MYOZYME 50mg powder for concentrate infusion solution medication leaflet

Myozyme 50 mg powder for concentrate for solution for infusion

One vial contains 50 mg of alglucosidase alfa.

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

*Human acid α-glucosidase is produced in Chinese hamster ovary cells (CHO) by recombinant DNAtechnology.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white powder.

Myozyme is indicated for long-term enzyme replacement therapy (ERT) in patients with a confirmeddiagnosis of Pompe disease (acid α-glucosidase deficiency).

Myozyme is indicated in adults and paediatric patients of all ages.

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

The recommended dose regimen of alglucosidase alfa is 20 mg/kg of body weight administered onceevery 2 weeks.

Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of allclinical manifestations of the disease.

Paediatric and older people

There is no evidence for special considerations when Myozyme is administered to paediatric patientsof all ages or older people.

The safety and efficacy of Myozyme in patients with renal or hepatic impairment have not beenevaluated and no specific dose regimen can be recommended for these patients.

Myozyme should be administered as an intravenous infusion.

Infusions should be administered incrementally. It is recommended that the infusion begin at an initialrate of 1 mg/kg/h and be gradually increased by 2 mg/kg/h every 30 minutes if there are no signs ofinfusion associated reactions (IARs) until a maximum rate of 7 mg/kg/h is reached. IARs are describedin section 4.8.

Home infusion

Infusion of Myozyme at home may be considered for patients who are tolerating their infusions welland have no history of moderate or severe IARs for a few months. The decision to have a patient moveto home infusion should be made after evaluation and upon recommendation by the treating physician.

Home infusion infrastructure, resources, and procedures, including training, must be established andavailable to the healthcare professional. Home infusion should be supervised by a healthcareprofessional who should be always available during the home infusion and for a specified time afterinfusion.

Dose and infusion rate should remain constant while at home, and not be changed withoutsupervision of a healthcare professional.

Appropriate information should be given by the treating physician and/or nurse to the patient and/orcaregiver prior to initiation of home infusion.

If the patient experiences adverse reactions during the home infusion, the infusion process should bestopped immediately, and appropriate medical treatment should be initiated (see section 4.4).

Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient careuntil no such adverse reaction is present.

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

Life threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of theexcipients listed in section 6.1, when rechallenge was unsuccessful (see sections 4.4 and 4.8).

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

Hypersensitivity/Anaphylactic reactions

Serious and life-threatening anaphylactic reactions, including anaphylactic shock, have been reportedin infantile- and late-onset patients during Myozyme infusions (see section 4.8). Because of thepotential for severe infusion associated reactions, appropriate medical support measures, includingcardiopulmonary resuscitation equipment, should be readily available when Myozyme is administered.

If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of Myozymeinfusion should be considered and appropriate medical treatment should be initiated. The currentmedical 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% ofthe patients treated with Myozyme in a late-onset clinical study developed infusion associatedreactions (IARs). IARs are defined as any related adverse event occurring during the infusion orduring the hours following infusion. Some reactions were severe (see section 4.8). A tendency wasobserved in infantile patients treated with a higher dose (40 mg/kg) to experience more symptomswhen developing IARs. Infantile onset patients who develop high IgG antibody titres appear to be athigher risk for developing more frequent IARs. However, IARs occurred regardless of antibody titres.

Patients with an acute illness (e.g. pneumonia, sepsis) at the time of Myozyme infusion appear to be atgreater risk for IARs. Careful consideration should be given to the patient’s clinical status prior toadministration of Myozyme. Patients should be closely monitored and all cases of IARs, delayedreactions and possible immunological reactions should be reported to the marketing authorisationholder.

Patients who have experienced IARs (and in particular anaphylactic reactions) should be treated withcaution when re-administering Myozyme (see sections 4.3 and 4.8). Mild and transient effects may notrequire medical treatment or discontinuation of the infusion. Reduction of the infusion rate, temporaryinterruption of the infusion, or pre-treatment, generally with oral antihistamine and/or antipyreticsand/or corticosteroids, has effectively managed most reactions. IARs may occur at any time during theinfusion 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, whichmay 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.

