean  ±  s.d. 
Median 

55.43 ± 14.44 
53.5 

53.00 ± 15.66 
49.0 

Week 78/Last Observation 
 

Mean  ±  s.d. 
Median 

56.67 ± 16.17 
55.5 

50.70 ± 14.88 
49.0 

Change from Baseline to Week 
78/Last Observation*  

Mean  ±  s.d 
Median 

1.25 ± 5.55 
0.0 

-2.3 ± 4.33 
-3.0 

Wilcoxon-Mann-Whitney Test p-value 0.0026 

*One patient who did not have data post baseline was excluded from the analyses. 

 
Late-onset Pompe disease; other clinical trials and analyses 
Three independent, open-label, single arm, investigator-initiated studies with Myozyme were 
conducted: 

• One study in Italy enrolled 74 late-onset patients with up to 48 months follow up. 
• One study in Germany enrolled 38 late-onset patients with 36 months follow up. 
• One study in the Netherlands enrolled 69 late-onset patients with a median follow-up of 23 

months.  
These three studies with Myozyme (with a follow up of at least 3 years in two studies and a median of 
23 months in the other study) suggested stabilisation or improvement of motor function and 
stabilisation of pulmonary function. 
 
In the above described study in 69 late-onset patients in the Netherlands, Myozyme showed an 
improvement in muscle strength. However, muscle function only improved in wheelchair independent 
patients and in those with less pronounced muscle weakness. 
 
In two additional open-label clinical trials with Myozyme with a follow-up of 24 months, ten patients 
with severe late-onset Pompe disease (moderate to severe motor impairment and assisted ventilation) 
showed a variable response on measures of motor and respiratory functions, mostly in the form of a 
modest improvement (AGLU03105, AGLU04107). 
 
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 (AGLU02804). Patients 
received 20 mg/kg Myozyme once every two weeks 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 once every two weeks for various periods of time between 6 months and 2.5 years. The 



14 

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 
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 
 
Infantile-onset Pompe disease 
In a pivotal trial including 18 patients, the pharmacokinetics of alglucosidase alfa were evaluated in 
15 patients with infantile-onset Pompe disease (all less than 6 months of age 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.  
 
Distribution and elimination 
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•h/ml for the 
20 mg/kg and 40 mg/kg dose groups. Mean plasma clearance (CL) was 21.4 ml/h/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. 
 
Linearity/non linearity 
Pharmacokinetics were dose proportional and did not change over time.  
 
The pharmacokinetics of alglucosidase alfa 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. 
 
Late-onset Pompe disease 
The pharmacokinetics of alglucosidase alfa were evaluated in a trial in 5 patients with late-onset 
Pompe disease aged 6-15 years who received 20 mg/kg alglucosidase alfa once every two weeks. 
There was no difference in the pharmacokinetic profile of alglucosidase alfa in these juvenile late-
onset patients compared to infantile-onset patients.  
 
The pharmacokinetics of alglucosidase alfa were studied in a population analysis of 32 late-onset 
Pompe disease patients from the randomized, double-blind, placebo-controlled study ranging in age 
from 21 to 70 years who received Myozyme 20 mg/kg once every two weeks. AUC∞ and Cmax were 
similar at week 0, 12 and 52 visits indicating alglucosidase alfa pharmacokinetics were not time-
dependent (Table 5). 
 
Distribution and elimination 
 



15 

Table 5:  Alglucosidase alfa pharmacokinetics after a single dose and after 12 and 52 weeks of 
therapy 
Parameter Week 0 Week 12 Week 52 
Cmax (µg/ml) 385 ± 106 349 ± 79 370 ± 88 
AUC∞ (µg•h/ml) 2672 ± 1140 2387 ± 555 2700 ± 1000 
CL (ml/h/kg) 8.1 ± 1.8 8.9 ± 2.3 8.2 ± 2.4 
Vss (ml/kg) 904 ± 1158 919 ± 1154 896 ± 1154 
Effective half-life (h) 2.4 ± 0.4 2.4 ± 0.3 2.5 ± 0.4 
 