The effect of IgG antibody formation on safety and efficacy has been evaluated in clinical trials andpost-marketing experience. In clinical studies, the majority of patients developed IgG antibodies toalglucosidase alfa and seroconversion typically occured within 3 months of treatment. Thus,development of IgG antibodies is expected to occur in most patients treated with Myozyme. Overall, acorrelation was not observed between the onset of IARs and the time of IgG antibody formation. IARscan occur across all levels of antibody titres, however a trend was observed for more frequent IARswith higher titres of IgG antibody. The clinical impact on efficacy is multifactorial, however thedevelopment of high and sustained IgG antibody titres is a contributing factor.

With regard to IOPD, a tendency was observed for patients treated with a higher dose (40 mg/kg) todevelop higher titres of IgG antibodies. Furthermore, Cross Reactive Immunologic Material (CRIM)status has been shown to be associated with immunogenicity and patients’ responses to enzymereplacement therapies. Negative CRIM status, indicating no endogenous enzyme is detected, is a riskfactor to develop high and sustained IgG antibody titres. This risk is higher among CRIM negativepatients versus CRIM-positive patients and is a contributing factor to a poor outcome . However, highand sustained IgG antibody titres has also occurred in a limited number of CRIM-positive patients,generally with very low endogenous enzyme.

With respect to LOPD patients, the majority showed either stabilizing or decreasing antibody titresover time. The development of high and sustained IgG antibody titres is infrequent in LOPD patients.

Thus, the impact of IgG antibodies is more limited for LOPD patients.

IgG antibody titres should be monitored based on clinical phenotype. Baseline serum samplecollection prior to the first infusion is strongly encouraged. For IOPD patients, regular monitoringduring first year of treatment (example: every 3 months) is suggested and subsequent monitoringdepending on clinical outcomes and antibody titres level. For LOPD patients, antibody developmentshould be assessed within 6 months and subsequent monitoring as clinically warranted based on safetyand efficacy considerations.

Patients who experience hypersensitivity reactions may also be tested for IgE antibodies toalglucosidase alfa and other mediators of anaphylaxis. Patients who develop IgE antibodies toalglucosidase alfa appear to be at a higher risk for the occurrence of IARs when Myozyme isre-administered (see section 4.8). Therefore, these patients should be monitored more closely duringadministration 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 Myozymeunder 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 observedin a few patients with Pompe disease treated with alglucosidase alfa and who had high IgG antibodytitres (≥ 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 periodicurinalysis among patients with high IgG antibody titres.

Patients should be monitored for signs and symptoms of systemic immune-mediated reactionsinvolving skin and other organs while receiving alglucosidase alfa. If immune-mediated reactionsoccur, discontinuation of the administration of alglucosidase alfa should be considered and appropriatemedical treatment initiated. The risks and benefits of re-administering alglucosidase alfa following animmune-mediated reaction should be considered. Some patients have been successfully rechallengedand continued to receive alglucosidase alfa under close clinical supervision.

Immunomodulation

Immunogenicity data from clinical trials and published literature in CRIM-negative infantile-onsetpatients (IOPD) suggests that the administration of immune tolerance induction (ITI) regimen given toalglucosidase alfa naive patients (prophylactic ITI) may be effective in preventing or reducing thedevelopment of High Sustained Antibody Titre (HSAT) against alglucosidase alfa. Data from a smallnumber of patients with HSAT, with or without inhibitory activity, showed limited ITI treatmenteffect. Better treatment responses were observed in younger patients with less advanced disease whoreceived prophylactic ITI before development of HSAT, which suggests that early initiation of ITI canresult 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 progressiveeffects of the disease on the respiratory muscles. Patients with Pompe disease treated withimmunosuppressive agents maybe at further increased risk of developing severe infections andvigilance is recommended. Fatal and life-threatening respiratory infections have been observed insome of these patients.

No interactions studies have been performed. Because it is a recombinant human protein, alglucosidasealfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

There is limited data from the use of alglucosidase alfa in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Myozyme should not be used during pregnancy unlessthe clinical condition of the woman requires treatment with alglucosidase alfa.

Limited data suggest that alglucosidase alfa is excreted in breast milk in very low concentrations. Noclinical effect is expected in a breastfed infant due to low breast milk transfer and poor bioavailability.

Breastfeeding during treatment with Myozyme may therefore be considered. As a precautionarymeasure, breastfeeding interruption for the first 24 hours after treatment may be considered.

There is too limited clinical data on the effects of alglucosidase alfa on fertility to evaluate its impact.

Preclinical data did not reveal any significant adverse findings (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. Becausedizziness, somnolence, tremor and hypotension have been reported as an infusion associated reaction,this may affect the ability to drive and use machines on the day of the infusion.

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 least2 patients are listed in Table 1 by System Organ Class. Adverse reactions were mostly mild tomoderate in intensity and almost all occurred during the infusion or during the 2 hours following theinfusion (infusion associated reactions, IARs). Serious infusion reactions including urticaria, rales,tachycardia, decreased oxygen saturation, bronchospasm, tachypnoea, periorbital oedema andhypertension have been reported.

Late-onset Pompe disease

In a placebo-controlled study lasting 78 weeks, 90 patients with late-onset Pompe disease, aged 10 to70 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 comparablebetween the two groups. The most common adverse reactions observed were IARs. Slightly morepatients in the Myozyme group than in the placebo group experienced IARs (28% versus 23%). Themajority of these reactions were non-serious, mild to moderate in intensity and resolvedspontaneously. Adverse reactions reported in at least 2 patients are listed in Table 1. Serious adversereactions reported in 4 patients treated with Myozyme were: angioedema, chest discomfort, throattightness, non-cardiac chest pain and supraventricular tachycardia. Reactions in 2 of these patientswere IgE-mediated hypersensitivity 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(cannot be estimated from the available data). Due to the small patient population, an adverse reactionreported in 2 patients is classified as common. Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

System Organ Frequency Adverse reaction Additional adverse

Class (Preferred Term Level) reactions4

Infantile-onset Late-onset Infantile- and Late-

Pompe disease1 Pompe disease2 onset Pompe disease

Immune system common Hypersensitivitydisorders

Psychiatric common Agitationdisorders not known Agitation

Restlessness

Nervous system common Tremor Dizzinessdisorders Paraesthesia

Headache3not known Tremor

Somnolence

Burning sensation

Eye disorders not known Conjunctivitis

Cardiac disorders very Tachycardiacommoncommon Cyanosisnot known Cardiac arrest

Bradycardia

Cyanosis

Palpitations

Vascular very Flushingdisorders commoncommon Hypertension Flushing

Pallornot known Hypertension

Vasoconstriction

Pallor

Respiratory, very Tachypnoeathoracic and common Coughmediastinal common Throat tightnessdisorders not known Respiratory arrest

Apnoea

Respiratory distress

Asthma

Bronchospasm

Wheezing

Pharyngeal oedema

Tachypnoea

Throat tightness

Throat irritation

Stridor

Cough

Hypoxia

Gastrointestinal very Vomitingdisorders commoncommon Retching Diarrhoea

Nausea Vomiting

Nausea3not known Abdominal pain

Retching

Dyspepsia

Dysphagia

Skin and very Urticariasubcutaneous common Rashtissue disorders common Erythema Urticaria

Rash maculopapular Rash papular

Rash macular Pruritus

Rash papular Hyperhidrosis

Pruritusnot known Periorbital oedema

Livedo reticularis

Lacrimation increased

Erythema

Hyperhidrosis

Palmar erythema

Transient skindiscoloration

Musculoskeletal common Muscle spasmsand connective Muscle twitchingtissue disorders Myalgianot known Arthralgia

Renal and urinary not known Nephrotic syndromedisorders Proteinuria

General disorders very Pyrexiaand commonadministration common Irritability Pyrexiasite conditions Chills Chest discomfort

Peripheral oedema

Local swelling

Fatigue3

Feeling hotnot known Chest pain

Face oedema

Feeling hot

Chills

Chest discomfort

Irritability

Peripheral coldness

Asthenia

Malaise

Feeling cold

Infusion site pain

Infusion site reaction

Infusion site swelling

Infusion siteinduration

Infusion siteextravasation

Infusion site erythema

Infusion site urticaria

Infusion site pruritus

Investigations very Oxygen saturationcommon decreasedcommon Heart rate increased Blood pressure

Blood pressure increasedincreased

Body temperatureincreasednot known Oxygen saturationdecreased

Heart rate increased

Blood pressuredecreased1 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.