There was no evidence that IgG antibodies to alglucosidase alfa affected pharmacokinetics. Higher 
mean clearance, lower mean AUC∞, and lower mean Cmax were observed in 5 patients who tested 
positive for inhibition of cellular uptake of enzyme. However, there was no apparent association 
between inhibition of uptake and the co-primary efficacy endpoints (see section 4.4). 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single and repeated dose toxicity. No significant adverse findings on embryofoetal 
development were observed in a mouse and a rabbit embryofoetal study and no significant adverse 
findings were observed in a mouse fertility and early embryonic development study. In the rabbit 
embryofoetal development study, following administration of Myozyme (10-40 mg/kg/day) with 
coadministration of diphenhydramine, a treatment-related increase in the incidence of abortions and 
early delivery was observed. This effect was partly attributable to maternal toxicity, as a significant 
decrease in feed consumption and body weight gain was observed. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol (E421) 
Sodium dihydrogen phosphate monohydrate (E339) 
Disodium phosphate heptahydrate (E339) 
Polysorbate 80 (E433) 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
3 years 
 
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. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 



16 

50 mg of powder in a vial (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 and other handling 
 
Myozyme has to be reconstituted with water for injections, then diluted with sodium chloride 9 mg/ml 
(0.9%) solution for injection 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). 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 lyophilised 
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 sodium chloride 9 mg/ml (0.9%) solution for injection, 
that will be replaced with reconstituted Myozyme. Slowly inject the reconstituted Myozyme directly 
into the sodium chloride 9 mg/ml (0.9%) solution for injection. 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.  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 



17 

Genzyme Europe B.V. 
Paasheuvelweg 25 
1105 BP Amsterdam 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/333/001-003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 March 2006  
Date of latest renewal: 29 March 2011 
 
 
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. 



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

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

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



19 

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

 
Name and address of the manufacturers of the biological active substance 
 
Genzyme Corporation 45, 51, 76, 74 and 80 New York Avenue, Framingham, MA 01701, United 
States 
Genzyme Flanders bvba, Cipalstraat 8, 2440 Geel, Belgium 
 
Name and address of the manufacturers responsible for batch release 
 
Genzyme Ireland Limited, IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs)  
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted 

• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted 
at the same time.  
 
 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



22 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 
 
 
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 
 
Excipients: 
Mannitol (E421) 
Sodium dihydrogen phosphate monohydrate (E339) 
Disodium phosphate heptahydrate (E339) 
Polysorbate 80 (E433) 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 vial  
powder for concentrate for solution for infusion. 
10 vials  
powder for concentrate for solution for infusion. 
25 vials  
powder for concentrate for solution for infusion. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only 
Read the package leaflet before use. 
Intravenous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 



23 

 
 
8. EXPIRY DATE 
 
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. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (at 2°C-8°C). 
 
 
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. 
Paasheuvelweg 25 
1105 BP Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/333/001  
EU/1/06/333/002 
EU/1/06/333/003  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 



24 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



25 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Myozyme 50 mg powder for concentrate for solution for infusion 
Alglucosidase alfa 
Intravenous use after reconstitution and dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
50 mg 
 
 
6. OTHER 
 
Store in a refrigerator (at 2°C-8°C). 
Genzyme Europe B.V.-NL 
 
 



26 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



27 

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 because it contains 
important information for you. 
. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4 
 
What is in this leaflet 
1. What Myozyme is and what it is used for 
2. What you need to know before you are given Myozyme 
3. How Myozyme is given 
4. Possible side effects 
5. How to store Myozyme 
6. Contents of the pack and other information 
 
 
1. What Myozyme is and what it is used for 
 
Myozyme is used to treat adults, children and adolescents of all ages who have a confirmed diagnosis 
of Pompe disease. 
 
People with Pompe disease have low levels of an enzyme called alpha-glucosidase. This enzyme helps 
the body control levels of glycogen (a type of carbohydrate). Glycogen provides the body with energy, 
but in Pompe disease the levels of glycogen can get too high. 
 
Myozyme contains an artificial enzyme called alglucosidase alfa – this can replace the natural enzyme 
which is lacking in Pompe disease. 
 
 
2. What you need to know before you are given Myozyme 
 
Do not use Myozyme: 
If you have experienced life-threatening allergic (hypersensitive) reactions to alglucosidase alfa or any 
of the other ingredients of this medicine (listed in section 6) and re-administration of the medicine 
was not successful. Symptoms of life-threatening allergic reactions include, but are not limited to, low 
blood pressure, very fast heart rate, difficulty breathing, vomiting, facial swelling, hives or rash. 
 