A small number of patients (<1%) in clinical trials and in the commercial setting developedanaphylactic 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 aconstellation of signs and symptoms, primarily respiratory, cardiovascular, oedematous and/orcutaneous 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, havebeen observed in some patients treated with alglucosidase alfa. The majority of patients weresuccessfully re-challenged with alglucosidase alfa using lower doses and/or pre-treatment with anti-inflammatory drugs and/or corticosteroids and have continued to receive treatment under close clinicalsupervision.

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 anaphylacticreaction.

Nephrotic syndrome as well as severe cutaneous reactions, possibly immune mediated, have beenreported with alglucosidase alfa including ulcerative and necrotizing skin lesions (see section 4.4).

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

In clinical studies doses up to 40 mg/kg body weight were used. IARs are more likely to occur withhigher dose or infusion rates than recommended (see section 4.4).

Symptoms and signs

IARs have been reported, which included:

* cyanosis, tachycardia, palpitations

* hypoxia, dyspnoea, cough

* dizziness, headache, dysgeusia

* hypertension, flushing

* tongue oedema, vomiting, diarrhoea, nausea

* chest pain, chest discomfort, throat tightness, pyrexia, chills, feeling cold, infusion siteerythema,

* myalgia

* erythema

In the event of overdose, the infusion rate should be reduced, or the infusion temporarily interrupted.

There is no known specific antidote for alglucosidase alfa overdose. The patient should be monitoredfor any signs or symptoms of adverse reactions and administered appropriate symptomatic treatmentimmediately.

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

ATC code: A16AB07.

Pompe disease

Pompe disease is a rare, progressive and fatal metabolic myopathy with an estimated global incidenceof 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 thelysosomal storage disorders as it is caused by a deficiency of a naturally occurring lysosomalhydrolase, acid α-glucosidase (GAA) that degrades lysosomal glycogen to glucose. Deficiency of thisenzyme leads to glycogen accumulation in various tissues, particularly cardiac, respiratory and skeletalmuscle, leading to the development of hypertrophic cardiomyopathy and progressive muscleweakness, including impairment of respiratory function.

The clinical presentation of Pompe disease can be described as a spectrum of disease which rangesfrom a rapidly-progressing infantile-onset form (onset of symptoms of Pompe disease typically withinthe first year of life and a very short, expected lifespan) to a less rapidly progressing late-onset form.

The infantile-onset form of Pompe disease is characterised by massive deposition of glycogen in theheart, and skeletal muscle always resulting in rapidly progressive cardiomyopathy, generalised muscleweakness and hypotonia. Motor development is often completely arrested, or if motor milestones areachieved, they are subsequently lost. Death typically occurs due to cardiac and/or respiratory failurebefore the age of one year.

In a retrospective natural history study in patients with infantile-onset Pompe disease (n=168), themedian 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 describedwhich 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 evenadulthood and is much less rapidly progressive than the infantile-onset form. Usually, it ischaracterised by the presence of sufficient residual GAA activity to preclude the development ofcardiomyopathy, however some cardiac involvement has been reported in up to approximately 4% ofpatients with late-onset Pompe disease.

Patients with late-onset Pompe disease typically present with progressive myopathy, predominantly ofthe proximal muscles in the pelvic and shoulder girdles, and varying degrees of respiratoryinvolvement, ultimately progressing to profound disability and/or the need for ventilatory support. Thetime course of disease progression is extremely variable and not predictable, with some patientsexperiencing a rapid deterioration in skeletal and respiratory muscle function leading to loss ofambulation and respiratory failure, others progressing less rapidly, and yet others presenting with adissociation in the progression of skeletal and respiratory muscle involvement.

It is postulated that Myozyme will restore lysosomal GAA activity resulting in stabilisation orrestoration 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 isunlikely.

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, historicallycontrolled clinical trial of 18 non-ventilated infantile-onset patients aged 6 months or less at the onsetof treatment. The untreated historical cohort was matched to the pivotal study population and wasderived from a retrospective natural history study (n=42) in patients with infantile-onset Pompedisease. Patients were randomized to receive either 20 mg/kg or 40 mg/kg once every two weeks for aperiod of 52 weeks. After a minimum of 52 weeks, 16 of these 18 patients were enrolled in anextension 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 ventilatorsupport. However, the invasive ventilator-free survival was not recorded in the untreated historicalcohort and a comparison of this endpoint is not possible. After 52 weeks of treatment, all 18 patientstreated with Myozyme were alive and 15 of these 18 patients were alive and free of invasiveventilatory support whereas 1 of 42 patients in the untreated historical cohort was alive at 18 months ofage. Two patients died and did not enter into the extension study. After 104 weeks of treatment, all16 patients who enrolled in the extension study were alive and 10 of these 16 patients were free ofinvasive ventilatory support. At the end of the study (with individual patient treatment durationsranging from 60 to 150 weeks; mean follow-up period of 119 weeks) 14 of 16 patients were alive and9 of 16 patients were alive and free of invasive ventilatory support. One additional patient died afterstudy end and another one after withdrawal from the study.

Comparison of survival curves from time of diagnosis versus the untreated historical cohort was madeusing a Cox proportional hazards regression analysis. Patients treated with Myozyme demonstratedprolonged survival as compared to survival in an untreated historical cohort (see Table 2).

Table 2: Results for endpoint survival using the Cox regression model

Historical Treatment 95%

Treated Reference Effect Hazard Confidence

Patients Comparator Endpoint Ratio 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 treatmentas 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 ventricularmass (LVM). After 52 weeks of treatment, LVM decreased from baseline in all 14 patients withavailable data and was within normal limits in 3 of 14 patients. After the first year (64 up to130 weeks) of treatment LVM further decreased in 8 patients. At 104 weeks of treatment LVMassessments 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 walkingindependently by the last study assessment (with individual patient treatment durations ranging from52 to 130 weeks; mean follow-up period of 94 weeks). An additional 4 patients made motordevelopment gains during the study and were sitting independently by the last study assessment (withindividual patient treatment durations ranging from 78 to 130 weeks; mean follow-up period of110 weeks), although they did not have functional use of the legs. The remaining 7 patients made noclinically significant motor gains or were unable to sustain the motor gains made and had very limitedmotor movement by the last study assessment (with individual patient treatment durations rangingfrom 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-agepercentiles (above the 3rd percentile), 14 of 15 patients (93.3%) were above the 3rd percentile forlength and 12 of 15 patients (80.0%) were above the 3rd percentile for head circumference. In thesecond year of treatment, 15 out of 17 patients had further improved weight-for-age percentiles (withindividual patient treatment durations ranging from 78 to 142 weeks; mean follow-up period of111 weeks), 10 out of 16 patients had further improved length-for-age percentiles (with individualpatient treatment durations ranging from 90 to 130 weeks; mean follow-up period of 113 weeks) and11 out of 15 patients had further improved head circumference-for-age percentiles (with individualpatient treatment durations ranging from 90 to 130 weeks; mean follow-up period of 110 weeks). At104 weeks of treatment, all 13 patients with available data had maintained or improved weight-for-agepercentiles (above the 3rd percentile), all 12 patients with available data were above the 3rd percentilefor 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 tosurvival, invasive ventilator-free survival, any ventilator-free survival, decrease in LVM, gains ingrowth parameters and acquisition of motor milestones. Based on these results the 20 mg/kg qow doseis 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 withpredominantly a non-typical form of infantile-onset Pompe disease who ranged in age from 6 monthsto 3.5 years at initiation of treatment. Patients received 20 mg/kg Myozyme once every two weeks for52 weeks except for 8 patients who received 40 mg/kg after at least 26 weeks of treatment. After52 weeks all patients continued treatment for a total duration of more than 3 years (168 weeks with amedian of 121 weeks).

The primary endpoint of the pivotal trial was the proportion of patients who were alive. After52 weeks of treatment, 16 of 21 patients (76.2%) treated with Myozyme were alive. After 104 weeksof treatment, 14 of 21 patients (66.7%) were alive and 1 patient was alive but had discontinued fromthe study. These proportions were maintained up to the end of the study (with individual patienttreatment durations ranging from 1 to 168 weeks; mean follow-up period of 109 weeks). In theuntreated historical cohort 5 of 47 patients (10.6%) for whom data were available, were alive at age30 months (2.5 years).

Survival in the treated patients was compared to survival in a similar historical cohort of untreatedsubjects using a Cox proportional hazards regression analysis (See Table 3).