Warnings and Precautions 
If you are treated with Myozyme, you may experience an infusion-associated reaction while you are 
being given the medicine or during the hours following the infusion. Such a reaction comprises 
different symptoms like low blood pressure, chest discomfort, throat tightness, face, lips or tongue 
swelling (angioedema), hives (urticaria), dizziness, rash, itchy skin, nausea, vomiting, cough and 
bronchospasm (see section 4 for an overview of all infusion-associated reactions). An infusion-
associated reaction can sometimes be very severe. If you experience a reaction like this, you should 
tell your doctor immediately. You may need to be given pre-treatment medicines to prevent an 
allergic reaction (e.g. antihistamines and/or corticosteroids) or to reduce fever (antipyretics). 
In studies doctors have used medicines to suppress the immune system to reduce the production of 
antibodies. Because you have Pompe disease, there is a risk that you get a severe infection of your 
airways or lungs. Using these medicines to suppress the immune system may further increase this risk. 



28 

If you experience severe ulcerative lesions of your skin, please inform your doctor. If you experience 
swelling of your lower limbs or generalized swelling, please inform your doctor. Your doctor should 
consider discontinuation of the administration of Myozyme and initiate appropriate medical treatment. 
Your doctor should consider the risks and benefits of re-administering Myozyme. 
 
Other medicines and Myozyme 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
Pregnancy and breast-feeding and fertility 
There is no experience of the use of Myozyme in pregnant women. You should not be given 
Myozyme during pregnancy unless clearly necessary. You are recommended to stop breast-feeding 
when you are given Myozyme. If you are pregnant or breast-feeding, think you may be pregnant or are 
planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
Take care when driving or using any tools or machines shortly after infusion of Myozyme, since you 
may experience dizziness. 
 
Myozyme contains sodium  
This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium free’. 
 
 
3. How Myozyme is given 
 
Myozyme will be given to you under the supervision of a doctor who is experienced in the treatment 
of Pompe disease. 
 
The dose you receive is based on your body weight. The recommended dosage of Myozyme is 20 mg 
per kg of body weight. It will be given to you once every 2 weeks. 
 
Use in children and adolescents 
The recommended dosage of Myozyme in children and adolescents is the same as in adults. 
 
Instructions for proper use 
Myozyme is given through a drip into a vein (by intravenous infusion). It is supplied as a powder 
which will be mixed with sterile water before it is given. 
 
If you are given more Myozyme than you should 
There is no experience with overdose of Myozyme.  
 
If you forget to use Myozyme 
If you have missed an infusion, please contact your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Side effects were mainly seen while patients were being given the medicine or shortly after (“infusion 
related effects”). Some of these infusion related side effects were serious or life-threatening. Life 
threatening reactions, including very severe generalised allergic reactions and anaphylactic shock, 
have been reported in some patients. Symptoms of such reactions include low blood pressure, very 
fast heart rate, difficulty breathing, vomiting, facial, lip or tongue swelling, hives or rash. Some 



29 

patients have experienced infusion related side effects in the form of flu-like symptoms, which lasted 
for a few days after completion of the infusion. 
Should you experience any reaction like this, please tell your doctor immediately. You may need to 
be given pre-treatment medicines to prevent an allergic reaction (e.g. antihistamines and/or 
corticosteroids) or to reduce fever (antipyretics). 
 
Very common: may affect more than 1 in 10 people 
• Hives 
• Rash 
• Increased heart rate 
• (Facial) flushing 
• Fever or increased body temperature 
• Cough 
• Increased breathing rate 
• Vomiting 
• Low level of oxygen in the blood 
 
Common: may affect up to 1 in 10 people 
• Paleness 
• Increased or high blood pressure 
• Bluish discolouration of the skin 
• Chills 
• Agitation 
• Tremor 
• Headache 
• Tingling 
• Pain or local reaction at the site of the drip 
• Dizziness 
• Irritability 
• Itchy skin 
• Retching 
• Swelling of the face, swelling of the throat or severe combined swelling of the face, throat and 

tongue due to a severe allergic reaction 
• Swelling of the arms and legs 
• Nausea 
• Chest discomfort 
• Throat tightness 
• Diarrhoea 
• Tiredness 
• Muscle pain 
• Muscle spasms 
• Severe ulcerative lesions of the skin 
• Redness of the skin 
 
Not known: frequency cannot be estimated from the available data 
• Swelling around the eyes 
• Abnormal breathing sounds, including a whistling sound 
• Difficulty in breathing (including shortness of breath) 
• Cold extremities (e.g. hands, feet) 
• Low blood pressure 
• Narrowing of the blood vessels causing blood flow to be decreased 
• Sudden constriction of bronchi restricting air going in and out the lungs (bronchospasm) 
• Feeling hot 