Table 3: Results for endpoint survival using the Cox regression model

Historical Treatment 95%

Treated Reference Effect Hazard Confidence

Patients Comparator Endpoint Ratio 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 treatmentas 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 atbaseline, 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 invasiveventilation at baseline continued to require ventilation throughout the study (4 patients survivedbeyond week 104 and one patient died).

After 52 weeks of treatment, LVM decreased from baseline in all 12 patients with available data andwas 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 LVMassessments 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 overbaseline as measured by raw scores and age-equivalent scores from baseline in the AIMS. Six of the11 patients with available data continued to make motor development gains beyond Week 52 (withindividual patient treatment durations ranging from 58 to 168 weeks; mean follow-up period of121 weeks), including 3 patients ambulatory and 3 patients with only functional sitting skills by thelast 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-upperiod of 140 weeks), including 4 patients with no significant motor skills in any of the positionsevaluated 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 demonstrateimprovement in cardiac function as well as stabilisation or improvements in growth parameters.

However, motor and respiratory responses to treatment have been more variable. Patients withinfantile-onset Pompe disease who demonstrated motor gains, had greater preservation of motorfunction and lower glycogen content in the quadriceps muscle at baseline. It is noteworthy that ahigher proportion of patients with better motor outcomes show stability or improvement in growthparameters (weight), while the large majority of patients, regardless of their motor outcomes orbaseline 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 becritical 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 reviewof patients naïve to ERT at the initiation of treatment and 1 clinical trial of patients already receivingalglucosidase alfa at time of initiating ITI.

A retrospective chart review at Duke Center identified 21 CRIM-negative IOPD patients of which19 patients were ERT naïve at the time of ITI initiation. Of the 21 patients, 16 survived through theend of this study, with a median time from ERT initiation to last assessment of 44.6 months (range: 5.7to 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 whoreceived ITI concomitantly to ERT initiation had a trend towards better survival rate than patientstreated with similar regimen at a later age. The study data demonstrated that prophylactic ITI preventsor reduces the occurrence of antibodies against alglucosidase alfa over time, which may maintainclinical 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-controlledstudy in 90 patients with late-onset Pompe disease who ranged in age from 10 to 70 years at initiationof treatment and were all naive to enzyme replacement therapy. Patients were randomized in a2:1 ratio and received 20 mg/kg Myozyme (n=60) or placebo (n=30) once every two weeks for78 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. After78 weeks, patients treated with Myozyme showed improvement in distance walked as measured by6MWT and stabilization of pulmonary function as measured by FVC % predicted as compared toplacebo-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 medianof 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

Myozyme Placebo(N = 60) (N = 30)6-Minute Walk Test Distance (meters)

Pre-treatment Baseline Mean ± s.d. 332.20 ± 126.69 317.93 ± 132.29

Median 360.0 339.0

Week 78/Last Observation Mean ± s.d. 357.85 ± 141.32 313.07 ± 144.69

Median 367.5 307.0

Change from Baseline to Mean ± s.d. 26.08 ± 64.41 -4.87 ± 45.24

Week 78/Last Observation* Median 15.0 -7.5

Wilcoxon-Mann-Whitney Test p-value 0.0283

Forced Vital Capacity (Percent of predicted normal)

Pre-treatment Baseline Mean ± s.d. 55.43 ± 14.44 53.00 ± 15.66

Median 53.5 49.0

Week 78/Last Observation Mean ± s.d. 56.67 ± 16.17 50.70 ± 14.88

Median 55.5 49.0

Change from Baseline to Week Mean ± s.d 1.25 ± 5.55 -2.3 ± 4.3378/Last Observation* Median 0.0 -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

Four independent, open-label, single arm, investigator-initiated studies with Myozyme wereconducted:

* One study in the Netherlands enrolled 102 late-onset patients with a median follow up of 5 years(60 months)

* 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 of23 months.

These four studies with Myozyme suggested stabilisation or improvement of motor function andstabilisation of pulmonary function, for up to 5 years in the study conducted in the Netherlands with102 late-onset patients.

In the above described study in 69 late-onset patients in the Netherlands, Myozyme showed animprovement in muscle strength. However, muscle function only improved in wheelchair independentpatients and in those with less pronounced muscle weakness.

The improvement in muscle strength was confirmed up to 5 years in the study conducted in the

Netherlands with 102 late-onset patients.

In two additional open-label clinical trials with Myozyme with a follow-up of 24 months, ten patientswith 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 amodest 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). Patientsreceived 20 mg/kg Myozyme once every two weeks for 26 weeks. All patients were freely ambulatoryand all but one patient did not require any form of ventilator support (1 patient required nocturnalnon-invasive ventilation). Of the 3 patients with significant pulmonary involvement atscreening/baseline (percentage predicted forced vital capacity in the sitting position ranging from58-67%), two demonstrated clinically meaningful improvements in FVC (+11.5% and +16.0%) in thesitting 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 alfa20-40 mg/kg once every two weeks for various periods of time between 6 months and 2.5 years. Thepulmonary 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 in2 patients. Benefits of treatment on motor function including the regaining of lost motor skills wereobserved in some patients. Only one patient became wheelchair-free. In this group of patients avariable response has also been seen with respect to motor function.

Late-onset Pompe disease; patient reported outcomes

An International Pompe Association (IPA)/Erasmus Medical Center (Netherlands) Pompe surveyevaluated the impact of Myozyme on different patient outcomes collected annually:

* Myozyme significantly reduced the risk of becoming wheelchair dependent: at any point duringfollow-up, wheelchair dependency was less likely in LOPD treated patients than untreatedpatients (hazard ratio: 0.36; 95% CI: 0.17, 0.75 in a study of 198 eligible patients with a medianfollow-up of 5 years). No effect on respiratory support was demonstrated in this study.

* After 3 years of treatment with Myozyme in 163 adult patients, the mean Fatigue Severity Scale(FSS) score improved significantly by 0.13 score points per year (p <0.001), indicatingtreatment helped to reduce fatigue in this study. Before treatment with Myozyme (medianfollow up of 4 years), the mean FSS score was stable at approximately 5.3 score points.

* Myozyme provided improvements and stabilisation in health-related quality of life andparticipation in 174 adult patients with a median follow-up period of 4 years (range 0.5-8) bothbefore and during treatment.

o After declining before treatment (-0.73 score points per year (sp/y); 95% CI: -1.07, -0.39), the Physical Component Summary measure of the SF36 patient reported surveyimproved in the first 2 years of Myozyme treatment (1.49 sp/y; 95% CI: 0.76, 2.21)and remained stable thereafter.

o After declining before treatment (-0.49 sp/year; 95% CI: -0.64, -0.34), the Rotterdam

Handicap Scale (RHS) stabilised under Myozyme (-0.02 sp/year; 95% CI: -0.17,0.13).

Finally, in the 5-year prospective study conducted in the Netherlands with 102 adult patients with

LOPD, the impact of treatment with Myozyme on daily life activities was measured by the Rasch-

Built Pompe-Specific Activity (R-PACT) scale. Compared to baseline, the R-PACT score improvedby 3.6 percentage points (p= 0.004) at 5 years of treatment, showing a benefit of Myozyme in thesepatients.

Pompe Registry

Medical or healthcare professionals are encouraged to register patients who are diagnosed with Pompedisease at www.registrynxt.com. Patient data will be anonymously collected in this Registry. Theobjectives of the “Pompe Registry” are to enhance the understanding of Pompe disease and to monitorpatients and their response to enzyme replacement therapy over time, with the ultimate goal ofimproving clinical outcomes for these patients.

Infantile-onset Pompe disease

In a pivotal trial including 18 patients, the pharmacokinetics of alglucosidase alfa were evaluated in15 patients with infantile-onset Pompe disease (all less than 6 months of age at treatment-onset) whoreceived 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) rangedfrom 178.2 to 263.7 µg/ml for the 20 mg/kg and 40 mg/kg dose groups respectively. The mean areaunder the plasma concentration-time curve (AUC∞) ranged from 977.5 to 1,872.5 µg*h/ml for the20 mg/kg and 40 mg/kg dose groups. Mean plasma clearance (CL) was 21.4 ml/h/kg and mean volumeof distribution at steady state (Vss) was 66.2 ml/kg for both dose groups with small between-subjectvariability of 15% and 11%, respectively. Mean plasma elimination half-life (t1/2) was 2.75 hours forthe two dose groups.

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 withinfantile-onset Pompe disease (all aged between 6 months and 3.5 years at treatment-onset) whoreceived doses of 20 mg/kg of alglucosidase alfa. In 12 patients with available data the AUC∞ and Cmaxwere approximately equivalent to those observed for the 20 mg/kg dose group in the pivotal trial. Thet½ 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 agefrom 21 to 70 years who received Myozyme 20 mg/kg once every two weeks. AUC∞ and Cmax weresimilar at week 0, 12 and 52 visits indicating alglucosidase alfa pharmacokinetics were not time-dependent (Table 5).

Distribution and elimination

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 limited evidence that IgG antibodies to alglucosidase alfa affected pharmacokinetics.

Higher mean clearance, lower mean AUC∞, and lower mean Cmax were observed in 5 patients whotested positive for inhibition of cellular uptake of enzyme. However, there was no apparent associationbetween inhibition of uptake and the co-primary efficacy endpoints (see section 4.4).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single and repeated dose toxicity. No significant adverse findings on embryofoetaldevelopment were observed in a mouse and a rabbit embryofoetal study and no significant adversefindings were observed in a mouse fertility and early embryonic development study. In the rabbitembryofoetal development study, following administration of Myozyme (10-40 mg/kg/day) withcoadministration of diphenhydramine, a treatment-related increase in the incidence of abortions andearly delivery was observed. This effect was partly attributable to maternal toxicity, as a significantdecrease in feed consumption and body weight gain was observed.

Administration of 40 mg/kg Myozyme intravenously once every other day in mice withcoadministration of diphenhydramine during the period of organogenesis through lactation producedan increase in mortality of offspring during the lactation period. There were no other effects on anyparameter evaluated including clinical observations or body weight gain in F1 generation pups.

Furthermore, no effect on sexual maturation, learning or memory, or the ability to produce anothergeneration occurred for the F1 generation mice.

Mannitol (E421)

Sodium dihydrogen phosphate monohydrate (E339)

Disodium phosphate heptahydrate (E339)

Polysorbate 80 (E433)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

After dilution, an immediate use is recommended. However, chemical and physical in-use stability hasbeen demonstrated for 24 hours at 2 to 8°C when stored under protection from light.

Store in a refrigerator (2°C - 8°C).

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

50 mg of powder in a vial (Type 1 glass) with a stopper (siliconised butyl) and a seal (aluminium) witha flip-off cap (plastic). Pack sizes of 1, 10 or 25 vials.

Not all pack sizes may be marketed.

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 anddilution should be performed in accordance with good practice rules, particularly for the respect ofasepsis.

Due to the proteinaceous nature of the product, particle formation may occur in the reconstitutedsolution and final infusion bags. Therefore, a 0.2 micron low protein binding in-line filter should beused for administration. It was demonstrated that the use of a 0.2 micron in-line filter removes visibleparticles 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 roomtemperature (approximately 30 minutes). Each vial of Myozyme is for single use only.

Use aseptic technique

Reconstitute each 50 mg vial of Myozyme with 10.3 ml water for injections. Add the water forinjections by slow drop-wise addition down the side of the vial and not directly onto the lyophilisedcake. Tilt and roll each vial gently. Do not invert, swirl or shake the vial. The reconstituted volume is10.5 ml containing 5 mg/ml, and appears as a clear, colourless to pale yellow solution which maycontain particles in the form of thin white strands or translucent fibres. Perform an immediateinspection of the reconstituted vials for particulate matter and discoloration. If upon immediateinspection foreign particles other than those described above are observed, or if the solution isdiscoloured, 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).

When reconstituted as above, the reconstituted solution in the vial contains 5 mg alglucosidase alfa perml. 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 eachvial until the volume for the patient’s dose is obtained. The recommended final concentration ofalglucosidase in the infusion bags ranges from 0.5 mg/ml to 4 mg/ml. Remove airspace within theinfusion 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 directlyinto the sodium chloride 9 mg/ml (0.9%) solution for injection. Gently invert or massage the infusionbag 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 localrequirements.

Sanofi B.V.

Paasheuvelweg 251105 BP Amsterdam

The Netherlands

EU/1/06/333/001-003

Date of first authorisation: 29 March 2006

Date of latest renewal: 21 February 2011

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

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