30 

• Increased sweating 
• Eyes tearing 
• Mottled skin 
• Restlessness 
• Wheezing  
• Decreased heart rate 
• Heart stopping 
• Chest pain (not in the heart) 
• Inflammation of membrane that covers eyeball and eyelid 
• Abdominal pain 
• Joint pain 
• Temporary suspension or sudden cessation of breathing 
• Protein loss in urine 
• Nephrotic Syndrome: swelling of lower limbs, generalized swelling and protein loss in urine 
• Swelling and thickening of the skin at infusion site in case of leakage of the product outside 

blood vessels 
 

Reporting of side effects  
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet.  
 
You can also report side effects directly via the national reporting system listed in Appendix V. By 
reporting side effects you can help provide more information on the safety of this medicine 
 
 
5. How to store  Myozyme 
 
Keep this medicine out of the sight and reach of children  
 
Do not use this medicine after the expiry date which is stated on the label after ‘EXP’. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C).  
 
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. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Myozyme contains 
 
-The active substance is alglucosidase alfa. One vial contains 50 mg of alglucosidase alfa. After 
reconstitution, the solution contains 5 mg of alglucosidase alfa per ml and after dilution the 
concentration varies from 0.5 mg to 4 mg/ml. 
-The other ingredients are  

• mannitol (E421),  
• sodium dihydrogen phosphate monohydrate (E339) 
• disodium phosphate heptahydrate (E339) 
• polysorbate 80 (E433). 

 



31 

What Myozyme looks like and contents of the pack 
Myozyme is a powder for concentrate for solution for infusion in a vial (50 mg/vial). Each pack 
contains 1, 10 or 25 vials. Not all pack sizes may be marketed. 
 
The powder is white to off-white. 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. 
Paasheuvelweg 25 
1105 BP Amsterdam 
 The Netherlands 
 
Manufacturer 
Genzyme Ireland Limited, IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland 
 



32 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien/ 
Luxembourg/Luxemburg 
Sanofi Belgium 
Tél/Tel: + 32 2 710 54 00 
 

Lietuva 
UAB „SANOFI-AVENTIS LIETUVA“ 
Tel. +370 5 275 5224 
 

България 
SANOFI BULGARIA EOOD 
Тел.: +359 (0)2 970 53 00 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel: +36 1 505 0050 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233086 111 
 

Malta 
Sanofi S.p.A. 
Tel: +39 02 39394275 
 

Danmark 
Sanofi A/S 
Tlf: +45 45 16 70 00 
 

Nederland 
Genzyme Europe B.V. 
Tel: +31 20 245 4000 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel.: 0800 04 36 996 
Tel. aus dem Ausland: +49 69 305 70 13 
 

Norge 
sanofi-aventis Norge AS 
Tlf: + 47 67 10 71 00 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel. +372 6 273 488 
 

Österreich 
sanofi-aventis GmbH 
Tel: + 43 1 80 185 – 0 

Ελλάδα 
sanofi-aventis AEBE  
Τηλ: +30 210 900 1600 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
  

Portugal 
Sanofi – Produtos Farmacêuticos, Lda. 
Tel: +351 21 35 89 400 
 

France 
sanofi-aventis France  
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 4800 
 

Ireland 
Sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel.:  +421 2 33 100 100 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: + 358 201 200 300 
 



33 

Italia 
Sanofi S.p.A. 
Tel: 800536389 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

United Kingdom 
Sanofi 
Tel +44 (0) 845 372 7101 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
----------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
 
Instructions for use – reconstitution, dilution and administration 
 
Myozyme has to be reconstituted with water for injections, then diluted with sodium chloride 9 mg/ml 
(0.9%) solution for injection 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). 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 using a syringe with a 
needle diameter not larger than 20 gauge. Add the water for injections by slow drop-wise addition 
down the side of the vial and not directly onto the lyophilised 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.  
 
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 using a syringe with a needle diameter not 



34 

larger than 20 gauge. 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 sodium chloride 9 mg/ml (0.9%) solution for injection, that will be replaced with 
reconstituted Myozyme. Slowly inject the reconstituted Myozyme directly into the sodium chloride 
9 mg/ml (0.9%) solution for injection. 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. 
 
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 dose 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/h and be gradually increased by 2 mg/kg/h every 30 minutes if there are no signs of 
IARs (Infusion Associated Reactions) until a maximum rate of 7 mg/kg/h is reached.  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET